Elevated Serum Luteinizing Hormone Levels Research Articles

Adult-type granulosa cell tumor associated with elevated luteinizing hormone: Two rare case reports.

Adult-type granulosa cell tumors (AGCTs), which account for 2% to 5% of all malignant ovarian tumors, are rare sex cord-stromal tumors that usually secrete excess estrogens, but they can also secrete androgens. We report 2 patients of childbearing age with AGCT who presented with the complaint of abnormal menstruation and elevated luteinizing hormone (LH), and mildly elevated testosterone. The ovarian tumors had hormonal activity. The 2 patients underwent laparoscopic left adnexectomy. The second patient underwent 4 cycles of chemotherapy with paclitaxel and carboplatin as adjuvant treatments. Their postoperative pathology confirmed AGCTs. Also, their menstrual cycle returned to normal, with normal serum LH and testosterone levels. There was no sign of recurrence. The cases suggest that elevated serum LH levels may be a sign of unknown tumors in cases of oligomenorrhea or secondary amenorrhea. It is useful to evaluate the serum levels of inhibin B and anti-Müllerian hormone to improve the early recognition of ovarian granulosa cell tumors.

Heme oxygenase 2 genetic variants alter hormonal and metabolic traits in polycystic ovary syndrome.

Oxidative stress and metabolic disorders are involved in the pathogenesis of polycystic ovary syndrome (PCOS). Heme oxygenase 2 (HMOX2) plays a critical role in preserving heme metabolism as well as in modulating glycolipid metabolism, oxidative stress, and inflammation. This study examined the correlation between HMOX2 G554A (rs1051308) and A-42G (rs2270363) genetic variants with the risk of PCOS and assessed the effects of these genotypes on clinical, hormonal, metabolic, and oxidative stress indices using a case-control design that included 1014 patients with PCOS and 806 control participants. We found that the allelic and genotypic frequencies of the HMOX2 G554A and A-42G polymorphisms were comparable between the PCOS and control groups in Chinese women (P > 0.05). Nevertheless, it was discovered that patients with the AA or AG genotype of A-42G polymorphism had notably elevated levels of estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH/FSH ratio, high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (apo)B, and/or apoB/apoA1 ratio than those with the GG genotypes (P < 0.05). Patients with the GG or AG genotype of G554A polymorphism had elevated serum levels of LH, FSH, E2, LH/FSH ratio, TC, HDL-C, LDL-C, apoB, and/or apoB/apoA1 ratio and lower 2-h glucose concentration compared with those with the AA genotype (P < 0.05). Our findings indicate a potential association between the genetic variants and endocrine abnormalities in the reproductive system and metabolic irregularities in glycolipid levels in patients, thus suggesting their potential role in the pathogenesis of PCOS.

Associations of Serum Follicle-Stimulating Hormone and Luteinizing Hormone Levels with Fat and Lean Mass during Menopausal Transition

Introduction: The association of serum follicle-stimulating hormone (FSH) levels with body fat mass remains inconclusive. Furthermore, little was known about the association of luteinizing hormone (LH) with body fat. This study aimed to investigate the associations of serum FSH and LH levels with fat and lean mass in women during menopausal transition. Methods: The data analyzed in this study were derived from the National Health and Nutrition Examination Survey from 1999 to 2002. Women aged from 35 to 60 years were eligible. Serum FSH and LH levels were assayed using the microparticle enzyme immunoassay technology. A dual energy X-ray absorptiometry was used to measure body fat mass and lean mass. Fat mass index (FMI) and fat-free mass index (FFMI) were respectively used to assess fat and lean mass. General linear regression was employed to examine the associations of serum FSH and LH levels with FMI and FFMI. Results: This study included 1,329 women. For the total participants, elevated serum FSH and LH levels were associated with an increased FMI (β = 0.004 and 0.007; 95% CI: 0.002, 0.006 and 0.004, 0.010, respectively) and a decreased FFMI (β = −0.004 and −0.007; 95% CI: −0.006, −0.002 and −0.010, −0.004, respectively). Furthermore, the significant associations of serum FSH and LH levels with FMI and FFMI were fully observed in postmenopausal women, especially in a certain range of higher serum FSH and LH quartiles. Conclusion: Elevated serum FSH and LH levels were associated with increased body fat mass but decreased lean mass in postmenopausal women but not in premenopausal women. Furthermore, only higher serum FSH and LH percentiles were associated with fat and lean mass in postmenopausal women.

