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What is Menopause ?
Menopause is the irreversible cessation of the female reproductive cycle and menses, which follows from a permanent loss of ovarian response
to gonadotropins. This change generally occurs spontaneously between the ages of 45 and 55 in American women, with an average age of 51. Destruction or cessation of function of the ovary prior to age 40 is referred to
as premature menopause. Simple hysterectomy terminates menstrual bleeding, but not ovarian function, and thus does not constitute a true menopause. Physiology
Although it has long been known that the menopausal ovary is nearly depleted of primary follicles, the hormonal events of the perimeno-pausal transition have still not been
completely elucidated. Cyclic bleeding ceases, and FSH and LH levels become greatly elevated in serum and urine. Usually the FSH increase is greater. The few remaining follicles do not respond to gonadotropin. Estradiol
levels become extremely low (10 to 25 pg/ML), and adrenal estrone becomes the major circulating estrogen. Adipose tissue also provides estrogen. Estrogen Deficiency State
Ovarian estrogen production is minimal after the menopause. Most estrogen is formed from peripheral conversion of androgen, 75% of which comes from the adrenal. There is
considerable evidence that this rate of conversion is greater in obese women, who therefore tend to have higher estrogen levels postmeno-pausally. Estrogen deficiency results in various symptomatic manifestation in
approximately 70% of postmenopausal women. Hot Flashes
Nearly 50% of menopausal women complain of sudden sensations of flushing and extreme warmth,
followed by profuse sweating and sometimes shaking or tremor. These episodes occur at irregular intervals from a few to many times a day and may awaken the patient at night. In about 15% of women they are severe enough
to limit normal daily activities. It is important to remember that this and other menopausal symptoms may have their onset prior to actual cessation of the menses, since estrogen levels fall progressively in the
perimeno-pausal period. Investigations have shown that these episodes, objectively identifiable by altered skin and core temperature and skin resistance, precede LH and FSH secretory rises by just a few minutes.
Estrogen replacement therapy (ERT) can completely eliminate this problem. Osteoporosis
Bone is a metabolically active tissue that is constantly being remodeled. Old bone
is reabsorbed by osteoclasts, and new bone is deposited by osteoblasts. Whether net bone loss or accretion occurs depends on the balance between the activities of these two kinds of cells.
Osteoporosis, or diffuse
osteopenia, is a condition of generally reduced bone mass resulting from a relatively long period of negative imbalance in the remodeling process. An accelerated rate of demineralization, from 2% to 5%/year, occurs at
the menopause (or with any other cause of severe estrogen deficiency) and has been well documented in a number of studies.
During the first 5 years after the menopause, calcium loss is primarily from trabecular bone
(e.g., vertebrae), whereas later calcium loss occurs nearly equally from trabecular and cortical bone (e.g., hip and long bones). Eventually, fractures may occur. Crush fractures of the vertebral bodies initially
predominate, causing back pain, loss of height, and stooped posture (dowager's hump).
Later in the course, fractures of the hip and forearm (e.g., distal radius or Colles) are common. Osteoporosis is more common in
Caucasian and Asian than in African-American women. Clinically significant fractures are five to eight times more common in women than in men.
Known risk factors for osteopo-rosis include estrogen deficient states,
cigarette smoking, family history, fine body structure (i.e., low peak bone mass at maturity), sedentary life style, prolonged bed rest, cigarette smoking, alcohol abuse, nulliparity, diabetes mellitus, and chronic
gluco-corticoid therapy.
Bone loss occurs with aging, menopause, disease, deficiencies of specific minerals (calcium) and vitamins (Vitamin D), and can occur as a result of medications, diseases, and surgical
procedures (oopho-rectomy). The most common endocrine disorders that lead to bone loss include abnormalities in sex hormones, thyroid hormones, parathyroid hormone (PTH), and adrenal steroids.
