Hormone replacement therapy: consensus and controversies.

While the use of menopausal hormone therapy [MHT] when initiated in women younger than 60 years is generally considered to have a good safety profile and to be associated with important treatment and prevention benefits, the length of therapy and the long-term risk benefit profile remains highly controversial.

Individualizing hormone-therapy according to cardiovascular risk.

Many women, including those with risk factors for cardiovascular disease (CVD), may desire the benefits associated with hormone therapy including protection from progression of CVD, osteoporotic fractures, urogenital atrophy, skin loss, dementia, and a reduction in overall mortality. Before initiating or continuing therapy, it is important to consider an accurate risk benefit analysis in all women. Importantly, when considering initiation of hormone replacement, it is important to consider a woman's age, number of years since her menopause, and a number of cardiovascular risk factors. Women with positive risk factors are at increased risk for hormone therapy, especially related to the initiation of high dose oral therapy. Use of low dose transdermal hormone therapy can reduce these risks. For women with a recent cardiovascular event, current thromboembolic disease, long-standing immobilization, or severe peripheral arterial disease, hormone replacement is generally not recommended. There is growing consensus that the benefit to risk profile for hormone therapy is high for healthy, low-risk women initiating therapy within 10 years of menopause or under age 60. However, special considerations are needed for women who are outside those boundaries or for those that have risk factors for cardiovascular disease.

Individualizing hormone-therapy according to cardiovascular risk.

There is growing consensus that the benefit to risk profile for hormone therapy is high for healthy, low-risk women initiating therapy within 10 years of menopause or under age 60. However, special considerations are needed for women who are outside those boundaries or for those that have risk factors for cardiovascular disease.

Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although observational studies suggest that estrogen replacement therapy (ERT) reduces cardiovascular morbidity and mortality in postmenopausal women, use of unopposed ERT for prevention of coronary heart disease in healthy postmenopausal women remains untested. OBJECTIVE: To determine the effects of unopposed ERT on the progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: University-based clinic. PATIENTS: 222 postmenopausal women 45 years of age or older without preexisting cardiovascular disease and with low-density lipoprotein cholesterol levels of 3.37 mmol/L or greater (>/=130 mg/dL). INTERVENTION: Unopposed micronized 17beta-estradiol (1 mg/d) or placebo. All women received dietary counseling. Women received lipid-lowering medication if their low-density lipoprotein cholesterol level exceeded 4.15 mmol/L (160 mg/dL). MEASUREMENTS: The rate of change in intima-media thickness of the right distal common carotid artery far wall in computer image processed B-mode ultrasonograms obtained at baseline and every 6 months during the 2-year trial. RESULTS: In a multivariable mixed-effects model, among women who had at least one follow-up measurement of carotid intima-media thickness (n = 199), the average rate of progression of subclinical atherosclerosis was lower in those taking unopposed estradiol than in those taking placebo (-0.0017 mm/y vs. 0.0036 mm/y); the placebo-estradiol difference between average progression rates was 0.0053 mm/y (95% CI, 0.0001 to 0.0105 mm/y) (P = 0.046). Among women who did not receive lipid-lowering medication (n = 77), the placebo-estradiol difference between average rates of progression was 0.0147 mm/y (CI, 0.0055 to 0.0240) (P = 0.002). Average rates of progression did not differ between estradiol and placebo recipients who took lipid-lowering medication (n = 122) (P > 0.2). CONCLUSIONS: Overall, the average rate of progression of subclinical atherosclerosis was slower in healthy postmenopausal women taking unopposed ERT with 17beta-estradiol than in women taking placebo. Reduction in the progression of subclinical atherosclerosis was seen in women who did not take lipid-lowering medication but not in those who took these medications.

Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate.

