Endocrinology of the menopause
Department of Obstetrics and Gynaecology, School of Medicine, Pusan National University, Pusan, Republic of Korea
Menopause means the last period or the cessation of normal menstruation and can occur either physiologically or artificially. It should be regarded as a hormone-deficient state. A number of somatic, physiological and psychological changes occur during the menopause but these symptoms can largely be reversed by correcting the hormone deficiency. However, some symptoms reflect social and personal circumstances, and not the endocrine events of the menopause [1, 2].
The average age of the menopause is between 50 and 52 years of age . In one study among Korean women, it was found to be 51.2 years . About 4–5 years before the menopause, many women, in fact more than 80%, complain of menstrual irregularity. Only about 10% of women cease menstruating abruptly with no prior period of menstrual abnormality.
Loss of oocytes and follicles ultimately results in a series of endocrine changes in the hypothalamic-pituitary-gonadal axis, and gradual diminution of oestrogen and inhibin occurs .
Several years before the menopause
Decreased levels of inhibin result in raised levels of follicle-stimulating hormone (FSH), which is the first laboratory indication of the perimenopause. The increased FSH induces rapid follicular development with consequent shortening of cycles. This change in menstrual cycle is due to a shortening of the follicular, but not the luteal, phase and may be the first clinical sign of the perimenopause (Table I) .
Inhibin, unlike gonadotropin surge inhibiting factor, selectively suppresses pituitary release of FSH. Inhibin is a non-steroidal inhibitor present in follicular fluid and its peptide moiety is synthesized by the granulosa cells and secreted into the follicular fluid. The decrease in inhibin secretion by the ovarian follicles begins early at around 35 years of age but accelerates after the age of 40 .
Table I: Changes in the menstrual cycle at approach of the menopause.
Near to the menopause
As the number of follicles is further decreased, oestrogen production continues to fall. When a level incompatible with induction of the luteinizing hormone (LH) surge is reached, ovulation may cease or, more frequently, may become irregular. Clinically, this is associated with irregular cycles and a shortened luteal phase, or anovulatory cycles with unopposed oestrogen stimulation and endometrial hyperplasia. Anovulatory cycles may be interspersed with ovulatory cycles. A period of amenorrhoea with elevated FSH and LH may mimic the menopause but is followed a few months later by an ovulatory cycle and normal gonadotropin levels . As ovulation ceases entirely, LH begins to rise with the onset of the menopause, but gonadotropin-releasing hormone (GnRH) remains the same.
The menopause is due to declining ovarian function as a result of exhaustion of the pool of primary follicles and associated decreased steroidogenesis. This disturbs the pituitary-hypothalamic feedback mechanisms causing a rise in pituitary gonado-tropins but with unchanged levels of hypothalamic GnRH. The combination of decreased inhibin and oestradiol levels is probably responsible for the early rise in FSH.
The primary basis for the progressive decrease and complete cessation of cyclic function of the female reproductive organs at the time of the menopause appears to lie in the ovary itself. There is continuing loss of the primordial follicles during intrauterine life and throughout the reproductive years until the menopause. After about the age of 35 years, the human ovary begins to decrease in weight and size, and contains much fewer oocytes and follicular structures and more atretic and degenerating follicles .
The female fetus starts in utero with approximately 6 million primordial follicles which decrease to 600,000 at birth, 300,000 at menarche and 10,000 or fewer near the time of the menopause. A few immature follicles may continue to undergo maturation and atresia even for a few years after the menopause. There have been some reports of postmenopausal ovulation.
It is important to realize that (1) the feedback mechanisms may cause readjustments between the pituitary and ovary as long as there are follicles remaining in the ovary to respond; (2) over a period of 1 or 2 years, reversal of laboratory findings as well as clinical signs and symptoms may occur.
In the menopausal ovary, although ovarian oestradiol and progesterone secretions are sharply reduced, the ovary is nevertheless capable of substantial steroidogenesis. The ovarian stroma cells as well as the adrenal cells have a steroidogenic capacity for producing androstenedione which is converted by the skin and appendages to oestrone .
The primary steroidogenic element of the postmenopausal ovary is the stroma, which frequently contains islands of ‘thecal’ cells and may have the appearance of a generalized bilateral thecal hyperplasia. The steroids secreted by the postmenopausal ovary in response to the stimulus from high concentrations of LH are primarily androgens (androstenedione, testosterone), but some oestradiol may also be produced (Table II). In in vitro studies, hyperplastic stroma, when stimulated, produces oestradiol.
Table II: Biosynthesis of steroids.
Extraglandular source of oestrogen
Oestrone accounts for most of the circulating oestrogen in the postmenopausal woman. Most of the oestrone is formed by the peripheral conversion of androstene-dione. After the menopause, the circulating level of androstenedione is about one-half of that seen prior to the menopause. Most of this postmenopausal androstenedione is derived from the adrenal gland, with only a small amount secreted by the ovary. The conversion rate of androstenedione to oestrone is significantly correlated with obesity (body size), because the peripheral conversion of androstenedione is mostly done at skin appendages, especially fat . The circulating oestradiol level after the menopause is approximately 10–20 pg/ml (40–70 pmol/l), most of which is derived from this conversion . The circulating level of oestrone is higher, the mean level being approximately 30–70 pg/ml (110–260 pmol/l). The average postmenopausal production rate of oestrone is approximately 45 mg/24 h (Table III).
Table III: Steroid hormone levels in pre- and postmenopausal women.
- The postmenopausal ovary exhibits direct secretion of very minimal amounts of oestrone and oestradiol.
- The ovarian stroma continues to be stimulated by LH to produce androstenedione and testosterone.
- Oestrone accounts for most of the circulating oestrogen in the postmenopausal woman, with an androstenedione-to-oestrone conversion by the skin and appendages.
- The levels of oestradiol and oestrone are strongly correlated with the percentage of the ideal body weight.
- Menopausal women have an oestrogen milieu that is lower than necessary for reproductive function.
The menopause could be regarded as a physiologic phenomenon that is protective in nature: protective from undesirable reproduction and the associated growth stimuli by oestrogen deficiency as a consequence of ovarian follicular exhaustion, and by the oestrogen-independent consequences of ageing.
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