Reduction In Luteinizing Hormone Research Articles

Subacute exposure to a mixture of tributyltin plus mercury impairs reproductive axis function, exacerbating premature ovarian insufficiency features and reducing fertility in female rats

Tributyltin (TBT) and mercury (Hg) are endocrine-disrupting chemicals that individually cause reproductive complications. However, the reproductive consequences of exposure to a mixture of TBT plus Hg are not well known. We hypothesized that exposure to a mixture of TBT plus Hg would alter hypothalamic-pituitary-gonadal (HPG) axis function. Female rats were exposed to this mixture daily for 15 days, after which chemical accumulation in the tissues, morphology, hormone levels, inflammation, fibrosis, and protein expression in the reproductive organs were assessed. Increases in tin (Sn) and Hg levels were detected in the serum, HPG axis, and uterus of TBT-Hg rats. TBT-Hg rats exhibited irregular estrous cycles. TBT-Hg rats showed an increase in gonadotropin-releasing hormone (GnRH) protein expression and follicle-stimulating hormone (FSH) levels and a reduction in luteinizing hormone (LH) levels. Reduced ovarian reserve, antral follicles, corpora lutea (CL) number, and estrogen levels and increased atretic and cystic follicles were found, suggesting that TBT-Hg exposure exacerbated premature ovarian insufficiency (POI) features. Furthermore, TBT-Hg rats exhibited increased ovarian mast cell numbers, expression of the inflammatory markers IL-6 and collagen deposition. Apoptosis and reduced gland number were observed in the uteri of TBT-Hg rats. A reduction in the number of pups/litter for 90 days was found in TBT-Hg rats, suggesting impaired fertility. Strong negative correlations were found between serum and ovarian Sn levels and ovarian Hg levels and ovarian reserve and CL number. Collectively, these data suggest that TBT plus Hg exposure leads to abnormalities in the HPG axis, exacerbating POI features and reducing fertility in female rats.

Profile of Linzagolix in the Management of Endometriosis, Including Design, Development and Potential Place in Therapy: A Narrative Review.

Estrogens play a critical role in the pathogenesis of endometriosis and it is logical to assume that lowering estradiol levels with oral gonadotropin-releasing hormone (GnRH) antagonists may prove effective, especially in women who fail to respond to progestogens. Indeed, due to progesterone resistance, oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis, but are ineffective in 33% of women. Oral GnRH antagonists have therefore been evaluated for management of premenopausal women with endometriosis-associated pelvic pain. The first publication on these drugs reported the efficacy of elagolix. The present paper is a narrative review of linzagolix, which is an orally administered GnRH receptor antagonist with low pharmacokinetic/pharmacodynamic variability. It binds to and blocks the GnRH receptor in the pituitary gland, resulting in a dose-dependent drop in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production. This reduction in LH and FSH levels in turn leads to a dose-dependent decline in estrogen. Phase 2 and 3 trials are reviewed and discussed here. There is a place for GnRH antagonists in the management of symptomatic endometriosis, and linzagolix with or without add-back therapy (ABT) is one option that can be used at low doses, avoiding the need for ABT, which is contraindicated in some patients.

Pituitary-gonadal hormones associated with respiratory failure in men and women hospitalized with COVID-19: an observational cohort study.

To explore pituitary-gonadal hormone concentrations and assess their association to inflammation, severe respiratory failure and mortality in hospitalized men and women with coronavirus disease 2019 (COVID-19) and compare these to hormone concentrations in hospitalized patients with bacterial community-acquired pneumonia (CAP), influenza virus CAP, and to concentrations in a reference group of healthy individuals. Serum concentrations of testosterone, estrone sulfate, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and interleukin-6 (IL-6) were measured within three days of admission. Associations were assessed by logistic regression analysis in patients with COVID-19, and results were reported as odds ratio with 95% confidence interval per two-fold reduction after adjustment for age, comorbidities, days to sample collection, and IL-6 concentrations. In total 278 with COVID-19, 21 with influenza virus CAP, and 76 with bacterial CAP were included. Testosterone concentrations were suppressed in men hospitalized with COVID-19, bacterial- and influenza virus CAP and moderately suppressed in women. Reductions in testosterone (OR 3.43 [1.14-10.30], p=0.028) and LH (OR 2.51 [1.28-4.92], p=0.008) were associated higher odds of mechanical ventilation (MV) in men with COVID-19. In women with COVID-19, reductions in LH (OR 3.34 [1.02-10-90], p=0.046) and FSH (OR 2.52 [1.01-6.27], p=0.047) were associated with higher odds of MV. Low testosterone and LH concentrations were predictive of severe respiratory failure in men with COVID-19, whereas low concentrations of LH and FSH predicted severe respiratory failure in women with COVID-19.

