The Menopause Transition: Signs, Symptoms, and Management Options

Nanette Santoro; Cassandra Roeca; Brandilyn A. Peters; Genevieve Neal-Perry

Disclosures

J Clin Endocrinol Metab. 2021;106(1):1-15. 

In This Article

Treatment

As outlined above, bothersome symptoms can develop years before the FMP and can be detrimental to quality of life. For this reason, providers who care for reproductively aging women should be comfortable offering effective menopausal therapy for symptom management during the menopause transition. A combination of bothersome symptoms with menstrual and laboratory changes evidenced by STRAW+10 is an indication to discuss treatment options with patients.[39]

Treatment options for menopausal symptoms include hormonal preparations, nonhormonal medications, and nonpharmacologic therapies. HT with estrogen is the most effective treatment for menopausal VMS and GSM. Women with significant sleep or mood disturbance during the menopause transition may also benefit from HT.[86] HT therapies are considered safe and effective in low-risk women without underlying coronary heart disease or history of breast cancer, age <60 years, and who are <10 years from menopause onset.[87] In the Women's Health Initiative (WHI), women with VMS experienced an 85% reduction in symptoms after treatment with estrogen plus progesterone.[88] The Heart and Estrogen/Progestin Replacement Study (HERS) showed a 27% improvement in VMS above placebo.[89] While the primary outcomes of WHI and HERS were cardiac disease, not symptoms of menopause, these findings highlight the benefit of estrogen therapy on VMS and best prescribing practices. However, these studies also demonstrate who will not benefit from HT, and possible deleterious effects of HT used in older women and women at increased risk for coronary heart disease.

HT and CVD

HT should not be used for the primary or secondary prevention of CVD. WHI, a primary prevention trial, compared conjugated equine estrogen (CEE) 0.625 mg plus 2.5 mg medroxyprogesterone acetate (MPA), or CEE alone in women without a uterus, vs placebo on CVD.[90] The trial CEE+MPA arm was stopped early due to increased rates of invasive breast cancer. CEE alone or with MPA was noted to increase risk of blood clot and stroke but to reduce hip fracture risk. CEE+MPA also increased the rate of CVD and showed a protective effect on colon cancer. Cumulative 18-year follow-up from this trial did not show increased all-cause, cardiac, or cancer mortality from either treatment arm.[91] The HERS trial was a double-blind, randomized trial of CEE 0.625 mg plus MPA 2.5 mg versus placebo in postmenopausal women with a uterus and coronary artery disease.[89] This study ran concurrent with the WHI and was undertaken to evaluate HT as secondary prevention of coronary artery disease. However, within the first year of the study, women in the HT arm experienced a significant increase in incidence of myocardial infarction, but continuation showed no further risk or benefit in subsequent years. The Kronos Early Estrogen Prevention Study sought to study the concept of early menopause being a window for estrogen therapy to promote long-term cardiovascular benefit.[92] They included women through age 58 who were less than 3 years from their LMP and studied oral CEE 0.45 mg daily versus transdermal 17-β estradiol 50 μg daily vs placebo. Treatment arms were combined with micronized progesterone 200 mg daily for 12 days a month. They found no difference in their primary outcome measure—carotid intima medial thickness—between groups. The Early Versus Late Intervention Trial with Estradiol (ELITE) Study[93] was designed to examine the relationship between menopause timing and HT initiation. Participants were stratified based on time from menopause (less than 6 years vs more than 10 years) and compared 1 mg of daily oral 17-β estradiol with 45 mg of progesterone per vagina for 10 days a month (if a uterus was present) vs placebo pill and placebo vaginal gel. They found less progression of carotid intima medial thickness in the treatment group in women <6 years from menopause, but not in those >10 years from menopause. The conclusion from more than 2 decades of study suggest that HT does not prevent CVD, and it should not be prescribed for this purpose. Alternatively, studies have not demonstrated mortality differences in women who do and do not take HT; an important point to understand and impart on patients prescribed HT for symptomatic purposes. In other words, concerns regarding increased risk for mortality should not be used to withhold the treatment of bothersome VMS in appropriately selected women.

HT and Breast Cancer

Risk of breast cancer is also a serious consideration prior to initiation of HT. Women with a history of breast cancer or high baseline risk should be advised to initiate nonhormonal alternatives for bothersome symptoms (Table 1). The WHI showed increased risk of invasive breast cancer with CEE and MPA.[90] The risk was detectable after 3 years of therapy.[94] However, in the primary publication of WHI findings, at a mean duration of use of 5.2 years, breast cancer risk was at the margin of statistical significance.[90] Because the risk of breast cancer with estrogen plus progestin HT regimens is incremental, and therefore small, year over year, clinical guidelines consider 5 years of treatment to be low risk. Breast cancer risk associated with HT in women without a uterus taking estrogen-only has been shown to be consistently reduced in the WHI.[95]

