Menopause

Fracture risk in women who discontinue therapy with bisphosphonates can be assessed by measuring bone mineral density at the time of discontinuation, but subsequent frequent monitoring appears to have little predictive value, according to researchers.

The findings were published online May 5 in JAMA Internal Medicine (doi:10.1001/jamainternmed.2014.1232).

Dr. Douglas Bauer of the University of California, San Francisco, and his colleagues looked at data from a trial of about 1,000 postmenopausal women aged 61-86 who had been treated for 4-5 years with alendronate and were randomized to an additional 5 years of alendronate treatment or placebo.

Among the 437 women assigned to placebo, 22% (n = 94) experienced one or more fractures during follow-up. Hip and neck BMD were assessed via dual-energy x-ray absorptiometry (DXA) at baseline and at 1 and 3 years, and bone turnover markers (BTMs) were also analyzed.

Neither 1-year changes in hip DXA nor 1- or 3-year changes in BTM levels were associated with fracture risk. Only age and lower hip BMD at the time of treatment discontinuation were significantly predictive of fracture, according to Dr. Bauer and his associates.

The relative hazard ratio was 1.87 (95% confidence interval, 1.20-2.92) for fracture risk in lowest tertile of baseline hip BMD, and 1.54 (95% CI, 1.26-1.85) per 5-year increase in age.

Yearly monitoring – recommended by many experts after discontinuation of bisphosphonates – should not be considered predictive of fractures, the researchers noted. It was "somewhat surprising that short-term changes in these individual measurements are not associated with fracture risk after discontinuation," they wrote.

The researchers cautioned clinicians and patients contemplating a drug holiday after 5 years of treatment to "be aware that short-term monitoring to detect individuals at higher risk who might resume bisphosphonate therapy, or initiate another therapy, may not add to risk prediction over and above age and BMD measured at the time of discontinuation."

The study’s limitations include its relatively small number of fractures observed, reducing its statistical power, and the use of a single bisphosphonate medication, Dr. Bauer acknowledged.

The researchers received no outside funding, though their findings were derived from an analysis of the placebo group of the FLEX trial, a manufacturer-sponsored study comparing extended alendronate sodium treatment with placebo in a large cohort of women treated 5 years on alendronate (JAMA 2006;296:2927-38).

Dr. Bauer reported no conflicts of interest related to the study; other study authors disclosed financial relationships with Amgen, GlaxoSmithKline, Merck, Novartis, Nycomed, and Eli Lilly.

Fracture risk in women who discontinue therapy with bisphosphonates can be assessed by measuring bone mineral density at the time of discontinuation, but subsequent frequent monitoring appears to have little predictive value, according to researchers.

The findings were published online May 5 in JAMA Internal Medicine (doi:10.1001/jamainternmed.2014.1232).

Dr. Douglas Bauer of the University of California, San Francisco, and his colleagues looked at data from a trial of about 1,000 postmenopausal women aged 61-86 who had been treated for 4-5 years with alendronate and were randomized to an additional 5 years of alendronate treatment or placebo.

Among the 437 women assigned to placebo, 22% (n = 94) experienced one or more fractures during follow-up. Hip and neck BMD were assessed via dual-energy x-ray absorptiometry (DXA) at baseline and at 1 and 3 years, and bone turnover markers (BTMs) were also analyzed.

Neither 1-year changes in hip DXA nor 1- or 3-year changes in BTM levels were associated with fracture risk. Only age and lower hip BMD at the time of treatment discontinuation were significantly predictive of fracture, according to Dr. Bauer and his associates.

The relative hazard ratio was 1.87 (95% confidence interval, 1.20-2.92) for fracture risk in lowest tertile of baseline hip BMD, and 1.54 (95% CI, 1.26-1.85) per 5-year increase in age.

Yearly monitoring – recommended by many experts after discontinuation of bisphosphonates – should not be considered predictive of fractures, the researchers noted. It was "somewhat surprising that short-term changes in these individual measurements are not associated with fracture risk after discontinuation," they wrote.

The researchers cautioned clinicians and patients contemplating a drug holiday after 5 years of treatment to "be aware that short-term monitoring to detect individuals at higher risk who might resume bisphosphonate therapy, or initiate another therapy, may not add to risk prediction over and above age and BMD measured at the time of discontinuation."

The study’s limitations include its relatively small number of fractures observed, reducing its statistical power, and the use of a single bisphosphonate medication, Dr. Bauer acknowledged.

The researchers received no outside funding, though their findings were derived from an analysis of the placebo group of the FLEX trial, a manufacturer-sponsored study comparing extended alendronate sodium treatment with placebo in a large cohort of women treated 5 years on alendronate (JAMA 2006;296:2927-38).

Dr. Bauer reported no conflicts of interest related to the study; other study authors disclosed financial relationships with Amgen, GlaxoSmithKline, Merck, Novartis, Nycomed, and Eli Lilly.

Fracture risk in women who discontinue therapy with bisphosphonates can be assessed by measuring bone mineral density at the time of discontinuation, but subsequent frequent monitoring appears to have little predictive value, according to researchers.

The findings were published online May 5 in JAMA Internal Medicine (doi:10.1001/jamainternmed.2014.1232).

Dr. Douglas Bauer of the University of California, San Francisco, and his colleagues looked at data from a trial of about 1,000 postmenopausal women aged 61-86 who had been treated for 4-5 years with alendronate and were randomized to an additional 5 years of alendronate treatment or placebo.

Among the 437 women assigned to placebo, 22% (n = 94) experienced one or more fractures during follow-up. Hip and neck BMD were assessed via dual-energy x-ray absorptiometry (DXA) at baseline and at 1 and 3 years, and bone turnover markers (BTMs) were also analyzed.

Neither 1-year changes in hip DXA nor 1- or 3-year changes in BTM levels were associated with fracture risk. Only age and lower hip BMD at the time of treatment discontinuation were significantly predictive of fracture, according to Dr. Bauer and his associates.

The relative hazard ratio was 1.87 (95% confidence interval, 1.20-2.92) for fracture risk in lowest tertile of baseline hip BMD, and 1.54 (95% CI, 1.26-1.85) per 5-year increase in age.

Yearly monitoring – recommended by many experts after discontinuation of bisphosphonates – should not be considered predictive of fractures, the researchers noted. It was "somewhat surprising that short-term changes in these individual measurements are not associated with fracture risk after discontinuation," they wrote.

The researchers cautioned clinicians and patients contemplating a drug holiday after 5 years of treatment to "be aware that short-term monitoring to detect individuals at higher risk who might resume bisphosphonate therapy, or initiate another therapy, may not add to risk prediction over and above age and BMD measured at the time of discontinuation."

The study’s limitations include its relatively small number of fractures observed, reducing its statistical power, and the use of a single bisphosphonate medication, Dr. Bauer acknowledged.

The researchers received no outside funding, though their findings were derived from an analysis of the placebo group of the FLEX trial, a manufacturer-sponsored study comparing extended alendronate sodium treatment with placebo in a large cohort of women treated 5 years on alendronate (JAMA 2006;296:2927-38).

Dr. Bauer reported no conflicts of interest related to the study; other study authors disclosed financial relationships with Amgen, GlaxoSmithKline, Merck, Novartis, Nycomed, and Eli Lilly.

Nearly one in every six women will experience chronic vulvar symptoms at some point, from ongoing itching to sensations of rawness, burning, or dyspareunia. Regrettably, clinicians generally are taught only a few possible causes for these symptoms, primarily infections such as yeast, bacterial vaginosis, herpes simplex virus, or anogenital warts. However, infections rarely produce chronic symptoms that do not respond, at least temporarily, to therapy.

In this two-part series, we focus on a total of 10 cases of vulvar symptoms, zeroing in on diagnosis and treatment. In this first part, we describe five patient scenarios illustrating the diagnosis and treatment of:

• lichen sclerosus
• vulvodynia
• lichen simplex chronicus
• lichen planus
• hidradenitis suppurativa.

In many chronic cases, more than one entity is the cause
Specific skin diseases, sensations of rawness from various external and internal irritants, neuropathy, and psychological issues are all much more common causes of chronic vulvar symptoms than infection. Moreover, most women with chronic vulvar symptoms have more than one entity producing their discomfort.

Very often, the cause of a patient’s symptoms is not clear at the first visit, with nonspecific redness or even normal skin seen on examination. Pathognomonic skin findings can be obscured by irritant contact dermatitis caused by unnecessary medications or overwashing, atrophic vaginitis, and/or rubbing and scratching. In such cases, obvious abnormalities must be eliminated and the patient reevaluated to definitively discover and treat the cause of the symptoms.

CASE 1. ANOGENITAL ITCHING AND DYSPAREUNIA
A 62-year-old woman schedules a visit to address her anogenital itching. She reports pain with scratching and has developed introital dyspareunia. On physical examination, you find a well-demarcated white plaque of thickened, crinkled skin (FIGURE 1). A wet mount shows parabasal cells and no lactobacilli.

Diagnosis: Lichen sclerosus and atrophic vagina.

Treatment: Halobetasol ointment, an ultra-potent topical corticosteroid, once or twice daily; along with estradiol cream (0.5 g intravaginally) 3 times a week.

Lichen sclerosus is a skin disease found most often on the vulva of postmenopausal women, although it also can affect prepubertal children and reproductive-age women. Lichen sclerosus is multifactorial in pathogenesis, including prominent autoimmune factors, local environmental factors, and genetic predisposition.¹

Although there is no cure for lichen sclerosus, the symptoms and clinical abnormalities usually can be well managed with ultra-potent topical corticosteroids. However, scarring and architectural changes are not reversible. Moreover, poorly controlled lichen sclerosus exhibits malignant transformation on anogenital skin in about 3% of affected patients.

The standard of care is application of an ultra-potent topical corticosteroid ointment once or twice daily until the skin texture normalizes again. The most common of such corticosteroids are clobetasol, halobetasol, and betamethasone dipropionate in an augmented vehicle (betamethasone dipropionate in the usual vehicle is only a medium-high medication in terms of potency.) One of us (L.E.) finds that some women experience irritation with generic clobetasol.

The ointment form of the selected corticosteroid is preferred, as creams are irritating to the vulva in most women because they contain more alcohols and preservatives than ointments do. The amount to be used is very small—far smaller than the pea-sized amount often suggested. By using this smaller amount, we avoid spread to the surrounding hair-bearing skin, which is at greater risk for steroid dermatitis and atrophy than the modified mucous membranes.

Related video: Lichen sclerosis: My approach to treatment Michael Baggish, MD

Even asymptomatic lichen sclerosus can progress
Most vulvologists agree that when the skin normalizes (not when symptoms subside), it is best to either decrease the frequency of application of the ultra-potent corticosteroid to two or three times a week, or to continue daily use with a lower-potency corticosteroid such as triamcinolone ointment 0.1%. Discontinuation of therapy usually results in recurrence.²

Treatment should not be based solely on symptoms, as asymptomatic lichen sclerosus can progress and cause permanent scarring and an increased risk for squamous cell carcinoma.

Although no studies have shown a decreased risk for squamous cell carcinoma with ongoing use of a corticosteroid, vulvologists have observed that malignant transformation occurs uniformly in the setting of poorly controlled lichen sclerosus. Immune dysregulation and inflammation may play an important role, so careful management to minimize inflammation may help prevent a malignancy.³

Secondary treatment choices
Secondary choices for lichen sclerosus include the topical calcineurin inhibitors tacrolimus (Protopic) and pimecrolimus (Elidel) but not testosterone, which has been shown to be ineffective. Tacrolimus and pimecrolimus are useful but often burn upon application, and they are “black-boxed” for cutaneous squamous cell carcinoma and lymphoma. Therefore, although squamous cell carcinoma associated with their use is extraordinarily uncommon, patients should be advised of these risks, particularly because lichen sclerosus already exhibits this association.

Most postmenopausal women with lichen sclerosus also exhibit hypothyroidism, so they should be monitored for this. However, thyroid function testing in 18 children showed no evidence of hypothyroidism in that age group (L.E. unpublished data).

Estrogen replacement may be advised
Postmenopausal women who have prominent introital lichen sclerosus or dyspareunia should receive estrogen replacement of some type so that there is only one cause, rather than two, for their dyspareunia, thinning, fragility, and inelasticity.

Women with well-controlled lichen sclerosus should be followed twice a year to ensure that their disease remains suppressed with ongoing therapy, and to evaluate for active disease, adverse effects of therapy, and the appearance of dysplasia or squamous cell carcinoma.

Women with lichen sclerosus occasionally experience discomfort after their clinical skin disease has cleared. These women now have developed vulvodynia triggered by their lichen sclerosus.

Related series: Vulvar Pain Syndromes—A 3-part roundtable
Part 1. Making the correct diagnosis (September 2011)
Part 2. A bounty of treatments—but not all of them proven (October 2011)
Part 3. Causes and treatment of vestibulodynia (November 2011)

CASE 2. IS IT REALLY CHRONIC YEAST INFECTION?
A 36-year-old woman consults you about her history of chronic yeast infection that manifests as introital burning, discharge, and dyspareunia. She is otherwise healthy, except for irritable bowel syndrome and fibromyalgia.

