Assessing and Treating Menopause

Introduction

In this module, we provide a broad overview of available options for the management of menopausal symptoms and how to assess for and manage common menopause-associated sequelae. We start by considering how the cultural perceptions of menopause and its symptoms may inform menopause management. Next, we discuss the treatment landscape for menopause symptoms, considering menopausal hormone therapy (MHT), non-hormonal pharmacologic options and non-pharmacologic options. In the last two sections, we look at how patients are assessed for osteoporosis, cardiovascular disease, and cognitive decline and how these common menopause-associated conditions are treated or prevented.

Cultural Considerations in Menopause Management

Although most (70-85%) women worldwide experience at least some symptoms during perimenopause, their type and severity can vary substantially depending on the woman’s cultural background, race, ethnicity, or living situation. A well-documented example is the prevalence of vasomotor symptoms (VMS) in perimenopause, which can be as high as 80% in Western countries but is reported by just 5-18% of women in Japan and South-East Asia. Research to date has documented that somatic symptoms (e.g., muscle, joint and back pain) are the most commonly reported perimenopausal symptoms outside of North America and Europe. Several explanations have been proposed to account for inter-regional variation, including differences in diet, physical activity, reproductive patterns and population structure differences; however, social factors (e.g., the relative social position of older women in a given society) and beliefs specific to the culture are perhaps even more important.

How symptoms are experienced and perceived is influenced by the cultural significance of menstruation in general, menopause and the individual symptom concerned. For example, one study found that women in Lebanon and Morocco group somatic symptoms (dizziness, fatigue, headaches) with emotional symptoms (anxiety, depression, nervousness), while women in Massachusetts and Spain consider these separate categories. Cultural perceptions and norms can also affect how symptoms are reported. For example, “chilliness” (hieshō; a sensation of cold even in otherwise warm surroundings) is a VMS that is much more common in Japan among women in perimenopause (~35%) than are “classical” hot flushes (HFs). In one study, Japanese American women living in Hawaii were found to be less likely to report HFs than White American women from the same town (Hilo); however, the prevalence of “objective” HFs (measured by sternal and nuchal skin conductance) was not different in these two groups, illustrating the importance of cultural and linguistic concepts around menopausal symptoms. Despite these and other cultural differences that have been documented to date, it is important to keep in mind that substantial intra-cultural differences among individual women exist as well.

Real and perceived differences in symptoms are only one aspect that can affect the management of menopause. Perhaps just as important is the general attitude of the culture to menopause in general. For example, in the modern West, menopause is medicalized and framed in a negative way (as reproductive or ovarian “failure”). In Turkey and the Arab world, menopause, although not medicalized, is also often perceived negatively. Nevertheless, in societies where menstruation is perceived as impure, its cessation can increase the status of a woman and may confer a degree of liberty from strict gender roles. In Indigenous American and Australian cultures, menopause is typically seen as a natural process that increases the wisdom and status of a woman.

The multitudinous cultural aspects should be considered in the decision surrounding menopause management, such as whether and what kind of treatment to initiate. Some cultures possess developed theoretical and therapeutic systems that may be complementary to modern medicine, including Ayurvedic medicine and traditional Chinese medicine (TCM). In TCM, menopause is conceptualized as a disorder of temperature and fluid balance regulation, which also regulates fertility and sterility; specific herbal preparations are used to alleviate menopausal symptoms.

Individualized Treatment Plans

Menopause is a normal physiological process that does not require treatment in the absence of bothersome symptoms. As briefly overviewed in the section above, significant cultural variation in the experience of both menopause and its symptoms exists, which warrants a careful discussion of whether treatment for symptoms is appropriate in each individual woman’s case. The two most common symptoms of perimenopause are VMS and genitourinary syndrome of menopause (GSM). Several options exists for the treatment of these symptoms; the most effective is MHT, but reasonably effective non-hormonal pharmacotherapy and non-pharmacologic therapies exist for women who do cannot or do not want to take MHT. Peri- and postmenopause may also be associated with sequelae such as osteoporosis, cardiovascular disease (CVD) and cognitive decline. Options for assessment and management of these conditions are discussed in dedicated sections below.

