The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomised trial.

AIMS/HYPOTHESIS: Recent clinical trials have found that the combination of conjugated equine oestrogen (CEO) and medroxyprogesterone has a protective effect on the incidence of type 2 diabetes. To determine the effect of CEO alone on the incidence of diabetes mellitus in postmenopausal women, we analysed the results of the Women's Health Initiative oestrogen-alone trial. METHODS: The Women's Health Initiative is a randomised, double-masked trial comparing the effect of daily 0.625 mg CEO with placebo during 7.1 years of follow-up of 10,739 postmenopausal women who were aged 50-79 years and had previously had a hysterectomy. Diabetes incidence was ascertained by self-report of treatment with insulin or oral hypoglycaemic medication. Fasting glucose, insulin and lipoproteins were measured in an 8.6% random sample of study participants, at baseline and at 1, 3 and 6 years. RESULTS: The cumulative incidence of treated diabetes was 8.3% in the oestrogen-alone group and 9.3% in the placebo group (hazard ratio 0.88, 95% CI 0.77-1.01, p=0.072). During the first year of follow-up, a significant fall in insulin resistance (homeostasis model assessment of insulin resistance) in actively treated women compared with the control subjects (Year 1 baseline between-group difference -0.53) was seen. However, there was no difference in insulin resistance at the 3- or 6-year follow-up. CONCLUSIONS/INTERPRETATION: Postmenopausal therapy with oestrogen alone may reduce the incidence of treated diabetes. The effect is smaller than that seen with oestrogen plus progestin. CEO should not, however, be used with the intention of preventing diabetes, as its well-described adverse effects preclude long-term use for primary prevention.

Quality of life in low-income menopausal women attending primary care clinics.

OBJECTIVE: To examine the quality of life and health status of a population of menopausal age primary care attendees that demographically has not been well represented in previous studies, and to describe the relationships between population characteristics and outcomes. DESIGN: Cross-sectional. SETTING: Community primary care clinics. PATIENT(S): Women 45-60 years of age within 5 years of their last period. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Participants provided demographic information and completed a series of questionnaires, including the Menopause Quality of Life Instrument (MENQOL) and the Short Form-36 health survey (SF-36). RESULT(S): Women who were employed, had higher levels of education, or higher levels of income reported better overall health and fewer menopausal symptoms. The study population scored significantly lower than the national norms on a summary survey of mental and physical health. There were no significant differences between ethnic groups with respect to either menopausal quality of life or health status. CONCLUSION(S): In a generally low income, poorly educated menopausal population, ethnicity did not significantly affect quality of life. Socioeconomic characteristics (less education and lower income) were associated with increased menopausal symptoms.

Impact of implementation of an embryo storage fee on embryo disposal activity.

OBJECTIVE: To examine the impact of implementation of a new fee for continued storage of cryopreserved embryos on the rate of requests for disposal of embryos. DESIGN: Retrospective cohort study. SETTING: A university-based assisted reproduction program. PATIENT(S): All patients with cryopreserved embryos. INTERVENTION(S): Implementation of a semiannual embryo storage fee of $100 to cover administrative and laboratory costs. MAIN OUTCOME MEASURE(S): The number of embryo disposal requests before and after implementation of the embryo storage fee was compared in relation to the activity of the cryopreserved embryo program as measured by number of frozen embryo transfers. RESULT(S): Annual requests for embryo disposal from 1992 through 1997 ranged from zero to three, which represented 0-5% of the annual frozen embryo program activity. In contrast, a significantly higher number of disposal requests (10, representing 18% of program activity) were received in 1998. CONCLUSION(S): Fees for storage of cryopreserved embryos seem to influence patients' decisions about disposal of cryopreserved embryos.

In vitro maturation of baboon oocytes retrieved at the time of cesarean section.

