The impact of subchronic hypercortisolemia on progesterone metabolism and the luteinizing hormone-progesterone axis in the cynomolgus monkey.

The purpose of the study was to assess the impact of subchronic hypercortisolemia on progesterone (P) metabolism and production and on peripheral LH levels in a nonhuman primate using a repeated measures experimental design. Osmotic pumps that released hydrocortisone phosphate (HP) at a dose of 15 mg/day were implanted sc in seven cynomolgus monkeys for two menstrual cycles. The pumps were filled with saline for the two control cycles, which either preceded (three animals) or followed (four animals) HP infusion. P metabolism, P production, and episodic secretion of LH were determined 8 +/- 1 days after the serum estradiol peak in the second control cycle and in the second cycle of HP infusion in each monkey, after iv bolus administration of 50 microCi [3H]P, followed by a 6-h blood sampling period. HP infusion elevated serum cortisol levels 1.6-fold. Serum P levels were decreased throughout the luteal phase by 58% (P < 0.01). The MCR of P and the volume of distribution at steady state of P were increased by 200% during HP infusion (both P < 0.005). The production rate of P was increased by HP treatment in five of seven monkeys. HP infusion increased the ratio of 20 alpha-[3H]dihydroprogesterone to [3H]P in serum from 0.5 to 1.0 (P < 0.05) while decreasing the fraction of [3H]P and its metabolites excreted in urine from 20% to 11% (P < 0.05). Serum LH levels, determined over a 5.25-h period in the luteal phase, were elevated by 200% during HP treatment (P < 0.05). Episodic secretion of LH during treatment was characterized by a 660% increase in the pulse amplitude (P < 0.05) and an apparent decrease in the pulse frequency. The results of this study provide evidence that moderate elevation of serum cortisol levels for two menstrual cycles in primates 1) increases the MCR of P, which may be the cause of the observed decrease in serum P levels; and 2) elevates serum LH levels by amplifying its pulse amplitude, which may result in a compensatory rise in the production rate of P.

Human follicular fluid insulin concentrations.

In mammals, insulin stimulates granulosa cell aromatase activity and steroid production and is a regulating factor of oocyte maturation. To assess the role of insulin in human follicular and oocyte maturation, human follicular fluid was obtained 32-36 h after hCG administration at the time of oocyte recovery for in vitro fertilization. Follicular fluid insulin levels, measured by RIA, ranged from undetectable (less than 2 microU/ml) to 65.4 microU/ml. In women treated with human menopausal gonadotropin (n = 21), clomiphene citrate (n = 4), and human menopausal gonadotropin/clomiphene citrate (n = 14), follicular fluid insulin concentrations were 18.0 +/- 4.3 (+/- SE), 10.2 +/- 4.2, and 12.0 +/- 3.8 microU/ml, respectively (P = NS). Similarly, there was no significant difference in follicular fluid insulin concentrations in follicles with mature (n = 33) or immature (n = 6) oocytes (13.3 +/- 2.7 vs. 24.7 +/- 9.5 microU/ml) or in oocytes which eventually did (n = 35) or did not (n = 4) fertilize (16.4 +/- 3.0 vs. 3.2 +/- 0.8 microU/ml). Follicular fluid insulin levels (n = 30) correlated positively with follicular fluid progesterone levels (P less than 0.05), but not with follicular fluid estradiol or androstenedione levels or the estradiol to androstenedione ratio. The relationship of follicular fluid insulin and progesterone levels suggests that, as in other mammals, follicular fluid insulin may have a physiological role in follicular maturation.

An attenuated form of congenital virilizing adrenal hyperplasia.

The families of two patients with hirsutism and oligomenorrhea were studied with iv ACTH (Cortrosyn) stimulation. The parents responded with a combined incremental rise of progesterone and 17-hydroxyprogesterone greater than 6.5 ng/dl.min, a response seen in the heterozygote parents of patients with congenital virilizing adrenal hyperplasia (CVAH). One sibling in one family responded as do heterozygous subjects, while two other siblings responded normally. The abnormal response of the two pairs of parents and the sibling along with the pattern of steroid secretion observed in the propositi suggest that the so-called adult-onset CVAH is a mild form of the homozygous state of CVAH.

Inhibitory effect of human follicular fluid upon the maturation of porcine oocytes in culture.

