Treatment Guidelines

Introduction

In this module, we summarize the most recent guidelines on the management of menopausal symptoms and menopause-associated sequelae issued by several professional societies globally, with a focus on North America. The guidelines discussed include:

• The 2022 Hormone Therapy Position Statement of The North American Menopause Society (henceforth the 2022 NAMS MHT Position Statement)
• The 2023 Non-hormone Therapy Position Statement of The North American Menopause Society (henceforth the 2023 NAMS Non-hormone Position Statement)
• The 2015 Endocrine Society Clinical Practice Guideline on Treatment of Symptoms of the Menopause
• The 2014 American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin 141: Management of Menopausal Symptoms (henceforth the 2014 ACOG Recommendations)
• The 2021 Society of Obstetricians and Gynaecologists of Canada Guideline: Menopause: Vasomotor Symptoms, Prescription Therapeutic Agents, Complementary and Alternative Medicine, Nutrition and Lifestyle (henceforth the 2021 SOGC Guideline)
• The 2020 Royal Australian and New Zealand College of Obstetricians and Gynaecologists 2020 Clinical Guidance: Managing Menopausal Symptoms (henceforth the 2020 RANZCOG Clinical Guidance)

Note that fezolinetant, an exciting new option for the management of menopausal symptoms (Assessment and Treatment), is not covered by any but the 2023 North American Menopause Society (NAMS), since it was only recently developed and approved (2023). In this module we also briefly discuss the evidence supporting the safety and efficacy of the treatment options recommended by the guidelines. For more information, we refer the reader to the clinical guideline publications themselves and the publications of the evidentially supportive trials.

The 2022 NAMS MHT Position Statement

The 2022 NAMS MHT Position Statement is the result of a review of the new evidence published since the release of the prior (2017) Position Statement. The review of pertinent literature was undertaken by a panel of clinicians and researched experts convened by the NAMS for the purpose of updating the recommendations about menopause hormone therapy (MHT). The fact that results from no single trial can be extrapolated to all women in menopause is explicitly acknowledged by the Position Statement, and the limitations of the Women’s Health Initiative (WHI) trials (see Assessment and Treatment) are explicitly mentioned. The Position Statement includes 117 recommendations and statements organized into 22 categories, according to specific themes, including:

• Explaining hormone therapy risk
• Formulation, dosing, routes of administration and safety
• FDA-approved indications
• Compounded bioidentical hormones
• Context-specific use categories (menopause symptoms; primary ovarian insufficiency; skin, hair and special senses; hormone therapy and quality of life; osteoporosis; joint pain; sarcopenia; gallbladder and liver; diabetes mellitus, metabolic syndrome and body composition; cognition; depression; cardiovascular disease and all-cause mortality; breast cancer; endometrial cancer; ovarian cancer; colorectal cancer; lung cancer)
• Duration of use, initiation after age 60 years and discontinuation of hormone therapy

Each specific recommendation is graded into one of the following three Levels, reflecting the quality of the supporting evidence: Level I (good and consistent scientific evidence), Level II (limited or inconsistent scientific evidence) and Level III (consensus and expert opinion). The Position Statement provides the following 5 concluding statements:

• Hormone therapy is the most effective treatment for vasomotor symptoms (VMS) and genitourinary syndrome of the menopause (GSM) and has been shown to prevent bone loss and fracture.
• Risks of hormone therapy differ for women, depending on type, dose, duration of use, route of administration, timing of initiation and whether a progestogen is needed. Treatment should be individualized using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation.
• For women aged younger than 60 years or within 10 years of menopause onset and without contraindications, the benefit-risk ratio appears favorable for treatment of bothersome VMS and for the prevention of bone loss and reduction of fracture. Based on the WHI trials, longer duration may be more favorable for estrogen therapy alone than for estrogen/progestogen combination therapy.
• For women who initiate hormone therapy more than 10 or 20 years from menopause onset or when aged 60 years or older, the benefit-risk ratio appears less favorable than for younger women because of greater absolute risks of coronary artery disease, stroke, venous thromboembolism and dementia.
• For GSM symptoms not relieved with nonhormone therapies, low-dose vaginal estrogen therapy or other government-approved therapies (e.g., vaginal dehydroepiandrosterone or oral ospemifene) are recommended.