OBJECTIVE: To evaluate the efficacy of lower doses of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for relieving vasomotor symptoms and vaginal atrophy. DESIGN: A randomized, double-blind, placebo-controlled trial (the Women's Health, Osteoporosis, Progestin, Estrogen study). SETTING: Study centers across the United States. PATIENT(S): Two thousand, six hundred, seventy-three healthy, postmenopausal women with an intact uterus, including an efficacy-evaluable population (n = 241 at baseline). INTERVENTION(S): Patients received for 1 year (13 cycles; in milligrams per day) CEE, 0.625; CEE, 0.625 and MPA, 2.5; CEE, 0.45; CEE, 0.45 and MPA, 2.5; CEE, 0.45 and MPA, 1.5; CEE, 0.3; CEE, 0.3 and MPA, 1.5; or placebo. MAIN OUTCOME MEASURE(S): Number and severity of hot flushes and Papanicolaou smear with vaginal maturation index (VMI) to assess vaginal atrophy. RESULT(S): In the efficacy-evaluable population, reduction in vasomotor symptoms was similar with CEE of 0.625 mg/d and MPA of 2.5 mg/d (the most commonly prescribed doses) and all lower combination doses. CEE of 0.625 mg/d alleviated hot flushes more effectively than the lower doses of CEE alone. VMI improved in all active treatment groups. CONCLUSION(S): Lower doses of CEE plus MPA relieve vasomotor symptoms and vaginal atrophy as effectively as commonly prescribed doses.

Markedly elevated levels of estrone sulfate after long-term oral, but not transdermal, administration of estradiol in postmenopausal women.

OBJECTIVE: To compare serum estrone sulfate (E1S) levels in postmenopausal women during long-term treatment with commonly prescribed doses of oral and transdermal estradiol (E2). DESIGN: A retrospective study performed in a University setting in the United States involving 33 healthy postmenopausal women. Two groups of postmenopausal women were studied: group 1 (n = 10) received 1 mg oral micronized E2 daily for 16 months; blood was drawn at 0, 7, and 15 months. Group 2 (n = 23) was randomized into three subgroups. Two of the subgroups (n = 8; n = 7) received E2 delivered at a rate of 0.05 mg/day and 0.1 mg/day, respectively, by transdermal patch, changed twice weekly; the third subgroup received a placebo (without E2) patch for 9 continuous months. Blood samples were drawn at 0, 6, and 9 months. Serum E1S and E2 were quantified by specific radioimmunoassays. Statistical analysis was performed by analysis of variance. RESULTS: After oral E2 treatment, E1S levels increased significantly (p < 0.01) from baseline, reaching an average level of 38.8 ng/mL at 15 months. After transdermal E2 treatment, E1S levels increased significantly, yet to a much lesser extent, reaching levels of 1.8 ng/mL and 3.2 ng/mL after 9 months of treatment with the 0.05 mg/day and 0.1 mg/day patches, respectively. CONCLUSIONS: Markedly elevated levels of E1S were found after long-term oral estrogen treatment. In comparison to the increase in E1S levels after long-term oral estrogen treatment, there was only a small increase in E1S levels after transdermal E2 therapy. This difference may be attributed to the higher dosage of oral E2 that is required because of the low bioavailability compared with the transdermal dosages.

HRT dosing regimens: continuous versus cyclic-pros and cons.

The introduction of new products, lower dosages, and better continuous and cyclic regimens allows for individualized treatment aimed at minimizing risk and side effects, while maximizing confidence and compliance. Since the major side effect of HRT that discourages long-term use is vaginal bleeding, newer regimens are designed to minimize it. The lowest doses of estrogen currently approved by the FDA for prevention of osteoporosis include 0.3 mg esterified estrogens, 0.025 microg transdermal estradiol patch, and 0.5 mg micronized estradiol. In most naturally menopausal women or those over 65 years of age, conjugated estrogen 0.3 mg (with adequate calcium intake) is protective against bone loss and cardiovascular disease. These low doses are often used with cyclic progestins every 3 to 4 months. Advantages of cyclic therapy using low-dose estrogen include minimal progestin exposure, low rate of withdrawal bleeding, lowered side effects, and, often, higher comfort level. Cyclic estrogen regimens with higher doses have been in use longer, but they often necessitate more frequent progestin treatment and may result in cyclic bleeding or breast tenderness. While HDL- and LDL-cholesterol changes are greater and more beneficial during higher-dose oral cyclic therapy, the large increase in triglycerides is of concern. The most commonly used continuous combined regimens include conjugated estrogen plus daily progestin orally or the combination estradiol/norethindrone acetate transdermal patch. Continuous combined regimens are simple and easy-to-use, and are designed to minimize bleeding. Multiple studies suggest that the mechanism of benefit provided by estrogen goes beyond estrogen's favorable impact on lipoproteins, which is blunted by daily use of synthetic progestins.

Comparison of estrogen and androgen levels after oral estrogen replacement therapy.