Human follicular fluid (hFFl) was harvested from follicles (5-15 mm) of human ovaries obtained at laparotomy. Addition of native hFFl, or a low molecular weight fraction of it, to the culture medium was found to inhibit the spontaneous maturation of cumulus-enclosed porcine oocytes. It was also found that hFFl inhibited progesterone secretion by the cumulus cells. The results extend earlier observations in other mammalian species, indicating that in the human, also, a specific oocyte maturation inhibitor is responsible for keeping the oocyte in meiotic arrest.

Gonadotropin output and response to LRH administration in congenital virilizing adrenal hyperplasia.

Three premenarchial, 2 primary amenorrheic, and 5 post-menarchial patients with congenital virilizing adrenal hyperplasia (CAH) were examined, utilizing frequent blood sampling techniques and the administration of synthetic luteinizing hormone-releasing hormone (LHRH) to determine whether a normal pattern of gonadotropin output occurs in CAH. Pulsatile gonadotropin output was not observed in premenarchial patients, but was seen in all who had had spontaneous menses. Bone age did not correlate with baseline or episodic gonadotropin output, or with response to LRH, but did reflect the past or present therapeutic control. The normal developmental progression of gonadotropin output was only documented in those patients who had been maintained at doses of suppressive glucocorticoids appropriate for body surface.

Gonadotropin output in congenital adrenal hyperplasia before and after adrenal suppression.

Basal release of gonadotropin and the response to an infusion of 100 mug of synthetic luteinizing hormone releasing hormone (LRH) were studied in a teenage girl with congenital adrenal hyperplasia (CAH). The initial study was done during a period of poor adrenal suppression, and second study was done after adequate adrenal suppression was achieved. To assess adrenal function, circulating levels of adrenal steroid hormones were evaluated continuously over a 24 h period. During the period increased production of adrenal androgens, the pattern of gonadotropin release was that of a prepubertal child. After 3 months of adrenal suppression the pattern of gonadotropin secretion was similar to that of a normal girl in mid-puberty. This demonstrates the rapid change from prepubertal to pubertal gonadotropin dynamics in a teenage patient following adequate suppression of androgens from the adrenal.

Body weight and amenorrhea.

Twenty-four women with primary and secondary amenorrhea were compared as to body weight, weight loss, estimated body fat content and loss, and history of failure to menstruate after discontinuing use of oral contraceptives. Simple weight loss is associated with menstrual dysfunction when over 30% of body fat is lost. Women using oral contraceptives who lose minor degrees of weight or body fat are at risk for the development of secondary amenorrhea.

Pulsatile gonadotropin output in menstrual dysfunction.

Patterns of gonadotorpin output were studied in normal individuals and in patients with menstrual dysfunction by radioimmunoassay measurement of LH and FSH output in samples taken every 20 minutes for 6-8 hours, and following administration of synthetic luteinizing hormone releasing hormone (LRH). Follicular phase LH pulses occurred every 1-2 hours, whereas those in the luteal phase occurred less frequently and with higher amplitude. FSH output was irregular, and had no correlation with LH dynamics. In anorixia nervosa, pulsatile LH activity was minimal, and the response to LRH variable, correlating somewhat with the clinical status of the patient. Pulsatile LH activity was observed in patients with postpill and postpartum amenorrhea, and also in one individual with a probable prolactin-producing pituitary tumor. Patients with polycystic ovarian disease had obvious LH pulsatile activity, with a greater amplitude and frequency than seen in the luteal phase, and a decrease in percentage increment, suggesting some difference in the hypothalamic-pituitary control mechanisms under these conditions. The character and pattern of the LH pulsatile activity does vary with different forms of menstrual dysfunction and may be predictive of the LRH response when considered in relation to the LH baseline values. Pulsatile LH activity, analyzed in conjunction with response patterns following LRH stimulation, may reflect the degree of hypothalamic dysfunction.

Effect of PGF2alpha in pseudopregnancy.

