Hypothalamic-pituitary-testis Axis Research Articles

Comprehensive transcriptomic analysis revealing the regulatory dynamics and networks of the pituitary-testis axis in sheep across developmental stages.

Spermatogenesis is a complex process intricately regulated by the hypothalamic-pituitary-testis (HPT) axis. However, research on the regulatory factors governing the HPT axis remains limited. This study addresses this gap by conducting a comprehensive analysis of transcriptomes from the pituitary and testis tissues across various developmental stages, encompassing embryonic day (E120), neonatal period (P0), pre-puberty (P90), and post-puberty day (P270). Utilizing edgeR and WGCNA, we identified stage-specific genes in both the pituitary and testis throughout the four developmental stages. Notably, 380, 242, 34, and 479 stage-specific genes were identified in the pituitary, while 886, 297, 201, and 3,678 genes were identified in the testis. Subsequent analyses unveiled associations between these stage-specific genes and crucial pathways such as the cAMP signaling pathway, GnRH secretion, and male gamete generation. Furthermore, leveraging single-cell data from the pituitary and testis, we identified some signaling pathways involving BMP, HGF, IGF, and TGF-β, highlighting mutual regulation between the pituitary and testis at different developmental stages. This study sheds light on the pivotal role of the pituitary-testis axis in the reproductive process of sheep across four distinct developmental stages. Additionally, it delves into the intricate regulatory networks governing reproduction, offering novel insights into the dynamics of the pituitary-testis axis within the reproductive system.

SARS-CoV-2 Infection and the Male Reproductive System: A Brief Review.

Many studies have suggested that SARS-CoV-2, directly or indirectly, can affect the male reproductive system, although the underlined mechanisms have not been completely elucidated yet. The purpose of this review is to provide a summary of the current data concerning the impact of SARS-CoV-2 infection on the male urogenital tract, with a particular emphasis on the testes and male fertility. The main data regarding the morphological alterations in the testes emerged from autoptic studies that revealed interstitial congestion, micro thrombosis, reduction of Sertoli, Leydig, and germinal cells, infiltrated immune cells, and atrophic seminiferous tubules consistent with orchitis. Furthermore, men with severe infection exhibit sperm parameter alterations, together with abnormalities of the hypothalamic-pituitary-testis axis, strongly suggesting that SARS-CoV-2 could increase the risk of male infertility. However, despite the inadequate number of longitudinal studies, spermatogenesis and sex hormone imbalance seem to improve after infection resolution. The yet unresolved question is whether the virus acts in a direct or/and indirect manner, as discordant data related to its presence in the testis and semen have been reported. Regardless of the direct effect, it has been postulated that the cytokine storm and the related local and systemic inflammation could strongly contribute to the onset of testis dysfunction, leading to male infertility. Therefore, multicentric and longitudinal studies involving a large number of patients are needed to understand the real impact of SARS-CoV-2 infection on male reproduction.

The Biochemical Effects of Silver Nanoparticles and Spirulina Extract on Experimentally Induced Prostatic Cancer in Rats

Prostate cancer (PCa) is the most diagnosed cancer in 112 countries and the second leading cause of death in men in 48 countries. We studied the outstanding agents silver nanoparticles (AgNPs) and Spirulina algae (Sp) for the management of PCa once as monotherapy or last as a combination. PCa in rats was induced using bicalutamide (Casodex®) and testosterone, followed by (7, 12-dimethylbenz[a]anthracene). Then, testosterone was injected s.c. for 3 months. Rats were divided into six groups, with 12 rats in each group. Group I was assigned as the control (co), group II as the PCa model, group III treated with AgNPs, group IV treated with Spirulina extract, group V treated with a combination of AgNPs plus Spirulina, and group VI treated with bicalutamide. The results show that AgNPs could normalize IL-6 levels and could overcome the hormonal disturbance induced in PCa rats along the hypothalamic–pituitary–testis axis. Spirulina revealed a significant reduction in the level of total and free prostatic specific antigen (PSA) to the same level as bicalutamide treatment, which was the same as the control group. Histopathological study revealed regression (75%) of the histological pattern of high-grade prostatic intraepithelial neoplasia (HGPIN) for Spirulina alone, and (50%) for bicalutamide. The best effect on IL-6 decline was reached with the AgNPs/Spirulina combination as well as bicalutamide treatment compared with the PCa group. Bicalutamide treatment significantly decreased the PSA concentration relative to the PCa group and reached the normal level. Adding Spirulina to AgNPs as a combination enhanced its effect on all mentioned drawbacks associated with PCa except hormonal imbalance that needs more adjustments.

