#409 Hormonal and Nonhormonal Therapy for Vasomotor Symptoms of Menopause

September 25, 2023 | By Matthew Watto, MD

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Master hormonal and nonhormonal therapies for menopausal symptoms including vasomotor symptoms (VMS).  We’re joined by Dr. Monica Christmas, @drmonicaxmas (UChicago Medicine). 

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Show Segments

• Intro
• Nonpharmacologic management of vasomotor symptoms (VMS)
• Non-hormonal therapy for menopause
• Taking a history for menopausal symptoms, VMS
• Hormone therapy (HT) risk assessment, counseling
• Prescribing Hormone therapy
• Troubleshooting hormone therapy
• Premature menopause and primary ovarian insufficiency
• Discontinuation of hormone therapy
• Outro

Menopause Pearls

1. Bothersome menopausal symptoms can start in a patient’s early to mid-forties even while they still have a regular menstrual cycle.  The duration of VMS is highly variable.
2. Recommended nonpharmacologic options for VMS include weight loss, hypnosis, and cognitive behavioral therapy. 
3. Recommended nonhormonal medications for VMS include SSRIs, SNRIs, gabapentin, oxybutynin, and fezolinetant.
4. Hormone therapy (HT) is our most effective therapy for VMS, but is not a cure-all for postmenopausal women experiencing weight gain, aging skin, low energy, thinning hair, or brain fog. 
5. Vaginal estrogen therapy (cream/vaginal tablet twice weekly or vaginal ring every 3 months) can be used indefinitely for genitourinary symptoms of menopause.
6. There is no firm age cutoff for discontinuation of HT.  Individualize the decision, discuss risks, utilize low doses, and prioritize transdermal HT. 
7. In the absence of contraindications, women with premature menopause, or surgical menopause should receive HT until the average age of menopause (~52 yo) to prevent bone loss and menopausal symptoms, and possibly reduce the risk of CV disease, overall mortality, and cognitive impairment. 

Taking a history 

Dr. Christmas notes menopausal symptoms are individualized so rather than focus on scales (which are good for research) she asks about bothersome symptoms and coping behaviors.  Note, symptoms can start in a patient’s early to mid-forties even while they still have a regular menstrual cycle.  In her experience, women are most symptomatic in the perimenopause transition, but the onset, severity, and duration of symptoms vary by patient.  She assesses how much symptoms are disrupting quality of life and looks for comorbid conditions (e.g. thyroid disease), medications (muscle relaxants, opioids), or other factors that may be contributing. 

Menopause has received lots of press lately (NY Times article, “Women Have Been Misled About Menopause”) with hormone therapy being touted as an antidote to aging, and various ailments.  

Nonhormonal therapy for VMS

Dr. Christmas likes to lay out options for treating symptoms of menopause, and let the patient choose.  She starts with lifestyle modifications, nonhormonal options, and then reviews hormonal therapy. 

• No dietary supplements have been shown to consistently perform better than placebo (NAMS, 2023), but if a patient feels like it’s helping, Dr Christmas does not discourage ongoing use.
• Weight loss may help decrease the severity of vasomotor symptoms (NAMS, 2023).  Dr. Christmas recommends exercise and healthy eating (often Mediterranean style) to promote weight loss and general well-being (expert opinion). 
• Cognitive behavior therapy (CBT) can help mitigate symptoms (NAMS, 2023) by improving thought patterns and responses to hot flashes. Patients can explore online CBT options.
• Hypnosis can also help (NAMS, 2023).  
• SSRIs, SNRIs, gabapentin, oxybutynin, and fezolinetant are nonhormonal prescription therapies with evidence of benefit (NAMS, 2023). 

Fezolinetant

The KNDy (kisspeptin, neurokinin B, and dynorphin) neurons hypersecrete neurokinin B during menopause, which affects the hypothalamic thermoregulatory center, disrupting temperature regulation.  Fezolinetant is a selective neurokinin B receptor-3 antagonist that mitigates the temperature dysregulation caused by hyperactive KNDy neurons (NAMS, 2023).  Liver enzymes need to be checked at 0, 3, 6, and 9 months for patients starting fezolinetant.  Headaches were a common side effect of fezolinetant, though similar to placebo (Johnson, 2023), but Dr. Christmas is cautious about this agent in patients with poorly controlled baseline headaches.

SSRIs, SNRIs, Gabapentin

Of these, only paroxetine is FDA approved for management of VMS, but other agents are frequently used off label.  Dr. Christmas mentions that decreased libido and weight gain can be an issue with some SSRIs.  Be sure to check for interactions with tamoxifen for women starting SSRIs because paroxetine and fluoxetine are not recommended, but venlafaxine, desvenlafaxine, escitalopram, or citalopram are safe options to co-prescribe with tamoxifen (NAMS, 2023).  Dr. Christmas mentions that she often chooses venlafaxine as her first line non-hormonal treatment choice (expert opinion).   Gabapentin is suggested to dose at 300mg at night, with up titration as tolerated and as needed (NAMS, 2023).