Neuroendocrine Determinants of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women and a major cause of anovulatory infertility. A diagnosis of PCOS is established based the presence of two out of three clinical symptoms, which are criteria accepted by the ESHRE/ASRM (European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine). Gonadotropin-releasing hormone (GnRH) is responsible for the release of luteinizing hormone, and follicle stimulating hormone from the pituitary and contributes a leading role in controlling reproductive function in humans. The goal of this review is to present the current knowledge on neuroendocrine determinations of PCOS. The role of such neurohormones as GnRH, and neuropeptides kisspeptin, neurokinin B, phoenixin-14, and galanin is discussed in this aspect. Additionally, different neurotransmitters (gamma-aminobutyric acid (GABA), glutamate, serotonin, dopamine, and acetylcholine) can also be involved in neuroendocrine etiopathogenesis of PCOS. Studies have shown a persistent rapid GnRH pulse frequency in women with PCOS present during the whole ovulatory cycle. Other studies have proved that patients with PCOS are characterized by higher serum kisspeptin levels. The observations of elevated serum kisspeptin levels in PCOS correspond with the hypothesis that overactivity in the kisspeptin system is responsible for hypothalamic-pituitary-gonadal axis overactivity. In turn, this causes menstrual disorders, hyperandrogenemia and hyperandrogenism. Moreover, abnormal regulation of Neurokinin B (NKB) is also suspected of contributing to PCOS development, while NKB antagonists are used in the treatment of PCOS leading to reduction in Luteinizing hormone (LH) concentration and total testosterone concentration. GnRH secretion is regulated not only by kisspeptin and neurokinin B, but also by other neurohormones, such as phoenixin-14, galanin, and Glucagon-like peptide-1 (GLP-1), that have favorable effects in counteracting the progress of PCOS. A similar process is associated with the neurotransmitters such as GABA, glutamate, serotonin, dopamine, and acetylcholine, as well as the opioid system, which may interfere with secretion of GnRH, and therefore, influence the development and severity of symptoms in PCOS patients. Additional studies are required to explain entire, real mechanisms responsible for PCOS neuroendocrine background.

Management of polycystic ovary syndrome among Indian women using myo-inositol and D-chiro-inositol.

Myo-Inositol and D-chiro-inositol (MI-DCI) are used in the treatment of polycystic Ovary syndrome (PCOS) due to their insulin-sensitizing actions. Therefore, it is of interest to evaluate the treatment patterns, clinical effectiveness and safety of MI-DCI combination in anagement of PCOS in Indian women. Data from 50 healthcare centers across India was collected between September 2019 and February 2020 and was used in the study. Women aged 12-45 years diagnosed with PCOS, who had received MI-DCI (550-150 mg) were included. The outcome parameters were change in weight, luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio, hirsutism, blood glucose and insulin levels, HOMA-IR, and lipid profile. A total of 283 women were included (mean age: 27.74 years; body mass index: 26.89 kg/m2); of which 197 (69.61%) reported reduction in weight after treatment with MI-DCI. The hirsutism scores considerably improved after treatment and the proportion of patients with, no hirsutism increased from 31.07% to 50.51% and moderate hirsutism reduced from 32.52% to 6.12% while, there were no patients with severe hirsutism after the treatment. There was a significant reduction in LH:FSH ratio (mean difference: 0.25 mg/dL; p=0.021), free testosterone (mean difference: 1.49; p<0.001) and dehydroepiandrosterone (mean difference: 21.49; P<0.001) levels after regular use of MI-DCI tablets. Treatment with MI-DCI resulted in significant improvement in insulin levels, HOMA-IR score, Fasting plasma glucose (FPG), post-prandial plasma glucose (PPG) and lipid profile. The therapy restored menstruation and spontaneous ovulation and significantly attenuated the LH/FSH ratio. Thus, MI-DCI (550-150 mg) has shown multidimensional benefits in improving the hormonal, glycemic, and lipid profile of women with PCOS with considerable efficacy and tolerability.