PD36-04 AROMATIZATION OF ENDOGENOUS TESTOSTERONE OCCURS PRIMARILY IN TESTICULAR LEYDIG CELLS

You have accessJournal of UrologyCME1 May 2022PD36-04 AROMATIZATION OF ENDOGENOUS TESTOSTERONE OCCURS PRIMARILY IN TESTICULAR LEYDIG CELLS Caroline Kang, Nahid Punjani, Jessica Marinaro, and Peter Schlegel Caroline KangCaroline Kang More articles by this author , Nahid PunjaniNahid Punjani More articles by this author , Jessica MarinaroJessica Marinaro More articles by this author , and Peter SchlegelPeter Schlegel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002594.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Endogenous testosterone (T) is produced by testicular Leydig cells that are rich in aromatase activity. Aromatization to estradiol (E2) can negatively regulate the hypothalamic-pituitary-testis (HPT) axis, thereby diminishing gonadotropin and T production as well as spermatogenesis. Exogenous T is exposed primarily to fat, muscle, and other peripheral tissues with limited exposure to testicular Leydig cells. We investigated the source of aromatization by comparing serum T:E2 ratios, as a surrogate for aromatase activity, in men with Klinefelter syndrome (KS) who have endogenous or exogenous testosterone production, that is, before and after the initiation of testosterone replacement therapy (TRT). METHODS: We performed a retrospective study of all adult men (> 20 years of age) with a diagnosis of KS undergoing sperm retrieval by microdissection testicular sperm extraction (mTESE) performed by a single surgeon at a tertiary infertility referral center between 1995-2020. Demographic data, along with hormone data (serum T and E2 levels) pre- and post-TRT were obtained from the electronic medical record. Patients not treated with TRT or with incomplete hormone data were excluded. Paired statistical analyses were completed to determine differences between hormone levels pre- and post-TRT initiation. RESULTS: A total of 35 men with KS were included in our final analysis. Median age was 32 years (interquartile range (IQR), 28 - 36), and median BMI was 25.9 kg/m2 (IQR, 24.6 - 30.8). The majority of our cohort was initiated on topical TRT (e.g., cream or gel; 26/35, 74.3%), while the remaining were treated with injectable or implanted TRT (9/35, 25.7%). Mean serum T increased from 239±134 ng/dL to 519±361 ng/dL (p=0.0003), while mean serum E2 increased from 30±22 pg/ml to 36±28 pg/ml (p=0.55) after initiation of TRT. Mean T:E2 ratio increased from 9.4±6.3 to 17.4±14.5 (p=0.0005) after initiation of TRT. CONCLUSIONS: Aromatization of T to E2 can result in suppression of the HPT axis and diminish both T production and spermatogenesis. After initiation of TRT, T:E2 ratios rose significantly due to an increase in T with relatively stable E2, suggesting that exogenous and endogenous T are not subject to the same cellular milieu and therefore differential aromatization. This finding has important implications in the treatment and counseling of men with infertility and abnormal hormone levels. Source of Funding: CK and JS are supported in part by the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e634 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Caroline Kang More articles by this author Nahid Punjani More articles by this author Jessica Marinaro More articles by this author Peter Schlegel More articles by this author Expand All Advertisement PDF DownloadLoading ...

Endocrine aberrations of human nonobstructive azoospermia.

Nonobstructive azoospermia (NOA) refers to the failure of spermatogenesis, which affects approximately 1% of the male population and contributes to 10% of male infertility. NOA has an underlying basis of endocrine imbalances since proper human spermatogenesis relies on complex regulation and cooperation of multiple hormones. A better understanding of subtle hormonal disturbances in NOA would help design and improve hormone therapies with reduced risk in human fertility clinics. The purpose of this review is to summarize the research on the endocrinological aspects of NOA, especially the hormones involved in hypothalamic–pituitary–testis axis (HPTA), including gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, estradiol, sex hormone binding globulin, inhibin B, anti-Müllerian hormone, and leptin. For the NOA men associated with primary testicular failure, the quality of currently available evidence has not been sufficient enough to recommend any general hormone optimization therapy. Some other NOA patients, especially those with hypogonadotropic hypogonadism, could be treated with hormonal replacement. Although these approaches have succeeded in resuming the fertility in many NOA patients, the prudent strategies should be applied in individuals according to specific NOA etiology by balancing fertility benefits and potential risks. This review also discusses how NOA can be induced by immunization against hormones.