Menopausal Hormone Therapy (MHT)

Hormone therapy for menopause has a long history (reviewed in references). Although not recognized as hormones at the time, the “rejuvenative” effects of extracts from animal gonads were recognized to improve menopausal symptoms in the late 19^th century. As biochemistry advanced in the 20^th century, these initial steps were followed in the 1920s through 1940s by the development of the first true hormonal preparations, including Emmenin (conjugated estriol derived from the urine of pregnant women) and Premarin (conjugated equine estrogens [CEE] derived from the urine of pregnant mares). The popularity of MHT rose dramatically in the 1960s and 1970s; in 1975, estrogen was the 5^th most commonly prescribed medicine in the United States. Two reports of substantially increased risk of endometrial cancer (up to 14 times for long-term use) temporarily dampened the enthusiasm for estrogen after they were published in 1975. The 1980s saw the use of estrogen increase again after evidence emerged that co-administration with progestogen was able to counteract the increased endometrial cancer risk of estrogen alone. The pendulum shifted again with the publication of primary results from the Women’s Health Initiative (WHI), a series of trials designed to test the effectiveness of MHT and other strategies for the reduction of CVD, breast and colorectal cancer and bone fractures. An increase in the risk of coronary artery disease (CAD), stroke, venous thromboembolism (VTE) and breast cancer was observed with estrogen + progestogen compared to the placebo, although the risk of colorectal cancer and osteoporotic fractures was decreased. As patients and practitioners became aware of these findings, a dramatic decrease in the use of MHT in the United States occurred within 5 months of publication, with a 46% and 28% reduction in estrogen + progestogen and estrogen only use, respectively. However, the findings of WHI were not without controversy; the trials were criticized for their design (testing only one CEE alone or in combination with a single progestogen, instead of multiple formulations) and their major conclusions were unduly generalized to all women despite the fact that most study participants were more than 10 years past their final menstrual period.

In the modern era, it is understood that MHT has a favorable risk:benefit ratio in recently menopausal women with moderate to severe menopausal symptoms. The most important lesson from the WHI studies is that the benefit of MHT should be assessed according to the clinical characteristics of the patient: primarily age (favorable in women <60 years of age), time after the final menstrual period (favorable in women <10 years since menopause) and the presence or absence of comorbidities. The type, dosage and administration route of MHT are also important considerations. Figure 3-1 schematically depicts the risks and benefits of MHT as they are understood today.

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The FDA has approved MHT for four indications in women in peri- and postmenopause: VMS, bone loss prevention, premature hypoestrogenism and moderate to severe vulvovaginal symptoms. Several formulations and delivery methods for MHT are available, including:

• Estrogens: Micronized 17β-estradiol, CEE, conjugated estrogens (CE) and ethinyl estradiol. Oral, transdermal (patches) and vaginal formulations are available. Systemic vaginal estrogen therapy is delivered via a vaginal ring with estradiol acetate (12.4 mg or 24.8 mg), which is replaced every 90 days. Systemic estrogen must be given with progesterone in women with a uterus to offset the risk of endometrial cancer. Estrogen alone may be given in women without a uterus, or if delivered locally (egg, low-dose vaginal estrogen therapy for GSM).
• Progestogen: Micronized progesterone, levonorgestrel, norethindrone acetate and medroxyprogesterone acetate (MPA). Combination estrogen + progestogen is available in oral and transdermal formulations. In some combinations, both hormones are taken daily, while in others estrogen is taken daily and progestogen is taken for 12-14 days of the months.

There is yet no data from high-quality studies to favor either transdermal or oral formulations over the other, but observational data suggest that transdermal MHT may carry a lower risk of VTE.

