Key Takeaways

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• An estimated 1.1 billion women* globally are expected to be menopausal by 2025. Menopausal symptoms (e.g., hot flashes, fatigue, night sweats, insomnia) occur in up to 75% of women. Menopause affects various aspects of overall health (e.g., bone, mental, heart, brain) and may impact daily livelihood, sexual relationships, and potential success in the workplace. A diagnosis is typically achieved via a combination of hormonal testing, which does not provide a definitive result, and menstrual cycle monitoring. Menopause is clinically diagnosed when a woman has gone 12 consecutive months without a menstrual period; however, 1 in 3 women have never been formally assessed by a physician and ~20% of women experience symptoms for over a year prior to diagnosis and treatment.
• Common treatments are typically either anti-depressants and/or hormone replacement therapies, of which there are 39 FDA, HPFB, and EMA approved therapies (estrogen, progestin, or estrogen + progestin) in various product types (e.g., patch, pill, shot, gel, vaginal ring). Other treatment options which may reduce menopausal symptoms include anti-seizure medications (e.g., gabapentin), selective estrogen receptor modulators (SERMs), and neurokinin-3 receptor antagonists (e.g., pavinetant, fezolinetant). However, current treatments only target symptoms of menopause (as opposed to delaying / reversing onset). Additionally, treatment success/side effects may vary significantly and women may experiment with different product types and dosages by trial and error before receiving optimal care.
• As menopause is estimated to be a $600B+ market opportunity, there is significant potential for improved care and personalized treatment options for women. Despite the clear unmet needs in diagnosing and treating menopause, it has been historically underrepresented in funding and research efforts. Research indicates that genetic variations may be tied to more severe menopause symptoms, higher side effects to treatment, decreased treatment efficacy, or increased risk of additional health conditions (e.g., Alzheimer’s). As menopause is a complex clinical condition impacted by multiple factors (e.g., genetic, physiologic, environmental), further research could uncover optimal treatment options tailored to each unique individual. 

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Menopause is a condition potentially relevant to 50% of the population, yet it receives relatively limited attention. Menopause not only causes numerous symptoms which can have drastic effects on quality of life, but is also associated with several health conditions such as cancer, diabetes, heart disease, obesity, osteoporosis, mental health issues, and neurodegenerative diseases. An estimated 1.1 billion women are expected to be menopausal by 2025, representing a ~$600B+ market opportunity. Common and potentially debilitating symptoms include fatigue, night sweats, hot flashes, insomnia, and depression (among other changes). The State of Menopause Study found that for women experiencing menopausal symptoms, ~20% do not see a provider for over a year and ~75% are not currently treating their symptoms. Additionally, 1 out of 3 women have never been formally assessed by a physician. Women may not seek care for a number of reasons, such as a lack of proper education regarding menopause or a lack of resources. One study found that 32% of women feel their doctor is not comfortable talking about menopause.

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There are dozens of treatment options ranging from estrogen creams to anti-depression medications to low-dose birth control pills and beyond. Women can manage symptoms via pills, injections, patches, hormones, supplements, and phone applications. However, women may have to experiment with various dosages or different drugs before finding one that most effectively improves their quality of life. 

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“... It’s important to remember that a woman is never past menopause. Perimenopause can go on for about 5 to 7 years and once you begin menopause, that is the rest of your life …”

• Dr. Eric Colton, OBGYN 

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FIGURE 1: DIAGNOSTIC & THERAPEUTIC LANDSCAPE FOR MENOPAUSE

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Menopause Diagnostics

Current testing for menopause typically evaluates hormone levels (e.g., FSH, LH, and estradiol). Testing can be performed either in a doctor’s office or via at-home test options (ranging from $10 - $130) such as Everlywell, Reveal, Thorne, myLAB Box, Perimenopause Test, and LetsGetChecked Female Hormone Test. Results indicate whether hormone levels are elevated or decreased but do not definitively diagnose menopause or perimenopause, leaving opportunity for improvement. Proper diagnosis could help women better understand and manage their symptoms, modify contraceptive options (if relevant), and start treatment earlier which could — which have downstream health benefits (e.g., decreased risk of mental health issues, neurodegenerative diseases, bone health).
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Pharmacogenomic testing could be one approach to a more personalized treatment plan. Anti-depressants such as paroxetine, venlafaxine, escitalopram and citalopram can treat some menopausal symptoms. However, genetic variations in liver enzymes CYP2D6 and CYP2C19 can affect drug efficacy, metabolism, and tolerability; <35% of North American women are normal metabolizers for both enzymes. Additionally, estradiol treatment success may vary based on differential estrogen metabolism potentially implicating genes involved in estrogen metabolism as well as the estrogen receptor gene.
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There may be untapped precision medicine opportunities for menopause treatment, as evidenced by several other biomarkers that are potentially associated with and relevant to menopause. For example, women carrying a gene variant (rs6025) in Factor V Leiden or the F2 gene may experience venous thromboembolism when treated with hormonal therapy. The interplay between hormone therapy and BRCA1/2 mutations for women with a previous history of cancer (e.g., breast, ovarian) is also important to consider. Additionally, variations in the MTHFR gene have been associated with early onset of menopause and have been linked to depression in menopausal women. There are also protein biomarkers such as those relevant to cardiovascular disease, inflammatory markers, glucose tolerance markers, endothelial markers, matrix metalloproteinases, hemostatic markers, and more that could also warrant further research. 
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Menopause Therapeutics

