10th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Menopause

G. Girardet and D. de Ziegler
Department of Obstetrics and Gynecology, Geneva University Hospital
Department of Obstetrics and Gynecology, Nyon Hospital

Definition

The "Menopause" is the permanent cessation of menstruation after the loss of ovarian activity. The " perimenopausal transition" is the year before menopause marked by irregularity of menstrual cycles. "Climacteric" or "Perimenopause" is the period of time where a woman passes from the reproductive stage of life through the perimenopausal transition and the menopause.

Based on cross sectional studies, the median age at menopause has been estimated between 50 and 52. Only current smokers may expect an earlier menopause with a shift of 1.5 years. Factors that did not affect the age of menopause were the use of oral contraception, and socioeconomic status. Median age means that only one half of the women in the study have reached menopause at this age. The range that included 95% of women was 44 to 56 years.

Mothers and daughters tend to experience menopause at the same age. Menopause is genetically determined probably through information coded on the X chromosome. There are families with higher incidence of premature menopause (< 40 years of age) but this also occurs sporadically.

The Perimenopause

The Perimenopause is a complex time in a woman’s life where unpredictable fluctuation in ovarian function and their physiologic consequences occur. Perimenopausal women with a high incidence of clinical symptoms seek medical advice more frequently than premenopausal or postmenopausal women. Because of a high incidence of dysfunctional uterine bleeding, Perimenopause is the time of a woman’s life with the peak rates of hysterectomy.

• Stock of Ovarian Oocytes

The ovary contains its greater number of oocytes at around the fifth month of gestation when about 7 million oocytes are present. After that time, the number is continuously reduced by atresia. At menarche their number is estimated at about 400 000. By menopause there are only about a thousand oocytes. After 40 years old, follicle number falls rapidly until menopause.

• Endocrinology at the Perimenopause

We still don't know everything about the hormonal features of the menopausal transition. A marked diminution of reproductive capacity precedes the Perimenopause by several years and may be referred to as a "Gametogenic ovarian failure". The concept of dissociation in ovarian function is appropriate. The gametogenic failure is announced by reduced inhibin secretion, rising FSH level and marked reduction of fecundity. This occurs with normal menstrual cycle and no obvious endocrine deficiency.

• Inhibin

Inhibin is a dimeric glycoprotein produced by the granulosa cells of the ovary. It has been documented to increased in puberty, fluctuate across the menstrual cycle and be undetectable after menopause. The major role of inhibin is the negative feedback regulation of the pituitary FSH secretion and synthesis. Low inhibin level may be associated with abnormal follicle development and contribute to anovulation and infertility. Another hypothesis would be that the altered and diminished function of the granulosa cells leads to a low level of inhibin, which may contribute to oocyte poor viability and fertilization.

• Gonadotropin level

The level of both gonadotropins has been shown to correlate positively with age. The rise in FSH precedes that of LH by almost a decade. After a woman enters the menopausal transition, the major endocrine finding is that of significant hormonal variability. Postmenopausal level of FSH can occur and be associated or followed by evidence suggestive of normal ovulation and luteal function. Postmenopausal FSH and LH can be associated with hot flushes and spontaneous disappearance of the hot flushes and gonadotropic level returning to those of normal reproductive function. After establishment of irregular cycles, different patterns of gonadotropin secretion are described and may occur in the same woman: normal level of FSH and LH, similar to that in younger woman, postmenopausal level associated with long menstrual cycles, increase of FSH alone or LH alone. Hormonal measurement may not be helpful in the menopausal transition because ovulatory cycles may occur after the measurement of postmenopausal level of FSH.

• Steroid Hormone Level

In a 40 years old woman, estradiol level can be the same as a younger woman, or lowered. Progesterone secretion can be normal in short cycle or associated with decreased luteal phase progesterone excretion or can even be absent in amenorrhea. It appears that a woman in the menopausal transition can experience a mixture of normal, long and short cycles.

- Short cycle may be associated with normal hormone level or high FSH and low estradiol or even hyperestrogenism (due to estrone and conjugate estrogens).

