Menopause

There are dozens of medications containing combinations of estrogen and progestin. I am often confused by the bewildering proliferation of generic brand names used to describe the same estrogen-progestin (E-P) regimen. For example, the combination medication containing ethinyl estradiol 20 µg plus norethindrone acetate (NEA) 1 mg is available under at least 5 different names: Lo Estrin 1/20 (Warner Chilcot), Junel 1/20 (Teva Pharmaceuticals), Microgestin Fe 1/20 (Mayne Pharma), Gildess 1/20 (Qualitest Pharmaceuticals), and Larin 1/20 (Novast Laboratories). To reduce the confusion, it is often useful to select a single preferred estrogen and progestin and use the dose combinations that are available to treat a wide range of gynecology problems (TABLE). In this editorial I focus on using various dose combinations of ethinyl estradiol and NEA to treat 3 common gynecologic problems.

CASE 1 Polycystic ovary syndrome

A 19-year-old woman reports 4 spontaneous menses in the past year and bothersome facial hair and acne. Her total testosterone concentration is at the upper limit of normal (0.46 ng/mL) and her sex hormone binding globulin (SHBG) concentration is at the lower limit of normal (35 nM). For treatment of the patient’s menstrual disorder, what is an optimal E-P combination?

Prioritize the use of an estrogen-dominant medication

Based on the Rotterdam criteria this woman has polycystic ovary syndrome (PCOS).¹ In women with PCOS, luteinizing hormone (LH) secretion is increased, stimulating excessive ovarian production of testosterone.² In addition, many women with PCOS have decreased hepatic secretion of SHBG, a binding protein that prevents testosterone from entering cells, resulting in excessive bioavailable testosterone.³ The Endocrine Society recommends that women with PCOS who have menstrual dysfunction or hirsutism be treated initially with a combination E-P hormone medication.¹ Combination E-P medications suppress pituitary secretion of LH, thereby reducing ovarian production of testosterone, and ethinyl estradiol increases hepatic secretion of SHBG, reducing bioavailable testosterone. These two goals are best accomplished with an oral E-P hormone medication containing ethinyl estradiol doses of 20 µg to 30 µg per pill. An E-P hormone medication containing pills with an ethinyl estradiol dose ≤ 10 µg-daily may stimulate less hepatic production of SHBG than a pill with an ethinyl estradiol dose of 20 µg or 30 µg daily.^4,5 In addition, E-P pills containing levonorgestrel suppress SHBG hormone secretion compared with E-P pills with other progestins.⁶ Therefore, levonorgestrel-containing E-P pills should not be prioritized for use in women with PCOS because the estrogen-induced increase in SHBG will be blunted by levonorgestrel.

CASE 2 Moderate to severe pelvic pain caused by endometriosis

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis lesions in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy showed endometriosis. Postoperatively, the patient was treated with an E-P pill containing 30 µg ethinyl estradiol and 0.15 mg desogestrel per pill using a continuous-dosing protocol. During the year following the laparoscopy, her pelvic pain symptoms gradually increased until they became severe, preventing her from performing daily activities on multiple days per month. She was prescribed elagolix but her insurance did not approve the treatment. What alternative treatment would you prescribe?

Continue to: Use progestin-dominant pills to treat pelvic pain...

Use progestin-dominant pills to treat pelvic pain

Cellular activity in endometriosis lesions is stimulated by estradiol and inhibited by a high concentration of androgenic progestins or androgens. This simplified endocrine paradigm explains the effectiveness of hormonal treatments that suppress ovarian estradiol production, including leuprolide, elagolix, medroxyprogesterone acetate, and NEA. For the woman in the above case, I would advocate for elagolix treatment but, following the insurance denial of the prescription, an alternative treatment for moderate or severe pelvic pain caused by endometriosis would be a progestin-dominant hormone medication (for example, NEA 5 mg daily). Norethindrone acetate 5 mg daily may be associated with bothersome adverse effects including weight gain (16% of patients; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%).⁷

I sometimes see women with moderate to severe pelvic pain caused by endometriosis being treated with norethindrone 0.35 mg daily. This dose of norethindrone is suboptimal for pain treatment because it does not reliably suppress ovarian production of estradiol. In addition, the cells in endometriosis lesions are often resistant to the effects of progesterone, requiring higher dosages to produce secretory or decidual changes. In most situations, I recommend against the use of norethindrone 0.35 mg daily for the treatment of pelvic pain caused by endometriosis.

Patients commonly ask if NEA 5 mg daily has contraceptive efficacy. Although it is not approved at this dosage by the US Food and Drug Administration as a contraceptive,⁸ norethindrone 0.35 mg daily is approved as a progestin-only contraceptive.⁹ Norethindrone acetate is rapidly and completely deacetylated to norethindrone and the disposition of oral NEA is indistinguishable from that of norethindrone (which is the FDA-approved dosage mentioned above). Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg daily has contraceptive efficacy, especially if there is good adherence with the daily medication.

CASE 3 Perimenopausal AUB

A 45-year-old woman reports varying menstrual cycle lengths from 24 to 60 days with very heavy menses in some cycles. Pelvic ultrasonography shows no abnormality. Endometrial biopsy shows a proliferative endometrium. Her serum progesterone level, obtained 1 week before the onset of menses, is < 3 ng/mL. She has no past history of heavy menses, easy bruising, excessive bleeding with procedures, or a family history of bleeding problems. She also reports occasional hot flashes that wake her from sleep.

Use an estrogen step-down regimen to manage postmenopause transition

This patient is likely in the perimenopause transition, and the abnormal uterine bleeding (AUB) is caused, in part, by oligo- or anovulation. Perimenopausal women with AUB may have cycles characterized by above normal ovarian estradiol production and below normal progesterone production, or frank anovulation.¹⁰ Elevated ovarian estrogen and low progesterone production sets the stage for heavy bleeding in the perimenopause, regardless of the presence of uterine pathology such as fibroids.

For perimenopausal women, one option for treatment of AUB due to anovulation is to prescribe an estrogen step-down regimen. For the 45-year-old woman in this case, initiating treatment with an E-P pill containing ethinyl estradiol 10 µg and NEA 1 mg will likely control the AUB and her occasional hot flash.¹¹ As the woman ages, the ethinyl estradiol dose can be decreased to pills containing 5 µg and then 2.5 µg, covering the transition into postmenopause. Once the woman is in the postmenopause, treatment with transdermal estradiol and oral micronized progesterone is an option to treat menopausal vasomotor symptoms.

Optimize estrogen and progestin treatment for your patients

Many gynecologic problems are effectively treated by estrogen and/or progestin steroids. The dose of estrogen and progestin should be tailored to the specific problem. For PCOS, the estrogen dose selected should be sufficient to safely stimulate hepatic SHBG production. For endometriosis, if a GnRH antagonist is not available to the patient, a high-dose progestin, such as NEA 5 mg, may be an effective treatment. During the perimenopause transition in a woman with AUB, a treatment plan using a sequential E-P step-down program might control symptoms and help smoothly glide the patient into the postmenopause. ●

There are dozens of medications containing combinations of estrogen and progestin. I am often confused by the bewildering proliferation of generic brand names used to describe the same estrogen-progestin (E-P) regimen. For example, the combination medication containing ethinyl estradiol 20 µg plus norethindrone acetate (NEA) 1 mg is available under at least 5 different names: Lo Estrin 1/20 (Warner Chilcot), Junel 1/20 (Teva Pharmaceuticals), Microgestin Fe 1/20 (Mayne Pharma), Gildess 1/20 (Qualitest Pharmaceuticals), and Larin 1/20 (Novast Laboratories). To reduce the confusion, it is often useful to select a single preferred estrogen and progestin and use the dose combinations that are available to treat a wide range of gynecology problems (TABLE). In this editorial I focus on using various dose combinations of ethinyl estradiol and NEA to treat 3 common gynecologic problems.

CASE 1 Polycystic ovary syndrome

A 19-year-old woman reports 4 spontaneous menses in the past year and bothersome facial hair and acne. Her total testosterone concentration is at the upper limit of normal (0.46 ng/mL) and her sex hormone binding globulin (SHBG) concentration is at the lower limit of normal (35 nM). For treatment of the patient’s menstrual disorder, what is an optimal E-P combination?

Prioritize the use of an estrogen-dominant medication

Based on the Rotterdam criteria this woman has polycystic ovary syndrome (PCOS).¹ In women with PCOS, luteinizing hormone (LH) secretion is increased, stimulating excessive ovarian production of testosterone.² In addition, many women with PCOS have decreased hepatic secretion of SHBG, a binding protein that prevents testosterone from entering cells, resulting in excessive bioavailable testosterone.³ The Endocrine Society recommends that women with PCOS who have menstrual dysfunction or hirsutism be treated initially with a combination E-P hormone medication.¹ Combination E-P medications suppress pituitary secretion of LH, thereby reducing ovarian production of testosterone, and ethinyl estradiol increases hepatic secretion of SHBG, reducing bioavailable testosterone. These two goals are best accomplished with an oral E-P hormone medication containing ethinyl estradiol doses of 20 µg to 30 µg per pill. An E-P hormone medication containing pills with an ethinyl estradiol dose ≤ 10 µg-daily may stimulate less hepatic production of SHBG than a pill with an ethinyl estradiol dose of 20 µg or 30 µg daily.^4,5 In addition, E-P pills containing levonorgestrel suppress SHBG hormone secretion compared with E-P pills with other progestins.⁶ Therefore, levonorgestrel-containing E-P pills should not be prioritized for use in women with PCOS because the estrogen-induced increase in SHBG will be blunted by levonorgestrel.

CASE 2 Moderate to severe pelvic pain caused by endometriosis

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis lesions in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy showed endometriosis. Postoperatively, the patient was treated with an E-P pill containing 30 µg ethinyl estradiol and 0.15 mg desogestrel per pill using a continuous-dosing protocol. During the year following the laparoscopy, her pelvic pain symptoms gradually increased until they became severe, preventing her from performing daily activities on multiple days per month. She was prescribed elagolix but her insurance did not approve the treatment. What alternative treatment would you prescribe?

Continue to: Use progestin-dominant pills to treat pelvic pain...

Use progestin-dominant pills to treat pelvic pain

Cellular activity in endometriosis lesions is stimulated by estradiol and inhibited by a high concentration of androgenic progestins or androgens. This simplified endocrine paradigm explains the effectiveness of hormonal treatments that suppress ovarian estradiol production, including leuprolide, elagolix, medroxyprogesterone acetate, and NEA. For the woman in the above case, I would advocate for elagolix treatment but, following the insurance denial of the prescription, an alternative treatment for moderate or severe pelvic pain caused by endometriosis would be a progestin-dominant hormone medication (for example, NEA 5 mg daily). Norethindrone acetate 5 mg daily may be associated with bothersome adverse effects including weight gain (16% of patients; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%).⁷

I sometimes see women with moderate to severe pelvic pain caused by endometriosis being treated with norethindrone 0.35 mg daily. This dose of norethindrone is suboptimal for pain treatment because it does not reliably suppress ovarian production of estradiol. In addition, the cells in endometriosis lesions are often resistant to the effects of progesterone, requiring higher dosages to produce secretory or decidual changes. In most situations, I recommend against the use of norethindrone 0.35 mg daily for the treatment of pelvic pain caused by endometriosis.

Patients commonly ask if NEA 5 mg daily has contraceptive efficacy. Although it is not approved at this dosage by the US Food and Drug Administration as a contraceptive,⁸ norethindrone 0.35 mg daily is approved as a progestin-only contraceptive.⁹ Norethindrone acetate is rapidly and completely deacetylated to norethindrone and the disposition of oral NEA is indistinguishable from that of norethindrone (which is the FDA-approved dosage mentioned above). Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg daily has contraceptive efficacy, especially if there is good adherence with the daily medication.

CASE 3 Perimenopausal AUB

A 45-year-old woman reports varying menstrual cycle lengths from 24 to 60 days with very heavy menses in some cycles. Pelvic ultrasonography shows no abnormality. Endometrial biopsy shows a proliferative endometrium. Her serum progesterone level, obtained 1 week before the onset of menses, is < 3 ng/mL. She has no past history of heavy menses, easy bruising, excessive bleeding with procedures, or a family history of bleeding problems. She also reports occasional hot flashes that wake her from sleep.

Use an estrogen step-down regimen to manage postmenopause transition

This patient is likely in the perimenopause transition, and the abnormal uterine bleeding (AUB) is caused, in part, by oligo- or anovulation. Perimenopausal women with AUB may have cycles characterized by above normal ovarian estradiol production and below normal progesterone production, or frank anovulation.¹⁰ Elevated ovarian estrogen and low progesterone production sets the stage for heavy bleeding in the perimenopause, regardless of the presence of uterine pathology such as fibroids.

For perimenopausal women, one option for treatment of AUB due to anovulation is to prescribe an estrogen step-down regimen. For the 45-year-old woman in this case, initiating treatment with an E-P pill containing ethinyl estradiol 10 µg and NEA 1 mg will likely control the AUB and her occasional hot flash.¹¹ As the woman ages, the ethinyl estradiol dose can be decreased to pills containing 5 µg and then 2.5 µg, covering the transition into postmenopause. Once the woman is in the postmenopause, treatment with transdermal estradiol and oral micronized progesterone is an option to treat menopausal vasomotor symptoms.

Optimize estrogen and progestin treatment for your patients

Many gynecologic problems are effectively treated by estrogen and/or progestin steroids. The dose of estrogen and progestin should be tailored to the specific problem. For PCOS, the estrogen dose selected should be sufficient to safely stimulate hepatic SHBG production. For endometriosis, if a GnRH antagonist is not available to the patient, a high-dose progestin, such as NEA 5 mg, may be an effective treatment. During the perimenopause transition in a woman with AUB, a treatment plan using a sequential E-P step-down program might control symptoms and help smoothly glide the patient into the postmenopause. ●

There are dozens of medications containing combinations of estrogen and progestin. I am often confused by the bewildering proliferation of generic brand names used to describe the same estrogen-progestin (E-P) regimen. For example, the combination medication containing ethinyl estradiol 20 µg plus norethindrone acetate (NEA) 1 mg is available under at least 5 different names: Lo Estrin 1/20 (Warner Chilcot), Junel 1/20 (Teva Pharmaceuticals), Microgestin Fe 1/20 (Mayne Pharma), Gildess 1/20 (Qualitest Pharmaceuticals), and Larin 1/20 (Novast Laboratories). To reduce the confusion, it is often useful to select a single preferred estrogen and progestin and use the dose combinations that are available to treat a wide range of gynecology problems (TABLE). In this editorial I focus on using various dose combinations of ethinyl estradiol and NEA to treat 3 common gynecologic problems.

CASE 1 Polycystic ovary syndrome

A 19-year-old woman reports 4 spontaneous menses in the past year and bothersome facial hair and acne. Her total testosterone concentration is at the upper limit of normal (0.46 ng/mL) and her sex hormone binding globulin (SHBG) concentration is at the lower limit of normal (35 nM). For treatment of the patient’s menstrual disorder, what is an optimal E-P combination?

Prioritize the use of an estrogen-dominant medication

Based on the Rotterdam criteria this woman has polycystic ovary syndrome (PCOS).¹ In women with PCOS, luteinizing hormone (LH) secretion is increased, stimulating excessive ovarian production of testosterone.² In addition, many women with PCOS have decreased hepatic secretion of SHBG, a binding protein that prevents testosterone from entering cells, resulting in excessive bioavailable testosterone.³ The Endocrine Society recommends that women with PCOS who have menstrual dysfunction or hirsutism be treated initially with a combination E-P hormone medication.¹ Combination E-P medications suppress pituitary secretion of LH, thereby reducing ovarian production of testosterone, and ethinyl estradiol increases hepatic secretion of SHBG, reducing bioavailable testosterone. These two goals are best accomplished with an oral E-P hormone medication containing ethinyl estradiol doses of 20 µg to 30 µg per pill. An E-P hormone medication containing pills with an ethinyl estradiol dose ≤ 10 µg-daily may stimulate less hepatic production of SHBG than a pill with an ethinyl estradiol dose of 20 µg or 30 µg daily.^4,5 In addition, E-P pills containing levonorgestrel suppress SHBG hormone secretion compared with E-P pills with other progestins.⁶ Therefore, levonorgestrel-containing E-P pills should not be prioritized for use in women with PCOS because the estrogen-induced increase in SHBG will be blunted by levonorgestrel.

CASE 2 Moderate to severe pelvic pain caused by endometriosis

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis lesions in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy showed endometriosis. Postoperatively, the patient was treated with an E-P pill containing 30 µg ethinyl estradiol and 0.15 mg desogestrel per pill using a continuous-dosing protocol. During the year following the laparoscopy, her pelvic pain symptoms gradually increased until they became severe, preventing her from performing daily activities on multiple days per month. She was prescribed elagolix but her insurance did not approve the treatment. What alternative treatment would you prescribe?

Continue to: Use progestin-dominant pills to treat pelvic pain...

