A double blind study to evaluate the effect of methyldopa on menopausal vasomotor flushes.

Vasomotor flush (VMF) is the most consistent symptom associated with the menopause. Nonsteroidal agents such as clonidine have been demonstrated to decrease VMF. Anecdotal reports suggested that VMF were reduced in hypertensive women receiving methyldopa, which is also an alpha2-adrenergic agonist. This study describes a double-blind cross-over placebo-controlled study to evaluate the effect of methyldopa on VMF. Diary reports were made and serum LH and digital skin temperature were measured in 10 menopausal women with 30 or more VMF/week and serum FSH levels of 40 mIU/ml or greater. The frequency of VMF, LH pulse, and temperature elevation during a 5-h observation period and VMF per week based on diary reports were compared for the baseline and fourth week of therapy with methyldopa (250 mg, three times daily) and placebo therapy. The patients reported some amelioration of VMF (P less than or equal to 0.02) during drug therapy. Objectively, only the frequency of LH peaks was decreased with methyldopa therapy (P less than or equal to 0.05). Because of significant side effects and minimal symptomatic improvement, methyldopa is not likely to be an acceptable therapy for VMF.

Peritoneal macrophages modulate human granulosa-luteal cell progesterone production.

Macrophages have been identified in the developing corpus luteum in several species, including man, and also constitute approximately 90% of cells in the peritoneal cavity. We studied the effect of peritoneal macrophages or blood monocytes on progesterone (P) synthesis by human granulosa cells from preovulatory follicles obtained at laparoscopy of 14 women undergoing in vitro fertilization. Pooled granulosa cells from follicles with mature ova were isolated by Ficoll-Hypaque gradient centrifugation. Washed granulosa cells (0.75 X 10(5)/ml) were incubated in Dulbecco's Minimum Essential Medium containing 20% calf serum with varying concentrations of pelvic macrophages (0.8-29 X 10(5)/ml) or fresh and mature blood monocytes (0.25-2.5 X 10(5)/ml). P production was determined by RIA of medium at 24-h intervals for 24-48 h. In situ concentrations of pelvic macrophages from 8 patients with tubal infertility increased cumulative P production to 140 +/- 17.8% (mean +/- SEM) of the control values. A similar increase (182 +/- 62.7%) was found with macrophages from 6 patients with endometriosis or unexplained infertility. Both fresh and mature monocytes stimulated P production to 225% and 261% of control values, respectively. Indomethacin (10(-4) M) or monoclonal antibody to somatomedin-C did not prevent stimulation of P production. These results suggest that peritoneal macrophages may exert luteotropic effects on cumulus cells while the ovulated oocyte resides in the tube, and incoming monocytes may be important in stimulating luteal cells in the developing corpus luteum.

Effects of neutralization of luteinizing hormone on corpus luteum function and cyclicity in Macaca fascicularis.

The primate corpus luteum (including the human) is thought to require continuous exposure to LH for normal progesterone production and menstrual cyclicity. Recently, normal luteal function was reported in rhesus monkeys after postovulatory hypophysectomy or treatment with an antagonist to GnRH. We studied the effects of neutralization of LH by specific antiserum in the fascicularis monkey. A potent antiserum to ovine LH, which cross-reacted with monkey pituitary extract, was produced in rabbits; this antiserum was administered daily to cycling monkeys during the midluteal phase. The pretreatment cycle duration was 32.4 +/- 1.7 (+/- SE) days, and luteal length was 16.5 +/- 0.8 days, with a midluteal progestin peak of 15.28 +/- 2.23 ng/ml. LH antiserum treatment resulted in a precipitous fall in serum progestin within 24 h, which remained low for the remainder of the cycle. All treated monkeys had premature menstrual bleeding, with mean cycle length shortened to 22.8 +/- 1.6 days (P less than 0.0005). These results confirm that the continuous presence of LH is essential for maintenance of corpus luteum function in this species of primate.

The effect of a low-dose oral contraceptive on serum testosterone levels in polycystic ovary disease.

A study was designed to determine the effect of a low-estrogen-dosage oral contraceptive on the serum concentration of testosterone-binding globulin (TBG) and total and unbound testosterone in patients with polycystic ovary disease (PCOD). Treatment with norethindrone 0.5 mg and ethinyl estradiol 0.035 mg (Modicon, Ortho) increased the TBG concentration and reduced the unbound serum testosterone concentration.

Clomiphene citrate therapy of infertile women with low luteal phase progesterone levels.