Eleven normal female volunteers received human chorionic gonadotropin (HCG) intramuscularly to induce a pseudopregnant state. Twenty-five milligrams of prostaglandin F2alpha (PGF2alpha) was administered intravenously at selected times during the luteal phase to demonstrate a luteolytic effect, or a local effect upon the endometrium producing early vaginal bleeding. Careful comparison of hormone levels and clinical details in these cycles showed that a) 1000 IU HCG daily does not consistently prolong the luteal phase; b) 2500 IU HCG daily does significantly prolong the luteal phase; c) HCG administration significantly increases progesterone and estradiol output in the treated luteal phase; d) prostaglandin administration at selected times during the luteal phase does not consistently decrease estradiol or progesterone output from the corpus luteum or induce early vaginal bleeding; e) prostaglandin F2alpha, a known stimulant of uterine contractility probably causes vaginal bleeding by mechanical means, as evidenced by show of menses in patients with progesterone levels elevated above normal; f) although variations in progesterone and estradiol output occurred during the hours of prostaglandin infusion, no consistent change was observed except for a compensatory rebound in progesterone output; g) prostaglandin F2alpha, in the dose utilized, is not a luteolytic agent.

Gonadotropin responses following luteinizing hormone releasing hormone administration in normal subjects.

Synthetic luteinizing hormone releasing hormone (LHRH), 100 mug, was administered intravenously to 29 normal individuals. In male subjects, both baseline and peak LH response values showed minimal variations between subjects. The FSH baseline and response were more variable. In normal females the FSH and LH baseline values and response to LHRH infusion showed greater variation than that seen in male subjects, and this variation correlated with the phase of the menstrual cycle. In perimenopausal women with elevated baseline gonadotropins, the absolute LH peak values were comparable to those seen during the periovulatory period of the menstrual cycle, while FSH baseline and peak values were unmistakably higher than those observed in the normally menstruating women. Three women under gonadotropic suppression by three different drugs were investigated; megestrol suppressed the LHRH response more effectively than either diethylstilbestrol or an oral contraceptive. The LHRH stimulation test reflects only the ability of the pituitary cell to release gonadotropins. In a normal individual, however, some justifiable assumptions can be made regarding the immediate past synthesis and release versus accumulation of pituitary LH.

Studies of pathophysiology in primary amenorrhea.

Patients with primary amenorrhea underwent stimulation with luteinizing hormone releasing hormone (LRH) before and after clomiphene administration to determine the maturational status of the hypothalamic-pituitary-gonadal axis, and to assess the development of feedback control mechanisms. Four patients with clinically recognizable conditions served as models. One patient had panhypopituitarism with undetectable baseline FSH and LH values, no response to LRH or clomiphene, and no detectable feedback control. One patient with a "specific" hypothalamic hypogonadotropism had low baseline gonadotropins with a normal response to LRH and no positive or negative feedback mechanisms reflected by no change in LRH response after clomiphene. A patient with delayed puberty due to low bodyweight had low FSH and LH baseline values and an "immature" response to clomiphene, characterized by lowered baseline gonadotropins and an increased peak LH following LRH stimulation. The fourth patient, with an adolescent polycystic ovarian syndrome, had a high baseline LH, normal FSH, hyperresponse to LRH, and a "mature feedback control" as evidenced by an increase in baseline FSH and LH, and a decrease in the LRH response while on clomiphene. The remaining patients showed inappropriate responses. They are regarded as having defects rather than dysfunctions, and the possible abnormalities are discussed in relation to the clinical findings.

Effect of clomiphene citrate on gonadotropin responses to LRH administration in secondary amenorrhea and oligomenorrhea.

Clomiphene citrate was administered to 17 patients with either secondary amenorrhea or oligomenorrhea to study its effect on hypothalamic-pituitary response. Measurement of pulsatile gonadotropin output was accomplished utilizing samples collected every 20 minutes for 6 to 8 hours before and after clomiphene administration. Response to 100 mug synthetic luteinizing hormone releasing hormone (LRH) was measured at the end of the sampling period. Patients with polycystic ovarian disease who ovulated showed increased baseline FSH and LH, decreased peak LH, and a decrease in the percentage increase over baseline for both LH and FSH. On patient wil clinical anorexia nervosa responded to clomiphene as an estrogen, with lowered baseline LH and FSH values. Patients with resolving anorexia responded to clomiphene as an antiestrogen, with increased baseline gonadotropins, and decreased gonadotropin peak values. A patient with a surgically treated chromophobe adenoma showed no change in parameters measured before and after clomiphene administration. Baseline and pulsatile LH output appear to reflect the tonic output of gonadotropin as affected by estrogen acting in a negative feedback system, and the peak response to LRH administration, the response to the positive feedback of estrogen. Thus, LRH stimulation in clomipheneresistent patients may be of value in diagnosing the site and degree of the defect and aid in improving therapy.