P-607 Basal serum luteinizing hormone and total testosterone levels do not impact the outcomes of in-vitro fertilization in women with polycystic ovarian syndrome (PCOS)

Abstract Study question Do basal serum luteinizing hormone (LH) and total testosterone (TT) levels affect the outcomes of patients with PCOS undergoing in vitro fertilization? Summary answer LH and TT does not impact number of mature oocytes, fertilization rates, and high-quality blastocysts frozen, in PCOS with GnRH-antagonist protocol IVF with hyper-responses. What is known already The impact of basal serum LH and TT levels on IVF outcomes is debatable. Worldwide, there are many clinics that will postpone ovarian stimulation until a lower basal LH or TT is obtained in women with PCOS based on the assumption that outcomes will subsequently be more successful. However, hormones are released in a pulsatile fashion and single levels are unlikely to reflect patient status. There is a paucity of research addressing this concern. Study design, size, duration We completed a single university-centre retrospective cohort study comparing the outcomes of PCOS patients undergoing freeze-all GnRH antagonist IVF cycles divided into 50% groupings for basal serum LH and TT levels between the dates of January, 2013 and December, 2019. There were 76 women identified and confirmed on chart review to have a diagnosis of PCOS per the 2003 Rotterdam criteria. Participants/materials, setting, methods Patients were divided into the 50% with the lowest LH levels(1.0-7.0 IU/L) and highest LH(7.1-29.0 IU/L). The same was done for TT(0.30-1.50 vs. 1.6-5.6 nmol/L). These two groups were compared using chi-square test and t-test as indicated. Demographics included: serum estradiol, follicle stimulating hormone, thyroid stimulating hormone, prolactin, TT, free testosterone, gravida, parity, female age, male age, semen analysis parameters, antral follicle count, and duration of infertility. IRB approval was obtained(2020-5971). Data is X±SD. Main results and the role of chance When assessing based on LH, there were no differences in demographics(P &amp;gt; 0.05 in all cases) except for TT(1.4±1.0 vs. 1.9±0.9 nmol/L-p=0.02) and free-testosterone(0.6±0.5 vs. 0.9±0.5 nmol/L-p=0.03). The number of oocytes collected(26.8±7.4 vs. 27.3±9.6-p=0.82), mature oocytes(19.9± 6.8 vs. 20.2±7.8-p=0.88), and frozen high-quality blastocysts(7.0±4.4 vs. 8.2±5.1-p=0.25) were similar. The percent of MII that fertilized(75%±16 vs. 74%±19-p=0.78), the percent of 2PN that grew to blastocysts(47%±23 vs. 55%±27-p=0.18) and the percent of MII that grew to blastocyst(35%±18 vs. 40%±19-p=0.25) were similar. Among subjects who underwent embryo transfer, clinical pregnancy rates(33% vs. 45%-p=0.36) and live birth rates(22% vs 32%-p=0.39) were similar when comparing lowest vs. highest percentile, respectively. When comparing demographics by TT grouping, differences were previous pregnancies(0.9±1.2 vs. 0.3±0.7-p=0.02), serum TSH(1.66±0.96 vs. 2.43±1.90 nmol/L-p=0.04), and duration of infertility(2.3±2.0 vs 3.7±2.7years-p=0.04). The number of oocytes collected(27.5±7.5 vs. 28.3±9.7-p=0.73), MII oocytes(20.5±6.9 vs. 20.4±8.3-p=0.98), and frozen high-quality blastocysts(6.9±4.0 vs. 8.1±5.7-p=0.32) were similar. The percent of MII that fertilized(73%±19 vs. 74%±17-p=0.96), the percent of 2PN that grew into blastocysts(48%±23 vs. 53%±28-p=0.50) and the percent of MII that grew to blastocyst(34%±17 vs. 38%±19-p=0.36) were similar. Among subjects undergoing embryo transfer, clinical pregnancy rates(46% vs. 44%-p=0.90) and live birth rates(38% vs 26%-p=0.33) were similar when comparing lowest vs. highest percentile respectively. Limitations, reasons for caution Our study was limited to GnRH-antagonist cycles with freeze all embryos. Thus, findings may not be applicable to IVF cycles with fresh embryo transfer. It is a retrospective study and therefore is at risk for inherent biases. Wider implications of the findings Our findings provide reassurance that elevated basal serum LH and TT levels do not impact IVF outcomes in hyper-responding patients and therefore should not result in cycle cancellation or delay in those with PCOS undergoing GnRH-antagonist cycles with anticipated hyper-responses. Trial registration number N/A

Animal models of polycystic ovary syndrome: A review of hormone-induced rodent models focused on hypothalamus-pituitary-ovary axis and neuropeptides.

BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age and a major cause of infertility; however, the pathophysiology of this syndrome is not fully understood. This can be addressed using appropriate animal models of PCOS. In this review, we describe rodent models of hormone‐induced PCOS that focus on the perturbation of the hypothalamic‐pituitary‐ovary (HPO) axis and abnormalities in neuropeptide levels.MethodsComparison of rodent models of hormone‐induced PCOS.Main findingsThe main method used to generate rodent models of PCOS was subcutaneous injection or implantation of androgens, estrogens, antiprogestin, or aromatase inhibitor. Androgens were administered to animals pre‐ or postnatally. Alterations in the levels of kisspeptin and related molecules have been reported in these models.ConclusionThe most appropriate model for the research objective and hypothesis should be established. Dysregulation of the HPO axis followed by elevated serum luteinizing hormone levels, hyperandrogenism, and metabolic disturbance contribute to the complex etiology of PCOS. These phenotypes of the human disease are recapitulated in hormone‐induced PCOS models. Thus, evidence from animal models can help to clarify the pathophysiology of PCOS.

The Non‐Peptide Vasopressin V1b Receptor Antagonist, SSR149415, Ameliorates Spermatogenesis Function in a Mouse Model of Chronic Social Defeat Stress

To determine the effects of SSR149415 on testis and spermatogenesis in male mice subjected to chronic social defeat stress, C57BL/6 male mice were divided into two groups: Control and Stress. Then Stress group was subdivided into four subgroups administered water, SSR149415 (1 mg/kg/day), SSR149415 (10 mg/kg/day), SSR149415 (30 mg/kg/day), respectively. The behavioral alterations revealed by social interaction test and open field test were measured. The physical indices, including body weight and gonad weight (testis and epididymis) as well as testis/body weight and cauda epididymis/body weight were detected. Serum hormones, including testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were determined. Sperm count and abnormality as well as testicular histology structure were assessed. The germ cells apoptosis were also evaluated. Chronic social defeat stress-induced behavioral abnormality, as well as gonad atrophy (testis and epididymis) was significantly alleviated in stressed male mice exposed to SSR149415. Regressed serum testosterone levels and elevated serum FSH and LH levels exhibited by stressed male mice were observably reversed following SSR149415 administration. Chronic social defeat stress-induced damage in testicular histology structure and semen quality were also improved after SSR149415 administration. In addition, SSR149415 significantly reversed chronic social defeat stress-induced germ cells apoptosis. Overall, we provide clear evidence indicating the amelioration of chronic social defeat stress-induced behavioral abnormality and testicular dysfunction via SSR149415, promoting the development of drug-directed therapy against this disease. J. Cell. Biochem. 118: 3891-3898, 2017. © 2017 Wiley Periodicals, Inc.

The Pleiotropic Effects of Excessive Luteinizing Hormone Secretion in Transgenic Mice

Luteinizing hormone (LH) is member of the glycoprotein hormone family of gonadotropins, which also includes the highly related human chorionic gonadotropin and follicle-stimulating hormone. The necessity of these factors for sustaining human fertility has been known for decades. In addition, elevated serum levels of LH have been associated with polycystic ovarian syndrome, suggesting that the appropriate balance of LH is critical for maintaining reproductive function. To dissect the biological consequences of aberrant LH signaling in vivo, several genetically engineered mouse models have been developed that overexpress LH or have increased LH signaling. These models underscore the importance of tightly regulated LH levels for normal reproductive function, and reveal novel roles for LH and gonadal hormones in tumorigenesis of multiple tissues, including the ovary, mammary gland, and pituitary. Thus, mice with altered LH signaling provide valuable tools in understanding normal reproduction and various pathological conditions.

