The menopause.

Symptoms due to estrogen deficiency begin in the perimenopausal years and progress as serum levels of this hormone decrease Vasomotor instability, manifested by hot flushes or night sweats, may persist for several months to a few years. Psychologic symptoms include anxiety, tension, depression, insomnia, palpitations, and headaches. Atrophy of the genital epithelium may result in senile vaginitis with symptoms of irritation, burning, pruritus, dyspareunia, and even vaginal bleeding. Even the lower urinary tract mucosa is dependent upon estrogen. Postmenopausal osteoporosis affects 25 to 50% of older women and increases the risk for vertebral, hip, and other fractures. Estrogen therapy for menopausal complaints has received adverse publicity because several reports have indicated that unopposed estrogens increase the risk of endometrial cancer. Added progestogen not only negates this risk but reduces the incidence of endometrial adenocarcinoma in estrogen-progestogen users to less than that observed in untreated women. Estrogen replacement therapy does not increase the risk of breast cancer; the incidence of this malignancy, however, was also less in the estrogen-progestogen users when compared with either the untreated women or from that expected from the national cancer surveys. In evaluating postmenopausal women for hormone replacement, the benefits of estrogen-progestogen therapy must be weighed against possible risks.

Reduced incidence of endometrial cancer among postmenopausal women treated with progestogens.

PIP: Because of adverse publicity regarding increased risk of endometrial cancer in women receiving estrogen therapy, a 2-year prospective study was conducted in 1976 to determine the incidence of endometrial cancer in postmenopausal women. A retrospective study for the year 1975 was also added. A postmenopausal survey card for each patient recorded the patient's visit and clinical data, as well as hormone therapies (estrogen, progestogen, androgen). Postmenopausal women never treated with hormones were also provided survey cards. A total of 2088 patient-years of estrogen use was recorded during the combined 3-year study period (1975-77). 8 of the estrogen users had a diagnosis of adenocarcinoma of the endometrium for an annual incidence rate of 3.8/1000 women. 2 endometrial cancers were detected in the estrogen-progestogen users for a cancer incidence rate of 0.5/1000 (3792 patient-years of observation); this finding suggests that progestogen provides better protection against endometrial cancer compared to estrogens. This difference between estrogen users and estrogen-progestogen users was statistically significant (p ? 0.01). 1 endometrial malignancy occurred among estrogen vaginal cream users, giving an incidence of 1.7/1000. The patient used Premarin vaginal cream (1 gm thrice weekly) for 7 months before the cancer was diagnosed. No endometrial cancer was diagnosed in both the progestogen and androgen groups. Overall, 14 endometrial cancers out of 8170 years of observation were diagnosed in this clinic; annual incidence rate for the study period was 1.7/1000. 199 women with endometrial hyperplasia (a precancerous lesion) were treated with progestogens for 3 to 6 months. The hyperplastic endometrium returned to normal in 96.5%. It was suggested that all postmenopausal women with intact uterus be given the Progestogen Challenge Test and that progestogens be given to the women each month as long as bleeding follows. This should prevent the development of endometrial cancer in most women.^ieng

Estrogen therapy and breast cancer in postmenopausal women.

During the 6-year period 1972-77, 123 postmenopausal women with breast cancer either had the disease diagnosed at Wilford Hall USAF Medical Center or were referred there for therapy. Their ages ranged from 33 to 90 (mean, 56.6 years). Of these women 64.2 percent had never taken hormones, 25.2 percent were estrogen users, 4.9 percent were estrogen-progestogen users, 4.9 percent had a history of hormone usage, and 1 patient was using estrogen vaginal cream. In a subgroup of 27 clinic patients (1975-77 period) during 14,548 patient-years of observation, breast cancer was diagnosed for an overall incidence of 185.6:100,000 women per year. Among the 27 patients, the annual incidence of breast cancer was highest in the untreated group at 410.5:100,000 women. In comparison, the incidence in the estrogen users was 137.7:100,000 women-a significant difference (p less than 0.01). The incidence in estrogen-progestogen users was 155.6:100,000 compared with the incidence in the untreated patients; this difference was also statistically significant (p less than 0.05). There was no significant difference in the incidence of breast cancer between the estrogen users (137.7:100,000) and the estrogen-progestogen users (155.6:100,000). These data indicate that estrogen therapy decreases the risk of breast cancer and that, unlike the situation with adenocarcinoma of the endometrium, progestogens do not offer additional protection from breast carcinoma.