Autophagy: a multifaceted player in the fate of sperm.

BACKGROUNDAutophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including cell differentiation and development. Emerging data indicate that autophagy is closely associated with male reproduction, especially the biosynthetic and catabolic processes of sperm. Throughout the fate of sperm, a series of highly specialized cellular events occur, involving pre-testicular, testicular and post-testicular events. Nonetheless, the most fundamental question of whether autophagy plays a protective or harmful role in male reproduction, especially in sperm, remains unclear.OBJECTIVE AND RATIONALEWe summarize the functional roles of autophagy in the pre-testicular (hypothalamic–pituitary–testis (HPG) axis), testicular (spermatocytogenesis, spermatidogenesis, spermiogenesis, spermiation) and post-testicular (sperm maturation and fertilization) processes according to the timeline of sperm fate. Additionally, critical mechanisms of the action and clinical impacts of autophagy on sperm are identified, laying the foundation for the treatment of male infertility.SEARCH METHODSIn this narrative review, the PubMed database was used to search peer-reviewed publications for summarizing the functional roles of autophagy in the fate of sperm using the following terms: ‘autophagy’, ‘sperm’, ‘hypothalamic–pituitary–testis axis’, ‘spermatogenesis’, ‘spermatocytogenesis’, ‘spermatidogenesis’, ‘spermiogenesis’, ‘spermiation’, ‘sperm maturation’, ‘fertilization’, ‘capacitation’ and ‘acrosome’ in combination with autophagy-related proteins. We also performed a bibliographic search for the clinical impact of the autophagy process using the keywords of autophagy inhibitors such as ‘bafilomycin A1’, ‘chloroquine’, ‘hydroxychloroquine’, ‘3-Methyl Adenine (3-MA)’, ‘lucanthone’, ‘wortmannin’ and autophagy activators such as ‘rapamycin’, ‘perifosine’, ‘metformin’ in combination with ‘disease’, ‘treatment’, ‘therapy’, ‘male infertility’ and equivalent terms. In addition, reference lists of primary and review articles were reviewed for additional relevant publications. All relevant publications until August 2021 were critically evaluated and discussed on the basis of relevance, quality and timelines.OUTCOMES(i) In pre-testicular processes, autophagy-related genes are involved in the regulation of the HPG axis; and (ii) in testicular processes, mTORC1, the main gate to autophagy, is crucial for spermatogonia stem cell (SCCs) proliferation, differentiation, meiotic progression, inactivation of sex chromosomes and spermiogenesis. During spermatidogenesis, autophagy maintains haploid round spermatid chromatoid body homeostasis for differentiation. During spermiogenesis, autophagy participates in acrosome biogenesis, flagella assembly, head shaping and the removal of cytoplasm from elongating spermatid. After spermatogenesis, through PDLIM1, autophagy orchestrates apical ectoplasmic specialization and basal ectoplasmic specialization to handle cytoskeleton assembly, governing spermatid movement and release during spermiation. In post-testicular processes, there is no direct evidence that autophagy participates in the process of capacitation. However, autophagy modulates the acrosome reaction, paternal mitochondria elimination and clearance of membranous organelles during fertilization.WIDER IMPLICATIONSDeciphering the roles of autophagy in the entire fate of sperm will provide valuable insights into therapies for diseases, especially male infertility.

Adrenal gland responses surgical castration and immunocastration by different compensatory manners to increase DHEA secretion

Androgen from the testis and weak androgens from the adrenal cortex may interact with each other and affect their synthesis and secretion due to their similar functions. The purpose of this study was to investigate the compensatory effect of adrenal in rats after immunocastration and surgical castration, and the interaction between the hypothalamic–pituitary–testis (HPT) axis and the hypothalamic–pituitary–adrenal (HPA) axis. 24 male SD rats aged 8 weeks were randomly divided into three groups and accepted treatments: surgical castration group, immunocastration group and control group. In both surgical castration and immunocastration groups, the secretion of adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone (DHEA) hormones was significantly increased compared with the control group (p < 0.05). In the HPT axis of the immunocastration group, the KISS1 expression was up-regulated, whereas GPR54, LH and LHR expression were down-regulated (p < 0.05). The expression levels of CRH, POMC and MC2R genes were also significantly up-regulated (p < 0.05). In addition, in the immunocastration group, the expression of adrenal LHR mRNA expression was decreased (p < 0.05). The expression of HPT axis genes and adrenal LHR were up-regulated in the surgical castration group (p < 0.05). These results show that in both immunocastration and surgical castration, adrenal androgen is increased, suggesting that the adrenal gland plays a compensatory role. Moreover, it also shows that different castration treatments have effects on adrenal steroid secretion through different mechanisms.

