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The effects of slight elevations in serum LH just before hCG administration on IVF cycle outcome were studied in 219 women undergoing retrieval. One hundred seven patients were stimulated using human menopausal gonadotropin (hMG), and 112 received clomiphene citrate and hMG. Serum LH, estradiol (E2), and progesterone concentrations were measured before and during controlled ovarian stimulation. Retrospectively the women were subdivided into three groups based on serum LH before hCG: Group I, less than 50% LH rise from baseline (BL) value (mean of day 2 and day 7); Group II, LH rise greater than or equal to 50% but less than 2 x BL; and, Group III, LH rise greater than or equal to 2 x BL. The fertilization and cleavage rates were similar in all groups. However, a greater than or equal to 50% rise in serum LH before hCG was associated with a significantly reduced IVF pregnancy rate.

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Steroid-secreting tumors of the testis have generally been considered to be of Leydig cell origin. Testicular tumors in patients with congenital adrenal hyperplasia have been thought to be adrenal rests, but no conclusive evidence supporting the hypothesis has been presented. We report a morphological and biochemical analysis of a patient with 21-hydroxylase deficiency who developed bilateral nodular hyperplasia of steroid-secreting tissue within the testis, despite suppression therapy with both exogenous glucocorticoids and testosterone. The tissue was formed of confluent nodules of homogenous cells. Electron microscopy showed the cells to have abundant smooth endoplasmic reticulum, well developed Golgi apparatus, and mitochondria with predominantly tubular cristae, features characteristic of steroid-secreting cells of adrenocortical origin. Crystals of Reinke were not observed. Functional studies in vivo showed a marked response to ACTH infusion, with 17-hydroxyprogesterone rising from 56 to 13,500 ng/mL, cortisol from less than 2 to 19 micrograms/dL, and testosterone from 369 to 629 ng/dL, with an attendant increase in testicular size and pain over 48 h. Receptor studies in vitro revealed no gonadotropin receptors, but abundant angiotensin-II receptors. Enzyme activity analysis in vitro showed undetectable 21-hydroxylase activity and an enzyme profile consistent with adrenocortical cells rather than Leydig cells. Based on these morphological and biochemical findings, we conclude that the nodular steroidogenic tissue that replaced this patient's testes was of adrenal origin. The study documents for the first time the development of adrenocortical tumors from adrenal rest tissue within the testis.

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The prolactin response to metoclopramide (MCP) was studied in 23 sexually immature males, 14 with isolated hypogonadotrophic hypogonadism (IHH) and nine with constitutional delayed puberty. Six of the 14 IHH patients had not been treated prior to our study, whereas eight had received long term therapy with testosterone or hCG for variable periods ranging from 1 to 20 years. We also measured the prolactin response to chlorpromazine (CPZ) in the untreated IHH men. In these untreated subjects, we observed a greatly diminished prolactin response after CPZ by comparison to that measured following MCP administration (peak 15 ng/ml, areas 86 units vs peak 43 ng/ml, area 416 units, respectively) (P less than 0.01). Furthermore, prolactin levels following MCP were similar in untreated (peak 43 ng/ml, area 416 units) and treated (peak 55 ng/ml, area 545 units, NS) IHH males as well as in boys with constitutional delayed puberty (peak 50 ng/ml, area 532 units, NS). In addition, responses in the three groups of patients were about half (P less than 0.01) those measured in normal men (peak 81 ng/ml, area 845 units). These data indicate that, unlike CPZ, MCP is not useful in distinguishing patients with hypogonadotrophic hypogonadism from boys with constitutional delayed puberty.

