Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study.

BACKGROUND: Observational studies in healthy women suggest postmenopausal hormone therapy reduces risk of coronary events. In contrast, in a recent clinical trial of women with coronary disease, a subgroup analysis demonstrated increased risk during the early months of therapy. Because higher levels of inflammation factors predict vascular disease outcomes, the effect of hormones on these factors is of interest. METHODS AND RESULTS: Four inflammation-sensitive factors, C-reactive protein, soluble E-selectin, von Willebrand factor antigen, and coagulation factor VIIIc were measured at baseline, 12, and 36 months in 365 participants of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, a randomized, placebo-controlled trial of the effects of 4 hormone preparations on cardiovascular disease risk factors. Compared with placebo, all 4 active preparations resulted in a large sustained increase in the concentration of C-reactive protein and a decrease in soluble E-selectin (P=0.0001). There were no effects of treatment on concentrations of von Willebrand factor or factor VIIIc. There were no differences in effects among treatment arms. Relative to placebo, when combining active treatment arms, final concentrations of C-reactive protein were 85% higher whereas E-selectin was 18% lower compared with baseline. CONCLUSIONS: Postmenopausal hormones rapidly increased the concentration of the inflammation factor C-reactive protein. Such an effect may be related to adverse early effects of estrogen therapy. In contrast, hormones reduced the concentration of soluble E-selectin, and this might be considered an anti-inflammatory effect. Because PEPI was not designed to assess clinical endpoints, studies of the impact of hormone-mediated changes in inflammation on risk of subsequent coronary events are needed.

Agreement in assessing endometrial pathology: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.

We report on agreement in interpreting endometrial biopsy specimens between the local and central pathologists of the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. This trial was a 3-year, multicenter, randomized, double-masked, placebo-controlled trial of four groups taking estrogen or estrogen/progestin combinations. A total of 1804 follow-up biopsies were performed in 596 subjects. Relative sensitivity and relative specificity using the diagnosis from the central pathologist as the gold standard and overall agreement are presented. Almost 90% of the diagnoses were reported normal by both readers. There were significant differences in agreement among clinics and treatment arms (p < 0.0001). The visit at which the biopsy specimen was obtained, age at baseline, prior postmenopausal estrogen use, parity, and drug adherence were not associated with agreement between the two readers. Higher proportions of disagreement were seen in two clinics (13% and 11%) compared with the other five clinics (2%-5%). Biopsy specimens from participants who were taking conjugated equine estrogens (CEE) only were more likely to be diagnosed differently by both readers (11%) than biopsy specimens from women taking a placebo (2%) or CEE combined with progestins (5%). Relative specificity varied from 86.4% to 98.9% among the clinics (p < 0.0001). Relative sensitivity was based on a small number of diagnoses, as few biopsy specimens were classified abnormal by the central pathologist. In patients assigned to CEE combined with progestin, 5 of the 7 biopsy specimens that were recorded abnormal by the central pathologist received a normal diagnosis locally. Our findings show that sample size requirements for study designs in which a central reader is used can be at least threefold lower than the requirements for designs relying on local diagnoses. Centralized protocols for endometrial histopathology reading and staff training are highly desirable in multicenter trials.

Comparison of the impact of transdermal versus oral estrogens on biliary markers of gallstone formation in postmenopausal women.