Leptin and inflammatory factors play a synergistic role in the regulation of reproduction in male mice through hypothalamic kisspeptin-mediated energy balance

BackgroundEnergy balance is closely related to reproductive function, wherein hypothalamic kisspeptin mediates regulation of the energy balance. However, the central mechanism of kisspeptin in the regulation of male reproductive function under different energy balance states is unclear. Here, high-fat diet (HFD) and exercise were used to change the energy balance to explore the role of leptin and inflammation in the regulation of kisspeptin and the hypothalamic-pituitary-testis (HPT) axis.MethodsFour-week-old male C57BL/6 J mice were randomly assigned to a normal control group (n = 16) or an HFD (n = 49) group. After 10 weeks of HFD feeding, obese mice were randomly divided into obesity control (n = 16), obesity moderate-load exercise (n = 16), or obesity high-load exercise (n = 17) groups. The obesity moderate-load exercise and obesity high-load exercise groups performed exercise (swimming) for 120 min/day and 120 min × 2 times/day (6 h interval), 5 days/week for 8 weeks, respectively.ResultsCompared to the mice in the normal group, in obese mice, the mRNA and protein expression of the leptin receptor, kiss, interleukin-10 (IL-10), and gonadotropin-releasing hormone (GnRH) decreased in the hypothalamus; serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels and sperm quality decreased; and serum leptin, estradiol, and tumor necrosis factor-α (TNF-α) levels and sperm apoptosis increased. Moderate- and high-load exercise effectively reduced body fat and serum leptin levels but had the opposite effects on the hypothalamus and serum IL-10 and TNF-α levels. Moderate-load exercise had anti-inflammatory effects accompanied by increased mRNA and protein expression of kiss and GnRH in the hypothalamus and increased serum FSH, LH, and testosterone levels and improved sperm quality. High-load exercise also promoted inflammation, with no significant effect on the mRNA and protein expression of kiss and GnRH in the hypothalamus, serum sex hormone level, or sperm quality. Moderate-load exercise improved leptin resistance and inflammation and reduced the inhibition of kisspeptin and the HPT axis in obese mice. The inflammatory response induced by high-load exercise may counteract the positive effect of improving leptin resistance on kisspeptin and HPT.ConclusionDuring changes in energy balance, leptin and inflammation jointly regulate kisspeptin expression on the HPT axis.

Peroxisome proliferator-activated receptor gamma expression along the male genital system and its role in male fertility.

Peroxisome proliferator-activated receptor gamma (PPARγ) acts as a ligand activated transcription factor and regulates processes, such as energy homeostasis, cell proliferation and differentiation. PPARγ binds to DNA as a heterodimer with retinoid X receptor and it is activated by polyunsaturated fatty acids and fatty acid derivatives, such as prostaglandins. In addition, the insulin-sensitizing thiazolidinediones, such as rosiglitazone, are potent and specific activators of PPARγ. PPARγ is present along the hypothalamic-pituitary-testis axis and in the testis, where low levels in Leydig cells and higher levels in Sertoli cells as well as in germ cells have been found. High amounts of PPARγ were reported in the normal epididymis and in the prostate, but the receptor was almost undetectable in the seminal vesicles. Interestingly, in the human and in pig, PPARγ protein is highly expressed in ejaculated spermatozoa, suggesting a possible role of PPARγ signaling in the regulation of sperm biology. This implies that both natural and synthetic PPARγ ligands may act directly on sperm improving its performance. Given the close link between energy balance and reproduction, activation of PPARγ may have promising metabolic implications in male reproductive functions. In this review, we first describe PPARγ expression in different compartments of the male reproductive axis. Subsequently, we discuss the role of PPARγ in both physiological and several pathological conditions related to the male fertility.