Use progestin-dominant pills to treat pelvic pain

Cellular activity in endometriosis lesions is stimulated by estradiol and inhibited by a high concentration of androgenic progestins or androgens. This simplified endocrine paradigm explains the effectiveness of hormonal treatments that suppress ovarian estradiol production, including leuprolide, elagolix, medroxyprogesterone acetate, and NEA. For the woman in the above case, I would advocate for elagolix treatment but, following the insurance denial of the prescription, an alternative treatment for moderate or severe pelvic pain caused by endometriosis would be a progestin-dominant hormone medication (for example, NEA 5 mg daily). Norethindrone acetate 5 mg daily may be associated with bothersome adverse effects including weight gain (16% of patients; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%).⁷

I sometimes see women with moderate to severe pelvic pain caused by endometriosis being treated with norethindrone 0.35 mg daily. This dose of norethindrone is suboptimal for pain treatment because it does not reliably suppress ovarian production of estradiol. In addition, the cells in endometriosis lesions are often resistant to the effects of progesterone, requiring higher dosages to produce secretory or decidual changes. In most situations, I recommend against the use of norethindrone 0.35 mg daily for the treatment of pelvic pain caused by endometriosis.

Patients commonly ask if NEA 5 mg daily has contraceptive efficacy. Although it is not approved at this dosage by the US Food and Drug Administration as a contraceptive,⁸ norethindrone 0.35 mg daily is approved as a progestin-only contraceptive.⁹ Norethindrone acetate is rapidly and completely deacetylated to norethindrone and the disposition of oral NEA is indistinguishable from that of norethindrone (which is the FDA-approved dosage mentioned above). Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg daily has contraceptive efficacy, especially if there is good adherence with the daily medication.

CASE 3 Perimenopausal AUB

A 45-year-old woman reports varying menstrual cycle lengths from 24 to 60 days with very heavy menses in some cycles. Pelvic ultrasonography shows no abnormality. Endometrial biopsy shows a proliferative endometrium. Her serum progesterone level, obtained 1 week before the onset of menses, is < 3 ng/mL. She has no past history of heavy menses, easy bruising, excessive bleeding with procedures, or a family history of bleeding problems. She also reports occasional hot flashes that wake her from sleep.

Use an estrogen step-down regimen to manage postmenopause transition

This patient is likely in the perimenopause transition, and the abnormal uterine bleeding (AUB) is caused, in part, by oligo- or anovulation. Perimenopausal women with AUB may have cycles characterized by above normal ovarian estradiol production and below normal progesterone production, or frank anovulation.¹⁰ Elevated ovarian estrogen and low progesterone production sets the stage for heavy bleeding in the perimenopause, regardless of the presence of uterine pathology such as fibroids.

For perimenopausal women, one option for treatment of AUB due to anovulation is to prescribe an estrogen step-down regimen. For the 45-year-old woman in this case, initiating treatment with an E-P pill containing ethinyl estradiol 10 µg and NEA 1 mg will likely control the AUB and her occasional hot flash.¹¹ As the woman ages, the ethinyl estradiol dose can be decreased to pills containing 5 µg and then 2.5 µg, covering the transition into postmenopause. Once the woman is in the postmenopause, treatment with transdermal estradiol and oral micronized progesterone is an option to treat menopausal vasomotor symptoms.

Optimize estrogen and progestin treatment for your patients

Many gynecologic problems are effectively treated by estrogen and/or progestin steroids. The dose of estrogen and progestin should be tailored to the specific problem. For PCOS, the estrogen dose selected should be sufficient to safely stimulate hepatic SHBG production. For endometriosis, if a GnRH antagonist is not available to the patient, a high-dose progestin, such as NEA 5 mg, may be an effective treatment. During the perimenopause transition in a woman with AUB, a treatment plan using a sequential E-P step-down program might control symptoms and help smoothly glide the patient into the postmenopause. ●

Women who receive pellet hormonal therapy may be significantly more likely to have side effects such as mood swings, anxiety, breast tenderness, hair pattern change, acne, and weight gain, compared with women who receive hormonal treatments that have been approved by the Food and Drug Administration, a study indicates.

In addition, abnormal uterine bleeding may be significantly more common in women who receive pellets than it is in women who receive Food and Drug Administration–approved options, according to the retrospective study, which was published online in Menopause.

Women receiving pellets also were more likely to undergo hysterectomy while on hormonal therapy, and they had higher supraphysiological levels of estradiol and total testosterone during treatment, compared with women on conventional therapy, the study of 539 women shows.

The findings, which had been presented at the North American Menopause Society annual meeting, were highlighted during a lecture at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.

The data are “not very reassuring at all,” said Robert P. Kauffman, MD, a professor of obstetrics and gynecology at Texas Tech University, Amarillo, who was not involved in the study.

Dr. Kauffman commented on the research during a review of concerns surrounding non–FDA-approved hormone replacement therapies at the ACOG meeting. Concerns include variations in compounded products, a lack of randomized, controlled trial data supporting their use, and ethical dilemmas that may exist if clinicians have financial incentives to provide compounded bioidentical hormone therapy over FDA-approved treatments.

No peer-reviewed studies show that compounded hormone creams or pellets are safer, more efficacious, or less likely to cause adverse effects, compared with FDA-approved products, Dr. Kauffman said.
 

Data from Pennsylvania

For the retrospective study, Xuezhi (Daniel) Jiang, MD, PhD, and colleagues identified postmenopausal patients in the Reading Hospital Electronic Medical Record System, including 10,801 on FDA-approved hormonal therapy and 1,061 on pellet hormonal therapy. Their analysis focused on data from the medical records of 384 women on pellet hormonal therapy and 155 women on FDA-approved hormonal therapy. Dr. Jiang is affiliated with the department of obstetrics and gynecology at Reading (Pa.) Hospital and Sidney Kimmel Medical College, Philadelphia.

The researchers examined data from 2005 to 2017 for patients in the pellet therapy group, and from 1985 to 2017 for patients in the conventional therapy group.

Patients in the conventional therapy group received 24 brands of FDA-approved hormone products; 4.5% received testosterone or methyltestosterone in addition to estrogen. Patients in the pellet therapy group had pellets prescribed by clinicians at two private practices in the hospital system that use this treatment approach. Patients in the pellet group received compounded estradiol and testosterone pellets made at a pharmacy in Tennessee.* Almost all of the patients in the pellet group received testosterone and estradiol pellets.

Low libido was listed as a reason why women started treatment for 83.5% of the pellet group versus 4.5% of the conventional therapy group.

In all, 57.6% of patients on pellet therapy had side effects, versus 14.8% on FDA-approved therapy, the researchers found. Patients on pellet hormonal therapy reported higher incidence of mood swings (7% vs. 1.9%), anxiety (18.5% vs. 5.8%), breast tenderness (10.1% vs. 2.6%), hair pattern change (13.5% vs. 2.6%), acne (8.6% vs. 1.3%), and weight gain (34.4% vs 4.5%), relative to patients on FDA-approved options.

Among those with an intact uterus when starting therapy (246 of those on pellets and 133 of those on FDA-approved treatments), abnormal uterine bleeding occurred in 55.3% on pellets, compared with 15.2% on FDA-approved treatments (adjusted odds ratio, 7.9). Hysterectomy secondary to abnormal uterine bleeding occurred in 20.3% of the patients on pellets versus 6.3% on FDA-approved treatments (aOR, 3.2).

In many cases, records show that patients chose to have a hysterectomy so they could continue pellet therapy without worrying about abnormal uterine bleeding, Dr. Jiang said in an interview.

Dr. Kauffman has seen patients on pellet therapy, usually implanted by family physicians, develop postmenopausal bleeding because of high levels of estrogen. “Our experience has been too that, if you have pellets, you are more likely to get a hysterectomy for bleeding issues. And I think these are the safety issues that need to be looked at on a broader scope,” he said in an interview.

Although hysterectomy may stop the bleeding, other safety risks may remain with pellet therapy, noted Sharon Winer, MD, MPH, an obstetrician and gynecologist with a subspecialty in reproductive endocrinology and infertility who practices in Beverly Hills, Calif.

Pellets, which are about the size of a grain of rice, typically are implanted in the hip, lower abdomen, or buttock and release hormones over 3-6 months. The pellets are not retrievable. “The question becomes, what if she has a new breast cancer diagnosis or a diagnosis where estrogen is contraindicated? She has got that estrogen already in her system,” Dr. Winer said.

“The hysterectomy may solve the bleeding problem ... but it doesn’t solve the safety problem overall,” said Dr. Winer, who also is a professor of obstetrics and gynecology and codirector of the reproductive endocrinology and infertility clinic at the University of Southern California, Los Angeles.

Elevated levels

Average peak serum estradiol was significantly higher in the pellet treatment group than in the conventional therapy group (237.70 pg/mL vs. 93.45 pg/mL), as was average peak serum testosterone (192.84 ng/dL vs. 15.59 ng/dL), the researchers reported. Patients on FDA-approved treatments were less likely to have had their hormone levels measured. How concentrations of hormone levels correlate with side effects is unclear, Dr. Jiang said.

The study was limited by its single-institution, retrospective design, and some patient characteristics differed between the treatment groups, the authors noted.

Still, “clinicians ought to be mindful of fully counseling patients on side effects identified in the current study,” Dr. Jiang and coauthors concluded. Clinicians also need to discuss potential risks of breast cancer, endometrial cancer, and cardiovascular disease with patients.

Many primary care clinicians rely on outdated information from the Women’s Health Initiative, published in 2002 and 2004, in their understanding of postmenopausal hormonal therapy and its risks and benefits, Dr. Jiang said. And some patients consider custom-compounded hormone therapy to be safer and more natural, “which is totally misleading.”

Pellets and other custom-compounded medicine containing testosterone may make patients feel better and more energetic, Dr. Jiang acknowledged. “That’s a reason why patients ... tend to stay on, even though they have side effects. The only issue is the safety.”

Additional questions remain. The researchers recently started to examine rates of breast cancer and abnormal breast pathology and mammogram results. “It’s a long journey,” he said.

Plenty of approved options

Custom-compounded medicines are not FDA approved and are not recommended by medical menopause societies, Dr. Jiang said. Meanwhile, plenty of approved hormone therapies, including bioidentical treatments, have safety data and are available.

A 2020 consensus study report from the National Academies of Sciences, Engineering, and Medicine that examined the use of compounded hormonal therapy and provides guidance for clinicians is a good start in addressing this major issue, he added.

A committee determined “there is insufficient evidence to support the overall clinical utility of [compounded bioidentical hormone therapies] as treatment for menopause and male hypogonadism symptoms.”

If an FDA-approved option is available, “I would always go with an FDA-approved product before I would go with a compounded product,” Dr. Winer said. A 2012 fungal meningitis outbreak linked to a compounding pharmacy highlighted risks associated with poor quality compounded drugs.

“I think at least now it is recognized that compounding is an issue that has got to be dealt with,” Dr. Winer said. “It is just that it is so widespread and it is sometimes under the radar ... that I think it is really hard for the FDA to get a handle on it.”

Dr. Winer has seen patients on compounded treatments who are underdosed and patients who are overdosed. “I’ve also seen patients who do quite well with it, but I’m not happy continuing it because tomorrow there may be inconsistency in potency or quality resulting in a different clinical response,” she said.

Nevertheless, compounded pharmacies are needed, Dr. Winer said. If she wants to give natural progesterone that is FDA approved but happens to be made with peanut oil, she will have a compounding pharmacy make it with canola oil instead if a patient has a peanut allergy, for example. Other patients need dosages that are so low that they are not available as FDA-approved products.

Dr. Jiang and Dr. Kauffman had no relevant financial disclosures. Dr. Winer has done work with AbbVie (related to endometriosis), TherapeuticsMD (related to a menopause bioidentical hormonal pill and vaginal estrogen product), and Biogix (related to an antioxidant supplement for menopause symptoms).

[email protected]

*This story was updated on 6/22/2021.

Women who receive pellet hormonal therapy may be significantly more likely to have side effects such as mood swings, anxiety, breast tenderness, hair pattern change, acne, and weight gain, compared with women who receive hormonal treatments that have been approved by the Food and Drug Administration, a study indicates.

In addition, abnormal uterine bleeding may be significantly more common in women who receive pellets than it is in women who receive Food and Drug Administration–approved options, according to the retrospective study, which was published online in Menopause.

Women receiving pellets also were more likely to undergo hysterectomy while on hormonal therapy, and they had higher supraphysiological levels of estradiol and total testosterone during treatment, compared with women on conventional therapy, the study of 539 women shows.

The findings, which had been presented at the North American Menopause Society annual meeting, were highlighted during a lecture at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.

The data are “not very reassuring at all,” said Robert P. Kauffman, MD, a professor of obstetrics and gynecology at Texas Tech University, Amarillo, who was not involved in the study.

Dr. Kauffman commented on the research during a review of concerns surrounding non–FDA-approved hormone replacement therapies at the ACOG meeting. Concerns include variations in compounded products, a lack of randomized, controlled trial data supporting their use, and ethical dilemmas that may exist if clinicians have financial incentives to provide compounded bioidentical hormone therapy over FDA-approved treatments.

No peer-reviewed studies show that compounded hormone creams or pellets are safer, more efficacious, or less likely to cause adverse effects, compared with FDA-approved products, Dr. Kauffman said.
 

Data from Pennsylvania

For the retrospective study, Xuezhi (Daniel) Jiang, MD, PhD, and colleagues identified postmenopausal patients in the Reading Hospital Electronic Medical Record System, including 10,801 on FDA-approved hormonal therapy and 1,061 on pellet hormonal therapy. Their analysis focused on data from the medical records of 384 women on pellet hormonal therapy and 155 women on FDA-approved hormonal therapy. Dr. Jiang is affiliated with the department of obstetrics and gynecology at Reading (Pa.) Hospital and Sidney Kimmel Medical College, Philadelphia.

The researchers examined data from 2005 to 2017 for patients in the pellet therapy group, and from 1985 to 2017 for patients in the conventional therapy group.

Patients in the conventional therapy group received 24 brands of FDA-approved hormone products; 4.5% received testosterone or methyltestosterone in addition to estrogen. Patients in the pellet therapy group had pellets prescribed by clinicians at two private practices in the hospital system that use this treatment approach. Patients in the pellet group received compounded estradiol and testosterone pellets made at a pharmacy in Tennessee.* Almost all of the patients in the pellet group received testosterone and estradiol pellets.

Low libido was listed as a reason why women started treatment for 83.5% of the pellet group versus 4.5% of the conventional therapy group.

In all, 57.6% of patients on pellet therapy had side effects, versus 14.8% on FDA-approved therapy, the researchers found. Patients on pellet hormonal therapy reported higher incidence of mood swings (7% vs. 1.9%), anxiety (18.5% vs. 5.8%), breast tenderness (10.1% vs. 2.6%), hair pattern change (13.5% vs. 2.6%), acne (8.6% vs. 1.3%), and weight gain (34.4% vs 4.5%), relative to patients on FDA-approved options.

Among those with an intact uterus when starting therapy (246 of those on pellets and 133 of those on FDA-approved treatments), abnormal uterine bleeding occurred in 55.3% on pellets, compared with 15.2% on FDA-approved treatments (adjusted odds ratio, 7.9). Hysterectomy secondary to abnormal uterine bleeding occurred in 20.3% of the patients on pellets versus 6.3% on FDA-approved treatments (aOR, 3.2).

In many cases, records show that patients chose to have a hysterectomy so they could continue pellet therapy without worrying about abnormal uterine bleeding, Dr. Jiang said in an interview.

Dr. Kauffman has seen patients on pellet therapy, usually implanted by family physicians, develop postmenopausal bleeding because of high levels of estrogen. “Our experience has been too that, if you have pellets, you are more likely to get a hysterectomy for bleeding issues. And I think these are the safety issues that need to be looked at on a broader scope,” he said in an interview.

Although hysterectomy may stop the bleeding, other safety risks may remain with pellet therapy, noted Sharon Winer, MD, MPH, an obstetrician and gynecologist with a subspecialty in reproductive endocrinology and infertility who practices in Beverly Hills, Calif.

Pellets, which are about the size of a grain of rice, typically are implanted in the hip, lower abdomen, or buttock and release hormones over 3-6 months. The pellets are not retrievable. “The question becomes, what if she has a new breast cancer diagnosis or a diagnosis where estrogen is contraindicated? She has got that estrogen already in her system,” Dr. Winer said.

“The hysterectomy may solve the bleeding problem ... but it doesn’t solve the safety problem overall,” said Dr. Winer, who also is a professor of obstetrics and gynecology and codirector of the reproductive endocrinology and infertility clinic at the University of Southern California, Los Angeles.

Elevated levels

Average peak serum estradiol was significantly higher in the pellet treatment group than in the conventional therapy group (237.70 pg/mL vs. 93.45 pg/mL), as was average peak serum testosterone (192.84 ng/dL vs. 15.59 ng/dL), the researchers reported. Patients on FDA-approved treatments were less likely to have had their hormone levels measured. How concentrations of hormone levels correlate with side effects is unclear, Dr. Jiang said.

The study was limited by its single-institution, retrospective design, and some patient characteristics differed between the treatment groups, the authors noted.

Still, “clinicians ought to be mindful of fully counseling patients on side effects identified in the current study,” Dr. Jiang and coauthors concluded. Clinicians also need to discuss potential risks of breast cancer, endometrial cancer, and cardiovascular disease with patients.

Many primary care clinicians rely on outdated information from the Women’s Health Initiative, published in 2002 and 2004, in their understanding of postmenopausal hormonal therapy and its risks and benefits, Dr. Jiang said. And some patients consider custom-compounded hormone therapy to be safer and more natural, “which is totally misleading.”

Pellets and other custom-compounded medicine containing testosterone may make patients feel better and more energetic, Dr. Jiang acknowledged. “That’s a reason why patients ... tend to stay on, even though they have side effects. The only issue is the safety.”

