Menopause

Hormone therapy – estradiol with or without progesterone – only limits the progression of subclinical atherosclerosis if it is initiated within 6 years of menopause onset, according to a report published online March 30 in the New England Journal of Medicine.

The “hormone-timing hypothesis” posits that hormone therapy’s beneficial effects on atherosclerosis depend on the timing of initiating that therapy relative to menopause. To test this hypothesis, researchers began the ELITE study (Early versus Late Intervention Trial with Estradiol) in 2002, using serial noninvasive measurements of carotid-artery intima-media thickness (CIMT) as a marker of atherosclerosis progression.

©pixologicstudio/Thinkstock.com

Several other studies since 2002 have reported that the timing hypothesis appears to be valid, wrote Dr. Howard N. Hodis of the Atherosclerosis Research Unit, University of Southern California, Los Angeles, and his associates.

Their single-center trial involved 643 healthy postmenopausal women who had no diabetes and no evidence of cardiovascular disease at baseline, and who were randomly assigned to receive either daily oral estradiol or a matching placebo for 5 years. Women who had an intact uterus and took active estradiol also received a 4% micronized progesterone vaginal gel, while those who had an intact uterus and took placebo also received a matching placebo gel.

The participants were stratified according to the number of years they were past menopause: less than 6 years (271 women in the “early” group) or more than 10 years (372 in the “late” group).

A total of 137 women in the early group and 186 women in the late group were assigned to active estradiol, while 134 women in the early group and 186 women in the late group were assigned to placebo. As expected, serum estradiol levels were at least 3 times higher among women assigned to active treatment, compared with those assigned to placebo.

The primary outcome – the effect of hormone therapy on CIMT progression – differed by timing of the initiation of treatment. In the “early” group, the mean CIMT progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo.

In contrast, in the “late” group, the rates of CIMT progression were not significantly different between estradiol and placebo, the investigators wrote (N Engl J Med. 2016;374:1221-31. doi: 10.1056/NEJMoa1505241).

This beneficial effect remained significant in a sensitivity analysis restricted only to study participants who showed at least 80% adherence to their assigned treatment. The benefit also remained significant in a post-hoc analysis comparing women who took estradiol alone against those who took estradiol plus progestogen, as well as in a separate analysis comparing women who used lipid-lowering and/or hypertensive medications against those who did not.

The findings add further evidence in favor of the hormone timing hypothesis. The effect of estradiol therapy on CIMT progression was significantly modified by time since menopause (P = .007 for the interaction), the researchers wrote.

Cardiac computer tomography (CT) was used as a different method of assessing coronary atherosclerosis in a subgroup of 167 women in the early group (88 receiving estradiol and 79 receiving placebo) and 214 in the late group (101 receiving estradiol and 113 receiving placebo). The timing of estradiol treatment did not affect coronary artery calcium and other cardiac CT measures. This is consistent with previous reports that hormone therapy has no significant effect on established lesions in the coronary arteries, the researchers wrote.

The ELITE trial was funded by the National Institute on Aging. Dr. Hodis reported having no relevant financial disclosures; two of his associates reported ties to GE and TherapeuticsMD.

Hormone therapy – estradiol with or without progesterone – only limits the progression of subclinical atherosclerosis if it is initiated within 6 years of menopause onset, according to a report published online March 30 in the New England Journal of Medicine.

The “hormone-timing hypothesis” posits that hormone therapy’s beneficial effects on atherosclerosis depend on the timing of initiating that therapy relative to menopause. To test this hypothesis, researchers began the ELITE study (Early versus Late Intervention Trial with Estradiol) in 2002, using serial noninvasive measurements of carotid-artery intima-media thickness (CIMT) as a marker of atherosclerosis progression.

©pixologicstudio/Thinkstock.com

Several other studies since 2002 have reported that the timing hypothesis appears to be valid, wrote Dr. Howard N. Hodis of the Atherosclerosis Research Unit, University of Southern California, Los Angeles, and his associates.

Their single-center trial involved 643 healthy postmenopausal women who had no diabetes and no evidence of cardiovascular disease at baseline, and who were randomly assigned to receive either daily oral estradiol or a matching placebo for 5 years. Women who had an intact uterus and took active estradiol also received a 4% micronized progesterone vaginal gel, while those who had an intact uterus and took placebo also received a matching placebo gel.

The participants were stratified according to the number of years they were past menopause: less than 6 years (271 women in the “early” group) or more than 10 years (372 in the “late” group).

A total of 137 women in the early group and 186 women in the late group were assigned to active estradiol, while 134 women in the early group and 186 women in the late group were assigned to placebo. As expected, serum estradiol levels were at least 3 times higher among women assigned to active treatment, compared with those assigned to placebo.

The primary outcome – the effect of hormone therapy on CIMT progression – differed by timing of the initiation of treatment. In the “early” group, the mean CIMT progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo.

In contrast, in the “late” group, the rates of CIMT progression were not significantly different between estradiol and placebo, the investigators wrote (N Engl J Med. 2016;374:1221-31. doi: 10.1056/NEJMoa1505241).

This beneficial effect remained significant in a sensitivity analysis restricted only to study participants who showed at least 80% adherence to their assigned treatment. The benefit also remained significant in a post-hoc analysis comparing women who took estradiol alone against those who took estradiol plus progestogen, as well as in a separate analysis comparing women who used lipid-lowering and/or hypertensive medications against those who did not.

The findings add further evidence in favor of the hormone timing hypothesis. The effect of estradiol therapy on CIMT progression was significantly modified by time since menopause (P = .007 for the interaction), the researchers wrote.

Cardiac computer tomography (CT) was used as a different method of assessing coronary atherosclerosis in a subgroup of 167 women in the early group (88 receiving estradiol and 79 receiving placebo) and 214 in the late group (101 receiving estradiol and 113 receiving placebo). The timing of estradiol treatment did not affect coronary artery calcium and other cardiac CT measures. This is consistent with previous reports that hormone therapy has no significant effect on established lesions in the coronary arteries, the researchers wrote.

The ELITE trial was funded by the National Institute on Aging. Dr. Hodis reported having no relevant financial disclosures; two of his associates reported ties to GE and TherapeuticsMD.

Hormone therapy – estradiol with or without progesterone – only limits the progression of subclinical atherosclerosis if it is initiated within 6 years of menopause onset, according to a report published online March 30 in the New England Journal of Medicine.

The “hormone-timing hypothesis” posits that hormone therapy’s beneficial effects on atherosclerosis depend on the timing of initiating that therapy relative to menopause. To test this hypothesis, researchers began the ELITE study (Early versus Late Intervention Trial with Estradiol) in 2002, using serial noninvasive measurements of carotid-artery intima-media thickness (CIMT) as a marker of atherosclerosis progression.

©pixologicstudio/Thinkstock.com

Several other studies since 2002 have reported that the timing hypothesis appears to be valid, wrote Dr. Howard N. Hodis of the Atherosclerosis Research Unit, University of Southern California, Los Angeles, and his associates.

Their single-center trial involved 643 healthy postmenopausal women who had no diabetes and no evidence of cardiovascular disease at baseline, and who were randomly assigned to receive either daily oral estradiol or a matching placebo for 5 years. Women who had an intact uterus and took active estradiol also received a 4% micronized progesterone vaginal gel, while those who had an intact uterus and took placebo also received a matching placebo gel.

The participants were stratified according to the number of years they were past menopause: less than 6 years (271 women in the “early” group) or more than 10 years (372 in the “late” group).

A total of 137 women in the early group and 186 women in the late group were assigned to active estradiol, while 134 women in the early group and 186 women in the late group were assigned to placebo. As expected, serum estradiol levels were at least 3 times higher among women assigned to active treatment, compared with those assigned to placebo.

The primary outcome – the effect of hormone therapy on CIMT progression – differed by timing of the initiation of treatment. In the “early” group, the mean CIMT progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo.

In contrast, in the “late” group, the rates of CIMT progression were not significantly different between estradiol and placebo, the investigators wrote (N Engl J Med. 2016;374:1221-31. doi: 10.1056/NEJMoa1505241).

This beneficial effect remained significant in a sensitivity analysis restricted only to study participants who showed at least 80% adherence to their assigned treatment. The benefit also remained significant in a post-hoc analysis comparing women who took estradiol alone against those who took estradiol plus progestogen, as well as in a separate analysis comparing women who used lipid-lowering and/or hypertensive medications against those who did not.

The findings add further evidence in favor of the hormone timing hypothesis. The effect of estradiol therapy on CIMT progression was significantly modified by time since menopause (P = .007 for the interaction), the researchers wrote.

Cardiac computer tomography (CT) was used as a different method of assessing coronary atherosclerosis in a subgroup of 167 women in the early group (88 receiving estradiol and 79 receiving placebo) and 214 in the late group (101 receiving estradiol and 113 receiving placebo). The timing of estradiol treatment did not affect coronary artery calcium and other cardiac CT measures. This is consistent with previous reports that hormone therapy has no significant effect on established lesions in the coronary arteries, the researchers wrote.

The ELITE trial was funded by the National Institute on Aging. Dr. Hodis reported having no relevant financial disclosures; two of his associates reported ties to GE and TherapeuticsMD.

To date, screening has not been found effective in reducing mortality from ovarian cancer. Collaborative trial investigators in the United Kingdom studied postmenopausal women in the general population to assess whether early detection by screening could decrease ovarian cancer mortality.

Details of the study
During 2001 to 2005, more than 200,000 UK postmenopausal women aged 50 to 74 years (mean age at baseline, 60.6 years) were randomly assigned to no screening, annual transvaginal ultrasound screening (TVUS), or annual multimodal screening (MMS) with serum CA 125 using the Risk of Ovarian Cancer Algorithm (ROCA), which takes into account changes in CA 125 levels over time. When ROCA scores indicated normal risk for ovarian cancer, women were advised to undergo repeat CA 125 assessment in 1 year. Women with intermediate risk were advised to repeat CA 125 assessment in 3 months, while high-risk women were advised to undergo TVUS.

With a median of 11.1 years of follow-up, ovarian cancer (including fallopian tube malignancies) was diagnosed in 1,282 participants (0.6%), with fatal outcomes among the 3 groups as follows: 0.34% in the no-screening group, 0.30% in the TVUS group, and 0.29% in the MMS group. Based on the results of a planned secondary analysis that excluded prevalent cases of ovarian cancer, annual MMS was associated with an overall average mortality reduction of 20% compared with no screening (P = .021). When the mortality reduction was broken down by years of annual screening, 0 to 7 years was associated with an 8% mortality reduction over no screening, and this jumped to 28% for 7 to 14 annual MMS screening years.

The overall average mortality reduction with TVUS compared with no screening was smaller than with MMS. With MMS, the number needed to screen to prevent 1 death from ovarian cancer was 641.

Assessing unnecessary treatment
False-positive screens that resulted in surgical intervention with findings of benign adnexal pathology or normal adnexa occurred in 14 and 50 per 10,000 screens in the MMS and TVUS groups, respectively. For each ovarian cancer detected in the MMS and TVUS groups, an additional 2 and 10 women, respectively, underwent surgery based on false-positive results.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This massive trial’s findings provide optimism that screening for ovarian cancer can indeed reduce mortality from this uncommon but too-often lethal disease. There are unanswered questions, however, which include the cost-effectiveness of MMS screening and how well this strategy can be implemented outside of a highly centralized and controlled clinical trial. While encouraging, these trial results should be viewed as preliminary until additional efficacy and cost-effectiveness data—and guidance from professional organizations—are available.
—ANDREW M. KAUNITZ, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

To date, screening has not been found effective in reducing mortality from ovarian cancer. Collaborative trial investigators in the United Kingdom studied postmenopausal women in the general population to assess whether early detection by screening could decrease ovarian cancer mortality.

Details of the study
During 2001 to 2005, more than 200,000 UK postmenopausal women aged 50 to 74 years (mean age at baseline, 60.6 years) were randomly assigned to no screening, annual transvaginal ultrasound screening (TVUS), or annual multimodal screening (MMS) with serum CA 125 using the Risk of Ovarian Cancer Algorithm (ROCA), which takes into account changes in CA 125 levels over time. When ROCA scores indicated normal risk for ovarian cancer, women were advised to undergo repeat CA 125 assessment in 1 year. Women with intermediate risk were advised to repeat CA 125 assessment in 3 months, while high-risk women were advised to undergo TVUS.

With a median of 11.1 years of follow-up, ovarian cancer (including fallopian tube malignancies) was diagnosed in 1,282 participants (0.6%), with fatal outcomes among the 3 groups as follows: 0.34% in the no-screening group, 0.30% in the TVUS group, and 0.29% in the MMS group. Based on the results of a planned secondary analysis that excluded prevalent cases of ovarian cancer, annual MMS was associated with an overall average mortality reduction of 20% compared with no screening (P = .021). When the mortality reduction was broken down by years of annual screening, 0 to 7 years was associated with an 8% mortality reduction over no screening, and this jumped to 28% for 7 to 14 annual MMS screening years.

The overall average mortality reduction with TVUS compared with no screening was smaller than with MMS. With MMS, the number needed to screen to prevent 1 death from ovarian cancer was 641.

Assessing unnecessary treatment
False-positive screens that resulted in surgical intervention with findings of benign adnexal pathology or normal adnexa occurred in 14 and 50 per 10,000 screens in the MMS and TVUS groups, respectively. For each ovarian cancer detected in the MMS and TVUS groups, an additional 2 and 10 women, respectively, underwent surgery based on false-positive results.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This massive trial’s findings provide optimism that screening for ovarian cancer can indeed reduce mortality from this uncommon but too-often lethal disease. There are unanswered questions, however, which include the cost-effectiveness of MMS screening and how well this strategy can be implemented outside of a highly centralized and controlled clinical trial. While encouraging, these trial results should be viewed as preliminary until additional efficacy and cost-effectiveness data—and guidance from professional organizations—are available.
—ANDREW M. KAUNITZ, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

To date, screening has not been found effective in reducing mortality from ovarian cancer. Collaborative trial investigators in the United Kingdom studied postmenopausal women in the general population to assess whether early detection by screening could decrease ovarian cancer mortality.

Details of the study
During 2001 to 2005, more than 200,000 UK postmenopausal women aged 50 to 74 years (mean age at baseline, 60.6 years) were randomly assigned to no screening, annual transvaginal ultrasound screening (TVUS), or annual multimodal screening (MMS) with serum CA 125 using the Risk of Ovarian Cancer Algorithm (ROCA), which takes into account changes in CA 125 levels over time. When ROCA scores indicated normal risk for ovarian cancer, women were advised to undergo repeat CA 125 assessment in 1 year. Women with intermediate risk were advised to repeat CA 125 assessment in 3 months, while high-risk women were advised to undergo TVUS.