Neurobehavioral, testicular and erectile impairments of chronic ketamine administration: Pathogenesis and ameliorating effect of N-acetyl cysteine

Ketamine, a dissociative anesthetic, recently has spread as a recreational drug. Its abuse lead to neurobehavioral disturbance in addition to toxic effects on other body organs. To evaluate the toxic effects of chronic administration of low ketamine doses on the memory, testicles, and erection, explore its pathophysiology through oxidative stress mechanism and examine the ameliorating effect of N-acetyl cysteine (NAC). A total of 40 male albino rats were assigned to control, vehicle, ketamine only I.P. (10 mg/kg), and ketamine (10 mg/kg) + NAC (150 mg/kg) groups. Assessment of memory affection and erectile function by Passive Avoidance, Novel Object Recognition, and copulatory tests were performed. Estimation of malondialdehyde (MDA), catalase (CAT), and total antioxidant capacity (TAC) in serum and prefrontal & hippocampal homogenate, and luteinizing hormone (LH), testosterone in serum were done. Prefrontal cortex, hippocampus, and testes were collected for histopathology. Chronic ketamine administration induced significant memory deficits (P < 0.05), reduced erectile function (P < 0.05), severe hypospermatogenesis, increased MDA, reduced CAT, TAC levels in serum, and tissue homogenate (P < 0.05) and reduction of LH, and testosterone (P < 0.05). Treatment with NAC resulted in significant improvement of memory function, improved erectile function, and decrease in oxidative injury in both serum and tissue homogenates. Testosterone and LH levels exhibited significant difference between treatment groups and controls (P < 0.05). NAC reduced the deleterious histopathological changes. These data suggest that long-term ketamine affects short and long memory, induces erectile and testicular dysfunction through oxidative stress. Co-administration with NAC ameliorates these toxic effects.

SAT-418 Estradiol Enhances the Inhibitory Effect of the Cytokine Interleukin 1B on Pulsatile LH Secretion in Female Mice

Inflammatory and infectious processes can disrupt reproduction function and fertility in a wide range of species including humans, domesticated species and laboratory animals. Immune cells produce cytokines in response to systemic stressors such as lipopolysaccharide and these cytokines have the potential to disrupt the central mechanisms controlling gonadotropin secretion and ovulatory cyclicity in females. When administered peripherally, interleukin (IL)1B, a member of the interleukin-1 family of cytokines, has been shown to inhibit the proestrus luteinizing hormone (LH) surge in intact female rats. However, in male gonadectomized rats, IL1B delivered via intraperitoneal (i.p.) injection does not alter LH secretion, so the effect of IL1B may depend on the presence of gonadal steroids. Here, we began by investigating whether peripheral IL1B can inhibit mean LH secretion in female mice and if estradiol is necessary for this inhibition. Female C57bl6 mice (10 wk) were ovariectomized and implanted with a silastic capsule containing oil or 100ng estradiol, which approximates a diestrus level. LH was measured prior to and 60, 120 and 180 min following i.p. administration of 2ng/g IL1B or saline (control) from tail-tip blood samples. In oil treated females, mean LH did not significantly change following saline, compared to pretreatment levels. Treatment with IL1B elicited a 39% reduction in LH at 120 min; LH was not significantly different 60 or 180 min following IL1B. In animals treated with estradiol, IL1B elicited a more rapid and robust reduction in LH at all three time points. LH was reduced by 50%, 71% and 68%, at 60, 120 and 180 min, respectively. These data indicate that estradiol enhances the LH response to peripheral IL1B. Based on these findings, we have conducted two experiments. First, we performed a study (N=13) to measure pulsatile LH prior to and following i.p. administration of 2ng/g IL1B or saline (control) in ovariectomized C57bl6 mice pretreated with estradiol. Second, we are investigating the neural pathways whereby IL1B may access the kisspeptin and GnRH circuit to influence LH pulsatility using c-Fos as a marker. These data suggest that estradiol affects neural pathways by which stress hormones influence reproduction and may indicate why women are differentially responsive to inflammatory signals depending on their ovarian cycle stage.

Reproductive performance of male mice after hypothalamic ghrelin administration.