Physical examination reveals a mild patchy redness of the vestibule and surrounding modified mucous membranes (FIGURE 2). Gentle probing with a cotton swab triggers exquisite pain in the vestibule, with slight extension to the labia minora. A wet mount shows no evidence of increased white blood cells, parabasal cells, clue cells, or yeast forms. Lactobacilli are abundant.

Diagnosis: Vulvodynia, with a nearly vestibulodynia pattern.

Treatment: Venlafaxine and pelvic floor physical therapy.

Vulvodynia is a genital pain syndrome defined as sensations of chronic burning, irritation, rawness, and soreness in the absence of objective disease and infection that could explain the discomfort. Vulvodynia occurs in approximately 7% to 8% of women.⁴

Vulvodynia generally is believed to be a multifactorial symptom, occurring as a result of pelvic floor dysfunction and neuropathic pain,^5,6 with anxiety/depression issues exacerbating symptoms. Some recent studies have shown the presence of biochemical mediators of inflammation in the absence of clinical and histologic inflammation.⁷ Discomfort often is worsened by infections or the application of common irritants (creams, panty liners, soaps, some topical anesthetics). Estrogen deficiency is another common exacerbating factor.

Women tend to exhibit other pain syndromes such as chronic headaches, fibromyalgia, temperomandibular disorder, or premenstrual syndrome, as well as prominent anxiety, depression, sleep disorder, and so on.

Almost uniformly present are symptoms of pelvic floor dysfunction, such as constipation, irritable bowel syndrome, and interstitial cystitis or urinary symptoms in the absence of a urinary tract infection. These women also are frequently unusually intolerant of medications.

Classifying vulvodynia
There are two primary patterns of vulvodynia. The first and most common is vestibulodynia, formerly called vulvar vestibulitis. The term vestibulitis was eliminated to reflect the absence of clinical and histologic inflammation. Vestibulodynia refers to pain that is always limited to the vestibule. Generalized vulvodynia, however, extends beyond the vestibule, is migratory, or does not include the vestibule.

Several vulvologists have found that many patients exhibit features of both types of vulvodynia, and these patterns probably exist on a spectrum. The difference is probably unimportant in clinical practice, except that vestibulodynia can be treated with vestibulectomy.

How we manage vulvodynia
We focus on pelvic floor physical therapy and on the provision of medication for neuropathic pain, which is initiated at very small doses and gradually increased to active doses.⁸ The medications used and the ultimate doses often required include:

• amitriptyline or desipramine 150 mg
• gabapentin 600 to 1,200 mg three times daily
• venlafaxine XR 150 mg daily
• pregabalin 150 mg twice a day
• duloxetine 60 mg a day.

Compounded amitriptyline 2% with baclofen 2% cream applied three times daily is beneficial for many patients, and topical lidocaine jelly 2% or ointment 5% (which often burns) can help provide immediate temporary relief.

Most patients require sex therapy and counseling for maximal improvement. Women with vestibulodynia in whom these therapies fail are good candidates for vestibulectomy if their pain is strictly limited to the vestibule. Fortunately, most women do not require this aggressive therapy.

Related article: Successful treatment of chronic vaginitis Robert L. Barbieri, MD (Editorial; July 2013)

CASE 3. SEVERE ITCHING DISRUPTS SLEEP
A 34-year-old patient reports excruciating itching, with disruption of daily activities and sleep. She has been treated for candidiasis on multiple occasions, but in your office her wet mount and confirmatory culture are negative. Physical examination reveals a pink, lichenified plaque with excoriation (FIGURE 3).

Diagnosis: Lichen simplex chronicus.

Treatment: Ultra-potent corticosteroid ointment applied very sparingly twice daily and covered with petroleum jelly. You also order nighttime sedation with amitriptyline to break the itch-scratch cycle. When the patient’s itching resolves and her skin clears, you taper her off the corticosteroid, warning her that recurrence is likely, and instruct her to restart the medication immediately should itching recur.

Lichen simplex chronicus (formerly called squamous hyperplasia or hyperplastic dystrophy, and also known as eczema, neurodermatitis, or localized atopic dermatitis) occurs when irritation from any cause produces itching in a predisposed person. The subsequent scratching and rubbing both produce the rash and exacerbate the irritation that drives the itching, even after the original cause is gone. The rubbing and scratching perpetuate the irritation and itching, producing the “itch-scratch” cycle.

The appearance of lichen simplex chronicus is produced by rubbing (where the skin thickens and lichenifies) or scratching (where the skin becomes red with linear erosions, called excoriations, caused by fingernails).

The initial trigger for lichen simplex chronicus often is an infection—often yeast—but overwashing, stress, sweat, heat, urine, irritating lubricants, and use of panty liners also may precipitate the itching. At the office visit, the original infection or other cause of irritation often is no longer present, and only lichen simplex chronicus can be identified.

How to treat lichen simplex chronicus
Management of lichen simplex chronicus requires very sparing application of an ultra-potent topical corticosteroid (clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle ointment) twice daily, with the ointment covered with petroleum jelly. Care also must be taken to avoid irritants.

In addition, nighttime sedation helps to interrupt the itch-scratch cycle by preventing rubbing during sleep.

When the skin appears normal and itching has resolved, taper the medication down or off, warning the patient that recurrence is common with any future irritation.

Restart therapy immediately upon recurrence to prevent lichenification and chronic problems.

Second-line medications include calcineurin inhibitors (tacrolimus or pimecrolimus). Although these agents do not contribute to atrophy, they are less effective than topical corticosteroids,⁹ cost more, and can cause burning upon application.

Unlike lichen sclerosus, lichen simplex chronicus does not always recur upon cessation of treatment, and there is no need for concern about an increased risk of malignancy or significant scarring.

Related article: New treatment option for vulvar and vaginal atrophy  Andrew M. Kaunitz, MD (News for your Practice; May 2013)

CASE 4. ORAL AND VULVAR INVOLVEMENT
A 73-year-old patient seeks your help in alleviating longstanding introital itching and rawness, with dyspareunia. She has tried topical estradiol cream intravaginally three times weekly in combination with weekly fluconazole, to no avail.

Physical examination reveals deep red patches and erosions of the vestibule, with complete resorption of the labia minora (FIGURE 4). Patchy redness of the vagina is apparent as well, so you examine the patient’s mouth and find deep redness of the gingivae and erosions of the buccal mucosae, with surrounding white, lacy papules. A wet mount shows a marked increase in lymphocytes and parabasal cells, with a pH of more than 7.

Diagnosis: After correlating the vulvar and oral findings, you make a diagnosis of lichen planus.

Treatment: You initiate halobetasol ointment twice daily, to be applied to the vulva. You also continue vaginal estradiol cream but add hydrocortisone acetate 200 mg compounded vaginal suppositories nightly, as well as clobetasol gel to be applied to oral lesions three times a day. You follow the patient closely for secondary yeast of the mouth and vagina.

Erosive multimucosal lichen planus is a disease of cell-mediated immunity that overwhelmingly affects menopausal women. The most common surfaces involved are the mouth, vagina, rectal mucosa, and vulva; usually, at least two surfaces are affected. The esophagus, extra-auditory canals, nasal mucosa, and eyes also can be involved. Dry, extragenital skin usually is not affected in the setting of erosive vulvovaginal lichen planus.

Vulvar lichen planus most often is controlled with ultra-potent topical corticosteroids (again, clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle), but other mucosal surfaces often are more difficult to manage. Although there is no definitive cure for this condition, careful local care, estrogen replacement, and suppression of oral and vulvovaginal candidiasis usually provide relief.

Calcineurin inhibitors (tacrolimus, pimecrolimus) sometimes are useful in patients who improve only partially after treatment with a topical corticosteroid, provided burning with application is tolerable.¹⁰ Systemic immunosuppressants such as hydroxychloroquine, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, cyclophosphamide, and tumor necrosis factor (TNF) alpha blockers (etanercept, adalimumab, infliximab), as well as oral retinoids, can be added for more recalcitrant disease.¹¹

How to manage disease that affects the vagina
When the vagina is involved in lichen planus, treatment is important to prevent scarring, as well as rawness and pain from irritant contact dermatitis caused by purulent vaginal secretions. Occasionally, a 25-mg hydrocortisone acetate rectal suppository inserted into the vagina nightly improves vaginal lichen planus, but sometimes more potent suppositories, such as doses of 100 to 200 mg, may be compounded. Dilators should be inserted daily to prevent vaginal synechiae.

Oral involvement requires targeted treatment
The mouth is almost always involved in lichen planus. If a dermatologist is not involved in patient care, a prescription for dexamethasone/nystatin elixir (50:50) (5 mL swish, hold, and spit four times daily) can improve oral symptoms remarkably. Alternatively, clobetasol gel applied to affected areas of the mouth three or four times daily can be helpful. Secondary yeast of the vagina and mouth are common with the use of topical corticosteroids.

Careful clinical follow-up is advised
Like uncontrolled lichen sclerosus, erosive lichen planus of the vulva produces scarring and sometimes eventuates into squamous cell carcinoma. Therefore, careful clinical surveillance is warranted. And therapy must be continued to prevent recurrence of lichen planus (as it must be for lichen sclerosus), scarring, and to decrease the risk of squamous cell carcinoma. And like lichen sclerosus, lichen planus sometimes triggers vulvodynia.

CASE 5. MULTIPLE BOILS IN THE GROIN
A 31-year-old morbidly obese African American woman comes to your office with continually evolving boils in the groin. A culture shows Bacterioides spp, Escherichia coli, and Peptococcus spp. In the past, multiple courses of various antibiotics have provided only modest relief.

Physical examination reveals fluctuant nodules, scars, and draining sinus tracts of the hair-bearing vulva and crural crease (FIGURE 5). The axillae are clear.

Diagnosis: Hidradenitis suppurativa.

Treatment: The patient begins taking minocycline 100 mg twice daily. Because she is a smoker, you refer her to an aggressive primary care provider for smoking cessation and weight loss management.

Three months later, the patient is developing only about two nodules a month, managed by early intralesional injections of triamcinolone acetonide.

Hidradenitis suppurativa is sometimes called inverse acne because the underlying pathogenesis is similar to cystic acne. Follicular plugging with keratin debris occurs, with additional keratin, sebaceous material, and normal skin bacteria trapped below the occlusion and distending the follicle. As the follicle wall stretches, thins, and allows for leakage of keratin debris into surrounding dermis, a brisk foreign-body response ­produces a noninfectious abscess.

Hidradenitis suppurativa affects more than 2% of the population.¹² It appears only in areas of the body that contain apocrine glands and in individuals who have double- or triple-outlet follicles that predispose them to follicular occlusion. Therefore, this disease has a genetic component.

Other risk factors include male sex, African genetic background, obesity, and smoking. The prevalence of metabolic syndrome is significantly higher in individuals with hidradenitis suppurativa than in the general population.¹³

Recommended management
Treatments include:

• chronic antibiotics with nonspecific anti-inflammatory activity (tetracyclines, erythromycin, clindamycin, and trimethoprim-sulfamethoxazole)
• intralesional injection of corticosteroids for early nodules (which often aborts their development)
• TNF alpha blockers (etanercept, adalimumab, infliximab)^14–16
• surgical removal of affected skin—the definitive therapy.

Note, however, that anogenital hidradenitis often is too extensive for surgery to be practical. In patients who have localized hidradenitis, primary excision is an excellent early therapy, provided the patient is advised that recurrence may occur in apocrine-containing nearby skin. Aggressive curettage of the roof of the cysts has been performed by some clinicians with good response.

Don’t overlook adjuvant approaches
Smoking cessation and weight loss often are useful.

Other therapies backed by anecdotal evidence include oral contraceptives or spironolactone for their anti-androgen effect, as well as metformin, a more recently studied agent.

Local care with antibacterial soaps and topical antibiotics may be useful for some women.

MORE CASES TO COME
In Part 2 of this series, which will appear in the June 2014 issue of OBG Management, we will discuss the following cases:

• atrophic vagina and atrophic vaginitis
• contact dermatitis
• vulvar aphthae
• desquamative inflammatory vaginitis
• psoriasis.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your letter to: [email protected] Please include the city and state in which you practice. 

Nearly one in every six women will experience chronic vulvar symptoms at some point, from ongoing itching to sensations of rawness, burning, or dyspareunia. Regrettably, clinicians generally are taught only a few possible causes for these symptoms, primarily infections such as yeast, bacterial vaginosis, herpes simplex virus, or anogenital warts. However, infections rarely produce chronic symptoms that do not respond, at least temporarily, to therapy.

In this two-part series, we focus on a total of 10 cases of vulvar symptoms, zeroing in on diagnosis and treatment. In this first part, we describe five patient scenarios illustrating the diagnosis and treatment of:

• lichen sclerosus
• vulvodynia
• lichen simplex chronicus
• lichen planus
• hidradenitis suppurativa.

In many chronic cases, more than one entity is the cause
Specific skin diseases, sensations of rawness from various external and internal irritants, neuropathy, and psychological issues are all much more common causes of chronic vulvar symptoms than infection. Moreover, most women with chronic vulvar symptoms have more than one entity producing their discomfort.

