Specialty Corner: Conventional and Non-Conventional Treatment Options for Post-Menopausal Symptoms

Up to 80 percent of post-menopausal women suffer from a variety of symptoms related to decreased estrogen. The most common symptoms are vasomotor symptoms (VMS) such as hot flashes and night sweats.  Painful intercourse, vaginal dryness, and urinary incontinence are considered vulvovaginal atrophy or part of the genitourinary syndrome of menopause (GSM). Each symptom is a result of a physiological change stemming from lack of estrogen and can last for a decade in some women.¹ As healthcare providers, it is important to address these symptoms to improve our patients’ quality of life. Hormone replacement therapy (HRT) commonly is prescribed  for these patients. However, HRT’s benefits need to be balanced with its risks. HRT poses a cardiovascular risk and is linked to breast cancer, blood clots, stroke and an increase in cardiovascular events.

In a randomized controlled trial, 16,608 postmenopausal women ages 50 to 79 years were assessed to look at the health benefits and risks of hormone therapy. Participants received conjugated equine estrogen (CEE) 0.625 mg/d, plus medroxyprogesterone acetate 2.5 mg/d or placebo. After a mean follow-up of approximately 5 years, the data and safety monitoring board recommended discontinuing the trial because the occurrence of invasive breast cancer exceeded the stopping boundary and they concluded that the risks of HRT outweighed the benefits. Absolute excess risks per 10,000 person-years attributable to HRT were seven more coronary heart disease events, eight more strokes, eight more pulmonary embolisms, and eight more invasive breast cancers, while absolute risk reductions per 10,000 person-years were six fewer colorectal cancers and five fewer hip fractures. The number of women experiencing these events was 100 more per 10,000 women taking hormone therapy than taking placebo. This study emphasized the need for non-hormone therapies for women who cannot or do not want to use hormone-based medications to treat their symptoms.²

The efficacy of paroxetine was established in two randomized, double-blind placebo- controlled clinical trials that demonstrated a modest benefit. The primary endpoints for both studies were the reduction from baseline in VMS frequency and severity at Week 12. The first illustrated a median reduction from baseline of 5.9 moderate-to-severe hot flashes per day with paroxetine as compared to 5.0 per day with placebo (p<0.01). At Week 12 of the second study, there was a median reduction from baseline of 5.6 moderate-to-severe hot flashes per day with paroxetine as compared to 3.9 per day with placebo (p<0.001). A decrease in the severity of symptoms also was seen in these clinical trials. This effect, however modest, was considered clinically significant for most women.⁵  Other selective serotonin reuptake inhibitors and combined serotonergic and norepinephrine reuptake inhibitors such as citalopram, fluoxetine, escitalopram, venlafaxine and desvenlafaxine, also have shown some effectiveness in symptom reduction.⁶

Gabapentin has been shown to be an effective treatment of hot-flash symptoms. A small, randomized, double- blind, placebo-controlled trial of 60 postmenopausal women was designed to assess the efficacy of estrogen and gabapentin in the treatment of moderate- to-severe hot flashes. Participants received either 0.625 mg/d of conjugated estrogen, placebo, or gabapentin titrated to 2,400 mg/d for 12 weeks and recorded their frequency and severity of hot flashes throughout the study. The results showed that the composite score for the severity and frequency of hot flashes, both with estrogen (72%, p=0.016) and gabapentin (71%, p=0.004), were greater than the reduction associated with placebo (54%). Gabapentin was considered as efficacious as estrogen in reducing hot flashes in women.⁷

In addition to prescription medications, there are some herbal supplements marketed for VMS that contain isoflavones and black cohosh. Isoflavones are estrogen- like compounds originating from plants and vegetables. The most widely studied source of isoflavones is soy. Soy isoflavones are metabolized into aglycones, geneistein and diadzen. These compounds have estrogenic activity but are 100 times less potent than endogenous estrogen. Studies have shown that the estrogenic effect is not linked to breast cancer or increased uterine thickness, but it is enough to stimulate the central nervous system, blood vessels, bones and skin. Soy isoflavone compositions containing higher concentrations of geneistein had a significant reduction of hot flashes over placebo.⁸