There are many treatment options available for menopause, including 39 menopausal hormone therapy (MHT) products (estrogen, progestin, or estrogen + progestin) approved by the FDA, HPFB, and EMA in various product types (e.g., patch, pill, shot, gel, vaginal ring). Other treatment options which may reduce menopausal symptoms include anti-depressants (e.g., SSRIs), anti-seizure medications (e.g., gabapentin), selective estrogen receptor modulators (SERMs), and neurokinin-3 receptor antagonists (e.g., pavinetant, fezolinetant). While these treatments may reduce the severity of symptoms for many women, they are not always effective and may cause side effects. Additionally, the primary goal of current treatments is to relieve hot flashes and, secondarily, other symptoms. These treatment options do not address concerns for women who may want to delay or reverse menopause (e.g., women undergoing chemotherapy, women who want to have children later in life). 
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Additional treatment options, such as testosterone treatment or localized estrogen application, may help target challenges with sexual health such as vaginal dryness and painful intercourse. However, these medications come with their own side effects and restrictions (e.g., may not be used in combination with alcohol). Subsequently, there is opportunity for improved solutions, with minimal side effects, that address quality of sex. 
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Due to the variance in outcomes or the taxing effect hormonal treatment can have on an individual, individual patient characteristics should be taken into consideration when prescribing treatment (including but not limited to genetics, age, clinical symptoms, medical history, diet / lifestyle / environmental factors, and additional health considerations). Studies have found that women may experience significant differences in long-term health outcomes despite comparable near-term treatment efficacy, underlining the conclusion that upfront-personalized treatment may be beneficial. Historically, treatment plans for menopause are decided via doctor / patient interactions, but there is significant opportunity for precision medicine to mitigate trial and error when determining personalized treatment plans.

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Broader Implications for Women’s Health & Wellbeing

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FIGURE 2: IMPACT OF MENOPAUSE ON WOMEN’S DAILY LIVES

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Independently, symptoms of menopause can have substantial impacts on wellbeing. For example, disturbed sleep brought on by night sweats caused by LH surges disrupting REM cycles can negatively impact physical and mental energy levels for days to come. Changes in hormone levels during menopause can have multiple effects, including loss of bone density, weight gain, and vaginal dryness. These experiences not only reduce ability and comfort to participate in previously enjoyed activities, but they can also catalyze the presence of other issues. For example, weight gain and osteoporosis can lead to hip fractures or even cardiovascular distress. Vaginal atrophy or dryness throughout menopause can be so severe that it halts sex lives, with ~50% of women ceasing sex as a result. 
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“... One place we are lacking is in sexual health. It is a huge, huge issue. We have all these drugs for men, but for women dealing with vaginal dryness and painful intercourse, there just aren’t good solutions or they come with the cost of potentially significant side effects …”

• Dr. Eric Colton, OBGYN
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When it comes to professional lives, additional symptoms such as brain fog, irritability, and headaches further generate negative impacts. This often occurs right at the peak of careers when women most commonly enter leadership positions. One survey found that 40% of respondents mentioned that their experience with menopause has a significant impact on their work. The severity of menopause may even lead to earlier retirement or job shifts for women, with 10% of women in the Mira survey mentioning having changed their job or having plans to change their job due to menopause. Another study found that 78% of women reported that menopause interfered with their daily lives.
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“... Hot flashes aren’t limited to at night. Imagine giving a presentation to a board of directors in a room full of men who may not understand menopause or may even crack jokes about it. For women experiencing a hot flash, it can be embarrassing and impactful; These women become diaphoretic. They turn beet-red. They experience a significant change in body temperature. There are beads of sweat. It can happen instantaneously and it won’t stop. And for 15% of women, this is a life-long occurrence [once they begin menopause] ...”
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• Dr. Eric Colton, OBGYN
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Additionally, women are at a higher risk for Alzheimer’s than men and there is some evidence that this risk may be associated with decreased estrogen levels post-menopause. Menopausal hormone therapy may reduce risks of cognitive memory decline, as evidenced in a recent study by University of Arizona Health Sciences that found women on hormone therapy were up to 58% less likely to develop neurodegenerative diseases. APOE expression is modulated by estrogen, and the APOE4 genotype has been linked to higher risk of Alzheimer’s. Additionally, polymorphism in genes related to estrogen synthesis and metabolism (e.g., CYP17, CYP19) may increase risk of Alzheimer’s. Additional studies could reveal potential improvements in treatment options that minimize symptoms of both menopause and Alzheimer’s. There is also potential that intervention with earlier treatment could help target both conditions.

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As elucidated above, the impacts of menopause can be severe and it can be a significant challenge for women in both their personal and professional lives. There is significant need and opportunity for further research in menopause (and more broadly in women’s health) to provide faster and more definitive diagnoses and support optimized treatment plans personalized to individuals’ unique clinical circumstances. There has been limited research regarding women’s hormone cycles and women were historically excluded from clinical trials altogether due to perceived complexity of menstrual cycles. However, this topic must be explored to obtain a complete picture for women’s health. Longitudinal multi-omic studies (e.g., genomic, proteomic, clinical symptoms) could unlock additional diagnostic and therapeutic biomarkers as well as previously unknown ties to other health issues. There is a large market opportunity surrounding menopause, and a clear white space for precision medicine to alleviate current challenges and unmet needs.
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Future Questions

1. What other opportunities for treatment selection exist to help efficiently manage menopause?

2. What are macro-trends surrounding menopause (e.g., impact of earlier onset of periods and later pregnancies on average in the broad population)? 

3. Could menopause treatments advance beyond symptom management (e.g., through restoring ovarian function or delaying onset of menopause)?

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Note

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* While this blog refers to the group of people experiencing menopause as women, it is important to recognize that there are people in this group who do not identify as women as well as women who do not experience menopause.

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