Very often, the cause of a patient’s symptoms is not clear at the first visit, with nonspecific redness or even normal skin seen on examination. Pathognomonic skin findings can be obscured by irritant contact dermatitis caused by unnecessary medications or overwashing, atrophic vaginitis, and/or rubbing and scratching. In such cases, obvious abnormalities must be eliminated and the patient reevaluated to definitively discover and treat the cause of the symptoms.

CASE 1. ANOGENITAL ITCHING AND DYSPAREUNIA
A 62-year-old woman schedules a visit to address her anogenital itching. She reports pain with scratching and has developed introital dyspareunia. On physical examination, you find a well-demarcated white plaque of thickened, crinkled skin (FIGURE 1). A wet mount shows parabasal cells and no lactobacilli.

Diagnosis: Lichen sclerosus and atrophic vagina.

Treatment: Halobetasol ointment, an ultra-potent topical corticosteroid, once or twice daily; along with estradiol cream (0.5 g intravaginally) 3 times a week.

Lichen sclerosus is a skin disease found most often on the vulva of postmenopausal women, although it also can affect prepubertal children and reproductive-age women. Lichen sclerosus is multifactorial in pathogenesis, including prominent autoimmune factors, local environmental factors, and genetic predisposition.¹

Although there is no cure for lichen sclerosus, the symptoms and clinical abnormalities usually can be well managed with ultra-potent topical corticosteroids. However, scarring and architectural changes are not reversible. Moreover, poorly controlled lichen sclerosus exhibits malignant transformation on anogenital skin in about 3% of affected patients.

The standard of care is application of an ultra-potent topical corticosteroid ointment once or twice daily until the skin texture normalizes again. The most common of such corticosteroids are clobetasol, halobetasol, and betamethasone dipropionate in an augmented vehicle (betamethasone dipropionate in the usual vehicle is only a medium-high medication in terms of potency.) One of us (L.E.) finds that some women experience irritation with generic clobetasol.

The ointment form of the selected corticosteroid is preferred, as creams are irritating to the vulva in most women because they contain more alcohols and preservatives than ointments do. The amount to be used is very small—far smaller than the pea-sized amount often suggested. By using this smaller amount, we avoid spread to the surrounding hair-bearing skin, which is at greater risk for steroid dermatitis and atrophy than the modified mucous membranes.

Related video: Lichen sclerosis: My approach to treatment Michael Baggish, MD

Even asymptomatic lichen sclerosus can progress
Most vulvologists agree that when the skin normalizes (not when symptoms subside), it is best to either decrease the frequency of application of the ultra-potent corticosteroid to two or three times a week, or to continue daily use with a lower-potency corticosteroid such as triamcinolone ointment 0.1%. Discontinuation of therapy usually results in recurrence.²

Treatment should not be based solely on symptoms, as asymptomatic lichen sclerosus can progress and cause permanent scarring and an increased risk for squamous cell carcinoma.

Although no studies have shown a decreased risk for squamous cell carcinoma with ongoing use of a corticosteroid, vulvologists have observed that malignant transformation occurs uniformly in the setting of poorly controlled lichen sclerosus. Immune dysregulation and inflammation may play an important role, so careful management to minimize inflammation may help prevent a malignancy.³

Secondary treatment choices
Secondary choices for lichen sclerosus include the topical calcineurin inhibitors tacrolimus (Protopic) and pimecrolimus (Elidel) but not testosterone, which has been shown to be ineffective. Tacrolimus and pimecrolimus are useful but often burn upon application, and they are “black-boxed” for cutaneous squamous cell carcinoma and lymphoma. Therefore, although squamous cell carcinoma associated with their use is extraordinarily uncommon, patients should be advised of these risks, particularly because lichen sclerosus already exhibits this association.

Most postmenopausal women with lichen sclerosus also exhibit hypothyroidism, so they should be monitored for this. However, thyroid function testing in 18 children showed no evidence of hypothyroidism in that age group (L.E. unpublished data).

Estrogen replacement may be advised
Postmenopausal women who have prominent introital lichen sclerosus or dyspareunia should receive estrogen replacement of some type so that there is only one cause, rather than two, for their dyspareunia, thinning, fragility, and inelasticity.

Women with well-controlled lichen sclerosus should be followed twice a year to ensure that their disease remains suppressed with ongoing therapy, and to evaluate for active disease, adverse effects of therapy, and the appearance of dysplasia or squamous cell carcinoma.

Women with lichen sclerosus occasionally experience discomfort after their clinical skin disease has cleared. These women now have developed vulvodynia triggered by their lichen sclerosus.

Related series: Vulvar Pain Syndromes—A 3-part roundtable
Part 1. Making the correct diagnosis (September 2011)
Part 2. A bounty of treatments—but not all of them proven (October 2011)
Part 3. Causes and treatment of vestibulodynia (November 2011)

CASE 2. IS IT REALLY CHRONIC YEAST INFECTION?
A 36-year-old woman consults you about her history of chronic yeast infection that manifests as introital burning, discharge, and dyspareunia. She is otherwise healthy, except for irritable bowel syndrome and fibromyalgia.

Physical examination reveals a mild patchy redness of the vestibule and surrounding modified mucous membranes (FIGURE 2). Gentle probing with a cotton swab triggers exquisite pain in the vestibule, with slight extension to the labia minora. A wet mount shows no evidence of increased white blood cells, parabasal cells, clue cells, or yeast forms. Lactobacilli are abundant.

Diagnosis: Vulvodynia, with a nearly vestibulodynia pattern.

Treatment: Venlafaxine and pelvic floor physical therapy.

Vulvodynia is a genital pain syndrome defined as sensations of chronic burning, irritation, rawness, and soreness in the absence of objective disease and infection that could explain the discomfort. Vulvodynia occurs in approximately 7% to 8% of women.⁴

Vulvodynia generally is believed to be a multifactorial symptom, occurring as a result of pelvic floor dysfunction and neuropathic pain,^5,6 with anxiety/depression issues exacerbating symptoms. Some recent studies have shown the presence of biochemical mediators of inflammation in the absence of clinical and histologic inflammation.⁷ Discomfort often is worsened by infections or the application of common irritants (creams, panty liners, soaps, some topical anesthetics). Estrogen deficiency is another common exacerbating factor.

Women tend to exhibit other pain syndromes such as chronic headaches, fibromyalgia, temperomandibular disorder, or premenstrual syndrome, as well as prominent anxiety, depression, sleep disorder, and so on.

Almost uniformly present are symptoms of pelvic floor dysfunction, such as constipation, irritable bowel syndrome, and interstitial cystitis or urinary symptoms in the absence of a urinary tract infection. These women also are frequently unusually intolerant of medications.

Classifying vulvodynia
There are two primary patterns of vulvodynia. The first and most common is vestibulodynia, formerly called vulvar vestibulitis. The term vestibulitis was eliminated to reflect the absence of clinical and histologic inflammation. Vestibulodynia refers to pain that is always limited to the vestibule. Generalized vulvodynia, however, extends beyond the vestibule, is migratory, or does not include the vestibule.

Several vulvologists have found that many patients exhibit features of both types of vulvodynia, and these patterns probably exist on a spectrum. The difference is probably unimportant in clinical practice, except that vestibulodynia can be treated with vestibulectomy.

How we manage vulvodynia
We focus on pelvic floor physical therapy and on the provision of medication for neuropathic pain, which is initiated at very small doses and gradually increased to active doses.⁸ The medications used and the ultimate doses often required include:

• amitriptyline or desipramine 150 mg
• gabapentin 600 to 1,200 mg three times daily
• venlafaxine XR 150 mg daily
• pregabalin 150 mg twice a day
• duloxetine 60 mg a day.

Compounded amitriptyline 2% with baclofen 2% cream applied three times daily is beneficial for many patients, and topical lidocaine jelly 2% or ointment 5% (which often burns) can help provide immediate temporary relief.

Most patients require sex therapy and counseling for maximal improvement. Women with vestibulodynia in whom these therapies fail are good candidates for vestibulectomy if their pain is strictly limited to the vestibule. Fortunately, most women do not require this aggressive therapy.

Related article: Successful treatment of chronic vaginitis Robert L. Barbieri, MD (Editorial; July 2013)

CASE 3. SEVERE ITCHING DISRUPTS SLEEP
A 34-year-old patient reports excruciating itching, with disruption of daily activities and sleep. She has been treated for candidiasis on multiple occasions, but in your office her wet mount and confirmatory culture are negative. Physical examination reveals a pink, lichenified plaque with excoriation (FIGURE 3).

Diagnosis: Lichen simplex chronicus.

Treatment: Ultra-potent corticosteroid ointment applied very sparingly twice daily and covered with petroleum jelly. You also order nighttime sedation with amitriptyline to break the itch-scratch cycle. When the patient’s itching resolves and her skin clears, you taper her off the corticosteroid, warning her that recurrence is likely, and instruct her to restart the medication immediately should itching recur.

Lichen simplex chronicus (formerly called squamous hyperplasia or hyperplastic dystrophy, and also known as eczema, neurodermatitis, or localized atopic dermatitis) occurs when irritation from any cause produces itching in a predisposed person. The subsequent scratching and rubbing both produce the rash and exacerbate the irritation that drives the itching, even after the original cause is gone. The rubbing and scratching perpetuate the irritation and itching, producing the “itch-scratch” cycle.

The appearance of lichen simplex chronicus is produced by rubbing (where the skin thickens and lichenifies) or scratching (where the skin becomes red with linear erosions, called excoriations, caused by fingernails).

The initial trigger for lichen simplex chronicus often is an infection—often yeast—but overwashing, stress, sweat, heat, urine, irritating lubricants, and use of panty liners also may precipitate the itching. At the office visit, the original infection or other cause of irritation often is no longer present, and only lichen simplex chronicus can be identified.

How to treat lichen simplex chronicus
Management of lichen simplex chronicus requires very sparing application of an ultra-potent topical corticosteroid (clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle ointment) twice daily, with the ointment covered with petroleum jelly. Care also must be taken to avoid irritants.

In addition, nighttime sedation helps to interrupt the itch-scratch cycle by preventing rubbing during sleep.

When the skin appears normal and itching has resolved, taper the medication down or off, warning the patient that recurrence is common with any future irritation.

Restart therapy immediately upon recurrence to prevent lichenification and chronic problems.

Second-line medications include calcineurin inhibitors (tacrolimus or pimecrolimus). Although these agents do not contribute to atrophy, they are less effective than topical corticosteroids,⁹ cost more, and can cause burning upon application.

Unlike lichen sclerosus, lichen simplex chronicus does not always recur upon cessation of treatment, and there is no need for concern about an increased risk of malignancy or significant scarring.

Related article: New treatment option for vulvar and vaginal atrophy  Andrew M. Kaunitz, MD (News for your Practice; May 2013)

CASE 4. ORAL AND VULVAR INVOLVEMENT
A 73-year-old patient seeks your help in alleviating longstanding introital itching and rawness, with dyspareunia. She has tried topical estradiol cream intravaginally three times weekly in combination with weekly fluconazole, to no avail.

Physical examination reveals deep red patches and erosions of the vestibule, with complete resorption of the labia minora (FIGURE 4). Patchy redness of the vagina is apparent as well, so you examine the patient’s mouth and find deep redness of the gingivae and erosions of the buccal mucosae, with surrounding white, lacy papules. A wet mount shows a marked increase in lymphocytes and parabasal cells, with a pH of more than 7.

Diagnosis: After correlating the vulvar and oral findings, you make a diagnosis of lichen planus.

Treatment: You initiate halobetasol ointment twice daily, to be applied to the vulva. You also continue vaginal estradiol cream but add hydrocortisone acetate 200 mg compounded vaginal suppositories nightly, as well as clobetasol gel to be applied to oral lesions three times a day. You follow the patient closely for secondary yeast of the mouth and vagina.

Erosive multimucosal lichen planus is a disease of cell-mediated immunity that overwhelmingly affects menopausal women. The most common surfaces involved are the mouth, vagina, rectal mucosa, and vulva; usually, at least two surfaces are affected. The esophagus, extra-auditory canals, nasal mucosa, and eyes also can be involved. Dry, extragenital skin usually is not affected in the setting of erosive vulvovaginal lichen planus.

Vulvar lichen planus most often is controlled with ultra-potent topical corticosteroids (again, clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle), but other mucosal surfaces often are more difficult to manage. Although there is no definitive cure for this condition, careful local care, estrogen replacement, and suppression of oral and vulvovaginal candidiasis usually provide relief.

Calcineurin inhibitors (tacrolimus, pimecrolimus) sometimes are useful in patients who improve only partially after treatment with a topical corticosteroid, provided burning with application is tolerable.¹⁰ Systemic immunosuppressants such as hydroxychloroquine, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, cyclophosphamide, and tumor necrosis factor (TNF) alpha blockers (etanercept, adalimumab, infliximab), as well as oral retinoids, can be added for more recalcitrant disease.¹¹

How to manage disease that affects the vagina
When the vagina is involved in lichen planus, treatment is important to prevent scarring, as well as rawness and pain from irritant contact dermatitis caused by purulent vaginal secretions. Occasionally, a 25-mg hydrocortisone acetate rectal suppository inserted into the vagina nightly improves vaginal lichen planus, but sometimes more potent suppositories, such as doses of 100 to 200 mg, may be compounded. Dilators should be inserted daily to prevent vaginal synechiae.

