Hypothalamic pituitary gonadal axis dysregulation in depressed women.

In order to examine HPG axis regulation in women with major depression, luteinizing hormone (LH) pulsativity was studied in 26 depressed and 24 normal women. Blood was sampled every 10 min for an 8-h period during the first week of their menstrual cycle. LH pulsatile release was analyzed using the computerized cluster analysis algorithm of Veldhuis and Johnson and spectral analysis. Compared to control women, depressed women had slower frequency dysrhythmic LH pulsatility. These results are consistent with a previously published pilot study which reported results of the first 23 subjects [Am. J. Psychiat. 154 (1997) 1454].

Luteinizing hormone pulse characteristics in depressed women.

OBJECTIVE: Luteinizing hormone (LH) pulse characteristics in depressed and normal women were compared to determine whether hypothalamic dysregulation in depression extends to the hypothalamic-pituitary-gonadal axis. METHOD: The subjects were 10 depressed and 13 normal comparison women admitted to a clinical research center. For each woman, an intravenous line was started and blood was withdrawn every 10 minutes for 8 hours. Blood samples were assayed for LH and LH pulse characteristics determined by using the computerized cluster algorithm of Veldhuis and Johnson. RESULTS: The depressed women differed significantly from the comparison women in LH pulse amplitude, rhythmicity, and area under the curve. CONCLUSIONS: Major depressive disorder is associated with abnormal regulation of luteinizing hormone. Gonadotropin regulation may provide a hormonal link between major depressive disorder and impaired fertility.

Evaluation for antisperm antibodies after storage of sperm in TEST-yolk buffer.

OBJECTIVE: To determine if TEST-yolk buffer, consisting of TES (N-tris [hydroxymethyl]-methyl-2-aminoethanesufonic acid), Tris (Tris[hydroxymethyl]aninomethane), and chicken egg yolk, affects the presence of antisperm antibodies on the sperm surface as detected by the immunobead test. DESIGN: A prospective study of antisperm antibodies on sperm surface before and after incubation in TEST-yolk buffer. Direct immunobead test and indirect immunobead test were done the day of collection of the semen sample to detect the presence of human immunoglobulin class G (IgG) and immunoglobulin class A (IgA); immunobead tests were repeated on the same sperm samples after 24 hours of storage in TEST buffer. SETTING: Academic tertiary institution. PARTICIPANTS: Patients undergoing evaluation for infertility. RESULTS: There was no significant difference in the outcome of the direct immunobead test after extending semen samples with TEST-yolk buffer for 24 hours at 4 degrees C. Eleven samples that were initially negative for IgG and 13 samples that were negative for IgA remained negative after 24-hour storage in TEST-yolk buffer. Eleven samples that were positive for IgG and nine samples that were positive for IgA by the direct immunobead test the first day remained positive the next day. Five extended sperm samples used in the indirect immunobead test with IgG positive serum gave positive results and four of five used with IgA positive serum gave positive results. CONCLUSIONS: These findings suggest that TEST-yolk buffer can be used to extend semen without affecting the presence of antibodies on the sperm surface as indicated by the direct immunobead test. The higher variability of the indirect immunobead tests indicates there may be some alteration of sperm antigens after storing in TEST-yolk buffer. These findings indicate that TEST-yolk buffer can be used to store semen for batched processing of samples or as a transport medium for delivery to a central laboratory for antibody testing.

A comparison of 17 beta-hydroxysteroid oxidoreductase type 1 and type 2 activity of cytosol and microsomes from human term placenta, ovarian stroma and granulosa-luteal cells.

A large body of evidence suggests multiple forms of 17 beta-hydroxysteroid oxidoreductase (17-HOR) regulate estrogen and androgen levels within gonadal and peripheral tissues. Two kinetically-differing 17-HOR activities have been detected in placental homogenates. 17-HOR type 1, found mainly in the cytosol, is highly reactive with estradiol-17 beta (E2) and estrone (E1) but not testosterone (T) (high E2/T activity ratio). Microsomal 17-HOR type 2 is reactive with both E2 and T (low E2/T activity ratio). In this study, 17-HOR activity of cytosol and microsomes from term placenta, ovarian stroma and granulosa-luteal cells was assayed under conditions which specifically differentiate between the two forms of the enzyme. Placenta had the highest activity with either E2 or T in both cytosol and microsomes and stroma the lowest. The highest specific activity with E2 and E1 was cytosolic in all samples. The highest specific activity with T was microsomal in placenta and ovarian stroma. E2/E1 activity ratios were comparable for cytosol and microsomes while E2/T activity ratios were comparable for placenta and stroma, but markedly elevated in granulosa-luteal (G-L) cell cytosol and microsomes. The results indicate trophoblast and ovarian stroma have more 17-HOR type 2 relative to type 1. G-L cells, in contrast, are relatively enriched in 17-HOR type 1 and thus have a greater capacity for net conversion of E1 to E2 under physiologic conditions. These differences may contribute to increasing serum and follicular fluid E2/E1 ratios during development of the dominant follicle.