Sixty-nine infertile women with a midluteal serum progesterone level of 4 to 14 ng/ml were treated with a graduated dosage schedule of clomiphene citrate until the progesterone level on day 21 was greater than 20 ng/ml. Thirty-one pregnancies occurred, 58% during the first adequate treatment cycle and 19% during the second cycle. The abortion rate was 23%. After 6 adequate treatment cycles, laparoscopic evaluation was performed on 28 of 39 patients who did not conceive. Pathology was noted in 57%. Seven of 17 patients with intraperitoneal causes of infertility conceived after alternative therapy. The corrected pregnancy rate was 60%. Results of this study suggest that low luteal phase progesterone levels may compromise fertility and that clomiphene citrate enhances pregnancy rates.

Factors affecting the pregnancy rate in clomiphene citrate induction of ovulation.

During the five years ending on December 31, 1981, 159 anovulatory and oligomenorrheic patients were treated with clomiphene citrate for induction of ovulation. Overall, 86% of these patients ovulated, and 49% of the patients who ovulated conceived. Life table analysis was employed to investigate factors contributing to reduced conception rates, including abnormal semen analysis, pelvic or tubal abnormalities, and poor cervical mucus. Elevated serum testosterone levels did not affect conception rates. The most significant factor contributing to reduced overall pregnancy rates was patient discontinuation of therapy. Cumulative pregnancy rates corrected for discontinuation approach 100% after ten cycles of therapy. During this period, the monthly probability of pregnancy (monthly fecundability) remained constant. Optimal pregnancy rates are attained if other infertility factors are corrected and treatment is continued for ten to 12 ovulatory cycles.

Relationship of age and pubertal development to ovulation in adolescent girls.

A random sample of adolescent girls, 13 to 16 years of age, were surveyed with multiple serum progesterone determinations. The presence of ovulation was correlated with various indexes of pubertal development, including a pubertal developmental index that was devised using a summation of developmental factors. There was a significant correlation of ovulation with breast development, pubic hair development, and with the developmental index.

Adrenal cortical response to circumcision in the neonate.

A study was designed to document the responsiveness of the hypothalamic-pituitary-adrenal axis to the stress of circumcision during the first 6 hours of life. There was a rise in both serum cortisol and cortisone levels in all infants studied. The rise in cortisol was greater than the rise in cortisone in all infants.

Fertility rates in men with normal semen characteristics: spermatozoal testing by induction of the acrosome reaction and Wright-Giemsa staining for subtle abnormal forms.

Little is known about the fertility potential of semen from men who fulfill the accepted criteria of normal semen quality. We examined retrospectively the fertility rates of semen donors with normal semen quality. Donor performance was evaluated in women who had no known infertility factors or had only ovulatory dysfunction corrected by clomiphene. Cycles of therapeutic donor insemination were monitored for ovulation, and pregnancy outcome was followed up. Pregnancy resulted from therapeutic donor insemination with 21 donors and did not result in pregnancy with five (the range of the percentage of cycles in which pregnancy occurred was zero to 31). The comparison of donor semen analysis characteristics with pregnancy rates indicated that the total number of motile spermatozoa per ejaculate correlated with pregnancy rate (P = .04). Cox proportional hazard regression analysis showed that when the value for percentage of abnormal forms was combined with the total number of motile spermatozoa, a significant negative association was found between abnormal forms and conception (P = .04). Experiments comparing semen from high-fertility donors (top quartile of pregnancy rate) and low-fertility donors (lowest quartile) demonstrated a greater proportion of spermatozoa with inducible acrosome reactions in the high-fertility group (P less than .05). A Wright-Giemsa stain used to detect subtle abnormal forms in spermatozoa did not discriminate between the groups. These data suggest that differences in fertility potential exist among donors, even though all may exceed the accepted criteria for normal semen quality. Differences in the ability of spermatozoa to capacitate or undergo the acrosome reaction may be a mechanism for diminished fertility in donors with normal semen characteristics.

The effect of age on female fecundity.

To determine the relationship between age and female fecundity, 210 women were studied prospectively. The subjects had negative infertility evaluations and were receiving therapeutic donor insemination. Life-table analysis was performed on 751 donor insemination cycles. For comparison, patients were divided into five separate age groups and into two separate groups, ages 19-34 and 35-45. Monthly fecundity and cumulative conception rates were calculated for each group. A significant difference was found when all age groups were compared (P = .05) and when those at or above age 35 and those below age 35 were compared (P less than .05). Frozen semen was used in 92% of all cycles. The average monthly fecundity of all patients treated with frozen semen was 16%. This study confirms a progressive decline in fecundity with age in a completely evaluated group of women undergoing therapeutic donor insemination and demonstrates that frozen semen can yield acceptable fecundity provided sufficient numbers of motile sperm are used for each procedure.