Additional questions remain. The researchers recently started to examine rates of breast cancer and abnormal breast pathology and mammogram results. “It’s a long journey,” he said.

Plenty of approved options

Custom-compounded medicines are not FDA approved and are not recommended by medical menopause societies, Dr. Jiang said. Meanwhile, plenty of approved hormone therapies, including bioidentical treatments, have safety data and are available.

A 2020 consensus study report from the National Academies of Sciences, Engineering, and Medicine that examined the use of compounded hormonal therapy and provides guidance for clinicians is a good start in addressing this major issue, he added.

A committee determined “there is insufficient evidence to support the overall clinical utility of [compounded bioidentical hormone therapies] as treatment for menopause and male hypogonadism symptoms.”

If an FDA-approved option is available, “I would always go with an FDA-approved product before I would go with a compounded product,” Dr. Winer said. A 2012 fungal meningitis outbreak linked to a compounding pharmacy highlighted risks associated with poor quality compounded drugs.

“I think at least now it is recognized that compounding is an issue that has got to be dealt with,” Dr. Winer said. “It is just that it is so widespread and it is sometimes under the radar ... that I think it is really hard for the FDA to get a handle on it.”

Dr. Winer has seen patients on compounded treatments who are underdosed and patients who are overdosed. “I’ve also seen patients who do quite well with it, but I’m not happy continuing it because tomorrow there may be inconsistency in potency or quality resulting in a different clinical response,” she said.

Nevertheless, compounded pharmacies are needed, Dr. Winer said. If she wants to give natural progesterone that is FDA approved but happens to be made with peanut oil, she will have a compounding pharmacy make it with canola oil instead if a patient has a peanut allergy, for example. Other patients need dosages that are so low that they are not available as FDA-approved products.

Dr. Jiang and Dr. Kauffman had no relevant financial disclosures. Dr. Winer has done work with AbbVie (related to endometriosis), TherapeuticsMD (related to a menopause bioidentical hormonal pill and vaginal estrogen product), and Biogix (related to an antioxidant supplement for menopause symptoms).

[email protected]

*This story was updated on 6/22/2021.

Women who receive pellet hormonal therapy may be significantly more likely to have side effects such as mood swings, anxiety, breast tenderness, hair pattern change, acne, and weight gain, compared with women who receive hormonal treatments that have been approved by the Food and Drug Administration, a study indicates.

In addition, abnormal uterine bleeding may be significantly more common in women who receive pellets than it is in women who receive Food and Drug Administration–approved options, according to the retrospective study, which was published online in Menopause.

Women receiving pellets also were more likely to undergo hysterectomy while on hormonal therapy, and they had higher supraphysiological levels of estradiol and total testosterone during treatment, compared with women on conventional therapy, the study of 539 women shows.

The findings, which had been presented at the North American Menopause Society annual meeting, were highlighted during a lecture at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.

The data are “not very reassuring at all,” said Robert P. Kauffman, MD, a professor of obstetrics and gynecology at Texas Tech University, Amarillo, who was not involved in the study.

Dr. Kauffman commented on the research during a review of concerns surrounding non–FDA-approved hormone replacement therapies at the ACOG meeting. Concerns include variations in compounded products, a lack of randomized, controlled trial data supporting their use, and ethical dilemmas that may exist if clinicians have financial incentives to provide compounded bioidentical hormone therapy over FDA-approved treatments.

No peer-reviewed studies show that compounded hormone creams or pellets are safer, more efficacious, or less likely to cause adverse effects, compared with FDA-approved products, Dr. Kauffman said.
 

Data from Pennsylvania

For the retrospective study, Xuezhi (Daniel) Jiang, MD, PhD, and colleagues identified postmenopausal patients in the Reading Hospital Electronic Medical Record System, including 10,801 on FDA-approved hormonal therapy and 1,061 on pellet hormonal therapy. Their analysis focused on data from the medical records of 384 women on pellet hormonal therapy and 155 women on FDA-approved hormonal therapy. Dr. Jiang is affiliated with the department of obstetrics and gynecology at Reading (Pa.) Hospital and Sidney Kimmel Medical College, Philadelphia.

The researchers examined data from 2005 to 2017 for patients in the pellet therapy group, and from 1985 to 2017 for patients in the conventional therapy group.

Patients in the conventional therapy group received 24 brands of FDA-approved hormone products; 4.5% received testosterone or methyltestosterone in addition to estrogen. Patients in the pellet therapy group had pellets prescribed by clinicians at two private practices in the hospital system that use this treatment approach. Patients in the pellet group received compounded estradiol and testosterone pellets made at a pharmacy in Tennessee.* Almost all of the patients in the pellet group received testosterone and estradiol pellets.

Low libido was listed as a reason why women started treatment for 83.5% of the pellet group versus 4.5% of the conventional therapy group.

In all, 57.6% of patients on pellet therapy had side effects, versus 14.8% on FDA-approved therapy, the researchers found. Patients on pellet hormonal therapy reported higher incidence of mood swings (7% vs. 1.9%), anxiety (18.5% vs. 5.8%), breast tenderness (10.1% vs. 2.6%), hair pattern change (13.5% vs. 2.6%), acne (8.6% vs. 1.3%), and weight gain (34.4% vs 4.5%), relative to patients on FDA-approved options.

Among those with an intact uterus when starting therapy (246 of those on pellets and 133 of those on FDA-approved treatments), abnormal uterine bleeding occurred in 55.3% on pellets, compared with 15.2% on FDA-approved treatments (adjusted odds ratio, 7.9). Hysterectomy secondary to abnormal uterine bleeding occurred in 20.3% of the patients on pellets versus 6.3% on FDA-approved treatments (aOR, 3.2).

In many cases, records show that patients chose to have a hysterectomy so they could continue pellet therapy without worrying about abnormal uterine bleeding, Dr. Jiang said in an interview.

Dr. Kauffman has seen patients on pellet therapy, usually implanted by family physicians, develop postmenopausal bleeding because of high levels of estrogen. “Our experience has been too that, if you have pellets, you are more likely to get a hysterectomy for bleeding issues. And I think these are the safety issues that need to be looked at on a broader scope,” he said in an interview.

Although hysterectomy may stop the bleeding, other safety risks may remain with pellet therapy, noted Sharon Winer, MD, MPH, an obstetrician and gynecologist with a subspecialty in reproductive endocrinology and infertility who practices in Beverly Hills, Calif.

Pellets, which are about the size of a grain of rice, typically are implanted in the hip, lower abdomen, or buttock and release hormones over 3-6 months. The pellets are not retrievable. “The question becomes, what if she has a new breast cancer diagnosis or a diagnosis where estrogen is contraindicated? She has got that estrogen already in her system,” Dr. Winer said.

“The hysterectomy may solve the bleeding problem ... but it doesn’t solve the safety problem overall,” said Dr. Winer, who also is a professor of obstetrics and gynecology and codirector of the reproductive endocrinology and infertility clinic at the University of Southern California, Los Angeles.

Elevated levels

Average peak serum estradiol was significantly higher in the pellet treatment group than in the conventional therapy group (237.70 pg/mL vs. 93.45 pg/mL), as was average peak serum testosterone (192.84 ng/dL vs. 15.59 ng/dL), the researchers reported. Patients on FDA-approved treatments were less likely to have had their hormone levels measured. How concentrations of hormone levels correlate with side effects is unclear, Dr. Jiang said.

The study was limited by its single-institution, retrospective design, and some patient characteristics differed between the treatment groups, the authors noted.

Still, “clinicians ought to be mindful of fully counseling patients on side effects identified in the current study,” Dr. Jiang and coauthors concluded. Clinicians also need to discuss potential risks of breast cancer, endometrial cancer, and cardiovascular disease with patients.

Many primary care clinicians rely on outdated information from the Women’s Health Initiative, published in 2002 and 2004, in their understanding of postmenopausal hormonal therapy and its risks and benefits, Dr. Jiang said. And some patients consider custom-compounded hormone therapy to be safer and more natural, “which is totally misleading.”

Pellets and other custom-compounded medicine containing testosterone may make patients feel better and more energetic, Dr. Jiang acknowledged. “That’s a reason why patients ... tend to stay on, even though they have side effects. The only issue is the safety.”

Additional questions remain. The researchers recently started to examine rates of breast cancer and abnormal breast pathology and mammogram results. “It’s a long journey,” he said.

Plenty of approved options

Custom-compounded medicines are not FDA approved and are not recommended by medical menopause societies, Dr. Jiang said. Meanwhile, plenty of approved hormone therapies, including bioidentical treatments, have safety data and are available.

A 2020 consensus study report from the National Academies of Sciences, Engineering, and Medicine that examined the use of compounded hormonal therapy and provides guidance for clinicians is a good start in addressing this major issue, he added.

A committee determined “there is insufficient evidence to support the overall clinical utility of [compounded bioidentical hormone therapies] as treatment for menopause and male hypogonadism symptoms.”

If an FDA-approved option is available, “I would always go with an FDA-approved product before I would go with a compounded product,” Dr. Winer said. A 2012 fungal meningitis outbreak linked to a compounding pharmacy highlighted risks associated with poor quality compounded drugs.

“I think at least now it is recognized that compounding is an issue that has got to be dealt with,” Dr. Winer said. “It is just that it is so widespread and it is sometimes under the radar ... that I think it is really hard for the FDA to get a handle on it.”

Dr. Winer has seen patients on compounded treatments who are underdosed and patients who are overdosed. “I’ve also seen patients who do quite well with it, but I’m not happy continuing it because tomorrow there may be inconsistency in potency or quality resulting in a different clinical response,” she said.

Nevertheless, compounded pharmacies are needed, Dr. Winer said. If she wants to give natural progesterone that is FDA approved but happens to be made with peanut oil, she will have a compounding pharmacy make it with canola oil instead if a patient has a peanut allergy, for example. Other patients need dosages that are so low that they are not available as FDA-approved products.

Dr. Jiang and Dr. Kauffman had no relevant financial disclosures. Dr. Winer has done work with AbbVie (related to endometriosis), TherapeuticsMD (related to a menopause bioidentical hormonal pill and vaginal estrogen product), and Biogix (related to an antioxidant supplement for menopause symptoms).

[email protected]

*This story was updated on 6/22/2021.

A 2,940-nm and 1,470-nm hybrid fractional laser was found to be safe and effective for treating the genitourinary syndrome of menopause (GSM), results from a pilot trial showed.

“The genitourinary syndrome of menopause causes suffering in breast cancer survivors and postmenopausal women,” Jill S. Waibel, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. A common side effect for breast cancer survivors is early onset of menopause that is brought on by treatment, specifically aromatase-inhibitor therapies, she noted.

The symptoms of GSM include discomfort during sex, impaired sexual function, burning or sensation or irritation of the genital area, vaginal constriction, frequent urinary tract infections, urinary incontinence, and vaginal laxity, said Dr. Waibel, owner and medical director of the Miami Dermatology and Laser Institute. Nonhormonal treatments have included OTC vaginal lubricants, OTC moisturizers, low-dose vaginal estrogen – which increases the risk of breast cancer – and systemic estrogen therapy, which also can increase the risk of breast and endometrial cancer. “So, we need a healthy, nondrug option,” she said.

The objective of the pilot study was to determine the safety and efficacy of the diVa hybrid fractional laser as a treatment for symptoms of genitourinary syndrome of menopause, early menopause after breast cancer, or vaginal atrophy. The laser applies tunable nonablative (1,470-nm) and ablative (2,940-nm) wavelengths to the same microscopic treatment zone to maximize results and reduce downtime. The device features a motorized precision guidance system and calibrated rotation for homogeneous pulsing.

“The 2,940-nm wavelength is used to ablate to a depth of 0-800 micrometers while the 1,470-nm wavelength is used to coagulate the epithelium and the lamina propria at a depth of 100-700 micrometers,” said Dr. Waibel, who is also subsection chief of dermatology at Baptist Hospital of Miami. “This combination is used for epithelial tissue to heal quickly and the lamina propria to remodel slowly over time, laying down more collagen in tissue.” Each procedure is delivered via a single-use dilator, which expands the vaginal canal for increased treatment area. “The tip length is 5.5 cm and the diameter is 1 cm,” she said. “The clear tip acts as a hygienic barrier between the tip and the handpiece.”

Study participants included 25 women between the ages of 40 and 70 with early menopause after breast cancer or vaginal atrophy: 20 in the treatment arm and 5 in the sham-treatment arm. Dr. Waibel performed three procedures 2 weeks apart. An ob.gyn. assessed the primary endpoints, which included the Vaginal Health Index Scale (VHIS), the Vaginal Maturation Index (VMI), the Female Sexual Function Index (FSFI) questionnaire, and the Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire. Secondary endpoints were histology and a satisfaction questionnaire.

Of the women in the treated group, there were data available for 19 at 3 months follow-up and 17 at 6 months follow-up. Based on the results in these patients, there were statistically significant improvements in nearly all domains of the FSFI treatment arm at 3 and 6 months when compared to baseline, especially arousal (P values of .05 at 3 months and .01 at 6 months) and lubrication (P values of .009 at three months and .001 at 6 months).

Between 3 and 6 months, patients in the treatment arm experienced improvements in four dimensions of the DIVA questionnaire: daily activities (P value of .01 at 3 months to .010 at 6 months), emotional well-being (P value of .06 at 3 months to .014 at 6 months), sexual function (P value of .30 at 3 months to .003 at 6 months), and self-concept/body image (P value of .002 at 3 months to .001 at 6 months).

As for satisfaction, a majority of those in the treatment arm were “somewhat satisfied” with the treatment and would “somewhat likely” repeat and recommend the treatment to friends and family, Dr. Waibel said. Results among the women in the control arm, who were also surveyed, were in the similar range, she noted. (No other results for women in the control arm were available.)

Following treatments, histology revealed that the collagen was denser, fibroblasts were more dense, and vascularity was more notable. No adverse events were observed. “The hybrid fractional laser is safe and effective for treating GSM, early menopause after breast cancer, or vaginal atrophy,” Dr. Waibel concluded. Further studies are important to improve the understanding of “laser dosimetry, frequency of treatments, and longevity of effect. Collaboration between ob.gyns. and dermatologists is important as we learn about laser therapy in GSM.”

Dr. Waibel disclosed that she is a member of the advisory board of Sciton, which manufactures the diVa laser. She has also conducted clinical trials for many other device and pharmaceutical companies.

[email protected]

A 2,940-nm and 1,470-nm hybrid fractional laser was found to be safe and effective for treating the genitourinary syndrome of menopause (GSM), results from a pilot trial showed.

“The genitourinary syndrome of menopause causes suffering in breast cancer survivors and postmenopausal women,” Jill S. Waibel, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. A common side effect for breast cancer survivors is early onset of menopause that is brought on by treatment, specifically aromatase-inhibitor therapies, she noted.

The symptoms of GSM include discomfort during sex, impaired sexual function, burning or sensation or irritation of the genital area, vaginal constriction, frequent urinary tract infections, urinary incontinence, and vaginal laxity, said Dr. Waibel, owner and medical director of the Miami Dermatology and Laser Institute. Nonhormonal treatments have included OTC vaginal lubricants, OTC moisturizers, low-dose vaginal estrogen – which increases the risk of breast cancer – and systemic estrogen therapy, which also can increase the risk of breast and endometrial cancer. “So, we need a healthy, nondrug option,” she said.

The objective of the pilot study was to determine the safety and efficacy of the diVa hybrid fractional laser as a treatment for symptoms of genitourinary syndrome of menopause, early menopause after breast cancer, or vaginal atrophy. The laser applies tunable nonablative (1,470-nm) and ablative (2,940-nm) wavelengths to the same microscopic treatment zone to maximize results and reduce downtime. The device features a motorized precision guidance system and calibrated rotation for homogeneous pulsing.

“The 2,940-nm wavelength is used to ablate to a depth of 0-800 micrometers while the 1,470-nm wavelength is used to coagulate the epithelium and the lamina propria at a depth of 100-700 micrometers,” said Dr. Waibel, who is also subsection chief of dermatology at Baptist Hospital of Miami. “This combination is used for epithelial tissue to heal quickly and the lamina propria to remodel slowly over time, laying down more collagen in tissue.” Each procedure is delivered via a single-use dilator, which expands the vaginal canal for increased treatment area. “The tip length is 5.5 cm and the diameter is 1 cm,” she said. “The clear tip acts as a hygienic barrier between the tip and the handpiece.”

Study participants included 25 women between the ages of 40 and 70 with early menopause after breast cancer or vaginal atrophy: 20 in the treatment arm and 5 in the sham-treatment arm. Dr. Waibel performed three procedures 2 weeks apart. An ob.gyn. assessed the primary endpoints, which included the Vaginal Health Index Scale (VHIS), the Vaginal Maturation Index (VMI), the Female Sexual Function Index (FSFI) questionnaire, and the Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire. Secondary endpoints were histology and a satisfaction questionnaire.

Of the women in the treated group, there were data available for 19 at 3 months follow-up and 17 at 6 months follow-up. Based on the results in these patients, there were statistically significant improvements in nearly all domains of the FSFI treatment arm at 3 and 6 months when compared to baseline, especially arousal (P values of .05 at 3 months and .01 at 6 months) and lubrication (P values of .009 at three months and .001 at 6 months).