Regression of Polycystic Ovaries by Estrogen Therapy.

Adolescent girls and single women with progressive hirsutism due to polycystic ovaries present a therapeutic dilemma. Clomiphene citrate is useful only to induce ovulation and has no beneficial effect on hirsutism. Surgical wedge resection of these ovaries usually arrests progression of hirsutism and restores ovulatory menses. Such treatment, however, is best reserved until such time as pregnancy would be an equal objective. Treatment of 5 patients by hypothalamic-pituitary-ovarian suppression with 100-mg estradiol pellets implanted subcutaneously every 6 months reduced ovarian size in all 5 patients and halted the progression of hirsutism.

Immediate postpartum oral contraception.

PIP: Oral contraceptives were administered on Postpartum Day 5 to 363 patients, 83 of whom were breast-feeding, to determine if bleeding quantity could be reduced and menstrual periods established earlier in the puerperium, to evaluate the effect on lactation, and to note if side effects could be minimized by initiating pill usage earlier postpartum; 245 patients, of whom 91 were breast-feeding, served as controls. All of the women were patients at the U.S. Air Force Hospital in Wiesbaden, West Germany. 54% of the lactating mothers on the pill were successfully breast-feeding at 6 weeks compared with 59% of the controls. 87% of the patients taking pills had their 1st menstrual period before 6 weeks postpartum compared with 23% of the controls. No significant decrease in quantity of bleeding was noted. Patients taking the pill did report a weight gain. The uterus returned to normal size sooner in the group taking the pill and there was less breast tenderness. 65% of the multigravida mothers taking the pill thought they had a more favorable postpartum course, 24% saw no difference, and 11% thought their postpartum experience was less favorable. Patient acceptance was excellent and no major porblems were encountered.^ieng

Changes in thyroid function tests during danazol therapy.

Danazol is a synthetic steroid with antigonadotropic properties useful in treating endometriosis, especially in young infertile women. Prior to its availability for clinical use in September 1976, thyroid function studies other than thyroid-stimulating hormone (TSH), which was normal, had not been reported. Soon after danazol began to be used in the infertility clinic to treat documented endometriosis, it was observed that changes occurred in thyroid function studies. While no patients manifested clinical evidence of hypothyroidism, all 8 patients receiving 800 mg of danazol daily for 1 to 5 months had laboratory evidence of decreased thyroid function. The triiodothyronine (T3) uptake was elevated and the total serum thyroxine (T4) was decreased. The finding that TSH and the free thyroid index (FTI) were normal confirmed that these patients were euthyroid during danazol therapy. The abnormality of thyroid function tests is believed to reflect an androgen-like reduction in thyroxine-binding protein rather than a true decrease in thyroid function or interference with the pituitary-thyroid axis.

Decreased incidence of breast cancer in postmenopausal estrogen-progestogen users.

In a prospective study at Wilford Hall USAF Medical Center from 1975 to 1981, 5563 postmenopausal women were followed for a total of 37,236 patient-years of observation. During these seven years, 53 patients were found to have breast cancer, for an incidence of 142.3:100,000 women per year. The mean age (+/- SD) of the patients with cancer was 56.9 +/- 8.24 years, and the mean age of the entire patient population was 56.8 +/- 6.75 years. The expected incidence of breast cancer in this age group, according to the Third National Cancer Survey (1975), is 188.3:100,000 women, and for ages 55 to 59, according to the National Cancer Institute Surveillance, Epidemiology, and End-Result Reporting (NCI SEER) data (1980), is 229.2:100,000. The lowest incidence of breast cancer (67.3:100,000) was observed in the estrogen-progestogen users and was significantly lower than that of the untreated group (342.3:100,000), with P less than or equal to .01. The incidence of the estrogen-progestogen users was also significantly lower than that expected from the NCI SEER data, with a relative risk of 0.3 (95% confidence interval, 0.1 to 0.8). The incidence of mammary malignancy in the estrogen users (141.0:100,000) was significantly lower than in the untreated group (342.3:100,000), with P less than or equal to .01. Although the incidence in the estrogen users was not significantly lower than that expected according to the NCI SEER data (relative risk = 0.7, 0.5 to 1.1), there was a trend in that direction. These data indicate that estrogen therapy for postmenopausal women does not increase the risk of breast cancer and may afford some protection. Added progestogen to postmenopausal estrogen therapy significantly decreases the risk for this malignancy.