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The direct effect of prolactin on rat adrenal steroidogenic enzyme activity was evaluated by measuring plasma and adrenal cytosol steroid levels and adrenal microsomal 3B-hydroxysteroid dehydrogenase/isomerase (3B-HSD), 21 hydroxylase (21-OHase) and mitochondrial 11-hydroxylase (11-OHase) after in vivo administration of purified rat prolactin (rPRL) to adult, female Sprague-Dawley rats. Animals were ovariectomized, hypophysectomized and replaced with ACTH. Two days after surgery rPRL was administered i.p. at doses of 1.0, 10.0 and 100.0 micrograms (micrograms) every 4 hours for 5 days to experimental animals. Control rats received vehicle injections. All rats were sacrificed by decapitation and blood and adrenal glands collected. The adrenals were pooled into each rPRL dose group and mitochondria, microsomes and cytosol prepared from each pool. The activities of 3B-HSD, 21-OHase and 11-OHase were measured using as substrates 14C-dehydroepiandrosterone, 14C-progesterone and 14C-deoxycorticosterone, respectively. Plasma prolactin levels rose from 9.9 +/- 2.5 ng/ml in the control animals to 166.0 +/- 37.7 ng/ml (p less than 0.001) in the 100 micrograms rPRL dose group. Plasma corticosterone levels were not statistically different in the experimental groups when compared to controls. However, adrenal weight was increased in the high dose rPRL group (34.9 +/- 0.9 mg vs 41.9 +/- 1.2 mg, p less than 0.025). Hyperprolactinemia did not influence microsomal 3B-HSD or mitochondrial 11-OHase activities but was associated with a dose dependent decrease in microsomal 21-OHase activity when compared to controls (p less than 0.001). Adrenal cytosol progesterone levels increased with increasing rPRL dose consistent with a 21-OHase block during hyperprolactinemia. These data suggest that prolactin has a direct effect on rat adrenal 21-OHase in vivo.

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We compared the adrenal steroid responses after synthetic ACTH-(1-24) (Cosyntropin) administration given by either continuous iv infusion or bolus injection in 11 normal women and 6 normal men. Each subject received 250 micrograms Cosyntropin as a bolus iv injection on 1 occasion and as a continuous 2-h iv infusion on another occasion, in random order. There was a 1-week interval between the studies. We measured the plasma levels of cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, progesterone, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, delta 5-androstenediol, androstenedione, and testosterone by RIA 15 and 0 min before and 30, 45, 60, and 120 min after administering ACTH. The steroid concentrations and their increments, ratios, or areas above baseline did not differ significantly between the bolus injection and the continuous infusion. Thus, at the dose of 250 micrograms, a bolus ACTH injection stimulates adrenal steroid secretion as effectively as a 2-h continuous ACTH infusion.

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To investigate whether hyperprolactinemia directly affects rat testicular steroidogenesis, we examined the effects of prolactin (PRL) on microsomal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) 17-hydroxylase (17-OH), 17,20-desmolase (17,20-D), 17-ketosteroid reductase (17-KSR) and aromatase enzyme activities. Adult hypophysectomized, gonadotropin-treated Fisher rats were rendered hyperprolactinemic by isografting pituitaries under the kidney capsule. The controls received skeletal muscle. All rats were sacrificed 7 days later and serum PRL was measured in each animal. PRL levels were 198 +/- 14 ng/ml in the hyperprolactinemic rats and 4.3 +/- 0.6 ng/ml in the controls (P less than 0.001). The testes were resected, pooled according to PRL levels, and microsomes were prepared from each pool. The activities of the 3 beta-HSD, 17-OH, 17,20-D, 17-KSR and aromatase were measured using as substrates 14C dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone, androstenedione and testosterone, respectively. Hyperprolactinemia was associated with significant decreases in 3 beta-HSD, 17-OH, 17,20-D, 17-KSR and aromatase activities when compared to controls (P less than 0.005). We conclude that prolactin may have a direct effect on rat testicular steroidogenesis which appears to be independent of changes in gonadotropin secretion.

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To elucidate whether the luteinizing hormone-releasing hormone (LHRH) analog D-Trp6-Pro9-NEt-LHRH (LHRHa) decreases plasma testosterone levels in male primates solely by inhibiting gonadotropin secretion or, in addition, by inhibiting testicular testosterone biosynthesis, we have investigated the effects of this drug on 6 infant male rhesus monkeys. Three animals received LHRHa (12 micrograms . kg . day s.c., experimental group), and 3 animals received saline injections (control group) during the first 2 mo of life. Mean plasma testosterone was significantly lower in the experimental group compared to the control group (54 +/- 7 ng/dl vs. 501 +/- 52 ng/dl, P less than 0.001). The experimental group also had significantly lower mean follicle-stimulating hormone (FSH; 5.1 +/- 0.2 microgram/ml vs. 9.6 +/- 0.7 microgram/ml, P less than 0.001), and bioactive luteinizing hormone (LH; 2.0 +/- 0.08 microgram/ml vs. 3.5 +/- 0.2 microgram/ml, P less than 0.001). To study whether LHRHa influences testicular function directly, all animals were treated with human chorionic gonadotropin (hCG; 100 mIU . kg . day i.m.) for 28 days beginning at 8 mo of age. During Days 15 through 28 we administered LHRHa 12 micrograms . kg . day s.c. to the experimental animals and saline injections to the control group. Plasma testosterone increased to 5827 +/- 557 ng/dl in the experimental group and 4440 +/- 897 ng/dl in the control group after 14 days of hCG treatment. Plasma testosterone concentrations decreased in both groups of animals from Days 15 to 28 fo the study. All steroid intermediates were similar in both groups of animals on Days 14 and 28.(ABSTRACT TRUNCATED AT 250 WORDS)