This prospective, randomized, double blind, parallel study was undertaken to elucidate further the potential mechanisms through which estrogens could promote the formation of cholesterol gallstones and to compare the impact of nonoral (transdermal) and oral estrogens on serum, hepatic, and biliary markers of estrogen action. Ninety-seven postmenopausal women were randomized to receive either transdermal estradiol (E2; 0.1 mg every 3.5 days; n = 48) or oral conjugated equine estrogens (1.25 mg every day; n = 49) for 8 weeks. Blood samples were drawn, and bile samples were obtained by cholecystokinin-stimulated duodenal drainage before and after 8 weeks of estrogen administration. The main outcome measures included serum FSH, LH, E2, estrone, estrone sulfate, sex hormone-binding globulin, lipid profiles, biliary cholesterol saturation index, cholesterol nucleation time, presence of cholesterol crystals in bile, as well as biliary arachidonate, PGE2, and mucous glycoproteins. Estrogens administered by both routes increased circulating estrogens and resulted in similar suppression of both gonadotropins. Sex hormone-binding globulin was clearly increased, and the changes in serum lipids were more pronounced with oral conjugated equine estrogens than with transdermal E2. The biliary cholesterol saturation index was significantly increased compared to the baseline values with both transdermal E2 (1.08 +/- 0.04 vs. 1.00 +/- 0.03; mean change, 8%) and oral conjugated equine estrogens (1.04 +/- 0.03 vs. 0.99 +/- 0.03; mean change, 6%); however, there was no difference between the treatments. The number of patients with cholesterol crystals detected in bile was similar after both estrogen regimens. Transdermal and oral estrogens decreased nucleation time in vitro, increased arachidonate and PGE2 levels, and minimally raised total glycoprotein concentrations. In conclusion, transdermal and oral estrogens exerted comparable nonhepatic effects, as evidenced by similar reductions of gonadotropin levels, but oral therapy exhibited substantially greater actions on hepatic markers of estrogen action. Both transdermal E2 and oral conjugated equine estrogens significantly elevated the biliary cholesterol saturation index and reduced the nucleation time. These results suggest that estrogens at the doses studied could promote gallstone formation by alteration of biliary lipids and cholesterol nucleation time that have been incriminated in this process.

Nafarelin vs. leuprolide acetate depot for endometriosis. Changes in bone mineral density and vasomotor symptoms. Nafarelin Study Group.

OBJECTIVE: To compare intranasal nafarelin and intramuscular leuprolide acetate (LA) depot in the management of endometriosis. STUDY DESIGN: A multicenter, prospective, randomized, double-placebo, double-blind study was conducted on subjects who had symptoms and signs of endometriosis and bone mineral density (BMD) within the age-appropriate normal range. For 6 months, 99 subjects received nafarelin, 200 micrograms twice daily, and placebo injections once monthly; 93 subjects received LA depot injections, 3.75 mg once monthly, and placebo nasal spray, twice daily. Subjects were followed throughout treatment and for six months after treatment. The main outcome measures were changes in endometriosis symptoms and signs, BMD measurements, subject-reported and objectively measured hot flushes and circulating estradiol concentrations. RESULTS: Nafarelin was as effective as LA depot in alleviating symptoms and signs of endometriosis. LA depot recipients lost significantly more BMD, had more days with subjective hot flushes and more objectively measured hot flushes than did nafarelin recipients. In the nafarelin group, estradiol levels were consistently higher than in the leuprolide depot group, with significant differences by month 3 of dosing. CONCLUSION: Nafarelin and LA depot were equally effective despite higher estradiol levels in nafarelin recipients. Nafarelin-treated subjects lost less BMD, had fewer days with hot flushes and had fewer objectively measured hot flushes.

Impact of overnight dexamethasone suppression on the adrenal androgen response to an oral glucose tolerance test in women with and without polycystic ovary syndrome.

In order to test the hypothesis that adrenocortical overactivity, possibly related to the stress of testing, may impact on the measurement of circulating androgen concentrations during glucose-induced hyperinsulinaemia, we prospectively screened 10 patients with the polycystic ovary syndrome (PCOS) and nine healthy control women with an oral glucose tolerance test (OGTT), before and after the administration of dexamethasone. Blood sampling was performed at 0, 30, 60, 90, and 120 min following the oral ingestion of 75 g of glucose, before and after the administration of 1.0 mg dexamethasone on the evening prior to testing. Total and free testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), cortisol, glucose and insulin were assessed during the 2 h OGTT. Women with PCOS had increased basal concentrations of free testosterone, total testosterone, androstenedione, and insulin compared to control women. In women with PCOS an acute decline in circulating concentrations of DHEAS occurred during the OGTT. In PCOS women there were no changes in other ovarian or adrenal androgens during OGTT before or following dexamethasone administration. In control women DHEA concentrations declined during the OGTT. Following overnight dexamethasone suppression in control women, circulating concentrations of DHEAS and testosterone also declined. It is concluded that: (i) in PCOS women only the concentration of circulating DHEAS decreased during glucose-induced hyperinsulinaemia and dexamethasone administration did not further alter androgen responses to an OGTT; (ii) it is possible that, in these hyperandrogenic patients, the insulin-related suppression of adrenocortical testosterone and DHEA is negated by their much greater ovarian secretion of these androgens; (iii) in control women DHEA concentrations acutely declined during the OGTT and the administration of dexamethasone resulted in the acute decline of DHEA, DHEAS, and testosterone; (iv) it appears that the stress related to testing impacts on the androgen response to OGTT, at least in healthy women.