It has been demonstrated that food intake and reproductive physiology are both simultaneously modulated to optimize reproductive success under fluctuating metabolic conditions. Ghrelin (GHRL) is an orexigenic peptide identified as the endogenous ligand of the growth hormone secretagogue receptor that is being investigated for its potential role on reproduction. Considering that data available so far are still limited and characterization of GHRL action mechanism on the reproductive system has not been fully elucidated, we studied the participation of hypothalamus in GHRL effects on sperm functional activity, plasma levels of gonadotropins and histological morphology in mice testes after hypothalamic infusion of 0.3 or 3.0 nmol/day GHRL or artificial cerebrospinal fluid (ACSF) at different treatment periods. We found that GHRL 3.0 nmol/day administration for 42 days significantly reduced sperm concentration (GHRL 3.0 nmol/day = 14.05 ± 2.44 × 106/mL vs ACSF = 20.33 ± 1.35 × 106/mL, P < 0.05) and motility (GHRL 3.0 nmol/day = 59.40 ± 4.20% vs ACSF = 75.80 ± 1.40%, P < 0.05). In addition, histological studies showed a significant decrease percentage of spermatogonia (GHRL 3.0 nmol/day = 6.76 ± 0.68% vs ACSF = 9.56 ± 0.41%, P < 0.05) and sperm (GHRL 3.0 nmol/day = 24.24 ± 1.92% vs ACSF = 31.20 ± 3.06%, P < 0.05). These results were associated with a significant reduction in luteinizing hormone and testosterone plasma levels (P < 0.05). As GHRL is an orexigenic peptide, body weight and food intake were measured. Results showed that GHRL increases both parameters; however, the effect did not last beyond the first week of treatment. Results presented in this work confirm that central GHRL administration impairs spermatogenesis and suggest that this effect is mediated by inhibition of hypothalamic-pituitary-gonadal axis.

Effect of Citrullus colocynthis hydro-alcoholic extract on hormonal and folliculogenesis process in estradiol valerate-induced PCOs rats model: An experimental study

Citrullus colocynthis (CCT) is used as the anti-diabetic and antioxidant agent. Polycystic ovarian syndrome (PCOS) is a reproductive disorder which level of gonadotropins and sexual hormones are imbalanced. We evaluated the effect of CCT hydro-alcoholic extract on hormonal and folliculogenesis process in estradiol valerate-induced PCOs rats' model. 40 female adult Wistar rats divided into five groups (n=8each: Group I (control) only injected by sesame oil as estradiol valerate solvent, group II (Sham) was orally received normal saline after estradiol valerate- induced polycystic ovarian syndrome (4 mg/rat estradiol valerate, intramuscularly), and three experimental groups, that after induction of PCOS within 60 days, received orally 50 mg/kg CCT extract (group III), 50mg/kg metformin (group IV), and CCT extract+ metformin (group V) for 20 days. The serum concentration level of luteinizing, testosterone and follicle stimulating hormones were measured using ELISA method and the serum concentration level of glucose were measured using the oxidative method (glucose meter). Histological study of ovary tissue carried out by hematoxylin-eosin staining. There was a significant reduction in luteinizing hormone and testosterone in III-V groups compared to Sham group, whereas follicle stimulating hormone in III-V groups was not significantly changed in comparison with Sham group. Histological investigations showed a significant increase in number of preantral and antral follicles and corpus luteum in the experimental groups compared to group II. Marked improvement in hormonal and histological symptoms of PCOS may be due to CCT effects hence, CCT can potentially be considered as an effective drug for treatment of PCOS.

Effects of Anabolic Androgenic Steroids on the Reproductive System of Athletes and Recreational Users: A Systematic Review and Meta-Analysis.