For specific recommendations and statements beyond this summary, please refer to the 2022 NAMS MHT Position Statement publication.

The 2023 NAMS Non-Hormone Position Statement

The 2023 NAMS Non-Hormone Position Statement updates the prior version of NAMS recommendations (2015) for the treatment of patients who are either ineligible for, or unwilling to take MHT. The review of evidence was performed by a panel of clinicians and experts, who provided a total of 39 recommendations, organized into the following five categories:

• Lifestyle
• Mind-body techniques
• Prescription therapies
• Dietary supplements
• Acupuncture, other treatments and technologies

Of the non-hormone therapies considered, the panel found enough evidence to recommend:

• Cognitive-behavioral therapy (CBT) (Level I)
• Clinical hypnosis (Level I)
• Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibits (SNRIs) (Level I)
• Gabapentin (Level I)
• Fezolinetant (Level I)
• Oxybutynin (Levels I-II)
• Weight loss (Levels II-III)
• Stellate ganglion block (Levels II-III)

The panel found sufficient evidence to not recommend (based on negative or insufficient evidence): paced respiration (Level I), supplements and herbal remedies (Levels I-II), cooling techniques, trigger avoidance, exercise, yoga, mindfulness-based interventions, relaxation, suvorexant, soy (food and extracts, including soy metabolite equol), cannabinoids, acupuncture, neural oscillation oscillation (Level II), chiropractic interventions, clonidine (Levels I-III), dietary changes and pregabalin (Level III).

For more details on the specific recommendations beyond this summary, please refer to the 2023 NAMS Non-Hormone Position Statement publication.

The 2015 Endocrine Society Clinical Practice Guideline

The first guideline on the treatment of menopause symptoms from the Endocrine Society was published in 2015, as a successor to an earlier (2010) scientific statement on hormone therapy. The 2015 guideline was formulated by a dedicated international task force of experts, and is broader in scope that the 2010 statement, addressing non-hormone therapies in addition to MHT. The guideline includes 34 recommendations and statements, organized into 5 categories (presented in Table 4-1). Each recommendation has a strength of recommendation score (strong or weak) and a quality of evidence score (very low, low, moderate, high), per the GRADE framework. The first two categories deal with definitions and general principles of maintaining good health in the menopause transition. The focus of the third and largest category is about the decision of if, when, and how to apply MHT to women with moderate to severe VMS. The fourth contains recommendations for women who are unable or unwilling to make MHT, while the fifth deals with options of the management of GSM.

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The 2014 ACOG Recommendations

In 2014, the ACOG published a set of clinical considerations and recommendations for the management of menopausal symptoms in their Clinical Practice Bulletin, intended to replace an earlier version published in 2001. These recommendations are evidence-based and, like the Endocrine Society guideline, address both MHT and non-hormonal therapy. They aim to provide guidance on the choice of specific MHT, selection of effective non-hormonal agents, appropriate use of complementary and alternative therapies, and the usefulness of behavioral and lifestyle changes. Hormonal and non-hormonal therapies for menopausal vaginal symptoms are also addressed. A summary of major recommendations, graded with respect to the quality of supporting evidence (A – good and consistent scientific evidence; B – limited or inconsistent scientific evidence; and C – consensus and expert opinion) and categorized on this basis, is shown in Table 4-2.

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The 2021 SOGC Guideline

The SOGC released their most recent guideline in 2021. The guideline includes 8 summary statements and 9 recommendations, formulated on the basis of evidence from the literature published between 2002 and 2020 and indexed in PubMed, MEDLINE, or the Cochrane library. Each statement is assigned a quality of evidence rating (high, moderate, low, very low), and each recommendation both a strength of recommendation (strong or weak) and a quality of evidence rating, per the GRADE system. The statements and recommendations are presented in Table 4-3.

Overall, the guidelines recognize that VMS can have a substantial negative effect on quality of life. Recommended therapies for VMS management during perimenopause include MHT, combined hormonal contraceptives, or estrogen combined with a levonorgestrel-releasing intrauterine system (LNG-IUS). For VMS symptoms in postmenopause, the guideline recommends MHT over other modalities, unless contraindicated. However, the guideline recognizes that not all women will want to use MHT and recommends that non-hormonal pharmacologic options be considered in cases where MHT is not appropriate to the patient. Lifestyle measures and traditional (culture-specific) therapies are also recognized as ancillary approaches. To offset the increased risk of osteoporosis, cardiovascular disease (CVD), and cognitive impairment, the guideline recommends MHT for women who enter menopause early.