Normalization of testosterone levels using a low estrogen-containing oral contraceptive in women with polycystic ovary syndrome.

Oral contraceptives reduce the elevated androgen levels in polycystic ovary disease. However, treatment with oral contraceptives is associated with undesirable side effects because of their high estrogen content. This study was undertaken to examine the effects of low estrogen-containing oral contraceptive (Loestrin:norethindrone acetate 1.5 mg and ethinyl estradiol 30 micrograms) on 25 women with polycystic ovary disease of ovarian origin. Loestrin treatment normalized the elevated luteinizing hormone and total and unbound testosterone levels and increased testosterone binding globulin levels. In a time-course study, unbound testosterone declined within a week of initiating treatment and by 12 to 16 weeks was completely normal. Reduction in hair growth and improvement in complexion were noted by about 12 to 16 weeks. Side effects of treatment were minimal.

Abnormal findings on hysterosalpingography: effects on fecundity in a donor insemination program using frozen semen.

OBJECTIVE: We sought to evaluate the effect of abnormal baseline hysterosalpingography (HSG) on subsequent fecundity during the first six cycles of treatment. METHODS: Hysterosalpingography was performed on 208 asymptomatic ovulatory women with no history of pelvic disease who were referred for donor insemination. The findings were categorized into five groups: 1) normal study, 2) uterine anomaly or filling defect with bilateral tubal patency, 3) normal uterine anatomy with unilateral tubal patency, 4) normal uterine anatomy with bilateral tubal blockage, and 5) normal uterine anatomy with hydrosalpinx. Subjects in groups 4 and 5 received inseminations only if patency of at least one fallopian tube was demonstrated with laparoscopy. Life-table analysis was performed to calculate the average monthly fecundity and cumulative conception rates for each group. The Mantel-Haenszel test was used to compare group fecundities. RESULTS: A total of 1460 donor insemination cycles were performed. The number of cycles in each group were as follows: group 1, 1173 (80%); group 2, 153 (10%); group 3, 90 (6.2%); group 4, 16 (1.1%); and group 5, 28 (1.9%). None of the patients in group 4 or 5 conceived. The cumulative conception rates in the first three groups were 46, 34, and 40%, respectively, and were not significantly different from one another (P greater than .05). Although a high incidence of uterine filling defects and unilateral tubal blockage was observed (19.2%), the incidence of an abnormal HSG finding that significantly decreased fecundity was only 2.8%. CONCLUSION: In women with no history of tubal or uterine disease, routine HSG before initiation of donor insemination is of limited value for identifying decreased treatment fecundity.

Amenorrhea-galactorrhea, hyperprolactinemia, and suprasellar pituitary enlargement as presenting features of primary hypothyroidism.

Two women who presented with amenorrhea-galactorrhea and hyperprolactinemia associated with x-ray evidence of pituitary enlargement and suprasellar extension were found to have primary hypothyroidism. Resolution of the pituitary enlargement and galactorrhea occurred after thyroid hormone replacement. Both women spontaneously ovulated and conceived, and normal pregnancies resulted. Amenorrhea, galactorrhea, and/or pituitary enlargement may be the principal manifestations of primary hypothyroidism. In such patients, it is imperative that primary hypothyroidism be excluded before drug or surgical therapy for presumed prolactinoma is undertaken. When these findings are due to primary hypothyroidism, thyroid hormone replacement alone is adequate therapy.

Retrograde menstruation in healthy women and in patients with endometriosis.

Blood was found in the peritoneal fluid in 90% of women with patent tubes at laparoscopy during perimenstrual time. If the fallopian tubes were occluded, then only 15% of patients had evidence of blood in the pelvis. Also, 90% of patients with endometriosis and eight of nine women on oral contraceptives had bloody fluid during the menstrual period. The present observations indicate that retrograde menstruation through the fallopian tubes into the peritoneal cavity is a very common physiologic event in all menstruating women with patent tubes.

Current management of a donor insemination program.

