F. Luzuy and A. Campana
Infertility and Gynecologic Endocrinology Clinic,
Department of Obstetrics and Gynecology,
University Cantonal Hospital, 1211 Geneva 14, Switzerland
All women who live beyond the age of 60 years and many of younger age experience a period of transition from the reproductive to the nonreproductive stage of life, of which the most striking feature is the cessation of menstruation, i.e., the menopause.
The population of postmenopausal women is increasing. Current American census data indicate that in the 1990’s the U.S. will approach a figure of 40 million women over 50 years of age. In France more than 8 million women, equivalent to nearly 30% of the female population, will be concerned. Women in more developed countries now live approximately one-third of their lives after ovarian failure. By the year 2000, the average life expectancy for women in developed countries is expected to be 80 to 85, and in developing countries 65 to 70 years (11). The problems of the menopausal period of life, because of the size of the older population alone, have achieved the status of a major public health concern.
Definition of terms
Menopause means the cessation of menstrual activity. The climacteric is the perimenopausal period of functional ovarian involution characterized by the occurrence of somatic and psychological signs and symptoms associated with changes in the endocrine system.
The following definitions have been recommended by a WHO Scientific Committee in 1980 (28):
- menopause: the permanent cessation of menstruation resulting from loss of ovarian follicular activity;
- perimenopause (or climacteric): the period immediately prior to the menopause (when the endocrinological, biological and clinical features of approaching menopause commence) and at least the first year after the menopause;
- postmenopause: dating from the menopause, although it cannot be determined until after a period of 12 months of spontaneous amenorrhea has been observed;
- premenopause: the whole of the reproductive period prior to the menopause.
There is a paucity of descriptive information about the age distribution of natural menopause in populations, and, in particular, very little is known concerning populations of non-European origin. Menopause occurs in American and European women, at median age of approximately 50 (11). Earlier menopause is associated with cigarette smoking (16) and living at high altitudes. Several observers have noted that unmarried and/or employed women have a slightly earlier median age at menopause (17).
The possibility that age at menopause has risen over the past 100 years has been argued, but there appears to be no solid evidence for a consistent secular change indicating a rise among European populations. There is, however, evidence of some fluctuations over time (21).
The vasomotor flush is viewed as the hallmark of the female climacteric, experienced to some degree by at least 80% of postmenopausal women. Although the flush can occur in the perimenopause, it is a major feature of postmenopause, lasting in most women for 1-2 years, but, in some (as many as 25-50%) for longer than 5 years (24).
Psychological complaints associated with the climacteric include fatigue, nervousness, headaches, insomnia, depression, irritability, and palpitations.
The fact that most of the psychological symptoms occur in the period preceding the cessation of menses, when the menstrual cycles are irregular or abnormal, raises the possibility that fluctuations in hormone levels are responsible rather than hormone deficiency. This view ascribes symptomatology to declining ovarian function. Mood symptoms may reflect a change in the brain, influenced by the changing levels of ovarian steroids. Alternatively, symptoms could reflect an imbalance elsewhere in the hypothalamic-pituitary-gonadal axis.
The psychological complaints may be explained by the " domino theory ": that is, if the flushes cause the woman to stay awake and the night sweats cause her to change the bed linen, she will understandably report insomnia and fatigue, which may lead to irritability and nervousness. However, many psychosocial factors may be important in determining women’s experience of the menopause. These factors include life events during the climacteric years, such as ending of the parental role, sociodemographic variables (social class, marital status, employment status, and social network), and personality (adaptive capacity) (10,15).
With extremely low estrogen production in the late postmenopausal age, or many years after castration, atrophy of all mucosal surfaces takes place, accompanied by vaginitis, pruritus, dyspareunia, and stenosis. Genitourinary atrophy leads to a variety of symptoms which affect the ease and quality of living. Urethritis with dysuria, urgency incontinence, and urinary frequency are further results of mucosal thinning, in this instance, of the urethra and bladder. Vaginal relaxation with cystocele, rectocele, uterine prolapse, and vulvar dystrophies are not consequences of estrogen deprivation (26).
Disturbances of sexuality.
A strong decrease in ovarian hormones brought about by menopause and occurring around the same time that production of adrenal androgens has reached a low point seems to contribute to the decline in female sexuality. Sexual anatomy and sexual responsiveness, as well as sexual attractiveness, appear to be supported by estrogens, but sexual desire appears to depend on androgens, particularly free testosterone (1).
Skin changes in the perimenopausal period.
The skin contains estrogen receptors and can metabolize estrogens actively. The estrogens affect the hyaluronic acid and water content in the sexual skin areas and seem to increase the skin thickness (4).
Long-term consequences of menopause
It is generally agreed that osteoporosis constitutes a reduction in the mass of bone tissue relative to the volume of the anatomical bone. The precise point at which such reduction should be regarded as abnormal and justify the definition " osteoporotic " is when the bone density is less than 1 g of mineral/cm2, below the fracture threshold. The determination of bone mass required for the recognition of osteoporosis should be performed by Dual Energy X Absorptiometry (DEXA).