With a median of 11.1 years of follow-up, ovarian cancer (including fallopian tube malignancies) was diagnosed in 1,282 participants (0.6%), with fatal outcomes among the 3 groups as follows: 0.34% in the no-screening group, 0.30% in the TVUS group, and 0.29% in the MMS group. Based on the results of a planned secondary analysis that excluded prevalent cases of ovarian cancer, annual MMS was associated with an overall average mortality reduction of 20% compared with no screening (P = .021). When the mortality reduction was broken down by years of annual screening, 0 to 7 years was associated with an 8% mortality reduction over no screening, and this jumped to 28% for 7 to 14 annual MMS screening years.

The overall average mortality reduction with TVUS compared with no screening was smaller than with MMS. With MMS, the number needed to screen to prevent 1 death from ovarian cancer was 641.

Assessing unnecessary treatment
False-positive screens that resulted in surgical intervention with findings of benign adnexal pathology or normal adnexa occurred in 14 and 50 per 10,000 screens in the MMS and TVUS groups, respectively. For each ovarian cancer detected in the MMS and TVUS groups, an additional 2 and 10 women, respectively, underwent surgery based on false-positive results.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This massive trial’s findings provide optimism that screening for ovarian cancer can indeed reduce mortality from this uncommon but too-often lethal disease. There are unanswered questions, however, which include the cost-effectiveness of MMS screening and how well this strategy can be implemented outside of a highly centralized and controlled clinical trial. While encouraging, these trial results should be viewed as preliminary until additional efficacy and cost-effectiveness data—and guidance from professional organizations—are available.
—ANDREW M. KAUNITZ, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

“SHOULD YOU ADOPT THE PRACTICE OF VAGINAL CLEANSING WITH POVIDONE-IODINE PRIOR TO CESAREAN DELIVERY?”
ROBERT L. BARBIERI, MD (EDITORIAL; JANUARY 2016)
In his January 2016 Editorial, Editor in Chief Robert L. Barbieri, MD, presented evidence supporting the practice of vaginal cleansing with povidone-iodine prior to cesarean delivery (CD) to prevent postoperative endometritis. He then asked readers if they would consider adopting such a practice. More than 250 readers weighed in through the Quick Poll at obgmanagement.com, and many readers sent in letters with follow-up questions and comments on controlling bacterial contamination, vaginal seeding, etc. Here are some of the letters, along with Dr. Barbieri’s response and the Quick Poll results.

A contradiction in definitions?
There seems to be a contradiction in definitions. The second sentence of the article defines endometritis as the presence of fever plus low abdominal tenderness. However, the studies presented state that vaginal cleansing pre-CD decreased endometritis but did not decrease postpartum fever. Is this not a discrepancy?
Nancy Kerr, MD, MPH
Albuquerque, New Mexico

A question about povidone-iodine
Have any studies been done on newborn iodine levels after vaginal cleansing with povidone-iodine prior to CD?
G. Millard Simmons Jr, MD
Hilton Head, Bluffton, South Carolina

Additional tips for controlling bacterial contamination
Dr. Barbieri’s editorial on vaginal cleansing prior to CD is eye opening. I have a few additional suggestions to control bacterial contamination.

First, I examine my patients in labor as few times as necessary, and I ask the nurses (RNs) not to place their fingers in the patient’s vagina while she is pushing. I remove the Foley catheter when I feel progress (descent of fetal head) is being achieved. In addition, physicians as well as RNs should consider changing their scrubs between deliveries, as I believe that bacterial contamination is splattered all over the place, especially into the birth canal. These methods have worked for me in my over-20 years of practice.

I also firmly remind the RN circulator to perform a generous vaginal cleanse with povidone-iodine, in addition to the usual intravenous prophylaxis, before hysterectomy.
Luis Leyva Jr, MD
Miami, Florida

Mixed feelings
My first reaction to this Editorial was: Is this a solution in search of a problem? That is to say, how much of a clinical problem is endometritis after CD? Are we really treating the proposed problem, and does treatment affect long-term outcomes?

Upon reflection, I have concluded that vaginal cleansing pre-CD does intuitively make sense. What sways me in this direction is that the practice is simple, easy, and inexpensive. Since we typically have the patient positioned for Foley catheter insertion, performing vaginal cleansing as we put in the Foley would be easy. If vaginal cleansing were to be done, I definitely would be in favor of doing such practice liberally—for all CDs to make vaginal cleansing part of the “routine.”

Keep in mind that we are still chasing a problem of little clinical significance.

The biggest accomplishment has been to get everyone to give antibiotics preoperatively rather than after cutting the umbilical cord. We knew that this was best practice as early as the late 1980s/early 1990s, and I have been fighting this battle ever since. Believe it or not, there are still a few holdouts.
George H. Davis, DO
Johnson City, Tennessee

Would vaginal cleansing benefit all women in labor?
Vaginal cleansing before CD reminds me of my residency days when all women having hysterectomies were admitted early and given povidone-iodine (Betadine) douches the evening before surgery (unless an iodine allergy was present).

While reading your Editorial, I had several thoughts and questions. 1) Since vaginal cleansing seems to benefit CD patients, might it not benefit all laboring patients? 2) Is the timing of vaginal cleansing critical? 3) Should we do vaginal cleansing on all laboring patients if timing is not critical?

I plan to bring up the topic of vaginal cleansing for CD with my colleagues at our next department meeting, since it seems like such a simple, logical, inexpensive, and beneficial thing to do.
Douglas G. Tolley, MD
Yuba City, California

An early study on using povidone-iodine gel before CD
When I was a chief resident at Kings County Hospital in 1973, we had a very high rate of post-CD endometritis. I conducted a small study on the use of povidone-iodine gel in the last month of pregnancy. Before commencing, we confirmed that the gel did not interfere with diagnosing ruptured membranes.

Obstetric service patients were randomly divided into “A” and “B” groups. The A patients were asked to use povidone-iodine gel at night for the last 2 weeks before their estimated due date. When admitted in labor, they were asked to confirm its use. When a resident diagnosed post-CD endometritis, we kept track of which group the patient was in and whether or not that patient had used povidone-iodine. Approximately 100 infected patients were evaluated from each group.

As it turned out, there were about 3 times the number of infections among the patients who did not use povidone-iodine than among those who said they used it. It did not seem to matter how many times povidone-iodine was used. The “As” who did not use povidone-iodine had results similar to the “Bs.”

It was many years ago, and the study design was crude. However, it does seem to support the suggestion for vaginal cleansing.
Steve Ross, MD
Port Jefferson, New York

Two different ideas about the vaginal biome
This Editorial is timely in that Dr. Dominguez-Bello and colleagues recently published an article in Nature Medicine titled, “Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer.”¹ Dr. Dominguez-Bello is one of the founders of the idea of “vaginal seeding,” or using the natural biome of the vagina on a newborn immediately after CD by swabbing the baby with the bacteria from the vagina.

I find it interesting that there are two very different ideas about the biome at this time. Vaginal seeding is a new trend that a few patients have asked about during prenatal care. The jury is still out on seeding, but a larger study is currently underway at New York University. Of course, infection is one of the risks of seeding. I appreciate hearing both sides of the issue.
Deborah Herchelroath, DO
Harrisburg, Pennsylvania

Reference

Dr. Barbieri responds
I would like to thank our readers for taking the time from their busy schedules to write about their clinical experiences and current practices for reducing infectious complications following CD.

Dr. Kerr raises the important issue of the apparent contradictory finding of the beneficial impact of vaginal cleansing on endometritis without a beneficial effect on the overall rate of fever. In the trial reported by Starr,¹ fever was defined as a temperature above 38˚C at any time after CD and endometritis was defined as a temperature above 38.4˚C PLUS uterine tenderness occurring more than 24 hours after CD. Given these 2 definitions one can understand the differential effect of vaginal cleansing on fever versus endometritis.

Dr. Simmons raises the intriguing question of the impact of an iodine-containing surgical preparation on newborn thyroid function. There are few studies addressing this issue. One study reports a transient increase in thyroid-stimulating hormone (TSH) levels in a small percentage of newborns whose mothers received an iodine preparation.² Another study reports no effect of an iodine surgical preparation on newborn thyroid function indices.³

I agree with the guidance of Drs. Leyva and Davis that we can help prevent postcesarean endometritis by minimizing the number of cervical examinations, changing scrubs between deliveries, and by ensuring that an intravenous anti‑ biotic is given before skin incision.

Dr. Tolley wonders if all women should receive vaginal cleansing, regardless of delivery route. It is possible that such an approach would be effective and it deserves study. Given the lower rate of endometritis following vaginal delivery compared with CD, many more women having a vaginal delivery would need to be treated to prevent one case of endometritis. Dr. Ross mentions his experience with the benefit of outpatient vaginal cleansing in the 2 weeks prior to delivery. Many general surgeons are recommending that their patients shower with chlorhexidine the day before surgery in order to reduce the rate of postoperative infection. Short-term and long-term outpatient vaginal cleansing prior to delivery deserves additional study.

Dr. Herchelroath raises the possibility that vaginal cleansing will decrease the ability of the newborn to develop a normal microbiome because it may not be exposed to sufficient vaginal bacteria. This possibility certainly deserves additional study.

The questions and guidance of our readers were incredibly helpful and stimulating. Thank you for sharing your perspective.

References

“CELL-FREE DNA SCREENING FOR WOMEN AT LOW RISK FOR FETAL ANEUPLOIDY” MARY E. NORTON, MD (JANUARY 2016)

The price of cfDNA screening is dropping
I found Dr. Norton’s article on cell-free DNA (cfDNA) screening for women at low risk for fetal abnormalities to be enlightening and educational. The section addressing cost-effectiveness, however, was somewhat obsolete. The referenced study by Cuckle and colleagues,¹ which estimated the cost of cfDNA per case of Down syndrome in low-risk patients at $3.6 million, was published in 2013. With 4 major companies in the market, the cost/benefit ratio has been changing rapidly. At least one company has dropped the cost of the cfDNA test nearly 80% from 2015 to 2016, making the above reference irrelevant. Recently, Ariosa dropped the price of their Harmony cfDNA test to just $119 in our area, regardless of a patient’s insurance or poverty level. This is significantly less than the cost of performing an early screen and is being welcomed by my patients even after substantial counseling on the test’s limitations in the low-risk population. Natera, another laboratory with a similar test, offers a low-cost option. However, patients must provide proof that their income is below a specified level.

Guidelines from the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) likely will have a hard time keeping up with the cost-effectiveness of noninvasive prenatal testing, as the price continues to be dynamic.
Samuel Wolf, DO
Panama City, Florida

Reference

“DOES THE DISCONTINUATION OF MENOPAUSAL HORMONE THERAPY AFFECT A WOMAN’S CARDIOVASCULAR RISK?”
ANDREW M. KAUNITZ, MD; JOANN E. MANSON, MD, DRPH; AND CYNTHIA A. STUENKEL, MD(EXAMINING THE EVIDENCE; DECEMBER 2015)

Disagrees with conclusion
In their expert commentary, Drs. Kaunitz, Manson, and Stuenkel state:

They support this claim by citing Heiss 2008.¹ In fact, however, the Women’s Health Initiative (WHI) data show opposite to their statement: In the WHI, all-cause mortality was increased among the women who were assigned to estrogen-progestin therapy (EPT) relative to those who were assigned to placebo within the 3 years of EPT cessation (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.95–1.39). More importantly, mortality was significantly increased among women who were originally assigned to EPT relative to those who were assigned to placebo and were at least 80% adherent with intervention (HR, 1.53; 95% CI, 1.04–2.24). Thus, the statement by Drs. Kaunitz, Manson, and Stuenkel is incorrect.

In addition to the WHI studies, data are available from at least 2 other randomized controlled trials addressing the issue of HT withdrawal. In the Heart and Estrogen/progestin Replacement Study (HERS) II,² the unblinded 2.7-year follow-up to the HERS trial, women originally assigned to EPT had a 3.3-fold higher rate of ventricular arrhythmia requiring resuscitation than women assigned to placebo (HR, 3.30; 95% CI, 1.08–10.10). During the first 6 months of posttrial follow-up of the Women’s Estrogen for Stroke Trial (WEST),³ there were 3 fatal strokes and 18 nonfatal strokes among the women originally randomized to estradiol therapy; there were 9 strokes (1 fatal and 8 nonfatal) among the women originally assigned to placebo (HR, 2.3; 95% CI, 1.1–5.0; P = .03).

In our study we detected that women who stopped HT, compared with women who continued HT, had a 2.3-fold (95% CI, 2.12–2.50) greater risk of cardiac death within the first post-HT year and a 1.3-fold (95% CI, 1.21–1.31) greater risk of cardiac death more than 1 year after stopping HT.⁴ In addition, women who stopped HT, compared with women who continuedHT, had a 2.5-fold (95% CI, 2.28–2.77) greater risk of dying from stroke within the first post-HT year and a 1.3-fold (95% CI, 1.19–1.31) greater risk of dying from stroke more than 1 year after stopping HT. We believe that these data substantially further our understanding of the posttrial data from WHI, as well as HERS and WEST. Thus, cumulative data support that HT withdrawal potentially has detrimental implications for women. In total, the data are highly informative when counseling women regarding use or discontinuation of HT.
Tomi Mikkola, MD
Helsinki, Finland

References

Drs. Kaunitz, Manson, and Stuenkel respond
We thank Dr. Mikkola for his response to our commentary, but we do not agree with his interpretation of the WHI reports or our conclusions. As we originally stated, the WHI trial of estrogen-only therapy (ET) and EPT provides an opportunity to observe outcomes in the largest randomized controlled trial of HT in healthy postmenopausal women. Our commentary was based on the most recent, 13-year follow-up of the WHI trials,¹ and we are confident in the accuracy of our presentation of the results.

As the debate apparently focuses on the safety of stopping HT, we wish to reiterate, for those who may not be familiar with the data, that, in the ET trial, all-cause mortality declined (although not significantly) after stopping ET, as summarized here:

 Similarly, in the EPT trial, as the following findings indicate, stopping HT did not increase all-cause mortality:

Again, these findings from the largest randomized trial of HT in healthy postmenopausal women are adequate for us to conclude that stopping HT does not elevate risk of mortality. Among all women participating in the WHI HT trials, HRs for coronary heart disease, pulmonary embolism, stroke, and cardiovascular disease mortality likewise were lower (better) after stopping treatment than during the intervention phase. The results for these outcomes in younger women followed similar patterns but, due to smaller numbers of events, could not be tested formally for differences in time trends.