A mechanism for the suppression of estrogen production in polycystic ovary syndrome.

In polycystic ovary syndrome (PCOS), follicle development arrests in the early antral stage when aromatase expression in the granulosa cells (GC) would normally occur. Despite high intrafollicular concentrations of androstenedione and bioactive FSH, in vivo estrogen biosynthesis remains low. When GC from PCOS follicles are stimulated with FSH in vitro, a marked stimulation of estrogen production occurs, suggesting that PCOS follicles contain an endogenous inhibitor of estrogen production. To test this hypothesis, GC from hyperstimulated women were cultured with increasing concentrations of follicular fluid (FF) from PCOS and normally cycling control women in the presence of androstenedione (10(-5) mol/L). FF from control women caused a small decrease (20%) in estradiol production. PCOS FF caused a dose-related inhibition of estradiol production (60%), indicating that there was significantly more inhibitory activity in PCOS FF. To determine whether abnormal androgen metabolism could play a role in inhibiting estradiol production in PCOS, we measured 5 alpha-androstane-3, 17-dione, a competitive inhibitor of aromatase activity, in serum and FF of control and PCOS women. 5 alpha-Androstane-3, 17-dione levels in serum were significantly elevated in PCOS. 5 alpha-Androstane-3, 17-dione levels were 1000-fold higher in PCOS FF than serum. Moreover, FF levels were markedly higher in PCOS follicles (P < 0.0001) than in normal dominant and cohort follicles. Dose-response studies revealed that the concentration of 5 alpha-androstane-3, 17-dione present in FF form normal dominant follicles (79.4 +/- 14.6 nmol/L) had little effect on estradiol production. In contrast, 5 alpha-androstane-3, 17-dione levels in PCOS FF (581.6 +/- 62.9 nmol/L) inhibited estradiol production by 75%. These data support the hypothesis that PCOS FF contains one or more endogenous inhibitors of aromatase activity and suggest that abnormally high 5 alpha-androstane-3, 17-dione levels in PCOS FF may be an important inhibitor of estradiol production.

Comparison of a gonadotropin-releasing hormone agonist and a low dose oral contraceptive given alone or together in the treatment of hirsutism.

Chronic GnRH agonist therapy lowers androgens and decreases androgen-dependent hair shaft diameter, but the resulting induction of hypoestrogenemia has limited its usefulness as a single agent. Estrogen- and progestin-containing oral contraceptives also reduce circulating androgen levels and are commonly used empirically for the treatment of hirsutism, but have not been evaluated in a blinded randomized controlled fashion. The present study is the first double masked trial to evaluate the combination use of a GnRH agonist and an estrogen-containing oral contraceptive and tests our hypothesis that these could synergistically reduce androgen levels and suppress hormone-dependent hair growth while avoiding the symptoms and risks of agonist-induced hypoestrogenemia. We enrolled 64 women in a 24-week blinded randomized controlled trial to compare placebo, nafarelin (NAF; 400 micrograms, intranasal spray, twice daily), norethindrone (1 mg), and ethinyl estradiol (NOR 1/35; 0.035 mg, daily, for 3 of 4 weeks), or combined use of NAF and NOR 1/35 for 24 weeks. At baseline and every 8 weeks, we measured gonadotropins, estrogens, androgens, and hair growth. Bone density was assessed by dual energy x-ray adsorptiometry, and hot flashes were measured objectively. Baseline total testosterone (T), free T, percent free T, and sex hormone-binding globulin-binding capacity were similar among groups. With treatment, significant reductions (P = 0.01) in total T were seen with combination and NAF only therapy. Significant increases (P < 0.001) in the sex hormone-binding globulin-binding capacity were seen in women given NOR 1/35 alone or in combination with NAF. Free T levels decreased to approximately half of baseline levels with combination treatment (17.9 to 6.4 nmol/L; P < 0.001) and NOR 1/35 alone (20.8 to 10.2 nmol/L; P < 0.001). There was a significant decrease in hair shaft diameter after combination therapy (P < 0.05) that was not seen with either agent alone. Combination therapy also prevented the hot flashes and bone loss that occurred with agonist alone. In summary, our results demonstrate that combination GnRH agonist and low dose oral contraceptive therapy is more effective than either agent alone in the treatment of hirsutism and avoids the hypoestrogenic complications that occur with agonist only therapy.