Between 3 and 6 months, patients in the treatment arm experienced improvements in four dimensions of the DIVA questionnaire: daily activities (P value of .01 at 3 months to .010 at 6 months), emotional well-being (P value of .06 at 3 months to .014 at 6 months), sexual function (P value of .30 at 3 months to .003 at 6 months), and self-concept/body image (P value of .002 at 3 months to .001 at 6 months).

As for satisfaction, a majority of those in the treatment arm were “somewhat satisfied” with the treatment and would “somewhat likely” repeat and recommend the treatment to friends and family, Dr. Waibel said. Results among the women in the control arm, who were also surveyed, were in the similar range, she noted. (No other results for women in the control arm were available.)

Following treatments, histology revealed that the collagen was denser, fibroblasts were more dense, and vascularity was more notable. No adverse events were observed. “The hybrid fractional laser is safe and effective for treating GSM, early menopause after breast cancer, or vaginal atrophy,” Dr. Waibel concluded. Further studies are important to improve the understanding of “laser dosimetry, frequency of treatments, and longevity of effect. Collaboration between ob.gyns. and dermatologists is important as we learn about laser therapy in GSM.”

Dr. Waibel disclosed that she is a member of the advisory board of Sciton, which manufactures the diVa laser. She has also conducted clinical trials for many other device and pharmaceutical companies.

[email protected]

A 2,940-nm and 1,470-nm hybrid fractional laser was found to be safe and effective for treating the genitourinary syndrome of menopause (GSM), results from a pilot trial showed.

“The genitourinary syndrome of menopause causes suffering in breast cancer survivors and postmenopausal women,” Jill S. Waibel, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. A common side effect for breast cancer survivors is early onset of menopause that is brought on by treatment, specifically aromatase-inhibitor therapies, she noted.

The symptoms of GSM include discomfort during sex, impaired sexual function, burning or sensation or irritation of the genital area, vaginal constriction, frequent urinary tract infections, urinary incontinence, and vaginal laxity, said Dr. Waibel, owner and medical director of the Miami Dermatology and Laser Institute. Nonhormonal treatments have included OTC vaginal lubricants, OTC moisturizers, low-dose vaginal estrogen – which increases the risk of breast cancer – and systemic estrogen therapy, which also can increase the risk of breast and endometrial cancer. “So, we need a healthy, nondrug option,” she said.

The objective of the pilot study was to determine the safety and efficacy of the diVa hybrid fractional laser as a treatment for symptoms of genitourinary syndrome of menopause, early menopause after breast cancer, or vaginal atrophy. The laser applies tunable nonablative (1,470-nm) and ablative (2,940-nm) wavelengths to the same microscopic treatment zone to maximize results and reduce downtime. The device features a motorized precision guidance system and calibrated rotation for homogeneous pulsing.

“The 2,940-nm wavelength is used to ablate to a depth of 0-800 micrometers while the 1,470-nm wavelength is used to coagulate the epithelium and the lamina propria at a depth of 100-700 micrometers,” said Dr. Waibel, who is also subsection chief of dermatology at Baptist Hospital of Miami. “This combination is used for epithelial tissue to heal quickly and the lamina propria to remodel slowly over time, laying down more collagen in tissue.” Each procedure is delivered via a single-use dilator, which expands the vaginal canal for increased treatment area. “The tip length is 5.5 cm and the diameter is 1 cm,” she said. “The clear tip acts as a hygienic barrier between the tip and the handpiece.”

Study participants included 25 women between the ages of 40 and 70 with early menopause after breast cancer or vaginal atrophy: 20 in the treatment arm and 5 in the sham-treatment arm. Dr. Waibel performed three procedures 2 weeks apart. An ob.gyn. assessed the primary endpoints, which included the Vaginal Health Index Scale (VHIS), the Vaginal Maturation Index (VMI), the Female Sexual Function Index (FSFI) questionnaire, and the Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire. Secondary endpoints were histology and a satisfaction questionnaire.

Of the women in the treated group, there were data available for 19 at 3 months follow-up and 17 at 6 months follow-up. Based on the results in these patients, there were statistically significant improvements in nearly all domains of the FSFI treatment arm at 3 and 6 months when compared to baseline, especially arousal (P values of .05 at 3 months and .01 at 6 months) and lubrication (P values of .009 at three months and .001 at 6 months).

Between 3 and 6 months, patients in the treatment arm experienced improvements in four dimensions of the DIVA questionnaire: daily activities (P value of .01 at 3 months to .010 at 6 months), emotional well-being (P value of .06 at 3 months to .014 at 6 months), sexual function (P value of .30 at 3 months to .003 at 6 months), and self-concept/body image (P value of .002 at 3 months to .001 at 6 months).

As for satisfaction, a majority of those in the treatment arm were “somewhat satisfied” with the treatment and would “somewhat likely” repeat and recommend the treatment to friends and family, Dr. Waibel said. Results among the women in the control arm, who were also surveyed, were in the similar range, she noted. (No other results for women in the control arm were available.)

Following treatments, histology revealed that the collagen was denser, fibroblasts were more dense, and vascularity was more notable. No adverse events were observed. “The hybrid fractional laser is safe and effective for treating GSM, early menopause after breast cancer, or vaginal atrophy,” Dr. Waibel concluded. Further studies are important to improve the understanding of “laser dosimetry, frequency of treatments, and longevity of effect. Collaboration between ob.gyns. and dermatologists is important as we learn about laser therapy in GSM.”

Dr. Waibel disclosed that she is a member of the advisory board of Sciton, which manufactures the diVa laser. She has also conducted clinical trials for many other device and pharmaceutical companies.

[email protected]

Primary ovarian insufficiency is not your mother’s early menopause, according to Laurie McKenzie, MD, a reproductive endocrinologist and associate professor of ob.gyn. at the University of Texas MD Anderson Cancer Center with a joint appointment at Baylor College of Medicine, both in Houston.

Known previously as primary ovarian failure, the syndrome of primary ovarian insufficiency (POI) no longer refers to a failure in part because of the term’s negative connotations but mostly because it’s not precisely accurate, Dr. McKenzie told attendees at the 2021 annual meeting of the American College of Obstetricians and Gynecologists on May 1.

“Many of these women, especially early on in diagnosis, may be experiencing some intermittent ovarian function, so it may not be a complete failure of the ovaries,” Dr. McKenzie said.

Although the condition is not common, affecting about 1% of the female population, “it’s the kind of thing that when a gynecologist has someone who has this walk into their office, you really need to know how to address it because these women are understandably very distressed.” Lauren Streicher, MD, a clinical professor of obstetrics and gynecology at Northwestern University, Chicago, said in an interview after attending the talk.

Women who develop POI lose ovarian activity before age 40, characterized by menstrual disturbance with raised gonadotropins and low estradiol. Symptoms include the hot flushes and night sweats characteristic of estrogen deficiency as well as vaginal symptoms, including dyspareunia and dryness. Other symptoms can include sleep disturbance, mood changes, poor concentration, stiffness, dry eyes, altered urinary frequency, low libido, and lack of energy.

Dr. McKenzie urged doctors to ask women about their symptoms if they present with amenorrhea because young women with primary amenorrhea rarely experience symptoms at presentation, “implying that these symptoms are due to estrogen withdrawal rather than estrogen deficiency,” she said. Diagnosis involves confirmation of 4-6 months of amenorrhea or oligomenorrhea and two measurements of elevated follicle-stimulating hormone (FSH). Following this work-up, clinicians should seek the cause of the condition.
 

Etiology of POI and associated conditions

A wide range of conditions or genetic factors can cause POI or be more likely in patients with POI, Dr. McKenzie said. Many women diagnosed with POI have chromosomal abnormalities, and there is no cutoff for genetic testing, she said. Most of these genetic causes (94%) are X chromosome abnormalities, including Turners-associated dysmorphic features, gonadal dysgenesis, and FMR1 anomalies. Autosomal gene mutations could also play a role in POI.

Although women with the full FMR1 mutation (Fragile X syndrome) do not have an increased risk of POI, those with the premutation (55-200 repeats) have a 13%-26% increased risk of developing POI, albeit no increased risk of intellectual disability. About 0.8%-7.5% of women with sporadic POI and up to 13% of women with a family history of POI have this genetic anomaly.

Autoimmune conditions may also develop or be related to POI, including hypothyroidism and adrenal insufficiency, Dr. McKenzie said. About 20% of adults with POI will develop hypothyroidism, so testing every 1-2 years is reasonable, though no formal screening guidelines exist. In women whose cause of POI is unknown or in whom you suspect an immune disorder, clinicians may consider screening for 21OH-Ab or adrenocortical antibodies. Patients with a positive 21OH-Ab or adrenocortical antibodies test should be referred to an endocrinologist to test adrenal function and rule out Addison disease.

Though diabetes mellitus has been linked to POI, not enough evidence exists to recommend screening women with POI for diabetes. There’s similarly no indication for infection screening, but infections can cause POI. Mumps oophoritis, for example, accounts for 3%-7% of POI cases. Cancer therapy, including radiotherapy and chemotherapy, and surgical treatment for cancer can result in POI.

“Smoking, alcohol, nutrition, and exposure to endocrine disruptors are implicated as influencing the age of menopause but are not readily diagnosable causes of POI,” Dr. McKenzie said. “Although not proven to cause POI, cigarette smoking is toxic to the ovaries and has been linked to an earlier age at menopause.” Then there are many women whose cause of POI is unknown.

To take all these possibilities into account, Dr. McKenzie described the complete diagnostic work-up recommended by ACOG:

• Menstrual irregularity for at least 3-4 months
• Test FSH and estradiol
• Test hCG, TSH, and prolactin
• If diagnosis is confirmed, test karyotype, FMR1 premutation, adrenal antibodies, and a pelvic sonogram.

However, she added during the Q&A after her talk, she is not sure why a sonogram is recommended or what additional information it might provide.
 

Long-term consequences of POI

Dr McKenzie noted that one study found a 2-year reduction in life expectancy among women who developed menopause before age 40. The reduced life expectancy linked to untreated POI is primarily caused by cardiovascular disease, she said. Women who undergo menopause aged between 35 and 40 years have a 50% greater risk of death related to ischemic heart disease than those ages 49-51, after adjusting for other comorbidities and confounders.

“Women with primary ovarian insufficiency should be advised on how to reduce cardiovascular risk factors by not smoking, taking regular exercise, and maintaining a healthy weight,” Dr McKenzie said.
 

No interventions have been shown to increase ovarian activity

Though fertility is substantially reduced in women with POI, it may not be completely gone. Several studies have found pregnancy rates ranging from 1.5% to 4.8%, and one study found that 25% of women with idiopathic POI had some evidence of ovarian function. Clinicians should therefore recommend women with POI use contraception if they do not want to conceive. Egg donation is an option for preserving fertility in women with POI but only before POI is solidly established.

“No interventions have been reliably shown to increase ovarian activity and natural conception rates,” Dr. McKenzie said.

For women who survive childhood or adolescent cancer and become pregnant, no evidence has shown an increased risk of congenital anomalies, but risk of low birth weight is elevated in babies whose mothers received anthracyclines. Treatment with anthracyclines and mediastinal radiotherapy have also been linked with cardiomyopathy and heart failure, so an echocardiogram prior to pregnancy is indicated in women with exposure to these or high-dose cyclophosphamide.

Abdominopelvic radiotherapy, however, has been linked to poor uterine function with a greater risk of late miscarriage, prematurity, low birth weight, stillbirth, neonatal hemorrhage, and postpartum hemorrhage.

“Pregnancies in women with Turner syndrome are very high risk and may have a maternal mortality as high as 3.5%,” Dr. McKenzie said, so these pregnancies require involvement of a cardiologist.

Other sequelae of POI can include increased bone resorption, net loss of bone (2%-3% annually soon after menopause) and reduced bone mineral density. Women should be getting 1,000 mg/day of calcium and 800 IU/day of vitamin D, but bone screening remains controversial in the field. Finally, providers should not ignore psychosocial effects of POI, including grief, diminished self esteem, and sadness, even more so, potentially, among adolescents.
 

Treatment of POI

Managing POI involves a two-pronged strategy of providing enough estrogen (estradiol, ethinyl estradiol, or conjugated equine estrogens) to mimic normal physiology and enough progestogen (synthetic or progesterone) to protect the endometrium from the mitogenic effect of estrogen.

The two primary options are hormone therapy and combination oral contraceptives. Hormone therapy might allow ovulation and pregnancy in some women, but combination oral contraceptive may feel less stigmatized in those who are still young, albeit with a potential risk for venous thromboembolism.

Continuous treatment tends to be easier and can involve breakthrough bleeding in younger patients; in postmenopausal women, breast cancer risk is higher but endometrial cancer risk is lower. Cyclic treatment mimics the endometrium’s normal function, resulting in bleeding that may help some women feel more “normal” and aids in knowing about a pregnancy. Those wanting to avoid bleeds and use contraception can use the levonorgestrel IUD off label.

Dr. Streicher said in an interview, “Not only is it critically important to recognize [long-term consequences] in this small group of women, but the lessons learned from young women who go though menopause can absolutely be extrapolated to women who go through menopause at an appropriate time.”

Dr. McKenzie had no disclosures. Dr. Streicher has consulted for Astellas Pharma and Church & Dwight, and she owns investments in InControl Medical and Sermonix Pharmaceutical.

Primary ovarian insufficiency is not your mother’s early menopause, according to Laurie McKenzie, MD, a reproductive endocrinologist and associate professor of ob.gyn. at the University of Texas MD Anderson Cancer Center with a joint appointment at Baylor College of Medicine, both in Houston.

Known previously as primary ovarian failure, the syndrome of primary ovarian insufficiency (POI) no longer refers to a failure in part because of the term’s negative connotations but mostly because it’s not precisely accurate, Dr. McKenzie told attendees at the 2021 annual meeting of the American College of Obstetricians and Gynecologists on May 1.

“Many of these women, especially early on in diagnosis, may be experiencing some intermittent ovarian function, so it may not be a complete failure of the ovaries,” Dr. McKenzie said.

Although the condition is not common, affecting about 1% of the female population, “it’s the kind of thing that when a gynecologist has someone who has this walk into their office, you really need to know how to address it because these women are understandably very distressed.” Lauren Streicher, MD, a clinical professor of obstetrics and gynecology at Northwestern University, Chicago, said in an interview after attending the talk.

Women who develop POI lose ovarian activity before age 40, characterized by menstrual disturbance with raised gonadotropins and low estradiol. Symptoms include the hot flushes and night sweats characteristic of estrogen deficiency as well as vaginal symptoms, including dyspareunia and dryness. Other symptoms can include sleep disturbance, mood changes, poor concentration, stiffness, dry eyes, altered urinary frequency, low libido, and lack of energy.

Dr. McKenzie urged doctors to ask women about their symptoms if they present with amenorrhea because young women with primary amenorrhea rarely experience symptoms at presentation, “implying that these symptoms are due to estrogen withdrawal rather than estrogen deficiency,” she said. Diagnosis involves confirmation of 4-6 months of amenorrhea or oligomenorrhea and two measurements of elevated follicle-stimulating hormone (FSH). Following this work-up, clinicians should seek the cause of the condition.
 

Etiology of POI and associated conditions

A wide range of conditions or genetic factors can cause POI or be more likely in patients with POI, Dr. McKenzie said. Many women diagnosed with POI have chromosomal abnormalities, and there is no cutoff for genetic testing, she said. Most of these genetic causes (94%) are X chromosome abnormalities, including Turners-associated dysmorphic features, gonadal dysgenesis, and FMR1 anomalies. Autosomal gene mutations could also play a role in POI.

Although women with the full FMR1 mutation (Fragile X syndrome) do not have an increased risk of POI, those with the premutation (55-200 repeats) have a 13%-26% increased risk of developing POI, albeit no increased risk of intellectual disability. About 0.8%-7.5% of women with sporadic POI and up to 13% of women with a family history of POI have this genetic anomaly.

Autoimmune conditions may also develop or be related to POI, including hypothyroidism and adrenal insufficiency, Dr. McKenzie said. About 20% of adults with POI will develop hypothyroidism, so testing every 1-2 years is reasonable, though no formal screening guidelines exist. In women whose cause of POI is unknown or in whom you suspect an immune disorder, clinicians may consider screening for 21OH-Ab or adrenocortical antibodies. Patients with a positive 21OH-Ab or adrenocortical antibodies test should be referred to an endocrinologist to test adrenal function and rule out Addison disease.

Though diabetes mellitus has been linked to POI, not enough evidence exists to recommend screening women with POI for diabetes. There’s similarly no indication for infection screening, but infections can cause POI. Mumps oophoritis, for example, accounts for 3%-7% of POI cases. Cancer therapy, including radiotherapy and chemotherapy, and surgical treatment for cancer can result in POI.

“Smoking, alcohol, nutrition, and exposure to endocrine disruptors are implicated as influencing the age of menopause but are not readily diagnosable causes of POI,” Dr. McKenzie said. “Although not proven to cause POI, cigarette smoking is toxic to the ovaries and has been linked to an earlier age at menopause.” Then there are many women whose cause of POI is unknown.

To take all these possibilities into account, Dr. McKenzie described the complete diagnostic work-up recommended by ACOG:

• Menstrual irregularity for at least 3-4 months
• Test FSH and estradiol
• Test hCG, TSH, and prolactin
• If diagnosis is confirmed, test karyotype, FMR1 premutation, adrenal antibodies, and a pelvic sonogram.