Granulosa cell tumor associated with secondary amenorrhea and serum luteinizing hormone elevation

Adult granulosa cell tumors (GCTs) are the most common type of ovarian sex cord tumors. Menstrual irregularity, menorrhagia, or even secondary amenorrhea is frequently observed in premenopausal women bearing GCTs with hormonal activity. We report herein a case of GCT in a patient presenting with secondary amenorrhea and serum luteinizing hormone elevation. A 28-year-old primigravid Japanese woman was admitted complaining of secondary amenorrhea of 2 years' duration. Pelvic examination, transvaginal ultrasonography, and magnetic resonance imaging demonstrated a left ovarian tumor 4 cm in diameter. Serum hormone assays revealed a follicle-stimulating hormone level of 4.8 mIU/ml, luteinizing hormone (LH) of 35.8 mIU/ml, estradiol of 24 pg/ml, progesterone of 1.6 ng/ml, and testosterone of 40 ng/dl. A left salpingo-oophorectomy was performed. The tumor was diagnosed as an adult-type GCT stage IIb (FIGO [International Federation of Obstetricians and Gynecologists], 1988). Spontaneous menstruation occurred soon after the surgery. Serum levels of LH also decreased to normal levels and showed cyclic changes during the menstrual cycle. Subsequently, the patient conceived and delivered a healthy female baby. The tumor recurred in the pelvis 50 months after the initial conservative surgery, with elevated serum LH levels of 36.0 mIU/ml and amenorrhea. The patient was treated by hysterectomy, right salpingo-oophorectomy, omentectomy, paraaortic and pelvic lymphadenectomy, and low anterior resection of the recto-sigmoid colon. Her hormone levels progressed to the postmenopausal state after this surgery. Although LH elevation in patients with GCT is rare and its mechanism is unknown, monitoring of serum LH may provide an additional tumor marker after conservative surgery in such patients.

Manganese Acts Centrally to Stimulate Luteinizing Hormone Secretion: A Potential Influence on Female Pubertal Development

Manganese (Mn), an essential element considered important for normal growth and reproduction, has been shown in adults to be detrimental to reproductive function when elevated. Because Mn can cross the blood-brain barrier and accumulate in the hypothalamus, and because it has been suggested that infants and children are potentially more sensitive to Mn than adults, we wanted to determine the effects of Mn exposure on puberty-related hormones and the onset of female puberty. We demonstrated that MnCl(2) when administered acutely into the third ventricle of the brain acts dose-dependently to stimulate luteinizing hormone (LH) release in prepubertal female rats. Incubation of hypothalami in vitro showed that this effect was due to a Mn-induced stimulation of luteinizing hormone releasing hormone (LHRH). Further demonstration that this is a hypothalamic site of action was shown by in vivo blockade of LHRH receptors and lack of a direct pituitary action of Mn to stimulate LH in vitro. To assess potential short-term effects, animals were supplemented with MnCl(2) (10 mg/kg) by gastric gavage from day 12 until day 29, or, in other animals, until vaginal opening (VO). Mn caused elevated serum levels of LH, follicle stimulating hormone, and estradiol, and it initiated a moderate but significant advancement in age at VO. Our results are the first to show that Mn can stimulate specific puberty-related hormones and suggest that it may facilitate the normal onset of puberty. They also suggest that Mn may contribute to precocious puberty if an individual is exposed to elevated levels of Mn too early in development.

Lack of effects of oxolinic acid on spermatogenesis in young adult and aged Wistar rats