Moreover, the data Dr. Mikkola cites from analyses conducted 3 years postcessation² reflected a borderline increased risk of cancer mortality that emerged in the EPT trial after stopping treatment. This clearly was related to the prolonged effects of EPT on breast cancer and other cancers, given the known latency period for cancer, and was not observed in the ET trial postcessation. The risk elevation in the EPT trial became attenuated with longer follow-up and, as of 13 years, the HRs for cancer mortality were 1.07 (0.93–1.23) in the EPT trial and 0.95 (0.81–1.13) in the ET trial.

It is interesting that Dr. Mikkola now inculcates his interpretation of his findings³ with those from secondary prevention trials such as the Heart and Estrogen/progestin Replacement Study and the Women’s Estrogen for Stroke Trial, neither of which was included as corroborative evidence in the discussion section of his originally published manuscript, and neither of which is considered applicable to healthy postmenopausal women taking HT for treatment of menopausal symptoms. Based on these findings, we do not recommend that clinicians counsel women that stopping HT increases their risk of cardiovascular or overall mortality. Thank you for the opportunity to clarify the evidence and our position.

References

“SHOULD YOU ADOPT THE PRACTICE OF VAGINAL CLEANSING WITH POVIDONE-IODINE PRIOR TO CESAREAN DELIVERY?”
ROBERT L. BARBIERI, MD (EDITORIAL; JANUARY 2016)
In his January 2016 Editorial, Editor in Chief Robert L. Barbieri, MD, presented evidence supporting the practice of vaginal cleansing with povidone-iodine prior to cesarean delivery (CD) to prevent postoperative endometritis. He then asked readers if they would consider adopting such a practice. More than 250 readers weighed in through the Quick Poll at obgmanagement.com, and many readers sent in letters with follow-up questions and comments on controlling bacterial contamination, vaginal seeding, etc. Here are some of the letters, along with Dr. Barbieri’s response and the Quick Poll results.

A contradiction in definitions?
There seems to be a contradiction in definitions. The second sentence of the article defines endometritis as the presence of fever plus low abdominal tenderness. However, the studies presented state that vaginal cleansing pre-CD decreased endometritis but did not decrease postpartum fever. Is this not a discrepancy?
Nancy Kerr, MD, MPH
Albuquerque, New Mexico

A question about povidone-iodine
Have any studies been done on newborn iodine levels after vaginal cleansing with povidone-iodine prior to CD?
G. Millard Simmons Jr, MD
Hilton Head, Bluffton, South Carolina

Additional tips for controlling bacterial contamination
Dr. Barbieri’s editorial on vaginal cleansing prior to CD is eye opening. I have a few additional suggestions to control bacterial contamination.

First, I examine my patients in labor as few times as necessary, and I ask the nurses (RNs) not to place their fingers in the patient’s vagina while she is pushing. I remove the Foley catheter when I feel progress (descent of fetal head) is being achieved. In addition, physicians as well as RNs should consider changing their scrubs between deliveries, as I believe that bacterial contamination is splattered all over the place, especially into the birth canal. These methods have worked for me in my over-20 years of practice.

I also firmly remind the RN circulator to perform a generous vaginal cleanse with povidone-iodine, in addition to the usual intravenous prophylaxis, before hysterectomy.
Luis Leyva Jr, MD
Miami, Florida

Mixed feelings
My first reaction to this Editorial was: Is this a solution in search of a problem? That is to say, how much of a clinical problem is endometritis after CD? Are we really treating the proposed problem, and does treatment affect long-term outcomes?

Upon reflection, I have concluded that vaginal cleansing pre-CD does intuitively make sense. What sways me in this direction is that the practice is simple, easy, and inexpensive. Since we typically have the patient positioned for Foley catheter insertion, performing vaginal cleansing as we put in the Foley would be easy. If vaginal cleansing were to be done, I definitely would be in favor of doing such practice liberally—for all CDs to make vaginal cleansing part of the “routine.”

Keep in mind that we are still chasing a problem of little clinical significance.

The biggest accomplishment has been to get everyone to give antibiotics preoperatively rather than after cutting the umbilical cord. We knew that this was best practice as early as the late 1980s/early 1990s, and I have been fighting this battle ever since. Believe it or not, there are still a few holdouts.
George H. Davis, DO
Johnson City, Tennessee

Would vaginal cleansing benefit all women in labor?
Vaginal cleansing before CD reminds me of my residency days when all women having hysterectomies were admitted early and given povidone-iodine (Betadine) douches the evening before surgery (unless an iodine allergy was present).

While reading your Editorial, I had several thoughts and questions. 1) Since vaginal cleansing seems to benefit CD patients, might it not benefit all laboring patients? 2) Is the timing of vaginal cleansing critical? 3) Should we do vaginal cleansing on all laboring patients if timing is not critical?

I plan to bring up the topic of vaginal cleansing for CD with my colleagues at our next department meeting, since it seems like such a simple, logical, inexpensive, and beneficial thing to do.
Douglas G. Tolley, MD
Yuba City, California

An early study on using povidone-iodine gel before CD
When I was a chief resident at Kings County Hospital in 1973, we had a very high rate of post-CD endometritis. I conducted a small study on the use of povidone-iodine gel in the last month of pregnancy. Before commencing, we confirmed that the gel did not interfere with diagnosing ruptured membranes.

Obstetric service patients were randomly divided into “A” and “B” groups. The A patients were asked to use povidone-iodine gel at night for the last 2 weeks before their estimated due date. When admitted in labor, they were asked to confirm its use. When a resident diagnosed post-CD endometritis, we kept track of which group the patient was in and whether or not that patient had used povidone-iodine. Approximately 100 infected patients were evaluated from each group.

As it turned out, there were about 3 times the number of infections among the patients who did not use povidone-iodine than among those who said they used it. It did not seem to matter how many times povidone-iodine was used. The “As” who did not use povidone-iodine had results similar to the “Bs.”

It was many years ago, and the study design was crude. However, it does seem to support the suggestion for vaginal cleansing.
Steve Ross, MD
Port Jefferson, New York

Two different ideas about the vaginal biome
This Editorial is timely in that Dr. Dominguez-Bello and colleagues recently published an article in Nature Medicine titled, “Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer.”¹ Dr. Dominguez-Bello is one of the founders of the idea of “vaginal seeding,” or using the natural biome of the vagina on a newborn immediately after CD by swabbing the baby with the bacteria from the vagina.

I find it interesting that there are two very different ideas about the biome at this time. Vaginal seeding is a new trend that a few patients have asked about during prenatal care. The jury is still out on seeding, but a larger study is currently underway at New York University. Of course, infection is one of the risks of seeding. I appreciate hearing both sides of the issue.
Deborah Herchelroath, DO
Harrisburg, Pennsylvania

Reference

Dr. Barbieri responds
I would like to thank our readers for taking the time from their busy schedules to write about their clinical experiences and current practices for reducing infectious complications following CD.

Dr. Kerr raises the important issue of the apparent contradictory finding of the beneficial impact of vaginal cleansing on endometritis without a beneficial effect on the overall rate of fever. In the trial reported by Starr,¹ fever was defined as a temperature above 38˚C at any time after CD and endometritis was defined as a temperature above 38.4˚C PLUS uterine tenderness occurring more than 24 hours after CD. Given these 2 definitions one can understand the differential effect of vaginal cleansing on fever versus endometritis.

Dr. Simmons raises the intriguing question of the impact of an iodine-containing surgical preparation on newborn thyroid function. There are few studies addressing this issue. One study reports a transient increase in thyroid-stimulating hormone (TSH) levels in a small percentage of newborns whose mothers received an iodine preparation.² Another study reports no effect of an iodine surgical preparation on newborn thyroid function indices.³

I agree with the guidance of Drs. Leyva and Davis that we can help prevent postcesarean endometritis by minimizing the number of cervical examinations, changing scrubs between deliveries, and by ensuring that an intravenous anti‑ biotic is given before skin incision.

Dr. Tolley wonders if all women should receive vaginal cleansing, regardless of delivery route. It is possible that such an approach would be effective and it deserves study. Given the lower rate of endometritis following vaginal delivery compared with CD, many more women having a vaginal delivery would need to be treated to prevent one case of endometritis. Dr. Ross mentions his experience with the benefit of outpatient vaginal cleansing in the 2 weeks prior to delivery. Many general surgeons are recommending that their patients shower with chlorhexidine the day before surgery in order to reduce the rate of postoperative infection. Short-term and long-term outpatient vaginal cleansing prior to delivery deserves additional study.

Dr. Herchelroath raises the possibility that vaginal cleansing will decrease the ability of the newborn to develop a normal microbiome because it may not be exposed to sufficient vaginal bacteria. This possibility certainly deserves additional study.

The questions and guidance of our readers were incredibly helpful and stimulating. Thank you for sharing your perspective.

References

“CELL-FREE DNA SCREENING FOR WOMEN AT LOW RISK FOR FETAL ANEUPLOIDY” MARY E. NORTON, MD (JANUARY 2016)

The price of cfDNA screening is dropping
I found Dr. Norton’s article on cell-free DNA (cfDNA) screening for women at low risk for fetal abnormalities to be enlightening and educational. The section addressing cost-effectiveness, however, was somewhat obsolete. The referenced study by Cuckle and colleagues,¹ which estimated the cost of cfDNA per case of Down syndrome in low-risk patients at $3.6 million, was published in 2013. With 4 major companies in the market, the cost/benefit ratio has been changing rapidly. At least one company has dropped the cost of the cfDNA test nearly 80% from 2015 to 2016, making the above reference irrelevant. Recently, Ariosa dropped the price of their Harmony cfDNA test to just $119 in our area, regardless of a patient’s insurance or poverty level. This is significantly less than the cost of performing an early screen and is being welcomed by my patients even after substantial counseling on the test’s limitations in the low-risk population. Natera, another laboratory with a similar test, offers a low-cost option. However, patients must provide proof that their income is below a specified level.

Guidelines from the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) likely will have a hard time keeping up with the cost-effectiveness of noninvasive prenatal testing, as the price continues to be dynamic.
Samuel Wolf, DO
Panama City, Florida

Reference

“DOES THE DISCONTINUATION OF MENOPAUSAL HORMONE THERAPY AFFECT A WOMAN’S CARDIOVASCULAR RISK?”
ANDREW M. KAUNITZ, MD; JOANN E. MANSON, MD, DRPH; AND CYNTHIA A. STUENKEL, MD(EXAMINING THE EVIDENCE; DECEMBER 2015)

Disagrees with conclusion
In their expert commentary, Drs. Kaunitz, Manson, and Stuenkel state:

They support this claim by citing Heiss 2008.¹ In fact, however, the Women’s Health Initiative (WHI) data show opposite to their statement: In the WHI, all-cause mortality was increased among the women who were assigned to estrogen-progestin therapy (EPT) relative to those who were assigned to placebo within the 3 years of EPT cessation (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.95–1.39). More importantly, mortality was significantly increased among women who were originally assigned to EPT relative to those who were assigned to placebo and were at least 80% adherent with intervention (HR, 1.53; 95% CI, 1.04–2.24). Thus, the statement by Drs. Kaunitz, Manson, and Stuenkel is incorrect.

In addition to the WHI studies, data are available from at least 2 other randomized controlled trials addressing the issue of HT withdrawal. In the Heart and Estrogen/progestin Replacement Study (HERS) II,² the unblinded 2.7-year follow-up to the HERS trial, women originally assigned to EPT had a 3.3-fold higher rate of ventricular arrhythmia requiring resuscitation than women assigned to placebo (HR, 3.30; 95% CI, 1.08–10.10). During the first 6 months of posttrial follow-up of the Women’s Estrogen for Stroke Trial (WEST),³ there were 3 fatal strokes and 18 nonfatal strokes among the women originally randomized to estradiol therapy; there were 9 strokes (1 fatal and 8 nonfatal) among the women originally assigned to placebo (HR, 2.3; 95% CI, 1.1–5.0; P = .03).

In our study we detected that women who stopped HT, compared with women who continued HT, had a 2.3-fold (95% CI, 2.12–2.50) greater risk of cardiac death within the first post-HT year and a 1.3-fold (95% CI, 1.21–1.31) greater risk of cardiac death more than 1 year after stopping HT.⁴ In addition, women who stopped HT, compared with women who continuedHT, had a 2.5-fold (95% CI, 2.28–2.77) greater risk of dying from stroke within the first post-HT year and a 1.3-fold (95% CI, 1.19–1.31) greater risk of dying from stroke more than 1 year after stopping HT. We believe that these data substantially further our understanding of the posttrial data from WHI, as well as HERS and WEST. Thus, cumulative data support that HT withdrawal potentially has detrimental implications for women. In total, the data are highly informative when counseling women regarding use or discontinuation of HT.
Tomi Mikkola, MD
Helsinki, Finland

References

Drs. Kaunitz, Manson, and Stuenkel respond
We thank Dr. Mikkola for his response to our commentary, but we do not agree with his interpretation of the WHI reports or our conclusions. As we originally stated, the WHI trial of estrogen-only therapy (ET) and EPT provides an opportunity to observe outcomes in the largest randomized controlled trial of HT in healthy postmenopausal women. Our commentary was based on the most recent, 13-year follow-up of the WHI trials,¹ and we are confident in the accuracy of our presentation of the results.

As the debate apparently focuses on the safety of stopping HT, we wish to reiterate, for those who may not be familiar with the data, that, in the ET trial, all-cause mortality declined (although not significantly) after stopping ET, as summarized here:

 Similarly, in the EPT trial, as the following findings indicate, stopping HT did not increase all-cause mortality:

Again, these findings from the largest randomized trial of HT in healthy postmenopausal women are adequate for us to conclude that stopping HT does not elevate risk of mortality. Among all women participating in the WHI HT trials, HRs for coronary heart disease, pulmonary embolism, stroke, and cardiovascular disease mortality likewise were lower (better) after stopping treatment than during the intervention phase. The results for these outcomes in younger women followed similar patterns but, due to smaller numbers of events, could not be tested formally for differences in time trends.

