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.

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 One of the women on the contraceptive regimen was withdrawn from the study because of poor compliance.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.

The effects of estrogen and progestin on endogenous opioid activity in oophorectomized women.

Sex steroids may modulate the secretion of beta-endorphin (beta-EP). Naloxone (Nal), an opioid antagonist, has been used as a probe of central opioid activity. Nal-evoked responses of PRL and LH were evaluated in the midluteal (ML) and late follicular (LF) phases of ovulatory women (Pre) and compared to responses of oophorectomized women before and after the administration of conjugated estrogens (CE) and again after CE and progestin administration. In the ML and LF phases, serum LH increased significantly (P less than 0.05 and P less than 0.01, respectively) during Nal infusion for 4 h, while PRL did not change. In oophorectomized women, there were no significant changes in LH or PRL during Nal infusion. After 3 weeks of CE treatment (1.25 mg daily), LH increased during Nal infusion (P less than 0.05), as did PRL (P less than 0.01). After treatment with CE and medroxyprogesterone acetate (MPA), LH and PRL both increased (P less than 0.05 and P less than 0.01, respectively). The area under the LH curve during Nal infusion after CE and MPA treatment was greater than that after CE alone. Both of these responses were comparable to those of the LF and ML phases of Pre women. During Nal infusion, LH pulse frequency increased in the ML compared to the LF phase of the cycle and, in oophorectomized women, was greater after CE and CE with MPA treatment compared to pretreatment values (P less than 0.05). LH amplitudes during Nal infusion were highest in the ML phase and after CE and MPA treatment in oophorectomized women, and these LH amplitudes were similar. No correlation was found between peripheral plasma beta-EP and Nal-evoked LH responses. No differences were evident in plasma beta-EP levels between Pre and oophorectomized women. In conclusion, 1) endogenous opioid activity is low in oophorectomized women; 2) treatment with estrogen increases opioid activity, and the addition of a progestin increases this activity further; and 3) these data support the contention that sex steroids exert a profound influence on endogenous opioid activity.

Differences in the ratio of bioactive to immunoreactive serum luteinizing hormone during vasomotor flushes and hormonal therapy in postmenopausal women.

With the recognition of differences between serum bioactive (bio) and immunoreactive (i) LH concentrations in various clinical situations, we measured changes in the bio:i LH ratio in postmenopausal (PM) women in response to iv GnRH, during the vasomotor flush, and in response to both estrogen and progestin treatment. Bio LH was measured using the mouse interstitial cell assay and LER 907 as standard, with conversion to milliinternational units per ml (Second International Reference Preparation of human menopausal gonadotropin). In 22 PM women, aged 42-56 yr, serum bio LH [455 +/- 73 (+/- SE) mIU/ml] and the bio:i LH ratio (8.3 +/- 0.7) were significantly higher than in premenopausal women (25.5 +/- 5 mIU/ml and 1.5 +/- 0.2, respectively; P less than 0.002). In response to 150 micrograms iv GnRH, there was a greater rise in levels of iLH and bioLH in PM women than in premenopausal women, but there were no changes in the bio:i LH ratio after GnRH. During nine flushing episodes in three women, documented by digital temperature and iLH pulses, there was a significant increase in the bio:i LH ratio (P less than 0.001). After treatment of seven PM women for 2 months with 0.625 mg conjugated estrogens and seven other PM women with 150 mg im depomedroxyprogesterone acetate, vasomotor symptoms decreased significantly. Serum iLH did not change after treatment, but bio:i LH ratios decreased significantly, and 7 of 14 women had levels in the premenopausal range. These data suggest that bioLH and the bio:i LH ratio correlate better than iLH with symptomatology in PM women.

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.

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.

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.

The significance of bleeding patterns in Norplant implant users.