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Hyperprolactinemia has been associated with several reproductive disorders. To investigate whether hyperprolactinemia directly affects rat ovarian function, we examined the ovarian histopathology and the activities of the four ovarian enzymes 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17-hydroxylase (17-OH), 17,20-desmolase (17,20-D) and aromatase in hyperprolactinemic rats and controls. Hypophysectomized, gonadotropin-treated Fisher rats were made hyperprolactinemic by isografting pituitary glands under the kidney capsule. The control animals received skeletal muscle. The ovaries were resected, pooled according to prolactin levels and microsomal enzyme activities were measured from each pool. Prolactin (PRL) levels were 344 +/- 23 ng/ml in the hyperprolactinemic rats and 18 +/- 5 ng/ml in the controls (p less than 0.001). Estradiol concentrations were 609 +/- 47 pg/ml in the hyperprolactinemic animals and 56 +/- 13 pg/ml in the controls (p less than 0.001). Ovarian and uterine weights were significantly higher in the hyperprolactinemic rats (p less than 0.02). Ovarian histopathology demonstrated benign polycystic transformation in the hyperprolactinemic animals. Hyperprolactinemia had no effect on 3 beta-HSD, but was associated with significant decreases in the 17-OH, 17,20-D and aromatase activities when compared to controls (p less than 0.001). We conclude that prolactin has a direct effect on rat ovarian function which appears to be independent of changes in gonadotropin secretion.

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Decreased sperm counts and impaired sperm motility are present in a substantial proportion of men with varicocele. Elevations in the temperature of the affected testis, and increased spermatic vein estradiol (E2) concentrations have been found in some of these patients. To investigate the possibility that increases in temperature lead to a pattern of testicular steroidogenesis that results in increased E2 synthesis, we have examined the effects of temperature changes on the activities of four important testicular steroidogenic enzymes. 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17-hydroxylase (17-OH), 17,20-desmolase (17,20-D) and aromatase activities were measured in the microsomal fraction of rat, pig and horse testes. Incubations were performed at 34 degrees C, 36 degrees C, and 38 degrees C. The activities of all 4 enzymes increased with each 2 degrees C temperature elevation in roughly proportional amounts. We conclude that minor elevations in incubation temperature are associated with increases in the in vitro activity of four key testicular steroidogenic enzymes.

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The luteinizing hormone releasing hormone analog D-Trp6-Pro9-Net-LHRH (LHRHa) inhibits rat testicular testosterone secretion. To determine whether LHRHa decreases serum testosterone concentrations solely by inhibiting gonadotropin secretion or, in addition, by influencing directly testicular testosterone biosynthesis, we examined the effects of LHRHa on the activities of 5 key testicular steroidogenic enzymes. Thirty hypophysectomized, hOG treated rats were given either LHRHa (1 micrograms sc/day) or saline during 7 days. The LHRHa treated animals exhibited a significant decrease of serum testosterone when compared to the control group (498 +/- 37 ng/dl vs 2044 +/- 105 ng/dl, mean +/- SEM, P less than 0.001). 17-Hydroxyprogesterone serum levels were also decreased in the LHRHa treated rats (61 +/- 6 ng/dl vs 93 +/- 7 ng/dl, P less than 0.005), while serum progesterone levels were similar in both groups of animals. These changes in steroid concentrations were associated with decreases in the microsomal enzyme activities of 17-hydroxylase (37 +/- 9 vs 654 +/- 41 pmol/mg protein/min, P less than 0.001), 17,20-desmolase (103 +/- 9 vs 522 +/- 47 pmol/mg protein/min, P less than 0.001), 3 beta-hydroxysteroid dehydrogenase (1.7 +/- 0.02 vs 4.1 +/- 0.1 nmol/mg protein/min, P less than 0.001), aromatase (95 +/- 7 vs 228 +/- 6 pmol/mg protein/min, P less than 0.001) and 17-ketosteroid reductase (167 +/- 9 vs 290 +/- 18 pmol/mg protein/min, P less than 0.01) in the LHRHa treated animals. These findings indicate that LHRHa can inhibit directly rat testicular testosterone biosynthesis.