Moreover, the data Dr. Mikkola cites from analyses conducted 3 years postcessation² reflected a borderline increased risk of cancer mortality that emerged in the EPT trial after stopping treatment. This clearly was related to the prolonged effects of EPT on breast cancer and other cancers, given the known latency period for cancer, and was not observed in the ET trial postcessation. The risk elevation in the EPT trial became attenuated with longer follow-up and, as of 13 years, the HRs for cancer mortality were 1.07 (0.93–1.23) in the EPT trial and 0.95 (0.81–1.13) in the ET trial.

It is interesting that Dr. Mikkola now inculcates his interpretation of his findings³ with those from secondary prevention trials such as the Heart and Estrogen/progestin Replacement Study and the Women’s Estrogen for Stroke Trial, neither of which was included as corroborative evidence in the discussion section of his originally published manuscript, and neither of which is considered applicable to healthy postmenopausal women taking HT for treatment of menopausal symptoms. Based on these findings, we do not recommend that clinicians counsel women that stopping HT increases their risk of cardiovascular or overall mortality. Thank you for the opportunity to clarify the evidence and our position.

References

“SHOULD YOU ADOPT THE PRACTICE OF VAGINAL CLEANSING WITH POVIDONE-IODINE PRIOR TO CESAREAN DELIVERY?”
ROBERT L. BARBIERI, MD (EDITORIAL; JANUARY 2016)
In his January 2016 Editorial, Editor in Chief Robert L. Barbieri, MD, presented evidence supporting the practice of vaginal cleansing with povidone-iodine prior to cesarean delivery (CD) to prevent postoperative endometritis. He then asked readers if they would consider adopting such a practice. More than 250 readers weighed in through the Quick Poll at obgmanagement.com, and many readers sent in letters with follow-up questions and comments on controlling bacterial contamination, vaginal seeding, etc. Here are some of the letters, along with Dr. Barbieri’s response and the Quick Poll results.

A contradiction in definitions?
There seems to be a contradiction in definitions. The second sentence of the article defines endometritis as the presence of fever plus low abdominal tenderness. However, the studies presented state that vaginal cleansing pre-CD decreased endometritis but did not decrease postpartum fever. Is this not a discrepancy?
Nancy Kerr, MD, MPH
Albuquerque, New Mexico

A question about povidone-iodine
Have any studies been done on newborn iodine levels after vaginal cleansing with povidone-iodine prior to CD?
G. Millard Simmons Jr, MD
Hilton Head, Bluffton, South Carolina

Additional tips for controlling bacterial contamination
Dr. Barbieri’s editorial on vaginal cleansing prior to CD is eye opening. I have a few additional suggestions to control bacterial contamination.

First, I examine my patients in labor as few times as necessary, and I ask the nurses (RNs) not to place their fingers in the patient’s vagina while she is pushing. I remove the Foley catheter when I feel progress (descent of fetal head) is being achieved. In addition, physicians as well as RNs should consider changing their scrubs between deliveries, as I believe that bacterial contamination is splattered all over the place, especially into the birth canal. These methods have worked for me in my over-20 years of practice.

I also firmly remind the RN circulator to perform a generous vaginal cleanse with povidone-iodine, in addition to the usual intravenous prophylaxis, before hysterectomy.
Luis Leyva Jr, MD
Miami, Florida

Mixed feelings
My first reaction to this Editorial was: Is this a solution in search of a problem? That is to say, how much of a clinical problem is endometritis after CD? Are we really treating the proposed problem, and does treatment affect long-term outcomes?

Upon reflection, I have concluded that vaginal cleansing pre-CD does intuitively make sense. What sways me in this direction is that the practice is simple, easy, and inexpensive. Since we typically have the patient positioned for Foley catheter insertion, performing vaginal cleansing as we put in the Foley would be easy. If vaginal cleansing were to be done, I definitely would be in favor of doing such practice liberally—for all CDs to make vaginal cleansing part of the “routine.”

Keep in mind that we are still chasing a problem of little clinical significance.

The biggest accomplishment has been to get everyone to give antibiotics preoperatively rather than after cutting the umbilical cord. We knew that this was best practice as early as the late 1980s/early 1990s, and I have been fighting this battle ever since. Believe it or not, there are still a few holdouts.
George H. Davis, DO
Johnson City, Tennessee

Would vaginal cleansing benefit all women in labor?
Vaginal cleansing before CD reminds me of my residency days when all women having hysterectomies were admitted early and given povidone-iodine (Betadine) douches the evening before surgery (unless an iodine allergy was present).

While reading your Editorial, I had several thoughts and questions. 1) Since vaginal cleansing seems to benefit CD patients, might it not benefit all laboring patients? 2) Is the timing of vaginal cleansing critical? 3) Should we do vaginal cleansing on all laboring patients if timing is not critical?

I plan to bring up the topic of vaginal cleansing for CD with my colleagues at our next department meeting, since it seems like such a simple, logical, inexpensive, and beneficial thing to do.
Douglas G. Tolley, MD
Yuba City, California

An early study on using povidone-iodine gel before CD
When I was a chief resident at Kings County Hospital in 1973, we had a very high rate of post-CD endometritis. I conducted a small study on the use of povidone-iodine gel in the last month of pregnancy. Before commencing, we confirmed that the gel did not interfere with diagnosing ruptured membranes.

Obstetric service patients were randomly divided into “A” and “B” groups. The A patients were asked to use povidone-iodine gel at night for the last 2 weeks before their estimated due date. When admitted in labor, they were asked to confirm its use. When a resident diagnosed post-CD endometritis, we kept track of which group the patient was in and whether or not that patient had used povidone-iodine. Approximately 100 infected patients were evaluated from each group.

As it turned out, there were about 3 times the number of infections among the patients who did not use povidone-iodine than among those who said they used it. It did not seem to matter how many times povidone-iodine was used. The “As” who did not use povidone-iodine had results similar to the “Bs.”

It was many years ago, and the study design was crude. However, it does seem to support the suggestion for vaginal cleansing.
Steve Ross, MD
Port Jefferson, New York

Two different ideas about the vaginal biome
This Editorial is timely in that Dr. Dominguez-Bello and colleagues recently published an article in Nature Medicine titled, “Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer.”¹ Dr. Dominguez-Bello is one of the founders of the idea of “vaginal seeding,” or using the natural biome of the vagina on a newborn immediately after CD by swabbing the baby with the bacteria from the vagina.

I find it interesting that there are two very different ideas about the biome at this time. Vaginal seeding is a new trend that a few patients have asked about during prenatal care. The jury is still out on seeding, but a larger study is currently underway at New York University. Of course, infection is one of the risks of seeding. I appreciate hearing both sides of the issue.
Deborah Herchelroath, DO
Harrisburg, Pennsylvania

Reference

Dr. Barbieri responds
I would like to thank our readers for taking the time from their busy schedules to write about their clinical experiences and current practices for reducing infectious complications following CD.

Dr. Kerr raises the important issue of the apparent contradictory finding of the beneficial impact of vaginal cleansing on endometritis without a beneficial effect on the overall rate of fever. In the trial reported by Starr,¹ fever was defined as a temperature above 38˚C at any time after CD and endometritis was defined as a temperature above 38.4˚C PLUS uterine tenderness occurring more than 24 hours after CD. Given these 2 definitions one can understand the differential effect of vaginal cleansing on fever versus endometritis.

Dr. Simmons raises the intriguing question of the impact of an iodine-containing surgical preparation on newborn thyroid function. There are few studies addressing this issue. One study reports a transient increase in thyroid-stimulating hormone (TSH) levels in a small percentage of newborns whose mothers received an iodine preparation.² Another study reports no effect of an iodine surgical preparation on newborn thyroid function indices.³

I agree with the guidance of Drs. Leyva and Davis that we can help prevent postcesarean endometritis by minimizing the number of cervical examinations, changing scrubs between deliveries, and by ensuring that an intravenous anti‑ biotic is given before skin incision.

Dr. Tolley wonders if all women should receive vaginal cleansing, regardless of delivery route. It is possible that such an approach would be effective and it deserves study. Given the lower rate of endometritis following vaginal delivery compared with CD, many more women having a vaginal delivery would need to be treated to prevent one case of endometritis. Dr. Ross mentions his experience with the benefit of outpatient vaginal cleansing in the 2 weeks prior to delivery. Many general surgeons are recommending that their patients shower with chlorhexidine the day before surgery in order to reduce the rate of postoperative infection. Short-term and long-term outpatient vaginal cleansing prior to delivery deserves additional study.

Dr. Herchelroath raises the possibility that vaginal cleansing will decrease the ability of the newborn to develop a normal microbiome because it may not be exposed to sufficient vaginal bacteria. This possibility certainly deserves additional study.

The questions and guidance of our readers were incredibly helpful and stimulating. Thank you for sharing your perspective.

References

“CELL-FREE DNA SCREENING FOR WOMEN AT LOW RISK FOR FETAL ANEUPLOIDY” MARY E. NORTON, MD (JANUARY 2016)

The price of cfDNA screening is dropping
I found Dr. Norton’s article on cell-free DNA (cfDNA) screening for women at low risk for fetal abnormalities to be enlightening and educational. The section addressing cost-effectiveness, however, was somewhat obsolete. The referenced study by Cuckle and colleagues,¹ which estimated the cost of cfDNA per case of Down syndrome in low-risk patients at $3.6 million, was published in 2013. With 4 major companies in the market, the cost/benefit ratio has been changing rapidly. At least one company has dropped the cost of the cfDNA test nearly 80% from 2015 to 2016, making the above reference irrelevant. Recently, Ariosa dropped the price of their Harmony cfDNA test to just $119 in our area, regardless of a patient’s insurance or poverty level. This is significantly less than the cost of performing an early screen and is being welcomed by my patients even after substantial counseling on the test’s limitations in the low-risk population. Natera, another laboratory with a similar test, offers a low-cost option. However, patients must provide proof that their income is below a specified level.

Guidelines from the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) likely will have a hard time keeping up with the cost-effectiveness of noninvasive prenatal testing, as the price continues to be dynamic.
Samuel Wolf, DO
Panama City, Florida

Reference

“DOES THE DISCONTINUATION OF MENOPAUSAL HORMONE THERAPY AFFECT A WOMAN’S CARDIOVASCULAR RISK?”
ANDREW M. KAUNITZ, MD; JOANN E. MANSON, MD, DRPH; AND CYNTHIA A. STUENKEL, MD(EXAMINING THE EVIDENCE; DECEMBER 2015)

Disagrees with conclusion
In their expert commentary, Drs. Kaunitz, Manson, and Stuenkel state:

They support this claim by citing Heiss 2008.¹ In fact, however, the Women’s Health Initiative (WHI) data show opposite to their statement: In the WHI, all-cause mortality was increased among the women who were assigned to estrogen-progestin therapy (EPT) relative to those who were assigned to placebo within the 3 years of EPT cessation (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.95–1.39). More importantly, mortality was significantly increased among women who were originally assigned to EPT relative to those who were assigned to placebo and were at least 80% adherent with intervention (HR, 1.53; 95% CI, 1.04–2.24). Thus, the statement by Drs. Kaunitz, Manson, and Stuenkel is incorrect.

In addition to the WHI studies, data are available from at least 2 other randomized controlled trials addressing the issue of HT withdrawal. In the Heart and Estrogen/progestin Replacement Study (HERS) II,² the unblinded 2.7-year follow-up to the HERS trial, women originally assigned to EPT had a 3.3-fold higher rate of ventricular arrhythmia requiring resuscitation than women assigned to placebo (HR, 3.30; 95% CI, 1.08–10.10). During the first 6 months of posttrial follow-up of the Women’s Estrogen for Stroke Trial (WEST),³ there were 3 fatal strokes and 18 nonfatal strokes among the women originally randomized to estradiol therapy; there were 9 strokes (1 fatal and 8 nonfatal) among the women originally assigned to placebo (HR, 2.3; 95% CI, 1.1–5.0; P = .03).

In our study we detected that women who stopped HT, compared with women who continued HT, had a 2.3-fold (95% CI, 2.12–2.50) greater risk of cardiac death within the first post-HT year and a 1.3-fold (95% CI, 1.21–1.31) greater risk of cardiac death more than 1 year after stopping HT.⁴ In addition, women who stopped HT, compared with women who continuedHT, had a 2.5-fold (95% CI, 2.28–2.77) greater risk of dying from stroke within the first post-HT year and a 1.3-fold (95% CI, 1.19–1.31) greater risk of dying from stroke more than 1 year after stopping HT. We believe that these data substantially further our understanding of the posttrial data from WHI, as well as HERS and WEST. Thus, cumulative data support that HT withdrawal potentially has detrimental implications for women. In total, the data are highly informative when counseling women regarding use or discontinuation of HT.
Tomi Mikkola, MD
Helsinki, Finland

References

Drs. Kaunitz, Manson, and Stuenkel respond
We thank Dr. Mikkola for his response to our commentary, but we do not agree with his interpretation of the WHI reports or our conclusions. As we originally stated, the WHI trial of estrogen-only therapy (ET) and EPT provides an opportunity to observe outcomes in the largest randomized controlled trial of HT in healthy postmenopausal women. Our commentary was based on the most recent, 13-year follow-up of the WHI trials,¹ and we are confident in the accuracy of our presentation of the results.

As the debate apparently focuses on the safety of stopping HT, we wish to reiterate, for those who may not be familiar with the data, that, in the ET trial, all-cause mortality declined (although not significantly) after stopping ET, as summarized here:

 Similarly, in the EPT trial, as the following findings indicate, stopping HT did not increase all-cause mortality:

Again, these findings from the largest randomized trial of HT in healthy postmenopausal women are adequate for us to conclude that stopping HT does not elevate risk of mortality. Among all women participating in the WHI HT trials, HRs for coronary heart disease, pulmonary embolism, stroke, and cardiovascular disease mortality likewise were lower (better) after stopping treatment than during the intervention phase. The results for these outcomes in younger women followed similar patterns but, due to smaller numbers of events, could not be tested formally for differences in time trends.

Moreover, the data Dr. Mikkola cites from analyses conducted 3 years postcessation² reflected a borderline increased risk of cancer mortality that emerged in the EPT trial after stopping treatment. This clearly was related to the prolonged effects of EPT on breast cancer and other cancers, given the known latency period for cancer, and was not observed in the ET trial postcessation. The risk elevation in the EPT trial became attenuated with longer follow-up and, as of 13 years, the HRs for cancer mortality were 1.07 (0.93–1.23) in the EPT trial and 0.95 (0.81–1.13) in the ET trial.

