9th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Menopause

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

Definition

Menopause has received various definitions. Most commonly, menopause is said to exist after amenorrhea has been established for = 6 months as a result of ovarian failure. Today however, we believe that the best definition of menopause refers to physiological mechanisms rather than remaining arbitrarily anchored in scholastic definitions. With this in mind, menopause should be seen as the ultimate phase of an aging process of the ovary that unravels for several years (6-8) and ultimately results in amenorrhea.

Based on cross sectional studies, the median age at menopause has been estimated between 50 and 52. This has remained remarkably constant throughout history (first reference about age at menopause given by the Greeks) with very little/no differences among races, irrespective of the variety of social status or dietary habits. Interestingly, the secular trend towards earlier puberty observed in Europe and Northern America in the 50's and 60's has not been followed by changes in menopausal age. Similarly, the factors that affect ovarian function and limit the total number of ovulations do not affect the age of menopause. This is particularly the case of repeated pregnancies or prolonged use of the birth control pill.

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. Exposure to toxic agents such as chemotherapy or environmental substances and notably tobacco advance the age of menopause.

Ovarian aging and menopause

Menopause or the cessation of ovarian function is the end stage of an aging process that starts some 6 to 8 years earlier. Originally, only the few months/years before menopause were recognized to be hormonally abnormal. During these months/years preceding menopause, abnormal, unscheduled and often heavy menses are common. Most often, these are the results of persistent and/or intermittent anovulation that leads to dysfunctional/breakthrough bleeding. These episodes have been recognized and linked to menopause for a long time. Collectively, they are known as perimenopausal disorders or symptoms. The common denomination of perimenopausal troubles is a loss of ovulatory function with a lack of cyclical production of progesterone before estrogen production stops. After some time (weeks/months) this results in unopposed proliferation of the endometrium and ultimately breakthrough bleeding. It may or may not be associated with endometrial hyperplasia which should always be ruled out, when confronted to perimenopausal bleeding disorders (endometrial aspiration). Collectively, these bleeding disorders reflect the tail end (last 1 to 2 years) of the whole aging process of the ovary. Most often but not always, perimenopause symptoms announce the imminence of menopause. The earlier years (4 to 6 before menopause) of the aging process of the ovary are clinically silent except for a sharp decline in fecundity. These early stages of ovarian aging whose only manifestations are infertility and some discrete hormonal changes (early follicular phase FSH) are often called "incipient" or "occult" ovarian failure.

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. This observation has let to believe that ovarian hormones can prevent coronary heart disease.

Hot flushes

Hot flushes (or flashes) (HF) are the emblematic symptoms of menopause. They consist of episodic phenomenons characterized by a sudden onset of upper body vasodilation (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 to detect 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 minerolometry 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 favourable 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 favourable 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.

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. Oocytes are offered by a surrogate donor. 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 terratogenicity linked to synthetic progestins.

Blood levels and ultrasounds

In real time medicine, hormone replacements are not very helpful when natural menopause occurs at the expected age (~ 50). In these cases, the symptomatology is most often amply confirmatory. Menopausal or premenopausal symptoms encountered in younger individuals warrant hormonal measurements and pelvic ultrasounds for definitive diagnosis. FSH and E₂ levels reflect ovarian function. In perimenopause, important changes can accompany intermittent episodes of ovarian function and failure. Hence, results should be interpreted as solely providing a trend. Ultrasounds allow measurements of ovarian volume, a marker of ovarian ageing less likely to be affected by intermittent fluctuations.