Genome-Wide Analysis and Function Prediction of Long Noncoding RNAs in Sheep Pituitary Gland Associated with Sexual Maturation

Long noncoding RNA (lncRNA) plays a crucial role in the hypothalamic-pituitary-testis (HPT) axis associated with sheep reproduction. The pituitary plays a connecting role in the HPT axis. However, little is known of their expression pattern and potential roles in the pituitary gland. To explore the potential lncRNAs that regulate the male sheep pituitary development and sexual maturation, we constructed immature and mature sheep pituitary cDNA libraries (three-month-old, TM, and nine-month-old, NM, respectively, n = 3) for lncRNA and mRNA high-throughput sequencing. Firstly, the expression of lncRNA and mRNA were comparatively analyzed. 2417 known lncRNAs and 1256 new lncRNAs were identified. Then, 193 differentially expressed (DE) lncRNAs and 1407 DE mRNAs were found in the pituitary between the two groups. Moreover, mRNA-lncRNA interaction network was constructed according to the target gene prediction of lncRNA and functional enrichment analysis. Five candidate lncRNAs and their targeted genes HSD17B12, DCBLD2, PDPK1, GPX3 and DLL1 that enriched in growth and reproduction related pathways were further filtered. Lastly, the interaction of candidate lncRNA TCONS_00066406 and its targeted gene HSD17B12 were validated in in vitro of sheep pituitary cells. Our study provided a systematic presentation of lncRNAs and mRNAs in male sheep pituitary, which revealed the potential role of lncRNA in male reproduction.

T-2 toxin impairs male fertility by disrupting hypothalamic-pituitary-testis axis and declining testicular function in mice

T-2 toxin could impair male reproductive function. But, the toxicity mechanism is still unclear. In this study, male Kunming mice were orally administrated with T-2 toxin at the doses of 0, 0.5, 1 or 2 mg/kg body weight for 28 days. The fertility, body weight, reproductive organs volume, daily sperm production (DSP), and sperm malformation rate were detected. The expressions of testosterone (T) biosynthetic enzymes, luteinizing hormone (LH)-receptor, follicle stimulating hormone (FSH)-receptor and androgen binding protein (ABP) in testis were detected. The serum hormone level of gonadotropin-releasing hormone (GnRH), FSH, LH, T and progesterone (P), and the mRNA expression of GnRH, GnRH-receptor, LH and FSH were measured. These results demonstrated that T-2 toxin decreased body weight, reproductive organs volume and DSP, increased sperm malformation rate. T-2 toxin impaired fertility by decreasing the mating index, fertility index, numbers of implantation sites and viable fetuses, and increasing the number of animal with resorptions. Meantime, T-2 suppressed testicular function by inhibiting T biosynthesis and decreasing FSHR, LHR and ABP expression. Furthermore, the serum reproductive hormone contents and key factors expression of hypothalamic-pituitary-testis (HPT) axis were decreased by T-2 toxin. In summary, T-2 toxin impaired the male fertility by disrupting HPT axis and impairing testicular function.

Delayed onset of puberty in male offspring from bisphenol A-treated dams is followed by the modulation of gene expression in the hypothalamic-pituitary-testis axis in adulthood.

Bisphenol A (BPA) is a synthetic endocrine-disrupting chemical of high prevalence in the environment, which may affect the function of the hypothalamic-pituitary-testis (HPT) axis in adult rats. The aim of the present study was to evaluate whether exposure to BPA during hypothalamic sexual differentiation at doses below the reproductive no observable adverse effect level of the World Health Organization causes changes in the regulation of the HPT axis. For this, 0.5 or 5mgkg-1 BPA was injected subcutaneously to the mothers from gestational day 18 to postnatal day (PND) 5. In adulthood (PND90), the mRNA expression of genes related to HPT axis was evaluated in hypothalamus, pituitary and testis. Hypothalamic expression of gonadotrophin-releasing hormone (Gnrh) and estrogen receptor 2 (Esr2) mRNA was increased in both BPA-treated groups compared to control group. In the pituitary, follicle stimulating hormone beta subunit (Fshb) and androgen receptor (Ar) mRNA expression was increased compared to control group in rats treated with 0.5mgkg-1 of BPA, whereas estrogen receptor 1 (Esr1) mRNA expression was only increased in the group treated with 5mgkg-1of BPA, compared to control group. In the testis, there was increased expression of FSH receptor (Fshr) and inhibin beta B subunit (Inhbb) transcripts only in rats treated with 0.5mgkg-1 of BPA. Serum testosterone and LH concentrations were increased in the group treated with 5mgkg-1of BPA. The results of the present study demonstrate for the first time that perinatal exposure to low doses of BPA during the critical period of hypothalamic sexual differentiation modifies the activity of the HPT axis in the offspring, with consequences for later life in adult rats.

