ERAAs for menopause treatment: Welcome the ‘designer estrogens’

OSPEMIFENE: FOR GENITOURINARY SYNDROME OF MENOPAUSE

Although ospemifene does not have the steroid structure of estrogen, it acts as an estrogen agonist specifically in the vaginal mucosa and an antagonist in other tissues.²⁸ It has been shown on Papanicolaou smears to reduce the number of parabasal cells and increase the number of intermediate and superficial cells after 3 months of treatment.²⁹

Ospemifene 60 mg taken orally with food is approved by the FDA to treat genitourinary syndrome of menopause.

Why ospemifene is needed

First-line treatment options for genitourinary syndrome of menopause include over-the-counter lubricants. However, there is no evidence that these products reverse vaginal atrophy,³⁰ and many women report no relief of symptoms with them.

While various local estrogen preparations positively affect genitourinary syndrome of menopause, some of them can be messy, which can limit-long term adherence.

In one of the largest surveys on genitourinary syndrome of menopause (the REVIVE survey—the Real Women’s View of Treatment Options for Menopausal Vaginal Changes²⁹), 59% of women reported that their vaginal symptoms negatively affected sexual activity. The problem affects not only the patient but also her sexual partner.³¹ Another large study showed that 38% of women and 39% of male partners reported that it had a worse-than-expected impact on their intimate relationships.³¹

Genitourinary syndrome of menopause also makes pelvic examinations difficult, may worsen or exacerbate cystitis, and may increase urinary tract infections.

Trials of ospemifene for genitourinary syndrome of menopause

To date, 3 randomized, double-blind clinical trials have demonstrated ospemifene 60 mg to be superior to placebo in treating genitourinary syndrome of menopause. Two were short-term (12-week) and showed significant positive changes in the percent of superficial cells, vaginal pH (lower is better), and number of parabasal cells, along with improvements in the Likert rating of both vaginal dryness and dyspareunia.^32,33

A long-term (52-week) randomized placebo-controlled trial compared ospemifene and placebo and showed significant improvement in vaginal maturation index and pH at weeks 12 and 52.³⁴ Other outcome measures included petechiae, pallor, friability, erythema, and dryness, all of which improved from baseline (P < .001). At the end of the trial, 80% of the patients who received ospemifene had no vaginal atrophy.

No serious adverse events were noted in any of the clinical trials to date, and a systemic review and meta-analysis demonstrated ospemifene to be safe and efficacious.³⁵ The most frequently reported reasons for discontinuation were hot flashes, vaginal discharge, muscle spasms, and hyperhidrosis, but the rates of these effects were similar to those with placebo.

Trial of ospemifene’s effect on bone turnover

As an estrogen receptor agonist in bone, ospemifene decreases the levels of bone turnover markers in postmenopausal women.³⁶ A study found ospemifene to be about as effective as raloxifene in suppressing bone turnover,³⁷ but ospemifene does not carry FDA approval for preventing or treating osteoporosis.

Other effects

In experiments in rats, the incidence of breast cancer appears to be lower with ospemifene, and the higher the dose, the lower the incidence.³⁸

Ospemifene also has antagonistic effects on uterine tissue, and no cases of endometrial hyperplasia or carcinoma have been reported in short-term or long-term studies.³⁵

Ospemifene has no effect however on vasomotor symptoms and may in fact worsen vasomotor symptoms in women suffering with hot flashes and night sweats. Further investigation into its long-term safety and effects on breast tissue and bone would provide more insight.

Ideal candidates for ospemifene

Ospemifene could help postmenopausal women with genitourinary syndrome of menopause for whom over-the-counter lubricants fail, who dislike local vaginal estrogen, or who decline systemic hormone therapy, and who do not meet the criteria for treatment with systemic hormone therapy.

CONJUGATED ESTROGENS AND BAZEDOXIFENE COMBINATION

A combination agent consisting of conjugated estrogens 0.45 mg plus bazedoxifene 20 mg has been approved by the FDA for treating moderate to severe vasomotor symptoms associated with menopause and also for preventing postmenopausal osteoporosis in women who have an intact uterus.

Trials of estrogen-bazedoxifene for vasomotor symptoms

The Selective Estrogen Menopause and Response to Therapy (SMART) trials^39,40 were a series of randomized, double-blind, placebo-controlled phase 3 studies evaluating the efficacy and safety of the estrogen-bazedoxifene combination in postmenopausal women.