The relationship between breast cancer survival and prior postmenopausal estrogen use.

The growth of breast cancer may be mediated by endogenous or exogenous sex steroid hormones, particularly estrogen. However, neither contraceptive nor noncontraceptive estrogen use has been associated definitively with an increased risk of developing breast cancer. In this study, we addressed a corollary question: If a postmenopausal woman develops carcinoma of the breast, is her survival affected by previous use of replacement estrogen? Two hundred fifty-six postmenopausal women with breast cancer entered our Tumor Registry between 1972-1981, inclusive. Of these, 174 took no replacement estrogen before the diagnosis (never-users), 21 had used estrogen previously (past users), and 61 were taking estrogen at the time of diagnosis (current users). Survival analysis revealed a median survival of less than 84 months after diagnosis for never- and past users and greater than 143 months for current users, but these differences were not significant when controlled for stage of disease at diagnosis. We conclude that prior postmenopausal estrogen replacement therapy does not compromise survival in women who subsequently develop carcinoma of the breast.

Antepartum pituitary infarction.

Antepartum pituitary infarction occurs only in insulin-dependent diabetic patients. It is manifested by severe headache, followed by decreasing insulin requirements. Delivery is frequently premature, with high fetal wastage and increased maternal mortality. During the puerperium, the first manifestation of pituitary deficiency, other than a lower insulin requirement than would be expected, is failure to lactate. Subsequent evaluation of pituitary function reveals variable deficiencies with loss of growth hormone and gonadotropins being most frequent. This case is the eighth report of this entity, and it represents the first patient to survive a pituitary infarction prior to the third trimester of pregnancy. Recognition of this syndrome is critical in order to ensure that the mother's health and the viability of the offspring be preserved.

Use of medroxyprogesterone acetate to prevent menopausal symptoms.

A number of patients with severe vasomotor symptoms of menopause, specifically hot flashes, are unable to take exogenous estrogens because of intolerance of contraindications. Others achieve less than satisfactory relief of symptoms with extrogen. A double-blind study was established to determine whether depomedroxyprogesterone acetate (DMPA) injectable (Depo-Provera, Upjohn) could be used as a satisfactory substitute in these patients. The basis of the study was to evaluate clinical impressions that some menopausal patients taking DMPA for other purposes achieved relief from these distressing symptoms. Fifty-seven patients were treated with DMPA, 150 mg IM monthly, and 12 controls were given 1.5 ml sterile saline IM monthly. Serum FSH and LH were measured initially and serially. Clinical response was determined by the patients' estimates of the frequency and severity of their hot flashes. Of 57 patients in the treatment group, 51 (89.5%) were relieved of symptoms compared to 3 of 12 (25%) in the control group. DMPA can be an effective alternate to estrogen therapy in selected menopausal patients.

Use of the progestogen challenge test to reduce the risk of endometrial cancer.