It is interesting that Dr. Mikkola now inculcates his interpretation of his findings³ with those from secondary prevention trials such as the Heart and Estrogen/progestin Replacement Study and the Women’s Estrogen for Stroke Trial, neither of which was included as corroborative evidence in the discussion section of his originally published manuscript, and neither of which is considered applicable to healthy postmenopausal women taking HT for treatment of menopausal symptoms. Based on these findings, we do not recommend that clinicians counsel women that stopping HT increases their risk of cardiovascular or overall mortality. Thank you for the opportunity to clarify the evidence and our position.

References

NEW ORLEANS – A decline in levels of anti-müllerian hormone as women approach menopause – a phenomenon dubbed ovarian decline – appears associated with clinical disability and brain atrophy in women with multiple sclerosis, according to the findings of a study of more than 400 women with multiple sclerosis followed up for a decade.

This “accumulation of disability” may explain the often rapid transition from a benign disease course to secondary progressive multiple sclerosis (MS) in women as they approach menopause, Dr. Jennifer S. Graves reported at a meeting held by at the Americas Committee for Treatment and Research in Multiple Sclerosis.

Earlier in life, females often have a more benign initial course of MS than males. The mean age of onset of primary progressive MS and secondary progressive MS are both approximately 45 years. The mean age of menopause is 51 years. Ovarian aging involves up to a 10-year period of decline in ovarian function. After age 50, “women catch up in terms of disability with males” with MS, said Dr. Graves of the University of California, San Francisco. One explanation could be that ovarian aging contributes to the development of progressive disease.

The objective was to determine if ovarian decline as measured by the levels of anti-müllerian hormone (AMH) is associated with clinical disability or brain atrophy in women with MS. The cohort of 412 female patients with MS (mean age, 43 years) was from the UCSF EPIC (Expression, Proteomics, Imaging, Clinical) study, which has followed more than 500 people with MS since 2004 with the aim of identifying factors that drive the disease. Also included were 180 healthy controls with the exact same mean age. AMH levels were measured using an ultrasensitive enzyme-linked immunosorbent assay at baseline and at years 3, 5, 8, 9, and 10. Brain magnetic resonance imaging data also were acquired.

When the data were adjusted for chronologic age, women with MS and healthy controls displayed similar AMH levels (P = .97), implying a normal follicular reserve and rate of ovarian decline in those with MS. White matter volume was associated with AMH levels at baseline (P = .047). The association did not persist when adjusted for age as well as disease duration and body mass index (P = .24), while ovarian reserve was associated with normalized gray matter volume (P = .049) and MS functional composite z scores (P = .036) at baseline. Scrutiny of the follow-up period revealed that a twofold decrease in AMH was associated with a 1.85-mm³ decrease in gray matter volume (P = .060) in MS patients. Almost a third of the MS patients had undetectable levels of AMH, which was associated with a 0.60-point higher expanded disability status scale score (P =.039)

The results support the hypothesized association of ovarian decline with increased severity of MS. Furthermore, AMH may be a useful biomarker of MS progression, said Dr. Graves. “The advantage of this biomarker would be that it captures biological activity in women in their 40s, and so could let you know of imminent change.”

Validation of the findings needs to be done.

The study was funded by the National Institutes of Health, National MS Society, Race to Erase MS, Foundation for the Cedars-Sinai Medical Center, Biogen, and Genentech. Dr. Graves had no relevant financial disclosures.

NEW ORLEANS – A decline in levels of anti-müllerian hormone as women approach menopause – a phenomenon dubbed ovarian decline – appears associated with clinical disability and brain atrophy in women with multiple sclerosis, according to the findings of a study of more than 400 women with multiple sclerosis followed up for a decade.

This “accumulation of disability” may explain the often rapid transition from a benign disease course to secondary progressive multiple sclerosis (MS) in women as they approach menopause, Dr. Jennifer S. Graves reported at a meeting held by at the Americas Committee for Treatment and Research in Multiple Sclerosis.

Earlier in life, females often have a more benign initial course of MS than males. The mean age of onset of primary progressive MS and secondary progressive MS are both approximately 45 years. The mean age of menopause is 51 years. Ovarian aging involves up to a 10-year period of decline in ovarian function. After age 50, “women catch up in terms of disability with males” with MS, said Dr. Graves of the University of California, San Francisco. One explanation could be that ovarian aging contributes to the development of progressive disease.

The objective was to determine if ovarian decline as measured by the levels of anti-müllerian hormone (AMH) is associated with clinical disability or brain atrophy in women with MS. The cohort of 412 female patients with MS (mean age, 43 years) was from the UCSF EPIC (Expression, Proteomics, Imaging, Clinical) study, which has followed more than 500 people with MS since 2004 with the aim of identifying factors that drive the disease. Also included were 180 healthy controls with the exact same mean age. AMH levels were measured using an ultrasensitive enzyme-linked immunosorbent assay at baseline and at years 3, 5, 8, 9, and 10. Brain magnetic resonance imaging data also were acquired.

When the data were adjusted for chronologic age, women with MS and healthy controls displayed similar AMH levels (P = .97), implying a normal follicular reserve and rate of ovarian decline in those with MS. White matter volume was associated with AMH levels at baseline (P = .047). The association did not persist when adjusted for age as well as disease duration and body mass index (P = .24), while ovarian reserve was associated with normalized gray matter volume (P = .049) and MS functional composite z scores (P = .036) at baseline. Scrutiny of the follow-up period revealed that a twofold decrease in AMH was associated with a 1.85-mm³ decrease in gray matter volume (P = .060) in MS patients. Almost a third of the MS patients had undetectable levels of AMH, which was associated with a 0.60-point higher expanded disability status scale score (P =.039)

The results support the hypothesized association of ovarian decline with increased severity of MS. Furthermore, AMH may be a useful biomarker of MS progression, said Dr. Graves. “The advantage of this biomarker would be that it captures biological activity in women in their 40s, and so could let you know of imminent change.”

Validation of the findings needs to be done.

The study was funded by the National Institutes of Health, National MS Society, Race to Erase MS, Foundation for the Cedars-Sinai Medical Center, Biogen, and Genentech. Dr. Graves had no relevant financial disclosures.

NEW ORLEANS – A decline in levels of anti-müllerian hormone as women approach menopause – a phenomenon dubbed ovarian decline – appears associated with clinical disability and brain atrophy in women with multiple sclerosis, according to the findings of a study of more than 400 women with multiple sclerosis followed up for a decade.

This “accumulation of disability” may explain the often rapid transition from a benign disease course to secondary progressive multiple sclerosis (MS) in women as they approach menopause, Dr. Jennifer S. Graves reported at a meeting held by at the Americas Committee for Treatment and Research in Multiple Sclerosis.

Earlier in life, females often have a more benign initial course of MS than males. The mean age of onset of primary progressive MS and secondary progressive MS are both approximately 45 years. The mean age of menopause is 51 years. Ovarian aging involves up to a 10-year period of decline in ovarian function. After age 50, “women catch up in terms of disability with males” with MS, said Dr. Graves of the University of California, San Francisco. One explanation could be that ovarian aging contributes to the development of progressive disease.

The objective was to determine if ovarian decline as measured by the levels of anti-müllerian hormone (AMH) is associated with clinical disability or brain atrophy in women with MS. The cohort of 412 female patients with MS (mean age, 43 years) was from the UCSF EPIC (Expression, Proteomics, Imaging, Clinical) study, which has followed more than 500 people with MS since 2004 with the aim of identifying factors that drive the disease. Also included were 180 healthy controls with the exact same mean age. AMH levels were measured using an ultrasensitive enzyme-linked immunosorbent assay at baseline and at years 3, 5, 8, 9, and 10. Brain magnetic resonance imaging data also were acquired.

When the data were adjusted for chronologic age, women with MS and healthy controls displayed similar AMH levels (P = .97), implying a normal follicular reserve and rate of ovarian decline in those with MS. White matter volume was associated with AMH levels at baseline (P = .047). The association did not persist when adjusted for age as well as disease duration and body mass index (P = .24), while ovarian reserve was associated with normalized gray matter volume (P = .049) and MS functional composite z scores (P = .036) at baseline. Scrutiny of the follow-up period revealed that a twofold decrease in AMH was associated with a 1.85-mm³ decrease in gray matter volume (P = .060) in MS patients. Almost a third of the MS patients had undetectable levels of AMH, which was associated with a 0.60-point higher expanded disability status scale score (P =.039)

The results support the hypothesized association of ovarian decline with increased severity of MS. Furthermore, AMH may be a useful biomarker of MS progression, said Dr. Graves. “The advantage of this biomarker would be that it captures biological activity in women in their 40s, and so could let you know of imminent change.”

Validation of the findings needs to be done.

The study was funded by the National Institutes of Health, National MS Society, Race to Erase MS, Foundation for the Cedars-Sinai Medical Center, Biogen, and Genentech. Dr. Graves had no relevant financial disclosures.

Chinese medicine needle acupuncture was about as effective as a sham blunt needle treatment in the relief of hot flashes, although women reported a 40% drop in symptoms with both treatments.

The findings, published online Jan. 18 in Annals of Internal Medicine, add to a growing, but conflicting body of evidence about the benefits of acupuncture in the treatment of menopause symptoms.

©edwardolive/Thinkstock.com

Prior to this study, two trials had demonstrated the effectiveness of acupuncture, compared with self care. And a pilot study had shown the effectiveness of acupuncture, compared with a noninsertive sham control. However, a Cochrane review found that acupuncture was more effective, compared with no treatment, and it had a moderate effect size, but was not effective when compared with a sham control (Cochrane Database Syst Rev. 2013 Jul 30;7:CD007410. doi:10.1002/14651858.CD007410.pub2).

The current trial, conducted at multiple sites in Australia, sought to add to the evidence with an adequately powered trial involving a sham control. But Carolyn Ee and her associates at the University of Melbourne noted that their study did not control for the nonspecific effects of acupuncture, such as regular interaction with a therapist.

The researchers randomly assigned 327 women aged older than 40 years who were in late menopause transition or postmenopause and experiencing at least seven moderate daily hot flashes to receive either a standardized Chinese medicine acupuncture treatment or a noninsertive, blunt needle sham acupuncture treatment. Patients received 10 treatments over 8 weeks, and they were assessed at 4 weeks, at the end of treatment, and at 3 and 6 months after treatment (Ann Intern Med. 2016; Jan 18. doi:10.7326/M15-1380.).

Both groups had about a 40% improvement in their hot flashes at the end of treatment, compared with their mean baseline hot flash score. The improvement was sustained at 3 and 6 months after the trial. In the acupuncture group, the mean hot flash scores at the end of treatment were 15.36, compared with 15.04 in the sham group, which was not statistically different. The researchers also found no advantage for acupuncture in quality of life, anxiety, or depression.

“Unless further high-quality evidence emerges, we cannot recommend skin-penetrating acupuncture as an efficacious treatment of this indication; the effects, if any, of acupuncture on these symptoms seem to be unrelated to needling,” the researchers wrote.

Some of the researchers reported receiving grant, scholarship, or fellowship support from the National Health and Medical Research Council of Australia, which funded the study.

[email protected]

On Twitter @maryellenny

Chinese medicine needle acupuncture was about as effective as a sham blunt needle treatment in the relief of hot flashes, although women reported a 40% drop in symptoms with both treatments.

The findings, published online Jan. 18 in Annals of Internal Medicine, add to a growing, but conflicting body of evidence about the benefits of acupuncture in the treatment of menopause symptoms.

©edwardolive/Thinkstock.com

Prior to this study, two trials had demonstrated the effectiveness of acupuncture, compared with self care. And a pilot study had shown the effectiveness of acupuncture, compared with a noninsertive sham control. However, a Cochrane review found that acupuncture was more effective, compared with no treatment, and it had a moderate effect size, but was not effective when compared with a sham control (Cochrane Database Syst Rev. 2013 Jul 30;7:CD007410. doi:10.1002/14651858.CD007410.pub2).

The current trial, conducted at multiple sites in Australia, sought to add to the evidence with an adequately powered trial involving a sham control. But Carolyn Ee and her associates at the University of Melbourne noted that their study did not control for the nonspecific effects of acupuncture, such as regular interaction with a therapist.

The researchers randomly assigned 327 women aged older than 40 years who were in late menopause transition or postmenopause and experiencing at least seven moderate daily hot flashes to receive either a standardized Chinese medicine acupuncture treatment or a noninsertive, blunt needle sham acupuncture treatment. Patients received 10 treatments over 8 weeks, and they were assessed at 4 weeks, at the end of treatment, and at 3 and 6 months after treatment (Ann Intern Med. 2016; Jan 18. doi:10.7326/M15-1380.).

Both groups had about a 40% improvement in their hot flashes at the end of treatment, compared with their mean baseline hot flash score. The improvement was sustained at 3 and 6 months after the trial. In the acupuncture group, the mean hot flash scores at the end of treatment were 15.36, compared with 15.04 in the sham group, which was not statistically different. The researchers also found no advantage for acupuncture in quality of life, anxiety, or depression.

“Unless further high-quality evidence emerges, we cannot recommend skin-penetrating acupuncture as an efficacious treatment of this indication; the effects, if any, of acupuncture on these symptoms seem to be unrelated to needling,” the researchers wrote.

Some of the researchers reported receiving grant, scholarship, or fellowship support from the National Health and Medical Research Council of Australia, which funded the study.

[email protected]

On Twitter @maryellenny

Chinese medicine needle acupuncture was about as effective as a sham blunt needle treatment in the relief of hot flashes, although women reported a 40% drop in symptoms with both treatments.

The findings, published online Jan. 18 in Annals of Internal Medicine, add to a growing, but conflicting body of evidence about the benefits of acupuncture in the treatment of menopause symptoms.

©edwardolive/Thinkstock.com

Prior to this study, two trials had demonstrated the effectiveness of acupuncture, compared with self care. And a pilot study had shown the effectiveness of acupuncture, compared with a noninsertive sham control. However, a Cochrane review found that acupuncture was more effective, compared with no treatment, and it had a moderate effect size, but was not effective when compared with a sham control (Cochrane Database Syst Rev. 2013 Jul 30;7:CD007410. doi:10.1002/14651858.CD007410.pub2).

The current trial, conducted at multiple sites in Australia, sought to add to the evidence with an adequately powered trial involving a sham control. But Carolyn Ee and her associates at the University of Melbourne noted that their study did not control for the nonspecific effects of acupuncture, such as regular interaction with a therapist.