A suggested algorithm for determining whether and which type of MHT is appropriate for the management of VMS is shown in Figure 3-2. Briefly, if only mild symptoms (ie, not affecting quality of life) are present, MHT is not an appropriate choice since risks outweigh benefits in these women. If bothersome, moderate to severe VMS are present, each patient should be assessed for contraindications to MHT, which include history of breast cancer, liver disease, prior stroke or myocardial infarction, documented or suspected estrogen-dependent cancer, history of VTE or pulmonary embolism and thrombophilia. If no contraindications are present, MHT may be appropriate, with the specific formulations and administration method depending on patient characteristics and preferences. If contraindications are present or the patient is unwilling to consider MHT, several non-hormonal alternatives exist (see Figure 3-2 and the sections below).

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Although not considered the first-line therapy for the management of GSM (Figure 3-3), MHT can still be useful in patients for whom over-the-counter (OTC) vaginal lubricants or moisturizers proved ineffective. Low-dose vaginal estrogen, vaginal prasterone (dehydroepiandrosterone, an estrogen prohormone), or oral ospemifene (a non-hormonal option) are equally appropriate and may be given based on patient preference.

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Non-Hormonal Pharmacological Options

Several non-hormonal pharmacological options for VMS exist. Although supported by clinical trial data, these options are generally less effective than MHT and are not FDA-approved (with the exception of paroxetine and fezolinetant). The options include selective serotonin reuptake inhibitors (SSRI; paroxetine, citalopram, escitalopram), serotonin norepinephrine reuptake inhibitors (SNRI; venlafaxine, desvenlafaxine), gabapentin, clonidine, oxybutynin and fezolinetant. See Figure 3-2 for the recommended dosage of these agents for VMS management. Fezolinetant, a novel neurokinin 3 (NK3) receptor antagonist, is detailed in a dedicated section below. For the treatment of GSM, OTC lubricants and moisturizers for vaginal use are considered the first-line therapy, with ospemifene (60 mg daily per os) a second-line non-hormonal option.

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Fezolinetant: a Novel Non-Hormonal Agent

Research into the physiological mechanisms of HFs has revealed that kisspeptin, neurokinin B and dynorphin (KNDy) neurons have an essential role in both thermoregulation and the gonadotropic hormonal axis (see Overview of Menopause and Menopause and Women’s Health). Briefly, the decline in estrogen levels causes KNDy neuron hypertrophy and increased stimulation of NK3 receptor by neurokinin B, which causes VMS. Fezolinetant is a small molecule which blocks the binding of neurokinin B to the NK3 receptor, modulating neural activity in the thermoregulatory regions in the hypothalamus, thus reducing the frequency and severity of VMS (Figure 3-4).

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The clinical safety and efficacy of fezolinetant was assessed in three randomized, double-blind, placebo-controlled phase 3 clinical trials: SKYLIGHT-1 and SKYLIGHT 2, which assessed both safety and efficacy and SKYLIGHT 4, a safety trial which assessed the effect of fezolinetant on endometrial health.

In SKYLIGHT 1, a total of 527 women 40-65 years of age with an average of ≥7 moderate-to-severe HFs were randomized (1:1:1) to receive either fezolinetant 30 mg (n=176), fezolinetant 45 mg (n=176), or a matching placebo (n=175) once daily. The mean change in frequency and severity of VSM from baseline to weeks 4 and 12 were the co-primary endpoints. Both doses of fezolinetant resulted in a significant reduction of VMS frequency and severity, compared to the placebo. In the fezolinetant 30 mg, 45 mg and the placebo groups, respectively, the daily frequency of VMS events was 10.7, 10.4 and 10.5 at baseline, 5.4, 5.2 and 7.3 at week 4, and 4.5, 4.1 and 6.9 at week 12. The change in mean least squares from baseline of VMS severity for the fezolinetant 30 mg, 45 mg and the placebo groups, respectively, was -0.42, -0.46 and -0.27 at week 4 and -0.60, -0.57 and -0.37 at week 12.