Anabolic androgenic steroids (AAS) are testosterone derivatives used by athletes and recreational users to improve athletic performance and/or enhance appearance. Anabolic androgenic steroids use may have serious and potentially irreversible adverse effects on different organs and systems, including the reproductive system. This systematic review and meta-analysis aimed to critically assess the impact of AAS use on the reproductive system of athletes and recreational users. An electronic literature search was conducted using the databases MEDLINE, CENTRAL, and Google Scholar. Studies were included when the following criteria were fulfilled: participants were athletes or recreational users of any age, sex, level or type of sport; AAS use of any type, dose, form or duration; AAS effects on the reproductive system were assessed as stated by medical history, clinical examination, hormone and/or semen analysis. Random-effects meta-analysis was performed to assess the weighted mean difference (WMD) of serum gonadotropin (luteinizing hormone, follicle-stimulating hormone) and testosterone levels compared with baseline, during the period of AAS use, as well as following AAS discontinuation. Thirty-three studies (three randomized clinical trials, 11 cohort, 18 cross-sectional, and one non-randomized parallel clinical trial) were included in the systematic review (3879 participants; 1766 AAS users and 2113 non-AAS users). The majority of the participants were men; only six studies provided data for female athletes. A meta-analysis (11 studies) was conducted of studies evaluating serum gonadotropin and testosterone levels in male subjects: (1) prior to, and during AAS use (six studies, n=65 AAS users; seven studies, n=59, evaluating gonadotropin and testosterone levels respectively); (2) during AAS use and following AAS discontinuation (four studies, n=35; six studies, n=39, respectively); as well as (3) prior to AAS use and following AAS discontinuation (three studies, n=17; five studies, n=27, respectively). During AAS intake, significant reductions in luteinizing hormone [weighted mean difference (WMD) -3.37IU/L, 95% confidence interval (CI) -5.05 to -1.70, p<0.001], follicle-stimulating hormone (WMD -1.73IU/L, 95% CI -2.67 to -0.79, p<0.001), and endogenous testosterone levels (WMD -10.75nmol/L, 95% CI -15.01 to -6.49, p<0.001) were reported. Following AAS discontinuation, serum gonadotropin levels gradually returned to baseline values within 13-24weeks, whereas serum testosterone levels remained lower as compared with baseline (WMD -9.40nmol/L, 95% CI -14.38 to -4.42, p<0.001). Serum testosterone levels remained reduced at 16weeks following discontinuation of AAS. In addition, AAS abuse resulted in structural and functional sperm changes, a reduction in testicular volume, gynecomastia, as well as clitoromegaly, menstrual irregularities, and subfertility. The majority of AAS users demonstrated hypogonadism with persistently low gonadotropin and testosterone levels, lasting for several weeks to months after AAS withdrawal. Anabolic androgenic steroid use results in profound and prolonged effects on the reproductive system of athletes and recreational users and potentially on fertility.

Histopathological and Biochemical Effects of Acute &amp; Chronic Tramadol drug Toxicity on Liver, Kidney and Testicular Function in Adult Male Albino Rats

Nowadays tramadol is becoming abused more popular among teens in most countries worldwide; especially between males. The aim of present study was to investigate the histopathological and biochemical profiles of acute and chronic toxic effects of tramadol hydrochloride on hepatic, renal and testicular functions. Materials and methods: Sixty male adult albino Sprague-Dawley rats were used in this experimental study. Rats were divided into three equal groups. Each group contained twenty rats. Group I: served as control group. Group II: representing acute tramadol toxicity and group III: representing tramadol dependent use daily for 60 days. Results: Histopathological results regarding hepatic tissues of group II displayed hemorrhage and cytolysis in the hepatocytes. In group III hepatic tissue showed complete cell membrane degeneration of hepatocytes when both groups compared to group I. Renal tissues in group II showed glomerular hemorrhage while in group III there was atrophied glomeruli with collapsed tufts, wide Bowman's space, degenerated tubules and cellular infiltration when both groups compared to group I. The histopathological examination of testicular tissues revealed atrophy of seminiferous tubules with interstitial calcification in group II. The histopathological lesions were inform of focal testicular degeneration with single or multiple layer of vacuolated spermatocytes, with a little evidence of spermatogenesis in group III when both groups were compared to group I. Biochemical results indicated that the levels of liver enzymes specific (ALT, AST and ALP) and serum bilirubin were significantly increased in group II and III when compared to the control group. Similarly for renal function, the levels of creatinine and blood urea nitrogen (BUN) were also significantly increased in group II and III when compared to control group. The sex hormones levels were significantly increased (estradiol (E2) and prolactin (PRL) compared to control group , while tramadol administration caused a significant decrease in testosterone level with a gradual reduction in luteinizing hormone ( LH) and follicular stimulating hormone ( FSH) as compared to control group. Conclusion: Evidence of histopathological and biochemical affection of hepatic, renal and sexual function evoked by acute toxicity of tramadol and its repeated administration for long periods. Recommendations: The necessity of designing a national awareness campaign to the public especially the youth to spotlights on the health hazards of tramadol abuse.

Histopathological and Biochemical Effects of Acute and Chronic Tramadol Drug Toxicity on Liver, Kidney and Testicular Function in Adult Male Albino Rats