HT Formulations

Estrogen formulations are present in multiple forms, including transdermal, oral, vaginal, and topical emulsions/sprays (Table 2). Systemic estrogen via transdermal, oral, or topical routes is advised for treatment of VMS, while local vaginal formulations are preferred if GSM is the predominant complaint. The preferred route of estrogen replacement is transdermal, as this may decrease the risk of thromboembolic events.[96] The Estrogen and Thromboembolism Risk Study was a case-control study that showed increased odds of venous thromboembolism in oral estrogen users compared with nonusers, while transdermal estradiol showed no measurable risk compared to nonusers. The Endocrine Society, American College of Obstetricians and Gynecologists, and North American Menopause Society recommend considering venous thromboembolism risk-benefit profiles of transdermal preparations.[87,97]

Systemic estrogen formulations must be taken with a progestin or uterine-level estrogen receptor antagonist to reduce the risk of endometrial hyperplasia and cancer from unopposed estrogen exposure.[98] Women with a uterus are advised to combine systemic estrogen therapy with cyclic or combined progestin. Vaginal formulations do not require progestin as these have not been shown to induce endometrial proliferation. Estrogen regimens are available as estrogen-only formulations, combined with progestin, or combined with a serum estrogen receptor modulator (SERM) and are FDA-approved for treatment of hot flashes (Table 2 and Table 3). Women taking estrogen-only formulations with a uterus can consider cyclic or continuous progestin regimens. Cyclic regimens include 200 mg micronized progesterone or 5 mg MPA for 12 days a month. Continuous regimens include 100 to 200 mg micronized progesterone or 2.5 mg MPA daily. Progestin should be taken at night to avoid side effects of drowsiness and nausea. An intrauterine device (IUD) with levonorgestrel can also inhibit endometrial proliferation for at least 5 years.[99,100] Irregular bleeding after initiation of HT is common but should resolve over 2 to 3 months. Continued or new-onset irregular bleeding in the setting of HT should prompt uterine evaluation to rule out endometrial neoplasia. Shared decision making with the patient should take place to determine when to discontinue therapy and should be reassessed yearly. A tapering plan rather than abrupt cessation is often best tolerated.

Nonhormonal Therapies

Nonhormonal therapies for menopause can also be considered in patients who are wary of initiating HT, or who have a contraindication to HT (Table 1). The only nonhormonal therapy approved for treatment of hot flashes is the selective serotonin reuptake inhibitor (SSRI), paroxetine 7.5 mg daily.[101] Other SSRIs such as escitalopram can be considered and have shown some efficacy, particularly in patients with a concurrent mood disorder[102] or poor sleep.[103] The selective-norepinephrine reuptake inhibitors (SNRI) venlafaxine and desvenlafaxine have been shown to improve VMS compared with placebo and low doses of estradiol.[104,105] Clonidine typically treats blood pressure; however, it has been shown to improve VMS.[106] Additionally, gabapentin has shown benefit in randomized trials over placebo for treatment of VMS.[107] Like micronized progestins, gabapentin should be taken at night to minimize side effects of drowsiness and dizziness, and dosing can be increased to 2- or 3-times daily as needed. Lastly, a recently completed phase 2 clinical trial using an NK3R antagonist shows promising treatment for mitigating VMS at the level of the hypothalamus.[108]

Nonpharmacologic Therapies

Nonpharmacologic therapies for treatment of menopausal symptoms are generally less studied, with minimal observational benefit, and many lack large trials conferring efficacy and safety. The MsFLASH research network performed several trials, one that showed cognitive behavior therapy for insomnia (CBT-I) helped reduce insomnia with persistence for nearly half a year.[109] Prolonged benefits were observed without an effect on VMS and after pooled analysis. The authors concluded cognitive behavior therapy for insomnia should be first-line therapy for women with midlife insomnia.[103] In another MsFLASH trial, yoga compared to usual activity was shown to reduce insomnia, but not VMS.[110] MsFLASH did not observe improvements in VMS, sleep, or mood with omega-3 supplementation, while an aerobic exercise intervention improved sleep and mood but not VMS.[111,112] The Herbal Alternatives for Menopause (HALT) randomized trial showed no benefit of black cohosh, multibotanicals, or soy on VMS compared with placebo, and possible worsening symptoms in the soy group.[113] The authors cited the inability to control for the impact of the whole-person treatment approach of naturopaths as a limitation of the study. Several acupuncture studies suggest a small benefit or no difference compared to sham acupuncture, which raise concerns about a placebo effect.[114,115] Women are advised to minimize stress, sleep next to a fan, dress in layers, consume cold beverages, and avoid potential dietary triggers such as caffeine, spicy food, and alcohol. For GSM, vaginal lubricants can be applied prior to intercourse and are available over the counter. Vaginal moisturizers can be applied with an applicator up to 3 times a day and can alleviate dyspareunia.

Summary

To summarize, in low-risk women who are <60 years of age and within 10 years of menopause onset, initiation of HT is a safe option for treatment of menopausal symptoms. Patients should undergo baseline risk assessment to determine risk of CVD and breast cancer, and thus appropriateness for HT. Patients should be advised that HT is for treatment of bothersome symptoms only and not for prevention of CVD. Local vaginal preparations should be considered for GSM-predominant symptoms and do not require use of progestin. Combined HT carries a long-term risk of breast cancer, and clinicians need to balance this risk against the benefits of extended use beyond 5 years. Symptomatic patients this may necessitate tapering HT while adding in non-HT regimens for relief. Patients who are not good candidates for HT have alternative therapies that can be trialed but may not be as effective and HT.

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