OBJECTIVE: To investigate the feasibility of oocyte retrieval at the time of cesarean delivery and the potential of such oocytes to undergo nuclear maturation in vitro using a baboon model and an established culture system. DESIGN: Randomized, controlled animal study. SETTING: Research foundation and university research laboratory. ANIMAL(S): Mature pregnant baboons. INTERVENTION(S): In vitro culture of aspirated oocytes with or without epidermal growth factor (EGF). MAIN OUTCOME MEASURE(S): Oocyte yield, germinal vesicle breakdown, polar body extrusion. RESULT(S): A total of 246 oocytes were retrieved (mean, 35; range, 14-67). Eighty-seven oocytes (35%) underwent germinal vesicle breakdown and 72 oocytes (29%) extruded a polar body. A chi2 analysis revealed no significant effect of EGF on outcome parameters. No effect of gestational age or maternal age on oocyte yield or development was observed. CONCLUSION(S): A sizeable proportion of oocytes obtained from puerperal primates exhibited the capacity to undergo nuclear maturation in vitro.

Exercise and reproductive dysfunction.

OBJECTIVE: To provide an overview of our current understanding of exercise-induced reproductive dysfunction and an approach to its evaluation and management. DESIGN: A MEDLINE search was performed to review all articles with title words related to menstrual dysfunction, amenorrhea, oligomenorrhea, exercise, and athletic activities from 1966 to 1998. The pathophysiology, proposed mechanisms, clinical manifestations, evaluation, and management of exercise-associated reproductive dysfunction were compiled. CONCLUSION(S): Exercise-induced menstrual irregularity appears to be multifactorial in origin and remains a diagnosis of exclusion. The underlying mechanisms are mainly speculative. Clinical manifestations range from luteal phase deficiency to anovulation, amenorrhea, and even delayed menarche. Evaluation should include a thorough history and a complete physical plus pelvic examination. Most cases are reversible with dietary and exercise modifications. Hormonal replacement in cases of a prolonged hypoestrogenic state with evidence of increased bone loss is recommended, although the long-term consequences of prolonged hormonal deficiency are ill-defined.

Efficacy of postal communication with patients who have cryopreserved pre-embryos.

OBJECTIVE: To compare the characteristics of patients who did and did not respond to a request for information regarding their cryopreserved pre-embryos. DESIGN: Mail survey. SETTING: Academic-assisted reproductive technology program. PATIENT(S): One hundred thirty-six patients with cryopreserved pre-embryos. INTERVENTION(S): Patients were surveyed by first-class mail regarding their plans for their cryopreserved pre-embryos and their interest in embryo donation. MAIN OUTCOME MEASURE(S): Age, number of stored pre-embryos, and duration of storage of responders and nonresponders at 6 weeks after mailing. RESULT(S): Eighty-three patients (62%) did not respond to the survey. Compared with responders, nonresponders were significantly older at the time of embryo cryopreservation, had fewer pre-embryos cryopreserved, and had the pre-embryos cryopreserved for a longer duration. Five responders (9%) expressed an interest in embryo donation. Three patients requested disposal of pre-embryos. Sixteen surveys (12%) were returned as undeliverable. As a group, these patients had the fewest pre-embryos cryopreserved and had the longest duration of storage. CONCLUSION(S): A disturbing number of patients with cryopreserved pre-embryos ignored efforts by our program to maintain contact. Older patients with few cryopreserved pre-embryos may require special attention to avoid abandonment.

A baboon (Papio hamadryas) with an isochromosome for the long arm of the X.

A 5.5-yr-old female baboon was evaluated for sexual immaturity. She was small for her age and had normal external female genitalia. However, she lacked cyclical perineal turgescence and displayed atypical coloration of the perineal skin. Laparoscopy revealed a small uterus and absence of both ovaries. Cytogenetic analysis revealed a 42,X,i(X)(q10) karyotype. DNA analysis using loci DXS1683, which maps to Xp22.1, and DXS297, which maps to Xq27.3, was consistent with inheritance of the normal X chromosome from the dam and formation of the isochromosome Xq from the paternal X.

Endometrial biopsy during hormone replacement cycle in donor oocyte recipients before in vitro fertilization-embryo transfer.