Oral involvement requires targeted treatment
The mouth is almost always involved in lichen planus. If a dermatologist is not involved in patient care, a prescription for dexamethasone/nystatin elixir (50:50) (5 mL swish, hold, and spit four times daily) can improve oral symptoms remarkably. Alternatively, clobetasol gel applied to affected areas of the mouth three or four times daily can be helpful. Secondary yeast of the vagina and mouth are common with the use of topical corticosteroids.

Careful clinical follow-up is advised
Like uncontrolled lichen sclerosus, erosive lichen planus of the vulva produces scarring and sometimes eventuates into squamous cell carcinoma. Therefore, careful clinical surveillance is warranted. And therapy must be continued to prevent recurrence of lichen planus (as it must be for lichen sclerosus), scarring, and to decrease the risk of squamous cell carcinoma. And like lichen sclerosus, lichen planus sometimes triggers vulvodynia.

CASE 5. MULTIPLE BOILS IN THE GROIN
A 31-year-old morbidly obese African American woman comes to your office with continually evolving boils in the groin. A culture shows Bacterioides spp, Escherichia coli, and Peptococcus spp. In the past, multiple courses of various antibiotics have provided only modest relief.

Physical examination reveals fluctuant nodules, scars, and draining sinus tracts of the hair-bearing vulva and crural crease (FIGURE 5). The axillae are clear.

Diagnosis: Hidradenitis suppurativa.

Treatment: The patient begins taking minocycline 100 mg twice daily. Because she is a smoker, you refer her to an aggressive primary care provider for smoking cessation and weight loss management.

Three months later, the patient is developing only about two nodules a month, managed by early intralesional injections of triamcinolone acetonide.

Hidradenitis suppurativa is sometimes called inverse acne because the underlying pathogenesis is similar to cystic acne. Follicular plugging with keratin debris occurs, with additional keratin, sebaceous material, and normal skin bacteria trapped below the occlusion and distending the follicle. As the follicle wall stretches, thins, and allows for leakage of keratin debris into surrounding dermis, a brisk foreign-body response ­produces a noninfectious abscess.

Hidradenitis suppurativa affects more than 2% of the population.¹² It appears only in areas of the body that contain apocrine glands and in individuals who have double- or triple-outlet follicles that predispose them to follicular occlusion. Therefore, this disease has a genetic component.

Other risk factors include male sex, African genetic background, obesity, and smoking. The prevalence of metabolic syndrome is significantly higher in individuals with hidradenitis suppurativa than in the general population.¹³

Recommended management
Treatments include:

• chronic antibiotics with nonspecific anti-inflammatory activity (tetracyclines, erythromycin, clindamycin, and trimethoprim-sulfamethoxazole)
• intralesional injection of corticosteroids for early nodules (which often aborts their development)
• TNF alpha blockers (etanercept, adalimumab, infliximab)^14–16
• surgical removal of affected skin—the definitive therapy.

Note, however, that anogenital hidradenitis often is too extensive for surgery to be practical. In patients who have localized hidradenitis, primary excision is an excellent early therapy, provided the patient is advised that recurrence may occur in apocrine-containing nearby skin. Aggressive curettage of the roof of the cysts has been performed by some clinicians with good response.

Don’t overlook adjuvant approaches
Smoking cessation and weight loss often are useful.

Other therapies backed by anecdotal evidence include oral contraceptives or spironolactone for their anti-androgen effect, as well as metformin, a more recently studied agent.

Local care with antibacterial soaps and topical antibiotics may be useful for some women.

MORE CASES TO COME
In Part 2 of this series, which will appear in the June 2014 issue of OBG Management, we will discuss the following cases:

• atrophic vagina and atrophic vaginitis
• contact dermatitis
• vulvar aphthae
• desquamative inflammatory vaginitis
• psoriasis.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your letter to: [email protected] Please include the city and state in which you practice. 

Nearly one in every six women will experience chronic vulvar symptoms at some point, from ongoing itching to sensations of rawness, burning, or dyspareunia. Regrettably, clinicians generally are taught only a few possible causes for these symptoms, primarily infections such as yeast, bacterial vaginosis, herpes simplex virus, or anogenital warts. However, infections rarely produce chronic symptoms that do not respond, at least temporarily, to therapy.

In this two-part series, we focus on a total of 10 cases of vulvar symptoms, zeroing in on diagnosis and treatment. In this first part, we describe five patient scenarios illustrating the diagnosis and treatment of:

• lichen sclerosus
• vulvodynia
• lichen simplex chronicus
• lichen planus
• hidradenitis suppurativa.

In many chronic cases, more than one entity is the cause
Specific skin diseases, sensations of rawness from various external and internal irritants, neuropathy, and psychological issues are all much more common causes of chronic vulvar symptoms than infection. Moreover, most women with chronic vulvar symptoms have more than one entity producing their discomfort.

Very often, the cause of a patient’s symptoms is not clear at the first visit, with nonspecific redness or even normal skin seen on examination. Pathognomonic skin findings can be obscured by irritant contact dermatitis caused by unnecessary medications or overwashing, atrophic vaginitis, and/or rubbing and scratching. In such cases, obvious abnormalities must be eliminated and the patient reevaluated to definitively discover and treat the cause of the symptoms.

CASE 1. ANOGENITAL ITCHING AND DYSPAREUNIA
A 62-year-old woman schedules a visit to address her anogenital itching. She reports pain with scratching and has developed introital dyspareunia. On physical examination, you find a well-demarcated white plaque of thickened, crinkled skin (FIGURE 1). A wet mount shows parabasal cells and no lactobacilli.

Diagnosis: Lichen sclerosus and atrophic vagina.

Treatment: Halobetasol ointment, an ultra-potent topical corticosteroid, once or twice daily; along with estradiol cream (0.5 g intravaginally) 3 times a week.

Lichen sclerosus is a skin disease found most often on the vulva of postmenopausal women, although it also can affect prepubertal children and reproductive-age women. Lichen sclerosus is multifactorial in pathogenesis, including prominent autoimmune factors, local environmental factors, and genetic predisposition.¹

Although there is no cure for lichen sclerosus, the symptoms and clinical abnormalities usually can be well managed with ultra-potent topical corticosteroids. However, scarring and architectural changes are not reversible. Moreover, poorly controlled lichen sclerosus exhibits malignant transformation on anogenital skin in about 3% of affected patients.

The standard of care is application of an ultra-potent topical corticosteroid ointment once or twice daily until the skin texture normalizes again. The most common of such corticosteroids are clobetasol, halobetasol, and betamethasone dipropionate in an augmented vehicle (betamethasone dipropionate in the usual vehicle is only a medium-high medication in terms of potency.) One of us (L.E.) finds that some women experience irritation with generic clobetasol.

The ointment form of the selected corticosteroid is preferred, as creams are irritating to the vulva in most women because they contain more alcohols and preservatives than ointments do. The amount to be used is very small—far smaller than the pea-sized amount often suggested. By using this smaller amount, we avoid spread to the surrounding hair-bearing skin, which is at greater risk for steroid dermatitis and atrophy than the modified mucous membranes.

Related video: Lichen sclerosis: My approach to treatment Michael Baggish, MD

Even asymptomatic lichen sclerosus can progress
Most vulvologists agree that when the skin normalizes (not when symptoms subside), it is best to either decrease the frequency of application of the ultra-potent corticosteroid to two or three times a week, or to continue daily use with a lower-potency corticosteroid such as triamcinolone ointment 0.1%. Discontinuation of therapy usually results in recurrence.²

Treatment should not be based solely on symptoms, as asymptomatic lichen sclerosus can progress and cause permanent scarring and an increased risk for squamous cell carcinoma.

Although no studies have shown a decreased risk for squamous cell carcinoma with ongoing use of a corticosteroid, vulvologists have observed that malignant transformation occurs uniformly in the setting of poorly controlled lichen sclerosus. Immune dysregulation and inflammation may play an important role, so careful management to minimize inflammation may help prevent a malignancy.³

Secondary treatment choices
Secondary choices for lichen sclerosus include the topical calcineurin inhibitors tacrolimus (Protopic) and pimecrolimus (Elidel) but not testosterone, which has been shown to be ineffective. Tacrolimus and pimecrolimus are useful but often burn upon application, and they are “black-boxed” for cutaneous squamous cell carcinoma and lymphoma. Therefore, although squamous cell carcinoma associated with their use is extraordinarily uncommon, patients should be advised of these risks, particularly because lichen sclerosus already exhibits this association.

Most postmenopausal women with lichen sclerosus also exhibit hypothyroidism, so they should be monitored for this. However, thyroid function testing in 18 children showed no evidence of hypothyroidism in that age group (L.E. unpublished data).

Estrogen replacement may be advised
Postmenopausal women who have prominent introital lichen sclerosus or dyspareunia should receive estrogen replacement of some type so that there is only one cause, rather than two, for their dyspareunia, thinning, fragility, and inelasticity.

Women with well-controlled lichen sclerosus should be followed twice a year to ensure that their disease remains suppressed with ongoing therapy, and to evaluate for active disease, adverse effects of therapy, and the appearance of dysplasia or squamous cell carcinoma.

Women with lichen sclerosus occasionally experience discomfort after their clinical skin disease has cleared. These women now have developed vulvodynia triggered by their lichen sclerosus.

Related series: Vulvar Pain Syndromes—A 3-part roundtable
Part 1. Making the correct diagnosis (September 2011)
Part 2. A bounty of treatments—but not all of them proven (October 2011)
Part 3. Causes and treatment of vestibulodynia (November 2011)

CASE 2. IS IT REALLY CHRONIC YEAST INFECTION?
A 36-year-old woman consults you about her history of chronic yeast infection that manifests as introital burning, discharge, and dyspareunia. She is otherwise healthy, except for irritable bowel syndrome and fibromyalgia.

Physical examination reveals a mild patchy redness of the vestibule and surrounding modified mucous membranes (FIGURE 2). Gentle probing with a cotton swab triggers exquisite pain in the vestibule, with slight extension to the labia minora. A wet mount shows no evidence of increased white blood cells, parabasal cells, clue cells, or yeast forms. Lactobacilli are abundant.

Diagnosis: Vulvodynia, with a nearly vestibulodynia pattern.

Treatment: Venlafaxine and pelvic floor physical therapy.

Vulvodynia is a genital pain syndrome defined as sensations of chronic burning, irritation, rawness, and soreness in the absence of objective disease and infection that could explain the discomfort. Vulvodynia occurs in approximately 7% to 8% of women.⁴

Vulvodynia generally is believed to be a multifactorial symptom, occurring as a result of pelvic floor dysfunction and neuropathic pain,^5,6 with anxiety/depression issues exacerbating symptoms. Some recent studies have shown the presence of biochemical mediators of inflammation in the absence of clinical and histologic inflammation.⁷ Discomfort often is worsened by infections or the application of common irritants (creams, panty liners, soaps, some topical anesthetics). Estrogen deficiency is another common exacerbating factor.

Women tend to exhibit other pain syndromes such as chronic headaches, fibromyalgia, temperomandibular disorder, or premenstrual syndrome, as well as prominent anxiety, depression, sleep disorder, and so on.

Almost uniformly present are symptoms of pelvic floor dysfunction, such as constipation, irritable bowel syndrome, and interstitial cystitis or urinary symptoms in the absence of a urinary tract infection. These women also are frequently unusually intolerant of medications.

Classifying vulvodynia
There are two primary patterns of vulvodynia. The first and most common is vestibulodynia, formerly called vulvar vestibulitis. The term vestibulitis was eliminated to reflect the absence of clinical and histologic inflammation. Vestibulodynia refers to pain that is always limited to the vestibule. Generalized vulvodynia, however, extends beyond the vestibule, is migratory, or does not include the vestibule.

Several vulvologists have found that many patients exhibit features of both types of vulvodynia, and these patterns probably exist on a spectrum. The difference is probably unimportant in clinical practice, except that vestibulodynia can be treated with vestibulectomy.

How we manage vulvodynia
We focus on pelvic floor physical therapy and on the provision of medication for neuropathic pain, which is initiated at very small doses and gradually increased to active doses.⁸ The medications used and the ultimate doses often required include:

• amitriptyline or desipramine 150 mg
• gabapentin 600 to 1,200 mg three times daily
• venlafaxine XR 150 mg daily
• pregabalin 150 mg twice a day
• duloxetine 60 mg a day.

Compounded amitriptyline 2% with baclofen 2% cream applied three times daily is beneficial for many patients, and topical lidocaine jelly 2% or ointment 5% (which often burns) can help provide immediate temporary relief.

Most patients require sex therapy and counseling for maximal improvement. Women with vestibulodynia in whom these therapies fail are good candidates for vestibulectomy if their pain is strictly limited to the vestibule. Fortunately, most women do not require this aggressive therapy.

