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The Menopause THE EVENTS OF THE MENOPAUSE

A. STUART MASON, M.D., F.R.C.P.

Consultant

Endocrinologist,

speaking the word menopause TRICTLY final cessation of menstruation. This

the grossly

means

gives

the

yesterday all was well, it also implies that a hysterectomy causes a menopause. Climacteric, meaning a period of change, is a better word because it expresses the all important concept of a time scale, but is not in common use. Therefore, let us stick to the word menopause and define it anew. The menopause is centred on the ovary and its in-built obsolescence. The events of the menopause start when the active ovary begins to fail and end with the final lapse of the ovary into inactivity. The duration of these events is extremely variable and cari cause as much trouble before menstruation ceases as after the last period. The end of the menopause merges in to the post-menopausal time. The functional unit of the adult ovary is the primordial follicle. Stimulated by the pituitary, one follicle develops each month as a hormone-producing organ. Compared to the life-long integrity of other endocrine glands, it is startling to consider that the whole life-span of the follicle is twenty-eight days. It is also not surprising that each succeeding follicle does not exactly match the functional performance of its predecessors. Follicles will continue to develop until there are none left to respond to the stimulus of the pituitary; this marks the end of the menopause. The obsolescence of the ovary is apparent even in the fetus. The thirty-two week fetus has around seven million primordial follicles; at birth the number has dropped to about two million and by puberty, when the first follicle begins to develop, only about 300,000 follicles are left. During _adult life approximately 400 follicles will have provided the hormones and the ova of the ovaries; the other follicles continue to atrophy and the last few capable of function may prove to be poor endocrine glands. What governs the rate of follicular degeneration is unknown but it is clearly a process that is not significantly altered by such things as the number of pregnancies or the taking of contratomorrow

erroneous

all has

idea of

changed;

ceptive steroids. When working normally the cycle of ovarian activity is controlled by a &dquo;biological clock&dquo; in the hypothalamus. This controls the pituitary by a gonadotrophin-releasing hormone that passes directly to the anterior

pituitary.

In turn the

pituitary

secretes

The London

Hospital

gonadotrophins, the first, follicle stimulating hor(FSH), makes the ovarian follicle develop and secrete oestrogen; the second, luteinising hormone (LH), is secreted in a sudden surge when oestrogen levels have reached a critical point to prompt ovulation

two

mone

and the creation of the corpus luteum in the ovary that secretes progesterone, while oestrogen secretion continues. The cyclical drop in pituitary gondadotrophin secretion causes the corpus luteum with its attendant follicular cells to degenerate. There is a close interaction between pituitary and ovarian function. The ovary makes oestrogen from cholesterol, converting it to pregnenolone, then to progesterone which is changed to androstenedione and on to oestradiol. Oestradiol is the oestrogen secreted by the ovary but it can be changed in the liver to oestrone and oestriol. All three oestrogens are natural in that they are formed in a woman’s body. It is worth noting that the corpus luteum secreting progesterone is using a more primitive pathway of synthesis than the oestrogen producing cells. It is also obvious that the aged follicle may be an inefficient hormone producer, either failing to develop a corpus luteum, thus cutting out progresterone secretion, or secreting androstenedione which can be converted in the body to testosterone, the male hormone. These events can be the initial hormonal disturbances of the menopause. Finally the pathways of steroid hormone synthesis are essentially the same in the adrenal cortex. When ovarian oestrogen production has finally ceased, androstenedione secreted from the adrenal can be converted to oestrone in. fatty tissues. Indeed the rate of conversion to oestrone can be related to the amount of fat tissues present in the body. Thus androstenedione is important when secreted by the ovary or the adrenal, not only as a source of male hormone but also as a source of oestrogen. The events of the menopause cannot be understood unless the normal activity of the ovary is appreciated. As follicles respond more and more inefficiently to the pituitary, there is a loss of progesterone secretion before much change in oestrogen secretion; however oestrogen secretion is liable to vary widely from cycle to cycle. The early symptoms of the menopause are often those of the premenstrual syndrome. As Dr. Dalton has done more than anyone to delineate this syndrome and its treatment I will not develop the theme.