The purpose of this study was to examine the bleeding patterns of 234 Norplant users during 5 years of use and to identify the bleeding patterns of users who conceived. During the first year of use, 26.6% of users had regular bleeding cycles, 66.3% had irregular cycles, and 7.1% were amenorrheic. By the fifth year of use, 62.5% of users had regular cycles, 37.5% had irregular cycles, and none had amenorrhea. Of the ten users who became pregnant, eight had regular menstrual cycles in the 6 months before the diagnosis of pregnancy, one had an irregular pattern, and one did not keep a bleeding record. None had amenorrhea. The 5-years cumulative pregnancy rate for patients with regular cycles was 17.4%; this was significantly higher (P less than .05) than the 5-year cumulative rates of 4.4% in users with irregular cycles and 0% in users with amenorrhea. This study indicates that during the first year of Norplant use, only 26.6% of users have regular cycles, but after the first year, 50-60% of users develop regular cycles. The bleeding patterns of women using Norplant improve after the first year of use, and those with regular cycles are at greatest risk for method failure.

Correlation of endometrial maturation with four methods of estimating day of ovulation.

Dating of maturity of the endometrium by histologic examination was correlated with four methods of ovulation detection in 13 cycling parous women. Histologic dating was assessed independently by two pathologists and correlated with the postovulatory duration as determined by daily transvaginal ultrasound scanning, serum LH measurements, basal body temperature (BBT), and subtraction of 14 days from the onset of menses. In addition, progesterone and estradiol (E2) were measured in daily serum samples. Dating of the endometrial biopsy was highly correlated (P less than .002) with the day of ovulation as determined by ultrasound, and was found to be within 2 days of the correct postovulatory day on evaluation of 25 of 26 (96.1%) of the interpretations. The accuracy of dating using the LH surge was 84.6% (22 of 26 interpretations), and with the BBT thermogenic shift was 76.9% (20 of 26 interpretations). However, dating of the endometrium was within 2 days of the correct day in only 17 of the 26 interpretations as determined by subtracting 14 days from the onset of the subsequent menses. The accuracy of dating was significantly better correlated (P less than .025) with days from ovulation as determined by ultrasound than as calculated from the onset of menses. There was a significant correlation between endometrial dating and the amount of progesterone (P less than .01) and E2 (P less than .01) secreted from the day of ovulation, as determined by transvaginal ultrasound, to the day of biopsy. These data confirm a strong correlation between endometrial dating and ovarian hormone secretion during the postovulatory phase.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of androgens on insulin resistance.

Insulin resistance (IR) in polycystic ovary syndrome (PCO) has been linked to hyperandrogenism and elevated luteinizing hormone (LH) levels. Fourteen patients with idiopathic hirsutism (IH), 13 with PCO, and 6 control subjects were investigated for assessment of the effects of serum LH, peripheral tissue androgens, and sex hormone-binding globulin (SHBG) on fasting immunoreactive insulin (IRI) levels. Serum LH, dehydroepiandrosterone sulfate, dihydrotestosterone, and 3 alpha-androstanediol, SHBG, and unbound testosterone (uT) were measured. Serum testosterone (T) showed a positive correlation with IRI (P less than 0.05), and SHBG showed a negative correlation (P less than 0.02). Unbound T showed a highly significant positive correlation (P less than 0.001), whereas dehydroepiandrosterone sulfate, dihydrotestosterone, and 3 alpha-androstanediol did not correlate. Gonadotropin-releasing hormone, administered to patients with IH, raised LH levels but did not change IRI levels. Spironolactone did not affect T or IRI in patients with IH but significantly lowered T and IRI in patients with PCO. It is suggested that IR is not related to LH or peripheral androgen metabolism but highly correlated with uT and SHBG, thus coupling two important factors in IR, obesity and the androgen level.

Prolactin response after gonadotropin-releasing hormone in the polycystic ovary syndrome.