Prolonged gonadotropin-releasing hormone agonist treatment of symptomatic endometriosis: the role of cyclic sodium etidronate and low-dose norethindrone "add-back" therapy.

OBJECTIVE: To examine the safety and efficacy of combining cyclic sodium etidronate and low-dose norethindrone with a long-acting GnRH agonist (GnRH-a) for prolonged therapy of symptomatic endometriosis. DESIGN: Prospective randomized open label study. SETTING: Tertiary care university-affiliated reproductive medicine program. PATIENTS: Nineteen regularly cycling women with laparoscopically diagnosed symptomatic endometriosis and 18 regularly cycling untreated controls without endometriosis. INTERVENTIONS: All patients received a depot preparation of the GnRH-a leuprolide acetate IM monthly for 48 weeks. Group I patients (n = 10) received supplemental sodium etidronate cycled with calcium carbonate as well as 2.5 mg norethindrone daily. Group II patients (n = 9) received only supplemental 10 mg norethindrone daily. Group III volunteers (n = 18) were untreated and followed for bone density changes. MAIN OUTCOME MEASURES: Disease extent at follow-up laparoscopy; pain, vasomotor, and vaginal symptom scores; bone mineral density (serial dual-energy roentgenogram absorptiometry scans); serum estrogens, lipids, and glucose and insulin response to glucose challenge. RESULTS: Painful symptoms and extent of endometriosis were reduced in both treatment groups. Despite maintenance of a chronically hypoestrogenic state for 48 weeks, no changes in bone density over time or in comparison to group III untreated controls were noted. Similarly, no evidence of significant vasomotor symptoms were reported in either treatment group. However, adverse changes over time in circulating low-density lipoprotein (LDL) cholesterol and apolipoprotein A1 levels as well as the ratio of high-density lipoprotein to LDL were noted only in group II. CONCLUSIONS: The combination of cyclic sodium etidronate and low-dose norethindrone with a long-acting GnRH-a served to safely prolong medical therapy of symptomatic endometriosis. Clinical efficacy was preserved while prophylaxis against significant hypoestrogenic side effects was achieved.

The relationship between circulating androgens, obesity, and hyperinsulinemia on serum insulin-like growth factor binding protein-1 in the polycystic ovarian syndrome.