However, she added during the Q&A after her talk, she is not sure why a sonogram is recommended or what additional information it might provide.
 

Long-term consequences of POI

Dr McKenzie noted that one study found a 2-year reduction in life expectancy among women who developed menopause before age 40. The reduced life expectancy linked to untreated POI is primarily caused by cardiovascular disease, she said. Women who undergo menopause aged between 35 and 40 years have a 50% greater risk of death related to ischemic heart disease than those ages 49-51, after adjusting for other comorbidities and confounders.

“Women with primary ovarian insufficiency should be advised on how to reduce cardiovascular risk factors by not smoking, taking regular exercise, and maintaining a healthy weight,” Dr McKenzie said.
 

No interventions have been shown to increase ovarian activity

Though fertility is substantially reduced in women with POI, it may not be completely gone. Several studies have found pregnancy rates ranging from 1.5% to 4.8%, and one study found that 25% of women with idiopathic POI had some evidence of ovarian function. Clinicians should therefore recommend women with POI use contraception if they do not want to conceive. Egg donation is an option for preserving fertility in women with POI but only before POI is solidly established.

“No interventions have been reliably shown to increase ovarian activity and natural conception rates,” Dr. McKenzie said.

For women who survive childhood or adolescent cancer and become pregnant, no evidence has shown an increased risk of congenital anomalies, but risk of low birth weight is elevated in babies whose mothers received anthracyclines. Treatment with anthracyclines and mediastinal radiotherapy have also been linked with cardiomyopathy and heart failure, so an echocardiogram prior to pregnancy is indicated in women with exposure to these or high-dose cyclophosphamide.

Abdominopelvic radiotherapy, however, has been linked to poor uterine function with a greater risk of late miscarriage, prematurity, low birth weight, stillbirth, neonatal hemorrhage, and postpartum hemorrhage.

“Pregnancies in women with Turner syndrome are very high risk and may have a maternal mortality as high as 3.5%,” Dr. McKenzie said, so these pregnancies require involvement of a cardiologist.

Other sequelae of POI can include increased bone resorption, net loss of bone (2%-3% annually soon after menopause) and reduced bone mineral density. Women should be getting 1,000 mg/day of calcium and 800 IU/day of vitamin D, but bone screening remains controversial in the field. Finally, providers should not ignore psychosocial effects of POI, including grief, diminished self esteem, and sadness, even more so, potentially, among adolescents.
 

Treatment of POI

Managing POI involves a two-pronged strategy of providing enough estrogen (estradiol, ethinyl estradiol, or conjugated equine estrogens) to mimic normal physiology and enough progestogen (synthetic or progesterone) to protect the endometrium from the mitogenic effect of estrogen.

The two primary options are hormone therapy and combination oral contraceptives. Hormone therapy might allow ovulation and pregnancy in some women, but combination oral contraceptive may feel less stigmatized in those who are still young, albeit with a potential risk for venous thromboembolism.

Continuous treatment tends to be easier and can involve breakthrough bleeding in younger patients; in postmenopausal women, breast cancer risk is higher but endometrial cancer risk is lower. Cyclic treatment mimics the endometrium’s normal function, resulting in bleeding that may help some women feel more “normal” and aids in knowing about a pregnancy. Those wanting to avoid bleeds and use contraception can use the levonorgestrel IUD off label.

Dr. Streicher said in an interview, “Not only is it critically important to recognize [long-term consequences] in this small group of women, but the lessons learned from young women who go though menopause can absolutely be extrapolated to women who go through menopause at an appropriate time.”

Dr. McKenzie had no disclosures. Dr. Streicher has consulted for Astellas Pharma and Church & Dwight, and she owns investments in InControl Medical and Sermonix Pharmaceutical.

Primary ovarian insufficiency is not your mother’s early menopause, according to Laurie McKenzie, MD, a reproductive endocrinologist and associate professor of ob.gyn. at the University of Texas MD Anderson Cancer Center with a joint appointment at Baylor College of Medicine, both in Houston.

Known previously as primary ovarian failure, the syndrome of primary ovarian insufficiency (POI) no longer refers to a failure in part because of the term’s negative connotations but mostly because it’s not precisely accurate, Dr. McKenzie told attendees at the 2021 annual meeting of the American College of Obstetricians and Gynecologists on May 1.

“Many of these women, especially early on in diagnosis, may be experiencing some intermittent ovarian function, so it may not be a complete failure of the ovaries,” Dr. McKenzie said.

Although the condition is not common, affecting about 1% of the female population, “it’s the kind of thing that when a gynecologist has someone who has this walk into their office, you really need to know how to address it because these women are understandably very distressed.” Lauren Streicher, MD, a clinical professor of obstetrics and gynecology at Northwestern University, Chicago, said in an interview after attending the talk.

Women who develop POI lose ovarian activity before age 40, characterized by menstrual disturbance with raised gonadotropins and low estradiol. Symptoms include the hot flushes and night sweats characteristic of estrogen deficiency as well as vaginal symptoms, including dyspareunia and dryness. Other symptoms can include sleep disturbance, mood changes, poor concentration, stiffness, dry eyes, altered urinary frequency, low libido, and lack of energy.

Dr. McKenzie urged doctors to ask women about their symptoms if they present with amenorrhea because young women with primary amenorrhea rarely experience symptoms at presentation, “implying that these symptoms are due to estrogen withdrawal rather than estrogen deficiency,” she said. Diagnosis involves confirmation of 4-6 months of amenorrhea or oligomenorrhea and two measurements of elevated follicle-stimulating hormone (FSH). Following this work-up, clinicians should seek the cause of the condition.
 

Etiology of POI and associated conditions

A wide range of conditions or genetic factors can cause POI or be more likely in patients with POI, Dr. McKenzie said. Many women diagnosed with POI have chromosomal abnormalities, and there is no cutoff for genetic testing, she said. Most of these genetic causes (94%) are X chromosome abnormalities, including Turners-associated dysmorphic features, gonadal dysgenesis, and FMR1 anomalies. Autosomal gene mutations could also play a role in POI.

Although women with the full FMR1 mutation (Fragile X syndrome) do not have an increased risk of POI, those with the premutation (55-200 repeats) have a 13%-26% increased risk of developing POI, albeit no increased risk of intellectual disability. About 0.8%-7.5% of women with sporadic POI and up to 13% of women with a family history of POI have this genetic anomaly.

Autoimmune conditions may also develop or be related to POI, including hypothyroidism and adrenal insufficiency, Dr. McKenzie said. About 20% of adults with POI will develop hypothyroidism, so testing every 1-2 years is reasonable, though no formal screening guidelines exist. In women whose cause of POI is unknown or in whom you suspect an immune disorder, clinicians may consider screening for 21OH-Ab or adrenocortical antibodies. Patients with a positive 21OH-Ab or adrenocortical antibodies test should be referred to an endocrinologist to test adrenal function and rule out Addison disease.

Though diabetes mellitus has been linked to POI, not enough evidence exists to recommend screening women with POI for diabetes. There’s similarly no indication for infection screening, but infections can cause POI. Mumps oophoritis, for example, accounts for 3%-7% of POI cases. Cancer therapy, including radiotherapy and chemotherapy, and surgical treatment for cancer can result in POI.

“Smoking, alcohol, nutrition, and exposure to endocrine disruptors are implicated as influencing the age of menopause but are not readily diagnosable causes of POI,” Dr. McKenzie said. “Although not proven to cause POI, cigarette smoking is toxic to the ovaries and has been linked to an earlier age at menopause.” Then there are many women whose cause of POI is unknown.

To take all these possibilities into account, Dr. McKenzie described the complete diagnostic work-up recommended by ACOG:

• Menstrual irregularity for at least 3-4 months
• Test FSH and estradiol
• Test hCG, TSH, and prolactin
• If diagnosis is confirmed, test karyotype, FMR1 premutation, adrenal antibodies, and a pelvic sonogram.

However, she added during the Q&A after her talk, she is not sure why a sonogram is recommended or what additional information it might provide.
 

Long-term consequences of POI

Dr McKenzie noted that one study found a 2-year reduction in life expectancy among women who developed menopause before age 40. The reduced life expectancy linked to untreated POI is primarily caused by cardiovascular disease, she said. Women who undergo menopause aged between 35 and 40 years have a 50% greater risk of death related to ischemic heart disease than those ages 49-51, after adjusting for other comorbidities and confounders.

“Women with primary ovarian insufficiency should be advised on how to reduce cardiovascular risk factors by not smoking, taking regular exercise, and maintaining a healthy weight,” Dr McKenzie said.
 

No interventions have been shown to increase ovarian activity

Though fertility is substantially reduced in women with POI, it may not be completely gone. Several studies have found pregnancy rates ranging from 1.5% to 4.8%, and one study found that 25% of women with idiopathic POI had some evidence of ovarian function. Clinicians should therefore recommend women with POI use contraception if they do not want to conceive. Egg donation is an option for preserving fertility in women with POI but only before POI is solidly established.

“No interventions have been reliably shown to increase ovarian activity and natural conception rates,” Dr. McKenzie said.

For women who survive childhood or adolescent cancer and become pregnant, no evidence has shown an increased risk of congenital anomalies, but risk of low birth weight is elevated in babies whose mothers received anthracyclines. Treatment with anthracyclines and mediastinal radiotherapy have also been linked with cardiomyopathy and heart failure, so an echocardiogram prior to pregnancy is indicated in women with exposure to these or high-dose cyclophosphamide.

Abdominopelvic radiotherapy, however, has been linked to poor uterine function with a greater risk of late miscarriage, prematurity, low birth weight, stillbirth, neonatal hemorrhage, and postpartum hemorrhage.

“Pregnancies in women with Turner syndrome are very high risk and may have a maternal mortality as high as 3.5%,” Dr. McKenzie said, so these pregnancies require involvement of a cardiologist.

Other sequelae of POI can include increased bone resorption, net loss of bone (2%-3% annually soon after menopause) and reduced bone mineral density. Women should be getting 1,000 mg/day of calcium and 800 IU/day of vitamin D, but bone screening remains controversial in the field. Finally, providers should not ignore psychosocial effects of POI, including grief, diminished self esteem, and sadness, even more so, potentially, among adolescents.
 

Treatment of POI

Managing POI involves a two-pronged strategy of providing enough estrogen (estradiol, ethinyl estradiol, or conjugated equine estrogens) to mimic normal physiology and enough progestogen (synthetic or progesterone) to protect the endometrium from the mitogenic effect of estrogen.

The two primary options are hormone therapy and combination oral contraceptives. Hormone therapy might allow ovulation and pregnancy in some women, but combination oral contraceptive may feel less stigmatized in those who are still young, albeit with a potential risk for venous thromboembolism.

Continuous treatment tends to be easier and can involve breakthrough bleeding in younger patients; in postmenopausal women, breast cancer risk is higher but endometrial cancer risk is lower. Cyclic treatment mimics the endometrium’s normal function, resulting in bleeding that may help some women feel more “normal” and aids in knowing about a pregnancy. Those wanting to avoid bleeds and use contraception can use the levonorgestrel IUD off label.

Dr. Streicher said in an interview, “Not only is it critically important to recognize [long-term consequences] in this small group of women, but the lessons learned from young women who go though menopause can absolutely be extrapolated to women who go through menopause at an appropriate time.”

Dr. McKenzie had no disclosures. Dr. Streicher has consulted for Astellas Pharma and Church & Dwight, and she owns investments in InControl Medical and Sermonix Pharmaceutical.

FDA guidance for power morcellation

“The FDA has granted marketing authorization for one containment system and continues to encourage innovation in this area” said the report. Olympus’ Pneumoliner is the only FDA cleared containment device to provide a laparoscopic option for appropriately identified patients undergoing myomectomy and hysterectomy. The containment system is sold with Olympus’ PK Morcellator, but the company says that it has made the Pneumoliner available to physicians choosing an alternate to the PK Morcellator, provided that there is device compatibility. The Pneumoliner “reduces the spread of benign tissue into the abdominal cavity, in which pathologies, like fibroids, may regrow when tissue or cells are inadvertently left behind,” according to Olympus.

For more information, visit : https://medical.olympusamerica.com/products/contained-tissue-extraction-system

Vaginal odor elimination gel

The gel is sold in 7 single-day applications, with a single tube used per day at bedtime to eliminate unwanted odor. To maintain freshness and comfort, a single tube of Relactagel can be used for 2 to 3 days after a woman’s menstrual cycle, says Kora Healthcare. The company warns that mild irritation can occur with product use during fungal infections or when small tears are present in the vaginal tissue and that use should be discontinued if irritation occurs. In addition, if trying to become pregnant Relatagel should not be used, advises Kora Healthcare, although the gel is not a contraceptive.

For more information, visit: https://www.relactagel.com/.

Intrauterine electrosurgery system

For more information, visit: https://medical.olympusamerica.com/

FDA guidance for power morcellation

“The FDA has granted marketing authorization for one containment system and continues to encourage innovation in this area” said the report. Olympus’ Pneumoliner is the only FDA cleared containment device to provide a laparoscopic option for appropriately identified patients undergoing myomectomy and hysterectomy. The containment system is sold with Olympus’ PK Morcellator, but the company says that it has made the Pneumoliner available to physicians choosing an alternate to the PK Morcellator, provided that there is device compatibility. The Pneumoliner “reduces the spread of benign tissue into the abdominal cavity, in which pathologies, like fibroids, may regrow when tissue or cells are inadvertently left behind,” according to Olympus.

For more information, visit : https://medical.olympusamerica.com/products/contained-tissue-extraction-system

Vaginal odor elimination gel

The gel is sold in 7 single-day applications, with a single tube used per day at bedtime to eliminate unwanted odor. To maintain freshness and comfort, a single tube of Relactagel can be used for 2 to 3 days after a woman’s menstrual cycle, says Kora Healthcare. The company warns that mild irritation can occur with product use during fungal infections or when small tears are present in the vaginal tissue and that use should be discontinued if irritation occurs. In addition, if trying to become pregnant Relatagel should not be used, advises Kora Healthcare, although the gel is not a contraceptive.

For more information, visit: https://www.relactagel.com/.

Intrauterine electrosurgery system

For more information, visit: https://medical.olympusamerica.com/

FDA guidance for power morcellation

“The FDA has granted marketing authorization for one containment system and continues to encourage innovation in this area” said the report. Olympus’ Pneumoliner is the only FDA cleared containment device to provide a laparoscopic option for appropriately identified patients undergoing myomectomy and hysterectomy. The containment system is sold with Olympus’ PK Morcellator, but the company says that it has made the Pneumoliner available to physicians choosing an alternate to the PK Morcellator, provided that there is device compatibility. The Pneumoliner “reduces the spread of benign tissue into the abdominal cavity, in which pathologies, like fibroids, may regrow when tissue or cells are inadvertently left behind,” according to Olympus.

For more information, visit : https://medical.olympusamerica.com/products/contained-tissue-extraction-system

Vaginal odor elimination gel

The gel is sold in 7 single-day applications, with a single tube used per day at bedtime to eliminate unwanted odor. To maintain freshness and comfort, a single tube of Relactagel can be used for 2 to 3 days after a woman’s menstrual cycle, says Kora Healthcare. The company warns that mild irritation can occur with product use during fungal infections or when small tears are present in the vaginal tissue and that use should be discontinued if irritation occurs. In addition, if trying to become pregnant Relatagel should not be used, advises Kora Healthcare, although the gel is not a contraceptive.

For more information, visit: https://www.relactagel.com/.

Intrauterine electrosurgery system

For more information, visit: https://medical.olympusamerica.com/

A novel therapy combining platelet-rich plasma (PRP) with follicle-stimulating hormone that is injected directly into the ovaries has the potential to restore ovarian function for women who experience early menopause, possibly allowing for pregnancy without the need for donor eggs.

“The resumption of ovarian function in our participants means women with early menopause could have the opportunity to pursue pregnancy through IVF [in vitro fertilization] using their own eggs,” the authors of the groundbreaking pilot study report.

In the small study, published online March 29 in Menopause, menstruation resumed within a mean of about 5 weeks for 11 of 12 patients with early menopause who were treated with the technique. One patient achieved a clinical pregnancy.

In commenting on the study, Stephanie S. Faubion, MD, medical director of the North American Menopause Society, was cautious in her interpretation, noting the need for more research in larger samples.

“Any pregnancy that results from a regenerative therapy is novel,” she told this news organization. “Still, we are a long way away from this being a standard therapy for women with premature ovarian insufficiency.”
 

Pilot study: Platelet-rich plasma combination with FSH

Early menopause is the cessation of ovarian function at or before the age of 45 years. It is estimated that 12.2% of women experience early menopause. For these women, currently, the only chance of becoming pregnant is with donor eggs.

PRP, an autologous plasma preparation containing more than 10 times the concentration of growth factors and active metabolites than normal plasma, has recently been shown to have the potential to restore the menstrual cycles in perimenopausal women, allowing IVF. It has also been shown to benefit women with premature ovarian insufficiency (POI). However, there have been few reports of pregnancies or live births.

Chao Chin Hsu, MD, PhD, of the National Taiwan University Hospital, Taipei, and colleagues investigated whether the combination of the activated PRP treatment with gondatrophins such as FSH could provide a more robust effect so as to sufficiently stimulate follicles. They used the intraovarian injection of the combination to treat a 38-year-old woman with POI.

The effort was successful, and the woman gave birth to healthy twins.

To further evaluate the approach, the authors conducted a pilot study involving 12 women with early menopause (mean age, 44.4 years) between November 2018 and November 2019.