Osteoporosis is more
effectively prevented than treated. The primary goal of prevention is to achieve as high a peak bone mass as genetically possible prior to skeletal maturity. This can be accomplished (l) with proper nutrition,
sufficient weight-bearing activity, and minimization of risk factors (smoking, excessive alcohol use, immobilization); (2) by continu-ing these beneficial habits throughout adulthood to maintain bone mass; and (3) by
using ERT in women at risk. Psychological Symptoms
Depending on the woman, the psychological response to the menopause may range from little or
none to profound alteration of affect and personality. Symptoms vary from minor irritability and emotional lability to severe depression and withdrawal from usual activities. Sexuality also is commonly affected, with
some women reporting an increase in libido attendant on release from worries about contraception, whereas other women have a reduction in sexual interest, usually associated with a perceived loss of attractiveness and
femininity. A number of studies have suggested that significant relief of psychological symptoms and an overall increase in sense of well-being and ability to concentrate may occur when estrogen replacement is
undertaken. Genital and Breast Atrophy
The female reproductive organs undergo striking changes at the time of the menopause. Pubic hair becomes sparse and lank, the labia
majora lose their fullness, and the skin and mucous membranes of the genitalia become thin and dry.
The vaginal pH becomes more alkaline as glandular secretion of glycogen is lost. This change and the mucosal
atrophy may result in a chronic vaginitis with itching, discharge, and local tenderness. Many women report decreased lubrication at intercourse and complain of dyspareunia.
The cervix, uterus, and fallopian tubes
also shrink. Estrogen deprivation is implicated in the relaxation of pelvic ligaments and muscles, which may result in uterine or bladder prolapse and contributes to stress incontinence. At the same time glandular
breast tissue involutes, and the breasts become shrunken and pendulous. There is a decrease in the erectile response of the nipple.
Estrogen Replacement Therapy and Hormone Replacement Therapy
Most of the adverse changes associated with menopause may be ameliorated or reversed by estrogen replacement therapy. Benefits
It is clear that use of estrogen (ERT) or estrogen and a progestin (HRT) is highly effective, compared with placebo, in suppressing the symptoms of the "hot flash."
Even low doses (0.01 mg of ethinyl estradiol daily or 0.625 mg of Premarin daily) are effective. Genital atrophy, vaginitis, and dyspareunia are all relieved by estrogen therapy, which may be systemic or local (by means
of estrogen-containing cream). Estrogen replacement has been shown to be effective not only in reducing calcium loss, but also in preserving bone density, even at relatively low doses. Estrogen replacement also reduces
the actual number of fractures in estrogen-deficient women. Thus, at present, long-term post-menopausal estrogen replacement is indicated for prevention of osteoporosis. Exogenous estrogens have beneficial effects
raising HDL (when taken orally), decreasing LDL cholesterol, and lowering the increased fibrinogen levels that are common in post-menopausal women. Androgens, on the other hand, do the opposite.
Numerous
epidemiological studies have shown that post-menopausal women taking estrogen replacement therapy have a significant reduction, on the order of 40 to 60%, of their risk of coronary events, CAD-related death, and
all-cause mortality compared with women not taking estrogen. The prevention of CAD may represent an even more compelling indication for ERT than does osteoporosis, as CAD is a much more common cause of disability and
death. Risks
Another important area to discuss is the risks of HRT. There is no evidence that HRT at post-menopausal doses increases hypertension or clotting abnormalities. Common
possible side-effects include withdrawal bleeding with cyclic dosing, spotting during the first three to six months with combined continuous therapy, mastalgia, edema, abdominal bloating, and increase in the size of
uterine leiomyomata. Rarely, symptoms of anxiety and depression can be worsened with initiation of HRT. Although there is no increase in asymptomatic gallstones, a 2.7-fold increase (3.4% to 9.8%) in cholecystectomy has
been noted. Breast Cancer
A possible increase in the incidence of breast cancer has long been a concern with HRT. This concern is very controversial, because most studies are observation or
small, there are conflicting results from many of the studies, and the number of women who develop breast cancer is so large that even a small change in the incidence of the disease will affect large numbers of women.
Some early studies, especially studies done in Europe, demonstrate an increase in breast cancer risk in current users of HRT, but many of these studies used unopposed estrogens that are not commonly prescribed in
the United States. There have been many studies since then that have shown no increase or even a decreased risk of cancer.
Modern studies have alleviated some fears about HRT's causing breast cancer. Recent
meta-analyses have shown that there is no evidence of an overall increased risk of breast cancer in women who have ever used post-menopausal estrogens.