OBJECTIVE: To assess the extent of accumulation of circulating estrone (E1), total and free estradiol (E2) and estrone sulfate (E1S) levels in postmenopausal women receiving prolonged oral E2 therapy and to determine the effect of increased estrogenicity on free testosterone levels. STUDY DESIGN: Descriptive study involving 14 healthy postmenopausal women during a three-year period. Group 1 (n = 7) took a placebo. Group 2 (n = 7) took 1 mg micronized E2 daily. Blood samples were taken at one, two and three years. E2, E1 and total testosterone were quantified by radioimmunoassay (RIA) following extraction and celite chromatography. Free testosterone and E2 were calculated. Sex hormone-binding globulin (SHBG) and E1S were quantified by RIA. RESULTS: In the control group, none of the hormone levels changed significantly. Free testosterone decreased 49% in women taking E2 replacement as compared to a 7% decline in women taking placebo. In women taking E2 replacement, E1, E2, E1S, free E2 and SHBG levels increased 10, 6, 51, 2 and 2 times, respectively, between baseline and year 3. CONCLUSION: E1, E2 and E1S levels significantly increased with E2 replacement. Free testosterone levels decreased with E2 replacement. Testosterone replacement may be warranted when giving postmenopausal women estrogen replacement therapy.

Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial.

BACKGROUND: AD, the most prevalent cause of dementia, affects twice as many women as men. Therapeutic options are limited, but results of prior studies support the hypothesis that estrogen treatment may improve symptoms of women with this disorder. METHODS: Forty-two women with mild-to-moderate dementia due to AD were enrolled into a randomized, double-blind, placebo-controlled, parallel-group trial of unopposed conjugated equine estrogens (1.25 mg/day) for 16 weeks. RESULTS: Outcome data were available for 40 women at 4 weeks and 36 women at 16 weeks. At both 4 and 16 weeks, there were no significant differences or statistical trends between treatment groups on the primary outcome measure (the cognitive subscale of the Alzheimer's Disease Assessment Scale), clinician-rated global impression of change, or caregiver-rated functional status. Exploratory analyses of mood and specific aspects of cognitive performance also failed to demonstrate substantial group differences. CONCLUSION: Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.

Hormone replacement therapy: reassessing the risks and benefits.

Although the association between postmenopausal hormone use and breast cancer has not been clarified, there is nothing indefinite about the survival advantage conferred by hormone replacement therapy. Cardiovascular and fracture-related deaths so outnumber breast cancer deaths that even women with family histories of the latter are likely to benefit from low-potency estrogen replacement.

Androgens and bone: clinical implications for menopausal women.

Osteoporosis is a common problem, affecting >28 million Americans, >/=75% of whom are postmenopausal women. In 1995 the cost of caring for patients with complications of osteoporosis was $14 billion. Of the 1.5 million osteoporotic fractures that occur in this country each year, the most serious are hip fractures. It is estimated that approximately 10% to 20% of women die within a year after a hip fracture. Numerous studies reveal that although osteoporotic fractures are preventable most women are not receiving or choosing to receive the medical care that they need to prevent them. Great strides have been made in establishing the importance of ovarian hormones in not only the pathophysiology but also the treatment of postmenopausal osteoporosis. Clinical studies show that estrogen and estrogen-androgen replacement therapies both prevent the development of osteoporosis, as determined by bone mineral density determinations and bone marker analyses. The addition of an androgen to hormone replacement therapy may prevent bone loss and stimulate bone formation.

Phase I prehysterectomy studies of the transcervical administration of quinacrine pellets.

To determine the safety of transcervical administration of quinacrine pellets as a method of voluntary female sterilization, three noncomparative Phase I clinical trials of the administration of 250 mg quinacrine were carried out in 21 women who were scheduled to undergo hysterectomy 24 h or one month later. Detailed results are presented for one of the trials using 10-min pellets. Six of 10 women had minor transitory complaints during the postinsertion 24-h follow-up period. Five women reported pelvic/abdominal cramping, one experienced headache, and one experienced dizziness. Blood chemistry values were not adversely influenced by the quinacrine. The average plasma level of quinacrine peaked at 3 h, 36.1 ng/ml, slightly lower than the value observed 4 h after oral administration of 200 mg in a previous study. An average of 27% of the administered dose was recovered in tampons. Quinacrine was detected in the plasma of two women at the four/six-week visit. Selected results are presented from two other trials that were halted because of slow recruitment. The transcervical administration of 250 mg of 10-min quinacrine pellets was well tolerated. However, based on recent mutagenicity testing and meetings with regulatory officials, it appears unlikely that the use of quinacrine for nonsurgical sterilization could be approved in the United States or Europe.