In contrast to several retrospective studies reporting an increased risk of endometrial cancer during the mid-1970s, especially in estrogens.gen-treated postmenopausal women, the number of cancers at Wilford Hall USAF Medical Center has steadily declined despite continued estrogen use. In a 4-year study from 1975 to 1978, there were 17 adenocarcinomas of the endometrium during 10,872 patient-years of observation, for an overall annual incidence of 156.4:100,000 women. The highest incidence of endometrial cancer (359.1:100,000) was found in those women using estrogens alone. The lowest incidence of cancer was observed in the estrogen-progestogen users (56.4:100,000) and was significantly lower (P less than .01) than that found in the estrogen users. The incidence of corpus malignancy in the estrogen-progestogen users was also significantly lower (P less than .05) than that observed in the untreated women (248.3:1000,000). The progestogen challenge test has been devised to identify postmenopausal women at greatest risk for adenocarcinoma of the endometrium. It is concluded that the use of this test will reduce the risk of endometrial cancer in both estrogen-treated postmenopausal women and women with increased endogenous estrogens.

The menopause: benefits and risks of estrogen-progestogen replacement therapy.

PIP: After reviewing the pathophysiology of the menopause, attention is directed to a review of the benefits of estrogen progestogen replacement therapy (vasomotor symptoms, urogenital atrophy, psychosomatic complaints, osteoporosis, cardiovascular disease, lipid metabolism); the risks of estrogen progestogen replacement therapy (endometrial cancer, endometrial hyperlasia, breast cancer, coagulation factors, gallbladder disease); and evaluation for estrogen therapy (nonoral estrogen administration). This author regards the menopause to be a hormonal deficiency state, and, like all endocrinopathies, should be managed as vigorously as need be, and without a necessary limitation of time. A wide variety of physical changes and symptoms have been associated with the climacteric. Some patients may only experience cessation of menses; others experience severe reactions that are occasionally disabling. Several factors may influence development of symptoms during the postmenopausal years, and the most important factor is probably the degree of estrogen depletion and the rate at which estrogen levels decrease. Additional factors may be an inherited or acquired propensity to withstand or succumb to the aging process and the psychologic impact of aging and the woman's ability to accept or deny the emotional changes of the menopause. The proven and almost universally accepted benefits of estrogen replacement therapy include relief of vasomotor symptoms, prevention of atrophic vaginitis, and prevention of osteoporosis. Estrogens may also help alleviate some of the psychogenic manifestations that menopause aggravates. Decreasing the risk of cardiovascular disease, particularly in oophorectomized young women may be another benefit by estrogen increased HDL cholesterol. 10 days of cyclic progestogen reduces the risk of endometrial cancer by preventing or treating estrogen induced endometrial hyperplasia. The risk of breast cancer has not been shown to be increased with estrogen therapy, and progestogens may provide additional protection for this tumor. The prognosis for breast carcinoma developing in hormone users is improved, most likely because of an earlier detection. Estrogens prevent demineralization of bone, and the addition of progestogen apparently promotes new bone formation. An increased risk of gallbladder disease may be associated with estrogen therapy, but this risk is minimal and has not been observed in all studies. There is no evidence that either estrogens or progestogens, in the small doses needed for menopause, increase the risk of thromboembolic disease. Newer routes of estrogen administration may further reduce the risks and increase the benefits.^ieng

The prevention of endometrial cancer in postmenopausal women with progestogens.

Due to adverse publicity alleging an increased risk of endometrial cancer with estrogen therapy, a prospective study was begun in 1976 to determine the incidence of this disease in postmenopausal women. During 5,025 patient-years of observation in 1976-1977, 6 adenocarcinomas of the endometrium were diagnosed for an incidence of 1.2:1,000 postmenopausal women per year. No endometrial malignancies were detected in 2,552 patient years of therapy with estrogens and progestogens. In 1,028 patient-years of observation where estrogens only was the therapy, there were 3 endometrial cancers for an incidence of 2.9:1,000. Adenocarcinoma of the endometrium was found in 2 of the untreated group, which gave an incidence of 3.0:1,000. The sixth endometrial cancer occurred in a patient using estrogen vaginal cream. During this same period, 139 perimenopausal and postmenopausal women were treated with progestogens for endometrial hyperplasia. The hyperplasia was reversed to normal endometrium in 133 patients (95.7%). Hyperplasia is a precancerous lesion and should be treated with either progestogens or hysterectomy. All postmenopausal women with a uterus should be given the Progestogen Challenge Test and the progestogen continued each month as long as bleeding follows. These methods will prevent most endometrial cancers.

