Menopause: Causes and Health Consequences

Menopause is associated with the cessation of the female reproductive span. While this is true, it has far more consequences for the female body. The hormonal changes accompanying menopause are associated with declines in cognition, cardiovascular health, and other aspects of life.

Definitions

The World Health Organization (WHO) defines menopause “as the permanent cessation of menstrual periods due to the loss of ovarian activity without any other pathological or physiological cause“ [1].

Menopause can be defined retrospectively as a point in time when a woman does not have menstrual cycles for 12 months after her final menstrual period [2]. This usually occurs between 45 and 55 years of age, but it differs depending on many factors, including by population [3]:

Menopause is tightly linked to female reproductive aging and ovarian reserve. In brief, females are born with a predetermined number of ovarian follicles, which can mature into eggs ready for fertilization. Once ovaries run out of suitable follicles, a woman undergoes menopause [4].

However, some women might experience early menopause (between 41 and 45) or premature menopause at age 40 or earlier. Early menopause can occur naturally if the ovaries stop egg production prematurely, or it can result from chemotherapy or surgical removal of the ovaries.

Premature menopause affects 1 in 250 women under 30 and 1 in 100 women under 40 [1, 5]. Apart from infertility, premature menopause also increases the risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis, and ischemic heart disease [6].

Factors impacting the timing of menopause

Since age at menopause has a wide range, researchers have studied what impacts its timing, including multiple genetic determinants [7, 8] as well as lifestyle and environmental factors.

Factors that increase early and premature menopause risk are cigarette smoking, being underweight, not giving birth to children (nulliparity), being a multiple-birth child, early age of first menstruation, short and/or very regular menstrual cycles between the ages of 18 to 22 years, and epilepsy [9-14].

Evolutionary theories of menopause

About one-third of the female lifespan is spent after menopause. From an evolutionary point of view, this doesn’t immediately make sense, as post-menopausal women can no longer pass on their genes, which would presumably make selecting for post-menopausal longevity impossible. However, this is what has actually occurred.

A decline in reproductive function with age is observed in different species, from nematodes and insects to birds and mammals [15]. The antagonistic pleiotropy theory offers a possible explanation for this situation, as genes that are advantageous for younger organisms can be harmful later in life [16]. In this case, genes that can help maximize reproduction during the early stages of life can lead to aging.

The relationship between follicular depletion and menopause may be an example of antagonistic pleiotropy. Follicular depletion is important for regulating menstrual cycles at younger reproductive ages; it suggests that selective pressure is not on menopause but on follicular depletion [3]. However, this leaves a question as to why “selection for follicular depletion to maintain regular ovarian cycles led to the evolution of complete reproductive cessation well before the end of potential lifespan in women, but not in the vast majority of other species” [3]. Early menopause is not experienced in most species, including chimpanzees and elephants, whose lifespan is similar to that of humans but do not completely lose reproductive ability with age [17]. Humans and a few species of toothed whales are the only vertebrates whose reproductive and somatic senescence do not occur together [18].

The researchers developed a few hypotheses regarding the evolutionary function of menopause in humans and the lengthy post-reproductive span. Some of the most popular are the mother, the reproductive conflict, and the grandmother hypotheses [3].

The mother hypothesis is based on the fact that human children require long parental care compared to other species, and the mother plays an essential function in that care. However, if the female is older, her risk of dying in childbirth is higher. Therefore, according to this hypothesis, menopause evolved to avoid that risk and instead ensure that a mother would invest her resources in raising the children she already has until they are independent [16].

The second hypothesis, the reproductive conflict hypothesis, is based on patrilocal societies, in which a married couple resides near the husband’s family. In such a case, the reproductive spans of generations would overlap, creating competition for resources needed for children between young females and their mothers-in-law.

The third hypothesis, the grandmother hypothesis [19], suggests that life following menopause serves as an adaptation to help raise grandchildren. Since, in the past, mothers had multiple offspring under their care, the help of grandmothers, with their expertise and resources, could help the offspring succeed.