Increased ascitic fluid prorenin in the ovarian hyperstimulation syndrome.

Three patients developed severe ovarian hyperstimulation syndrome (OHS) as a complication of ovarian hyperstimulation for in vitro fertilization. These patients presented with ovarian enlargement, vascular volume depletion, pleural effusions, and exudative ascites. A unique feature of the ascites in OHS was the markedly elevated renin concentration, the majority of which was prorenin. We speculate the renin-angiotensin system (RAS) may play a pathophysiologic role in the localized capillary leak that develops in OHS.

Epidermal growth factor in human follicular fluid stimulates mouse oocyte maturation in vitro.

OBJECTIVE: To study the effect of human follicular fluid (FF) and the specific contribution of its epidermal growth factor (EGF) component on the in vitro maturation of cumulus-enclosed mouse oocytes. DESIGN: A previously described mouse oocyte model system was used to study the effect of FF on oocyte maturation before and after extraction of EGF by immunoprecipitation. Follicular fluid specimens enclosing both mature and immature human oocytes were tested. MAIN OUTCOME MEASURES: The endpoints assessed were the percentage of oocytes undergoing germinal vesicle breakdown (GVBD) and polar body one formation at different intervals over a 24-hour period and the final degree of cumulus expansion achieved. RESULTS: A concentration-related stimulatory effect of mature FF was noted when compared with the spontaneous increase of GVBD and polar body one formation observed for the EGF-free control medium. Overall, the effect of immature FF was inhibitory. After extraction of EGF from FF by immunoprecipitation from both immature and mature FF, the rates of GVBD and polar body one formation were decreased in both groups. The addition of 5 ng/mL of EGF to the extracted groups reversed this effect on polar body one formation. Cumulus expansion was maximal for oocytes incubated with mature FF and minimal for those incubated with EGF-free media. CONCLUSIONS: The positive effect of mature human FF on mouse oocyte maturation and cumulus expansion is to a large extent because of the presence of EGF.

Direct positive effect of epidermal growth factor on the cytoplasmic maturation of mouse and human oocytes.

OBJECTIVE: Immature mammalian oocytes cultured in vitro undergo inadequate cytoplasmic maturation and hence have a limited potential for fertilization. Our primary objective was to determine if the addition of epidermal growth factor (EGF) to the in vitro culture system would have a positive effect on oocyte cytoplasmic maturation. DESIGN: We studied the effect of different EGF concentrations on both denuded and cumulus-enclosed mouse oocytes cultured in vitro. MAIN OUTCOME MEASURES: The percentage of oocytes undergoing germinal vesicle breakdown (GVBD) and polar body one formation over time as a function of EGF concentration was determined. RESULTS: A dose-related positive effect of EGF on both GVBD and polar body one formation over time was observed for mouse oocytes. As well, a similar effect of EGF was seen on immature human oocytes that had not been stimulated with exogenous gonadotropins. CONCLUSIONS: The use of EGF may allow for the performance of successful in vitro fertilization procedures using immature human oocytes retrieved during unstimulated cycles.

Pregnancy-induced changes in prolactinomas as assessed with computed tomography.

Seven women with prolactin-secreting pituitary microadenomas and three with persistent hyperprolactinemia after surgical adenomectomies were evaluated with computed tomography to assess the effect of pregnancy on the volume of pituitary prolactinomas and hyperfunctioning pituitary tissue. In one patient a microadenoma enlarged to become a macroadenoma. Tumor enlargement occurred in the remaining six patients with microadenomas. None of the patients with previously resected adenomas exhibited hypertrophy of residual pituitary tissue or tumor recurrence after pregnancy.

Endometrial biopsies during treatment with subcutaneous pulsatile gonadotropin-releasing hormone and luteal-phase human chorionic gonadotropin.