Contraception in the 1990s.

Contraceptive technology has recently provided the market place with new barrier methods, new progestin oral contraceptives, an injectable contraceptive, the female condom, new male condoms, and the contraceptive implant. During the last decade, epidemiologists have clearly defined the non-contraceptive benefits of current contraceptive methods that include decreased infections, protection from various cancers, protection from many gynecologic problems that lead to surgery, as well as symptomatic relief from many gynecologic conditions. In conjunction with medical specialists, contraceptive researchers have established the increased safety and benefits of various contraceptive choices in women with medical conditions that, until recently, were contra-indications for their use. That these advances have occurred despite multiple legal and scientific assaults gives hope that the field will continue to grow.

PIP: In the face of legal challenges and adverse scientific publications that threaten the acceptance of various methods of contraception, this article reviews the forms of contraception currently available in the US and assesses their safety, efficacy, and medical benefits. Information is provided on 1) male and female condoms, which offer protection from pregnancy and from sexually transmitted diseases; 2) the spermicide Nonoxynol-9, which kills harmful microorganisms but is toxic to vaginal epithelium; 3) the contraceptive sponge; 4) the diaphragm (used with spermicides) and cervical cap; 5) Norplant, which is associated with troublesome side effects but still scores 78% satisfaction ratings; 6) Depo-Provera, which has been associated with bone loss; and 7) IUDs, which were used by 10% of women in the 1970s but are used by less than 2% today. The bulk of the report is devoted to oral contraceptives (OCs), which are described as "one of the most thoroughly studied pharmacological agents of the 20th century." The risks associated with OC use are reviewed, as are such topics as failure rates, mechanism of action, side effects, beneficial effects, effects of use on cancer rates, safety for breast-feeding women, contraindications, and the risk of venous thromboembolism associated in recent studies with formulations containing third-generation progestins. It is concluded that the development of contraceptive technology is being guided by a new emphasis on protecting health while preventing pregnancy.

Decreased central opioid activity in premenstrual syndrome: luteinizing hormone response to naloxone.

OBJECTIVE: To evaluate central opioid activity in women with prospectively documented premenstrual syndrome (PMS) and control women in the mid- and late luteal phases of the menstrual cycle. METHODS: Blood was collected every 15 minutes 1 hour before (0800) and 2 hours after treatment (0900-1100). The treatment was administered in a randomized fashion and consisted of naloxone 1 or 4 mg or placebo, and blood was assayed for luteinizing hormone (LH). Baseline estradiol, progesterone, and prolactin were measured at 0800 and 0900 hours. RESULTS: There was a significant increase in LH area under the curve and mean LH in response to naloxone in the midluteal phase in the control (P < .001). The PMS subjects did not display a significant increase in LH concentration in response to naloxone in the midluteal phase. There were no significant LH responses to naloxone in either group in the late luteal phase. There were no significant differences in estradiol, progesterone, or prolactin concentrations or estrogen to progesterone ratios between groups. CONCLUSION: Control women have an enhanced central opioid tone during the midluteal phase that diminishes and becomes minimal in the late luteal phase of the menstrual cycle. In contrast, women with PMS have a loss of central opioid tone during the midluteal phase as indicated by the loss of LH response to naloxone. This attenuated central opioid tone in women with PMS as compared with asymptomatic control women may play a role in the pathophysiology of PMS.

A contraceptive vaginal ring releasing norethindrone acetate and ethinyl estradiol.

A core design contraceptive vaginal ring (CVR) releasing 650 mcg of norethindrone acetate (NA) and 10, 20, 30 or 65 mcg of ethinyl estradiol (EE) daily was developed and tested in 99 women. The CVR inhibited ovulation well with 30 or 65 mcg EE. Vaginal bleeding was better controlled than in 23 control women using NA/EE oral contraceptives. Side effects were comparable to controls for the 20 and 30 mcg EE CVR. The 65 mcg EE CVR resulted in an unacceptably high level of nausea. The 20 and 30 mcg EE CVR caused an increase in serum HDL cholesterol and triglycerides. Total cholesterol was unchanged. Angiotensinogen and sex hormone binding globulin-binding capacity were increased in a subgroup of the 20 and 30 mcg EE CVR subjects, similar to that of 20 controls using EE/gestodene oral contraceptives. This new CVR offers an excellent contraceptive alternative with the best performance provided by the 30 mcg EE dose.