The administration of gonadotropin-releasing hormone (GnRH) has been shown to stimulate prolactin (PRL) release under certain conditions. The authors compared PRL responses after GnRH in normoprolactinemic patients with the polycystic ovary syndrome (PCO) with those of normal ovulatory women in the follicular phase. Seven of 15 patients had a significant increase in PRL after GnRH, whereas none of the control subjects had a positive response. After 1 week of oral L-dopa, the responders no longer exhibited this positive response. Baseline PRL levels in responding patients with PCO were similar to levels in control subjects, whereas nonresponding patients with PCO had higher PRL levels. Baseline follicle-stimulating hormone (FSH)/luteinizing hormone (LH) ratios were higher in patients with a positive response. The positive PRL response after GnRH was not correlated with baseline serum LH, the LH/FSH ratio, delta maximum LH responses, serum testosterone (T), unbound T, or baseline PRL. The positive response correlated positively with serum levels of unbound estradiol (P less than 0.05) and serum unbound estradiol/unbound T ratios (P less than 0.01). These data suggest that under certain conditions a subgroup of patients with PCO may demonstrate a positive PRL response after GnRH. Dopamine, gonadotropins, and estrogen may play a role in this interaction.

Characteristics of ovarian follicular development in Norplant users.

Daily transvaginal ultrasound (US) scanning of the ovaries to assess follicular development and daily blood sampling were performed on 19 Norplant (Leiras, Turku, Finland) subdermal contraceptive implant users who had regular menstrual cycles and on 10 normally cycling women. Three groups were identified in the implant users based on US finding. Six (31.6%) of the implant users had US findings that were consistent with a normal ovulatory pattern. However, their mean peak luteinizing hormone levels and peak midluteal phase progesterone (P) levels were significantly lower than control values. Eleven (57.9%) users had persistent follicles, and 2 users (10.5%) had no follicular development. These data suggest that after 2 to 4 years of use, about one third of Norplant users with regular bleeding patterns may ovulate but most have deficient luteal P levels. In this small study, the presence of persistent follicular enlargement in implant users was common.

The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women.

Spironolactone (S) has been used successfully for the treatment of hirsutism. We evaluated whether the effects of S on serum androgens and hair growth are dose-related and whether S affects secreted androgens to the same degree as peripherally derived androgens. Two groups of 15 hirsute patients, similarly matched, received either 100 or 200 mg S daily for 3 months. Serum total testosterone (T) decreased significantly (P less than 0.05) and to a similar degree with both dosages, whereas unbound T was unaltered. Dehydroepiandrosterone sulfate was unaltered, whereas androstenedione decreased with 200 mg S (P less than 0.05). Peripherally derived serum dihydrotestosterone decreased to a similar degree with 100 and 200 mg S (P less than 0.05), whereas 5 alpha-androstane-3 alpha-17 beta-diol (3 alpha-diol) increased (P less than 0.05) similarly with both dosages. Serum 3 alpha-diol glucuronide (3 alpha-diol-G) increased with both dosages, but not significantly. Anagen hair shaft diameters decreased significantly in both groups by 19% +/- 8% and 30% +/- 4% (P less than 0.05). No correlation was found between hair growth and serum androgens. Because serum unbound T was largely unaltered by S, it is suggested that the antiandrogenic effects of S are primarily related to its peripheral effect. However, there is no good clinical marker for this effect as levels of 3 alpha-diol and 3 alpha-diol-G increase.

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.

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.

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.

Ovulation inhibition with nafarelin acetate nasal administration for six months.