Only one of three major meta-analyses has shown an increased
risk, and then only after at least 15 years of use. If there is a slight increase in breast cancer risk, then other risk factors for breast cancer and the relative benefits of HRT also must be considered.
Endometrial Cancer
Unopposed estrogen therapy has been associated with endometrial cancer in women with an intact uterus. Endometrial hyperplasia, which is thought to be a precursor to
cancer, occurs in 20% to 30% of patients who receive unopposed estrogen therapy. Although women who develop endometrial carcinoma while on estrogens have a more favorable prognosis, some cancers are still invasive.
However, adding 10 to 14 days of a progestin or continuous progestins to estrogen actually carries a lower risk on hyperplasia and carcinoma than non-estrogen users have. Patient Selection
Good health is more than just the absence of disease. Part of the definition may be based on improvement, in the sense of the well-being and improved quality of life that have
been demonstrated in most studies of HRT. If the patient has no contraindications to therapy and is willing to assume the effort and cost of long-term therapy, all of the beneficial effects of HRT should be considered.
Gorsky, et al., found that unopposed estrogen use for 25 years in 10,000 healthy women would, at age 50, result in 642 saved lives from heart disease and hip fracture and 68 excess deaths from breast and uterine
cancer, for a net of 574 lives saved. Women in different risk groups (e.g., at risk for coronary artery disease, osteoporosis, or breast cancer) must consider their own risk-to-benefit ratio and decide if HRT is best
for them. Contraindications to HRT include pregnancy, undiagnosed abnormal genital bleeding, impaired liver function, acute thromboembolic disease, history of thromboembolic disease with hormone use, and a history of
breast or endometrial carcinoma (see below). Estrogen is contraindicated in women with a history of endometriosis because of possible reactivation of the disease. It also is not recommended in women with active
gallbladder disease because of changes in the bile, and should be used with caution in patients with uterine leiomyomata or a history of menstrual migraines. Survivors of Breast Cancer
The standard of care in the United States is to discourage the use of HRT in survivors of breast cancer, and the ACOG considers breast cancer a contraindication to HRT. Many
researchers postulate that when a patient is "cured" of breast cancer, there actually are minimal micro-metastases at "immunologic pease" with the body. This would account for the long disease-free
intervals associated with this disease. It is feared that adding HRT will upset this balance. However, some researchers have called for further outcomes research, since this standard is based more on theoretical
considerations than on research and most of the research does not account for the life-saving, noncancer effects of HRT. There currently is not enough information to make definitive statements. Dosage and Administration
Estrogens from animal sources have been widely available in oral form for many years. Now oral forms derived from plant sources and synthesized de novo also are available.
Oral estrogens were first derived from pregnant mares' urine, which continues to be a major source. Some animal rights groups object to conjugated equine estrogens on the grounds that collection of the mares' urine is
cruel to the animals. However, most of their arguments are based on old case reports and emotional appeals. Canadian animal welfare and vetrinary groups dispute the position of PETA and its allies.
One problem with
oral estrogens is that they must pass through the liver after absorption. This causes measurable changes in clotting factors, but any clinical effect of these changes in unlikely.
Transdermal estrogens are now
available. They do not cause clotting changes, and they do favorably affect hot flashes, cholesterol, and bone density, but their positive cholesterol effects may be less than oral estrogens. Their only major unique
problem is skin irritation, which usually can be avoided by application on the buttocks and regular rotation of application sites.
Intravaginal estrogens are effective in relieving local symptoms of estro-gen
deficiency, but do not have a major effect on other parameters. Short-term application of intravagin-al estrogens after an inflammatory or atypical post-menopausal Pap smear is often used to "normalize" the
cervical epithelium. ESTROGEN
If a woman has an intact uterus, unopposed estrogens are associated with endometrial hyperplasia and carcinoma. Therefore, almost all such women
should also be given a progestin. In women who have had a hysterectomy, progestins need not be added, and unopposed estrogens are most commonly used. In the past, estrogens were given for 25 days of each month, with
a 5-day drug-free period to simulate a "normal cycle." However the amount of estradiol in the blood from HRT is usually below the amount present during menses in a pre-menopausal woman. Today, many authors
advocate the use of continuous estrogen therapy because there are no proven benefits to the drug-free intervals, the regimen is more complex and harder to comply with, and symptoms may recur during this period.