Hormone replacement therapy and breast cancer.

Numerous studies on oestrogen replacement therapy have failed to incriminate the use of exogenous oestrogen as a cause of breast cancer in post-menopausal women. Since so many variables influence breast cancer risk, it has not been possible for any single study to evaluate every potential risk factor included in the epidemiological and clinical reports on hormone use and carcinoma of the breast. The relative risk (RR) for breast cancer in oestrogen users has been found to vary from 0.4 to 3.4, with the vast majority of investigators reporting an RR very close to 1.0, or no increased risk at all. There is growing evidence that progesterone deficiency may increase the risk for breast cancer in some women. At least three studies have indicated that the addition of progestogen to oestrogen replacement therapy may significantly decrease the risk for carcinoma of the breast. It was observed that the RR of breast cancer varied from 0.47 to 0.89 in these studies when oestrogen-progestogen users were compared with unopposed oestrogen users. However, it is pointed out that progestogens are not added to oestrogen replacement therapy to negate an increased risk of breast cancer from unopposed oestrogens, since oestrogen therapy does not increase the risk. Combination oestrogen-progestogen therapy is recommended for hormone replacement treatment, even in women who have had a hysterectomy, because it will reduce the risk for breast cancer in some women.

Prevention of endometrial cancer with progestogens.

Unopposed oestrogen replacement therapy increases the risk of endometrial cancer in post-menopausal women. However, the addition of progestogen to the oestrogen therapy reduces the risk of endometrial carcinoma by preventing and effectively treating hyperplasia of the endometrium. In a 5-yr prospective study with a further 4 yr of follow-up (1975-83), 31 adenocarcinomas of the endometrium were detected over 27243 patient-years of observation, for an incidence of 113.8:100 000 women. The first report on the results of the study appeared in 1978; this paper presents further results. The lowest incidence of endometrial cancer (49.0:100 000) was observed among the oestrogen-progestogen users and the highest (390.6:100 000) among the unopposed oestrogen users. Not only was the incidence of endometrial carcinoma significantly lower in the oestrogen-progestogen users than in those using unopposed oestrogens (P less than or equal to 0.0001), but it was also significantly lower than that among the non-hormone users (245.5:100 000 with P less than or equal to 0.0005). Endometrial hyperplasia had been diagnosed previously in 12 of the 31 patients with adenocarcinoma (38.7%) from 4 mth to 8 yr before the detection of cancer. When given for 7-10 days each month progestogens are effective in reversing hyperplasia and restoring a normal endometrium in 94.5% of patients treated within 3-6 mth. The progestogen challenge test was devised to identify post-menopausal women at greatest risk for adenocarcinoma of the endometrium. It is concluded that the use of this test will reduce the risk of endometrial cancer in both oestrogen-treated post-menopausal women and women with increased endogenous oestrogens.

Role of progestogens in the prevention of breast cancer.

The incidence of breast cancer has continued to decrease each year at Wilford Hall United States Air Force Medical Center with the ever-increasing use of combined progestogen-oestrogen replacement therapy over the past 12 yr. By 1983, the overall incidence of breast cancer had fallen to 53.9:100 000. The lowest rate for the 9 yr of a prospective study to 1983 was seen among the oestrogen-progestogen users (66.8:100 000) although it was also slightly reduced in both the unopposed oestrogen users (142.3:100 000 and the oestrogen vaginal cream users (116.3:100 000). The incidence was significantly lower in both the oestrogen-progestogen users and the oestrogen users (P less than or equal to 0.01) as compared with untreated women (343.5:100 000). These data further strengthen the growing evidence that the addition of progestogen to oestrogen decreases the risk of mammary malignancy.

Management of postmenopausal bleeding to prevent endometrial cancer.