All of these concepts have pitfalls, and various studies have offered support to them but suggest that they have shortcomings [9, 20-22].

Hormonal changes

The ovaries are hormone-producing organs. They produce estradiol and progesterone, two hormones essential in regulating ovulation [23].

Estrogen (E2, 17β-estradiol) is a female sex hormone. The onset of menopause leads to a decrease in estrogen levels to the levels of age-matched men [24]. This has profound consequences for the functioning of the entire female body. For example, a growing body of evidence suggests that a menopause-related decrease in estrogen levels increases female susceptibility to neurological issues.

Changes in estrogen levels also impact metabolic processes. Estrogen has a role in raising HDL (“good”) cholesterol, reducing LDL (“bad”) cholesterol, causing vasodilation (widening of blood vessels resulting from relaxation of the blood vessel’s muscular wall), and protecting against osteoporosis [25-27].

The brain can produce estrogen, which has been found to affect both emotion and cognition [28]. It was also described to have neuroprotective properties by modulating many molecular pathways [29-31]. A neuroprotective effect is also suggested by the incidence and mortality rates of stroke, which differ between men and women at different stages of their lives. Before menopause, these rates are lower in women than in men, but after menopause, it is the other way around [28].

Hormone replacement therapy

Since menopause is associated with a drop in estrogen, its symptoms can be addressed by hormone replacement therapy (HRT), which can be offered to peri- or early postmenopausal women. However, HRT is not a one-size-fits-all approach, as the strength and duration of specific menopausal symptoms and the risks of side effects vary from woman to woman. Therefore, HRT is only administered under the guidance of medical professionals.

As part of HRT, a woman with an intact uterus is likely to be prescribed progestogens alongside estrogen. The role of progestogens is to protect the endometrium from the excessive proliferation of cells (endometrial hyperplasia) and endometrial cancer [32, 33].

Both progestogen and estrogen can be delivered in different ways, including orally, transdermally (patch, gel, or spray), and subcutaneous implants, with various chemical formulations, doses, and schedules. Each of those approaches has distinct advantages and side effects [34-36].

Cognitive decline

Menopause and cognitive decline are linked as early as the peri-menopausal period, when some women can experience mild cognitive impairment [1]. As the menopausal transition progresses, cognitive impairment seems to affect even 70% of postmenopausal women [1], with memory loss being the most frequently reported [37].

Studies suggest that mild cognitive impairment can be preceded by menopause-related subjective memory impairment. This subjective cognitive decline is linked to later-life Alzheimer’s disease [38]. Some research has found that Alzheimer’s disease has a three-stage manifestation: subjective memory impairment, then mild cognitive impairment, and finally dementia [39].

While all older women will experience menopause, not all will develop Alzheimer’s disease nor suffer from cognitive decline. More research is needed to address who is the most at risk. Still, some factors that impact the risk of developing Alzheimer’s include sex hormone levels, genes, comorbid diseases (such as cardiovascular disease), and the environment [28].

The researchers believe that there is a relationship between cognitive decline symptoms and stress and depression present in the initial transition into menopause [40]. Whether depression contributes to memory dysfunction or vice versa is still debated. However, there is some emerging evidence to support the claim that depression might be the first sign of cognitive decline [41].

The increased risk of depression during the early stages of menopause provides a link between menopause-related estrogen loss and neurological changes [40]. HRT during perimenopause can significantly reduce depression risk [42-44]. The timing of estrogen therapy seems to be essential, since postmenopausal women do not seem to benefit from this treatment [45, 46].

Surgically induced menopause, such as through ovarian removal (oophorectomy), also increases the risk of depression and dementia [47, 48].

Not all women who experience mild cognitive decline have dementia afterward, and their cognitive abilities can also improve over time [1].

Estrogen replacement therapy seems to impact menopausal and postmenopausal women’s cognitive abilities. Multiple papers addressing the relationship between HRT and dementia, conducted in the 1990s, showed a decreased risk of dementia and Alzheimer’s disease in women undergoing HRT [49-55]. This prompted significant interest and more studies addressing this relationship.