Prolonged treatment with oxolinic acid is known to elevate serum luteinizing hormone (LH) levels, resulting in induction of Leydig cell tumors in rats. In a carcinogenicity study of the compound, tubular atrophy of the testis was also increased, suggesting that oxolinic acid might affect spermatogenesis. The present study was therefore performed using rats of different ages with a particular focus on seminiferous tubule alteration and its relation to Leydig cell proliferation. Young adult (7 weeks of age) and aged (52 weeks of age) males of the Wistar strain were administered oxolinic acid at dietary concentrations of 0 (basal diet), 300, 1000 or 3000 ppm for 4 (all groups), 13 (0 and 3000 ppm groups), 26 (0 and 3000 ppm groups), or 52 weeks (0 and 3000 ppm groups of aged rats). Serum LH levels were elevated in both young adult and aged animals treated with 3000 ppm at most examined time points. While testosterone levels were also increased at the early time points in young adult, this was not the case in older animals. Elevation of the incidences of foci and/or focal hyperplasia of Leydig cells was noted but was only slight limited to aged rats treated with 3000 ppm after 26 weeks. Furthermore, it did not appear to be related to seminiferous tubular alteration. No treatment-related histopathological abnormalities could be detected in any treatment group, and morphometrical stage analysis of spermatogenesis conducted for the control and 3000 ppm-treated groups demonstrated no lesions. These results provide strong evidence that prolonged oxolinic treatment does not directly induce testicular toxicity or altered spermatogenesis in either young adult or aged rats, except for slight increase of Leydig cell proliferative lesions caused by elevated serum LH levels. Aged rats might have higher sensitivity than young adults to the effects of oxolinic acid on proliferative lesions of Leydig cells.

Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome.

Our preliminary family studies have suggested that some female first-degree relatives of women with polycystic ovary syndrome (PCOS) have hyperandrogenemia per se. It was our hypothesis that this may be a genetic trait and thus could represent a phenotype suitable for linkage analysis. To investigate this hypothesis, we examined 115 sisters of 80 probands with PCOS from unrelated families. PCOS was diagnosed by the combination of elevated serum androgen levels and </=6 menses per year with the exclusion of secondary causes. The sisters were compared with 70 healthy age- and weight-comparable control women with regular menses, no clinical evidence of hyperandrogenemia, and normal glucose tolerance. Twenty-two percent of the sisters fulfilled diagnostic criteria for PCOS. In addition, 24% of the sisters had hyperandrogenemia and regular menstrual cycles. Circulating testosterone (T) and nonsex hormone-binding globulin-bound testosterone (uT) levels in both of these groups of sisters were significantly increased compared with unaffected sisters and control women (P < 0.0001 for both T and uT). Probands, sisters with PCOS, and hyperandrogenemic sisters had elevated serum luteinizing hormone levels compared with control women. We conclude that there is familial aggregation of hyperandrogenemia (with or without oligomenorrhea) in PCOS kindreds. In affected sisters, only one-half have oligomenorrhea and hyperandrogenemia characteristic of PCOS, whereas the remaining one-half have hyperandrogenemia per se. This familial aggregation of hyperandrogenemia in PCOS kindreds suggests that it is a genetic trait. We propose that hyperandrogenemia be used to assign affected status in linkage studies designed to identify PCOS genes.

Acute stress suppresses the N-methyl-D-aspartate-induced luteinizing hormone release in the ovariectomized estrogen-primed rat.

The effects of N-methyl-D-aspartate (NMDA) and luteinizing hormone releasing hormone (LH-RH) on luteinizing hormone (LH) secretion were examined in ovariectomized estrogen-primed rats under nonstressed and acutely stressed conditions. The basal LH levels were significantly elevated 15 min after the onset of acute immobilization stress, but were not altered in emotionally stressed or nonstressed rats. Intravenous injections of 10 and 40 mg/kg NMDA significantly elevated serum LH levels by 161 and 212%, respectively, from baseline within 10 min in nonstressed animals. However, the NMDA-induced LH release was significantly reduced when tested 30 min after the onset of acute immobilization stress. Acute emotional stress, which did not affect the baseline LH, also suppressed the LH release response to NMDA, suggesting that the reduced LH responses to NMDA in stressed animals was not due to the elevated baseline level. Pituitary LH release responses to LH-RH were not affected by acute immobilization. We conclude from these results: (1) acute immobilization stress exerts both stimulatory and inhibitory effects on LH release, while acute emotional stress has only an inhibitory effect in estrogen-primed ovariectomized rats; (2) this inhibition occurs at the suprapituitary level, and (3) it involves a suppression of the responsiveness of the hypothalamic LH-RH neuronal system to the excitatory amino acid input.