OBJECTIVE: Our purpose was to evaluate the relationship of obesity, hyperinsulinemia, and hyperandrogenemia on serum insulin-like growth factor binding protein-1 levels in women with the polycystic ovarian syndrome. STUDY DESIGN: Insulin-like growth factor binding protein-1, insulin, and androgen levels were studied during a 3-hour intravenous glucose tolerance test in 16 women with polycystic ovarian syndrome (nine obese and seven nonobese) and 20 healthy control women (10 obese and 10 nonobese). RESULTS: Positive correlations were observed between basal (r = 0.77, p = 0.04) and area under curve (r = 0.86, p < 0.001) insulin-like growth factor binding protein-1 with basal androstenedione in the nonobese women with polycystic ovarian syndrome but not in other groups of women examined or between other androgens and insulin-like growth factor binding protein-1. An inverse relationship was observed between log area under curve insulin-like growth factor binding protein-1 levels and log body mass index in polycystic ovarian syndrome (r = -0.54, p = 0.03) and in normal women (r = -0.43, p = 0.06). The log area under curve insulin-like growth factor binding protein-1 level was approximately an inverse linear function of log area under curve insulin response for both women with polycystic ovarian syndrome (r = -0.70, p < 0.001) and control women (r = -0.72, p < 0.001). Additionally, after the area under curve insulin response during intravenous glucose tolerance testing was controlled for, the decline in area under curve insulin-like growth factor binding protein-1 responses was on average 66% less in both obese and nonobese women with polycystic ovarian syndrome compared with same-weight controls (95% confidence interval 110% to 270%, p = 0.04). CONCLUSION: These data indicate that insulin and body mass index are the major determinants of circulating insulin-like growth factor binding protein-1 and that chronic hyperandrogenemia does not appear to further reduce serum insulin-like growth factor binding protein-1 levels in obese or normal-weight women with polycystic ovarian syndrome.

Development of endometrial cancer in women on estrogen and progestin hormone replacement therapy.

The presenting symptoms, hormonal regimens, treatment modalities, tumor pathology, and follow-up of 25 women developing endometrial cancer while receiving postmenopausal estrogen and progestin therapy were investigated retrospectively. Patients were interviewed and hormone therapies were confirmed through medical records. Pathology specimens were reviewed. Patients received conjugated estrogens (n = 20) or another estrogen (n = 5). For those on conjugated estrogens, the mean daily dose was 0.68 mg, monthly duration was 24.9 days, and monthly dose was 17.0 mg. Women also received medroxyprogesterone acetate (n = 23) or norethindrone acetate (n = 2). The most common regimen was sequential medroxyprogesterone acetate, at a mean daily dose of 7.5 mg, monthly duration of 9.3 days, and monthly dose of 68 mg (mean duration = 5.7 years). Most tumors were low stage and grade, with few demonstrating grade 3 disease (n = 2) or greater than 50% myometrial invasion (n = 2). Twenty-three (92%) had disease limited to the uterus, while two had stage IIIA disease. All are alive and disease-free after a median follow-up of 26 months. Estrogen and progestin therapy does not prevent endometrial cancer in all patients. Women who developed this tumor on sequential therapy in general received less than the recommended guidelines for daily dosage and monthly duration of progestin. Most patients had early-stage and low-grade disease. Continued vigilance in the care of women on hormone replacement therapy is necessary even when combination therapy is prescribed.

Transdermal estradiol. A potentially improved method of hormone replacement.

Estrogen replacement is usually administered as an oral preparation. Concerns have been expressed about the impact these oral preparations have on hepatic function. This paper reviews studies of one nonoral preparation that delivers estradiol into the systemic circulation by use of a transdermal system. Support for this delivery system for treating menopausal symptoms and, potentially, for avoiding side effects is presented.

Changes of ovarian hormonal function with aging.

Striking changes of ovarian function occur with aging. These changes begin subtly with reductions of fecundability being observed after age 25. The transition from reproductive to postreproductive life is characterized by menstrual irregularity including anovulation, or short luteal phases. The most prominent hormonal changes at the menopause are drastic reductions of estradiol and progesterone secretion by the ovary, reflecting the cessation of folliculogenesis and ovulation. Elevations of gonadotropins and reduction of inhibin levels also reflect the loss of folliculogenesis and ovulation. There are accompanying decreases of ovarian androgen secretion; however, the postmenopausal gonad directly secretes more testosterone after, than before, the menopause.

The influence of luteinizing hormone and insulin on sex steroids and sex hormone-binding globulin in the polycystic ovarian syndrome.