Related article: Successful treatment of chronic vaginitis Robert L. Barbieri, MD (Editorial; July 2013)

CASE 3. SEVERE ITCHING DISRUPTS SLEEP
A 34-year-old patient reports excruciating itching, with disruption of daily activities and sleep. She has been treated for candidiasis on multiple occasions, but in your office her wet mount and confirmatory culture are negative. Physical examination reveals a pink, lichenified plaque with excoriation (FIGURE 3).

Diagnosis: Lichen simplex chronicus.

Treatment: Ultra-potent corticosteroid ointment applied very sparingly twice daily and covered with petroleum jelly. You also order nighttime sedation with amitriptyline to break the itch-scratch cycle. When the patient’s itching resolves and her skin clears, you taper her off the corticosteroid, warning her that recurrence is likely, and instruct her to restart the medication immediately should itching recur.

Lichen simplex chronicus (formerly called squamous hyperplasia or hyperplastic dystrophy, and also known as eczema, neurodermatitis, or localized atopic dermatitis) occurs when irritation from any cause produces itching in a predisposed person. The subsequent scratching and rubbing both produce the rash and exacerbate the irritation that drives the itching, even after the original cause is gone. The rubbing and scratching perpetuate the irritation and itching, producing the “itch-scratch” cycle.

The appearance of lichen simplex chronicus is produced by rubbing (where the skin thickens and lichenifies) or scratching (where the skin becomes red with linear erosions, called excoriations, caused by fingernails).

The initial trigger for lichen simplex chronicus often is an infection—often yeast—but overwashing, stress, sweat, heat, urine, irritating lubricants, and use of panty liners also may precipitate the itching. At the office visit, the original infection or other cause of irritation often is no longer present, and only lichen simplex chronicus can be identified.

How to treat lichen simplex chronicus
Management of lichen simplex chronicus requires very sparing application of an ultra-potent topical corticosteroid (clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle ointment) twice daily, with the ointment covered with petroleum jelly. Care also must be taken to avoid irritants.

In addition, nighttime sedation helps to interrupt the itch-scratch cycle by preventing rubbing during sleep.

When the skin appears normal and itching has resolved, taper the medication down or off, warning the patient that recurrence is common with any future irritation.

Restart therapy immediately upon recurrence to prevent lichenification and chronic problems.

Second-line medications include calcineurin inhibitors (tacrolimus or pimecrolimus). Although these agents do not contribute to atrophy, they are less effective than topical corticosteroids,⁹ cost more, and can cause burning upon application.

Unlike lichen sclerosus, lichen simplex chronicus does not always recur upon cessation of treatment, and there is no need for concern about an increased risk of malignancy or significant scarring.

Related article: New treatment option for vulvar and vaginal atrophy  Andrew M. Kaunitz, MD (News for your Practice; May 2013)

CASE 4. ORAL AND VULVAR INVOLVEMENT
A 73-year-old patient seeks your help in alleviating longstanding introital itching and rawness, with dyspareunia. She has tried topical estradiol cream intravaginally three times weekly in combination with weekly fluconazole, to no avail.

Physical examination reveals deep red patches and erosions of the vestibule, with complete resorption of the labia minora (FIGURE 4). Patchy redness of the vagina is apparent as well, so you examine the patient’s mouth and find deep redness of the gingivae and erosions of the buccal mucosae, with surrounding white, lacy papules. A wet mount shows a marked increase in lymphocytes and parabasal cells, with a pH of more than 7.

Diagnosis: After correlating the vulvar and oral findings, you make a diagnosis of lichen planus.

Treatment: You initiate halobetasol ointment twice daily, to be applied to the vulva. You also continue vaginal estradiol cream but add hydrocortisone acetate 200 mg compounded vaginal suppositories nightly, as well as clobetasol gel to be applied to oral lesions three times a day. You follow the patient closely for secondary yeast of the mouth and vagina.

Erosive multimucosal lichen planus is a disease of cell-mediated immunity that overwhelmingly affects menopausal women. The most common surfaces involved are the mouth, vagina, rectal mucosa, and vulva; usually, at least two surfaces are affected. The esophagus, extra-auditory canals, nasal mucosa, and eyes also can be involved. Dry, extragenital skin usually is not affected in the setting of erosive vulvovaginal lichen planus.

Vulvar lichen planus most often is controlled with ultra-potent topical corticosteroids (again, clobetasol, halobetasol, or betamethasone dipropionate in an augmented vehicle), but other mucosal surfaces often are more difficult to manage. Although there is no definitive cure for this condition, careful local care, estrogen replacement, and suppression of oral and vulvovaginal candidiasis usually provide relief.

Calcineurin inhibitors (tacrolimus, pimecrolimus) sometimes are useful in patients who improve only partially after treatment with a topical corticosteroid, provided burning with application is tolerable.¹⁰ Systemic immunosuppressants such as hydroxychloroquine, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, cyclophosphamide, and tumor necrosis factor (TNF) alpha blockers (etanercept, adalimumab, infliximab), as well as oral retinoids, can be added for more recalcitrant disease.¹¹

How to manage disease that affects the vagina
When the vagina is involved in lichen planus, treatment is important to prevent scarring, as well as rawness and pain from irritant contact dermatitis caused by purulent vaginal secretions. Occasionally, a 25-mg hydrocortisone acetate rectal suppository inserted into the vagina nightly improves vaginal lichen planus, but sometimes more potent suppositories, such as doses of 100 to 200 mg, may be compounded. Dilators should be inserted daily to prevent vaginal synechiae.

Oral involvement requires targeted treatment
The mouth is almost always involved in lichen planus. If a dermatologist is not involved in patient care, a prescription for dexamethasone/nystatin elixir (50:50) (5 mL swish, hold, and spit four times daily) can improve oral symptoms remarkably. Alternatively, clobetasol gel applied to affected areas of the mouth three or four times daily can be helpful. Secondary yeast of the vagina and mouth are common with the use of topical corticosteroids.

Careful clinical follow-up is advised
Like uncontrolled lichen sclerosus, erosive lichen planus of the vulva produces scarring and sometimes eventuates into squamous cell carcinoma. Therefore, careful clinical surveillance is warranted. And therapy must be continued to prevent recurrence of lichen planus (as it must be for lichen sclerosus), scarring, and to decrease the risk of squamous cell carcinoma. And like lichen sclerosus, lichen planus sometimes triggers vulvodynia.

CASE 5. MULTIPLE BOILS IN THE GROIN
A 31-year-old morbidly obese African American woman comes to your office with continually evolving boils in the groin. A culture shows Bacterioides spp, Escherichia coli, and Peptococcus spp. In the past, multiple courses of various antibiotics have provided only modest relief.

Physical examination reveals fluctuant nodules, scars, and draining sinus tracts of the hair-bearing vulva and crural crease (FIGURE 5). The axillae are clear.

Diagnosis: Hidradenitis suppurativa.

Treatment: The patient begins taking minocycline 100 mg twice daily. Because she is a smoker, you refer her to an aggressive primary care provider for smoking cessation and weight loss management.

Three months later, the patient is developing only about two nodules a month, managed by early intralesional injections of triamcinolone acetonide.

Hidradenitis suppurativa is sometimes called inverse acne because the underlying pathogenesis is similar to cystic acne. Follicular plugging with keratin debris occurs, with additional keratin, sebaceous material, and normal skin bacteria trapped below the occlusion and distending the follicle. As the follicle wall stretches, thins, and allows for leakage of keratin debris into surrounding dermis, a brisk foreign-body response ­produces a noninfectious abscess.

Hidradenitis suppurativa affects more than 2% of the population.¹² It appears only in areas of the body that contain apocrine glands and in individuals who have double- or triple-outlet follicles that predispose them to follicular occlusion. Therefore, this disease has a genetic component.

Other risk factors include male sex, African genetic background, obesity, and smoking. The prevalence of metabolic syndrome is significantly higher in individuals with hidradenitis suppurativa than in the general population.¹³

Recommended management
Treatments include:

• chronic antibiotics with nonspecific anti-inflammatory activity (tetracyclines, erythromycin, clindamycin, and trimethoprim-sulfamethoxazole)
• intralesional injection of corticosteroids for early nodules (which often aborts their development)
• TNF alpha blockers (etanercept, adalimumab, infliximab)^14–16
• surgical removal of affected skin—the definitive therapy.

Note, however, that anogenital hidradenitis often is too extensive for surgery to be practical. In patients who have localized hidradenitis, primary excision is an excellent early therapy, provided the patient is advised that recurrence may occur in apocrine-containing nearby skin. Aggressive curettage of the roof of the cysts has been performed by some clinicians with good response.

Don’t overlook adjuvant approaches
Smoking cessation and weight loss often are useful.

Other therapies backed by anecdotal evidence include oral contraceptives or spironolactone for their anti-androgen effect, as well as metformin, a more recently studied agent.

Local care with antibacterial soaps and topical antibiotics may be useful for some women.

MORE CASES TO COME
In Part 2 of this series, which will appear in the June 2014 issue of OBG Management, we will discuss the following cases:

• atrophic vagina and atrophic vaginitis
• contact dermatitis
• vulvar aphthae
• desquamative inflammatory vaginitis
• psoriasis.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your letter to: [email protected] Please include the city and state in which you practice. 

In this 5-minute audiocast, Dr. Krychman offers key takeaways from his seminar, "Sexuality in the Elder Woman," at the 62nd Annual Clinical Meeting of the American College of Obstetricians and Gynecologists.

In this 5-minute audiocast, Dr. Krychman offers key takeaways from his seminar, "Sexuality in the Elder Woman," at the 62nd Annual Clinical Meeting of the American College of Obstetricians and Gynecologists.

In this 5-minute audiocast, Dr. Krychman offers key takeaways from his seminar, "Sexuality in the Elder Woman," at the 62nd Annual Clinical Meeting of the American College of Obstetricians and Gynecologists.

Applying topical liquid lidocaine to the vulvar vestibule prior to penetration allows for comfortable intercourse in breast cancer survivors with severe menopausal dyspareunia, according to findings from a randomized, controlled study involving 46 women.

During a double-blind phase of the study, patients randomized to apply 4% aqueous lidocaine had less intercourse pain than those who applied saline (median pain scores of 1.0 and 5.3 out of 10, respectively), according to Dr. Martha F. Goetsch of Oregon Health and Science University, Portland, who will report the finding at the annual meeting of the American Congress of Obstetricians and Gynecologists.

During an open-label phase of the study in which all patients were allowed to apply lidocaine, 37 of 41 (90%) reported comfortable penetration, and sexual distress scores decreased from a median of 30.5 to a median of 14. Additionally, 17 of 20 women (85%) who were abstaining from intercourse because of the discomfort had resumed penetrative intimacy, said Dr. Goetsch, whose abstract was awarded first prize among oral presentations by ACOG.

Patients included in the study were estrogen-deficient breast cancer survivors with severe penetrative dyspareunia not associated with pelvic muscle or organ pain. All had severe vulvovaginal atrophy. During the 1-month blinded phase of the study, the women applied either the lidocaine or the saline to the vulvar vestibule for 3 minutes prior to penetration. Effects of twice-weekly tampon insertion or intercourse were documented in a diary. No partners complained of numbness resulting from the lidocaine.

The findings are notable, because breast cancer survivors number in the millions in the United States alone.

"They often suffer from severe dyspareunia and are urged to refrain from using estrogen, which is the therapy most effective for dyspareunia in menopause," Dr. Goetsch said in an interview.

Furthermore, prior research has focused primarily on vaginal atrophy as the cause of dyspareunia in postmenopausal women.

"This study showed that pain could be prevented even though atrophy was unchanged," she said, noting that this suggests that perhaps atrophy is the wrong therapeutic focus.

"Success came with therapy to the vestibule, not the vagina," she said.

Dr. Goetsch reported having no disclosures.

Applying topical liquid lidocaine to the vulvar vestibule prior to penetration allows for comfortable intercourse in breast cancer survivors with severe menopausal dyspareunia, according to findings from a randomized, controlled study involving 46 women.

During a double-blind phase of the study, patients randomized to apply 4% aqueous lidocaine had less intercourse pain than those who applied saline (median pain scores of 1.0 and 5.3 out of 10, respectively), according to Dr. Martha F. Goetsch of Oregon Health and Science University, Portland, who will report the finding at the annual meeting of the American Congress of Obstetricians and Gynecologists.

During an open-label phase of the study in which all patients were allowed to apply lidocaine, 37 of 41 (90%) reported comfortable penetration, and sexual distress scores decreased from a median of 30.5 to a median of 14. Additionally, 17 of 20 women (85%) who were abstaining from intercourse because of the discomfort had resumed penetrative intimacy, said Dr. Goetsch, whose abstract was awarded first prize among oral presentations by ACOG.

Patients included in the study were estrogen-deficient breast cancer survivors with severe penetrative dyspareunia not associated with pelvic muscle or organ pain. All had severe vulvovaginal atrophy. During the 1-month blinded phase of the study, the women applied either the lidocaine or the saline to the vulvar vestibule for 3 minutes prior to penetration. Effects of twice-weekly tampon insertion or intercourse were documented in a diary. No partners complained of numbness resulting from the lidocaine.

The findings are notable, because breast cancer survivors number in the millions in the United States alone.

"They often suffer from severe dyspareunia and are urged to refrain from using estrogen, which is the therapy most effective for dyspareunia in menopause," Dr. Goetsch said in an interview.

