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

Signs and Symptoms

The median duration of the menopause transition is approximately 4 years.[12] Symptoms of menopause typically start off mild and then increase in prevalence later in the transition as prolonged amenorrhea and hypoestrogenism predominate. Irregular bleeding patterns, with changes in period frequency and bleeding duration, may be one of the earliest signs of the menopause transition, and are often associated with anovulation.[20] Symptoms are most prevalent and severe during the first 1 to 2 years after the FMP.[39] Unfortunately, earlier symptom development in the transition portends a longer duration of bothersome symptoms, and some women will experience bothersome symptoms for more than a decade.[12] While AMH has been shown to help predict time to natural menopause, its predictive effect lessens with increasing age.[40,41] A prospective study of AMH levels predicting early menopause of women aged 35 to 44 years showed for every decrease of AMH by 0.10 ng/mL below 2 ng/mL, a 14% higher risk of early menopause before age 45.[42] Thus, AMH levels may help guide clinicians in combination with symptom assessment to determine who is at risk for menopause and initiate appropriate treatment.

Vasomotor Symptoms and the Cardiovascular System

Hot flashes, or vasomotor symptoms (VMS), affect the majority of women undergoing the menopause transition and can significantly impair quality of life. Hot flashes last several minutes, starting with a flushing sensation that spreads along the upper body. These symptoms are due to a rapid rise in body temperature with accompanying vasodilation. On average, hot flashes persist 4 to 5 years, but for nearly a quarter of women they may continue for as long as 10 years.[43,44] There are also racial and ethnic differences in the intensity and duration of hot flashes, with African American women experiencing the burden of the longest and most intense symptomology.[45] Hot flashes are thought to occur due to a physiologic narrowing of the hypothalamic thermoregulatory system that regulates core body temperature in response to estrogen deprivation. Reduced estrogen levels correspond to higher norepinephrine, along with lower serotonin levels and upregulation of its receptor (5-HT2A).[46–48] Menopausal women supplemented with estrogen demonstrated higher core temperature sweating thresholds and reduced frequency of hot flashes compared with placebo.[49] Furthermore, KNDy neurons are suspected to propagate hot flashes, as ablation or blockade of the NK3R in both mice and human studies has improved symptoms.[50,51] Among the various interventions available, hormone replacement therapy (HT) is the most effective treatment for management of bothersome VMS of menopause not associated with a mood disorder.

Although VMS are common and generally believed to be benign, severe and prolonged VMS are associated with greater cardiovascular risk burden[52] and future events.[53] Some of the cardiovascular risk has been attributed to loss of endothelial function concurrent with menopause and likely related to the loss of estrogen.[54,55] It is not known whether treatment of severe or late onset hot flashes attenuates their associated cardiovascular risks.

Genitourinary

Genitourinary symptoms of menopause (GSM) include changes to the lower genital tract that occur in response to estrogen deprivation. Symptoms include atrophy of the vulva and vagina, vaginal dryness, vaginal narrowing and shortening, uterine prolapse, and urinary incontinence.[56] These changes can cause dyspareunia, irritation, and increased risk for urinary tract infections. Estrogen deprivation reduces blood flow to the vagina, which reduces vaginal secretions, increases vaginal pH, decreases surface epithelium and increases parabasal cells. Connective tissue dehydration leads to architectural narrowing of the vagina and vestibule, and atrophy of the vulva.[57] Estrogen replacement has been shown to alleviate most GSM symptoms except for urinary incontinence.

Mood

Mood changes marked by increased depression and anxiety are common during the menopause transition. SWAN studied perimenopausal women over 5 years and found that depressive symptoms peaked in the late perimenopause.[58] While women with a history of depression are at risk for future depression, women without a preexisting history are at risk during menopause, with a 16% prevalence of new-onset depression and/or anxiety.[59] Longitudinal studies suggest a longer menopause transition is associated with depression, probably due to increased symptoms.[60] Other risk factors for depression as women approach the menopause transition include nulliparity, separation from a prior spouse, premenstrual symptoms, and smoking.[61] Hormone changes and neurosteroids are believed to contribute to dysregulation of the gamma amino butyric acid (GABA) balance between GABA-A and GABA-B to increase vulnerability to depression during this time of life.[62] Adverse early life events may also play a role in predisposing women to adverse mood in midlife.[63] Interestingly, HT may improve mood in the absence of significantly reducing VMS in perimenopausal women. Although VMS associate with new onset of depressive mood, a reciprocal relationship between VMS and new onset of major depression is not as clearly demonstrated.[64,65]