Background: Nowadays tramadol is becoming abused more popular among teens in most countries worldwide; especially between males. The aim of present study was to investigate the histopathological and biochemical profiles of acute and chronic toxic effects of tramadol hydrochloride on hepatic, renal and testicular functions. Materials and methods: Sixty male adult albino Sprague-Dawley rats were used in this experimental study. Rats were divided into three equal groups. Each group contained twenty rats. Group I: served as control group. Group II: representing acute tramadol toxicity and group III: representing tramadol dependent use daily for 60 days. Results: Histopathological results regarding hepatic tissues of group II displayed hemorrhage and cytolysis in the hepatocytes. In group III hepatic tissue showed complete cell membrane degeneration of hepatocytes when both groups compared to group I. Renal tissues in group II showed glomerular hemorrhage while in group III there was atrophied glomeruli with collapsed tufts, wide Bowman's space, degenerated tubules and cellular infiltration when both groups compared to group I. The histopathological examination of testicular tissues revealed atrophy of seminiferous tubules with interstitial calcification in group II. The histopathological lesions were inform of focal testicular degeneration with single or multiple layer of vacuolated spermatocytes, with a little evidence of spermatogenesis in group III when both groups were compared to group I. Biochemical results indicated that the levels of liver enzymes specific (ALT, AST and ALP) and serum bilirubin were significantly increased in group II and III when compared to the control group. Similarly for renal function, the levels of creatinine and blood urea nitrogen (BUN) were also significantly increased in group II and III when compared to control group. The sex hormones levels were significantly increased (estradiol (E2) and prolactin (PRL) compared to control group , while tramadol administration caused a significant decrease in testosterone level with a gradual reduction in luteinizing hormone ( LH) and follicular stimulating hormone ( FSH) as compared to control group. Conclusion: Evidence of histopathological and biochemical affection of hepatic, renal and sexual function evoked by acute toxicity of tramadol and its repeated administration for long periods. Recommendations: The necessity of designing a national awareness campaign to the public especially the youth to spotlights on the health hazards of tramadol abuse.

Toxic effects of Mn2O3 nanoparticles on rat testis and sex hormone.

Background and Objective:The safety of Mn2O3 nanoparticles (which are extensively used in industries) on male reproductive system is not known. Hence, we investigated the effects of Mn2O3 nanoparticles on male reproductive system.Materials and Methods:A total of 40 Wistar adult male rats were randomly assigned to four groups of 10 rats each. Three groups received Mn2O3 solution in concentrations of 100, 200, and 400 ppm orally for 14 days; the control group received equal volume of saline solution. Blood samples and testicles were collected for analysis.Results:Significant reduction in luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, spermatogonial cells, primary spermatocyte, spermatid and Leydig cell was observed in the Mn2O3 nanoparticles treated groups compared with controls.Conclusion:Mn2O3 nanoparticles significantly reduce FSH, LH, and testosterone levels resulting in a significant reduction in testicular cytology.

Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide

Tamoxifen and fenretinide have been extensively studied and exhibit breast cancer-preventing activity. We aimed to assess their effect on sex hormones, sex hormone binding globulin (SHBG) and retinol, and their association with mammographic density (MD) and breast cancer events. In a double-blind, placebo-controlled trial, premenopausal women at risk for breast cancer were randomized to tamoxifen 5 mg/day, fenretinide, both agents, or placebo for 2 years. We measured MD and circulating concentrations of follicle-stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, testosterone, androstenedione, dehydro-epiandrosteronesulfate, prolactin, SHBG, and retinol at baseline and on yearly intervals. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models. Low-dose tamoxifen markedly and enduringly increased SHBG, whereas the increases in testosterone, estradiol, and prolactin and reduction in LH weakened after 1 year. Fenretinide increased testosterone and androstenedione and decreased retinol. MD correlated directly with SHBG and inversely with retinol. After a median follow-up of 12 years, the 10-year cumulative incidence of breast cancer events was 37 % in women with SHBG ≤ 59.3 nmol/L, 22 % in women with SHBG between 59.3 and 101 nmol/L, and 19 % in women with SHBG > 101 nmol/L (P = 0.018). The difference among SHBG tertiles remained statistically significant at multivariable analysis: HR = 2.26 (95 % CI 1.04, 4.89) for the lowest versus the highest tertile. We conclude that low-dose tamoxifen or fenretinide exhibits favorable hormonal profiles as single agents, further supporting their administration for prevention of breast cancer in premenopause. Notably, SHBG levels were inversely associated with breast neoplastic events.

