Menopause means permanent cessation of menstruation at the end of reproductive life due to loss of ovarian follicular activity. It is the point of time when last and final menstruation occurs. The clinical diagnosis is confirmed following stoppage of menstruation (amenorrhea) for twelve consecutive months without any other pathology. As such, a woman is declared to have attained menopause only retrospectively. Serum follicle-stimulating hormone (FSH) level is found elevated around the period of menopause (45-55 years).
Menopause transition is the period of time during which a woman passes from the reproductive to the non- reproductive stage. This phase covers 4-7 years on either side of menopause. Menopause transition is associated with elevated serum FSH levels and variable length of menstrual cycle and/or missed menses. Perimenopause is the time starting few years before continuing after the period of onset of menopause. Climacteric refers to the time after the cessation of reproductive function. Postmenopause is the phase of life that comes after the menopause.
Age at which menopause occurs is genetically predetermined. The age of menopause is not related to age of menarche or age at last pregnancy. It is variably related to lactation, use of oral pill, socioeconomic condition, race, height. Thinner women have early menopause. However, cigarette smoking and severe malnutrition living in high altitude may cause early menopause. The age of menopause ranges between 45-55 years, average being 47 years. Late menopause is seen in women with high parity or higher BMI, Earlier menopause is seen in cases following chemotherapy, ovarian resection. Due to increased life expectancy, especially in affluent society, about one-third of life span will be spent during the period of estrogen deficiency stage with long-term symptomatic and metabolic complications
Few years prior to menopause, along with depletion of the ovarian follicles, the follicles become resistant to pituitary gonadotropins. As a result, effective folliculogenesis is impaired with diminished estradiol production. There is a significant fall in the serum level of estradiol from 50-300 pg/mL before menopause to 10-20 pg/mL after menopause. This decreases the negative feedback effect on hypothalamo-pituitary axis resulting in increase in FSH. The increase in FSH is also due to diminished inhibin. Inhibin, a peptide, is secreted by the granulosa cells of the ovarian follicle. The increase of luteinizing hormone (LH) occurs subsequently. Anti- Müllerian hormone (AMH), a glycoprotein is secreted by the granulosa cells. Levels of AMH decrease progressively during the menopause transition. Disturbed folliculogenesis during this period may result in anovulation, oligoovulation, premature corpus luteum or corpus luteal insufficiency. The sustained level of estrogens may even cause endometrial hyperplasia and clinical manifestation of menstrual abnormalities prior to menopause.
The mean cycle length is significantly shorter. This is due to shortening of the follicular phase of the cycle. Luteal phase length remains constant. In late menopausal transition, there is accelerated rate of follicular depletion. Ultimately, no more follicles are available and even some exist, they are resistant to gonadotropins.
Following menopause, the predominant estrogen is estrone and to a lesser extent estradiol. Serum level of estrone (30-70 pg/ml.) is higher than that of estradiol (10-20 pg/mL). The major source of estrone is peripheral conversion (aromatization) of androgens from adrenals (mainly) and ovaries. The aromatization occurs at the level of muscle and adipose tissue. The trace amount of estradiol is derived from peripheral conversion of estrone and androgens. Compared to estradiol, estrone is biologically less potent. With times, the sources fail to supply the precursors of estrogen and about 5-10 years after menopause, there is a sharp fall in estrogen and also the trophic hormones. The woman is said to be in a state of true menopause.
After menopause, the stromal cells of the ovary continue to produce androgens because of increase in LH. The main androgens are androstenedione and testosterone. Though the secretion of androgens from postmenopausal ovary are more, their peripheral levels are reduced due to conversion of androgens to estrone in adipose tissue. However, the cumulative effect is decrease in estrogen: androgen ratio. This results in increased facial hair growth and change in voice. As the obese patient converts more androgens into estrone, they are less likely to develop symptoms of estrogen deficiency and osteoporosis. But, they are vulnerable to endometrial hyperplasia and endometrial carcinoma. A trace amount of progesterone detected is probably adrenal in origin. AMH levels are decreased markedly due to loss of ovarian reserve.
The secretions of both FSH and LH are increased due to absent negative feedback effect of estradiol and inhibin or due to enhanced responsiveness of pituitary to gonadotropin-releasing hormone (GnRH). Rise in FSH is about 10-20 fold whereas that of LH is about 3-fold. GnRH pulse section is increased both in frequency and amplitude. During menopause, there is fall in the level of prolactin and inhibin. Fall in the level of inhibin, lead to increase in the level of FSH from the pituitary. Ultimately, due to physiologic aging GnRH and both FSH, LH decline along with decline of estrogens.
The characteristic symptom of menopause is 'hot flash. Hot flash is characterized by sudden feeling of heat followed by profuse sweating. There may also be the symptoms of palpitation, fatigue and weakness. The physiologic changes with hot flashes are perspiration and cutaneous vasodilation. Both these two functions are under central thermoregulatory control. Low estrogen level is a prerequisite for hot flash Hot flash coincides with GnRH pulse secretion with increase in serum LH level. It may last for 1-10 minutes and may be at times unbearable. Sleep may be disturbed due to night sweats. The thermoregulatory center in association with GnRH center in the hypothalamus is involved in the etiology of hot flash. Gonadotropins (LH) are thought to be involved.
Neurotransmitters (norepinephrine, serotonin) are involved to lower the threshold of thermoregulatory zone identified in the mucous membrane of urethra, bladder vagina and the pelvic floor muscles. Estrogen plays an important role to maintain the epithelium of vagina urinary bladder and the urethra. Estrogen deficiency produces atrophic epithelial changes in these organs. This may cause dyspareunia and dysuria.
Estradiol deficiency leads to vaginal dryness or atrophy. Estrogen replacement reverses atropic changes. It can be given orally or vaginally. 17 ẞ-estradiol tablet or conjugated equine estrogen (CEE) cream is effective in relieving symptoms. Risks of endometrial hyperplasia is less with vaginal tablets than that of cream. Vaginal lubricants (water soluble) and moisturizers (K-Y jelly) are commonly used.
Minimal trauma may cause vaginal bleeding. Dyspareunia, vaginal infections, dryness, pruritus and leukorrhea are also common. The urinary symptoms are urgency, dysuria and recurrent urinary tract infection and stress incontinence. Estrogen deficiency is often associated with decreased sexual desire. This may be due to psychological changes (depression anxiety) as well as atrophic changes of the genitourinary system.
There is thinning, loss of elasticity and wrinkling of the skin. Skin collagen content and thickness decrease by 1-2% per year. 'Purse string' wrinkling around the month and 'crow feet' around the eyes are the characteristics. Estrogen receptors are present in the skin and maximum are present in the facial skin. Estrogen replacement can prevent this skin loss during menopause. After menopause, there is some loss of pubic and axillary hair and slight balding. This may be due to low level of estrogen with normal level of testosterone.
There is increased frequency of anxiety, headache, insomnia, irritability, dysphasia and depression. They also suffer from dementia, mood swing and inability to concentrate. Estrogen increases opioid (neurotransmitter) activity in the brain and is known to be important for memory. Estrogen improves cerebral perfusion and cognition. However, it is not clear whether estrogen therapy prevents vascular dementia and Alzheimer disease. Due to estrogen deficiency oxidation of LDL and foam cell formation cause vascular endothelial injury, cell death and smooth muscle proliferation. These women develop insulin resistance and central (android) obesity. All these lead to vascular atherosclerotic changes, vasoconstriction and thrombus formation.
Risks of ischemic heart disease, coronary artery disease and strokes cardiovascular disease (CVD) are increased due to estrogen deficiency when compared to premenopausal women.