Pulsatile gonadotropin output and response to luteinizing hormone releasing hormone (LRH) in primary amenorrhea.

The pulsatile gonadotropin output and resonse to luteinizing hormone releasing hormone (LRH) administration was evaluated in 23 patients with primary amenorrhea. Pulsatile LH output and associated FSH pulses were readily observed in patients with hypergonadotropism. Responses in patients with congenital adrenal hyperplasia varied with the adequacy of the prior therapeutic management, which in turn apparently determined the maturational status of the individual. A patient with Kallmann's syndrome had both FSH and LH pulsatile activity. Patients thought to have simple delayed puberty had normal baseline gonadotropin values, and regular LH pulsations, but no correlation of FSH and LH pulsatile activity. Correlated analysis of LRH response and pulsatile gonadotropin activity may allow differentiation of individuals showing a normal progression of maturation from those with maturational dysfunction.

Diagnostic use of luteinizing hormone releasing hormone in primary amenorrhea.

Thirty-eight patients with primary amenorrhea were evaluated by the administration of luteinizing hormone releasing hormone (LHRH). The LHRH stimulation test was not helpful in differentiating those patients who will proceed to normal menses from those who will continue to have prolonged dysfunction. Similar responses were observed in patients with different pathology, which indicates that the LHRH test must be utilized in conjunction with a carefully planned evaluation if it is to be useful in differentiating a hypothalamic from a pituitary defect. The finding of a patient with hypergonadotropism by serum radioimmunoassay and negative gonadotropins by bioassay suggests that the radioimmunoassay may detect a biologically inactive molecule and indicates that both assays are essential in the evaluation of primary amenorrhea.

Gonadotropin response to luteinizing hormone releasing hormone administration in secondary amenorrhea and galactorrhea syndromes.

Luteinizing hormone releasing hormone (LHRH), 100 mug, was administered to 60 patients with secondary amenorrhea. No side effects or adverse reactions occurred. Delayed FSH and LH peak outputs were observed in patients receiving LHRH subcutaneously rather than intravenously, but responses were otherwise comparable. The majority of patients with secondary amenorrhea had responses which fell into the 95% confidence limits of responses for normal ovulating women. Responses of patients with different forms of dysfunction may be similar, and patients with similar pathology may respond quite differently. The LHRH stimulation test may assist in the diagnosis of particular hypothalamic, pituitary, or gonadal dysfunction, but it must be used clinically in the context of a carefully integrated study.

Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone.

The safety and efficacy of a daily combination of micronized estradiol (E2) (0.7-1.05 mg) and progesterone (200-300 mg) were evaluated in ten menopausal women with moderate to severe vasomotor symptoms and/or vaginal atrophy over a 12-month study interval. For comparison, five similar women were placed on conjugated estrogens, 0.625 mg daily, and medroxyprogesterone acetate, 10 mg daily, for the first 10 days of each calendar month for 12 months. Patients were evaluated at 0, 1, 3, 6, and 12 months. Estrogens rose significantly from baseline in both groups (P less than .01). Progesterone increased significantly above baseline in the E2 and progesterone group (P less than .01), but did not change in the conjugated estrogens and medroxyprogesterone acetate users. All women on E2 and progesterone had a decrease in total cholesterol and an increase in high-density lipoprotein cholesterol from baseline (P less than .01). Those on conjugated estrogens and medroxyprogesterone acetate had no significant change from baseline in total cholesterol; however, they did have an increase in high-density lipoprotein cholesterol values (P less than .01). In the E2 and progesterone group, the endometrial histology became completely quiescent and there was no uterine bleeding after 6 months of observation. Four of five women on conjugated estrogens and medroxyprogesterone acetate continued regular withdrawal bleeding throughout the study period, but no endometrial hyperplasia was encountered. This study demonstrates that the daily administration of a combination of micronized E2 and progesterone results in symptomatic improvement, minimal side effects, an improved lipid profile, and amenorrhea without endometrial proliferation or hyperplasia in menopausal women.

Comparison of late luteal phase endometrial biopsies using the Novak curette or PIPELLE endometrial suction curette.