Hypothalamic Integration of Nutrient Status and Reproduction in the Sheep

Nutrient availability is a determinant of reproductive success. It is well known that inadequate nutrition results in reproductive failure due to a number of factors including delay of puberty or anoestrous in post-pubertal animals. The lack of nutrients is detected primarily by changes in circulating nutrient molecules and hormones and communicated directly or indirectly to the hypothalamus and brain stem for integration. The general effect is that low nutrition leads to increased appetite stimulation and reduced reproductive performance. When nutrition is adequate, the reverse is true. Both aspects will be the focus of this review. One result of the lack of nutrients is a reduction in luteinizing hormone (LH) concentrations and pulse frequency. Nutrient signals, such as glucose availability, hormonal signals, such as insulin and leptin, and neuroendocrine signals, such as neuropeptide Y and corticotropin-releasing hormone, have been clearly demonstrated to interact to produce changes in LH and reproductive success. Other signals, such as fatty acids, ghrelin, agouti-related peptide, melanin-concentrating hormone, orexin, melanocyte-stimulating hormone, kisspeptin, neurokinin, dynorphin and gonadotropin inhibitory hormone may also play a role in integrating nutrition and reproduction. This review will focus on the major features of the reciprocal control of appetite and reproduction in sheep.

Oxidative stress and phthalate-induced down-regulation of steroidogenesis in MA-10 Leydig cells

Previous studies have shown that phthalate exposure can suppress steroidogenesis. However, the affected components of the steroidogenic pathway, and the mechanisms involved, remain uncertain. We show that incubating MA-10 Leydig cells with mono-(2-ethylhexyl) phthalate (MEHP) resulted in reductions in luteinizing hormone (LH)-stimulated cAMP and progesterone productions. cAMP did not decrease in response to MEHP when the cells were incubated with cholera toxin or forskolin. Incubation of MEHP-treated cells with dibutyryl-cAMP, 22-hydroxycholesterol or pregnenolone inhibited the reductions in progesterone. Increased levels of reactive oxygen species (ROS) occurred in response to MEHP. In cells in which intracellular glutathione was depleted by buthionine sulfoximine pretreatment, the increases in ROS and decreases in progesterone in response to MEHP treatment were exacerbated. These results indicate that MEHP inhibits MA-10 Leydig cell steroidogenesis by targeting LH-stimulated cAMP production and cholesterol transport, and that a likely mechanism by which MEHP acts is through increased oxidative stress.

Tryptophan Hydroxylase: A Target for Neuroendocrine Disruption

Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin (5-HT) synthesis, performs an essential role in the maintenance of serotonergic functions in the central nervous system (CNS), including regulation of the neuroendocrine system controlling reproduction. The results of recent studies in a teleost model of neuroendocrine disruption, Atlantic croaker, indicated that hypothalamic TPH is a major site of interference of hypothalamic–pituitary–gonadal function by environmental stressors. The effects of exposure to two different types of environmental stressors, low dissolved oxygen (hypoxia) and a polychlorinated biphenyl mixture (Aroclor 1254), on the stimulatory brain serotonergic system controlling reproductive neuroendocrine function in Atlantic croaker are reviewed. Exposure to both stressors produced decreases in TPH activity, which were accompanied by a fall in hypothalamic 5-HT and gonadotropin-releasing hormone (GnRH I) content in the preoptic-anterior hypothalamic area and were associated with reduction in luteinizing hormone (LH) secretion and gonadal development. Pharmacological restoration of hypothalamic 5-HT levels after exposure to both stressors also restored neuroendocrine and reproductive functions, indicating that the serotonergic system is an important site for hypoxia- and Aroclor 1254-induced inhibition of reproductive neuroendocrine functions. The mechanisms underlying downregulation of TPH activity by these stressors remain unclear but may involve alterations in hypothalamic antioxidant status. In support of this hypothesis, treatment with an antioxidant, vitamin E, was found to reverse the inhibitory effects of Aroclor 1254 on TPH activity. The results suggest that TPH is a major target for neuroendocrine disruption by diverse environmental stressors.

Luteinizing hormone reduction by the male potency herb, Butea superba Roxb.

To determine if Butea superba Roxb., a traditional Thai male potency herb, has androgenic activity in 60-day-old male Wistar rats, we measured its effects on the pituitary-testicular axis and sex organs. Intact and orchidectomized adult male rats were subdivided into five groups (10 rats/group): distilled water, Butea superba (BS)-10, BS-50, BS-250, and testosterone propionate (TP). They received 0, 10, 50, and 250 mg·kg body weight(-1)·day(-1) BS in distilled water by gavage and 6 mg·kg body weight(-1)·day(-1) TP sc, respectively, during the 30-day treatment period. Blood was collected every 15 days and luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone were measured. Changes of weight and histological appearance of sex organs were determined at the end of the 30-day treatment and 15-day post-treatment periods. TP treatment reduced serum FSH and LH levels and significantly increased the weight of the seminal vesicles and epididymis, in accordance with histopathological changes, in both intact and orchidectomized rats. No changes in serum testosterone, LH, and FSH levels were observed in any of the intact rats treated with BS, but a significant increase in seminal vesicle weight was observed only in the BS-250 group. Although a significant reduction in serum LH was detected in the BS-50 and BS-250 groups of orchidectomized rats, no significant change in weight or histology of sex organs was observed. Thus, we conclude that B. superba needs endogenous testosterone to work synergistically to stimulate the accessory sex organ of intact animals and can potentially exhibit an LH reduction effect in orchidectomized animals.