What to know about the Women’s Health Initiative  

At the time of the Women’s Health Initiative (WHI), researchers had already established that hormone therapy was an effective therapy for menopausal symptoms.  The WHI was designed to look at the safety of hormone replacement therapy in healthy postmenopausal women with primary outcomes including invasive breast cancer and coronary heart disease (nonfatal myocardial infarction and coronary heart disease death) (Rossouw, 2002).  The average age of women in the WHI was 63, and hormone therapy was prescribed regardless of bothersome menopausal symptoms.  The trial was stopped early after a mean of 5.2 years for excess risk of heart disease events, stroke, pulmonary embolism, and invasive breast cancers (Rossouw, 2002). 

Hormone therapy for Menopause

Hormone therapy (HT) is approved for four indications

1. Vasomotor symptoms of menopause (VMS)
2. Prevention of osteoporosis, but NOT treatment
3. Premature menopause (before the age of 40 yo) e.g. Primary ovarian insufficiency, bilateral oophorectomy)
4. Vulvovaginal atrophy (genitourinary symptoms of menopause)

Unfortunately, HT is not a cure-all for postmenopausal women experiencing weight gain, aging skin, low energy, thinning hair, or brain fog. 

Current guidelines recommend consideration of hormone therapy for women under 60 years of age or less than 10 years from menopause with moderate to severe vasomotor symptoms (NAMS, 2022). 

Hormone Therapy Risk Assessment 

Ask about prior venous thromboembolism (VTE), and assess for risk of or known heart disease, and estrogen-sensitive cancers (breast, ovarian, endometrial).  Prior VTE was classically considered a contraindication to HT, but some hematologists co-prescribe HT with anticoagulation (episode #280 HMB, Anticoagulation & Coagulopathy). 

Recall our discussion on assessing CVD and breast cancer risk from episode #396 at SGIM2023:

“Presenters shared this algorithm to assess cardiovascular (CV) risk of HT 1) Assess for existing cardiovascular disease and avoid HT if present. 2) Identify existing CV risk factors and calculate ASCVD risk score. Avoid HT if high ASCVD risk score or a coronary artery calcium score (CAC) above 100. Use shared decision-making if intermediate CV risk. HT is probably safe if low CV risk.

Presenters shared this algorithm to assess breast cancer risk of HT 1) assess for a personal or strong family history of breast or ovarian cancer, or chest radiation before 30 years old. Avoid HT if present. 2) Calculate a Gail score. Avoid HT if high risk by Gail. Use shared decision-making if intermediate risk. The absence of a uterus would favor treatment if intermediate risk. Recommend HT if low Gail risk score.”

Vaginal Estrogen Therapy

Vaginal estrogen therapy (VET) can be prescribed for genitourinary symptoms of menopause (e.g. recurrent urinary tract infections, urinary frequency/urgency, vaginal dryness, pain, or bleeding with intercourse).   VET dosing is significantly lower than systemic HT and does not carry the risks of VTE/CVD or endometrial hyperplasia so is safe in many patients who may not qualify for HRT.  VET can be used indefinitely.  VET options include vaginal cream, insert, tablet (used twice weekly) or ring (replaced every 90 days).  Dr. Christmas counsels patients to expect about eight weeks before maximum results (expert opinion).  Most VET is low dose and does not contain adequate estrogen dosing to treat VMS (NAMS, 2020).

Caption: Vaginal Estrogen Options slide reproduced with permission of Dr. Monica Christmas

Note: in the slide above, estradiol acetate vaginal ring 12.4mg/24.8mg (Femring) is approved for treatment of genitourinary symptoms of menopause, as well as VMS, and contains systemic dose HT.  

Systemic Hormone Therapy

Systemic hormone therapy is currently the most effective treatment for vasomotor symptoms of menopause (VMS).  Patients with a uterus require estrogen and progesterone therapy (due to risk of endometrial hyperplasia with estrogen alone), while patients without a uterus can receive estrogen therapy alone.  Dr. Christmas has shared the slides embedded throughout this section highlighting a wide range of formulations for providing estrogen and/or progesterone therapy to treat vasomotor symptoms of menopause.  The bad news is that the choice of estrogen and progesterone formulation will often be dictated by cost/insurance.  The good news is that all of the formulations are efficacious. 

Combined estrogen and progesterone therapy comes in pill or patch options.  Downsides include less flexible estrogen dosing. 

Estrogen options include oral tablets, transdermal patches/gels/topical emulsion, vaginal ring (high dose), or transdermal spray. 

Progesterone options include oral tablets, levonorgestrel intrauterine device (IUD), or vaginal gel. IUDs remain in place during treatment; progesterone tablets or gels can be taken cyclically or continuously. 

• Dr. Christmas notes the progesterone IUD works well for women with irregular perimenopausal bleeding because it often stops bleeding altogether (expert opinion).
• Withdrawal bleeding may occur in postmenopausal women taking cyclic oral progesterone (12-14 days per month), but usually does not occur when taken continuously.