A high incidence of luteal phase defect (LPD) has been reported using subcutaneous pulsatile gonadotropin-releasing hormone for induction of ovulation. We reviewed all patients treated with the combination of subcutaneous pulsatile gonadotropin-releasing hormone during the follicular phase and human chorionic gonadotropin during the luteal phase (GnRH-hCG) who underwent endometrial biopsy during a treatment cycle. All of these patients had biopsy-proven LPD which persisted despite traditional therapy with progesterone vaginal suppositories and/or clomiphene citrate. The mean number of biopsies out of phase per patient prior to GnRH-hCG treatment was 2.8 +/- 0.2 (+/- SEM). When treated with GnRH-hCG, 15/16 patients (94%) showed a normal endometrial biopsy. The probability of this result occurring by chance alone allowing for a 50% treatment independent correction rate is less than .001. These results show that the combination of subcutaneous pulsatile gonadotropin-releasing hormone and luteal-phase human chorionic gonadotropin can result in normal endometrial maturation in a high percentage of cycles when administered as described. It appears to be an effective alternative to traditional treatment modalities for luteal phase defect should one be needed.

Pregnancy following renal transplantation in class T diabetes mellitus.

Nine cases of pregnancy complicated by diabetes and prior renal transplantation are reviewed. Maternal and fetal death occurred in a patient with foot and leg ulcers associated with preexisting peripheral vascular disease. Pregnancy-induced hypertension occurred in six cases. Spontaneous weight-bearing fractures occurred in two patients. No episodes of renal allograft rejection occurred. Evidence of fetal compromise was present in six cases. All fetuses were delivered by cesarean section prior to term, with live births occurring from 31 1/2 to 36 weeks' gestation. A single case of hypospadias was the only congenital defect. Prepregnancy screening for complications of diabetes and renal transplantation is advised and euglycemia should be achieved before and during pregnancy. Advanced diabetic vascular disease puts these gestations at significant risk.

Alternative indications for pulsatile gonadotropin-releasing hormone therapy in infertile women.

Three groups of women with different types of ovulatory dysfunction who had failed to conceive on conventional therapy were treated with pulsatile gonadotropin-releasing hormone (GnRH). Group A consisted of nine patients with luteal phase defect; group B included four patients with apparently normal menstrual cycles but disordered folliculogenesis seen by serial ultrasound examinations; and group C consisted of eight patients who exhibited anovulation or irregular ovulation. GnRH was administered subcutaneously or intravenously in dosages varying from 5 micrograms to 20 micrograms, with pulse frequency of 2 to 3 hours in 53 cycles. Forty-one cycles were ovulatory. Four pregnancies resulted, one ending in miscarriage at 12 weeks' gestation. Our results indicate that GnRH may be used as an alternative to the prevalent therapeutic methods for ovulatory dysfunction. Only those women who had anovulation and abnormal basal levels of serum luteinizing hormone were resistant to GnRH therapy.

Intrauterine insemination: the University of Minnesota experience.

Forty-five patients initiated intrauterine insemination between October 1981 and August 1983. Indications for insemination included poor semen (count less than 20 X 10(6)/ml and/or motility less than 40%), poor cervical mucus, presence of sperm antibodies, unexplained poor postcoital tests, or various combinations of the above. During this time period, 374 inseminations were performed in 163 cycles and resulted in eight pregnancies in the 45 patients receiving artificial insemination by homologous donor, for an overall pregnancy rate of 17.4%. The fact that five of the pregnancies occurred in the first insemination cycle and two in the second cycle was felt to indicate a cause-and-effect relationship. A trial of intrauterine insemination in selected patients would appear to be warranted.

Estrogen replacement therapy.

The use of estrogen replacement therapy in postmenopausal women is under close scrutiny. The indications and side effects of replacement therapy are reviewed, and recommendations regarding its use are made. Hot flashes, atrophy of the vaginal epithelium, and prevention of osteoporosis have been established as indications for estrogen replacement therapy. Prevention of cardiovascular disease, aging changes of skin, and the occurrence of mental illness have also been suggested as indications, but beneficial effects of estrogen replacement therapy for these problems have not been clearly established. Studies have shown that side effects of estrogen replacement therapy include endometrial cancer, hypertension, gallbladder disease, and angina pectoris. Breast cancer may also be a risk factor, but a consensus of opinion has not been established. Pulmonary embolism, cerebral vascular accident, or myocardial infarction has not been associated with estrogen replacement therapy. The use of progesterone with estrogen replacement therapy has been shown to reduce the occurrence rate of endometrial carcinoma, but it does not prevent all the actions of estrogen. Oral administration of estrogen is the preferred route despite misgivings about portal absorption and liver metabolism. Further studies must examine this question. Various agents have been shown to be effective in treating some climacteric symptoms. These include progesterone for hot flashes and calcium for the prevention of osteoporosis. Other agents may also be effective but have not been tested critically.