The women received intraovarian injection with PRP prepared from 40 mL of autologous peripheral blood combined with recombinant FSH.

Following the treatment, 11 of the 12 women experienced resumption of menstruation within a mean of 37 days. For seven patients, menstruation resumed within a month; for three, it resumed within about 2 months; and for one, it resumed after approximately 3 months.

Of note, the menstrual cycles were mostly irregular, with an interval of about 45.6 days.

The women’s average serum FSH level dropped significantly from 70.5 IU/L at baseline to 26.2 IU/L within days of treatment, as did the average luteinizing hormone level (34.8 before and 14.3 IU/L after treatment), indicative of improved ovary function.

For six participants, 10 oocyte retrieval procedures were performed after a mean of about 2 months. Thirteen mature eggs were retrieved, and fertilization via intracytoplasmic sperm injection was attempted, resulting in 10 fertilized oocytes.

Cleavage-stage embryos were transferred into two of the participants. One achieved a clinical pregnancy, defined as a pregnancy that was confirmed by ultrasound and by the presence of a fetal heartbeat. The pregnancy ended in miscarriage at 7 weeks’ gestation.

The length of controlled ovarian stimulation necessary for follicle growth ranged from 8 to 14 days, which the authors note is similar to that seen with women of normal reproductive age.

“Although the use of PRP in reproductive medicine is considered experimental, we demonstrated the restoration of ovarian function in early menopausal women who adopted whole dimension subcortical ovarian injection of PRP/gonadotropin,” the authors write.

“Most remarkably, an early menopausal woman achieved pregnancy after the treatment followed by IVF with her mature ovulating follicle,” they report.
 

Mechanisms, caveats

The mechanisms thought to underlie the success of the approach include increases in ovarian vascularization and stromal cell proliferation and reductions in oxidative stress and cell death in ovaries, the authors explain.

Key caveats with the treatment include the fact that anesthesia and laparoscopy are required, and precise administration is required at 15 injection sites in 1-2 mm of the ovarian subcortical area, which can be difficult to achieve, Dr. Hsu said in an interview.

“If a new instrument could be developed in which physicians can carry out this treatment through a vaginal approach, like the transvaginal retrieval of eggs in IVF treatments,” the approach could become more acceptable, Dr. Hsu added.

The authors call for studies with larger sample sizes and say it will also be interesting to determine effects in different groups: For example, women with cancer who have undergone chemotherapy.

Dr. Faubion, who is director of the Mayo Clinic Women’s Health, Rochester, Minn., says the causes of early menopause could be important in determining the treatment’s efficacy.

“[The therapy’s] success may depend on the reason the woman experienced early menopause: For instance, due to chemotherapy, radiation, virus, autoimmune disease, genetic mutation, or other cause,” she said.

She also noted that cost could be an important factor.

“I don’t see a cost estimate, but it will be substantial,” she said. “So, even if the success rate improves as this technique is further studied, cost and the invasive nature of the treatment may prove to be substantial barriers to this therapy becoming mainstream,” she said.

The authors and Dr. Faubion have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A novel therapy combining platelet-rich plasma (PRP) with follicle-stimulating hormone that is injected directly into the ovaries has the potential to restore ovarian function for women who experience early menopause, possibly allowing for pregnancy without the need for donor eggs.

“The resumption of ovarian function in our participants means women with early menopause could have the opportunity to pursue pregnancy through IVF [in vitro fertilization] using their own eggs,” the authors of the groundbreaking pilot study report.

In the small study, published online March 29 in Menopause, menstruation resumed within a mean of about 5 weeks for 11 of 12 patients with early menopause who were treated with the technique. One patient achieved a clinical pregnancy.

In commenting on the study, Stephanie S. Faubion, MD, medical director of the North American Menopause Society, was cautious in her interpretation, noting the need for more research in larger samples.

“Any pregnancy that results from a regenerative therapy is novel,” she told this news organization. “Still, we are a long way away from this being a standard therapy for women with premature ovarian insufficiency.”
 

Pilot study: Platelet-rich plasma combination with FSH

Early menopause is the cessation of ovarian function at or before the age of 45 years. It is estimated that 12.2% of women experience early menopause. For these women, currently, the only chance of becoming pregnant is with donor eggs.

PRP, an autologous plasma preparation containing more than 10 times the concentration of growth factors and active metabolites than normal plasma, has recently been shown to have the potential to restore the menstrual cycles in perimenopausal women, allowing IVF. It has also been shown to benefit women with premature ovarian insufficiency (POI). However, there have been few reports of pregnancies or live births.

Chao Chin Hsu, MD, PhD, of the National Taiwan University Hospital, Taipei, and colleagues investigated whether the combination of the activated PRP treatment with gondatrophins such as FSH could provide a more robust effect so as to sufficiently stimulate follicles. They used the intraovarian injection of the combination to treat a 38-year-old woman with POI.

The effort was successful, and the woman gave birth to healthy twins.

To further evaluate the approach, the authors conducted a pilot study involving 12 women with early menopause (mean age, 44.4 years) between November 2018 and November 2019.

The women received intraovarian injection with PRP prepared from 40 mL of autologous peripheral blood combined with recombinant FSH.

Following the treatment, 11 of the 12 women experienced resumption of menstruation within a mean of 37 days. For seven patients, menstruation resumed within a month; for three, it resumed within about 2 months; and for one, it resumed after approximately 3 months.

Of note, the menstrual cycles were mostly irregular, with an interval of about 45.6 days.

The women’s average serum FSH level dropped significantly from 70.5 IU/L at baseline to 26.2 IU/L within days of treatment, as did the average luteinizing hormone level (34.8 before and 14.3 IU/L after treatment), indicative of improved ovary function.

For six participants, 10 oocyte retrieval procedures were performed after a mean of about 2 months. Thirteen mature eggs were retrieved, and fertilization via intracytoplasmic sperm injection was attempted, resulting in 10 fertilized oocytes.

Cleavage-stage embryos were transferred into two of the participants. One achieved a clinical pregnancy, defined as a pregnancy that was confirmed by ultrasound and by the presence of a fetal heartbeat. The pregnancy ended in miscarriage at 7 weeks’ gestation.

The length of controlled ovarian stimulation necessary for follicle growth ranged from 8 to 14 days, which the authors note is similar to that seen with women of normal reproductive age.

“Although the use of PRP in reproductive medicine is considered experimental, we demonstrated the restoration of ovarian function in early menopausal women who adopted whole dimension subcortical ovarian injection of PRP/gonadotropin,” the authors write.

“Most remarkably, an early menopausal woman achieved pregnancy after the treatment followed by IVF with her mature ovulating follicle,” they report.
 

Mechanisms, caveats

The mechanisms thought to underlie the success of the approach include increases in ovarian vascularization and stromal cell proliferation and reductions in oxidative stress and cell death in ovaries, the authors explain.

Key caveats with the treatment include the fact that anesthesia and laparoscopy are required, and precise administration is required at 15 injection sites in 1-2 mm of the ovarian subcortical area, which can be difficult to achieve, Dr. Hsu said in an interview.

“If a new instrument could be developed in which physicians can carry out this treatment through a vaginal approach, like the transvaginal retrieval of eggs in IVF treatments,” the approach could become more acceptable, Dr. Hsu added.

The authors call for studies with larger sample sizes and say it will also be interesting to determine effects in different groups: For example, women with cancer who have undergone chemotherapy.

Dr. Faubion, who is director of the Mayo Clinic Women’s Health, Rochester, Minn., says the causes of early menopause could be important in determining the treatment’s efficacy.

“[The therapy’s] success may depend on the reason the woman experienced early menopause: For instance, due to chemotherapy, radiation, virus, autoimmune disease, genetic mutation, or other cause,” she said.

She also noted that cost could be an important factor.

“I don’t see a cost estimate, but it will be substantial,” she said. “So, even if the success rate improves as this technique is further studied, cost and the invasive nature of the treatment may prove to be substantial barriers to this therapy becoming mainstream,” she said.

The authors and Dr. Faubion have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A novel therapy combining platelet-rich plasma (PRP) with follicle-stimulating hormone that is injected directly into the ovaries has the potential to restore ovarian function for women who experience early menopause, possibly allowing for pregnancy without the need for donor eggs.

“The resumption of ovarian function in our participants means women with early menopause could have the opportunity to pursue pregnancy through IVF [in vitro fertilization] using their own eggs,” the authors of the groundbreaking pilot study report.

In the small study, published online March 29 in Menopause, menstruation resumed within a mean of about 5 weeks for 11 of 12 patients with early menopause who were treated with the technique. One patient achieved a clinical pregnancy.

In commenting on the study, Stephanie S. Faubion, MD, medical director of the North American Menopause Society, was cautious in her interpretation, noting the need for more research in larger samples.

“Any pregnancy that results from a regenerative therapy is novel,” she told this news organization. “Still, we are a long way away from this being a standard therapy for women with premature ovarian insufficiency.”
 

Pilot study: Platelet-rich plasma combination with FSH

Early menopause is the cessation of ovarian function at or before the age of 45 years. It is estimated that 12.2% of women experience early menopause. For these women, currently, the only chance of becoming pregnant is with donor eggs.

PRP, an autologous plasma preparation containing more than 10 times the concentration of growth factors and active metabolites than normal plasma, has recently been shown to have the potential to restore the menstrual cycles in perimenopausal women, allowing IVF. It has also been shown to benefit women with premature ovarian insufficiency (POI). However, there have been few reports of pregnancies or live births.

Chao Chin Hsu, MD, PhD, of the National Taiwan University Hospital, Taipei, and colleagues investigated whether the combination of the activated PRP treatment with gondatrophins such as FSH could provide a more robust effect so as to sufficiently stimulate follicles. They used the intraovarian injection of the combination to treat a 38-year-old woman with POI.

The effort was successful, and the woman gave birth to healthy twins.

To further evaluate the approach, the authors conducted a pilot study involving 12 women with early menopause (mean age, 44.4 years) between November 2018 and November 2019.

The women received intraovarian injection with PRP prepared from 40 mL of autologous peripheral blood combined with recombinant FSH.

Following the treatment, 11 of the 12 women experienced resumption of menstruation within a mean of 37 days. For seven patients, menstruation resumed within a month; for three, it resumed within about 2 months; and for one, it resumed after approximately 3 months.

Of note, the menstrual cycles were mostly irregular, with an interval of about 45.6 days.

The women’s average serum FSH level dropped significantly from 70.5 IU/L at baseline to 26.2 IU/L within days of treatment, as did the average luteinizing hormone level (34.8 before and 14.3 IU/L after treatment), indicative of improved ovary function.

For six participants, 10 oocyte retrieval procedures were performed after a mean of about 2 months. Thirteen mature eggs were retrieved, and fertilization via intracytoplasmic sperm injection was attempted, resulting in 10 fertilized oocytes.

Cleavage-stage embryos were transferred into two of the participants. One achieved a clinical pregnancy, defined as a pregnancy that was confirmed by ultrasound and by the presence of a fetal heartbeat. The pregnancy ended in miscarriage at 7 weeks’ gestation.

The length of controlled ovarian stimulation necessary for follicle growth ranged from 8 to 14 days, which the authors note is similar to that seen with women of normal reproductive age.

“Although the use of PRP in reproductive medicine is considered experimental, we demonstrated the restoration of ovarian function in early menopausal women who adopted whole dimension subcortical ovarian injection of PRP/gonadotropin,” the authors write.

“Most remarkably, an early menopausal woman achieved pregnancy after the treatment followed by IVF with her mature ovulating follicle,” they report.
 

Mechanisms, caveats

The mechanisms thought to underlie the success of the approach include increases in ovarian vascularization and stromal cell proliferation and reductions in oxidative stress and cell death in ovaries, the authors explain.

Key caveats with the treatment include the fact that anesthesia and laparoscopy are required, and precise administration is required at 15 injection sites in 1-2 mm of the ovarian subcortical area, which can be difficult to achieve, Dr. Hsu said in an interview.

“If a new instrument could be developed in which physicians can carry out this treatment through a vaginal approach, like the transvaginal retrieval of eggs in IVF treatments,” the approach could become more acceptable, Dr. Hsu added.

The authors call for studies with larger sample sizes and say it will also be interesting to determine effects in different groups: For example, women with cancer who have undergone chemotherapy.

Dr. Faubion, who is director of the Mayo Clinic Women’s Health, Rochester, Minn., says the causes of early menopause could be important in determining the treatment’s efficacy.

“[The therapy’s] success may depend on the reason the woman experienced early menopause: For instance, due to chemotherapy, radiation, virus, autoimmune disease, genetic mutation, or other cause,” she said.

She also noted that cost could be an important factor.

“I don’t see a cost estimate, but it will be substantial,” she said. “So, even if the success rate improves as this technique is further studied, cost and the invasive nature of the treatment may prove to be substantial barriers to this therapy becoming mainstream,” she said.

The authors and Dr. Faubion have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

It’s time for a large-scale phase 2 study into whether supplementary estrogen can relieve multiple sclerosis (MS) symptoms in menopausal women with the disease, a neurologist told colleagues at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

This kind of research should explore the effects of aging, including in the brain, and “focus on what is preventable – this dramatic and abrupt loss of estrogen in women with MS,” said Rhonda Voskuhl, MD, of the Brain Research Institute at the University of California, Los Angeles.

“This is a call to action. There’s a huge gap that needs to be filled,” she added in an interview. “Not enough attention has been paid to menopause and cognitive issues in MS and even in healthy women.”

Research has found that many women with MS experience a decline in function during menopause, she said. “They’re having a worsening of their preexisting disabilities,” she noted, due to neurodegeneration.

Dr. Voskuhl highlighted a 2016 study, for instance, that found postmenopausal women with MS on hormone replacement therapy reported better physical function and quality of life than did their counterparts after adjustment for covariates. She also pointed to a 2019 study that concluded that “natural menopause seems to be a turning point to a more progressive phase of MS.”

Estrogen appears to play a significant role. “It’s involved in synaptic plasticity,” she said. “That’s why the disabilities are worsening.”

Dr. Voskuhl supports a year-long, randomized and controlled study of estrogen supplementation in 150-200 participants. The goal, she said, is “not just to prevent loss and bad things from happening but also make improvements.”

In healthy patients, she said, outcomes should include cognitive decline in menopause, cognitive domain outcomes, and region-specific biomarkers in the frontal cortex and hippocampus instead of global cognition and global brain volume. In patients with MS, she said, the focus should be on worsening of disability with emphasis on specific disabilities such as walking and region-specific biomarkers for the motor cortex and spinal cord.

“We need to be looking at cortical gray matter, which we know is responsive to estrogen,” Dr. Voskuhl said. She led a 2018 placebo-controlled study that found women with MS who took estrogen supplements appeared to experience localized sparing of progressive gray matter, which the researchers linked to improved results in cognitive testing. The findings, the study authors wrote, suggest “a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.”

What about men? Does hormone loss worsen their MS? Dr. Voskuhl said there seems to be a connection between lower levels of testosterone and more disability in men with MS. But their situation is different. Loss of testosterone in men is gradual and happens over decades instead of over the short period of menopause in women, she said.

Jennifer Graves, MD, a neurologist at the University of California, San Diego, agreed that it’s time for further research into estrogen supplementation in MS. As she noted, “we don’t know the exact biological mechanism that might link perimenopause with developing a more progressive type of MS.”

She added: “An overall decrease in estrogen may be at play but there are other biological changes around menopause. We must also take care in studies to try to separate out what might be due to ovarian aging versus other types of aging processes that might be happening at the same time.”

Dr. Voskuhl disclosed that she is an inventor on university patents for use of estriol and estrogen receptor–beta ligands as treatments. Dr. Graves reports no relevant disclosures.

It’s time for a large-scale phase 2 study into whether supplementary estrogen can relieve multiple sclerosis (MS) symptoms in menopausal women with the disease, a neurologist told colleagues at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

This kind of research should explore the effects of aging, including in the brain, and “focus on what is preventable – this dramatic and abrupt loss of estrogen in women with MS,” said Rhonda Voskuhl, MD, of the Brain Research Institute at the University of California, Los Angeles.

“This is a call to action. There’s a huge gap that needs to be filled,” she added in an interview. “Not enough attention has been paid to menopause and cognitive issues in MS and even in healthy women.”

Research has found that many women with MS experience a decline in function during menopause, she said. “They’re having a worsening of their preexisting disabilities,” she noted, due to neurodegeneration.

Dr. Voskuhl highlighted a 2016 study, for instance, that found postmenopausal women with MS on hormone replacement therapy reported better physical function and quality of life than did their counterparts after adjustment for covariates. She also pointed to a 2019 study that concluded that “natural menopause seems to be a turning point to a more progressive phase of MS.”

Estrogen appears to play a significant role. “It’s involved in synaptic plasticity,” she said. “That’s why the disabilities are worsening.”

Dr. Voskuhl supports a year-long, randomized and controlled study of estrogen supplementation in 150-200 participants. The goal, she said, is “not just to prevent loss and bad things from happening but also make improvements.”

In healthy patients, she said, outcomes should include cognitive decline in menopause, cognitive domain outcomes, and region-specific biomarkers in the frontal cortex and hippocampus instead of global cognition and global brain volume. In patients with MS, she said, the focus should be on worsening of disability with emphasis on specific disabilities such as walking and region-specific biomarkers for the motor cortex and spinal cord.