OBJECTIVE: To examine the usefulness of a trial cycle of hormone replacement therapy (HRT) and endometrial biopsy before the actual ET cycle in recipients of donated oocytes. DESIGN: Retrospective review. SETTING: Clinical practice at the South Texas Fertility Center, San Antonio, Texas. PATIENT(S): Thirty-six concurrent patients who underwent a trial cycle of HRT with endometrial biopsy before the ET cycle with donated oocytes fertilized in vitro. INTERVENTION(S): Patients > or =40 years of age received 100 mg of i.m. progesterone in oil daily; patients <40 years of age received 50 mg daily. Endometrial biopsies were performed during the late luteal phase of the trial cycle. MAIN OUTCOME MEASURE(S): Histologic dating of the biopsy specimens was correlated with the chronologic date of the biopsy. RESULT(S): Five of 20 patients > or =40 years of age had out-of-phase biopsies. All 16 patients <40 years of age had in-phase biopsies. All out-of-phase biopsies subsequently were corrected with higher doses of progesterone. Pregnancy rates after fresh and frozen ETs were not significantly different between the two age groups. CONCLUSION(S): Patients > or =40 years of age are at risk of having out-of-phase endometrial biopsies while they are receiving standard HRT despite receiving higher doses of progesterone. Trial HRT cycles with endometrial biopsies are recommended.

Suppression of luteal phase, but not midcycle, prolactin levels by chronic follicular phase opiate antagonism.

OBJECTIVE: To investigate whether establishment and maintenance of chronic opioid blockade throughout the follicular phase of the menstrual cycle influences midcycle and luteal phase prolactin levels. DESIGN: Randomized, double-blind, crossover study. SETTING: Academic research environment. PATIENT(S): Volunteers, aged 21-35 years, with regular menstrual cycles. INTERVENTION(S): Naltrexone (50 mg) or placebo were administered on cycle days 2-14. Blood samples were obtained in the early follicular phase and in the periovulatory and midluteal phases of the menstrual cycle. MAIN OUTCOME MEASURE(S): Serum prolactin levels. RESULT(S): In the early follicular phase, serum prolactin levels were equivalent in naltrexone (12.0 +/- 2.7 microgram/L; mean +/- SE) and placebo (12.1 +/- 2.9 micrograms/L) cycles. A statistically significant increase in serum prolactin was observed on the day of the LH surge (naltrexone: 22.6 +/- 3.7 micrograms/L; placebo: 21.7 +/- 2.7 micrograms/L; P < 0.05 versus early follicular phase), but no difference between treatments was observed. However, midluteal prolactin levels were statistically significantly lower in naltrexone cycles compared with placebo cycles (12.6 +/- 3.3 versus 15.4 +/- 3.0 micrograms/L; P < 0.05). CONCLUSION(S): Chronic blockade of opioid activities during the follicular phase does not affect midcycle prolactin increments, but withdrawal of opioid blockade may enhance opioid effects on prolactin levels in the luteal phase.

Increase in androgen:estrogen ratio specifically during low-dose follicle-stimulating hormone therapy for polycystic ovary syndrome.

OBJECTIVES: To compare changes in serum androgens in women with polycystic ovary syndrome (PCOS) during ovulation induction with low-dose versus conventional urofollitropin. DESIGN: Prospective case-control study. SETTING: Tertiary-care reproductive medicine center. SUBJECTS: Thirty-three women with PCOS who failed to conceive with clomiphene citrate therapy. INTERVENTIONS: Urofollitropin (low-dose, 75 IU; conventional dose, 150 IU) was administered IM daily. Therapy was monitored by serum E2 and vaginal sonography. Hormone determinations were performed by immunoassay. MAIN OUTCOME MEASURES: Serum E2, androstenedione (A), T, and LH levels. RESULTS: On the day of hCG administration, patients treated with low-dose therapy exhibited significantly higher ratios of A to E2 (3.5 +/- 0.5 versus 2.2 +/- 0.3 [mean +/- SEM]) and T to E2 (1.5 +/- 0.3 versus 1.0 +/- 0.1) compared with conventional urofollitropin therapy. The number of follicles > or = 16 mm in diameter was significantly lower with low-dose therapy (2.7 +/- 0.6 versus 5.4 +/- 0.4). CONCLUSIONS: Although low-dose therapy was associated with a reduction in the number of recruited follicles, the increase in androgen to E2 associated with this therapy may adversely affect oocyte quality and may explain the relatively high miscarriage rate reported in PCOS patients with this therapy.