Pregnancy and systemic lupus erythematosus.

Eleven patients with 18 pregnancies occurring during the course of systemic lupus erythematosus (SLE) were reviewed. Ten had long-standing lupus glomerulonephritis and a single patient developed glomerulonephritis during pregnancy. Patients were divided into those without (Group A) and those with (Group B) clinical evidence of renal disease or active SLE at conception. In Group A there were 10 pregnancies in five patients; all pregnancies were uncomplicated, except for mild superimposed pre-eclampsia in two, and all resulted in term delivery. Eight pregnancies in six patients occurred in Group B; four pregnancies were complicated by severe (2) or mild (1) superimposed pre-eclampsia and the onset of glomerulonephritis (1), resulting in three premature deliveries and a spontaneous abortion. The remaining four pregnancies were uncomplicated but resulted in one term delivery, one elective abortion, and two spontaneous abortions. None of the patients developed either renal failure or a rapidly progressive course following pregnancy.

The clitoral index: a bioassay of androgenic stimulation.

The glans clitoris is a target organ that is responsive to androgenic stimuli and enlarges throughout life. The size of the glans clitoris can be quantitated by determining the clitoral index (CI), which is the product of the sagittal and transverse diameters of the glans. Four hundred ten patients, ranging in age from 17 to 35 years, were examined. Ninety-five percent of 249 normal women had a CI less than 35 mm2. Of 85 patients with clitoromegaly (CI greater than 35 mm2) in addition to at least 1 other clinical sign of excess adrogenic stimulation, 53 (62%) had abnormally high values for either or both total serum testosterone and 17-ketosteroid levels. The CI is a useful bioassay for the clinical recognition of excess androgenic stimulation.

Serum 17beta-estradiol. Index of follicular maturation during gonadotropin therapy.

Thirteen patients with hypogonadotropic hypogonadism were treated with human menopausal gonadotropins (hMG) and human chorionic gonadotropin (hCG) to induce ovulation. Daily serum 17beta-estradiol (E2) assays were used to monitor the ovarian response to HMG. Apparent ovulation, documented by basal body temperatures, occurred in 41 of 53 hMG-hCG treatment cycles. Thirteen pregnancies occurred in 8 of the 13 patients. One twin pregnancy resulted. The hyperstimulation syndrome did not occur. Our data indicate that an optimal pregnancy rate with a minimum risk of hyperstimulation can be achieved when ovulation is induced 24 hours after the preovulatory serum E2 concentration has reached 500 to 900 pg/ml. Ovulation is induced by administering 10,000 IU and 5000 IU hCG on successive days. In addition, we now routinely give two or three injections of 2500 IU hCG at subsequent 3- to 4-day intervals to support the corpus luteum.

PIP: 13 patients with hypogonadotropic hypogonadism were treated with human menopausal gonadotropin (HMG) and human chorionic gonadotropin (HCG) to induce ovulation. Daily serum 17beta-estradiol (E2) assays were used to monitor the ovarian response to HMG. Apparent ovulation, documented by basal body temperatures, occurred in 41 of 53 HMG-HCG treatment cycles. 13 pregnancies occurred in 8 of the 13 patients. 1 twin pregnancy resulted. The hyperstimulation syndrome was absent. The data indicate that an optimal pregnancy rate with a minimum risk of hyperstimulation can be achieved when ovulation is induced 24 hours after the preovulatory serum E2 concentration has reached 500-900 pg/ml. Ovulation is induced by administering 10,000 IU and 5000 IU HCG on successive days. In addition, 2-3 injections of 2500 IU HCG at subsequent 3-4 day intervals to support the corpus luteum are given routinely.

Unconjugated estriol and 15alpha-hydroxyestriol in complicated pregnancies.

Simultaneous determinations of unconjugated estriol and 15alpha-hydroxyestriol (E4) levels in maternal serum were studied serially to ascertain the relative usefulness of these estrogens as indicators of fetal welfare. Complicated pregnancies included 16 patients with pre-eclampsia and/or hypertension, six patients with severe Rh-isoimmunization, 12 patients with diabetes mellitus, of which four had vascular disease, three patients with fetal death in utero, and three twin pregnancies. Retrospective analysis failed to indicate a clinically useful role for serum E4 determinations in the evaluation of fetal welfare during high-risk pregnancies.