Cognition

Cognitive decline is mostly associated with somatic aging rather than menopause. Several studies have refuted the benefits of estrogen on cognitive function. The Women's Health Initiative Mental Status Trial (WHIMS) included women 65 years or older who were free of dementia, and it found that the risk of Alzheimer's doubled in women who had received conjugated equine estrogen.[66] A secondary analysis of this cohort found the underlying presence of cardiovascular disease (CVD) at the time of study enrollment, particularly history of myocardial infarction or invasive vascular procedure, was associated with cognitive decline.[67] This implicates underlying CVD, rather than estrogen replacement, on deteriorating cognitive function. Analysis of the SWAN cohort evaluated the effect of menopause and HT on cognition.[68] Indeed, cognitive functioning declines during the menopause transition, but appears to return to baseline by the transition's end. This study suggested a limited decline, however, a secondary analysis of the cohort for a follow-up of 6.5 years found age-related processing speed and memory decline, suggesting within-woman age-related cognitive decline persisting beyond the menopausal transition.[69] When estrogen hormone therapy was initiated in perimenopausal women it protected cognitive performance, but when initiated in postmenopausal women it verged on harm.[68] The Cognitive Affective Study of the Kronos Early Estrogen Prevention Study (KEEPS-Cog) treated early postmenopausal women with 4 years of HT but found no appreciable difference in cognition compared with placebo,[70] suggesting that HT neither harms nor improves cognition in early postmenopausal women.

Sleep

Natural aging is associated with sleep decline; however, most research suggests that the menopausal transition magnifies sleep deterioration. A survey of more than 12 000 women in SWAN showed that nearly 40% of women reported difficulty with sleeping that correlated with timing of the menopausal transition but remained independent of age.[71] This menopause-associated sleep disturbance is not fully explained by increased nocturnal VMS, as a subanalysis of SWAN showed poor sleep in patients without VMS.[71] They found the pattern of sleep disturbance appears in the early menopause transition but peaks in the late transition and levels remain generally unchanged through postmenopause.[71] The Canadian Longitudinal Study of Women showed that women in postmenopause had a harder time falling asleep and were more likely to have obstructive sleep apnea than women in premenopause or perimenopause.[72] Women who report sleep difficulty may have associated factors, including depression and anxiety, smoking, obstructive sleep apnea, and lower physical activity.[71] The Penn Ovarian Aging Study, after 14 years of follow-up of midlife women, concluded that only a small proportion of women experience sleep difficulties directly related to ovarian decline.[73]

Libido

Decreased sexual desire is prevalent during the menopause transition and may affect as much as 10% of women.[74] The Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking (PRESIDE) study showed increased problems with sexual desire in women 45 to 64 years compared with both older and younger females.[75] Less than half of these women have concurrent depression.[76] The hypoestrogenism and decline in testosterone levels associated with aging are hypothesized to contribute to these symptoms. Testosterone replacement in women with and without ovaries has been performed and has shown modest benefit on sexual desire and satisfaction per sexual episode.[77] Importantly, large studies evaluating both the efficacy and safety of testosterone replacement, particularly risk of breast cancer, in menopausal women are lacking.[78] There are 2 pharmaceutical agents approved for treating hypoactive sexual desire disorder in premenopausal women, bremelanotide (Vyleesi) and flibanserin (Addyi). Bremelanotide is a melanocortin receptor agonist that activates several receptor types, most notably MC1R and MC4R in the central nervous system.[79] Flibanserin is a 5-HT1A receptor agonist and 5-HT2A receptor antagonist.[80,81] There are currently no FDA-approved formulations for postmenopausal women with low libido.

Bone

Estrogen is a potent antiresorptive agent at the bone level, and thus hypoestrogenism of menopause marks a period of increased rate of bone resorption. Osteoporotic fractures affect half of women after age 50.[82] Estrogen promotes osteoblasts and increases calcium absorption from the intestines.[83] Loss of estrogen decreases calcium absorption which promotes osteoclast-mediated bone resorption via upregulated parathyroid hormone. Peak anabolic bone mineral density is achieved around age 30 and progressively declines thereafter at approximately 0.7% per year.[84] Rates of bone loss increase dramatically starting a year before the FMP and persist up to 3 years with rates of bone loss as high as 5% per year, then slows again to approach the rate of loss prior to menopause.[85]

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