The researchers randomly assigned 327 women aged older than 40 years who were in late menopause transition or postmenopause and experiencing at least seven moderate daily hot flashes to receive either a standardized Chinese medicine acupuncture treatment or a noninsertive, blunt needle sham acupuncture treatment. Patients received 10 treatments over 8 weeks, and they were assessed at 4 weeks, at the end of treatment, and at 3 and 6 months after treatment (Ann Intern Med. 2016; Jan 18. doi:10.7326/M15-1380.).

Both groups had about a 40% improvement in their hot flashes at the end of treatment, compared with their mean baseline hot flash score. The improvement was sustained at 3 and 6 months after the trial. In the acupuncture group, the mean hot flash scores at the end of treatment were 15.36, compared with 15.04 in the sham group, which was not statistically different. The researchers also found no advantage for acupuncture in quality of life, anxiety, or depression.

“Unless further high-quality evidence emerges, we cannot recommend skin-penetrating acupuncture as an efficacious treatment of this indication; the effects, if any, of acupuncture on these symptoms seem to be unrelated to needling,” the researchers wrote.

Some of the researchers reported receiving grant, scholarship, or fellowship support from the National Health and Medical Research Council of Australia, which funded the study.

[email protected]

On Twitter @maryellenny

The longer a woman’s reproductive years last, the less she may be prone to postmenopausal depression, a large meta-analysis has determined.

The risk of depression declined by 2% for every 2 premenopausal years after age 40. Women who entered menopause after age 40 experienced a 50% decrease in the risk of depression, compared with women who experienced premature menopause, Dr. Marios K. Georgakis and colleagues reported Jan. 6 in JAMA Psychiatry (2016. doi:10.1001/jamapsychiatry.2015.2653).

Thinkstock/Thinkstock.com

The findings suggest that longer exposure to endogenous estrogens mediates the pathophysiology of late-life depression, wrote Dr. Georgakis of the National and Kapodistrian University of Athens and coauthors.

“If confirmed in prospective and culturally diverse studies … these findings could have a significant clinical effect by allowing for the identification of a group of women at higher risk for depression who may benefit from psychiatric monitoring or estrogen-based therapies.”

The meta-analysis comprised 14 studies that included 67,714 women. They controlled for numerous factors, including age, body mass index, obesity, smoking, and hormone therapy. However, only two controlled for past depression – one of the biggest risk factors for recurring depression.

In addition to the 2% decline per 2 premenopausal years after 40, a subanalysis of three studies examining severe depression found a 5% decreased risk for the same time measure. Another analysis of women with premature menopause found a doubling in the risk of depression for those who experienced menopause before age 40.

Estrogen is known to have neuroprotective and antidepressive properties, and the brain is richly endowed with estrogen receptors, the authors said. The exact pathway of protection against depression, however, remains unknown. Potentiation of neurotransmitters and moderation of atherosclerosis might play protective roles.

“Given the results of our study, it remains to be investigated whether women with menopause at younger ages could benefit by preventive use of hormone therapy against late-life depression, provided that adverse effects associated with long-term use are considered,” the authors said. “In this context, the development of estrogen receptor subtype–specific ligands could decrease the proportion of estrogen therapy adverse effects.”

Neither Dr. Georgakis nor any of the coauthors declared any financial conflicts.

[email protected]

The longer a woman’s reproductive years last, the less she may be prone to postmenopausal depression, a large meta-analysis has determined.

The risk of depression declined by 2% for every 2 premenopausal years after age 40. Women who entered menopause after age 40 experienced a 50% decrease in the risk of depression, compared with women who experienced premature menopause, Dr. Marios K. Georgakis and colleagues reported Jan. 6 in JAMA Psychiatry (2016. doi:10.1001/jamapsychiatry.2015.2653).

Thinkstock/Thinkstock.com

The findings suggest that longer exposure to endogenous estrogens mediates the pathophysiology of late-life depression, wrote Dr. Georgakis of the National and Kapodistrian University of Athens and coauthors.

“If confirmed in prospective and culturally diverse studies … these findings could have a significant clinical effect by allowing for the identification of a group of women at higher risk for depression who may benefit from psychiatric monitoring or estrogen-based therapies.”

The meta-analysis comprised 14 studies that included 67,714 women. They controlled for numerous factors, including age, body mass index, obesity, smoking, and hormone therapy. However, only two controlled for past depression – one of the biggest risk factors for recurring depression.

In addition to the 2% decline per 2 premenopausal years after 40, a subanalysis of three studies examining severe depression found a 5% decreased risk for the same time measure. Another analysis of women with premature menopause found a doubling in the risk of depression for those who experienced menopause before age 40.

Estrogen is known to have neuroprotective and antidepressive properties, and the brain is richly endowed with estrogen receptors, the authors said. The exact pathway of protection against depression, however, remains unknown. Potentiation of neurotransmitters and moderation of atherosclerosis might play protective roles.

“Given the results of our study, it remains to be investigated whether women with menopause at younger ages could benefit by preventive use of hormone therapy against late-life depression, provided that adverse effects associated with long-term use are considered,” the authors said. “In this context, the development of estrogen receptor subtype–specific ligands could decrease the proportion of estrogen therapy adverse effects.”

Neither Dr. Georgakis nor any of the coauthors declared any financial conflicts.

[email protected]

The longer a woman’s reproductive years last, the less she may be prone to postmenopausal depression, a large meta-analysis has determined.

The risk of depression declined by 2% for every 2 premenopausal years after age 40. Women who entered menopause after age 40 experienced a 50% decrease in the risk of depression, compared with women who experienced premature menopause, Dr. Marios K. Georgakis and colleagues reported Jan. 6 in JAMA Psychiatry (2016. doi:10.1001/jamapsychiatry.2015.2653).

Thinkstock/Thinkstock.com

The findings suggest that longer exposure to endogenous estrogens mediates the pathophysiology of late-life depression, wrote Dr. Georgakis of the National and Kapodistrian University of Athens and coauthors.

“If confirmed in prospective and culturally diverse studies … these findings could have a significant clinical effect by allowing for the identification of a group of women at higher risk for depression who may benefit from psychiatric monitoring or estrogen-based therapies.”

The meta-analysis comprised 14 studies that included 67,714 women. They controlled for numerous factors, including age, body mass index, obesity, smoking, and hormone therapy. However, only two controlled for past depression – one of the biggest risk factors for recurring depression.

In addition to the 2% decline per 2 premenopausal years after 40, a subanalysis of three studies examining severe depression found a 5% decreased risk for the same time measure. Another analysis of women with premature menopause found a doubling in the risk of depression for those who experienced menopause before age 40.

Estrogen is known to have neuroprotective and antidepressive properties, and the brain is richly endowed with estrogen receptors, the authors said. The exact pathway of protection against depression, however, remains unknown. Potentiation of neurotransmitters and moderation of atherosclerosis might play protective roles.

“Given the results of our study, it remains to be investigated whether women with menopause at younger ages could benefit by preventive use of hormone therapy against late-life depression, provided that adverse effects associated with long-term use are considered,” the authors said. “In this context, the development of estrogen receptor subtype–specific ligands could decrease the proportion of estrogen therapy adverse effects.”

Neither Dr. Georgakis nor any of the coauthors declared any financial conflicts.

[email protected]

SAN DIEGO – The use of hormone therapy was associated with a lower urine albumin-to-creatinine ratio and a decreased risk of albuminuria, results from a cross-sectional study suggest.

“This may be useful information for providers taking care of menopausal women who are considering the use of hormone therapy for vasomotor symptoms and are worried about the systemic effects of these medications,” lead study author Dr. Andrea G. Kattah said in an interview after the annual meeting of the American Society of Nephrology. “Though our data only show an association and not cause and effect, hormone therapy is associated with better kidney function in this study.”

Results from many animal studies suggest that estrogen can have beneficial effects on the kidneys, noted Dr. Kattah, who conducted the research with Dr. Vesna D. Garovic and colleagues in the division of hypertension and nephrology at the Mayo Clinic, Rochester, Minn.

“In addition, in human studies of chronic kidney disease, premenopausal women tend to have slower progression of kidney disease than men,” she said. “Studies on the effects of hormone therapy on kidney function in women have had variable results. We wanted to look at the association of hormone therapy and renal function in a large, multiethnic cohort with well-defined health conditions that may confound the relationship between hormone therapy and renal disease.”

Study participants included 2,217 women enrolled in the Family Blood Pressure Program, a multinetwork effort to study the genetics of hypertension. During a study visit between 2000 and 2004, the women completed questionnaires about medical history, menopausal status, and use of hormone therapy (HT) in the past month. Clinicians also took their blood pressure, measured their body mass index, and drew blood to determine levels of serum creatinine and urine albumin-to-creatinine ratio (UACR).

Of the 2,217 women, 673 were on HT and 1,544 were not, and their mean ages were 60 years and 63 years, respectively.

In unadjusted analysis, Dr. Kattah and her associates found that UACR was significantly lower in those on HT, compared with those who were not (3.5 mg/g creatinine vs. 5.2 mg/g creatinine, respectively, P less than .001), as was the number of women with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m² (7% vs. 10%, P = .003).

After adjusting for renal and cardiovascular risk factors including age, race, smoking, diabetes, hypertension, and family history of hypertension, the use of HT was still significantly associated with a lower UACR and decreased risk of microalbuminuria (odds ratio, 0.61). The association between HT and eGFR of less than 60 mL/min per 1.73 m² was no longer significant after adjustment, but there was a trend toward higher eGFR and fewer women with an eGFR of less than 60 mL/min per 1.73 m² among those on HT.

“Not surprisingly, the women taking hormone therapy were different than those who were not, and they generally had fewer health problems, such as diabetes and hyperlipidemia,” Dr. Kattah said. “However, after taking these differences into account in our models, we still found a significant decrease in the risk of having microalbuminuria in those on hormone therapy.”

Dr. Kattah acknowledged certain limitations of the study, including the fact that its design is “cross-sectional and cannot answer the question of whether or not hormone therapy can improve kidney function.

In addition, “we do not have data on how long women were taking hormone therapy, which other studies have suggested is an important factor.”

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – The use of hormone therapy was associated with a lower urine albumin-to-creatinine ratio and a decreased risk of albuminuria, results from a cross-sectional study suggest.

“This may be useful information for providers taking care of menopausal women who are considering the use of hormone therapy for vasomotor symptoms and are worried about the systemic effects of these medications,” lead study author Dr. Andrea G. Kattah said in an interview after the annual meeting of the American Society of Nephrology. “Though our data only show an association and not cause and effect, hormone therapy is associated with better kidney function in this study.”

Results from many animal studies suggest that estrogen can have beneficial effects on the kidneys, noted Dr. Kattah, who conducted the research with Dr. Vesna D. Garovic and colleagues in the division of hypertension and nephrology at the Mayo Clinic, Rochester, Minn.

“In addition, in human studies of chronic kidney disease, premenopausal women tend to have slower progression of kidney disease than men,” she said. “Studies on the effects of hormone therapy on kidney function in women have had variable results. We wanted to look at the association of hormone therapy and renal function in a large, multiethnic cohort with well-defined health conditions that may confound the relationship between hormone therapy and renal disease.”

Study participants included 2,217 women enrolled in the Family Blood Pressure Program, a multinetwork effort to study the genetics of hypertension. During a study visit between 2000 and 2004, the women completed questionnaires about medical history, menopausal status, and use of hormone therapy (HT) in the past month. Clinicians also took their blood pressure, measured their body mass index, and drew blood to determine levels of serum creatinine and urine albumin-to-creatinine ratio (UACR).

Of the 2,217 women, 673 were on HT and 1,544 were not, and their mean ages were 60 years and 63 years, respectively.

In unadjusted analysis, Dr. Kattah and her associates found that UACR was significantly lower in those on HT, compared with those who were not (3.5 mg/g creatinine vs. 5.2 mg/g creatinine, respectively, P less than .001), as was the number of women with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m² (7% vs. 10%, P = .003).

After adjusting for renal and cardiovascular risk factors including age, race, smoking, diabetes, hypertension, and family history of hypertension, the use of HT was still significantly associated with a lower UACR and decreased risk of microalbuminuria (odds ratio, 0.61). The association between HT and eGFR of less than 60 mL/min per 1.73 m² was no longer significant after adjustment, but there was a trend toward higher eGFR and fewer women with an eGFR of less than 60 mL/min per 1.73 m² among those on HT.

“Not surprisingly, the women taking hormone therapy were different than those who were not, and they generally had fewer health problems, such as diabetes and hyperlipidemia,” Dr. Kattah said. “However, after taking these differences into account in our models, we still found a significant decrease in the risk of having microalbuminuria in those on hormone therapy.”

Dr. Kattah acknowledged certain limitations of the study, including the fact that its design is “cross-sectional and cannot answer the question of whether or not hormone therapy can improve kidney function.

In addition, “we do not have data on how long women were taking hormone therapy, which other studies have suggested is an important factor.”

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – The use of hormone therapy was associated with a lower urine albumin-to-creatinine ratio and a decreased risk of albuminuria, results from a cross-sectional study suggest.

“This may be useful information for providers taking care of menopausal women who are considering the use of hormone therapy for vasomotor symptoms and are worried about the systemic effects of these medications,” lead study author Dr. Andrea G. Kattah said in an interview after the annual meeting of the American Society of Nephrology. “Though our data only show an association and not cause and effect, hormone therapy is associated with better kidney function in this study.”

Results from many animal studies suggest that estrogen can have beneficial effects on the kidneys, noted Dr. Kattah, who conducted the research with Dr. Vesna D. Garovic and colleagues in the division of hypertension and nephrology at the Mayo Clinic, Rochester, Minn.

“In addition, in human studies of chronic kidney disease, premenopausal women tend to have slower progression of kidney disease than men,” she said. “Studies on the effects of hormone therapy on kidney function in women have had variable results. We wanted to look at the association of hormone therapy and renal function in a large, multiethnic cohort with well-defined health conditions that may confound the relationship between hormone therapy and renal disease.”

Study participants included 2,217 women enrolled in the Family Blood Pressure Program, a multinetwork effort to study the genetics of hypertension. During a study visit between 2000 and 2004, the women completed questionnaires about medical history, menopausal status, and use of hormone therapy (HT) in the past month. Clinicians also took their blood pressure, measured their body mass index, and drew blood to determine levels of serum creatinine and urine albumin-to-creatinine ratio (UACR).