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The 2020 RANZCOG Clinical Guidance

The RANZCOG developed its first statement on the management of menopausal symptoms in 1995 and published its current Clinical Guidance on this topic in 2020. The 2020 Guidance was developed by the Women’s Health Committee within RANZCOG on the basis of an updated literature review and clinical consensus. The Committee produced 23 specific recommendations, summarized in Table 4-4. Most of the recommendations address appropriate uses of MHT therapy, i.e., for which patients it is appropriate, and in which formulations. Each recommendation is graded according to the Australian National Health and Medical Research Council (NHMRC) Levels of Evidence and Grades of Recommendations for Developers of Guidelines system; grade A denotes evidence that can be trusted to guide practice, grade B evidence that can be trusted to guide practice in most situations, grade C evidence that provides some support for the recommendation (but care should be taken in its application) and grade D evidence that is weak (and thus the recommendation must be applied with caution).

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Evidence Supporting Available Hormonal and Non-Hormonal Therapies for Menopause

A large body of evidence supports the efficacy and safety of MHT for the management of menopausal symptoms, with smaller but robust support for non-hormonal treatments.

Major Studies Supporting the Safety and Efficacy of MHT and Other Menopause Treatments

A number of major double-blind, randomized, controlled trials support the efficacy and safety of MHT and other interventions in the management of menopause symptoms and associated comorbidities. In order of publication, these include:

• Postmenopausal Estrogen/Progestin Interventions (PEPI) trial (1995), which found that treatment with conjugated equine estrogens (CEE) at a daily dose of 0.625 mg/d, alone or in combination with several progestogen formulations, had better cardioprotective effects (improving lipoproteins) than the placebo in the study population (875 healthy women in the postmenopause, 45 to 64 years of age).
• The Heart and Estrogen/progestin Replacement Study (HERS) trial, conducted in 1998, designed to investigate the effects of estrogen/progestin (E/P) combination therapy on the risk of coronary heart disease (CHD) events in postmenopausal women with existing coronary artery disease (CAD). HERS found E/P therapy did not significantly reduce the risk of CHD events, such as heart attacks or death from heart disease, in this population.
• In contrast the HERS trial reported an unexpected increase in the risk of certain cardiovascular events, particularly during the first year of treatment with hormone therapy. This finding was one of the first to raise concerns about the overall safety and efficacy of hormone replacement therapy for preventing heart disease in postmenopausal women with existing CAD.
• Women's Health, Osteoporosis, Progestin, Estrogen study (2001), which found that, in comparison to the placebo, all tested doses of CEE (0.625, 0.45 and 0.3 mg/day), alone or in combination with a progestogen, significantly reduced the frequency and severity of HFs and reduced vaginal atrophy, in the study population (2673 women in the postmenopause).
• Women’s Health Initiative (WHI) trials (2002 and 2004), by far the largest and most influential trials of MHT, found an increased risk of VTE and stroke in participants (women in the postmenopause 50-79 years of age) with a uterus (n=16,608) who were on CEE with or without a progestogen and increased risk of breast cancer for those on CEE with a progestogen; in participants without a uterus (n=10,739), an increased risk of stroke was observed. Both trials, however, found a beneficial effect of MHT in the reduced risk of osteoporotic fracture, and the trial in women with a uterus found a reduced risk of colorectal cancer. As mentioned in Assessment and Treatment, the WHI trials were criticized for testing only one CEE and CEE/progestogen formulation and dosage, as well as for the demographics of the study population, with the majority of women being 10 years or more past their final menstrual period, and later trials challenged the generalizability of the WHI findings to younger women in the postmenopause.
  • Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH), a series of diverse trials (published between 2011 and 2018) with the following findings:
  • Escitalopram (10-20 mg/day) significantly reduced the frequency and severity of HFs in women in the menopause, compared to the placebo (study n=205)
  • Low-dose estradiol (0.5 mg/day) and low-dose venlafaxine XR (75 mg/day) each significantly reduced (compared to the placebo) the frequency and severity of VMS in a population of 339 peri- and post-menopausal women
  • Escitalopram, low-dose estradiol and venlafaxine significantly reduced the frequency of VMS symptoms compared to the placebo in a population of 899 women in the peri- and postmenopause; aerobic exercise, yoga and omega-3 supplementation had no effect on VMS symptoms
  • Cognitive behavioral therapy for insomnia (CBT-I) delivered over the phone was more effective at reducing insomnia in a population of 106 women in the peri- and post-menopause than telephone-based menopause education
  • Low-dose (10 μg) vaginal estradiol and a vaginal moisturizer, in combination with a topical and oral placebo, respectively, were not more effective than a dual placebo at reducing vulvovaginal symptoms in a population of 302 women in the postmenopause.
• Early versus Late Intervention Trial with Estradiol (ELITE) study (2016), which found that, in a population of 643 women in postmenopause, an oral estradiol (1 mg/day) plus progestogen (45 mg) vaginal gel treatment resulted in a slower increase (compared to the placebo) in carotid artery intima-media thickness (CIMT; a measure of sub-clinical atherosclerosis) in women whose menopause began <6 years prior to randomization, while the rate of CIMT increase was not affected by the same treatment in women whose menopause began ≥10 years before randomization.
• Kronos Early Estrogen Prevention Study (KEEPS) trial (2019), which found that MHT with oral CEE (0.45 mg/day) or transdermal estradiol (50 μg/day) initiated early during the postmenopause (<3 years after menopause) was not effective (compared to the placebo) at slowing atherosclerosis (as measured by CIMT), but neither did it exacerbate it. While this finding was not consistent with the ELITE trial, it is important to note that the dosage of MHT used in KEEPS was lower than in ELITE.