REVIEW

Circulating levels of luteinizing hormone (LH) are essential for the production of steroid hormones that regulate the timing of ovulation and target tissue responses, as well as maintenance of the corpus luteum and therefore early pregnancy. Clinical and basic science observations show that elevated levels of serum LH during the follicular phase of the menstrual cycle are not only unnecessary for follicular maturation but are deleterious to normal reproductive processes. These elevations may occur as a result of administration of exogenous LH or through an endogenous pathological process (i.e. polycystic ovarian disease, PCOD). Resting levels of LH, synergizing with locally produced IGFs, inhibin and perhaps other growth factors, are adequate for normal follicular growth and steroidogenesis. Elevations in serum LH above these resting levels may result in increased androgen production that diminishes follicular function and reduces early embryo viability. Elevated LH levels during the preovulatory period may also negatively influence post-ovulatory events such as conception and implantation. With these facts in mind, the best results for ovulation induction would be expected with purified follicle-stimulating hormone (FSH) administration to women following gonadotrophin releasing hormone (GnRH) down-regulation. It is hoped that this review provides the reader with an analysis of the complex series of events that regulate normal follicular maturation. The reevaluation of the two cell-two gonadotrophin theory suggests that during the preovulatory period, resting levels of LH are adequate for normal follicular maturation. Indeed, overstimulation of the ovary with excessive amounts of LH may diminish the ability of that target organ to produce fertile ova.(ABSTRACT TRUNCATED AT 250 WORDS)

Testicular function and Leydig cell ultrastructure in long-term bilaterally cryptorchid rams.

This study was conducted to investigate the effects of bilateral cryptorchidism induced in adult rams on testicular function and Leydig cell ultrastructure. The results indicated that long-term bilateral cryptorchidism resulted in decreased testicular size, degeneration of seminiferous tubules, elevated serum LH levels, maintenance of normal testosterone concentrations in peripheral and spermatic vein serum, impairment of the magnitude and duration of androgen response to exogenous luteinizing hormone (LH), a 13-fold reduction in total number of Leydig cells/paired testes, and a 3-fold hypertrophy in the average size of remaining Leydig cells. Based on quantitative morphometry, the hypertrophied Leydig cells exhibited significant increases in the volume of intracellular organelles, including the cell nucleus, mitochondria, smooth and rough endoplasmic reticulum, lysosome-like bodies and lipid vesicles. Quantitatively, the hypertrophy alone was not enough to offset the loss in number of Leydig cells and was insufficient to explain the maintenance of normal levels of testosterone in jugular and spermatic venous blood. The additional mechanisms responsible for production of normal serum testosterone levels in the cryptorchid ram remain to be elucidated.

Characterization of pituitary calcium-activated, phospholipid-dependent protein kinase: redistribution by gonadotropin-releasing hormone.

We report the presence in the rat pituitary of a calcium-activated, phospholipid-dependent protein kinase (C kinase), originally described by Takai et al. [Takai, Y., Kishimoto, A., Iwasa, Y., Kawahara, Y., Mori, T. & Nishizuka, Y. (1979) J. Biol. Chem. 254, 3692-3695]. Enzyme activity is absolutely dependent on the simultaneous presence of Ca2+ and phospholipid--in particular, phosphatidylserine. The presence of small amounts of unsaturated diacylglycerol greatly increases the apparent affinity of the enzyme for Ca2+ and phosphatidylserine. Pituitary C kinase is mostly soluble (70%) and partly particulate (30%). Although the soluble form of the enzyme can be detected in a crude cytosol preparation, the particulate form is detectable only after solubilization and anion-exchange chromatography. Administration of a gonadotropin-releasing hormone (Gn-RH) agonist analog, [D-Ser(But)6]des-Gly10-Gn-RH-N-ethylamide, to ovariectomized rats resulted in elevated serum luteinizing hormone levels (245%) accompanied by a decrease in the cytosolic form of the enzyme (60%) and an increase in the particulate form (300%) after 5 min. This apparent activation of the particulate form seems to result from translocation of a soluble C kinase to the membrane. Several endogenous substrate proteins for C kinase ranging from 16 to 100 kDa were identified in pituitary cytosol. Pituitary C kinase might be involved in signal-transduction mechanisms in Gn-RH action, in particular, and in other hypophysiotropic hormones, in general, which operate by means of stimulation of phosphoinositide turnover during which diacylglycerol is liberated.