Of the 2,217 women, 673 were on HT and 1,544 were not, and their mean ages were 60 years and 63 years, respectively.

In unadjusted analysis, Dr. Kattah and her associates found that UACR was significantly lower in those on HT, compared with those who were not (3.5 mg/g creatinine vs. 5.2 mg/g creatinine, respectively, P less than .001), as was the number of women with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m² (7% vs. 10%, P = .003).

After adjusting for renal and cardiovascular risk factors including age, race, smoking, diabetes, hypertension, and family history of hypertension, the use of HT was still significantly associated with a lower UACR and decreased risk of microalbuminuria (odds ratio, 0.61). The association between HT and eGFR of less than 60 mL/min per 1.73 m² was no longer significant after adjustment, but there was a trend toward higher eGFR and fewer women with an eGFR of less than 60 mL/min per 1.73 m² among those on HT.

“Not surprisingly, the women taking hormone therapy were different than those who were not, and they generally had fewer health problems, such as diabetes and hyperlipidemia,” Dr. Kattah said. “However, after taking these differences into account in our models, we still found a significant decrease in the risk of having microalbuminuria in those on hormone therapy.”

Dr. Kattah acknowledged certain limitations of the study, including the fact that its design is “cross-sectional and cannot answer the question of whether or not hormone therapy can improve kidney function.

In addition, “we do not have data on how long women were taking hormone therapy, which other studies have suggested is an important factor.”

The researchers reported having no financial disclosures.

[email protected]

Due to advancements in surgical treatment, chemotherapy, and radiation therapy, gynecologic cancer survival rates are continuing to improve and quality of life is evolving into an even more significant focus in cancer care.

Roughly 30%-40% of all women with a gynecologic malignancy will experience climacteric symptoms and menopause prior to the anticipated time of natural menopause (J Clin Oncol. 2009 Mar 10;27[8]:1214-9). Cessation of ovarian estrogen and progesterone production can result in short-term as well as long-term sequelae, including vasomotor symptoms, vaginal dryness, osteoporosis, and mood disturbances. Iatrogenic menopause after cancer treatment can be more sudden and severe when compared with the natural course of physiologic menopause. As a result, determination of safe, effective modalities for treating these symptoms is of particular importance for survivor quality of life.

Both combination and estrogen-only hormone replacement therapy (HT) provide greater improvement in these specific symptoms and overall quality of life than placebo as demonstrated in several observational and randomized control trials (Cochrane Database Syst Rev. 2009 Apr 15;[2]:CD004143).

Endometrial cancer

Endometrial cancer is the most common gynecologic malignancy, with approximately 54,000 new cases anticipated in the United States in 2015. Twenty-five percent of these new cases will be in premenopausal women, and with an ever-increasing obesity rate, this number may continue to climb.

Women with early-stage Type 1 endometrial cancer who have vasomotor symptoms after surgery may be offered a short course of estrogen-based HT at the lowest effective dose following hysterectomy/bilateral salpingo-oophorectomy and staging procedure (J Clin Oncol. 2006 Feb 1;24[4]:587-92). For women with genitourinary symptoms, vaginal moisturizers and/or low-dose vaginal estrogen are reasonable options. Unfortunately, there are no data to guide the use of estrogen replacement therapy in women with Type 2 endometrial cancers (Gynecol Oncol. 2011 Aug;122[2]:447-54).

Ovarian cancer

There is minimal data implicating a hormonal causation to ovarian carcinogenesis. Most women with epithelial ovarian cancer do not express tumor estrogen or progesterone receptors. Treatment will result in abrupt, iatrogenic menopause, raising the question of whether it is safe to use HT in patients with epithelial ovarian cancer.

Multiple studies have failed to demonstrate a difference in 5-year survival rates in women with epithelial cancer using HT for 2 years or less (JAMA. 2009 Jul 15;302[3]:298-305, Eur J Gynaecol Oncol. 2000;21[2]:192-6, Cancer. 1999 Sep 15;86[6]:1013-8). As such, symptomatic patients could be offered a course of HT; however, caution should be exercised in women with estrogen/progesterone–expressing tumors or nonepithelial tumors. As with endometrial cancer patients, the lowest effective doses should be prescribed.

Cervical cancer

Most cervical squamous and adenocarcinomas are not hormone dependent. For women with early-stage squamous cell carcinoma, ovarian conservation may be possible or oophoropexy may be offered. However, for many patients, bilateral salpingo-oophorectomy at the time of hysterectomy is more common, and the local effect of radiation therapy can result in vaginal atrophy with subsequent dyspareunia or ovarian failure from radiation scatter. Even for patients who undergo oophoropexy, radiation scatter may still result in ovarian failure. In a few observational studies, there are no data to infer that cervical cancer is hormonally related or that survival rates are decreased.

Currently, HT use in cervical cancer survivors is considered safe. Of note, for women with more advanced-stage cervical cancer and who received chemoradiation for primary treatment, combination therapy with estrogen and progesterone may be more appropriate if the uterus remains in situ. However, for women who have undergone hysterectomy, combination therapy with progesterone may not be warranted and estrogen alone (orally or vaginally) is acceptable (Gynecol Oncol. 2011 Aug;122[2]:447-54)

Nonhormonal therapies

Women presenting with menopausal symptoms in whom estrogen therapy is contraindicated or not desired can also consider using nonhormonal therapies as an alternative. These include selective serotonin reuptake inhibitors (SSRIs) and alpha-2 adrenergic agonists, such as clonidine. Albeit not as effective as HT, these alternative therapies are reasonable options, particularly for management of vasomotor symptoms.

From a limited number of observational studies and a few randomized trials, short-term hormone replacement therapy does not present increased risk to survivors of gynecologic cancers. Additionally, patients have the added option of using nonhormonal therapies, which may provide some benefit. The decision to institute HT should occur after a thorough discussion of the potential to optimize symptom control and the theoretical risk of stimulating quiescent malignant disease.

Dr. Staley is a resident physician in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. They reported having no relevant financial disclosures.

Due to advancements in surgical treatment, chemotherapy, and radiation therapy, gynecologic cancer survival rates are continuing to improve and quality of life is evolving into an even more significant focus in cancer care.

Roughly 30%-40% of all women with a gynecologic malignancy will experience climacteric symptoms and menopause prior to the anticipated time of natural menopause (J Clin Oncol. 2009 Mar 10;27[8]:1214-9). Cessation of ovarian estrogen and progesterone production can result in short-term as well as long-term sequelae, including vasomotor symptoms, vaginal dryness, osteoporosis, and mood disturbances. Iatrogenic menopause after cancer treatment can be more sudden and severe when compared with the natural course of physiologic menopause. As a result, determination of safe, effective modalities for treating these symptoms is of particular importance for survivor quality of life.

Both combination and estrogen-only hormone replacement therapy (HT) provide greater improvement in these specific symptoms and overall quality of life than placebo as demonstrated in several observational and randomized control trials (Cochrane Database Syst Rev. 2009 Apr 15;[2]:CD004143).

Endometrial cancer

Endometrial cancer is the most common gynecologic malignancy, with approximately 54,000 new cases anticipated in the United States in 2015. Twenty-five percent of these new cases will be in premenopausal women, and with an ever-increasing obesity rate, this number may continue to climb.

Women with early-stage Type 1 endometrial cancer who have vasomotor symptoms after surgery may be offered a short course of estrogen-based HT at the lowest effective dose following hysterectomy/bilateral salpingo-oophorectomy and staging procedure (J Clin Oncol. 2006 Feb 1;24[4]:587-92). For women with genitourinary symptoms, vaginal moisturizers and/or low-dose vaginal estrogen are reasonable options. Unfortunately, there are no data to guide the use of estrogen replacement therapy in women with Type 2 endometrial cancers (Gynecol Oncol. 2011 Aug;122[2]:447-54).

Ovarian cancer

There is minimal data implicating a hormonal causation to ovarian carcinogenesis. Most women with epithelial ovarian cancer do not express tumor estrogen or progesterone receptors. Treatment will result in abrupt, iatrogenic menopause, raising the question of whether it is safe to use HT in patients with epithelial ovarian cancer.

Multiple studies have failed to demonstrate a difference in 5-year survival rates in women with epithelial cancer using HT for 2 years or less (JAMA. 2009 Jul 15;302[3]:298-305, Eur J Gynaecol Oncol. 2000;21[2]:192-6, Cancer. 1999 Sep 15;86[6]:1013-8). As such, symptomatic patients could be offered a course of HT; however, caution should be exercised in women with estrogen/progesterone–expressing tumors or nonepithelial tumors. As with endometrial cancer patients, the lowest effective doses should be prescribed.

Cervical cancer

Most cervical squamous and adenocarcinomas are not hormone dependent. For women with early-stage squamous cell carcinoma, ovarian conservation may be possible or oophoropexy may be offered. However, for many patients, bilateral salpingo-oophorectomy at the time of hysterectomy is more common, and the local effect of radiation therapy can result in vaginal atrophy with subsequent dyspareunia or ovarian failure from radiation scatter. Even for patients who undergo oophoropexy, radiation scatter may still result in ovarian failure. In a few observational studies, there are no data to infer that cervical cancer is hormonally related or that survival rates are decreased.

Currently, HT use in cervical cancer survivors is considered safe. Of note, for women with more advanced-stage cervical cancer and who received chemoradiation for primary treatment, combination therapy with estrogen and progesterone may be more appropriate if the uterus remains in situ. However, for women who have undergone hysterectomy, combination therapy with progesterone may not be warranted and estrogen alone (orally or vaginally) is acceptable (Gynecol Oncol. 2011 Aug;122[2]:447-54)

Nonhormonal therapies

Women presenting with menopausal symptoms in whom estrogen therapy is contraindicated or not desired can also consider using nonhormonal therapies as an alternative. These include selective serotonin reuptake inhibitors (SSRIs) and alpha-2 adrenergic agonists, such as clonidine. Albeit not as effective as HT, these alternative therapies are reasonable options, particularly for management of vasomotor symptoms.

From a limited number of observational studies and a few randomized trials, short-term hormone replacement therapy does not present increased risk to survivors of gynecologic cancers. Additionally, patients have the added option of using nonhormonal therapies, which may provide some benefit. The decision to institute HT should occur after a thorough discussion of the potential to optimize symptom control and the theoretical risk of stimulating quiescent malignant disease.

Dr. Staley is a resident physician in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. They reported having no relevant financial disclosures.

Due to advancements in surgical treatment, chemotherapy, and radiation therapy, gynecologic cancer survival rates are continuing to improve and quality of life is evolving into an even more significant focus in cancer care.

Roughly 30%-40% of all women with a gynecologic malignancy will experience climacteric symptoms and menopause prior to the anticipated time of natural menopause (J Clin Oncol. 2009 Mar 10;27[8]:1214-9). Cessation of ovarian estrogen and progesterone production can result in short-term as well as long-term sequelae, including vasomotor symptoms, vaginal dryness, osteoporosis, and mood disturbances. Iatrogenic menopause after cancer treatment can be more sudden and severe when compared with the natural course of physiologic menopause. As a result, determination of safe, effective modalities for treating these symptoms is of particular importance for survivor quality of life.

Both combination and estrogen-only hormone replacement therapy (HT) provide greater improvement in these specific symptoms and overall quality of life than placebo as demonstrated in several observational and randomized control trials (Cochrane Database Syst Rev. 2009 Apr 15;[2]:CD004143).

Endometrial cancer

Endometrial cancer is the most common gynecologic malignancy, with approximately 54,000 new cases anticipated in the United States in 2015. Twenty-five percent of these new cases will be in premenopausal women, and with an ever-increasing obesity rate, this number may continue to climb.

Women with early-stage Type 1 endometrial cancer who have vasomotor symptoms after surgery may be offered a short course of estrogen-based HT at the lowest effective dose following hysterectomy/bilateral salpingo-oophorectomy and staging procedure (J Clin Oncol. 2006 Feb 1;24[4]:587-92). For women with genitourinary symptoms, vaginal moisturizers and/or low-dose vaginal estrogen are reasonable options. Unfortunately, there are no data to guide the use of estrogen replacement therapy in women with Type 2 endometrial cancers (Gynecol Oncol. 2011 Aug;122[2]:447-54).

Ovarian cancer

There is minimal data implicating a hormonal causation to ovarian carcinogenesis. Most women with epithelial ovarian cancer do not express tumor estrogen or progesterone receptors. Treatment will result in abrupt, iatrogenic menopause, raising the question of whether it is safe to use HT in patients with epithelial ovarian cancer.

Multiple studies have failed to demonstrate a difference in 5-year survival rates in women with epithelial cancer using HT for 2 years or less (JAMA. 2009 Jul 15;302[3]:298-305, Eur J Gynaecol Oncol. 2000;21[2]:192-6, Cancer. 1999 Sep 15;86[6]:1013-8). As such, symptomatic patients could be offered a course of HT; however, caution should be exercised in women with estrogen/progesterone–expressing tumors or nonepithelial tumors. As with endometrial cancer patients, the lowest effective doses should be prescribed.

Cervical cancer

Most cervical squamous and adenocarcinomas are not hormone dependent. For women with early-stage squamous cell carcinoma, ovarian conservation may be possible or oophoropexy may be offered. However, for many patients, bilateral salpingo-oophorectomy at the time of hysterectomy is more common, and the local effect of radiation therapy can result in vaginal atrophy with subsequent dyspareunia or ovarian failure from radiation scatter. Even for patients who undergo oophoropexy, radiation scatter may still result in ovarian failure. In a few observational studies, there are no data to infer that cervical cancer is hormonally related or that survival rates are decreased.

Currently, HT use in cervical cancer survivors is considered safe. Of note, for women with more advanced-stage cervical cancer and who received chemoradiation for primary treatment, combination therapy with estrogen and progesterone may be more appropriate if the uterus remains in situ. However, for women who have undergone hysterectomy, combination therapy with progesterone may not be warranted and estrogen alone (orally or vaginally) is acceptable (Gynecol Oncol. 2011 Aug;122[2]:447-54)

Nonhormonal therapies

Women presenting with menopausal symptoms in whom estrogen therapy is contraindicated or not desired can also consider using nonhormonal therapies as an alternative. These include selective serotonin reuptake inhibitors (SSRIs) and alpha-2 adrenergic agonists, such as clonidine. Albeit not as effective as HT, these alternative therapies are reasonable options, particularly for management of vasomotor symptoms.