A recent array of products also contains equol, a metabolite of diadzen, as the isoflavone. Some women do not have the capability to metabolize diadzen into equol, which may play a role in the efficacy of diadzen. Studies have shown that there is potential for its effectiveness in reducing hot flashes in postmenopausal women.⁸ Because of the lack of regulation of over- the-counter herbal supplements, it’s difficult to determine which products containing soy isoflavones can truthfully claim an evidence-based benefit in improving VMS. Another common product used for VMS, black cohosh, has a similar limitation. Black cohosh (Cimicifuga racemosa) was thought to have estrogenic properties, increasing uterine thickness when used for 4-12 weeks.⁹ More recent studies have shown that it has selective estrogen receptor modulator (SERM)-like action.¹⁰  There also is evidence of serotonergic and anti-inflammatory properties that may play a role in relieving VMS.¹¹

The efficacy of black cohosh also remains to be determined. A 2012 Cochrane review of 16 randomized controlled trials found that black cohosh was no more effective than placebo in reducing the frequency of hot flashes. This review led the North American Menopause Society to the conclusion that the evidence to support black cohosh is lacking.¹² Since that Cochrane review, two individual studies revealed that 12 weeks of 13 mg of Ze 450, a standardized ethanolic extract of black cohosh, is superior to placebo in reducing hot flashes.³ A few studies showed a safety concern with black cohosh causing hepatotoxicity, which led to a warning being placed on all black cohosh- containing products. Most studies did not monitor safety, but the available ones had very few reports of hepatotoxic effects.¹³

Localized topical estrogenic therapies are effective for the GSM.  However, vaginal CEE cream or the estradiol-releasing ring may result in higher serum estrogen than tablet or systemic formulations and can cause more uterine bleeding and other adverse effects.  There are some women for whom these remedies are not effective, so they must turn to HRT to relieve their symptoms. Other than FDA-approved conjugated estrogens and progesterone, there is another form of HRT called compounded bioidentical hormone therapy (CBHT). This form of treatment consists of hormones that are derived from plants and compounded for each patient.¹⁴  These preparations are not FDA-approved and consist of oral, vaginal and transdermal formulations.

Common examples of CBHT include tri- estrogen (estriol, estrone and estradiol 8:1:1), bi-estrogen (estriol and estradiol 8:2 or 9:1) and progesterone. The doses listed on the label are the total amounts of all components in the compound, which can be misleading to inexperienced clinicians.¹⁴  There is ongoing debate about the safety and efficacy of CBHT versus FDA-approved hormone therapy.

The Endocrine Society does not recommend CBHT for VMS.¹⁵  Because of the variability among compounded products, the evidence supporting its safety and efficacy is lacking. The risks associated with estrogen based CBHT are not entirely minimized when compared to FDA-approved hormone therapy.  The risks may be greater in that there is no governing body to monitor the level of quality of the medications and ensure proper standards are met.  It has been observed that patients who use CBHT have a higher incidence of endometrial cancer versus those using FDA-approved hormone therapy.¹⁶

The appeal for CBHT is the individuality of treatment. It originally was thought to be beneficial for patients who were intolerant to a dose or a non-medicinal (filler) component of an FDA-approved product. However, over the past few decades, many formulations of HRT have become commercially available. As such, FDA-approved therapies now can be selected rather than one needing to rely on compounding pharmacies to customize a preparation.

In conclusion, there are multiple alternatives for post-menopausal women who are ineligible to receive HRT or would prefer something different. Non-hormonal prescription remedies such as paroxetine and gabapentin have shown benefit in reducing VMS without the cardiovascular risk associated with HRT. Similarly, herbal products are not known to have a high cardiovascular risk, but it is difficult to have clear expectations for efficacy given the different standards for non-prescription therapy. Lastly, CBHT is a non-conventional hormonal treatment option available without prescription. More randomized controlled trials are needed to compare CBHT to FDA-approved HT preparations.

This may, however, turn out to be a difficult and monumental task, because so many formulations can be compounded as a result of so little regulation of CHBT products.  

Disclosure statement: All authors of this article have no financial disclosures to report.

References available here.