Androgen Receptor Abnormalities in Identical Twins With Oligospermia. Clinical and Biochemical Studies

Identical twin brothers presented with oligospermia, small testes, normal male phenotypes, elevated serum luteinizing hormone levels, and normal or elevated serum testosterone levels. Both men had low to low-normal cytosol androgen receptor binding capacity in cultured fibroblasts from pubic skin biopsy specimens. Qualitative abnormalities of cellular androgen receptors were suggested by low-normal or low nuclear androgen uptake in fibroblasts from both brothers as well as abnormal thermolability and subnormal molybdate stabilization of androgen receptors from one brother. In vivo androgen sensitivity was assessed in one twin following administration of testosterone or the non-aromatizable androgen fluoxymesterone. Fluoxymesterone suppressed serum luteinizing hormone and serum testosterone/estradiol-binding globulin, and although testosterone suppressed both serum luteinizing hormone and serum follicle-stimulating hormone, the suppression of serum luteinizing hormone by testosterone was subnormal. Both subjects showed marked exaggeration of the serum 17-hydroxyprogesterone increase after administration of human chorionic gonadotropin, despite normal serum testosterone increases, suggesting a block in testicular 17,20-desmolase, which converts 17-hydroxyprogesterone to testosterone. These studies suggest that oligospermia and block of the enzyme 17,20-desmolase may be the earliest manifestations of androgen resistance, and the finding of the syndrome of oligospermia, normal male phenotype, and androgen receptor abnormalities in identical twins indicates a genetic etiology of this disorder.

Androgen receptor abnormalities in identical twins with oligospermia: Clinical and biochemical studies

Identical twin brothers presented with oligospermia, small testes, normal male phenotypes, elevated serum luteinizing hormone levels, and normal or elevated serum testosterone levels. Both men had low to low-normal cytosol androgen receptor binding capacity in cultured fibroblasts from pubic skin biopsy specimens. Qualitative abnormalities of cellular androgen receptors were suggested by low-normal or low nuclear androgen uptake in fibroblasts from both brothers as well as abnormal thermolability and subnormal molybdate stabilization of androgen receptors from one brother. In vivo androgen sensitivity was assessed in one twin following administration of testosterone or the non-aromatizable androgen fluoxymesterone. Fluoxymesterone suppressed serum luteinizing hormone and serum testosterone/estradiol-binding globulin, and although testosterone suppressed both serum luteinizing hormone and serum follicle-stimulating hormone, the suppression of serum luteinizing hormone by testosterone was subnormal. Both subjects showed marked exaggeration of the serum 17-hydroxyprogesterone increase after administration of human chorionic gonadotropin, despite normal serum testosterone increases, suggesting a block in testicular 17,20-desmolase, which converts 17-hydroxyprogesterone to testosterone. These studies suggest that oligospermia and block of the enzyme 17,20-desmolase may be the earliest manifestations of androgen resistance, and the finding of the syndrome of oligospermia, normal male phenotype, and androgen receptor abnormalities in identical twins indicates a genetic etiology of this disorder.

Pituitary androgen receptors and the resistance of long-term castrated rams to the androgenic control of luteinizing hormone (LH) secretion

Luteinizing hormone (LH) responses of short-term (24 h) and long-term (6 mo) castrated rams to testosterone replacement therapy were investigated. Testosterone filled Silastic capsules which maintained physiological concentrations of testosterone in blood (∼3.2ng/ml) prevented the postcastration rise in serum LH of short-term castrated rams but failed to effectively reduce the established elevated serum LH levels in long-term castrated rams. The LH response to exogenous LHRH was also suppressed in the short-term castrated rams, whereas the response was increased in direct proportion to basal LH levels in long-term castrates. The possibility that a change in pituitary androgen receptors may explain the resistance of long-term castrates to testosterone feedback was examined. For this purpose, a cytosolic androgen receptor binding assay was developed using tritiated methyltrienolone (R1881) as the labeled ligand and dextran-charcoal to separate free and protein-bound steroid. Stable, high affinity ( K d = 0.3–1.5 nM), saturable binding of R1881 was demonstrated in pituitary cytosol from both intact and castrate rams. Relative binding specificities in intact rams, however, suggested partial binding to a progestin-binding component, whereas receptor binding in long-term castrates was androgen specific. For this reason, androgen receptor binding was studied after addition of triamcinolone acetonide to occupy apparent progestin binding sites. We observed no differences in either androgen receptor concentration (4.10 ± 0.70 versus 3.23 ± 0.45fmol/mg protein; Mean ± SD) nor ligand affinity at 0°C ( K d = 0.66 ± 0.34 versus 0.40 ± 0.08 nM) in 6 mo compared to 24-h castrate rams. These data indicate that the inability of androgens to suppress gonadotropin secretion in long-term castrate rams is unlikely to be related to specific changes in pituitary cytosol androgen receptors.

Selective release of luteinizing hormone by 3 alpha-hydroxy-5 alpha-pregnan-20-one in immature ovariectomized estrogen-primed rats.

This study investigated the role of 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP) in the modulation of gonadotropin secretion using the immature ovariectomized (OVX) rat primed with a low dose of estradiol. A treatment regimen of either 0.2 or 0.4 mg/kg of 3 alpha,5 alpha-THP given in conjunction with estradiol for 4 days significantly increased levels of serum luteinizing hormone (LH) but had no effect on serum follicle-stimulating hormone (FSH). Estrogen-primed rats receiving a single injection of 3 alpha,5 alpha-THP at 0930 h showed an increase in serum and pituitary LH levels at 1200 h and 1500 h. At 1800 h, only pituitary levels of LH remained significantly higher than controls. An injection of 3 alpha,5 alpha-THP at 1230 h in estrogen-primed rats resulted in enhanced levels of pituitary LH at 1500 h and elevated levels of both serum and pituitary LH at 1800 h. When 3 alpha,5 alpha-THP was given at 0930 h and 1230 h, elevated serum levels of LH were maintained for over 6 h. The administration of pentobarbital (Pb) 30 min after an injection of 3 alpha,5 alpha-THP at 0930 h or 1230 h prevented the increases in serum LH at 1200 h, 1500 h or 1800 h. This suggests that LH-releasing hormone (LHRH) is involved in mediating the LH response by 3 alpha,5 alpha-THP. There was no change in the sensitivity of the pituitary to LHRH following 3 alpha,5 alpha-THP treatment, indicating the absence of a pituitary effect of this steroid.

Psychological stress and increases in urinary norepinephrine metabolites, platelet serotonin, and adrenal androgens in women with polycystic ovary syndrome

Twenty-three women with polycystic ovary syndrome, 10 women with hypothalamic-pituitary dysfunction, and 50 control subjects were studied in an attempt to investigate the prevalence of psychological stress and its possible relationship to various hormonal parameters. Norepinephrine (NE) excretion, as reflected by urinary 3-methoxy-4-hydroxyphenylglycol (MHPG), and urinary 3-methoxy-4-hydroxymandelic acid (VMA), platelet serotonin, plasma adrenocorticotrophic hormone (ACTH), urinary free cortisol, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione (Adione), dehydroepiandrosterone (DHEA), its sulfate (DHEA-S), Δ5-androstenediol (Δ5-Adiol), testosterone (T), and unbound estradiol (E2) were measured. In addition, psychological stress was assessed by means of questionnaires modified from the Schedule of Recent Experiences, in which a Life Events Inventory was scored between 1 and 100. Women with polycystic ovary syndrome had significantly elevated levels of serum LH, LH:FSH ratios, unbound E2, Adione, DHEA, Δ5-Adiol, T, and DHEA-S (p < 0.01). The number of Major Life Events (events scored on the questionnaire above 60) was significantly higher in women with polycystic ovary syndrome than in control women and women with hypothalamic-pituitary dysfunction (p < 0.05). Urinary MHPG and platelet serotonin levels were also significantly higher in women with polycystic ovary syndrome (p < 0.05), whereas VMA was normal. Levels of plasma ACTH and urinary free cortisol were similar in all groups. There was a significant positive correlation between MHPG and DHEA-S, MHPG and LH, and LH and T levels in women with polycystic ovary syndrome and those with hypothalamic-pituitary dysfunction (p < 0.01). VMA also correlated with DHEA-S (p < 0.05). In conclusion, psychological stress may be more prevalent in women with polycystic ovary syndrome and may be associated with elevated levels of MHPG and platelet serotonin. Because we have found that MHPG, but not VMA, correlated with LH, and because both MHPG and VMA correlated with DHEA-S, we hypothesize here that psychological stress and neurotransmitter levels may be linked to some of the hormonal derangements, including inappropriate gonadotropin secretion and elevated adrenal androgen levels in women with polycystic ovary syndrome.