Furthermore, prior research has focused primarily on vaginal atrophy as the cause of dyspareunia in postmenopausal women.

"This study showed that pain could be prevented even though atrophy was unchanged," she said, noting that this suggests that perhaps atrophy is the wrong therapeutic focus.

"Success came with therapy to the vestibule, not the vagina," she said.

Dr. Goetsch reported having no disclosures.

Applying topical liquid lidocaine to the vulvar vestibule prior to penetration allows for comfortable intercourse in breast cancer survivors with severe menopausal dyspareunia, according to findings from a randomized, controlled study involving 46 women.

During a double-blind phase of the study, patients randomized to apply 4% aqueous lidocaine had less intercourse pain than those who applied saline (median pain scores of 1.0 and 5.3 out of 10, respectively), according to Dr. Martha F. Goetsch of Oregon Health and Science University, Portland, who will report the finding at the annual meeting of the American Congress of Obstetricians and Gynecologists.

During an open-label phase of the study in which all patients were allowed to apply lidocaine, 37 of 41 (90%) reported comfortable penetration, and sexual distress scores decreased from a median of 30.5 to a median of 14. Additionally, 17 of 20 women (85%) who were abstaining from intercourse because of the discomfort had resumed penetrative intimacy, said Dr. Goetsch, whose abstract was awarded first prize among oral presentations by ACOG.

Patients included in the study were estrogen-deficient breast cancer survivors with severe penetrative dyspareunia not associated with pelvic muscle or organ pain. All had severe vulvovaginal atrophy. During the 1-month blinded phase of the study, the women applied either the lidocaine or the saline to the vulvar vestibule for 3 minutes prior to penetration. Effects of twice-weekly tampon insertion or intercourse were documented in a diary. No partners complained of numbness resulting from the lidocaine.

The findings are notable, because breast cancer survivors number in the millions in the United States alone.

"They often suffer from severe dyspareunia and are urged to refrain from using estrogen, which is the therapy most effective for dyspareunia in menopause," Dr. Goetsch said in an interview.

Furthermore, prior research has focused primarily on vaginal atrophy as the cause of dyspareunia in postmenopausal women.

"This study showed that pain could be prevented even though atrophy was unchanged," she said, noting that this suggests that perhaps atrophy is the wrong therapeutic focus.

"Success came with therapy to the vestibule, not the vagina," she said.

Dr. Goetsch reported having no disclosures.

MADRID – Menopause is blamed for many things, but it’s unlikely to be the reason for the increased risk of severe asthma or worse quality of life in elderly asthmatic women, a study suggests.

"The increased unadjusted asthma severity and need for health care utilization in postmenopausal women are more likely due to other factors like age and other comorbidities rather than menopause per se," Dr. Joe Zein said at the world congress of the American College of Chest Physicians.

The investigators used a propensity score matching method to analyze the effect of menopause on asthma severity, quality of life, and health care utilization in 166 menopausal and 538 premenopausal women enrolled in the Severe Asthma Research program from 2002 to 2011. Subsequent multivariate logistic regression analyses were used to adjust for the covariates of age at enrollment, hypertension, gastroesophageal reflux disease (GERD), and hormone therapy, which was used in only 35 menopausal women.

Compared with premenopausal women, menopausal women were older and reported less atopy and more comorbidities, such as higher body mass index, diabetes mellitus, hypertension, GERD, obstructive sleep apnea, sinusitis, and nasal polyps, said Dr. Zein, a pulmonologist at Cleveland Clinic.

Menopausal women also had lower lung function and higher neutrophil percentage in both induced sputum and bronchoalveolar lavage fluid.

Severe asthma was present in 31% (167/538) of premenopausal and 72% (119/166) of menopausal women.

In unadjusted analysis, the risk of severe asthma was almost sixfold higher in menopausal women (odds ratio, 5.62; 95% confidence interval 3.83-8.26), but dropped dramatically in the adjusted analysis (OR, 1.46), he said.

Menopausal women also had lower average scores than did premenopausal women (4.06 vs. 4.56) on the 7-point Asthma Quality of Life Questionnaire, with 7 being "not impaired at all" and 1 being "severely impaired." The mean difference between groups pointed to worse quality of life among menopausal women in unadjusted analysis (–0.5), but again this faded after multivariate adjustment (0.31; 95% C.I. –0.30 to 0.93).

Similar trends were observed for health care utilization including emergency department visits (unadjusted OR, 1.33; adjusted OR, 1.15) and hospitalization (unadjusted OR, 2.93; adjusted OR, 0.70), Dr. Zein said.

Finally, an analysis stratified by menopausal status that looked at the association between enrollment age and the probability of severe asthma, suggested a rise in severe asthma among premenopausal women and those in early menopause, followed by a steady decline around age 55 years. Two possible hypotheses are that insulin resistance is higher during the period around menopause and thus may worsen asthma and that estrogen levels initially rise during early menopause before declining and also may increase asthma severity, Dr. Zein said.

"We don’t know exactly, but I think we should not look at menopause as one entity."

Several studies have tried to tease out the effects of menopause and aging on asthma severity, with conflicting results.

A recent study reported that menopausal women in their fifties and sixties are more than twice as likely to be hospitalized for asthma as men the same age (Ann. Allergy Asthma Immunol. 2013;111:176-81).

The Harvard Nurses Health Study, however, found that postmenopausal women who never used hormone therapy had a significantly lower age-adjusted risk of asthma than premenopausal women (Am. J. Respir. Crit. Care Med. 1995;152:1183-8).

The role of estrogen in asthma remains controversial, Dr. Zein observed. The incidence of asthma is twice as high among boys during childhood, but this switches during puberty when girls have a higher incidence of asthma as well as asthma-related hospitalizations and health care utilization, he noted.

Dr. Zein reported no financial disclosures; a coauthor reported grant monies from the National Institutes of Health.

[email protected]

MADRID – Menopause is blamed for many things, but it’s unlikely to be the reason for the increased risk of severe asthma or worse quality of life in elderly asthmatic women, a study suggests.

"The increased unadjusted asthma severity and need for health care utilization in postmenopausal women are more likely due to other factors like age and other comorbidities rather than menopause per se," Dr. Joe Zein said at the world congress of the American College of Chest Physicians.

The investigators used a propensity score matching method to analyze the effect of menopause on asthma severity, quality of life, and health care utilization in 166 menopausal and 538 premenopausal women enrolled in the Severe Asthma Research program from 2002 to 2011. Subsequent multivariate logistic regression analyses were used to adjust for the covariates of age at enrollment, hypertension, gastroesophageal reflux disease (GERD), and hormone therapy, which was used in only 35 menopausal women.

Compared with premenopausal women, menopausal women were older and reported less atopy and more comorbidities, such as higher body mass index, diabetes mellitus, hypertension, GERD, obstructive sleep apnea, sinusitis, and nasal polyps, said Dr. Zein, a pulmonologist at Cleveland Clinic.

Menopausal women also had lower lung function and higher neutrophil percentage in both induced sputum and bronchoalveolar lavage fluid.

Severe asthma was present in 31% (167/538) of premenopausal and 72% (119/166) of menopausal women.

In unadjusted analysis, the risk of severe asthma was almost sixfold higher in menopausal women (odds ratio, 5.62; 95% confidence interval 3.83-8.26), but dropped dramatically in the adjusted analysis (OR, 1.46), he said.

Menopausal women also had lower average scores than did premenopausal women (4.06 vs. 4.56) on the 7-point Asthma Quality of Life Questionnaire, with 7 being "not impaired at all" and 1 being "severely impaired." The mean difference between groups pointed to worse quality of life among menopausal women in unadjusted analysis (–0.5), but again this faded after multivariate adjustment (0.31; 95% C.I. –0.30 to 0.93).

Similar trends were observed for health care utilization including emergency department visits (unadjusted OR, 1.33; adjusted OR, 1.15) and hospitalization (unadjusted OR, 2.93; adjusted OR, 0.70), Dr. Zein said.

Finally, an analysis stratified by menopausal status that looked at the association between enrollment age and the probability of severe asthma, suggested a rise in severe asthma among premenopausal women and those in early menopause, followed by a steady decline around age 55 years. Two possible hypotheses are that insulin resistance is higher during the period around menopause and thus may worsen asthma and that estrogen levels initially rise during early menopause before declining and also may increase asthma severity, Dr. Zein said.

"We don’t know exactly, but I think we should not look at menopause as one entity."

Several studies have tried to tease out the effects of menopause and aging on asthma severity, with conflicting results.

A recent study reported that menopausal women in their fifties and sixties are more than twice as likely to be hospitalized for asthma as men the same age (Ann. Allergy Asthma Immunol. 2013;111:176-81).

The Harvard Nurses Health Study, however, found that postmenopausal women who never used hormone therapy had a significantly lower age-adjusted risk of asthma than premenopausal women (Am. J. Respir. Crit. Care Med. 1995;152:1183-8).

The role of estrogen in asthma remains controversial, Dr. Zein observed. The incidence of asthma is twice as high among boys during childhood, but this switches during puberty when girls have a higher incidence of asthma as well as asthma-related hospitalizations and health care utilization, he noted.

Dr. Zein reported no financial disclosures; a coauthor reported grant monies from the National Institutes of Health.

[email protected]

MADRID – Menopause is blamed for many things, but it’s unlikely to be the reason for the increased risk of severe asthma or worse quality of life in elderly asthmatic women, a study suggests.

"The increased unadjusted asthma severity and need for health care utilization in postmenopausal women are more likely due to other factors like age and other comorbidities rather than menopause per se," Dr. Joe Zein said at the world congress of the American College of Chest Physicians.

The investigators used a propensity score matching method to analyze the effect of menopause on asthma severity, quality of life, and health care utilization in 166 menopausal and 538 premenopausal women enrolled in the Severe Asthma Research program from 2002 to 2011. Subsequent multivariate logistic regression analyses were used to adjust for the covariates of age at enrollment, hypertension, gastroesophageal reflux disease (GERD), and hormone therapy, which was used in only 35 menopausal women.

Compared with premenopausal women, menopausal women were older and reported less atopy and more comorbidities, such as higher body mass index, diabetes mellitus, hypertension, GERD, obstructive sleep apnea, sinusitis, and nasal polyps, said Dr. Zein, a pulmonologist at Cleveland Clinic.

Menopausal women also had lower lung function and higher neutrophil percentage in both induced sputum and bronchoalveolar lavage fluid.

Severe asthma was present in 31% (167/538) of premenopausal and 72% (119/166) of menopausal women.

In unadjusted analysis, the risk of severe asthma was almost sixfold higher in menopausal women (odds ratio, 5.62; 95% confidence interval 3.83-8.26), but dropped dramatically in the adjusted analysis (OR, 1.46), he said.

Menopausal women also had lower average scores than did premenopausal women (4.06 vs. 4.56) on the 7-point Asthma Quality of Life Questionnaire, with 7 being "not impaired at all" and 1 being "severely impaired." The mean difference between groups pointed to worse quality of life among menopausal women in unadjusted analysis (–0.5), but again this faded after multivariate adjustment (0.31; 95% C.I. –0.30 to 0.93).

Similar trends were observed for health care utilization including emergency department visits (unadjusted OR, 1.33; adjusted OR, 1.15) and hospitalization (unadjusted OR, 2.93; adjusted OR, 0.70), Dr. Zein said.

Finally, an analysis stratified by menopausal status that looked at the association between enrollment age and the probability of severe asthma, suggested a rise in severe asthma among premenopausal women and those in early menopause, followed by a steady decline around age 55 years. Two possible hypotheses are that insulin resistance is higher during the period around menopause and thus may worsen asthma and that estrogen levels initially rise during early menopause before declining and also may increase asthma severity, Dr. Zein said.

"We don’t know exactly, but I think we should not look at menopause as one entity."

Several studies have tried to tease out the effects of menopause and aging on asthma severity, with conflicting results.

A recent study reported that menopausal women in their fifties and sixties are more than twice as likely to be hospitalized for asthma as men the same age (Ann. Allergy Asthma Immunol. 2013;111:176-81).

The Harvard Nurses Health Study, however, found that postmenopausal women who never used hormone therapy had a significantly lower age-adjusted risk of asthma than premenopausal women (Am. J. Respir. Crit. Care Med. 1995;152:1183-8).

The role of estrogen in asthma remains controversial, Dr. Zein observed. The incidence of asthma is twice as high among boys during childhood, but this switches during puberty when girls have a higher incidence of asthma as well as asthma-related hospitalizations and health care utilization, he noted.

Dr. Zein reported no financial disclosures; a coauthor reported grant monies from the National Institutes of Health.

[email protected]

SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.

In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).

Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.

Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."

Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."

Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D₃ and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D₃ and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.

The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).

Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.

Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.

Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.

"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."

"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."

Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."

Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.

[email protected]

SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.

In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).

Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.

Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."

Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."

Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D₃ and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D₃ and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.

The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).

Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.

Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.

Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.

"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."

"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."

Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."

Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.

[email protected]

SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.

In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).

Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.

Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."

Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."

Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D₃ and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D₃ and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.

The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).

Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.

Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.

Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.

"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."

"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."

Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."

Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.