One of the studies sparked controversy, as it contradicted earlier results. This was the Women’s Health Initiative Memory Study (WHIMS), a randomized, double-blind, placebo-controlled clinical trial that recruited 4,532 women. The authors concluded: “Estrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older” [56]. Two decades later, this study still makes the relationship between hormone therapy and dementia risk uncertain [57].

Researchers have quested to explain these contradicting results. One popular explanation is referred to as the critical window hypothesis. This hypothesis suggests that HRT, to be effective, needs to be administered during the ‘critical window’ shortly after the menopausal transition [58, 59].

A wide range of studies has been done to address this hypothesis. Additionally, data from previously conducted studies was reanalyzed based on the relationship between age and HRT treatment. Multiple studies found that women who started HRT closer to their age at menopause had a lower risk of Alzheimer’s disease and dementia and improved cognitive performance [60-64].

However, there is also plenty of evidence that opposes the critical window hypothesis. For example, some studies do not show improvement in cognition in recently postmenopausal women on HRT [65, 66]. Other studies show improvements in cognition among older women receiving HRT [67, 68]. There are also studies that show no impact of HRT on cognition [69, 70].

Such variability in results suggests that other, yet-to-be-discovered, variables play a role in the success or failure of HRT in postmenopausal women.

Cardiovascular health

Postmenopausal women have a greater incidence of cardiovascular problems than premenopausal women do [71]. Multiple studies also report that early menopause, compared to menopause in the mid-forties or fifties, is linked to a 30-50% higher risk of cardiovascular diseases [72, 73].

Research suggests that the link between cardiovascular diseases and early menopause might be bidirectional [74]. Pooled data of over 170,000 women from nine studies suggests a twofold increase in the risk of early menopause (before 45) if a female experiences her first cardiovascular disease event before 35 years of age, compared to women without any premenopausal cardiovascular disease events [75].

Studies have also explored the risk of cardiometabolic diseases following surgical menopause (without estrogen therapy use), suggesting higher cardiometabolic disease risks in women who experienced surgical menopause compared to natural menopause. Some of those studies suggest that estrogen-replacement therapy might help to mitigate the risk [76. 77].

HRT and its impact on cardiovascular health were also investigated in women undergoing natural menopause. As part of the Women’s Health Initiative Randomized Trials (WHIRT), 27,347 postmenopausal women were followed up on for 18 years. A study using this data found that neither estrogen-only nor combined progestogen therapy led to an increased risk of cardiovascular-related mortality [78].

Similarly to cognitive health, cardiovascular health seems to be impacted by the timing of HRT treatment. The window of opportunity of HRT, with or without progestogen, for cardiovascular health has been supported by several studies, including some randomized controlled trials [32, 79, 80].

Musculoskeletal health

Musculoskeletal function problems, such as joint stiffness, musculoskeletal pain, intervertebral disc thinning, osteoarthritic joint changes, and loss of muscle mass (sarcopenia) are exacerbated by menopause, and many of them are linked to menopause-related estrogen loss. While lifestyle interventions such as diet, exercise, or weight optimization can help manage the symptoms of those conditions, HRT can also be an option for some of them [81-83].

An analysis of the Women’s Health Initiative randomized trial of 10,739 postmenopausal women who have had a hysterectomy and who received estrogen-alone therapy showed “modest but sustained reduction in the frequency of joint pain” [84].

However, there is no consensus regarding HRT’s effect on muscle strength in menopausal women. A meta-analysis of 23 studies of postmenopausal women who took estrogen-based hormone therapy found a roughly 5% improvement in strength comparred to a control group [85]. On the other hand, a more recent meta-analysis of 12 studies of 4474 postmenopausal women aged 50 years and older undergoing either estrogen-progesterone combination HRT or estrogen-only HRT concluded that the results “did not show a significant beneficial or detrimental association of HRT with muscle mass” [86].