“We need to be looking at cortical gray matter, which we know is responsive to estrogen,” Dr. Voskuhl said. She led a 2018 placebo-controlled study that found women with MS who took estrogen supplements appeared to experience localized sparing of progressive gray matter, which the researchers linked to improved results in cognitive testing. The findings, the study authors wrote, suggest “a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.”

What about men? Does hormone loss worsen their MS? Dr. Voskuhl said there seems to be a connection between lower levels of testosterone and more disability in men with MS. But their situation is different. Loss of testosterone in men is gradual and happens over decades instead of over the short period of menopause in women, she said.

Jennifer Graves, MD, a neurologist at the University of California, San Diego, agreed that it’s time for further research into estrogen supplementation in MS. As she noted, “we don’t know the exact biological mechanism that might link perimenopause with developing a more progressive type of MS.”

She added: “An overall decrease in estrogen may be at play but there are other biological changes around menopause. We must also take care in studies to try to separate out what might be due to ovarian aging versus other types of aging processes that might be happening at the same time.”

Dr. Voskuhl disclosed that she is an inventor on university patents for use of estriol and estrogen receptor–beta ligands as treatments. Dr. Graves reports no relevant disclosures.

It’s time for a large-scale phase 2 study into whether supplementary estrogen can relieve multiple sclerosis (MS) symptoms in menopausal women with the disease, a neurologist told colleagues at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

This kind of research should explore the effects of aging, including in the brain, and “focus on what is preventable – this dramatic and abrupt loss of estrogen in women with MS,” said Rhonda Voskuhl, MD, of the Brain Research Institute at the University of California, Los Angeles.

“This is a call to action. There’s a huge gap that needs to be filled,” she added in an interview. “Not enough attention has been paid to menopause and cognitive issues in MS and even in healthy women.”

Research has found that many women with MS experience a decline in function during menopause, she said. “They’re having a worsening of their preexisting disabilities,” she noted, due to neurodegeneration.

Dr. Voskuhl highlighted a 2016 study, for instance, that found postmenopausal women with MS on hormone replacement therapy reported better physical function and quality of life than did their counterparts after adjustment for covariates. She also pointed to a 2019 study that concluded that “natural menopause seems to be a turning point to a more progressive phase of MS.”

Estrogen appears to play a significant role. “It’s involved in synaptic plasticity,” she said. “That’s why the disabilities are worsening.”

Dr. Voskuhl supports a year-long, randomized and controlled study of estrogen supplementation in 150-200 participants. The goal, she said, is “not just to prevent loss and bad things from happening but also make improvements.”

In healthy patients, she said, outcomes should include cognitive decline in menopause, cognitive domain outcomes, and region-specific biomarkers in the frontal cortex and hippocampus instead of global cognition and global brain volume. In patients with MS, she said, the focus should be on worsening of disability with emphasis on specific disabilities such as walking and region-specific biomarkers for the motor cortex and spinal cord.

“We need to be looking at cortical gray matter, which we know is responsive to estrogen,” Dr. Voskuhl said. She led a 2018 placebo-controlled study that found women with MS who took estrogen supplements appeared to experience localized sparing of progressive gray matter, which the researchers linked to improved results in cognitive testing. The findings, the study authors wrote, suggest “a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.”

What about men? Does hormone loss worsen their MS? Dr. Voskuhl said there seems to be a connection between lower levels of testosterone and more disability in men with MS. But their situation is different. Loss of testosterone in men is gradual and happens over decades instead of over the short period of menopause in women, she said.

Jennifer Graves, MD, a neurologist at the University of California, San Diego, agreed that it’s time for further research into estrogen supplementation in MS. As she noted, “we don’t know the exact biological mechanism that might link perimenopause with developing a more progressive type of MS.”

She added: “An overall decrease in estrogen may be at play but there are other biological changes around menopause. We must also take care in studies to try to separate out what might be due to ovarian aging versus other types of aging processes that might be happening at the same time.”

Dr. Voskuhl disclosed that she is an inventor on university patents for use of estriol and estrogen receptor–beta ligands as treatments. Dr. Graves reports no relevant disclosures.

Vitamin D deficiency detected at the time of multiple sclerosis (MS) diagnosis is associated with cognitive impairment and may also impact disability, according to new research that adds to the known adverse relationship between low vitamin D and MS.

“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.

“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.

The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Low vitamin D and MS

Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.

“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”

To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.

Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.

At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.

The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).

Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).

Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).

Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).

Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.

Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”

The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.

“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.

“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
 

Vitamin D also linked to long-term cognitive function

The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.

That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.

“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.

The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Vitamin D deficiency detected at the time of multiple sclerosis (MS) diagnosis is associated with cognitive impairment and may also impact disability, according to new research that adds to the known adverse relationship between low vitamin D and MS.

“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.

“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.

The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Low vitamin D and MS

Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.

“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”

To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.

Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.

At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.

The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).

Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).

Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).

Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).

Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.

Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”

The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.

“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.

“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
 

Vitamin D also linked to long-term cognitive function

The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.

That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.

“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.

The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Vitamin D deficiency detected at the time of multiple sclerosis (MS) diagnosis is associated with cognitive impairment and may also impact disability, according to new research that adds to the known adverse relationship between low vitamin D and MS.

“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.

“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.

The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Low vitamin D and MS

Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.

“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”

To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.

Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.

At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.

The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).

Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).

Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).

Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).

Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.

Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”

The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.

“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.

“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
 

Vitamin D also linked to long-term cognitive function

The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.

That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.

“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.

The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Menopause is a key time to monitor women for the development or increase of cardiovascular risk factors, according to a new consensus statement developed by the Task Force on Gender of the European Society of Cardiology and a multidisciplinary ESC working group on Women’s Health in Menopause.

“After menopause, traditional cardiovascular risk factors are adversely affected – particularly hypertension,” wrote Angela H.E.M. Maas, MD, of Radboud University Medical Center, Nijmegen, Netherlands, and colleagues.

“Since the first ESC consensus paper on the management of cardiovascular risk in perimenopausal women was published in 2007, we have a greater understanding on the role of female-specific risk factors for cardiovascular disease (CVD),” they said.

In a consensus statement published in the European Heart Journal, the authors presented clinical guidance for diagnosis and management of cardiovascular risk factors during the menopause transition. The transition to menopause increases a woman’s risk for developing several CVD risk factors, including central adiposity, increased insulin resistance, a proatherogenic lipid profile, and autonomic dysfunction that can contribute to increased heart rate variability, according to the statement.

Estrogen changes may affect ischemic disease

In general, obstructive coronary artery disease (CAD) strikes women later than men, but coronary vasomotor conditions are a common cause of ischemic heart disease in women with or without CAD, the authors noted.

“Lower estrogen levels after menopause are related to altered vascular function, enhanced inflammation, and up-regulation of other hormonal systems such as the renin–angiotensin–aldosterone system, the sympathetic nervous system, and reduced nitric oxide–dependent vasodilation,” they wrote. They recommended use of the coronary artery calcium score for screening middle-aged women who are symptomatic or at intermediate cardiovascular risk.

The transition to menopause causes changes in lipid profiles, and a rise in blood pressure in particular “may be both a direct effect of hormonal changes on the vasculature and metabolic changes with aging,” but hypertension in early post menopause is “often poorly managed,” the authors noted.

Compared with asymptomatic women, women who suffer from severe menopausal symptoms often have increased cardiovascular disease risk factors. For example, the Women’s Health Initiative (WHI) study showed a 48% increased risk of incident diabetes at follow-up in women with severe symptoms of hot flashes and night sweats, the authors wrote. Clinicians should also be aware of the increased immune reactivity that occurs during and after menopause and the increased CVD risk associated with autoimmune and endocrine disorders, they said.
 

Multiple strategies to reduce risk

Strategies to address the cardiovascular risk in menopause include assessing glucose, lipid levels, and blood pressure during the transition to menopause, according to the statement.

In addition, they recommended increasing employer awareness of menopause, as changes may interfere with working ability. A healthy lifestyle including healthy diet and regular exercise can help reduce cardiovascular risks and relieve symptoms. Menopausal hormone therapy (MHT) may be indicated to relieve symptoms, including symptoms of depression, and provide cardioprotection for younger women around the time of menopause, according to the statement.

However, “MHT is not recommended in women at high CV risk and after a previous CVD event,” and all women should be assessed for cardiovascular risk factors before starting MHT, they emphasized.
 

Results raise awareness of cardiovascular health and menopause link

“Over the past 20 years, our knowledge of how menopause might contribute to cardiovascular disease has dramatically evolved,” said Samar El Khoudary, MD, of the University of Pittsburg, in an interview.

“We have accumulated data that consistently point to the menopause transition as a time of change in cardiovascular health. As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” she said. “The goal is to raise awareness for both health care providers and women of the significant adverse cardiovascular health changes accompanying the menopause transition and to point out the importance of adopting prevention strategies early during this stage,” she explained.

The impact of the hormonal changes of menopause on CVD risk “is very complex,” Dr. El Khoudary said. “Until now, we could not prove that using estrogen therapy is cardioprotective,” she emphasized. “Studies point to the need to consider the timing of hormone use, as well as types and route of administration,” she noted. “The truth is that, although the menopause transition is associated with an acceleration in CVD risk, the exact mechanism still is not completely clear. Hormone changes contribute, but they are not the ultimate contributor,” she added.

 

Research gaps include data on lifestyle and behavioral interventions

“Irrespective of the accumulating findings showing adverse changes in multiple cardiovascular health parameters, as women transition through menopause, we do not have data documenting current status of ideal cardiovascular health components during the menopause transition among women,” said Dr. El Khoudary. “The limited data we have [suggest] that a very small proportion of women transitioning through menopause eat a healthy diet (less than 20%) or practice physical activity (about7.2%) at a level that matches the current recommendations,” she noted.

“Lifestyle and behavioral interventions are critical to maintain a healthy heart and reduce heart disease; we do not have adequate randomized clinical trials testing these interventions specifically during the menopause transition,” she said.

“Similarly, we are in need of randomized clinical trials of therapeutic interventions such as lipid-lowering medications and menopause hormone therapy in women transitioning through menopause,” said Dr. El Khoudary. “This high-risk population has not been the focus of previous clinical trials, leaving us with questions of how the results from these studies might apply to women during the menopause transition,” she said.
 

Consensus invites collaboration

“I commend the group for putting together a statement that crosses practice and specialty boundaries,” said Lubna Pal, MD, of Yale School of Medicine, New Haven, Conn., in an interview. Although the statement does not present novel information, it “has the power of unifying the various providers by bringing focus on the individual elements spanning a woman’s life that cumulatively determine her lifetime health risk,” she said. Preeclampsia may be a risk factor for cardiovascular disease later in life, and events in reproductive age may determine a woman’s trajectory during the transition to menopause and beyond, Dr. Pal noted.

“The consensus statement will likely be read by internists and family medicine providers as well as ob.gyns.; it encourages all those involved in caring for female patients to take on the responsibility of ‘passing on the baton,’ such that all women who are deemed at an enhanced risk for cardiovascular disease are assured due diligence in care through stringent surveillance and timely interventions,” said Dr. Pal. “It is a call for the various providers who care for women at distinct stages of life to work together toward a shared goal of optimizing every woman’s health across her lifespan,” she said.

“More research is needed for us to better understand the mechanisms at play” in the development of cardiovascular risk and in understanding the continuity of changes across women’s lifespans, Dr. Pal said. “We have associations, but not much information about causation,” she emphasized. However, the statement promotes the dissemination of information about women’s health and sensitizes providers to the potential and the power of preventive care. “We should be much more liberal and loud in holding conversations about risk quantification and risk reduction, and this statement is a resounding effort toward identifying and mitigating long-term cardiovascular risk, even if only through promoting a healthier lifestyle in those deemed at risk,” she added.  

The statement received no outside funding. Lead author Dr. Maas had no financial conflicts to disclose. Dr. El Khoudary had no financial conflicts to disclose. Dr. Pal had no relevant financial conflicts to disclose.

Menopause is a key time to monitor women for the development or increase of cardiovascular risk factors, according to a new consensus statement developed by the Task Force on Gender of the European Society of Cardiology and a multidisciplinary ESC working group on Women’s Health in Menopause.

“After menopause, traditional cardiovascular risk factors are adversely affected – particularly hypertension,” wrote Angela H.E.M. Maas, MD, of Radboud University Medical Center, Nijmegen, Netherlands, and colleagues.

“Since the first ESC consensus paper on the management of cardiovascular risk in perimenopausal women was published in 2007, we have a greater understanding on the role of female-specific risk factors for cardiovascular disease (CVD),” they said.

In a consensus statement published in the European Heart Journal, the authors presented clinical guidance for diagnosis and management of cardiovascular risk factors during the menopause transition. The transition to menopause increases a woman’s risk for developing several CVD risk factors, including central adiposity, increased insulin resistance, a proatherogenic lipid profile, and autonomic dysfunction that can contribute to increased heart rate variability, according to the statement.

Estrogen changes may affect ischemic disease

In general, obstructive coronary artery disease (CAD) strikes women later than men, but coronary vasomotor conditions are a common cause of ischemic heart disease in women with or without CAD, the authors noted.

“Lower estrogen levels after menopause are related to altered vascular function, enhanced inflammation, and up-regulation of other hormonal systems such as the renin–angiotensin–aldosterone system, the sympathetic nervous system, and reduced nitric oxide–dependent vasodilation,” they wrote. They recommended use of the coronary artery calcium score for screening middle-aged women who are symptomatic or at intermediate cardiovascular risk.

The transition to menopause causes changes in lipid profiles, and a rise in blood pressure in particular “may be both a direct effect of hormonal changes on the vasculature and metabolic changes with aging,” but hypertension in early post menopause is “often poorly managed,” the authors noted.

Compared with asymptomatic women, women who suffer from severe menopausal symptoms often have increased cardiovascular disease risk factors. For example, the Women’s Health Initiative (WHI) study showed a 48% increased risk of incident diabetes at follow-up in women with severe symptoms of hot flashes and night sweats, the authors wrote. Clinicians should also be aware of the increased immune reactivity that occurs during and after menopause and the increased CVD risk associated with autoimmune and endocrine disorders, they said.
 

Multiple strategies to reduce risk

Strategies to address the cardiovascular risk in menopause include assessing glucose, lipid levels, and blood pressure during the transition to menopause, according to the statement.

In addition, they recommended increasing employer awareness of menopause, as changes may interfere with working ability. A healthy lifestyle including healthy diet and regular exercise can help reduce cardiovascular risks and relieve symptoms. Menopausal hormone therapy (MHT) may be indicated to relieve symptoms, including symptoms of depression, and provide cardioprotection for younger women around the time of menopause, according to the statement.

However, “MHT is not recommended in women at high CV risk and after a previous CVD event,” and all women should be assessed for cardiovascular risk factors before starting MHT, they emphasized.
 

Results raise awareness of cardiovascular health and menopause link

“Over the past 20 years, our knowledge of how menopause might contribute to cardiovascular disease has dramatically evolved,” said Samar El Khoudary, MD, of the University of Pittsburg, in an interview.

“We have accumulated data that consistently point to the menopause transition as a time of change in cardiovascular health. As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” she said. “The goal is to raise awareness for both health care providers and women of the significant adverse cardiovascular health changes accompanying the menopause transition and to point out the importance of adopting prevention strategies early during this stage,” she explained.

The impact of the hormonal changes of menopause on CVD risk “is very complex,” Dr. El Khoudary said. “Until now, we could not prove that using estrogen therapy is cardioprotective,” she emphasized. “Studies point to the need to consider the timing of hormone use, as well as types and route of administration,” she noted. “The truth is that, although the menopause transition is associated with an acceleration in CVD risk, the exact mechanism still is not completely clear. Hormone changes contribute, but they are not the ultimate contributor,” she added.

 

Research gaps include data on lifestyle and behavioral interventions

“Irrespective of the accumulating findings showing adverse changes in multiple cardiovascular health parameters, as women transition through menopause, we do not have data documenting current status of ideal cardiovascular health components during the menopause transition among women,” said Dr. El Khoudary. “The limited data we have [suggest] that a very small proportion of women transitioning through menopause eat a healthy diet (less than 20%) or practice physical activity (about7.2%) at a level that matches the current recommendations,” she noted.

“Lifestyle and behavioral interventions are critical to maintain a healthy heart and reduce heart disease; we do not have adequate randomized clinical trials testing these interventions specifically during the menopause transition,” she said.

“Similarly, we are in need of randomized clinical trials of therapeutic interventions such as lipid-lowering medications and menopause hormone therapy in women transitioning through menopause,” said Dr. El Khoudary. “This high-risk population has not been the focus of previous clinical trials, leaving us with questions of how the results from these studies might apply to women during the menopause transition,” she said.
 

Consensus invites collaboration

“I commend the group for putting together a statement that crosses practice and specialty boundaries,” said Lubna Pal, MD, of Yale School of Medicine, New Haven, Conn., in an interview. Although the statement does not present novel information, it “has the power of unifying the various providers by bringing focus on the individual elements spanning a woman’s life that cumulatively determine her lifetime health risk,” she said. Preeclampsia may be a risk factor for cardiovascular disease later in life, and events in reproductive age may determine a woman’s trajectory during the transition to menopause and beyond, Dr. Pal noted.