It has been estimated (19) that 50% of women will have an osteoporotic fracture during their life. In reality the prevalence of vertebral fractures cannot be reliably assessed since they do not result in admission to hospital or specific treatments, and all statements about their prevalence must remain pure estimates. The incidence of Colles and vertebral fractures increases soon after the menopause, whereas the incidence of hip fracture increases more slowly with age until approximately age 70 when the incidence increases significantly. The cumulative life-time risk at 50 years of age for either Colles fracture or hip fracture in women is 15%. Approximately 20% of women who sustain a fracture of the neck of the femur will die as a direct result of their injury (24).
The hormonal changes that accompany the menopause are associated with the onset of bone loss, which then proceeds at an average rate of about 1% per annum. This loss of bone is not uniformly distributed throughout the skeleton, the relative loss of trabecular bone (which comprises 20% of the skeleton) being greater than the relative loss of cortical bone (which comprises 80% of the skeleton). A study of the premenopausal daughters of women with osteoporosis revealed a reduction in bone mass, suggesting either a genetic influence or sharing of a lifestyle which produces a relatively low peak bone mass (25). The risk of fracture depends upon 2 factors: the bone mass achieved at maturity and the subsequent rate of bone loss.
With estrogen replacement therapy (ERT), we can expect a 50 to 60% decrease in fractures of arm and hip, and when estrogen is supplemented with calcium, an 80% reduction in vertebral compression fractures can be observed. The positive impact of hormone replacement therapy (HRT) on bone has been demonstrated to take place even in women over age 65 (24). An analysis of ageing women’s calcium needs indicated a greater requirement than previously appreciated. Women on estrogen replacement require a total of 1000 mg elemental calcium per day, since the average woman receives only 500 mg of calcium in her diet, the minimal daily supplement required is an additional 500 mg. Patients who already have had clinically significant osteoporosis should be treated more vigorously. Treatment should also include active metabolites of vitamin D and fluoride.
In developed countries, cardiovascular diseases (CVD) are now the leading causes of death. A protective effect of estrogen replacement therapy on heart disease is effective and is well demonstrated by numerous studies (27). When an overall risk-benefit equation is considered with HRT in postmenopausal women, the suggested protective effect against CVD appears to be the strongest benefit, overriding all other advantages and outweighing the risks. When Ross et al. (20) computed the effects of ERT on mortality, they calculated that if ischemic heart disease was reduced by 50% (RR = 0.5) the net reduction in mortality afforded by estrogens would be almost 40%.
The protective effect of estrogen is achieved by specific pharmacological consequences: changes in plasma lipoproteins and direct action on coronary arteries. Natural estrogens can be safely given to women at risk but synthetic and equine estrogens should be avoided for those women who are hypertensive, those who have varicose veins, or suffer from hypercholesterolemia.
Hormone replacement therapy (HRT)
Estrogens normally promote mitotic growth of the endometrium. Abnormal tissue growth patterns, cystic hyperplasia, adenomatous hyperplasia, atypia, and early carcinoma have been associated with unopposed estrogen activity (26).
There are two points worthy of special mention:
- The risk of endometrial cancer with ERT is duration-dependent.
- There is an increased risk of endometrial cancer for many years after discontinuation of treatment with unopposed cyclic estrogens.
It is now apparent, however, that the risk can be reduced by the addition of a progestational agent to the program. The optimal number of days for progestin administration is 12-14 days. Gambrell (13) demonstrated a lower incidence of endometrial cancer in patients receiving estrogen and progestins than in untreated patients. The protective effect of progestins against endometrial cancer may be through an ability to decrease nuclear estradiol receptors, antagonize deoxyribonucleic acid synthesis, and decrease cell multiplication.
Unlike endometrial cancer, the incidence of breast cancer continues to rise, and factors which increase the relative risk (RR) of breast cancer have a common theme: low parity, first childbirth after 30, obesity, anovulation, early menarche, and late menopause (26). The role of ERT in the development of breast cancer remains controversial (2,5,8,12,14,18,23), but several well-designed studies showed a moderate increased risk after long-term use (3).
Do progestins have an effect upon the risk of breast cancer?
We have evidence today that progestogens (2) increase mitosis in breast epithelial tissue, and in practice the problem remains completely controversial. The sparse data suggest that combination therapy may enhance breast cancer risk (3). Until further research defines the role of progestins in breast cancer, progestin use should not be recommended in post-hysterectomy patients.
Different types of estrogens and progestins
What types of estrogen are available?
There are two types of estrogens: synthetic and natural. Synthetic estrogens, as prescribed in the oral contraceptive, exert a pharmacological effect. To achieve this, they possess greater potency than the natural estrogens, and alter the production rates of various factors involved in fibrinolysis/coagulation within the liver. For this reason, synthetic estrogens have no place in HRT. For HRT, it is preferable to use natural estrogens like 17ß-estradiol or estradiol valerate, and to prescribe minimal dose necessary in maintaining the axial and peripheral bone mass.
There are many routes of administration, (oral, parenteral, and vaginal). The major difference between oral and non-oral administration is the avoidance of the gastrointestinal tract and " first pass " effect on the liver with the non-oral route.
Oral administration. Results in an initial rapid conversion of estradiol to estrone in the gut mucosa. Thus, estrogens are largely absorbed into the portal venous system to the liver (" first pass ") where they are further metabolized and inactivated. These effects have a number of consequences: first, by increasing HDL-cholesterol, triglycerides* and renin substrate*. Second, by decreasing LDL-cholesterol and antithrombin III* (dose-dependent*).
Non-oral administration. Non-oral estrogens, whether transdermal patches, percutaneous cream, or subcutaneous implants, avoid the " first pass " effect on the liver. Estrogens can be preferentially delivered directly into the systemic circulation. Percutaneous administration achieves significant changes in lipids and lipoproteins only after 6 months of treatment. But there is no increase in renin substrate or change in clotting factors (7).
In clinical practice, the choice of the administration route devolves upon patient and clinician preference in the majority of patients. Oral therapy need only be avoided in those women considered to be susceptible to the hepatic effects (labile blood pressure, hypertriglyceridemia, or a previous history of venous thromboembolism) (6).
Choice of progestins.
There are two types of progestins: synthetic and natural. The synthetic progestogens have been classified into two major groups: those that are structurally related to progesterone (e.g., medroxyprogesterone acetate, medrogestone, chlormadinone acetate, promegestone, and dydrogesterone) and those structurally related to testosterone (e.g., norethisterone and norgestrel). The latter group antagonize estrogen benefits on plasma lipoproteins (9,21).
Treatment regimens vary from one country to another. Today progestogens may be added sequentially or as combined/continuous with the estrogens (26).
There are two sequential methods which have been in general use. The first method involves estrogen administration from the 1st through the 25th day of each month, as a convenient aid to remembering the routine. During the last 12 days of estrogen administration, a daily dose of progestogen is added. In the other sequential method, estrogen is taken every day throughout the month and the progestational agent is administered daily for the first 12-14 days of the month. In the combined/continuous treatment lower doses are effective in reducing the target tissue content of estrogen receptor, and reduces the unwanted reactions, progestin-dependant: weight gain, fluid retention, breast tenderness, withdrawal bleeding, and/or depression.
Combined/continuous estrogen therapy appears to minimize the risk of endometrial hyperplasia, which may also increase compliance. Withdrawal bleeding influences patient compliance for a large part, but the majority of bleeding occurs within the first 3 months of therapy and is associated with perimenopausal status and weight >65 kg. It has been suggested (22), and it is our opinion, that the perimenopausal patient should start with cyclic therapy for 1-3 years and later shift to continuous therapy.
Contraindications to HRT
The contraindications to HRT according to the guidelines of the Multidisciplinary Group on Menopause of our Hospital are listed in Table 1.
Screening before and during treatment
A general physical examination should be performed, including measurement of height, weight, and blood pressure. Breast and pelvic examinations (with cervical smear if appropriate) should be performed. Before commencing HRT all women should have a mammogram. No additional investigations are required in most women. The indication for lipid screening may be interesting for the identification of patients at risk. In our menopause clinic, glycemia, triglycerides, total cholesterol, and HDL-cholesterol are routinely performed.
The first follow-up visit takes place towards the end of a 3-month course of HRT. This visit is very important in order to evaluate side effects and to adjust the dosage if necessary. It is a standard practice to record the weight and blood pressure at each visit. We recommend that certain women in high-risk groups undergo mammography every year, e.g. women with a strong, relevant family history of breast cancer or previous relevant surgically confirmed benign breast disease. No additional tests are required for most women. Follow-up measurement of serum cholesterol may help to record and motivate hypercholesterolemia patients on HRT and low-cholesterol diets. For each patient we give some dietary recommendations (particularly on calcium supplementation, and low-cholesterol diet).
It is also necessary to counsel the patient on lifestyle issues, such as:
- Nutritional dietary changes.
- Change in lifestyle (smoking, drugs, alcohol).
- Social support, education, and counselling.
When is D&C needed in women receiving combined estrogen/progestational regimens? Regular endometrial sampling is not required if the following criteria are fulfilled:
- The withdrawal bleeding is not heavier than the " normal " period.
- The withdrawal bleed lasts for a similar duration to the " normal " period.
- The withdrawal bleeding starts with orally administered estrogens on the 10th/11th day of progestogen addition or later, and with transdermal estrogens on the 8th/9th day of oral progestogen therapy or later.
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