However, HRT showed effectiveness in preserving bone density, preventing osteoporosis, and reducing the risk of osteoporosis-related fractures. Osteoporosis is a skeletal disorder that leads to bone mass reduction and deterioration of bone tissue, leading to increased fracture risk. Menopause-related estrogen loss contributes to the acceleration of bone density loss [32].

A review of 28 studies that included 33,426 participants concluded that HRT was associated with a reduced risk of total, hip, and vertebral fractures. However, the reviewers suggested that the effectiveness of HRT is reduced at the cessation of treatment, or when it is started after 60 years of age [87]. However, there are also studies suggesting that HRT has a protective effect against bone loss and osteoporotic fracture even after it is discontinued [88].

HRT in managing other menopausal symptoms

Menopause is associated with many symptoms that lower the quality of life. HRT can be used to address many of those symptoms. Some of the most common menopause symptoms are vasomotor symptoms, such as hot flashes and night sweats, which can lead to sleep disturbances, increased tiredness, anxiety, and depressed mood and are associated with palpitations [32].

A study that reviewed 24 double-blind, randomized, placebo-controlled trials that included over 3,000 participants concluded that using oral hormone therapy, compared to placebo, was “highly effective in alleviating hot flushes and night sweats.” However, there is still a need to analyze differences between hormonal doses, product types, or regimens [89].

Menopause might also be associated with decreased sexual desire and arousal. In such cases, leading international menopausal societies recommend using testosterone therapy at levels within the female physiological range [90].

Problems with sexual dysfunction can also arise from other menopause-related symptoms such as painful sexual intercourse or urethral syndrome, a painful or burning sensation during urination, urinary urgency, and frequency. Those results result from vaginal, lower urinary tract, and pelvic floor tissue atrophy caused by the menopause-related loss of collagen. To remedy this, topical vaginal estrogen therapy is often recommended. Estrogen positively impacts blood supply to those tissues, vaginal lubrication, and restoration of acidic pH [32, 91, 92].

Risks associated with HRT

One of the main reasons for concern about HRT is the risk of breast cancer. Recently published recommendations regarding hormone therapy in menopausal women cite literature that suggests that this risk may depend on the therapy used [32, 93, 94].

For example, the literature suggests that estrogen and progestogen HRT is associated with an increased risk of breast cancer, but compared to placebo, they have no significant difference in breast cancer mortality. When estrogen is used alone, different studies show either a slight increase, no increase, or a decrease in the risk of breast cancer and a significant reduction in breast cancer mortality compared with placebo [95, 96].

There are also reports suggesting a link between stroke and HRT. For example, data from the WHIRT study showed an increased risk of stroke among women taking estrogen, whether or not it was combined with progestogen [87].

Another review of 19 randomized clinical trials of 40,410 post-menopausal women reported an increased risk of stroke among the women who started treatment more than 10 years after menopause but not the women who started hormone therapy less than 10 years after menopause [80].

The dose and route of the administration seem to matter, as one of the comparative analyses of stroke risk found that low doses of estrogen delivered by patch did not increase stroke risk compared to controls. However, the risk was increased for women using high-dose patches and women who took hormones orally [98].

The method of administration also significantly affects the risk of blood clots in veins (venous thromboembolisms). In an observational study of 80,396 women aged 40-79 with a primary diagnosis of venous thromboembolism and 391,494 female controls, a transdermal method of HRT administration was not associated with this condition. The same study reported that oral therapy, when compared to controls, was associated with a significantly increased risk of venous thromboembolism. This risk was increased whether or not the estrogen was part of a combined preparation [99].

Similar results were obtained in different studies, with some reporting higher risks among users of combined estrogen and progestogen compared to estrogen-only therapy and differences among different pharmacological classes of progestogens in venous thromboembolism risk [100].

Conclusions

The research into menopausal transition has many unexplored areas and unanswered questions. Years of research focused only on male model organisms contributed to many gaps in the knowledge of female biology that need to be addressed in the future to give women well-informed recommendations regarding treatments and risks associated with them.

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