Association of serum beta-hCG levels with myosalpingeal invasion and viable trophoblast mass in tubal pregnancy.

OBJECTIVE: To test the hypothesis that myosalpingeal invasion and viable trophoblast mass are associated with serum beta-hCG levels in tubal-ampullary pregnancy. METHODS: Twenty-seven salpingectomy specimens of tubal-ampullary pregnancies were assessed for the presence or absence of myosalpingeal invasion. The mass of viable trophoblast was quantified in terms of the number of high-power fields (x400) occupied. The cases were stratified into three groups: small, less than one field; medium, one or two fields; and large, more than two fields and/or embryo present. Beta-hCG was measured before the procedure (mIU/mL, Third International Standard). RESULTS: The mean (+/- standard error of the mean) beta-hCG level for the nine cases exhibiting myosalpingeal invasion was significantly higher than for the 18 cases without invasion (13,665 +/- 2986 versus 2169 +/- 870 mIU/mL; P = .0001). Beta-hCG levels greater than or equal to 5400 mIU/mL predicted myosalpingeal invasion in eight of nine cases (positive predictive value 89%). In contrast, levels less than 5400 mIU/mL were associated with lack of myosalpingeal invasion in 17 of 18 cases (negative predictive value 94%). The volume of trophoblast mass correlated with both beta-hCG levels (r = 0.647, P = .0003) and myosalpingeal invasion (r = 0.735, P = .0001). There was no invasion in the 13 cases in the group with small trophoblast mass, whereas two of five cases in the medium-mass group displayed myosalpingeal invasion. In this group, the mean beta-hCG for cases with myosalpingeal invasion was higher than in the cases without invasion (16,917 +/- 117 versus 3799 +/- 1094 mIU/mL; P = .003). In the group with large trophoblast mass, seven of nine specimens showed myosalpingeal invasion. CONCLUSION: Both myosalpingeal invasion and viable trophoblast mass correlate positively with serum levels of beta-hCG. Myosalpingeal invasion is highly likely when beta-hCG levels reach 5400 mIU/mL.

Use of a gonadotropin releasing hormone agonist before vaginal surgery for cervical leiomyomas. A report of two cases.

Two cases of cervical myoma were treated with combined medical/surgical therapy using a gonadotropin releasing hormone agonist (GnRH-a) and transvaginal cervical myomectomy. Patients were treated with depot GnRH-a (leuprolide acetate) for two months followed by myomectomy. This approach allowed successful treatment with short hospitalization (< 24 hours). Potential benefits of this regimen include decreased intraoperative blood loss, outpatient management, decreased morbidity, decreased hospital expense and preservation of reproductive potential by avoiding hysterectomy.

Effects of chronic nocturnal opiate antagonism on the menstrual cycle.

OBJECTIVE: Opioids generally suppress gonadotropin secretion. We investigated whether chronic opiate antagonism would affect the occurrence or timing of menstrual cycle events. STUDY DESIGN: Opiate blockade was maintained in nine normal volunteers from cycle days 1 through 13 with naltrexone. A double-blind, placebo-controlled crossover design was used. Serum estradiol and progesterone were measured daily. Vaginal ultrasonography was performed daily beginning cycle day 10. Endometrial biopsies were performed 10 to 12 days after ovulation. Nonparametric paired data analysis was used. RESULTS: No significant differences in the following menstrual cycle parameters were detected between naltrexone and placebo cycles: cycle length (25.4 +/- 0.9 vs 25.7 +/- 0.5 days), maximum follicle size (21.5 +/- 1.0 vs 20.8 +/- 1.1 mm), peak serum progesterone (15.8 +/- 1.8 vs 15.2 +/- 2.2 ng/ml), or integrated serum progesterone (108.1 +/- 12.8 vs 101.2 +/- 14.6 ng/ml/day). Histologic endometrial development was normal in all subjects during naltrexone cycles. CONCLUSION: These data suggest that naltrexone-suppressible opioid activity does not play a significant role in the regulation of follicular events in normal women.