[email protected]

In October 2013, the Women’s Health Initiative (WHI) investigators published a comprehensive overview of findings from their two hormone therapy (HT) trials, including extended follow-up representing 13 years of cumulative data.¹ When I analyzed this latest WHI report, I initially focused almost exclusively on the data presented in figures and tables within the article itself, as well as on supplemental data presented on the Internet.² Only then did I read the discussion comments by its authors. I would recommend this approach to anyone who has not yet reviewed this publication.

Overall, the WHI investigators maintain a negative stance toward the preventive and therapeutic benefits of menopausal HT. In my opinion, they also under-emphasize the importance of time since menopause in patient selection. These are the same WHI investigators who initially published un-adjudicated data³ and who delayed reporting age-stratified data.⁴ They also erroneously concluded that HT might increase the risk of ovarian cancer, even though their own data showed otherwise.^5,6

The tables and figures contain the most important data point from this extended WHI follow-up: a reduction in all-cause mortality among women who initiated HT within 10 years of menopause, whether they used estrogen-alone (hysterectomized women) or estrogen-progestin therapy (women with an intact uterus), compared with women in the placebo group.¹

Related Article: When should a menopausal woman discontinue hormone therapy? Andrew M. Kaunitz, MD (Cases in Menopause, February 2014)

DO THE RISKS OF HT REALLY OUTWEIGH THE BENEFITS?
The dramatic benefits of estrogen-alone HT, in particular, recently were highlighted by Sarrel and colleagues in an analysis that suggests that as many as 90,000 deaths may have occurred after publication of the initial WHI findings, when estrogen therapy was widely withheld.⁷ The study by Sarrel and colleagues also was highlighted in a recent issue of this journal.⁸

However, based on a “global index,” which has not been validated, the WHI investigators concluded that the risks of estrogen-progestin therapy outweigh the benefits regardless of age. Yet, the global index does not include all key concerns, omitting several quality-of-life concerns, including sleep disturbance, work productivity, and sexual function, as well as type 2 diabetes mellitus, osteoarthritis, and nonosteoporotic musculoskeletal problems. Nor does the global index provide individual weights.

Although the WHI data show reductions in the incidence of some serious chronic diseases, such as osteoporotic fracture and cardiovascular disease (in women within 10 years of menopause), Manson and colleagues make the blanket statement that HT should not be used for disease prevention, although they admit that it may be a “reasonable option for the management of moderate to severe menopausal symptoms among generally healthy women during early menopause.”¹

Related Article: Update on Osteoporosis Steven R. Goldstein, MD (December 2013)

For some time, Wulf H. Utian, MD, PhD, a founder of both the International Menopause Society and the North American Menopause Society, has been calling for an independent commission to reevaluate all of the major WHI reports “to determine whether the data justified the conclusions drawn.”⁹ I support his call and suggest that this latest WHI publication be included in that reevaluation. The fact that total mortality is reduced among women using HT—according to the WHI’s own data—is not only impressive, it argues for, not against, the use of HT for chronic disease reduction.

KEEP YOUR EYE ON THE DATA
I have no doubt that medical history books will note the destructive effects of misinterpretation of WHI data. Until then, it is up to all practitioners and educators to counsel our patients and our trainees about menopause and menopausal HT and to look beyond the textual conclusions of WHI reports to assess the data themselves.

Other important research, such as the Study of Women’s Health Across the Nation (SWAN), shows that untreated menopausal women fall off the work productivity ladder.¹⁰ This is important because economic stability is a critical component of health and wellness. I have heard many women remark that someone will have to “pry” their hormones out of their “cold, dead hands”—meaning that they intend to take HT even if it shortens their lifespan—which is ironic, given that HT is likely to extend their lifespan!

Coronary heart disease (CHD) is the major killer of American women, and the long-term WHI data actually suggest that HT can prevent it, provided it is initiated within 10 years of menopause. In a two-part article, Hodis and Mack shrewdly compare the risks associated with HT with those associated with other commonly used medications in women’s health.^11,12 They note that evidence-based data from randomized, clinical trials are very reassuring, as HT-associated risks are rare (less than 1 event per 1,000 women treated)—and even rarer when HT is initiated within 10 years of menopause. HT reduces CHD and total mortality, whereas aspirin and statins (as primary preventives) do not.^11,12

Related Article: Update: Menopause Andrew M. Kaunitz, MD (May 2010)

THE BOTTOM LINE
We need to look at the totality of the data on menopausal HT, evaluate our patients individually, treat those who are truly hormonally deficient and suffering, and counsel them that many of the harms linked to HT have been exaggerated.

The pendulum is finally swinging back toward a more balanced assessment of the benefits and risks of HT, indicating that it may be appropriate for primary prevention of cardiovascular disease, osteoporosis, and type 2 diabetes—and thus can potentially expand the lifespan. It’s up to us to communicate this fact to our patients.

TELL US WHAT YOU THINK!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice.
We will consider publishing your letter and in a future issue.
Send your letter to: [email protected]
Please include the city and state in which you practice.
Stay in touch! Your feedback is important to us!

In October 2013, the Women’s Health Initiative (WHI) investigators published a comprehensive overview of findings from their two hormone therapy (HT) trials, including extended follow-up representing 13 years of cumulative data.¹ When I analyzed this latest WHI report, I initially focused almost exclusively on the data presented in figures and tables within the article itself, as well as on supplemental data presented on the Internet.² Only then did I read the discussion comments by its authors. I would recommend this approach to anyone who has not yet reviewed this publication.

Overall, the WHI investigators maintain a negative stance toward the preventive and therapeutic benefits of menopausal HT. In my opinion, they also under-emphasize the importance of time since menopause in patient selection. These are the same WHI investigators who initially published un-adjudicated data³ and who delayed reporting age-stratified data.⁴ They also erroneously concluded that HT might increase the risk of ovarian cancer, even though their own data showed otherwise.^5,6

The tables and figures contain the most important data point from this extended WHI follow-up: a reduction in all-cause mortality among women who initiated HT within 10 years of menopause, whether they used estrogen-alone (hysterectomized women) or estrogen-progestin therapy (women with an intact uterus), compared with women in the placebo group.¹

Related Article: When should a menopausal woman discontinue hormone therapy? Andrew M. Kaunitz, MD (Cases in Menopause, February 2014)

DO THE RISKS OF HT REALLY OUTWEIGH THE BENEFITS?
The dramatic benefits of estrogen-alone HT, in particular, recently were highlighted by Sarrel and colleagues in an analysis that suggests that as many as 90,000 deaths may have occurred after publication of the initial WHI findings, when estrogen therapy was widely withheld.⁷ The study by Sarrel and colleagues also was highlighted in a recent issue of this journal.⁸

However, based on a “global index,” which has not been validated, the WHI investigators concluded that the risks of estrogen-progestin therapy outweigh the benefits regardless of age. Yet, the global index does not include all key concerns, omitting several quality-of-life concerns, including sleep disturbance, work productivity, and sexual function, as well as type 2 diabetes mellitus, osteoarthritis, and nonosteoporotic musculoskeletal problems. Nor does the global index provide individual weights.

Although the WHI data show reductions in the incidence of some serious chronic diseases, such as osteoporotic fracture and cardiovascular disease (in women within 10 years of menopause), Manson and colleagues make the blanket statement that HT should not be used for disease prevention, although they admit that it may be a “reasonable option for the management of moderate to severe menopausal symptoms among generally healthy women during early menopause.”¹

Related Article: Update on Osteoporosis Steven R. Goldstein, MD (December 2013)

For some time, Wulf H. Utian, MD, PhD, a founder of both the International Menopause Society and the North American Menopause Society, has been calling for an independent commission to reevaluate all of the major WHI reports “to determine whether the data justified the conclusions drawn.”⁹ I support his call and suggest that this latest WHI publication be included in that reevaluation. The fact that total mortality is reduced among women using HT—according to the WHI’s own data—is not only impressive, it argues for, not against, the use of HT for chronic disease reduction.

KEEP YOUR EYE ON THE DATA
I have no doubt that medical history books will note the destructive effects of misinterpretation of WHI data. Until then, it is up to all practitioners and educators to counsel our patients and our trainees about menopause and menopausal HT and to look beyond the textual conclusions of WHI reports to assess the data themselves.

Other important research, such as the Study of Women’s Health Across the Nation (SWAN), shows that untreated menopausal women fall off the work productivity ladder.¹⁰ This is important because economic stability is a critical component of health and wellness. I have heard many women remark that someone will have to “pry” their hormones out of their “cold, dead hands”—meaning that they intend to take HT even if it shortens their lifespan—which is ironic, given that HT is likely to extend their lifespan!

Coronary heart disease (CHD) is the major killer of American women, and the long-term WHI data actually suggest that HT can prevent it, provided it is initiated within 10 years of menopause. In a two-part article, Hodis and Mack shrewdly compare the risks associated with HT with those associated with other commonly used medications in women’s health.^11,12 They note that evidence-based data from randomized, clinical trials are very reassuring, as HT-associated risks are rare (less than 1 event per 1,000 women treated)—and even rarer when HT is initiated within 10 years of menopause. HT reduces CHD and total mortality, whereas aspirin and statins (as primary preventives) do not.^11,12

Related Article: Update: Menopause Andrew M. Kaunitz, MD (May 2010)

THE BOTTOM LINE
We need to look at the totality of the data on menopausal HT, evaluate our patients individually, treat those who are truly hormonally deficient and suffering, and counsel them that many of the harms linked to HT have been exaggerated.

The pendulum is finally swinging back toward a more balanced assessment of the benefits and risks of HT, indicating that it may be appropriate for primary prevention of cardiovascular disease, osteoporosis, and type 2 diabetes—and thus can potentially expand the lifespan. It’s up to us to communicate this fact to our patients.

TELL US WHAT YOU THINK!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice.
We will consider publishing your letter and in a future issue.
Send your letter to: [email protected]
Please include the city and state in which you practice.
Stay in touch! Your feedback is important to us!

In October 2013, the Women’s Health Initiative (WHI) investigators published a comprehensive overview of findings from their two hormone therapy (HT) trials, including extended follow-up representing 13 years of cumulative data.¹ When I analyzed this latest WHI report, I initially focused almost exclusively on the data presented in figures and tables within the article itself, as well as on supplemental data presented on the Internet.² Only then did I read the discussion comments by its authors. I would recommend this approach to anyone who has not yet reviewed this publication.

Overall, the WHI investigators maintain a negative stance toward the preventive and therapeutic benefits of menopausal HT. In my opinion, they also under-emphasize the importance of time since menopause in patient selection. These are the same WHI investigators who initially published un-adjudicated data³ and who delayed reporting age-stratified data.⁴ They also erroneously concluded that HT might increase the risk of ovarian cancer, even though their own data showed otherwise.^5,6

The tables and figures contain the most important data point from this extended WHI follow-up: a reduction in all-cause mortality among women who initiated HT within 10 years of menopause, whether they used estrogen-alone (hysterectomized women) or estrogen-progestin therapy (women with an intact uterus), compared with women in the placebo group.¹

Related Article: When should a menopausal woman discontinue hormone therapy? Andrew M. Kaunitz, MD (Cases in Menopause, February 2014)

DO THE RISKS OF HT REALLY OUTWEIGH THE BENEFITS?
The dramatic benefits of estrogen-alone HT, in particular, recently were highlighted by Sarrel and colleagues in an analysis that suggests that as many as 90,000 deaths may have occurred after publication of the initial WHI findings, when estrogen therapy was widely withheld.⁷ The study by Sarrel and colleagues also was highlighted in a recent issue of this journal.⁸

However, based on a “global index,” which has not been validated, the WHI investigators concluded that the risks of estrogen-progestin therapy outweigh the benefits regardless of age. Yet, the global index does not include all key concerns, omitting several quality-of-life concerns, including sleep disturbance, work productivity, and sexual function, as well as type 2 diabetes mellitus, osteoarthritis, and nonosteoporotic musculoskeletal problems. Nor does the global index provide individual weights.

Although the WHI data show reductions in the incidence of some serious chronic diseases, such as osteoporotic fracture and cardiovascular disease (in women within 10 years of menopause), Manson and colleagues make the blanket statement that HT should not be used for disease prevention, although they admit that it may be a “reasonable option for the management of moderate to severe menopausal symptoms among generally healthy women during early menopause.”¹

Related Article: Update on Osteoporosis Steven R. Goldstein, MD (December 2013)

For some time, Wulf H. Utian, MD, PhD, a founder of both the International Menopause Society and the North American Menopause Society, has been calling for an independent commission to reevaluate all of the major WHI reports “to determine whether the data justified the conclusions drawn.”⁹ I support his call and suggest that this latest WHI publication be included in that reevaluation. The fact that total mortality is reduced among women using HT—according to the WHI’s own data—is not only impressive, it argues for, not against, the use of HT for chronic disease reduction.

KEEP YOUR EYE ON THE DATA
I have no doubt that medical history books will note the destructive effects of misinterpretation of WHI data. Until then, it is up to all practitioners and educators to counsel our patients and our trainees about menopause and menopausal HT and to look beyond the textual conclusions of WHI reports to assess the data themselves.