“The consensus statement will likely be read by internists and family medicine providers as well as ob.gyns.; it encourages all those involved in caring for female patients to take on the responsibility of ‘passing on the baton,’ such that all women who are deemed at an enhanced risk for cardiovascular disease are assured due diligence in care through stringent surveillance and timely interventions,” said Dr. Pal. “It is a call for the various providers who care for women at distinct stages of life to work together toward a shared goal of optimizing every woman’s health across her lifespan,” she said.

“More research is needed for us to better understand the mechanisms at play” in the development of cardiovascular risk and in understanding the continuity of changes across women’s lifespans, Dr. Pal said. “We have associations, but not much information about causation,” she emphasized. However, the statement promotes the dissemination of information about women’s health and sensitizes providers to the potential and the power of preventive care. “We should be much more liberal and loud in holding conversations about risk quantification and risk reduction, and this statement is a resounding effort toward identifying and mitigating long-term cardiovascular risk, even if only through promoting a healthier lifestyle in those deemed at risk,” she added.  

The statement received no outside funding. Lead author Dr. Maas had no financial conflicts to disclose. Dr. El Khoudary had no financial conflicts to disclose. Dr. Pal had no relevant financial conflicts to disclose.

Menopause is a key time to monitor women for the development or increase of cardiovascular risk factors, according to a new consensus statement developed by the Task Force on Gender of the European Society of Cardiology and a multidisciplinary ESC working group on Women’s Health in Menopause.

“After menopause, traditional cardiovascular risk factors are adversely affected – particularly hypertension,” wrote Angela H.E.M. Maas, MD, of Radboud University Medical Center, Nijmegen, Netherlands, and colleagues.

“Since the first ESC consensus paper on the management of cardiovascular risk in perimenopausal women was published in 2007, we have a greater understanding on the role of female-specific risk factors for cardiovascular disease (CVD),” they said.

In a consensus statement published in the European Heart Journal, the authors presented clinical guidance for diagnosis and management of cardiovascular risk factors during the menopause transition. The transition to menopause increases a woman’s risk for developing several CVD risk factors, including central adiposity, increased insulin resistance, a proatherogenic lipid profile, and autonomic dysfunction that can contribute to increased heart rate variability, according to the statement.

Estrogen changes may affect ischemic disease

In general, obstructive coronary artery disease (CAD) strikes women later than men, but coronary vasomotor conditions are a common cause of ischemic heart disease in women with or without CAD, the authors noted.

“Lower estrogen levels after menopause are related to altered vascular function, enhanced inflammation, and up-regulation of other hormonal systems such as the renin–angiotensin–aldosterone system, the sympathetic nervous system, and reduced nitric oxide–dependent vasodilation,” they wrote. They recommended use of the coronary artery calcium score for screening middle-aged women who are symptomatic or at intermediate cardiovascular risk.

The transition to menopause causes changes in lipid profiles, and a rise in blood pressure in particular “may be both a direct effect of hormonal changes on the vasculature and metabolic changes with aging,” but hypertension in early post menopause is “often poorly managed,” the authors noted.

Compared with asymptomatic women, women who suffer from severe menopausal symptoms often have increased cardiovascular disease risk factors. For example, the Women’s Health Initiative (WHI) study showed a 48% increased risk of incident diabetes at follow-up in women with severe symptoms of hot flashes and night sweats, the authors wrote. Clinicians should also be aware of the increased immune reactivity that occurs during and after menopause and the increased CVD risk associated with autoimmune and endocrine disorders, they said.
 

Multiple strategies to reduce risk

Strategies to address the cardiovascular risk in menopause include assessing glucose, lipid levels, and blood pressure during the transition to menopause, according to the statement.

In addition, they recommended increasing employer awareness of menopause, as changes may interfere with working ability. A healthy lifestyle including healthy diet and regular exercise can help reduce cardiovascular risks and relieve symptoms. Menopausal hormone therapy (MHT) may be indicated to relieve symptoms, including symptoms of depression, and provide cardioprotection for younger women around the time of menopause, according to the statement.

However, “MHT is not recommended in women at high CV risk and after a previous CVD event,” and all women should be assessed for cardiovascular risk factors before starting MHT, they emphasized.
 

Results raise awareness of cardiovascular health and menopause link

“Over the past 20 years, our knowledge of how menopause might contribute to cardiovascular disease has dramatically evolved,” said Samar El Khoudary, MD, of the University of Pittsburg, in an interview.

“We have accumulated data that consistently point to the menopause transition as a time of change in cardiovascular health. As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” she said. “The goal is to raise awareness for both health care providers and women of the significant adverse cardiovascular health changes accompanying the menopause transition and to point out the importance of adopting prevention strategies early during this stage,” she explained.

The impact of the hormonal changes of menopause on CVD risk “is very complex,” Dr. El Khoudary said. “Until now, we could not prove that using estrogen therapy is cardioprotective,” she emphasized. “Studies point to the need to consider the timing of hormone use, as well as types and route of administration,” she noted. “The truth is that, although the menopause transition is associated with an acceleration in CVD risk, the exact mechanism still is not completely clear. Hormone changes contribute, but they are not the ultimate contributor,” she added.

 

Research gaps include data on lifestyle and behavioral interventions

“Irrespective of the accumulating findings showing adverse changes in multiple cardiovascular health parameters, as women transition through menopause, we do not have data documenting current status of ideal cardiovascular health components during the menopause transition among women,” said Dr. El Khoudary. “The limited data we have [suggest] that a very small proportion of women transitioning through menopause eat a healthy diet (less than 20%) or practice physical activity (about7.2%) at a level that matches the current recommendations,” she noted.

“Lifestyle and behavioral interventions are critical to maintain a healthy heart and reduce heart disease; we do not have adequate randomized clinical trials testing these interventions specifically during the menopause transition,” she said.

“Similarly, we are in need of randomized clinical trials of therapeutic interventions such as lipid-lowering medications and menopause hormone therapy in women transitioning through menopause,” said Dr. El Khoudary. “This high-risk population has not been the focus of previous clinical trials, leaving us with questions of how the results from these studies might apply to women during the menopause transition,” she said.
 

Consensus invites collaboration

“I commend the group for putting together a statement that crosses practice and specialty boundaries,” said Lubna Pal, MD, of Yale School of Medicine, New Haven, Conn., in an interview. Although the statement does not present novel information, it “has the power of unifying the various providers by bringing focus on the individual elements spanning a woman’s life that cumulatively determine her lifetime health risk,” she said. Preeclampsia may be a risk factor for cardiovascular disease later in life, and events in reproductive age may determine a woman’s trajectory during the transition to menopause and beyond, Dr. Pal noted.

“The consensus statement will likely be read by internists and family medicine providers as well as ob.gyns.; it encourages all those involved in caring for female patients to take on the responsibility of ‘passing on the baton,’ such that all women who are deemed at an enhanced risk for cardiovascular disease are assured due diligence in care through stringent surveillance and timely interventions,” said Dr. Pal. “It is a call for the various providers who care for women at distinct stages of life to work together toward a shared goal of optimizing every woman’s health across her lifespan,” she said.

“More research is needed for us to better understand the mechanisms at play” in the development of cardiovascular risk and in understanding the continuity of changes across women’s lifespans, Dr. Pal said. “We have associations, but not much information about causation,” she emphasized. However, the statement promotes the dissemination of information about women’s health and sensitizes providers to the potential and the power of preventive care. “We should be much more liberal and loud in holding conversations about risk quantification and risk reduction, and this statement is a resounding effort toward identifying and mitigating long-term cardiovascular risk, even if only through promoting a healthier lifestyle in those deemed at risk,” she added.  

The statement received no outside funding. Lead author Dr. Maas had no financial conflicts to disclose. Dr. El Khoudary had no financial conflicts to disclose. Dr. Pal had no relevant financial conflicts to disclose.

Postmenopausal women not only have larger brain volume than women who are premenopausal, but they also experience larger reductions in brain volume over time, reported Ananthan Ambikairajah of the Centre for Research on Ageing, Health and Wellbeing, Australian National University, Canberra, and associates. Their report was published in Menopause.

In this large population-based cohort of 5,072 women aged 37-73 years, the goal of the study was to look at links between brain volume and measures of menstruation history, such as menopausal status, age at menopause, age at menarche, and the duration of a woman’s reproductive stage, but to do so within the context of how it relates to dementia prevalence. Citing a study in The Lancet Neurology, the authors noted that the age-standardized prevalence for dementia is 17% higher in women than in men, and they speculated that it may be important to look beyond age for answers.
 

What about menstrual history and Alzheimer’s disease?

According to the Framingham Study in Neurology, the remaining lifetime risk of Alzheimer’s disease (AD) is nearly double for a 65-year-old woman (12%) compared with a 65-year-old man (6.3%), leading Mr. Ambikairajah and associates to conclude that “menstruation history may also be particularly relevant, given that it is unique to female aging.” They further speculated, citing several related studies, that because AD pathology is initiated decades prior to the onset of clinical signs, menstruation history and its effects on brain health may, in fact, be reflected in brain volume.

Postmenopausal women had 0.82% and 1.33% larger total brain and hippocampal volume, respectively, compared with premenopausal women. Postmenopausal women had a 23% greater decrease in total brain volume but not in hippocampal volume over time, compared with premenopausal women.

As Braak and Braak illustrated in Acta Neuropathologica, chronic inflammation has been linked to brain shrinkage “consistent with the pattern of results in the present study,” Mr. Ambikairajah and colleagues noted, adding that longitudinal neuroimaging/biomarker studies are needed to explore this further.

What made this study unique was its ability to match pre- and postmenopausal women for age, a critically important attribute “given that aging and menopause both progress concurrently, which can make it difficult to determine the individual contribution of each for measures of brain health,” the authors explained.

In an interview, Constance Bohon, MD, an ob.gyn. in private practice and assistant clinical professor, George Washington University, Washington, observed: “The conclusion [in this study] is that an early age of menarche, delayed age of menopause and increased duration of the reproductive stage is negatively associated with brain volume.”
 

What of the neuroprotective effects of endogenous estrogen?

“Their findings are not consistent with a neuroprotective effect of endogenous estrogen exposure on brain volume,” she noted, adding that the study “did not assess the effect of exogenous estrogen on brain volume. Neither was the effect of exogenous or endogenous estrogen on cerebral blood flow assessed. In a study published in Obstetrics & Gynecology, the conclusion was that oophorectomy before the age of natural menopause is associated with a decrease in cognitive impairment and dementia. There was no assessment of brain volume or cerebral blood flow. Likewise in a report published in Neurobiology of Aging, Maki P and Resnick S M. concluded that estrogen helps maintain hippocampal and prefrontal function as women age,” observed Dr. Bohon, noting that the study did not assess brain volume.

“It is unclear whether the most predictive assessment for worsening cognition and dementia is the finding of decreased total brain volume, decreased hippocampal volume, or decreased cerebral blood flow. The effect of both endogenous and exogenous estrogen on the risk for dementia needs further evaluation,” she cautioned.

Mr. Ambikairajah cited one financial disclosure; the remaining contributors had no relevant disclosures.

Postmenopausal women not only have larger brain volume than women who are premenopausal, but they also experience larger reductions in brain volume over time, reported Ananthan Ambikairajah of the Centre for Research on Ageing, Health and Wellbeing, Australian National University, Canberra, and associates. Their report was published in Menopause.

In this large population-based cohort of 5,072 women aged 37-73 years, the goal of the study was to look at links between brain volume and measures of menstruation history, such as menopausal status, age at menopause, age at menarche, and the duration of a woman’s reproductive stage, but to do so within the context of how it relates to dementia prevalence. Citing a study in The Lancet Neurology, the authors noted that the age-standardized prevalence for dementia is 17% higher in women than in men, and they speculated that it may be important to look beyond age for answers.
 

What about menstrual history and Alzheimer’s disease?

According to the Framingham Study in Neurology, the remaining lifetime risk of Alzheimer’s disease (AD) is nearly double for a 65-year-old woman (12%) compared with a 65-year-old man (6.3%), leading Mr. Ambikairajah and associates to conclude that “menstruation history may also be particularly relevant, given that it is unique to female aging.” They further speculated, citing several related studies, that because AD pathology is initiated decades prior to the onset of clinical signs, menstruation history and its effects on brain health may, in fact, be reflected in brain volume.

Postmenopausal women had 0.82% and 1.33% larger total brain and hippocampal volume, respectively, compared with premenopausal women. Postmenopausal women had a 23% greater decrease in total brain volume but not in hippocampal volume over time, compared with premenopausal women.

As Braak and Braak illustrated in Acta Neuropathologica, chronic inflammation has been linked to brain shrinkage “consistent with the pattern of results in the present study,” Mr. Ambikairajah and colleagues noted, adding that longitudinal neuroimaging/biomarker studies are needed to explore this further.

What made this study unique was its ability to match pre- and postmenopausal women for age, a critically important attribute “given that aging and menopause both progress concurrently, which can make it difficult to determine the individual contribution of each for measures of brain health,” the authors explained.

In an interview, Constance Bohon, MD, an ob.gyn. in private practice and assistant clinical professor, George Washington University, Washington, observed: “The conclusion [in this study] is that an early age of menarche, delayed age of menopause and increased duration of the reproductive stage is negatively associated with brain volume.”
 

What of the neuroprotective effects of endogenous estrogen?

“Their findings are not consistent with a neuroprotective effect of endogenous estrogen exposure on brain volume,” she noted, adding that the study “did not assess the effect of exogenous estrogen on brain volume. Neither was the effect of exogenous or endogenous estrogen on cerebral blood flow assessed. In a study published in Obstetrics & Gynecology, the conclusion was that oophorectomy before the age of natural menopause is associated with a decrease in cognitive impairment and dementia. There was no assessment of brain volume or cerebral blood flow. Likewise in a report published in Neurobiology of Aging, Maki P and Resnick S M. concluded that estrogen helps maintain hippocampal and prefrontal function as women age,” observed Dr. Bohon, noting that the study did not assess brain volume.

“It is unclear whether the most predictive assessment for worsening cognition and dementia is the finding of decreased total brain volume, decreased hippocampal volume, or decreased cerebral blood flow. The effect of both endogenous and exogenous estrogen on the risk for dementia needs further evaluation,” she cautioned.

Mr. Ambikairajah cited one financial disclosure; the remaining contributors had no relevant disclosures.

Postmenopausal women not only have larger brain volume than women who are premenopausal, but they also experience larger reductions in brain volume over time, reported Ananthan Ambikairajah of the Centre for Research on Ageing, Health and Wellbeing, Australian National University, Canberra, and associates. Their report was published in Menopause.

In this large population-based cohort of 5,072 women aged 37-73 years, the goal of the study was to look at links between brain volume and measures of menstruation history, such as menopausal status, age at menopause, age at menarche, and the duration of a woman’s reproductive stage, but to do so within the context of how it relates to dementia prevalence. Citing a study in The Lancet Neurology, the authors noted that the age-standardized prevalence for dementia is 17% higher in women than in men, and they speculated that it may be important to look beyond age for answers.
 

What about menstrual history and Alzheimer’s disease?

According to the Framingham Study in Neurology, the remaining lifetime risk of Alzheimer’s disease (AD) is nearly double for a 65-year-old woman (12%) compared with a 65-year-old man (6.3%), leading Mr. Ambikairajah and associates to conclude that “menstruation history may also be particularly relevant, given that it is unique to female aging.” They further speculated, citing several related studies, that because AD pathology is initiated decades prior to the onset of clinical signs, menstruation history and its effects on brain health may, in fact, be reflected in brain volume.

Postmenopausal women had 0.82% and 1.33% larger total brain and hippocampal volume, respectively, compared with premenopausal women. Postmenopausal women had a 23% greater decrease in total brain volume but not in hippocampal volume over time, compared with premenopausal women.

As Braak and Braak illustrated in Acta Neuropathologica, chronic inflammation has been linked to brain shrinkage “consistent with the pattern of results in the present study,” Mr. Ambikairajah and colleagues noted, adding that longitudinal neuroimaging/biomarker studies are needed to explore this further.

What made this study unique was its ability to match pre- and postmenopausal women for age, a critically important attribute “given that aging and menopause both progress concurrently, which can make it difficult to determine the individual contribution of each for measures of brain health,” the authors explained.

In an interview, Constance Bohon, MD, an ob.gyn. in private practice and assistant clinical professor, George Washington University, Washington, observed: “The conclusion [in this study] is that an early age of menarche, delayed age of menopause and increased duration of the reproductive stage is negatively associated with brain volume.”
 

What of the neuroprotective effects of endogenous estrogen?

“Their findings are not consistent with a neuroprotective effect of endogenous estrogen exposure on brain volume,” she noted, adding that the study “did not assess the effect of exogenous estrogen on brain volume. Neither was the effect of exogenous or endogenous estrogen on cerebral blood flow assessed. In a study published in Obstetrics & Gynecology, the conclusion was that oophorectomy before the age of natural menopause is associated with a decrease in cognitive impairment and dementia. There was no assessment of brain volume or cerebral blood flow. Likewise in a report published in Neurobiology of Aging, Maki P and Resnick S M. concluded that estrogen helps maintain hippocampal and prefrontal function as women age,” observed Dr. Bohon, noting that the study did not assess brain volume.

“It is unclear whether the most predictive assessment for worsening cognition and dementia is the finding of decreased total brain volume, decreased hippocampal volume, or decreased cerebral blood flow. The effect of both endogenous and exogenous estrogen on the risk for dementia needs further evaluation,” she cautioned.

Mr. Ambikairajah cited one financial disclosure; the remaining contributors had no relevant disclosures.