- Long cycle may be associated with abnormal gonadotropins and low estradiol during most of their length. At the end of a long cycle one may recorded an increase in estradiol followed sometime by sign of an ovulation (sign of a luteinisation). A long cycle may also be found with normal steroids level and high gonadotropin level.

A fall in circulating androgens is associated with aging and may precede menopause. This fall may play a role in the well being and sexual function and be more important than previously thought.

• Changes in menstrual pattern

The alteration of ovarian steroids secretion as a consequence of oocyte and follicles depletion result in modifications of the menstrual cycle. However, these modifications are also aging related and due to pathologic related changes in the uterus. Anovulation increases from 8% at 31 years old to 16% at 45. 20% of perimenopausal women experience menorraghia, or metrorraghia. From these, 9% have a genital tract malignancy and 14% have endometrial hyperplasia. 70% experience oligomenorrhea and 12% have regular cycles to the onset of postmenopause amenorrhea. Benign pelvic causes of menstrual symptoms are common: uterine myoma, adenomyosis, endometriosis, and endometrial polyps are responsible for about 50% of cases of menorraghia.

Endocrinology at the Menopause

• Gonadotropin level

The increased circulating level of FSH and LH result from increased pituitary excretion of gonadotropins without a change in their metabolism.

• Steroid Hormone Level

With the cessation of menstruation estradiol falls steeply during the first 12 months and then shows only a slight decline over the ensuing years. Estrone, a weaker estrogen and estrone sulfate, its metabolite, fall at and after menopause and estrone is higher in postmenopausal women than in younger women. Estrone sulfate has no biologic activity; it becomes active when sulfate is cleared as it occurs in many tissues. After menopause, the major source of estradiol is from the peripheral aromatization of androgens.

Menopause is also associated with a decrease in ovarian androgen secretion. The secretion of androstenedione falls more than the ovarian secretion of testosterone. This results in a decrease in circulating testosterone in most postmenopausal women. However some postmenopausal women maintain the same level of testosterone than younger women or even higher.

• Adrenal

Adrenal secretes androgen precursors like dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione and testosterone. Adrenal is the only source of DHEAS. Menopause doesn’t change the circulating level of DHEAS. There is a decline in DHEA and DHEAS with age, independent of menopause. Cortisol and Aldosterone are not altered by menopause.

Symptoms and consequences

The loss of the ovarian function and the resulting hypoestrogenaemia are the source of an array of symptoms experienced by women. These include the well-known hot flushes (HF) and sleep disorders. Women also often encounter psychological symptoms at/or just before the age of menopause that used to receive psychiatric interpretations but are now attributed to declining E₂ levels. These include depressive feelings, psychological irritability and cognitive impairments (approximately 15 years later, on average).

Aside of easily recognizable symptoms, menopause is responsible for an increase in daily bone loss and overall risk of coronary heart disease (CHD). Ultimately, postmenopausal bone loss increases the risk of osteoporosis that becomes clinically evident. The increase in CHD seen after menopause leads to similar CHD incidences among men and women above 50. On the contrary, women appear to benefit from relative protection prior to that age.

Hot flushes

Hot flushes (or flashes) (HF) are the emblematic symptoms of menopause. They consist of episodic phenomenon characterized by a sudden onset of upper body vasodilatation (flashes) associated with intense perspiration (flushes). The sudden episode is often preceded by short unpleasant psychological symptoms (such as feeling oppressed) that are often strong enough to awaken patients at night. HFs occur at variable frequency which can be up to one every 60 minutes at the maximum. Each episode lasts 2 to 3 minutes. They are timely related to (but not dependant upon) episodic LH elevations. They do not occur in circumstances where no GnRH is produced endogenously (e.g. Kalmann syndrome). Any phenomenon which occurs more often than once an hour or which last more than 10 minutes is likely not to be a true HF. Characteristically, individuals who have never been exposed to E₂ such as untreated Turner syndromes for example never experience HF. Exposure to E₂ followed by withdrawal from treatment however, results in HF in these patients.