The late luteal phase endometrial biopsy is an important part of the evaluation of patients with recurrent spontaneous abortion or infertility. The procedure can be painful and, if an adequate amount of tissue is not obtained, may have to be repeated. In this report, the results of endometrial biopsies performed in the late luteal phase with either the Novak curette or the PIPELLE Endometrial Suction Curette were analyzed retrospectively. The two techniques did not differ in the number of biopsy specimens found to have inadequate tissue for diagnosis; however, patients who underwent biopsy with the PIPELLE recalled significantly less pain associated with the procedure. When used in premenopausal patients undergoing endometrial biopsy during the late luteal phase, the PIPELE provided adequate tissue with preservation of glandular, stromal, and capsular architecture.

Complications of pregnancy in infertile couples: routine treatment versus assisted reproduction.

Ninety pregnancies conceived by infertile couples using assisted reproductive technologies and 86 pregnancies conceived by infertile couples with routine infertility treatment were analyzed to determine the outcome of and the complications experienced during the pregnancies. Pregnancies ending after 24 weeks' gestation were evaluated for the following complications: pregnancy-induced hypertension, diabetes mellitus, preterm labor, premature rupture of membranes, placenta previa, and fetal growth retardation. A matched control group of normal fertile patients admitted to the obstetric service at Vanderbilt University Medical Center was used to compare the incidence of pregnancy complications among the groups. In the group treated by assisted reproduction, 81 pregnancies were singleton and nine were multiple gestations, whereas in the routine group, 84 were singleton and two were multiple gestations. In the group treated by assisted reproduction, 29 of 90 gestations (32%) ended before 24 weeks, compared with 18 of 86 (21%) in the routine group, a nonsignificant difference. Mean birth weight and gestational age were similar among the three groups for singleton gestations. Among multiple gestations, the mean (+/- standard error of the mean [SEM]) birth weights were 2513 +/- 115, 724 +/- 57, and 2282 +/- 132 g in the group treated by assisted reproduction, the group receiving routine methods, and the control group, respectively (P less than .001 when those treated by routine methods were compared with the other two groups). The mean (+/- SEM) gestational ages were 36 +/- 1.2, 26.5 +/- 2.0, and 35.5 +/- 1.2 weeks, respectively (P less than .01 comparing those treated by routine methods and the other two groups).(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of follicular growth with "pure" FSH in patients with anovulation and elevated LH levels.

Ovarian follicular growth was stimulated in 4 patients with clomiphene resistant polycystic ovary (PCO)-like disease, with "pure" human pituitary FSH during 10 cycles. In 8 cycles additional hCG was given to induce ovulation. Serum LH and FSH and plasma estradiol and progesterone were determined daily. From the response patterns of steroidogenesis, four functional stages of follicular development can be distinguished, each subsequent stage being characterized by an increasing spontaneous estradiol production and a decreasing capacity to produce extra estradiol in response to stimulation with additional hCG. It is concluded that the unpredictable response to gonadotropin stimulation of patients with PCO-like disease is due to the varying state of development of the follicles at the start of the stimulation. The suggestion is made, based on the different responses in 3 cycles of the same patient (EW), that the lack of positive estrogen feedback in patients with PCO-like disease may be a hyposensitivity to estrogens rather than an absolute insensitivity.

Salpingitis or oophoritis: what causes fever following oocyte aspiration and embryo transfer?

BACKGROUND: Febrile morbidity following in vitro fertilization and embryo transfer (IVF-ET) is a rare but possibly serious complication. This report describes a case of salpingitis after IVF-ET and discusses the possible reasons for febrile morbidity following this common procedure. CASE: A 37-year-old woman undergoing IVF-ET for tubal factor infertility developed sudden, severe pelvic pain, fever, and leukocytosis 24 hours after ET. Laparoscopy revealed bilateral suppurative pyosalpinges with cystic, hemorrhagic ovaries. Pain, fever, and leukocytosis resolved with conservative surgery and intravenous antibiotic therapy. CONCLUSIONS: This case presents laparoscopic documentation of a rare complication of oocyte aspiration and/or ET, namely, salpingitis. Possibilities for the development of salpingitis following IVF-ET include activation of quiescent bacteria within the fallopian tubes from a previous pelvic infection, puncture of the bowel during oocyte aspiration, inoculation of the pelvis with cervicovaginal flora during oocyte aspiration, and introduction of bacteria-laden secretions or air into the fallopian tubes during ET. Although rare, the possibility of severe pelvic infection following IVF-ET warrants consideration of prophylactic antibiotic coverage.