The SKYLIGHT 2 trial had a design identical to SKYLIGHT 1. A total of 501 women were randomly assigned to the three treatment groups (n=167 for placebo, n=166 for fezolinetant 30 mg and n=167 for fezolinetant 45 mg). All four co-primary endpoints were met, with both fezolinetant groups achieving significant reductions in VMS frequency and severity at week 4 and week 12. The frequency of VMS events was reduced from a mean baseline value of 11.23, 11.79 and 11.59 per day in the fezolinetant 30 mg, 45 mg and placebo groups, respectively, to 5.79, 5.67 and 8.08 per day at week 4 and 4.80, 4.49 and 6.73 per day at week 12. At week 4, the change from baseline in VMS severity (mean least squares) was -0.47, -0.61 and -0.32 for fezolinetant 30 mg, 45 mg and the placebo, respectively; at week 12, the change from baseline was -0.64, -0.77 and -0.48.

Fezolinetant treatment led to significant improvements in the quality of life generally (assessed by the Menopause-Specific Quality of Life [MENQOL] questionnaire) and sleep quality specifically (assessed by the Patient-Reported Outcomes Measurement Information System Sleep Disturbance—Short Form 8b [PROMIS SD SF 8b] questionnaire) as early as week 4 in both SKYLIGHT 1 and 2; these improvements were maintained at week 12 and beyond in the fezolinetant 45 mg group.

Fezolinetant was generally well tolerated in SKYLIGHT 1 and 2, with a low frequency (<2%) of serious treatment-emergent adverse events (TEAEs) that was comparable between the three treatment groups. The most common AEs were COVID-19 (the study was underway during COVID-19 pandemic), headache and upper respiratory tract infection. Additional safety data were collected in SKYLIGHT 4, a 52-week safety study that randomized a total of 1,830 women to the same three groups as in the two efficacy SKYLIGHT trials. The primary endpoints were TEAEs, endometrial hyperplasia and endometrial malignancy. No apparent safety signals for fezolinetant use were uncovered in SKYLIGHT 4. The rate of serious study-drug related TEAEs was low (<1%) and comparable between groups. Endometrial safety results (assessed in the 599 participants who agreed to undergo biopsies) were within expected rates, with 1 case of endometrial hyperplasia (0.5%) in the fezolinetant 45 mg group and 1 case of endometrial malignancy (0.5%) in the fezolinetant 30 mg group.

Based on the positive safety and efficacy results from the SKYLIGHT clinical trials, fezolinetant received FDA approval for the treatment of moderate to severe vasomotor symptoms due to menopause in May 2023. The FDA-approved dosage of fezolinetant is one 45 mg tablet per day, taken with or without food. With its proven safety and efficacy and a rapid onset of action (reaching a steady-state plasma concentration after only two daily doses), fezolinetant represents a major advance and presents a novel treatment option for women with bothersome VMS symptoms who are either ineligible for MHT or eligible but averse to MHT (an estimated 56% in Europe, 54% in the United States and 79% in Japan).

Non-Pharmacological Options

For women who are unable or unwilling to use pharmacologic therapy, or for whom pharmacotherapy did not yield desired results, several non-pharmacologic options exist, albeit with generally lower efficacy. These include mind-body techniques, exercise, weight loss, herbal medicine, phytoestrogen supplements (e.g., S-equol) and other traditional techniques (yoga, TCM, acupuncture). Of these, mind-body techniques have the best efficacy data, with randomized controlled trials supporting the efficacy of hypnosis and cognitive behavioral therapy for the reduction of VMS. Other interventions listed above have mixed evidential support. Herbal therapies with purported but not uncertain efficacy include black cohosh (Cimicifuga racemosa), wild yam (genus Diascorea), dong quai (Angelica sinensis) and maca (Lepidium meyenii), among others. Additional interventions that may be helpful on a case-by-case basis include dressing in layers, wearing “breathable” clothes and cooling oneself with cold packs or fans.