The primary goal in management of postmenopausal bleeding is to insure that no malignancy is present. In this study of 3,682 climacteric women, 340 patients (9.2%) presented with postmenopausal bleeding during an 18-mth period. The pathology at curettage was reported as normal endometrium in 33.8%, atrophic endometrium in 24.7%, and hyperplasia in 39.1%. Adenocarcinoma of the endometrium was diagnosed in only 5 patients (1.5%), a reduction from 3.0% found in a previous study performed in 1972-1973. The second goal in management of postmenopausal bleeding is to identify and treat those patients with endometrial hyperplasia since this is a precancerous lesion. Cyclic progestogens were given to 105 of 133 women with hyperplasia of the endometrium for 3-6 mth and curettage repeated. The hyperplasia reverted to normal endometrium in 101 of the 105 patients (96.2%). In those 4 women with persistent hyperplasia after progestogen therapy, a hysterectomy was performed. Hysterectomy was the primary therapy for 20 women with hyperplasia because of associated findings such as leiomyomata uteri. The incidence of curettage was highest in the untreated women (23.2%), lowest in the estrogen-progestogen users (3.9%) and indicated in 14.2% of those patients receiving estrogens alone.

The protective role of progesterone in the prevention of endometrial cancer.

An association between endometrial hyperplasia and corpus cancer has long been suspected. Genetically predisposed women are at greater risk of developing endometrial cancer if subjected to long uninterrupted period of estrogen stimulation. Endometrial cancer need not be inevitable if 14 day courses of an oral progestogen are continued for as long as is necessary; in some women, however, the lesions will progress and, therefore, should be carefully followed with repeated endometrial biopsies. Epidemiological evidence suggests a true link between unopposed estrogens and early, less invasive endometrial cancer, and progestogens appear capable of protecting against the development of cancer and hyperplasia, although complete protection has not yet been achieved. The protective action of progestogens is supported by the fact the none developed endometrial cancer in a series of 490 women of reproductive age who received continuous estrogens by way of pellet implants of 17 beta estradiol for conception control for 1--10 years. Evidence for the protective action of progestogens in estrogen-treated menopausal women was less solid than in non-menopausal women but was nonetheless considerable. Our study of 1058 women, 45 years of age and older, receiving continuous estrogens by way of 17 beta estradiol pellets over a period varying from 1 to 21 years, revealed that the incidence of cancer was not greater and was possibly less than that expected in an untreated population of menopausal women.

Sex steroids and cancer.

Hormones, particularly estrogens, have been suspected for many years of being carcinogens. Retrospective studies from the mid-1970s indicate that unopposed estrogen replacement therapy increases the risk for endometrial cancer. However, recent reports have failed to incriminate even unopposed estrogens for any significantly increased risk of breast cancer. Added progestogen, in proper duration and dosage, almost completely negates the estrogen-increased risk for adenocarcinoma of the endometrium. There is increasing evidence that progestogen added to estrogen replacement may decrease the risk for carcinoma of the breast in some women.

Clinical use of progestins in the menopausal patient: dosage and duration.

Although estrogens are the principal hormone needed by postmenopausal women, there are many benefits of progestins. There is some increased risk of endometrial cancer from estrogen-replacement therapy; however, added progestin decreases this risk to less than that observed in untreated postmenopausal women. Climacteric women at the greatest risk of endometrial cancer can be identified by the progestin challenge test. There may also be some protection from breast cancer in progestin-treated postmenopausal women. Progestins are effective in managing the increased breast tenderness and aggravation of fibrocystic breast disease that may occur in some estrogen-treated postmenopausal women. Both estrogens and progestins are effective in retarding the progression of osteoporosis, but estrogen-progestin combination therapy may promote new bone formation. Long-acting injectable progestins are effective in relieving vasomotor symptoms. Finally, progestins also reduce the incidence of postmenopausal bleeding and the necessity of diagnostic curettage. The progestin should be continued for ten days each month as long as the patient experiences withdrawal bleeding. When withdrawal bleeding ceases, the progestin may be discontinued. However, the progestin challenge test should be repeated annually to ensure that the endometrium is not being stimulated by either exogenous therapy or increased endogenous estrogens.