Short term treatment with leuprolide acetate is a successful adjunct to surgical therapy of leiomyomas of the uterus.

Gonadotropin releasing hormone analogs (GnRHa) have been used to induce a reduction in the size of leiomyomas of the uterus after three to six months of therapy. However, none of the studies have noted a significant decrease in size by the first month. Additionally, the results of two reports have suggested long term therapy with GnRHa induced significant aberrations of serum lipoproteins. To evaluate whether or not analog treatment for a short course (two months) would be efficacious, 27 patients with leiomyomas documented by examination of the pelvic area and vaginal ultrasound, who desired to preserve reproductive potential, had myomectomies two and one-half months after commencing depot leuprolide acetate therapy. The reduction in size of the uterus was 35 percent by the first month and the average reduction in the total volume was 44 percent after two months of treatment (474 +/- 364 to 265 +/- 173 milliliters; p less than 0.01). Furthermore, the size of the uterus, determined by examination, decreased significantly from 13.6 +/- 4.0 weeks initially to 10.1 +/- 3.0 weeks preoperatively (p less than 0.0001). Estradiol levels became menopausal by one month of therapy and remained suppressed preoperatively. Menopausal symptoms were well tolerated. Cholesterol, high density lipoprotein, extremely low density lipoprotein and triglyceride levels were not altered by analog treatment, although low density lipoprotein increased from 117 to 130 milligrams per deciliter. A short course of depot leuprolide acetate reduced the size of leiomyomas and surgical tissue planes were preserved, facilitating removal of leiomyomas, and furthermore, there was no significant clinical alteration in lipoprotein or triglyceride levels.

Embryo transfer to the uterus or the fallopian tube after in vitro fertilization yields similar results.

The outcome of ZIFT and IVF-ET was compared in consecutive nontubal factor patients in a prospective fashion. Groups did not differ in characteristics and were matched by the number of prezygotes/pre-embryos transferred. Overall, implantation, pregnancy, miscarriage, and ongoing PRs were not statistically different. These results suggest that ZIFT offers no significant advantage over IVF-ET for the treatment of nontubal infertility.

Sonographic appearance of the endometrium: the predictive value for the outcome of in-vitro fertilization in stimulated cycles.

We evaluated the predictive value for pregnancy of the endometrial thickness and pattern assessed by vaginal sonography on the day of human chorionic gonadotrophin (HCG) injection and the day of embryo transfer in 74 stimulated cycles for in-vitro fertilization (IVF) which were analysed prospectively. Thickness was measured from the echogenic interface of the endometrial-myometrium junction in transverse fundal sections. The distribution of endometrial pattern on the day of HCG was 19 A (poor quality) cases (25.7%) and 55 B (good quality) cases (74.3%). On the day of embryo transfer, 16 out of the 19 A cases (84%) remained as A pattern, while the remaining three cases (16%) had changed to B pattern; of the 55 B cases, 29 (53%) remained the same, while 26 cases (47%) changed to A pattern. There was no significant correlation between the endometrial pattern on the day of HCG and/or on the day of embryo transfer and the peak serum oestradiol levels, the number of preovulatory oocytes aspirated, the serum progesterone levels and oestradiol: progesterone ratio on the day of transfer. In contrast, on the day of HCG, endometrial thickness correlated with serum oestradiol levels on that day (P = 0.02). The presence of pattern A on the day of HCG was associated with a lower pregnancy rate [three out of 19 cases, (15.8%)], compared to pattern B [16 out of 55 cases, (29.1%)], although this was not statistically significant (P greater than 0.05). On the day of embryo transfer, comparable pregnancy rates between A pattern [11 out of 42 cases, (26.1%)] and B pattern [eight out of 32 cases, (25%)] were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Performance of cryopreserved pre-embryos obtained in in vitro fertilization cycles with or without a gonadotropin-releasing hormone agonist.