Other important research, such as the Study of Women’s Health Across the Nation (SWAN), shows that untreated menopausal women fall off the work productivity ladder.¹⁰ This is important because economic stability is a critical component of health and wellness. I have heard many women remark that someone will have to “pry” their hormones out of their “cold, dead hands”—meaning that they intend to take HT even if it shortens their lifespan—which is ironic, given that HT is likely to extend their lifespan!

Coronary heart disease (CHD) is the major killer of American women, and the long-term WHI data actually suggest that HT can prevent it, provided it is initiated within 10 years of menopause. In a two-part article, Hodis and Mack shrewdly compare the risks associated with HT with those associated with other commonly used medications in women’s health.^11,12 They note that evidence-based data from randomized, clinical trials are very reassuring, as HT-associated risks are rare (less than 1 event per 1,000 women treated)—and even rarer when HT is initiated within 10 years of menopause. HT reduces CHD and total mortality, whereas aspirin and statins (as primary preventives) do not.^11,12

Related Article: Update: Menopause Andrew M. Kaunitz, MD (May 2010)

THE BOTTOM LINE
We need to look at the totality of the data on menopausal HT, evaluate our patients individually, treat those who are truly hormonally deficient and suffering, and counsel them that many of the harms linked to HT have been exaggerated.

The pendulum is finally swinging back toward a more balanced assessment of the benefits and risks of HT, indicating that it may be appropriate for primary prevention of cardiovascular disease, osteoporosis, and type 2 diabetes—and thus can potentially expand the lifespan. It’s up to us to communicate this fact to our patients.

TELL US WHAT YOU THINK!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice.
We will consider publishing your letter and in a future issue.
Send your letter to: [email protected]
Please include the city and state in which you practice.
Stay in touch! Your feedback is important to us!

SAN DIEGO – Moderate exercise reduced the risk of stroke by 12%-22% and appeared to offset some of the increased stroke risk from postmenopausal hormone therapy. We spoke to Sophia S. Wang, Ph.D., about her study and to Dr. Bruce Ovbiagele for his perspective on the findings.

SAN DIEGO – Moderate exercise reduced the risk of stroke by 12%-22% and appeared to offset some of the increased stroke risk from postmenopausal hormone therapy. We spoke to Sophia S. Wang, Ph.D., about her study and to Dr. Bruce Ovbiagele for his perspective on the findings.

SAN DIEGO – Moderate exercise reduced the risk of stroke by 12%-22% and appeared to offset some of the increased stroke risk from postmenopausal hormone therapy. We spoke to Sophia S. Wang, Ph.D., about her study and to Dr. Bruce Ovbiagele for his perspective on the findings.

SAN DIEGO – Moderate exercise significantly reduced the risk of stroke in women and seemed to offset much but not all of the increased stroke risk in postmenopausal women on hormone therapy, a large retrospective study found.

A self-reported history of moderate-to-strenuous physical activity in the prior 3 years was associated with a roughly 20%-30% lower risk for stroke in an analysis of data on 133,479 women in the California Teachers Study who had been followed every 4-5 years since 1995 by questionnaire, Sophia S. Wang, Ph.D., and her associates reported.

They linked the data set with hospitalization data during 1996-2010 to identify 2,416 ischemic strokes and 710 hemorrhagic strokes in the cohort that were validated by a review of medical records.

The strongest reduction in stroke risk was seen in women who reported moderate physical activity such as brisk walking, recreational tennis, golf, volleyball, or cycling on level streets. Women who reported in 1995-1996 questionnaires that they had engaged in moderate activity in the prior 3 years were 12%-22% less likely to develop a stroke, depending on the amount of activity each week, compared with inactive women who reported less than a half-hour per week of moderate activity.

"You don’t have to climb a mountain" to gain the stroke-reducing benefits of exercise, Dr. Wang said in an interview at the International Stroke Conference. And the fact that people tend to overreport how much they exercise when surveyed makes the findings "particularly robust," she said.

Indeed, reports of strenuous activity were not significantly associated with lower stroke risk. Strenuous activity included swimming laps, aerobics, running, calisthenics, jogging, basketball, racquetball, or cycling on hills. Risk levels ranged from an increase of 3% to a reduction of 18% with strenuous activity, compared with inactive women.

Because most women who exercised strenuously also reported moderate activity, the investigators combined those two activity categories and again found approximately a 20% reduction in stroke risk that clearly was being driven by the benefits of moderate activity, said Dr. Wang of Beckman Research Institute at the City of Hope, Duarte, Calif. Stroke risk reductions ranged from 15%-23% in the combined activity analysis for the 1995-1996 surveys.

Surveyed again in 2005-2006, women who reported moderate or strenuous activity in the prior 3 years were 12%-20% less likely to develop a stroke, compared with inactive women, she said at the meeting, sponsored by the American Heart Association.

More than 5 hours of activity wasn’t more beneficial than fewer hours, she added. Stroke reduction benefits seemed greatest with 3.5-5 hours of activity per week, which was associated with a 23% risk reduction in the earlier survey and a 29% reduction in the later survey. With more than 5 hours, the risk reduction was 17% and 27%, respectively.

In inactive postmenopausal women, current hormone use was associated with a 59% higher risk for stroke and former hormone use was associated with a 16% increased risk, compared with postmenopausal women who didn’t use hormones, Dr. Wang said. However, the elevated stroke risk with hormone use fell in women who exercised, compared with those who didn’t.

In current hormone users, stroke risk was 37% higher in women who reported 0.51-3.5 hours of moderate or strenuous activity per week and 29% higher in women who reported more than 3.5 hours of activity per week, compared with non-hormone users. In former hormone users, stroke risk was 15% higher in those who reported 0.51-3.5 hours of activity per week and 5% higher in those who exercised more than 3.5 hours per week, compared with non-hormone users.

Because of smaller numbers of women in the subset analyses of postmenopausal hormone use, these differences between groups did not reach statistical significance, Dr. Wang said.

She and her associates plan further studies related to these findings, including whether or not activity levels may help prevent stroke in women who’ve already had a stroke, she said.

Dr. Wang and her colleagues reported having no financial disclosures. The National Institute of Neurological Disorders and Stroke funded the study.

[email protected]

On Twitter @sherryboschert

SAN DIEGO – Moderate exercise significantly reduced the risk of stroke in women and seemed to offset much but not all of the increased stroke risk in postmenopausal women on hormone therapy, a large retrospective study found.

A self-reported history of moderate-to-strenuous physical activity in the prior 3 years was associated with a roughly 20%-30% lower risk for stroke in an analysis of data on 133,479 women in the California Teachers Study who had been followed every 4-5 years since 1995 by questionnaire, Sophia S. Wang, Ph.D., and her associates reported.

They linked the data set with hospitalization data during 1996-2010 to identify 2,416 ischemic strokes and 710 hemorrhagic strokes in the cohort that were validated by a review of medical records.

The strongest reduction in stroke risk was seen in women who reported moderate physical activity such as brisk walking, recreational tennis, golf, volleyball, or cycling on level streets. Women who reported in 1995-1996 questionnaires that they had engaged in moderate activity in the prior 3 years were 12%-22% less likely to develop a stroke, depending on the amount of activity each week, compared with inactive women who reported less than a half-hour per week of moderate activity.

"You don’t have to climb a mountain" to gain the stroke-reducing benefits of exercise, Dr. Wang said in an interview at the International Stroke Conference. And the fact that people tend to overreport how much they exercise when surveyed makes the findings "particularly robust," she said.

Indeed, reports of strenuous activity were not significantly associated with lower stroke risk. Strenuous activity included swimming laps, aerobics, running, calisthenics, jogging, basketball, racquetball, or cycling on hills. Risk levels ranged from an increase of 3% to a reduction of 18% with strenuous activity, compared with inactive women.

Because most women who exercised strenuously also reported moderate activity, the investigators combined those two activity categories and again found approximately a 20% reduction in stroke risk that clearly was being driven by the benefits of moderate activity, said Dr. Wang of Beckman Research Institute at the City of Hope, Duarte, Calif. Stroke risk reductions ranged from 15%-23% in the combined activity analysis for the 1995-1996 surveys.

Surveyed again in 2005-2006, women who reported moderate or strenuous activity in the prior 3 years were 12%-20% less likely to develop a stroke, compared with inactive women, she said at the meeting, sponsored by the American Heart Association.

More than 5 hours of activity wasn’t more beneficial than fewer hours, she added. Stroke reduction benefits seemed greatest with 3.5-5 hours of activity per week, which was associated with a 23% risk reduction in the earlier survey and a 29% reduction in the later survey. With more than 5 hours, the risk reduction was 17% and 27%, respectively.

In inactive postmenopausal women, current hormone use was associated with a 59% higher risk for stroke and former hormone use was associated with a 16% increased risk, compared with postmenopausal women who didn’t use hormones, Dr. Wang said. However, the elevated stroke risk with hormone use fell in women who exercised, compared with those who didn’t.

In current hormone users, stroke risk was 37% higher in women who reported 0.51-3.5 hours of moderate or strenuous activity per week and 29% higher in women who reported more than 3.5 hours of activity per week, compared with non-hormone users. In former hormone users, stroke risk was 15% higher in those who reported 0.51-3.5 hours of activity per week and 5% higher in those who exercised more than 3.5 hours per week, compared with non-hormone users.

Because of smaller numbers of women in the subset analyses of postmenopausal hormone use, these differences between groups did not reach statistical significance, Dr. Wang said.

She and her associates plan further studies related to these findings, including whether or not activity levels may help prevent stroke in women who’ve already had a stroke, she said.

Dr. Wang and her colleagues reported having no financial disclosures. The National Institute of Neurological Disorders and Stroke funded the study.

[email protected]

On Twitter @sherryboschert

SAN DIEGO – Moderate exercise significantly reduced the risk of stroke in women and seemed to offset much but not all of the increased stroke risk in postmenopausal women on hormone therapy, a large retrospective study found.

A self-reported history of moderate-to-strenuous physical activity in the prior 3 years was associated with a roughly 20%-30% lower risk for stroke in an analysis of data on 133,479 women in the California Teachers Study who had been followed every 4-5 years since 1995 by questionnaire, Sophia S. Wang, Ph.D., and her associates reported.

They linked the data set with hospitalization data during 1996-2010 to identify 2,416 ischemic strokes and 710 hemorrhagic strokes in the cohort that were validated by a review of medical records.

The strongest reduction in stroke risk was seen in women who reported moderate physical activity such as brisk walking, recreational tennis, golf, volleyball, or cycling on level streets. Women who reported in 1995-1996 questionnaires that they had engaged in moderate activity in the prior 3 years were 12%-22% less likely to develop a stroke, depending on the amount of activity each week, compared with inactive women who reported less than a half-hour per week of moderate activity.

"You don’t have to climb a mountain" to gain the stroke-reducing benefits of exercise, Dr. Wang said in an interview at the International Stroke Conference. And the fact that people tend to overreport how much they exercise when surveyed makes the findings "particularly robust," she said.

Indeed, reports of strenuous activity were not significantly associated with lower stroke risk. Strenuous activity included swimming laps, aerobics, running, calisthenics, jogging, basketball, racquetball, or cycling on hills. Risk levels ranged from an increase of 3% to a reduction of 18% with strenuous activity, compared with inactive women.

Because most women who exercised strenuously also reported moderate activity, the investigators combined those two activity categories and again found approximately a 20% reduction in stroke risk that clearly was being driven by the benefits of moderate activity, said Dr. Wang of Beckman Research Institute at the City of Hope, Duarte, Calif. Stroke risk reductions ranged from 15%-23% in the combined activity analysis for the 1995-1996 surveys.

Surveyed again in 2005-2006, women who reported moderate or strenuous activity in the prior 3 years were 12%-20% less likely to develop a stroke, compared with inactive women, she said at the meeting, sponsored by the American Heart Association.

More than 5 hours of activity wasn’t more beneficial than fewer hours, she added. Stroke reduction benefits seemed greatest with 3.5-5 hours of activity per week, which was associated with a 23% risk reduction in the earlier survey and a 29% reduction in the later survey. With more than 5 hours, the risk reduction was 17% and 27%, respectively.

In inactive postmenopausal women, current hormone use was associated with a 59% higher risk for stroke and former hormone use was associated with a 16% increased risk, compared with postmenopausal women who didn’t use hormones, Dr. Wang said. However, the elevated stroke risk with hormone use fell in women who exercised, compared with those who didn’t.

In current hormone users, stroke risk was 37% higher in women who reported 0.51-3.5 hours of moderate or strenuous activity per week and 29% higher in women who reported more than 3.5 hours of activity per week, compared with non-hormone users. In former hormone users, stroke risk was 15% higher in those who reported 0.51-3.5 hours of activity per week and 5% higher in those who exercised more than 3.5 hours per week, compared with non-hormone users.

Because of smaller numbers of women in the subset analyses of postmenopausal hormone use, these differences between groups did not reach statistical significance, Dr. Wang said.

She and her associates plan further studies related to these findings, including whether or not activity levels may help prevent stroke in women who’ve already had a stroke, she said.

Dr. Wang and her colleagues reported having no financial disclosures. The National Institute of Neurological Disorders and Stroke funded the study.

[email protected]

On Twitter @sherryboschert