From the Guidelines
Menopause is a natural biological process characterized by the permanent cessation of menstruation due to the depletion of ovarian follicles and declining ovarian function, with the most recent evidence suggesting that the pathophysiology centers on the gradual decrease in estrogen production, particularly estradiol, as the ovaries contain fewer viable follicles with age 1. The pathophysiology of menopause involves a complex interplay of hormonal, cellular, and tissue changes.
- The decline in estrogen production, particularly estradiol, is the primary driver of the physiological changes associated with menopause.
- The hypothalamic-pituitary-ovarian axis responds to declining estrogen by increasing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in an attempt to stimulate the ovaries, creating a characteristic hormonal profile of elevated FSH and LH with decreased estrogen.
- These hormonal changes directly cause the common symptoms of menopause, including:
- Vasomotor symptoms like hot flashes and night sweats, which result from disruption of the thermoregulatory center in the hypothalamus.
- Vaginal dryness and atrophy, which occur as estrogen-dependent tissues thin and lose elasticity.
- Bone density decreases as estrogen no longer inhibits osteoclast activity, leading to osteoporosis risk.
- Sleep disturbances, mood changes, and cognitive effects stem from estrogen's influence on neurotransmitters and receptors in the brain.
- Metabolic changes occur, including increased central adiposity and altered lipid profiles, raising cardiovascular risk. The dynamics of declining follicle numbers play a crucial role in the pathophysiology of menopause, as the depletion of ovarian follicles leads to a decrease in estrogen production and an increase in FSH and LH levels 1.
- The median age of menopause in women in the United States is 51 years, but ovarian production of estrogen and progestin begins to decrease years before the complete cessation of menses.
- The average woman in the United States who reaches menopause has a life expectancy of nearly 30 years, and the probability of developing various chronic diseases over her lifetime is significant, with estrogen or progestin influencing many of these causes of morbidity in older women. The most recent and highest quality study, published in 2021, highlights the importance of hormonal changes in the pathophysiology of menopause, and the need for careful consideration of the benefits and risks of hormone replacement therapy in the management of menopausal symptoms and prevention of chronic diseases 1.
From the FDA Drug Label
Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
The pathophysiology of menopause involves hormonal changes, specifically a decline in estrogen levels.
- Estrogen plays a crucial role in maintaining bone density and cardiovascular health.
- The decline in estrogen levels leads to an increase in bone resorption, resulting in osteoporosis.
- The decrease in estrogen also affects the vascular system, leading to an increased risk of cardiovascular disease.
- Additionally, the decline in estrogen levels can cause vasomotor symptoms, such as hot flashes and night sweats.
- The dynamic equilibrium of metabolic interconversions of estrogens is also affected, leading to changes in the metabolism of estrogens.
- The enterohepatic recirculation of estrogens is altered, resulting in changes to the circulating levels of estrogens. However, the provided text does not directly explain the pathophysiology of menopause, including the causes of typical symptoms and changes to hormones, cells, and tissues involved, and the dynamics of declining follicle numbers 2.
From the Research
Pathophysiology of Menopause
The pathophysiology of menopause is a complex process involving changes in hormones, cells, and tissues. The decline in estrogen levels, particularly 17β-estradiol (E2), is a key factor in the development of menopausal symptoms 3. This decline is caused by the depletion of ovarian follicles, which leads to a decrease in the production of estrogen and other hormones.
Hormonal Changes
The hormonal changes that occur during menopause include:
- A decline in estrogen levels, which can lead to symptoms such as hot flashes, sleep disturbances, and mood fluctuations 4
- A decrease in progesterone levels, which can contribute to symptoms such as irregular menstrual cycles and mood changes 5
- An increase in follicle-stimulating hormone (FSH) levels, which is a response to the decline in estrogen levels 6
- A decrease in inhibin B levels, which reflects the decline in ovarian follicle numbers 6
- A decrease in testosterone levels, which can occur during reproductive life, but may remain stable or even increase during menopause 6
- A decline in dehydroepiandrosterone (DHEA) and DHEAS levels, which occurs with age and is not specifically related to menopause 6
Cellular and Tissue Changes
The cellular and tissue changes that occur during menopause include:
- A decline in the number of ovarian follicles, which leads to a decrease in estrogen production 7
- Atresia of follicles, which is the process by which follicles degenerate and are reabsorbed by the body 7
- Changes in the lining of the uterus, which can lead to symptoms such as vaginal dryness and pain during intercourse 3
- Changes in bone density, which can lead to an increased risk of osteoporosis 3
Dynamics of Declining Follicle Numbers
The decline in follicle numbers is a gradual process that occurs over many years. The rate of follicle loss accelerates in the last decade of menstrual life, leading to a significant decrease in estrogen production 7. The decline in follicle numbers is caused by a combination of factors, including:
- The continuous utilization of a fixed store of primordial follicles 7
- The loss of follicles through atresia, rather than ovulation 7
- The effects of aging on the ovary, including the accumulation of damage to molecules and the changing hormonal environment 7
Typical Symptoms
The typical symptoms of menopause include: