Definition

Menopause defines the cessation periods. According to data from Western countries the average age of menopause is 51.5 years, and it has not changed over the last 100 years. When menopause occurs before the age of 40 it is named premature menopause, and when it occurs before the age of 45 it is named early menopause. A woman’s age at menopause is strongly related with her mother’s age at menopause.  Risk of early menopause is higher in women whose mothers have experienced early menopause. Women with previous deliveries experience menopause later than women without deliveries, as women who have used oral contraceptives experience menopause later than women who has not used contraceptive pills. Women smoking more than 10 cigarettes per day experience menopause 1.5 years earlier on average compared to women who do not smoke. Surgical removal of one of the ovaries, chemo or radiotherapy for cancer treatment, endometriosis are among the other factors that cause early menopause.

Symptoms and signs

Bleeding patterns  The main symptom of menopause is the cessation of menses. Absence of menstrual bleeding for more than 6 months in a woman over 45 years of age is usually associated with menopause. Hot flushes and vaginal dryness accompanying the cessation of periods supports the diagnosis. Occasionally bleeding may occur following periods of amenorrhea. Such bleeding must be carefully evaluated because it may be related to a condition called endometrial hyperplasia which is abnormal thickening of the endometrium.

Hot flushes and sweating  These symptoms are present in 70% of women after menopause. In 55% of women they are severe enough to adversely affect daily life. A sweating episode follows an acute feeling of heat starting from the head and upper body. The exact cause of this phenomenon is not clear. It may be more frequent at nights and disrupt sleep.

Urogenital atrophy  Decreasing estrogen levels cause vaginal dryness and thinning of the vaginal lining rendering sexual intercourse at times very painful for the woman. Sometimes spotting like bleeding may occur. Thinning of the vaginal lining decreases the resistance against microorganisms and recurrent vaginal infections may be occasionally encountered.

Osteoporosis  This is one of the most important long term consequences of menopause. There’s not sufficient data on its prevalence in our country. Data is derived from European and North American countries.  However, it is difficult to extrapolate this data to our women due to different nutritional, exercise and smoking patterns.  Furthermore, Turkey is a southern country and people are exposed to more sunlight than in northern countries making the development of osteoporosis less likely. 

There are two kinds of osteoporosis, postmenopausal osteoporosis (rapid bone loss in women following menopause) and senile osteoporosis (osteoporosis occurring in the older age period in both genders). Several risk factors for osteoporosis are identified. These are early or surgical menopause, inadequate intake of milk and diary products which are rich in calcium, insufficient exposure to sunlight, sedentary life style, smoking, family history of osteoporosis and fractures, and not taking estrogen supplementation after menopause. 

Coronary artery disease  In women, plaque formation and thickening of the muscular layer of arteries accelerate with menopause and after 70 years of age the risk of death due to heart attack equals to risk in men. Theoretically, risk attenuation with its administration would be among the most important beneficial effect of hormone replacement therapy.  However, clinical studies have demonstrated that this is not the case and hormone replacement is no longer recommended for prevention of coronary artery disease. Adverse changes occur in blood lipids in the postmenopausal period, and cholesterol and triglyceride levels increase. There are changes in coagulation factors with menopause and there is a relative increase in coagulation. Hence risk of coronary artery disease and stroke increase due to activation of the coagulation cascade.  Depsite its favorable effects on the arterial wall, hormone replacement may have adverse effects on the coagulation cascade making thrombus formation more likely. 

Memory and cognitive impairment  Memory decreases with age. It is thought to decrease more rapidly after menopause. Cognitive functions such as attention, concentration also attenuate with menopause.

Mood changes  It is known that menopause dramatically effects woman body and it may cause physical and emotional instability. Many women experience emotional and psychological changes as well as physical changes in the menopausal period. Psychological and mental changes in the menopausal period can be examined under four major headings:

Many menopausal women frequently experience mood changes such as anxiety, fragility, irritability, loss of energy, and aversion. It is not clear if these changes are due to hormonal changes of menopause or due to midlife crisis.  One thing is clear that menopause does not cause major depression. But previously present mood disorders or depression can be exacerbated or can relapse during menopause. A general state of unhappiness is present in women during the menopausal transition. Fatigue, easy loss of temper, crying episodes, and memory problems are frequently encountered.

Ineffectiveness of estrogen for treatment of clinical depression has been demonstrated in clinical trials. Estrogen can be administered together with an appropriate SRI in these patients.  Estrogen alone can be sufficient for women experiencing mild mood changes.

Studies show that socio-cultural and personal factors are more important than hormonal factors in triggering depression during menopause. Loss of reproductive potential, youth and young appearance, change of body contours, sleeplessness leading to tiredness, and decreased libido cause anxiety. However,  growth of children, end of school problems, being respected as a middle aged woman in the family and society, being relieved from several previous responsibilities, and having more time for oneself can open new horizons for a person.  A woman can enjoy this new and long period awaiting herself. In addition to estrogen replacement, physicians have important responsibilities for motivating women for acquisition of new activities, decreasing stress, exercising, and regulating bad dietary habits.

Sexual desire  The effect of menopause on libido is not clear. Several psychological changes related to menopause can adversely affect the libido. Vaginal secretions and sexual desire decrease in menopausal women, especially if they do not receive hormone replacement. Painful sexual intercourse and decrease in the frequency of orgasm are among the most common post menopausal symptoms. It is reported that 86% of postmenopausal women never achieve an orgasm. Estrogen and androgen replacement usually restores sexual desire.

Examinations and laboratory tests

A careful personal history and physical examination is mandatory. A detailed family history must be taken and conditions that prevent hormone replacement therapy must be sought.

Required laboratory tests are listed below: 

PAP smear:  The interval between tests can be as long as 3 years if there had been no abnormal results in previous tests.
Ultrasonographic evaluation of ovaries and endometrium
Complete blood count
Lipid profile: Total cholesterol, HDL and LDL cholesterol and triglycerides
Liver function tests: ALT, AST
Cardiac risk markers: CRP, homocysteine
TSH: Subtle hypothyroidism is prevalent among women, so annual testing is recommended.
Mammography: Annual mammography is recommended between 40 and 60 years of age.

Ultrasonography is used for evaluation of a suspected lesion in mammography. Liquid or solid lesions can be discriminated with ultrasonography. Mammography reveals limited information in women with dense breasts. Estrogen therapy makes mammographic evaluation more difficult by increasing breast density. Mammography is inadequate for breast evaluation in women with breast implants, MRI should be used instead.

Bone mineral density measurement: It is especially important for women with known risk factors for osteoporosis but refuse hormone replacement therapy. It is not necessary for women without risk factors or already receiving hormone replacement, because results do not change management.

Genetic risk profiling: This has gained importance in recent years. It is not commonly applied due to high cost of the tests. Identification of women with high risk genetic profile serves to detect women who would benefit or be harmed with medication.

Hormone replacement therapy

Options

Estrogen (E) only: This is the preferred method of hormone replacement for women whose uterus is removed. Estrogen is usually taken continuously through the mouth or administered as skin patches (transdermal treatment).
Estrogen with progesterone (P): In women with an intact uterus estrogen replacement alone increases the risk of endometrial hyperplasia (thickening of the inner lining of the uterus) and endometrial cancer.  Therefore, progesterone should be combined with estrogen. E + P therapy is usually given in a cyclic fashion to women who have recently entered menopausal or who are in the perimenopausal period. Continuous E + P therapy is implemented after one year. Regular menstrual bleeding is experienced in the cyclic treatment whereas women do not bleed during continuous treatment.  Progesterone can be given orally, vaginally or locally by means of progesterone releasing intra uterine device.
Androgen supplementation alone or with estrogens: Decreasing androgen secretion from the ovary is held responsible for decreasing libido in the menopausal period. This is the logic behind androgen replacement. Sexual desire and fantasies are shown to be increased in women receiving androgens. Dose titration should be done very carefully. High androgen levels cause unwanted hair growth, oily skin, pimples, or other skin problems.
Hormone like substances (Tibolone): This is a non steroidal substance acting by binding to estrogen, progesterone and androgen receptors. It is used continuously and devoid of many side effects of estrogens. It does not cause bleeding. Risk of breast cancer is lower with tibolone compared to estrogens.
Phytoestrogens (plant derived estrogen like substances): Black cohosh and isoflavin are the substances in this group. They exert weak estrogenic effects in the human body. They are shown to decrease acute symptoms of menopause such as hot flushes or vaginal dryness in some studies, but other studies yielded conflicting results. They are generally preferred for women who do not want to take estrogens or have conditions precluding estrogen use. Their effects on the long term adverse effects of menopause are not clear.

Routes

Hormones can be applied orally (pills), intranasally (nasal sprays), transdermally (skin patches), vaginally (suppositories inserted into the vagina), or locally into the uterus. Estrogens are usually given orally or transdermally and they exert similar effects via both routes. Oral route is preferred for women with high cholesterol levels whereas transdermal route is preferred for women with high triglyceride levels. Transdermal application bypasses the liver and thus inactivation and the drug reaches target tissues directly. Transdermal application of estrogen causes less discomfort in stomach or bowel, and provides more constant blood levels. Vagina, external genitalia, endometrium (inner lining of the uterus), breast, central nervous system and vessel walls are the target tissues of estrogen.

When local complaints such as vaginal dryness are more prominent, estrogens should be applied as vaginal gels or capsules. Systemic treatment is not necessary for women without other complaints.

Benefits

Hot flushes: Twenty-five percent of menopausal women have no hot flushes, 50% experience moderate hot flushes, while the remaining 25% experience severe hot flushes that adversely affect daily life. Episodes of sweating usually accompany hot flushes at nights. Night sweats cause sleep disturbances, hence tiredness and nervousness during the day. This is one of the worst conditions affecting quality of life. Hot flushes decrease and eventually subside within 6 months to 2 years. However, 20% of women continue to experience bothersome hot flushes even after being menopausal for over 2 years.  Estrogen replacement ameliorates hot flushes very effectively. Effectiveness of estrogen replacement with regard to elimination of hot flushes has been proved in placebo controlled trials. Estrogens can be administered orally or by skin patches. Women with an intact uterus must take progesterone with estrogens. If hormone replacement is stopped abruptly hot flushes start again, so the dose of hormones should be gradually tapered off.  Alternative treatments include clonidine and plant soy derived estrogens.  However, these options are not as effective as estrogen.   

Urogenital atrophy (vaginal thinning): External genital organs and the vagina starts undergoing atrophy within 1 year after menopause if hormones are not administered. There is loosening and thinning of the external genital organs. Vagina becomes dry and narrow thus rendering sexual intercourse more difficult. Urinary incontinence is also due to genital atrophy. Thinned vaginal tissue becomes vulnerable to infections. For women presenting with vaginal dryness without hot flushes local estrogen therapy will be sufficient. Locally applied estrogens do not enter the systemic circulation in significant amounts and do not necessitate progesterone co-treatment for protection against endometrial hyperplasia and cancer. For women who do not want to take local estrogens over the counter lubricant gels may relieve pain during intercourse.

Osteoporosis (Bone loss): Osteoporosis is a prevalent and important issue in both North America and Europe. Loss of calcium from the bones is accelerated after menopause and risk of fractures increase. Most common sites of fractures are the spine, femoral neck and the wrist. Spinal fractures can occur without considerable trauma and sometimes spontaneously.  Fractures of the wrist and the femoral neck are more common in winter due to accidental falls.  Risk of death due to complications of a hip fracture is approximately 16% in the 3 months following the fracture. Osteoporosis has been named the silent killer.  It does not cause any symptoms until a significant proportion of bone is lost, and eventually becomes evident with a fracture sometimes even after an insignificant trauma or an accidental fall.

Bone density increases until the age of 35 in both men and women, and starts to decrease slowly thereafter. Genetic factors, smoking, sedentary life style, inadequate exposure to sunlight, deficiency of the diet in dairy products can prevent reaching maximal bone mineral density. Women carrying these factors may have significant bone loss even before entering menopause.

Estrogen treatment effectively prevents osteoporosis development and stops the progression of established disease.  Estrogen treatment may increase the bone density in some cases. Hormone replacement decreases fracture risk by 30% for vertebrae and pelvis, and by 24% for whole body. North American Menopause Society (NAMS) recommends hormone replacement therapy, for more than 5 years, for women with bone loss and high risk for fractures. Particularly women not taking other forms of bone protecting treatments should receive hormone replacement.

Hormone replacement is not considered the first line treatment for the purpose of prevention of bone loss in women without other menopausal symptoms. For women on hormone replacement for other reasons, it is recommended to continue treatment under close supervision, in women with high risk of fractures or established bone loss. Women on hormone replacement do not need additional medication for prevention of osteoporosis.

Alzheimer’s disease: Relation between hormone replacement and Alzheimer’s has been evaluated in four studies. A risk reduction of 67% for Alzheimer’s disease has been shown in women starting hormone replacement therapy early after menopause. But estrogens have no effect on already established disease. It is not known whether estrogen benefits women with a family history for Alzheimer’s. It is not widely accepted to prescribe estrogens for this indication.  There is need for data derived from well designed studies to establish the relationship between hormone replacement treatment and Alzheimer’s disease. 

Cancer of the colon and rectum: One third of deaths in North American women is due to cancer. Colon cancer is more frequent in women between 60 to 75 years of age. Studies evaluating estrogen replacement and colon cancer relation have shown that hormone replacement decreases the risk by 50%. It is not known by which mechanism estrogen decreases the risk of colon cancer, Decrease of carcinogenic bile acids in women receiving hormones has been implicated.

Risks

Cardiovascular disease and stroke: Until recently, hormone replacement was believed to decrease the frequency of cardiac events particularly coronary artery disease (CAD).  Decreased risk of death from cardiac events in women receiving hormone replacement was first shown in the Framingham study back in 1976. Subsequent studies, mostly case control, cross sectional, or observational, showed that estrogens exerted beneficial vascular effects via direct effects on vessel walls, on blood lipids, and on clotting parameters. In 2001 the Women’s Health Initiative (WHI), the only prospective randomized study, which was prematurely terminated at 5.2 years, showed that combined estrogen + progestin therapy did not decrease the risk of coronary disease, but conversely increased it. This study has been a milestone in hormone replacement therapy, and since then hormone therapy is preferred in risk free women and applied in a tailored fashion to suit the needs of the individual patient. WHI study has some limitations that preclude generalization of its results. The most important of these limitations is study population’s being restricted to women over 60 years of age. Hormone replacement would theoretically benefit younger women who have just become menopausal and have no established vascular disease.

WHI study has also showed that risk of stroke is increased in women receiving hormone replacement therapy. Risk of sudden death or stroke due to occlusion of brain vessels is higher in women taking hormone replacement. Relative risk is reported to be 1.44. Increased risk could not be attributed to risk factors such as hypertension and diabetes. Prescription of hormone replacement to women with congenital coagulation disorders, without being aware of the condition, is thought to be the reason. In women on hormone replacement, risk of clot formation in veins (venous thrombosis) is twice the risk in women who are not on treatment. Low prevalence of congenital coagulation disorders like Factor V Leiden mutation and protrombin gene mutation, render universal pretreatment screening of clotting disorders not cost effective as a community based policy. Hormone replacement therapy is absolutely contraindicated in women with history of previous venous thrombosis, as the risk is 5 fold increased in these women.

Breast cancer: Breast cancer is the leading cause of cancer related death in women and hormone replacement therapy increases the risk. Relative risk was found to be 1.24 in the WHI study. Risk is not increased in women who have taken treatment for less than 5 years. Risk of death due to breast cancer was not found to be different between women on hormone replacement therapy and women not receiving therapy.  Breast cancer is diagnosed early in women who take hormone treatment because they are under close surveillance. Additionally natural history of breast cancer and biologic behavior of cancer is better and progression of cancer is slower in women on hormone replacement.  Risk of breast cancer is not increased in women taking estrogen only treatment.

Hormone replacement can be prescribed to women without a family history of breast cancer, women without a history of excision of precancerous lesions if they have menopause related symptoms (i.e. hot flushes). Annual mammographic controls are recommended.  It should be noted that estrogen treatment increases mammographic breast density. This renders interpretation of mammography difficult.

Risk – benefit assessment of hormone replacement and recommendations

When hormone replacement therapy is evaluated in terms of benefits and risks under the light of current data, the treatment appears to be more harmful than beneficial. However, it should be kept in mind that data pertaining to women between ages of 50 to 60 years, who need hormone replacement the most, is quite limited. Hormone replacement is the best means of alleviating short term menopausal symptoms in carefully evaluated and selected women. Prescription of hormone replacement to only symptomatic women, in the lowest adequate dose for the shortest possible time (less than 5 years) is the accepted mode of approach today. Hormone replacement can be continued under close surveillance in women with ongoing symptoms and thus who do not want cessation of therapy.

Alternative treatments in menopause

Concerns for postmenopausal hormone treatment, has diverted physicians as well as patients, towards prescription of herbal and non hormonal treatments. But definitive data on long term effects of these treatments is lacking. 30 to 60% of symptomatic menopausal women are taking natural products or phytoestrogens (herbal estrogens) or undergoing alternative treatment modalities like acupuncture or yoga. Although phytoestrogens offer some relief from hot flushes, the magnitude of the effect is not more than placebo. Prospective double blind randomized studies failed to show a significant difference between phytoestrogens and placebo. Additionally phytoestrogens are not effective in relieving vaginal dryness, bone loss or urinary complaints. Furthermore, they are not more effective than placebo on cognitive functions and mood.

It must be remembered that herbal remedies are not free of harmful effects. Formulation, manufacturing, and titration of herbal drugs are not standardized. There are no well defined rules for dosing or duration of treatment.

Menopause is a natural process that covers a long period in a woman’s lifespan. The first step towards symptom free living of this period is implementation of necessary life style modifications. Gaining new hobbies, increasing physical activity, decreasing fat intake, increasing vegetable and fruit consumption are recommended. Daily 30 minutes walks decrease the frequency of hut flushes and increase strength of bones. Calcium rich foods should be consumed to prevent bone loss. Tea, coffee and spices are not recommended as they trigger hot flushes.

Chromosomal abnormalities
Autoimmune diseases
Estrogen synthesis disorders
Metabolic diseases
Cancer treatment (Chemotherapy or radiotherapy)

There is no characteristic finding but some women may experience hot flushes even while they still have periods, and this may be the earliest sign of premature menopause. Patients usually present with infertility or cessation of menses.

Premature ovarian failure is diagnosed with assessment of levels of FSH, LH and Estradiol, which reflect ovarian functions. FSH and LH are found to be elevated while estradiol is decreased. Genetic assessment must be done in women who have early menopause before the age of 30. 10 to 20% of these young women may spontaneously start menstruating again. So, hormone levels must be periodically checked.

Estrogen replacement is the mainstay of treatment of hot flushes, vaginal dryness and bone loss. Spontaneous pregnancies may occur in women who are genetically normal and receive hormone replacement therapy. The probability of spontaneous ovulation and pregnancy is higher if FSH levels are found to be below 40 IU/L on one or more occasions. But ovarian failure is regarded to be irreversible if FSH level is over 100 IU/L.