Additional Studies Supporting the Current Treatment Options for VMS and GSM

The data supporting the safety and efficacy of fezolinetant, the most recent non-hormonal agent for VMS management to receive FDA approval, is discussed in Module 3. The efficacy of paroxetine (7.5-12.5 mg/day), until the approval of fezolinetant the only non-hormonal therapy for menopause symptoms to receive FDA approval, in HF and sleep disturbance reduction is supported by the aggregate findings of four randomized clinical trials of varying quality. A body of evidence from 18 RCTs supports the use of other selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs). Data from 7 randomized controlled trials (RCTs) of gabapentin show that it is effective in reducing HF frequency and severity. Another meta-analysis of 21 RCTs confirmed the efficacy of gabapentin at HF reduction; gabapentin and antidepressants had similar efficacy for VMS control, but lower than that of estrogen, while pregabalin failed to demonstrate efficacy. Two trials support the efficacy of clonidine for the reduction of tamoxifen-induced VMS (in women who were taking tamoxifen as a breast cancer treatment). An analysis of 29 RCTs including a total od 8,311 patients found that vaginal estrogen, vaginal prasterone (dehydroepiandrosterone) and oral ospemifene all had a significant effect in controlling GSM, with prasterone and ospemifene significantly improving sexual function.

Complementary and Alternative Medicine for Menopausal Symptoms

Complementary and alternative approaches may prove helpful for some patients who do not respond to, or cannot tolerate, the more standard therapies for menopausal symptoms. Complementary approaches with evidential support include:

• Hypnosis, which has demonstrated efficacy in VMS control in several RCTs, initially in women with breast cancer and later in the general population; one trial reported an efficacy equivalent to venlafaxine.
• Cognitive behavioral therapy (CBT), an integrative psychological intervention that may combine patient education, motivational interviewing, relaxation techniques and other strategies; CBT is supported by data from several RCTs, including MENOS 1, MENOS 2, and others.

Both of the above interventions are recommended by the NAMS and considered appropriate for VMS control by the SOGC and RANZCOG.

Complementary approaches that have not demonstrated consistent efficacy in RCTs include biofeedback and relaxation training, yoga, aromatherapy, herbal preparations, phytoestrogens, vitamin E supplementation and alternative healing systems (reflexology, homeopathy, acupuncture and traditional Chinese medicine); see reference for a review of the available data on these approaches.