PROGESTERONE
Regardless of the regimen, the lowest dose of pro-gestin possible that protects against endometrial hyperplasia should be used to minimize the adverse cardio-vascular
effects. In the perimeno-pausal period (2 years before and after menses cessation), cyclic pro-gestins such as 5 mg to 10 mg of medroxyprogesterone, given for 10 to 14 days each cycle, are the preferred method of
therapy. Beyond the perimenopausal period, when endogenous estrogen production has reached baseline, progestins can be given cyclically or continuously every day. Although spotting is common during the first six
months of combined continuous HRT, as many as 95% of users will experience amenorrhea in one year. Studies have shown that giving combined continuous estrogen and progestin therapy provides equal endometrial protection
and increases patient compliance over cyclic dosing with progestins. Constant therapy is beneficial in treating hot flashes, alleviating urogenital atrophy, lowering cholesterol, and halting osteoporosis. The most
common dosages of medroxyprogesterone acetate for continuous therapy are 2.5 mg or 5 mg daily. There is a slightly higher rate of spotting, and fewer women achieve amenorrhea at one year with the 2.5 mg dose, so the 5
mg dose is sometimes preferred. If a woman experiences uterine bleeding after cessation of menses on a continuous combined therapy, an endometrial biopsy is mandatory. Studies have been conducted using progestins
every 2 to 3 months instead of monthly or continuously. Although there are minimal side-effects with this regimen and endometrial hyperplasia rates are less than with ERT, hyperplasia is more common than with typical
HRT regimens. Long-term studies on hyperplasia and beneficial effects have yet to be carried out. ALTERNATIVE THERAPIES
HRT will not be acceptable or tolerated in all women,
and alternatives do exist for menopausal problems. Alternative drugs for treating hot flashes include progestins such as megestrol acetate and clonidine. Lubricants can counteract vaginal dryness, and Kegel exercises or
surgery may help with incontinence.
Regular exercise, coupled with 1500 mg of calcium and 400 IU of vitamin D per day can decrease the bone loss associated with osteoporosis. Regular exercise, good diet, and
non-smoking will help prevent heart disease and is recommended for all patients, regardless of the use of HRT. Written by:
E.J. Mayeaux, Jr., M.D.
Associate Professor of Family Medicine
Clinical Associate Professor of Obstetrics and Gynecology
Louisiana State University Medical Center Shreveport, Louisiana Medications for Menopause and HRT
Clomid,Serophene(Clomiphene citrate)
Nolvadex(Tamoxifen citrate)
The antiestrogens tamoxifen and clomiphene are used primarily for the treatment of breast cancer and female
infertility,respectively.These agents are used therapeutically for their antiestrogenic actions,but they can produce estrogenic as well as antiestrogenic effects.Both agents competitively block estradiol binding to its
receptor,but the specific pharmacological activity they produce depends upon the species,the tissue and the cellular endpoint measure.Consequently, these agents act as antagonist or partial agonists depending upon the
contex in which they are used. Premarin
The medication used by post-menopausal women for hormone replacement therapy.It contain
estrogens(female hormones)which are responsible for a wide variety of bodily functions including; improvement in cardiovascular function,prevention of osteoporosis,improvement in memory, prevention of wrinkles,reduced
acne and facial hair growth and maintenance of vagina lubrication. Premarin is also referred to as conjujgayed equine estrogens. Premarin is composed of more than 20 different compounds which are purified
from the urine of pregnant mares. Premarin has been available longer than any other medication used for hormone replacement and is the gold standard to which other medications are compared. For most women,
0.625mg. is the minimum effective dose that is demonstrated to prevent osteoporosis and improve cardiovascular function.
Provera (Medroxyprogesterone acetate)
Progestational agents are useful as second-line hormonal therapy for metastatic,hormone-dependent breast cancer and in the management of endometrial carcinoma previously treated
by surgery and radiotherapy. Medroxyprogesterone acetate(MPA) is the progestin most commonly used in hormone replacement regimens. It has less androgenic activity than other progestin. |