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Osteogenesis imperfecta (OI) and Paget's disease of bone occurred in a patient whose brother has Paget's disease. Several other relatives have the dominant variety of OI. The familial occurrence of the two diseases is presumably due to chance and, to our knowledge, has not been previously reported. Examination of iliac crest bone biopsy specimens showed mild changes of both diseases in the proband. Electron microscopy of the bone collagen demonstrated type I collagen fibers, which are reduced in number, decreased in diameter, and stellate rather than smooth in outline. Three populations of collagen fibers were observed in the bone. The synthesis of type I collagen by dermal fibroblasts was diminished in the proband and affected relatives, but it was normal in the unaffected relatives. Since collagen fibers with a stellate outline have not been observed in OI bone, an intriguing question is the effect to the putative Paget agent (? viral) on collagen synthesis in OI.

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Testosterone biosynthesis by Leydig cells can be modulated by estradiol. This modulation appears to occur at the 17-hydroxylase and 17,20-desmolase stage. In this study we have examined the effects of estradiol and progesterone on the activities of the 17-hydroxylase (17-OH) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in rat ovarian tissue, to examine the hypothesis that estradiol may regulate these enzymes in the ovary as well as in the testis. Estradiol capsule implants produced a decrease in 17-OH activity (0.5 +/- 0.05 vs. 2.1 +/- 0.1 nmol/mg protein/min, mean +/- SEM, p less than 0.001), and an increase in 3 beta-HSD activity (15.5 +/- 0.9 vs 9.7 +/- 0.7 nmol/mg protein/min p less than 0.001). Progesterone injections produced a decrease in both 17-OH (0.9 +/- 0.1 vs. 2.3 +/- 0.2 p less than 0.005) and 3 beta-HSD (2.5 +/- .4 vs. 8.6 +/- 0.5; p less than 0.005) activities. We conclude that estradiol decreases 17-OH activity in the ovary as it does in the testis. This, coupled with an increase in 3 beta-HSD may explain the pre-ovulatory increase in progesterone seen in many species. Progesterone seems to decrease the steroidogenic activity of the ovarian tissue, perhaps offering an explanation for the gonadotropin resistance seen in corpus luteus bearing ovaries.

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We have correlated the concentrations of serum LH, estradiol and progesterone with the activities of 2 ovarian steroid biosynthetic enzymes during the rat estrous cycle. Ovarian 3 beta-hydroxysteroid dehydrogenase isomerase (3-beta HSD) activity decreased from 29 +/- 6 nmol/mg protein/min (mean +/- SEM) in diestrus, to 7 +/- 0.4 nmol/mg protein/min in late proestrus (p less than 0.005), and subsequently increased to 36 +/- 9 nmol/mg protein/min in metestrus (p less than 0.01). Ovarian 17-hydroxylase (17-OH) activity decreased from early to late proestrus (3.3 +/- 0.2 vs 2.2 +/- 0.2 nmol/mg protein/min, p less than 0.0025), and subsequently increased to 3.9 +/- 0.2 in metestrus (p less than 0.001). Serum LH, estradiol and progesterone peaked during proestrus, and reached a nadir during estrus. We conclude that the activities of 3-beta HSD and 17-OH in the rat ovary vary markedly during the estrous cycle. These changes may underlie the pattern of steroid secretion characteristic of this process.

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A 20-year experience with idiopathic retroperitoneal fibrosis (RPF) is presented (6 cases). Its gynecologic manifestations with the simulation of pelvic malignancy is discussed. Three of the patients presented with pelvic masses, one of these a para-vaginal mass. In one patient, RPF followed or was concurrent with invasive squamous cell carcinoma of the cervix, of which this is the first reported case. The subject of RPF is reviewed with the modes of management and evidence for an autoimmune etiology. Thrombocytopenia, a previously unreported finding with RPF, was noted in three of the six patients. The reversal of the A/G ratio in these patients is discussed, correlating this finding with the progression of azotemia.

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