OBJECTIVE: To examine the relationship between hyperinsulinemia, sex hormone-binding globulin (SHBG), and body mass index (BMI) on LH-induced hyperandrogenemia in patients with polycystic ovarian syndrome (PCOS). DESIGN: Insulin responses during an oral glucose tolerance test (OGTT) were assessed in 25 consecutive women with PCOS and 20 control women matched for BMI. Insulin responses and sensitivity (SI) were also determined using a frequently sampled intravenous glucose tolerance test (IVGTT). SETTING: The clinical research center at a university medical center. MAIN OUTCOME MEASURES: Serum LH, SI, and basal, peak, and area under the curve (AUC-insulin responses) were determined and correlated with SHBG, androstenedione (A), T, and free T concentrations. RESULTS: Compared with controls, the AUC-insulin response during OGTT was greater in PCOS, with an average increase of 44%. During IVGTT, AUC-insulin response was also significantly higher in PCOS versus controls, with an average increase of 53%. In addition, SI was reduced in PCOS versus controls with an average decrease of 53%. The average differences in oral- and intravenous-glucose-induced hyperinsulinemia and in insulin sensitivity between PCOS and controls were relatively constant across the entire physiological range of BMI. In PCOS, baseline LH showed strong positive correlations with baseline A and T. However, there were no significant correlations between either basal, peak, or AUC-insulin response during OGTT and IVGTT with basal T or A concentrations or between insulin and androgen levels measured at 30-minute intervals throughout the OGTT. However, basal, peak, and AUC-insulin responses during OGTT were strongly correlated with fasting SHBG binding capacity. CONCLUSIONS: These data are consistent with the hypothesis that hyperinsulinemia in PCOS influences the biologically active component of T by lowering SHBG concentrations while having little apparent impact on LH-induced secretion of androgens in vivo.

Effects of sodium etidronate in combination with low-dose norethindrone in patients administered a long-acting GnRH agonist: a preliminary report.

OBJECTIVE: To assess the efficacy of combining sodium etidronate with low doses of the 19-nor-testosterone progestin norethindrone or using high doses of norethindrone alone as prophylaxis against the vasomotor instability and bone density loss induced by GnRH agonists alone. METHODS: Eleven patients enrolled in this randomized study received the long-acting GnRH agonist leuprolide acetate 3.75 mg intramuscularly every 4 weeks for 24 weeks. Six patients (group I) self-administered sodium etidronate 400 mg/day orally for 14 days followed by calcium carbonate 500 mg/day orally for the next 42 days during three 56-day cycles. This regimen was supplemented by norethindrone 2.5 mg/day orally. Five patients (group II) self-administered norethindrone 10 mg/day orally. Two sets of controls were used. Group III consisted of ten previously reported patients who received the same GnRH agonist only. Group IV comprised 12 regularly cycling untreated controls. Bone mineral density, vasomotor symptoms, circulating estrogens, and lipids were assessed serially. RESULTS: The significant vasomotor instability (P < .01) and bone mineral density loss (-4.8 +/- 0.9%; P < .05) experienced by patients in group III was prevented in those in groups I and II despite maintenance of a persistent hypoestrogenic state. Bone density changes in groups I and II were similar to those in untreated controls (group IV). Persistent decreases in high-density lipoprotein (HDL) cholesterol (P = .005) and increases in the low-density lipoprotein-to-HDL ratio (P < .05) were noted only in group II patients receiving supplemental high-dose norethindrone. CONCLUSION: These preliminary data suggest that the addition of cyclic sodium etidronate in combination with low-dose norethindrone to GnRH agonists is an effective means of ameliorating the hypoestrogenic side effects induced by GnRH agonist alone.

Preventive effects of transdermal 17 beta-estradiol on osteoporotic changes after surgical menopause: a two-year placebo-controlled trial.

OBJECTIVE: The purpose of our study was to evaluate the effects of three dosages of transdermally administered 17 beta-estradiol on markers of bone loss in women who had recently undergone surgical menopause. STUDY DESIGN: This was a 2-year, randomized, double-blind, placebo-controlled study that reviewed 127 women stratified by age. Biochemical indicators of bone metabolism in urine and serum were periodically assessed, as was bone mineral content of the lumbar spine and radius. Statistical analysis examined the percent changes from baseline in bone mineral density by using an analysis of covariance with treatment as a factor and the baseline value as a covariant, by performing all-pairwise comparisons among the three estradiol groups, and by testing for a linear dose-response relationship. RESULTS: After 2 years of therapy, a significant dose-response relationship was detected. CONCLUSION: This 2-year study demonstrates that transdermally administered 17 beta-estradiol is a safe and effective regimen for preventing bone loss in recently postmenopausal women.