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71 OF OESTROGEN DEFICIENCY WHEN OESTROGEN deficiency takes over as the dominant feature of the menopause, various things happen. The lack of adequate ovarian response disturbs the pituitary; LH levels increase but do not show the ovulatory surge. Later the levels of FSH become markedly raised, well above the LH levels, and remain raised for the rest of life. The combination of raised FSH and low oestrogen levels appears to cause the characteristic hot flushes (or flashes in America). These, and the other manifestations of oestrogen deficiency, seem very dependent on the tempo of ovarian failure. Abrupt deprivation of oestrogen, as with removal of the ovaries, produces far more disturbance than a gentle decline in function. It must be remembered that oestrogen formation in the body continues long after the amounts produced have become insufficient to produce a menstrual flow. It is well known that hot flushes can be relieved by oestrogen in doses that do not suppress the high levels of FSH. It is equally well known that the genital tract atrophy which may be so troublesome a feature of oestrogen deficiency is relieved by oestrogen. Less well recognized are the aches and pains due to connective tissue changes induced by oestrogen lack and the varied emotional disturbances that may be related to oestrogen deficiency. At this point the whole perspective of a woman’s middle years has to be considered. While acknowledging that many symptoms are due to lack of oestrogen and relieved by replacement therapy, it must not be forgotten that the body is aging through the middle years and that family relationships are changing and may produce psychological strains with varied symptoms, often difficult to distinguish from those caused by a marked fall in oestrogen secretion. This particularly applies to sexual desire and performance. Often such problems have a dual causation. In general the body adapts to minimal oestrogen and the overt ill-health due to ovarian failure may disappear when the ovary has finally failed. In some cases this is because sufficient oestrogen is made from adrenal androstenedione. The aging skin may lose texture from lack of oestrogen but the process of aging is not dominated by hormonal deficiency. Breast tissue shrinks but the contour of the breast may be preserved by fat deposition. Thinning of bone starts somewhat abruptly at the menopause and continues throughout the years. Undoubtedly the bone becomes much thinner in the absence of oestrogen and it is very probable that a significant part of bone loss could be halted with oestrogen therapy, thus diminishing the high incidence of fractures in old age. The most difficult correlation to discern is the link between ovarian function and age-related disease of the arteries. Coronary thrombosis is extremely rare before the menopause and its prevalence among women rises sharply in the post-menopausal years. However,, the oestrogen containing contraceptive pill increases the prevalence of venous thrombosis particularly in the menopausal women and there is a hint that it may increase the risk of coronary thrombosis.

CONSEQUENCES

Oestrogens do increase the blood fats which may thickening of arteries and they also do alter coagulation factors in the blood towards a thrombotic tendency. There are so many other factors involved that no clear picture has emerged and the benefits of continuing a level of blood oestrogen after the menopause are no more clear than the possibility that oestrogen deficiency enhances vascular degeneration. enhance

There is the unproven view that there is a critical post-menopausal level of oestrogen, below which vascular disease increases, above which the prevalence of thrombosis increases. One certain fact about the oestrogen deficiency after the menopause is the continuing atrophy of the genital tract. This can give rise to trouble at any time during or after the failure of ovarian activity. The vagina becomes thinned, shrunken and dry, its lining cells changing character. The cells lining the bladder also change in a similar manner and urgency of micturition may result. The uterus shrinks and its lining, the endometrium, virtually disappears, hence the absence of menstruation. Oestrogen therapy reverses the atrophy of the whole genital tract and will stimulate growth of the endometrium. Consequently oestrogens are usually given in cycles of treatment to allow breakdown of the endometrium and a menstrual flow in the days when treatment is stopped. This imitates the normal action of the functioning ovary. In many instances the amount of oestrogen necessary to preserve a healthy genital tract is not large enough to promote menstruation.

CANCER RISKS Two MONTHS ago a new danger was made public. Cancer of the endometrium had been shown to be related to the amount of oestrogen production by the post-menopausal body, but now it has been shown the oestrogen therapy appears to increase the risk of developing this cancer. Of course this does not concern the woman who has had a hysterectomy. The natural risk is one in a thousand women per year, rising with oestrogen therapy to about six. This applies to oestrogen therapy alone. It may well be that the addition of progestogen would be protective as it antagonizes some actions of oestrogen and does . diminish the effect of oestrogen on the endometrium. It is true that the first hormonal deficiency of incipient ovarian failure is low progesterone production, but this is often neglected when oestrogen deficiency becomes dominant. The possible carcinogenic action of unopposed oestrogen on the endometrium gives an insight as to the long-term effects of progesterone deficiency. In conclusion the events, duration and tempo of the menopause are due to failure of ovarian function. This reflects on the activity of the pituitary, the whole genital tract and most other body tissues. The adjustment of tissues to an altered hormonal environment, the secretion of oestrogen from the adrenal, and the unrelated changes of aging makes a very complicated and illustrate how much more there is to

problem know.

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The menopause: the events of the menopause.

The menopause is centered on the ovary and its in-built obsolescence. The events of the menopause start when the active ovary begins to fail and end w...
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