From a limited number of observational studies and a few randomized trials, short-term hormone replacement therapy does not present increased risk to survivors of gynecologic cancers. Additionally, patients have the added option of using nonhormonal therapies, which may provide some benefit. The decision to institute HT should occur after a thorough discussion of the potential to optimize symptom control and the theoretical risk of stimulating quiescent malignant disease.

Dr. Staley is a resident physician in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. They reported having no relevant financial disclosures.

This recently published study from Finland generated headlines when its authors concluded that stopping HT elevates the risk of mortality from cardiovascular disease (CVD), including cardiac and cerebrovascular events. Using nationwide data, investigators compared the CVD mortality rate among women who discontinued HT during the years 1994 through 2009 (n = 332,202) with expected (not actual) CVD mortality rates in the background population.
Within the first year after HT discontinuation, elevations in death rates from cardiac events and stroke were noted (standardized mortality ratio, 1.26 and 1.63, respectively), while in the subsequent year, reductions in such mortality were observed (P<.05 for all comparisons).
The absolute increased risk of death from cardiac events reported within the first year after discontinuation of HT was 4 deaths per 10,000 woman-years of exposure. The absolute risk of death from stroke was 5 additional events per 10,000 woman-years. This level of risk is considered to be rare.

How these data compare to those of other studiesIn contrast with these Finnish data, findings from the Women’s Health Initiative—the largest randomized trial of menopausal HT—do not indicate an increase in mortality or an increase in coronary heart or stroke events among women stopping HT.^1,2
It seems likely that limitations associated with the Finnish observational data account for this discordance. For example, Mikkola and colleagues did not know why women discontinued HT, raising the possibility that women with symptoms suggestive of CVD or development of new risk factors preferentially stopped HT, potentially introducing important bias into the Finnish analysis.

What this evidence means for practiceWomen and their clinicians should make decisions regarding whether to continue, reduce the dose, or discontinue HT through shared decision making, focusing on individual patient quality of life parameters as well as changing risk concerns related to such entities as cancer, CVD, and osteoporosis.³ Dramatic as they are, findings from this Finnish report should not impact how we counsel women regarding use or discontinuation of HT.
—Andrew M. Kaunitz, MD; JoAnn E. Manson, MD, DrPH; and Cynthia A. Stuenkel, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

This recently published study from Finland generated headlines when its authors concluded that stopping HT elevates the risk of mortality from cardiovascular disease (CVD), including cardiac and cerebrovascular events. Using nationwide data, investigators compared the CVD mortality rate among women who discontinued HT during the years 1994 through 2009 (n = 332,202) with expected (not actual) CVD mortality rates in the background population.
Within the first year after HT discontinuation, elevations in death rates from cardiac events and stroke were noted (standardized mortality ratio, 1.26 and 1.63, respectively), while in the subsequent year, reductions in such mortality were observed (P<.05 for all comparisons).
The absolute increased risk of death from cardiac events reported within the first year after discontinuation of HT was 4 deaths per 10,000 woman-years of exposure. The absolute risk of death from stroke was 5 additional events per 10,000 woman-years. This level of risk is considered to be rare.

How these data compare to those of other studiesIn contrast with these Finnish data, findings from the Women’s Health Initiative—the largest randomized trial of menopausal HT—do not indicate an increase in mortality or an increase in coronary heart or stroke events among women stopping HT.^1,2
It seems likely that limitations associated with the Finnish observational data account for this discordance. For example, Mikkola and colleagues did not know why women discontinued HT, raising the possibility that women with symptoms suggestive of CVD or development of new risk factors preferentially stopped HT, potentially introducing important bias into the Finnish analysis.

What this evidence means for practiceWomen and their clinicians should make decisions regarding whether to continue, reduce the dose, or discontinue HT through shared decision making, focusing on individual patient quality of life parameters as well as changing risk concerns related to such entities as cancer, CVD, and osteoporosis.³ Dramatic as they are, findings from this Finnish report should not impact how we counsel women regarding use or discontinuation of HT.
—Andrew M. Kaunitz, MD; JoAnn E. Manson, MD, DrPH; and Cynthia A. Stuenkel, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

This recently published study from Finland generated headlines when its authors concluded that stopping HT elevates the risk of mortality from cardiovascular disease (CVD), including cardiac and cerebrovascular events. Using nationwide data, investigators compared the CVD mortality rate among women who discontinued HT during the years 1994 through 2009 (n = 332,202) with expected (not actual) CVD mortality rates in the background population.
Within the first year after HT discontinuation, elevations in death rates from cardiac events and stroke were noted (standardized mortality ratio, 1.26 and 1.63, respectively), while in the subsequent year, reductions in such mortality were observed (P<.05 for all comparisons).
The absolute increased risk of death from cardiac events reported within the first year after discontinuation of HT was 4 deaths per 10,000 woman-years of exposure. The absolute risk of death from stroke was 5 additional events per 10,000 woman-years. This level of risk is considered to be rare.

How these data compare to those of other studiesIn contrast with these Finnish data, findings from the Women’s Health Initiative—the largest randomized trial of menopausal HT—do not indicate an increase in mortality or an increase in coronary heart or stroke events among women stopping HT.^1,2
It seems likely that limitations associated with the Finnish observational data account for this discordance. For example, Mikkola and colleagues did not know why women discontinued HT, raising the possibility that women with symptoms suggestive of CVD or development of new risk factors preferentially stopped HT, potentially introducing important bias into the Finnish analysis.

What this evidence means for practiceWomen and their clinicians should make decisions regarding whether to continue, reduce the dose, or discontinue HT through shared decision making, focusing on individual patient quality of life parameters as well as changing risk concerns related to such entities as cancer, CVD, and osteoporosis.³ Dramatic as they are, findings from this Finnish report should not impact how we counsel women regarding use or discontinuation of HT.
—Andrew M. Kaunitz, MD; JoAnn E. Manson, MD, DrPH; and Cynthia A. Stuenkel, MD

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

SAN FRANCISCO – Denosumab was superior to zoledronic acid (ZA) in building bone at the lumber spine, total hip, and femoral neck in postmenopausal women with osteoporosis previously treated with oral bisphosphonate therapy in a randomized phase III trial. This study is one more piece of level I evidence to support the effectiveness of transitioning to denosumab in such patients.

“In postmenopausal women with osteoporosis on prior oral bisphosphonates for 2 or more years, transitioning to denosumab resulted in significantly greater increases in bone mineral density [BMD], compared with zoledronic acid at all measured skeletal sites,” said lead author Dr. Paul D. Miller of the Colorado Center for Bone Research, Lakewood, Colo.

Alice Goodman/Frontline Medical News

Speaking at the annual meeting of the American College of Rheumatology, Dr. Miller said: “This study completes a suite of trials that show transitioning from oral bisphosphonates to denosumab provides greater increases in bone mineral density and reduction in bone turnover markers, compared to maintaining therapy with another bisphosphonate.”

“Adherence rates to oral bisphosphonates are low,” he continued. “Patients who are intolerant to or fail other bisphosphonates may cycle from one bisphosphonate to another, but clinical benefits are not shown. Previous trials have shown that denosumab increased bone mineral density in women previously treated with oral bisphosphonates, whereas zoledronic acid did not, in women previously treated with alendronate.”

A prospective, double-blind, double-dummy, randomized trial was mounted to compare denosumab given subcutaneously at 60 mg every 6 months (n = 321) vs. ZA 5 mg once a year (n = 322) in postmenopausal women with osteoporosis who were intolerant to or who failed oral bisphosphonate therapy after at least 2 years of treatment.

Baseline characteristics were similar between both treatment arms. Median age was 69 years. About 38% had previous osteoporotic fracture. Bone mineral density T scores were similar between groups. Prior oral bisphosphonate exposure was a median of 6.4 years. Bone turnover marker levels were similar between the two arms.

For the primary endpoint, at 12 months, denosumab achieved a greater increase in BMD at all sites, compared with ZA: a 2.1% difference was observed at the lumbar spine and a 1.4% difference at the total hip.

Changes in bone turnover markers over time were more favorable with denosumab, he continued. Serum C-terminal cross-linking telopeptide (CTX) level was maintained in the denosumab arm and increased with ZA over 12 months. A similar pattern was observed with procollagen type 1 N-terminal propeptide (P1NP).

Adverse events were comparable between both groups. Serious adverse events were reported in 7.8% in the denosumab arm versus 9.1% in the ZA arm, but this difference was not statistically significant. Slightly more hypersensitivity adverse events were reported in the denosumab group: 3.8% versus 1.9% for ZA. The number of osteoporotic-related fractures was doubled in the ZA arm: 7 for denosumab vs. 15 for ZA.

Dr. Miller told listeners that this is the fourth study to show that denosumab is effective in osteoporotic patients previously on oral bisphosphonates, including prior risedronate, ibandronate, and alendronate.

SAN FRANCISCO – Denosumab was superior to zoledronic acid (ZA) in building bone at the lumber spine, total hip, and femoral neck in postmenopausal women with osteoporosis previously treated with oral bisphosphonate therapy in a randomized phase III trial. This study is one more piece of level I evidence to support the effectiveness of transitioning to denosumab in such patients.

“In postmenopausal women with osteoporosis on prior oral bisphosphonates for 2 or more years, transitioning to denosumab resulted in significantly greater increases in bone mineral density [BMD], compared with zoledronic acid at all measured skeletal sites,” said lead author Dr. Paul D. Miller of the Colorado Center for Bone Research, Lakewood, Colo.

Alice Goodman/Frontline Medical News

Speaking at the annual meeting of the American College of Rheumatology, Dr. Miller said: “This study completes a suite of trials that show transitioning from oral bisphosphonates to denosumab provides greater increases in bone mineral density and reduction in bone turnover markers, compared to maintaining therapy with another bisphosphonate.”

“Adherence rates to oral bisphosphonates are low,” he continued. “Patients who are intolerant to or fail other bisphosphonates may cycle from one bisphosphonate to another, but clinical benefits are not shown. Previous trials have shown that denosumab increased bone mineral density in women previously treated with oral bisphosphonates, whereas zoledronic acid did not, in women previously treated with alendronate.”

A prospective, double-blind, double-dummy, randomized trial was mounted to compare denosumab given subcutaneously at 60 mg every 6 months (n = 321) vs. ZA 5 mg once a year (n = 322) in postmenopausal women with osteoporosis who were intolerant to or who failed oral bisphosphonate therapy after at least 2 years of treatment.

Baseline characteristics were similar between both treatment arms. Median age was 69 years. About 38% had previous osteoporotic fracture. Bone mineral density T scores were similar between groups. Prior oral bisphosphonate exposure was a median of 6.4 years. Bone turnover marker levels were similar between the two arms.

For the primary endpoint, at 12 months, denosumab achieved a greater increase in BMD at all sites, compared with ZA: a 2.1% difference was observed at the lumbar spine and a 1.4% difference at the total hip.

Changes in bone turnover markers over time were more favorable with denosumab, he continued. Serum C-terminal cross-linking telopeptide (CTX) level was maintained in the denosumab arm and increased with ZA over 12 months. A similar pattern was observed with procollagen type 1 N-terminal propeptide (P1NP).

Adverse events were comparable between both groups. Serious adverse events were reported in 7.8% in the denosumab arm versus 9.1% in the ZA arm, but this difference was not statistically significant. Slightly more hypersensitivity adverse events were reported in the denosumab group: 3.8% versus 1.9% for ZA. The number of osteoporotic-related fractures was doubled in the ZA arm: 7 for denosumab vs. 15 for ZA.

Dr. Miller told listeners that this is the fourth study to show that denosumab is effective in osteoporotic patients previously on oral bisphosphonates, including prior risedronate, ibandronate, and alendronate.

SAN FRANCISCO – Denosumab was superior to zoledronic acid (ZA) in building bone at the lumber spine, total hip, and femoral neck in postmenopausal women with osteoporosis previously treated with oral bisphosphonate therapy in a randomized phase III trial. This study is one more piece of level I evidence to support the effectiveness of transitioning to denosumab in such patients.

“In postmenopausal women with osteoporosis on prior oral bisphosphonates for 2 or more years, transitioning to denosumab resulted in significantly greater increases in bone mineral density [BMD], compared with zoledronic acid at all measured skeletal sites,” said lead author Dr. Paul D. Miller of the Colorado Center for Bone Research, Lakewood, Colo.

Alice Goodman/Frontline Medical News

Speaking at the annual meeting of the American College of Rheumatology, Dr. Miller said: “This study completes a suite of trials that show transitioning from oral bisphosphonates to denosumab provides greater increases in bone mineral density and reduction in bone turnover markers, compared to maintaining therapy with another bisphosphonate.”

“Adherence rates to oral bisphosphonates are low,” he continued. “Patients who are intolerant to or fail other bisphosphonates may cycle from one bisphosphonate to another, but clinical benefits are not shown. Previous trials have shown that denosumab increased bone mineral density in women previously treated with oral bisphosphonates, whereas zoledronic acid did not, in women previously treated with alendronate.”

A prospective, double-blind, double-dummy, randomized trial was mounted to compare denosumab given subcutaneously at 60 mg every 6 months (n = 321) vs. ZA 5 mg once a year (n = 322) in postmenopausal women with osteoporosis who were intolerant to or who failed oral bisphosphonate therapy after at least 2 years of treatment.

Baseline characteristics were similar between both treatment arms. Median age was 69 years. About 38% had previous osteoporotic fracture. Bone mineral density T scores were similar between groups. Prior oral bisphosphonate exposure was a median of 6.4 years. Bone turnover marker levels were similar between the two arms.

For the primary endpoint, at 12 months, denosumab achieved a greater increase in BMD at all sites, compared with ZA: a 2.1% difference was observed at the lumbar spine and a 1.4% difference at the total hip.

Changes in bone turnover markers over time were more favorable with denosumab, he continued. Serum C-terminal cross-linking telopeptide (CTX) level was maintained in the denosumab arm and increased with ZA over 12 months. A similar pattern was observed with procollagen type 1 N-terminal propeptide (P1NP).

Adverse events were comparable between both groups. Serious adverse events were reported in 7.8% in the denosumab arm versus 9.1% in the ZA arm, but this difference was not statistically significant. Slightly more hypersensitivity adverse events were reported in the denosumab group: 3.8% versus 1.9% for ZA. The number of osteoporotic-related fractures was doubled in the ZA arm: 7 for denosumab vs. 15 for ZA.

Dr. Miller told listeners that this is the fourth study to show that denosumab is effective in osteoporotic patients previously on oral bisphosphonates, including prior risedronate, ibandronate, and alendronate.