Depot leuprolide acetate with estrogen and progestin add-back for long-term treatment of premenstrual syndrome.

OBJECTIVE: To test the effectiveness and safety of long-term depot leuprolide acetate (GnRH-a) plus estrogen and progestin add-back therapy in the treatment of moderate and severe premenstrual syndrome (PMS). DESIGN: A prospective trial with each patient serving as her own control. SETTING: University teaching hospital. PARTICIPANTS: Ten women with regular menstrual cycles complaining of moderate to severe PMS. Premenstrual syndrome was diagnosed when symptoms increased > or = 25% during the luteal phase. TREATMENT: Four-week cycles of IM injections of placebo or GnRH-a with all patients receiving saline (placebo), the first cycle followed by 12 cycles of GnRH-a, 7.5 mg. Conjugated equine estrogen (0.625 mg/d) was started Monday through Saturday within the first cycle and increased as needed. Medroxyprogesterone acetate (MPA), 10 mg/d, was taken orally for 10 days after 4, 8, and 12 cycles of GnRH-a therapy. MAIN OUTCOME MEASURES: Changes in three symptom categories (water retention, pain, and psychological function), serum levels of total cholesterol and HDL, HDL-2, and LDL cholesterol, E2, and estrone. Endometrial biopsy was obtained 1 day after the end of the 12th GnRH-a cycle, and bone density was assessed using quantitative computer tomography at the end of the 12th GnRH-a cycle. RESULTS: During treatment, there was a significant decrease compared with baseline and placebo in all three symptom categories. There were no significant changes in lipids. Endometrial biopsies revealed progestational changes with no evidence of hyperplasia. Quantitative computer tomography bone density dropped 3.7 on average compared with baseline after 12 months of treatment, but this was not statistically significant. CONCLUSION: Gonadotropin-releasing hormone agonist therapy with hormonal add-back therapy is effective in treating PMS symptoms with progressive improvement over a 12-month period. This therapy prevents changes in lipids and adequately protects the endometrium with the addition of MPA every 4th cycle. Quantitative computer tomography bone density dropped at 12 months; further examination of bone changes is necessary.

Multicenter randomized comparative trial of two low-dose triphasic combined oral contraceptives containing desogestrel or norethindrone.

OBJECTIVE: To compare a new triphasic oral contraceptive (OC) containing desogestrel and ethinyl estradiol (DSG/EE) with triphasic norethindrone/ethinyl estradiol (NE/EE) regarding effects on clinical efficacy, cycle control, and safety indices. METHODS: In an open-label, comparative multicenter study, 407 subjects were randomized to a triphasic preparation containing DSG/EE and 405 subjects to a triphasic preparation containing NE/EE. The women were observed during six cycles of OC use. RESULTS: The contraceptive efficacy of the triphasic DSG/EE OC was at least comparable to that of triphasic NE/EE. No pregnancies were reported with DSG/EE, whereas there were two pregnancies with NE/EE, both user failures. Cycle control with triphasic DSG/EE was statistically superior to that with triphasic NE/EE. Acceptability was excellent with both preparations as measured by the low discontinuation rates (particularly for adverse menstrual experiences). No thromboembolic or other serious drug-related adverse experiences were reported. The incidence of other drug-related adverse experiences was generally low and decreased with time in both groups. No adverse effects were seen in terms of blood pressure, body weight, laboratory indices, cervical cytology, and breast nodularity. CONCLUSION: Triphasic DSG/EE is an effective and safe OC with excellent acceptability and cycle control superior to that of triphasic NE/EE.

New progestins--clinical experiences: gestodene.