A group of 24 women with normal menstrual cycles were treated with nafarelin acetate administered in doses of either 125 micrograms or 250 micrograms daily intranasally for 6 months. Each subject was studied for one ovulatory control cycle, six treatment cycles, and post-treatment until the return of ovulation was documented. Once a week progesterone, estradiol, follicle stimulating hormone, and luteinizing hormone were measured in the serum. Acute hormone responses to nafarelin acetate were determined on day 1, day 98 and day 186 of treatment. Two subjects failed to complete the treatment phase. One subject using the 250 micrograms daily dose of nafarelin acetate discontinued treatment on the sixth day because of heavy uterine bleeding. One subject using the 125 micrograms daily dose of the study drug terminated treatment on day 126 because of a 21-pound weight gain. There were significantly less presumed ovulatory cycles at the higher dose (2 out of 60 cycles) than at the lower dose (10 out of 54 cycles) (p less than 0.01). On the average menstrual cycles were reestablished 28.5 +/- 8.3 (S.D.) days after discontinuing the 125 micrograms daily dose and 33.7 +/- 17.9 (S.D.) days after terminating the 250 micrograms daily dose. With the higher dose of nafarelin acetate there were significantly fewer bleeding episodes, less number of days of bleeding, and longer cycles. During the treatment phase the area under the LH curve was significantly less and the acute response of LH in the last week of treatment was significantly less with the higher dose of drug. With both doses of nafarelin acetate the acute responses of LH, FSH and estradiol were significantly greater on day 1 than on either day 98 or day 186. Side effects observed during this study included galactorrhea (2 subjects) and vasomotor symptoms (7 subjects).

GnRH agonists as contraceptive agents: predicted significantly reduced risk of breast cancer.

Gonadotrophin-releasing hormone agonists (GnRHAs) were investigated as contraceptive agents from the late 1970's to the mid-1980's. They were abandoned as they appeared to offer no advantage over conventional combination-type oral contraceptives (COCs). This conclusion appears to be incorrect. We propose here a contraceptive regimen of a depot formulation of a GnRHA plus add-back estrogen and intermittent progestogen. The dose of add-back sex-steroids is substantially less than that in COCs; this reduction in sex-steroids should lead to a major reduction in lifetime breast cancer occurrence.

Quantitation of RU 486 in human plasma by HPLC and RIA after column chromatography.

Chromosorb column chromatography was used for separation of RU 486 from its immunologically cross-reacting metabolites prior to quantitative analysis by radioimmunoassay (RIA) or high-performance-liquid chromatography (HPLC). The results of the two assay methods were in good agreement with each other (r = 0.99, n = 29). The retention time of RU 486 in our HPLC system was 2.5 min. Plasma concentrations of RU 486 were measured by HPLC up to 48 h following single oral administration of 100, 400, 600 and 800 mg of RU 486 to female volunteers. The plasma peak concentrations (2.0-2.5 micrograms/ml) were reached within the first hour. After redistribution, the plasma concentrations of RU 486 were not significantly affected by the doses studied but remained in the same range throughout the 48 hours. The plasma half-life between 24 and 48 hours was 27 hours or more. We conclude that HPLC is valuable in studies on the metabolism and pharmacokinetics of RU 486, but a less laborious RIA method after Chromosorb column chromatography is suitable and gives reliable results in large-scale clinical studies.

Pregnancy termination with a high and medium dosage regimen of RU 486.

Sixty healthy pregnant women who wished to terminate their pregnancy and who were no more than 49 days pregnant were treated with one of three different dose regimens of a synthetic progesterone receptor blocker, RU 486. Serum cortisol was measured to determine the antiglucocorticoid effects of this compound. The high dose but shorter treatment regimen (400 mg/day RU 486 X 4 days or 200 mg/day X 4 days) was associated with a high (greater than 80%) rate of side effects, especially nausea, vomiting, weakness and heavy bleeding and a low rate of success (10%). A group of 50 subjects received the medium dose but longer treatment regimen (100 mg/day X 7 days). This group had less side effects (40-60%) and a 72.3% success rate of complete abortion. The AM cortisol values were significantly elevated in all treatment groups but higher in those receiving the high dose. These values returned to normal one week following cessation of treatment. Medium dose but longer duration (100 mg/day X 7 days) of RU 486 treatment is associated with a higher success rate and less side effects than higher dose therapy administered over a shorter period. There were no predictive indices to determine which subjects would respond successfully. The reason for the failure of the drug in 30% of the subjects on the medium dose is not known at this time.