Low luteinizing hormone enhances spatial memory and has protective effects on memory loss in rats

Though several studies have suggested that estradiol improves hippocampal-dependent spatial memory, the effects of other hormones in the hypothalamic–pituitary–gonadal axis on memory have largely been ignored. Estradiol and luteinizing hormone (LH) are generally inversely related and LH may significantly affect spatial memory. Ovariectomized (ovx) rats treated with Antide (a gonadotropin releasing hormone receptor antagonist) had low LH levels and showed enhanced spatial memory, comparable to treatment with estradiol. Antide-treated ovx females retained spatial memory longer than estradiol-treated ovx females. Deficits in spatial memory are a primary symptom of neurodegenerative disorders including Alzheimer's disease (AD). Treatment with Antide prevented spatial memory deficits in a neurotoxin-induced model typical of early AD. These data suggest that memory impairments seen in female rats after ovariectomy or women after menopause may be due to high LH levels and that a reduction in LH enhances memory. These results also implicate an LH lowering agent as a potential preventative therapy for AD.

Hair Loss in Women

Female pattern hair loss (FPHL) is a clinical problem that is becoming more common in women. Female alopecia with androgen increase is called female androgenetic alopecia (FAGA) and without androgen increase is called female pattern hair loss. The clinical picture of typical FAGA begins with a specific "diffuse loss of hair from the parietal or frontovertical areas with an intact frontal hairline." Ludwig called this process "rarefaction." In Ludwig's classification of hair loss in women, progressive type of FAGA, 3 patterns were described: grade I or minimal, grade II or moderate, and grade III or severe. Ludwig also described female androgenetic alopecia with male pattern (FAGA.M) that should be subclassified according to Ebling's or Hamilton-Norwood's classification. FAGA.M may be present in 4 conditions: persistent adrenarche syndrome, alopecia caused by an adrenal or an ovarian tumor, posthysterectomy, and as an involutive alopecia. A more recent classification (Olsen's classification of FPHL) proposes 2 types: early- and late-onset with or without excess of androgens in each. The diagnosis of FPHL is made by clinical history, clinical examination, wash test, dermoscopy, trichoscan, trichograms and laboratory test, especially androgenic determinations. Topical treatment of FPHL is with minoxidil, 2-5% twice daily. When FPHL is associated with high levels of androgens, systemic antiandrogenic therapy is needed. Persistent adrenarche syndrome (adrenal SAHA) and alopecia of adrenal hyperandrogenism is treated with adrenal suppression and antiandrogens. Adrenal suppression is achieved with glucocorticosteroids. Antiandrogens therapy includes cyproterone acetate, drospirenone, spironolactone, flutamide, and finasteride. Excess release of ovarian androgens (ovarian SAHA) and alopecia of ovarian hyperandrogenism is treated with ovarian suppression and antiandrogens. Ovarian suppression includes the use of contraceptives containing an estrogen, ethinylestradiol, and a progestogen. Antiandrogens such as cyproterone acetate, always accompanied by tricyclic contraceptives, are the best choice of antiandrogens to use in patients with FPHL. Gonadotropin-releasing hormone agonists such as leuprolide acetate suppress pituitary and gonadal function through a reduction in luteinizing hormone and follicle-stimulating hormone levels. Subsequently, ovarian steroid levels also will be reduced, especially in patients with polycystic ovary syndrome. When polycystic ovary syndrome is associated with insulin resistance, metformin must be considered as treatment. Hyperprolactinemic SAHA and alopecia of pituitary hyperandrogenism should be treated with bromocriptine or cabergoline. Postmenopausal alopecia, with previous high levels of androgens or with prostatic-specific antigen greater than 0.04 ng/mL, improves with finasteride or dutasteride. Although we do not know the reason, postmenopausal alopecia in normoandrogenic women also improves with finasteride or dutasteride at a dose of 2.5 mg per day. Dermatocosmetic concealment with a hairpiece, hair prosthesis as extensions, or partial hairpieces can be useful. Lastly, weight loss undoubtedly improves hair loss in hyperandrogenic women.