Gestodene, one of three new gonane progestins, is the most potent on a per weight basis in regard to progestational effects and has little or no estrogenic effect. In in vivo animal studies, gestodene also has less androgenic activity compared with progestins found in older combination oral contraceptive formulations. It binds to mineralocorticoid receptors and consequently is a competitive aldosterone inhibitor, leading to speculation that it may be beneficial in hypertensive patients. Numerous large clinical trials have shown that the combination of gestodene and ethinyl estradiol is as effective in preventing pregnancies as other oral contraceptives presently on the market. Irregular bleeding and spotting rates appear to be at least as good as older formulations. In general, studies show that the incidence of side effects associated with the progestin and estrogen components tends to be low, with very little impact on lipid and carbohydrate metabolism. Gestodene-containing oral contraceptives have been associated with small increases in clotting factors, generally because of the estrogen component, with compensatory changes in the fibrinolytic system. Although gestodene-containing oral contraceptives have been used in Europe since 1987, they have not been available in the United States except for use in clinical trials. At present, a triphasic formulation containing 50 to 100 micrograms of gestodene plus 30 to 40 micrograms of ethinyl estradiol is awaiting approval by the Food and Drug Administration.

Changes in mammographic densities induced by a hormonal contraceptive designed to reduce breast cancer risk.

BACKGROUND: It has been known for some time that oral contraceptives substantially reduce the risk of endometrial and ovarian cancer, but they do not reduce the risk of breast cancer. A hormonal contraceptive regimen has been developed which uses a gonadotropin-releasing hormone against (GnRHA) to suppress ovarian function, and this regimen includes the administration of very low doses of both estrogen and progestogen. This hormonal contraceptive regimen attempts to minimize exposure of the breast epithelium to these steroids and to preserve the maximum beneficial effects of estrogen, while still preventing endometrial hyperplasia. PURPOSE: Our purpose was to determine whether changes occurred in mammographic densities between baseline and 1 year for women on this hormonal contraceptive regimen with reduced estrogen and progestogen levels compared with women in a control group. METHODS: Twenty-one women were randomly assigned in a 2:1 ratio to the GnRHA-based contraceptive group (14 women) or to a control group (seven women). The contraceptive group received the following: 7.5 mg leuprolide acetate depot by intramuscular injection every 28 days; 0.625 mg conjugated estrogen by mouth for 6 days out of 7 every week; and 10 mg medroxyprogesterone acetate orally for 13 days every fourth 28-day cycle. The control group received no medication. Baseline and 1-year follow-up mammograms of contraceptive and control subjects were reviewed in a blinded fashion by two radiologists. RESULTS: Comparison of the changes between the baseline and 1-year mammograms in the two groups of women showed significant (P = .039) reduction in mammographic densities at 1 year for women on the contraceptive regimen. Assessing the reduction in mammographic densities by noting the fineness of fibrous septae showed a highly significant (P = .0048) difference in the contraceptive regimen group. One of the women on the contraceptive regimen was withdrawn from the study because of poor compliance. CONCLUSION: The reduced estrogen and progestogen exposures to the breast that were achieved by the hormonal contraceptive regimen resulted in substantial reductions in follow-up mammographic densities at 1 year compared with baseline. Although there is no direct evidence that such a reduction in densities will lead to a reduced risk of breast cancer, indirect evidence for a protective effect of this regimen is that early menopause reduces breast cancer risk, and that menopause is associated with a reduction in mammographic densities.

PIP: In California, physicians randomly assigned 21 women aged 25-40 to either the contraceptive group or the control group as part of a study aimed to determine whether or not a hormonal contraceptive regimen with reduced estrogen and progestogen levels affects mammographic densities. Eligibility criteria included premenopausal women with a 5-fold greater than normal risk of breast cancer, no prior cancer, bone mineral density not less than 2 standard deviations below normal, normal cholesterol, and a normal physical and pelvic examination. The contraceptive group received intramuscular injection of 7.5 mg leuprolide acetate depot every 28 days, 0.625 mg oral conjugated estrogen for 6 out of 7 days every week, and 10 mg oral medroxyprogesterone acetate for 13 days every fourth 28-day cycle. The reduction in mammographic densities in women on the contraceptive regimen between baseline and 1 year was significantly different than that of the controls whose mammographic densities remained essentially the same (p = 0.039). Cases had significantly more change in fibrous septae between baseline and 1 year than did controls (+0.82 units vs. -0.07; p = 0.0048). These results indicate that lower levels of estrogen and progestogen reduces mammographic densities, which may reduce the risk of breast cancer since increased mammographic densities are linked to an increased risk of breast cancer. Reduced mitotic activity in breast epithelial cells during menopause and with lower levels of estrogen and progestogen (i.e., reduced mammographic densities) suggest that early menopause may also protect against breast cancer.