HF are generated by episodic resetting of the hypothalamic center that controls basal body temperature (BBT), or thermostat. In castrated individuals (male or female), the thermostat looses some of its precision for controlling BBT. This is reflected by a tendency for a slight but constant upward slide over time of the reference temperature setting. The thermostat therefore lets BBT progressively increase above its original reference value. Yet, at intermittent intervals the thermostat resets itself, readjusting the original setting for BBT. Intermittent resetting of the reference temperature results in abrupt deployment of physiological mechanisms aiming at rapidly dissipating excess heat. This triggers profuse perspiration and upper body vasodilatation. The phenomenon is abrupt in its onset and ends when the new temperature setting has been reached, usually after a few minutes. Rather than reflecting an isolated phenomenon, HF should be seen as a readily identifiable manifestation of E2 deprivation on brain function. Hence, improper functioning of the hypothalamic center that controls BBT should be linked to other neurological symptoms of E2 deprivation less easy clinically measurable.

Bone mass and osteoporosis

Throughout life, bone undergoes a constant remodeling process. Hence, at any given time in life, bone mass is the net result of bone formation and resorption. A variety of factors influence both bone formation and resorption. Adults in hypoestrogenic state display an increase in bone resorption resulting in increased urinary calcium excretion that hampers bone mass if it persits over time. The same is seen in castrated males. Recent data indicate that in females and males, bone resorption is controlled by E₂ (in males, after local aromatization of T). The net rate of bone loss varies during the post-menopausal years. Rapid at first, bone loss becomes less important over time but the bone balance remains negative throughout post-menopausal years. Bone mass or mineral density can now be easily and precisely measured non evasively with a variety of densitometer systems. The precision of measurements allows detecting hormone related changes in bone mass occurring within 6 to 12 months. When enough bone has been lost so that the deficit becomes identifiable on simple X-rays, or spontaneous fractures occur, the condition known as osteoporosis is considered existent. By and large, in the absence of hormone replacement therapy (HRT), osteoporosis is feared starting approximately 15 years after menopause. A variety of factors can hasten or delay the appearance of osteoporosis. Genetic and racial factors will influence both total bone mass at the time of menopause and the rate of loss after menopause. At one end of the spectrum, women of Northern European descent (blond, blue eyes), show frailer bones than women of Southern Europe or of black origin. Within each race, individuals may have higher or lower post-menopausal loss rates. Finally, environmental factors and notably smoking are known to increase bone loss and osteoporosis risk. The feared consequences of osteoporosis are fractures including stress fractures of vertebrae resulting in disgracious and potentially painful deformations of the spine. Hip fracture is another dreadful consequence of menopause. Bone mass or mineralometry can be measured in women who hesitate about using HRT and in individuals whose risk is unexpectedly high in order to document that the HRT regimen selected suffices. Repeated measurements must be done at 12 or 24 months.

Coronary heart disease (CHD)

Before menopause, the incidence of CHD is notably lower in women when compared to men of the same age. After menopause however, the incidence of CHD increases in women and starts to parallel that of men. This observation has been the starting point of our current views on female hormones and CHD. Specifically, the lower incidence of CHD in women before menopause has been seen as reflecting a relative protective factor of ovarian hormones against CHD.

Because oral estrogens induce a favorable alteration of the lipid profile, the beneficial effect of ovarian hormones on the cardiovascular system has been originally attributed to E₂. There are now numerous evidences that E₂ also exerts beneficial effects directly on vessels. This includes NO mediated vasodilatation, decreased intra luminal proliferation of smooth muscle cells and favorable vasoreactive response to Ach (vasodilatation). The above not withstanding, there are now preliminary albeit, converging indications that progesterone, the second ovarian hormone, also exerts beneficial cardiovascular effects of its own.

Based on the observation of an increase in CHD after menopause, it has become crucial to determine the possibility of prolonging with HRT the relative protection endowed to women during their reproductive years.