Bioidentical hormones

This term can be misleading because there are both compounded and government-approved bioidentical hormones.  Government-approved bioidentical hormones (estradiol, estrone, micronized progesterone) are regulated for purity and efficacy by the FDA (in the US) (NAMS, 2022). Compounded bioidentical hormones are prepared by a compounding pharmacist using a provider’s prescription and may contain multiple hormones (estradiol, estrone, estriol, DHEA, testosterone, progesterone) in unapproved combinations given by untested routes (subdermal implants, pellets, or troches) (NAMS, 2022).  Dr. Christmas informs patients that bioidentical hormones still confer the same risks (e.g. VTE, breast cancer, cardiovascular disease, etc).

Pro tips on hormone therapy

• Dr. Christmas often starts estrogen at a medium dose, which in her experience works for the majority of patients
• She prefers non oral estrogen (patches, cream, ring) if possible to avoid the first-pass liver effect and theoretical increase in clotting factors and subsequent VTE risk (expert opinion, Sobel 2022)
• Avoid patches in 1) the patient with sensitive skin because irritation is likely and 2) the patient who performs heavy exercise or water sports because it might not stay in place
• Estrogen creams and gels need to dry on the skin before holding small pets or children to avoid incidental transfer of the compound.  Warn patients that some formulations may stain clothes.
• Patients without a uterus on estrogen monotherapy, especially if surgical menopause, tend to need higher doses of estrogen because they “don’t have the synergy between estrogen and progesterone”.  Patients with a uterus can often get by on a lower estrogen dose because progesterone provides some symptom benefit (expert opinion, Prior, 2018)

Hormone therapy vs. Oral Contraceptive Pills

• Oral contraceptive pills (OCPs), aka birth control, contain higher doses of hormones to block ovulation and prevent pregnancy compared to the dose used for hormone therapy (HT) after menopause where the goal is a physiologic level to prevent symptoms. 
• Some patients who cannot tolerate OCPs will be able to tolerate HT because the dose is lower (expert opinion).

Taking OCPs as Menopause Approaches

About 90 percent of people go through menopause by 55 years old.  Thus, it might be reasonable for a woman in her late 40s to remain on OCPs until age 55 if she lacks risk factors (obesity, smoking, poorly controlled hypertension, diabetes) and wants to continue (expert opinion).  However, Dr. Christmas encourages the lowest dose of birth control and evaluates such patients at least annually to monitor blood pressure, mammograms, etc.  Alternatively, these patients can switch to a progesterone IUD.  If bothersome symptoms of menopause occur after stopping OCPs, then the patient can start HT.  Some women prefer to transition straight from OCPs to HT, but they’d need to be wary of pregnancy risk if uncertain about menopause status. 

Premature Menopause/ Primary Ovarian Insufficiency

Premature menopause occurs when a woman under 40 has gone a full year without a period and/or has labs six months apart in the menopausal range (low estrogen, FSH elevated).  By contrast, in primary ovarian insufficiency (POI), periods are irregular, the FSH level may be borderline or high, and the estrogen level can vary.  Dr. Christmas notes that patients with primary ovarian insufficiency have waning ovarian function and might warrant birth control if they wish to avoid pregnancy (Christian-Maitre, 2021). 

In the absence of contraindications, women with premature menopause or surgical menopause should be given hormone therapy until the average age of menopause (~52 yo) to prevent bone loss, menopausal symptoms, and possibly reduce the risk of cardiovascular disease, overall mortality, and cognitive impairment (NAMS, 2022).

Discontinuing Hormone Therapy

Most women have the most severe symptoms within the first five years of menopause (Avis, 2018), so in the past, it was common to discontinue HT after five years.  Current guidelines (NAMS, 2022) recommend careful consideration of HT risks as women reach ages above 60 years old and more than 10 years from menopause.  For healthy women with ongoing VMS, continuing HT beyond age 65 yo is reasonable with appropriate counseling and regular risk assessment (NAMS, 2022).  In Dr. Christmas’ experience, many patients are willing to come off HT, but some prefer to continue.  She looks for transdermal options, since observation studies suggest a lower cardiovascular risk, including VTE and stroke (NAMS, 2022), and uses the lowest effective dose with ongoing annual risk assessment. 

Dr. Christmas’ Take Home Points 

1. Menopause is ubiquitous and inextricably tied to the aging process. There is no treatment [including hormone therapy] that will reverse aging.
2. Diet, exercise, and self-care are a bigger part of overall well-being and managing the menopause transition than medications.

Links

1. The Goldfinch (book)
2. Check out the Menopause Priority Setting Partnership ​https://obgyn.uchicago.edu/research/menopause-priority-setting-partnership 

Goal

Listeners will evaluate and treat vasomotor symptoms of menopause

Learning objectives

After listening to this episode listeners will…

1. Counsel patients about the hormonal and nonhormonal treatment options for vasomotor symptoms of menopause
2. Discuss the risk and benefits of hormonal therapy for menopause

Disclosures

Dr. Christmas reports a previous financial relationship with Fertility IQ (the relationship has ended). The Curbsiders report no relevant financial disclosures. 

Citation

Watto MF, Christmas M, Heublein M, Williams PN. “#409 Hormonal and Nonhormonal Therapy for Vasomotor Symptoms of Menopause”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast Final publishing date September 25, 2023.