Substantial evidence now exists to show that considerable maternal-fetal morbidity may result from microbiologic transmitted diseases that can be transmitted through artificial insemination by donor. In the present decade it has become increasingly clear that the use of fresh semen is potentially hazardous and its use has been discouraged by both the CDC and AFS. To minimize this risk, donor insemination programs should establish their own guidelines to thoroughly evaluate potential semen donors via history, physical examination, and laboratory evaluation before the use of donor semen after cryopreservation and quarantine. The management of a donor insemination program in the future requires uniform procedures for rigorous genetic and microbiologic screening before the selection and use of semen donors for artificial insemination.

A case of severe ovarian hyperstimulation in a healthy oocyte donor.

OBJECTIVE: To report an unexpected case of severe ovarian hyperstimulation syndrome (OHSS) and to compare E2 levels and number of follicles to other oocyte donors. SETTING: Private assisted reproduction technology center. PATIENTS: Healthy oocyte donors with normal menstrual cyclicity. INTERVENTIONS: Prophylactic and therapeutic use of human serum albumin infusions. MAIN OUTCOME MEASURE: The clinical development of signs and symptoms of severe OHSS. RESULTS: More than 60% of other oocyte donors had higher E2 levels and 12% had higher number of follicles without associated OHSS. CONCLUSION: The risk of developing severe OHSS cannot be predicted accurately to be low even in the absence of "risk factors."

Effect of clomiphene citrate on corticosteroid-binding globulin and serum progesterone levels during ovulation induction.

Mid-luteal phase serum progesterone, cortisol, and corticosteroid-binding globulin concentrations were measured in 46 conception cycles and in 19 ovulatory, non-conception cycles in patients with spontaneous ovulation and following ovulation induction with clomiphene citrate (Clomid) or human menopausal gonadotropin. Significant elevations (P less than 0.05) of serum corticosteroid-binding globulin were noted in patients under therapy with Clomid. This effect was not secondary to elevated serum estrogen levels. This alteration in serum binding protein levels appears to be secondary to a direct effect of Clomid on hepatic synthesis and may have significance in relation to progesterone binding and metabolism during ovulation induction with Clomid.

The role of aerobic and anaerobic semen cultures in asymptomatic couples undergoing in vitro fertilization: effects on fertilization and pregnancy rates.

OBJECTIVE: To determine if routine semen culture is useful in asymptomatic couples undergoing in vitro fertilization and embryo transfer (IVF-ET). DESIGN: Prospective data collection. SETTING: All cultures and IVF cycles were performed at the University of North Carolina in Chapel Hill, North Carolina. PARTICIPANTS: All asymptomatic couples undergoing IVF-ET from January 1989 through January 1990. INTERVENTIONS: Aerobic and anaerobic cultures were performed on semen samples obtained before IVF. MAIN OUTCOME MEASURES: Quantitative semen cultures were evaluated for both aerobic and anaerobic bacterial isolates. Fertilization and pregnancy rates (PRs) were compared in patients with positive and negative semen cultures. RESULTS: Eighty percent of cultures contained at least one bacterial isolate. Three of the four most commonly isolated bacteria were normal skin flora. Positive culture results had no effect on either fertilization or PRs. CONCLUSIONS: Bacterial contamination is common with semen collection, yet routine semen cultures are not beneficial in asymptomatic couples undergoing IVF-ET.

A satellite system for assisted reproductive technologies: an evaluation.

The University of North Carolina at Chapel Hill (UNC) Satellite System for Assisted Reproductive Technologies (ART) was initiated in 1984, and now serves most of North Carolina and parts of two adjoining states. The system was established to enhance the care of infertile couples at the community level, to assure a sufficiently large volume of patients at UNC Hospitals to support appropriate quality control measures, and to allow couples undergoing ART to have most of their care in their own community. This paper reports an assessment of the outcome of this program. Neither pregnancy rates, nor any other measurable result of the program differed between patients managed in the satellites and those cared for at UNC Hospitals.

Transient hyperprolactinemia during cycle stimulation and its influence on oocyte retrieval and fertilization rates.

Prolactin (PRL) has been shown to have inhibitory effect on follicle-stimulating hormone induced aromatase activity and estrogen biosynthesis in human granulosa cells cultured in vitro. To investigate the validity of the hypothesis that transient hyperprolactinemia during controlled ovarian hyperstimulation might influence follicular steroidogenesis and oocyte maturation, we measured serum PRL, estradiol, and progesterone before aspiration of oocytes in women undergoing ovarian stimulation (n = 108) in in vitro fertilization-embryo transfer. No correlation was detected between PRL and total number oocytes, number mature oocytes, fertilization rate, cleavage rate, and pregnancy rate. Transient elevation of PRL was a common finding in patients (57%) but was not associated with a poor clinical outcome.