Recent data (HERS study) indicate that synthetic progestins and medroxy progesterone acetate (MPA) notably, completely antagonize the beneficial effects of estrogens. Recent data indicated that natural progesterone on the contrary, does not negate the benefit of estrogen therapy and may even have a positive action of its own.

Vulvovaginal symptoms

Vulvovaginal symptoms, in contrast to vasomotor disturbances are progressive; they don’t heal without an appropriate treatment. Urogenital symptoms can results in years of suffering with a significant impact on quality of life. In the general population over 60 years old, the prevalence of vaginal dryness is 43%, and the prevalence of vaginal burning is 10%. Of the 60% that are sexually active, 40% complain of dyspareunia. Beside vulvovaginal symptoms, urinary incontinence tends to increase with a prevalence of more than 70% after 60. Less than 50% of symptomatic women ask their doctor for advice in case of vulvovaginal or urinary symptoms.

The atrophic vulva loses most of its collagen, adipose and water-retaining ability and the number of epithelial glands, or the amount of secretion, diminish. The vulva then becomes thin and dry. The vagina shortens and narrows; the vaginal walls become thinner, less elastic, pale and dry. The vaginal surface become friable, with petechiae, ulcerations and bleeding occurs with minimal trauma, for example speculum insertion. With repeated ulceration and bleeding, healing may lead to adhesion of the vaginal wall, especially in non-sexually active women.

Premature menopause

Menopause can occur prematurely (< 40 years of age) either idiopathically or as a result of identifiable endogenous (autoimmune disease associated or not with other endocrine disorders) or exogenous causes (exposure to toxic substances such as chemotherapy). Premature ovarian failure (POF) differs from regular menopause by the age of its occurrence and its consequences on fecundity in women of reproductive age.

The diagnosis of POF is usually simple. The finding, low E₂ and high FSH levels should be confirmatory. Results however, must be repeated with > 2 measurements because of the important consequences linked to this diagnosis. Assessing the ovarian volume by ultrasounds helps to distinguish idiopathic cases (premature menopause) from rare occurrences of insensitive ovaries such as encountered in isolated or multiple autoimmune endocrine deficiencies. The latter cases are more prone to have, yet rarely and unpredictably, clinical recoveries of ovarian function.  This also warrants attempts at inducing ovulations, a futile exercise in true premature menopause. On the contrary, POF with small (atrophic) ovaries is definitive.

The consequences of POF are more dreadful than regular menopause because in the end, the amount of bone lost depends directly from the number of year spent after menopause. Hence, in the absence of treatment, a person having reached menopause at 35 will suffer at 60 the same amount of bone loss as normally expected at the age of 75, i.e., 15 years after menopause. Early menopause is therefore a strong indication for HRT in order to avoid osteoporosis.

When menopause occurs during the normal reproductive years, women commonly query about the possibilities to restore their reproductive potential. Since the advent of IVF, it is now possible to allow POF women to become pregnant and give birth through oocyte donation. Here exogenous hormones are used to prime endometrial receptivity in the POF recipient. A surrogate donor offers oocytes. Larger (physiologic) amounts of E₂ are needed as compared to common HRT regimens. Moreover, natural progesterone should be used exclusively because of the possibility of teratogenicity linked to synthetic progestins.

Menopause as an opportunity

Menopause is a normal, physiologic event. The middle age, depending on the culture and specially in the occidental world, is characterized by many negative events, like the loss of the reproductive function and inability to conceive, the feeling of aging and the possible loss of health, the multiple responsibility of the older generation with old depending parents and the new generation. Many of the complains may be explained by psychological and sociocultural influences. On the other hand, research findings provide considerable evidences that sex steroids alter brain neurotransmitters in several ways to affect mood.

Medical intervention at this time of a woman’s life should be considered as an opportunity to provide preventive care. These check-up and advise should include family planning, control of alcohol consumption, prevention of cardiovascular disease (control of high blood pressure, cholesterol, diabetes, body weight, stop smoking,), prevention of osteoporosis, cancer screening and treatment of urologic troubles.