Long-term effects of transdermal estradiol with and without medroxyprogesterone acetate.

OBJECTIVE: To study the long-term biological and metabolical effects of estradiol (E2) administered by transdermal therapeutic systems with and without the addition of medroxyprogesterone acetate (MPA). DESIGN: Open, randomized, comparative trial. SETTING: The reproductive endocrine unit of a tertiary care university-affiliated hospital. PATIENTS: Fifty-seven postmenopausal women were given E2 transdermally, whereas 28 were randomized to take MPA by mouth. Fifteen premenopausal women were studied for comparison. INTERVENTIONS: Estradiol, 0.1 mg, was administered by a transdermal therapeutic system for 24.5 of 28 days and was cycled for 96 weeks. Medroxyprogesterone acetate, 10 mg, was given for days 13 to 25 of each 28-day cycle (E+P group), whereas the remainder received E2 only. MAIN OUTCOME MEASURES: Serum E2, estrone (E1), luteinizing hormone, follicle-stimulating hormone, low-density, high-density, very low-density, and total cholesterol, triglycerides, blood pressure, renin substrate, plasma renin activity, and serum aldosterone levels were measured in all subjects at baseline and in the postmenopausal women every 24 weeks until the end of study. RESULTS: Mean +/- SE levels of E2 rose significantly from baseline at 24 weeks to 426 and 355 pmol/L for the E only and E+P groups, respectively. Smaller increases of estrone (E1) were observed to 263 and 244 pmol/L for the same respective groups. As expected, baseline levels of both gonadotropins were elevated, fell significantly with E2 administration, but remained increased in comparison with values observed in younger women. Decreases of total and low-density lipoprotein (LDL) cholesterol were observed in both groups that reached statistical significance at 48 weeks or later with the exception of LDL cholesterol in the E only group. No significant change of high-density lipoprotein or very low-density lipoprotein cholesterol or triglycerides was observed. There were reductions of mean systolic and diastolic blood pressures in both groups that reached significance at 72 weeks. Mean baseline plasma renin substrate, plasma renin activity, and serum aldosterone levels were within the ranges observed in younger, healthy women and did not change significantly with E2 administration in either group. CONCLUSION: These data support the long-term efficacy and safety of this form of replacement therapy, particularly in combination with MPA, in women with a uterus.

A prospective randomized comparison of luteal phase versus concurrent follicular phase initiation of gonadotropin-releasing hormone agonist for in vitro fertilization.

OBJECTIVE: To compare the effects of gonadotropin-releasing hormone agonist (GnRH-a) initiation either preceding or concurrent with controlled ovarian hyperstimulation (COH) in patients undergoing in vitro fertilization-embryo transfer (IVF-ET). DESIGN: Fifty-five patients were prospectively randomized to receive either GnRH-a on cycle day 21 before COH until ovarian suppression was achieved (group I) or GnRH-a concurrently with COH commencing on cycle day 3 (group II). MAIN OUTCOME MEASURES: Serum gonadotropin and ovarian steroid hormone levels, as well as fertilization, spontaneous abortion, and live birth rates. RESULTS: Twenty-six patients in group I and 29 patients in group II underwent COH for IVF-ET. Patients in group II had significantly higher serum luteinizing hormone, progesterone, and testosterone levels during stimulation with human menopausal gonadotropins (hMG) before oocyte retrieval (P < 0.05). Despite similar fertilization, biochemical, and clinical pregnancy rates, the spontaneous abortion rate was higher in group II (5/6) compared with group I (1/7) (P < 0.05). Thus, the live birth rate/retrieval for group I was 6 of 24 (25%) as compared with that of group II, which was 1 of 26 (3.8%) (P < 0.05). CONCLUSIONS: The initiation of GnRH-a in the follicular phase concurrently with hMG is associated with evidence of premature luteinization, hyperandrogenemia, and poorer pregnancy outcome compared with luteal phase administration of GnRH-a before hMG for IVF-ET.