The SMART-2 trial³⁹ evaluated the combination of conjugated estrogens (either 0.45 mg or 0.625) plus bazedoxifene 20 mg and found both dosages significantly reduced the number and severity of hot flashes at weeks 4 and 12 (P < .001). At week 12, the combination with 0.45 mg of estrogen reduced vasomotor symptoms from baseline by 74% (10.3 hot flashes per week at baseline vs 2.8 at week 12); the combination with 0.625 mg of estrogen reduced vasomotor symptoms by 80% (10.4 vs 2.4 flashes); and placebo reduced them by 51% (10.5 vs 5.4 flashes).

For bone density. The SMART-1 trial⁴⁰ showed that the estrogen-bazedoxifene combination in both estrogen dosages significantly increased mean lumbar spine bone mineral density (P < .001) and total hip bone mineral density (P < .05) from baseline at 12 and 24 months compared with placebo. Increases in density tended to be higher with the higher estrogen dose (0.625 mg), but less with higher doses of bazedoxifene.⁴¹ At 24 months, the increase in bone mineral density was even greater than in women treated with raloxifene.⁴² However, the effect of estrogen-bazedoxifene on the incidence of fractures remains to be studied.

For genitourinary syndrome of menopause. The SMART-3 trial showed that treatment with conjugated estrogens plus bazedoxifene (0.45/20 mg or 0.625/20 mg) was more effective than placebo in increasing the percent of superficial and intermediate cells and decreased the number of parabasal cells at 12 weeks compared with placebo (P < .01).⁴³ Both doses also significantly decreased the mean vaginal pH and improved vaginal dryness.

Patients treated with estrogen-bazedoxifene for a minimum of 12 weeks in a double-blind placebo-controlled study also showed a significant improvement in sexual function and quality-of-life measurements based on 3 well-defined scales, which included ease of lubrication, satisfaction with treatment, control of hot flashes, and sleep parameters.⁴³

Low rates of side effects

To evaluate this regimen’s antagonistic effects on uterine tissue, endometrial hyperplasia was diagnosed by blinded pathologists using endometrial biopsies taken at 6, 12, and 24 months or more if cancer was a suspected diagnosis. At 12 and 24 months of treatment, the incidence of hyperplasia with bazedoxifene 20 or 40 mg at doses of either 0.45 or 0.625 mg of conjugated estrogens was less than 1%, which was similar to placebo rates over the 24 months.⁴⁴ The lowest dose studied, bazedoxifene 10 mg, did not prevent hyperplasia with conjugated estrogens 0.45 or 0.625 mg, and its use was discontinued.

Rates of amenorrhea with bazedoxifene 20 or 40 mg and conjugated estrogens 0.45 or 0.625 mg were very favorable (83%–93%) and similar to those with placebo.⁴⁵ For women with continued bleeding on hormone therapy requiring multiple evaluations, or for women who won’t accept the risk of bleeding on hormone therapy, conjugated estrogens and bazedoxifene may be a sustainable option. However, any woman with abnormal bleeding should undergo prompt immediate evaluation.

A typical side effect of estrogen replacement therapy is breast tenderness. For women seeking vasomotor symptom treatment but who experience breast tenderness, this may be a deterrent from continuing hormone therapy. As shown in the SMART-1 and SMART-2 trials,⁴⁶ conjugated estrogens and bazedoxifene did not cause an increase in breast tenderness, which may enhance medication adherence.

Ideal candidates for conjugated estrogens plus bazedoxifene

This product could help postmenopausal women who have an intact uterus and are suffering with moderate to severe vasomotor symptoms and genitourinary syndrome of menopause who cannot tolerate the side effects of hormone therapy such as bleeding, bloating, or breast tenderness, or who prefer to take an estrogen but without a progestin. It is also ideal for women at higher risk of osteoporosis.

WHO SHOULD GET WHAT?

Not all postmenopausal women have vasomotor symptoms, genitourinary syndrome of menopause, or bone loss. For those who do, standard hormone therapy is an option.

For those who have symptoms and a lower threshold of side effects such as breast tenderness and vaginal bleeding, a combination of an estrogen plus an ERAA (eg, bazedoxifene) is an option.

For women who have no vasomotor symptoms but do have genitourinary syndrome of menopause and don’t want local vaginal treatment, ospemifene is an option.

For women with no vasomotor symptoms but who have bone loss and increased risk of estrogen receptor-positive breast cancer, raloxifene is a good option.

Both premenopausal and postmenopausal women who are at increased risk for breast cancer should be considered for tamoxifen chemoprevention. Postmenopausal women with a uterus at increased risk for breast cancer should be considered for raloxifene, as it has no uterine effect. Raloxifene is not indicated in premenopausal women.

No woman at increased risk of venous thromboembolism is a candidate for ERAA treatment or for oral estrogen. However, the clinician has multiple options to improve quality of life and work productivity and reduce office visits of women at midlife, especially when they are individually assessed and treated.