OBJECTIVE: To evaluate the viability and potential for pregnancy of cryopreserved/thawed pre-embryos obtained after ovarian stimulation using gonadotropin-releasing hormone agonist (GnRH-a) adjunct therapy. DESIGN: Retrospective clinical evaluation of all patients receiving a gonadotropin ovarian stimulation protocol (follicle-stimulating hormone/human menopausal gonadotropin [FSH/hMG]) with/without GnRH-a. SETTING: Academic tertiary clinical care unit. PATIENTS: Patients receiving leuprolide acetate (LA)/FSH/hMG (n = 136: LA in the luteal phase; long protocol) were compared with patients receiving FSH/hMG alone (n = 130) within the same time-frame in our program (April 1987 through October 1989). INTERVENTIONS: All patients had both a cycle in which pre-embryos were transferred fresh and a cycle of thaw of cryopreserved pre-embryos (frozen at the pronuclear stage in a slow freeze-thaw protocol using 1,2 propanediol) transferred in monitored natural cycles. MAIN OUTCOME MEASURES: Groups were similar in age, etiology of infertility, and cycle day 3 serum FSH levels; a significantly higher (P less than 0.001) number of preovulatory oocytes was recovered in the GnRH-a group. Both groups of patients were transferred an equal number of pre-embryos at the time of IVF. Cycles with frozen/thawed pre-embryos were evaluated based on the analysis of the three main variables that demonstrate cryopreservation efficiency: survival rate, implantation rate, and term pregnancy rate (PR). RESULTS: Non-GnRH-a group (113 transfers): pre-embryo survival, 71.5%; PR/transfer, 24.7%; implantation rate, 16.0%; GnRH-a group (125 transfers): pre-embryo survival 71.6%; PR/transfer, 32.8%; implantation rate, 12.0% (no significant differences). CONCLUSIONS: The use of GnRH-a produced pre-embryos of equal aptitude for development after cryopreservation at the pronuclear stage when compared with a similar gonadotropin stimulation treatment without GnRH-a.

The gonadotropin-releasing hormone agonist stimulation test--a sensitive predictor of performance in the flare-up in vitro fertilization cycle.

OBJECTIVE: To evaluate the initial versus early pattern of estradiol (E2) change after administration of a gonadotropin-releasing hormone agonist (GnRH-a), i.e., the GnRH-a stimulation test versus E2 pattern, respectively, as predictors of ovarian response and pregnancy in in vitro fertilization (IVF) patients stimulated with a flare-up protocol. DESIGN: Prospective study in a consecutive group of patients. SETTING: Tertiary care, institutional setting. PATIENTS: Two hundred twenty-eight patients entered and completed the study. The only patients excluded from study were those anticipated to have polycystic ovarian disease, those with a single ovary, or those with an ovarian cyst(s). INTERVENTIONS: Patients were stimulated with a GnRH-a flare-up protocol beginning on menstrual day 2. MAIN OUTCOME: Evaluation of the GnRH-a stimulation test and the E2 pattern as predictors of the number of mature oocytes retrieved and pregnancy. RESULTS: The GnRH-a stimulation test but not the E2 pattern was predictive of the number of mature oocytes retrieved (r = 0.53, P less than 1 X 10(-5) and pregnancy (chi 2 = 8.5, P = 0.04). The E2 pattern was predictive of the duration and number of ampules of gonadotropin required for stimulation. CONCLUSION: The GnRH-a stimulation test is a sensitive predictor of performance in the flare-up IVF cycle.