Di-(2-ethylhexyl) phthalate inhibits testosterone level through disturbed hypothalamic–pituitary–testis axis and ERK-mediated 5α-Reductase 2

Di-(2-ethylhexyl) phthalate (DEHP) has reproductive toxicity and can affect male reproductive development. In order to clarify adverse effects of DEHP on testicular physiology and testosterone production, Sprague-Dawley (SD) rats were dosed daily with DEHP by gavage for 30days; TM3 cells (mouse Leydig cell line) were treated with DEHP for 24h after pretreatment with vitamin C or U0126. Results indicated that the hypothalamic–pituitary–testis (HPT) axis was disturbed and serum testosterone, LH and FSH levels were decreased following DEHP exposure. Histomorphological changes of rat testes were also observed, such as deformed seminiferous tubules, aggregated chromatin, multiple vacuoles, swollen mitochondria, apoptotic germ cells and Sertoli cells, as well as increased Leydig cell numbers. Moreover, DEHP caused oxidative stress in vivo and in vitro and then induced the ERK pathway, which was required to mediate 5α-Reductase 2 and scavenger receptor class B-1 (SRB1) levels. However, levels of steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD), P450 17α-hydroxylase/17.20 lyase (P450c17), and P450 side-chain cleavage enzyme (P450scc) were not significantly altered after DEHP exposure. Taken together, DEHP-disturbed HPT axis and induced 5α-Reductase 2 contribute to the reduction of serum testosterone level. The activated ERK pathway is required to modulate expressions of 5α-Reductase 2 and SRB1.

The expression of several reproductive hormone receptors can be modified by perfluorooctane sulfonate (PFOS) in adult male rats

This study was undertaken to evaluate the possible role of several reproductive hormone receptors on the disruption of the hypothalamic-pituitary-testis (HPT) axis activity induced by perfluorooctane sulfonate (PFOS). The studied receptors are the gonadotropin-releasing hormone receptor (GnRHr), luteinizing hormone receptor (LHr), follicle-stimulating hormone receptor (FSHr), and the androgen receptor (Ar). Adult male rats were orally treated with 1.0; 3.0 and 6.0 mg of PFOS kg−1 d−1 for 28 days. In general terms, PFOS can modify the relative gene and protein expressions of these receptors in several tissues of the reproductive axis. At the testicular level, apart from the expected inhibition of both gene and protein expressions of FSHr and Ar, PFOS also stimulates the GnRHr protein and the LHr gene expression. The receptors of the main hormones involved in the HPT axis may have an important role in the disruption exerted by PFOS on this axis.

Heat-stress-induced metabolic changes and altered male reproductive function.

Heat stress can cause systemic physiological and biochemical alterations in living organisms. In reproductive systems, heat stress induces germ cell loss and poor quality semen. However, until now, little has been known about such a complex regulation process, particularly in the perspective of metabolism. In this study, serum, hypothalamus, and epididymis samples derived from male SD (Sprague-Dawley) rats being exposed to high environmental temperature (40 °C) 2 h per day for 7 consecutive days were analyzed using metabonomics strategies based on GC/TOFMS. Differentially expressed metabolites reveal that the energy metabolism, amino acid neurotransmitters, and monoamine neurotransmitters pathways are associated with heat stress, in accordance with changes of the three upstream neuroendocrine system pathways in the SNS (sympathetic adrenergic system), hypothalamic pituitary adrenal axis (HPA), and hypothalamic pituitary testis axis (HPT) axis. Many of these metabolites, especially in the epididymis, were found to be up-regulated, presumably due to a self-preserving action to resist the environmental hot irritation to maintain normal functioning of the male reproductive system.

Evaluation of Endocrine Profile, Hypothalamic–Pituitary–Testis Axis and Semen Quality in Multiple Sclerosis

Several endocrine and sexual disturbances have been demonstrated in multiple sclerosis (MS) patients of both sexes. The endocrine profile, hypothalamic-pituitary-testis (HPT) axis and semen quality were evaluated in male patients with MS. A total of 68 male MS patients aged 18 years or older were recruited. Forty-eight age-matched healthy male volunteers served as controls. All subjects underwent complete physical examination and routine semen analysis. Two blood samples were drawn from each participant at 15-min intervals for the determination of the resting levels of: luteinising-hormone (LH), follicle-stimulating hormone (FSH), prolactin, testosterone, oestradiol and sex hormone binding globulin. The HPT axis was assessed using gonadotrophin-releasing hormone (GnRH) and human chorionic gonadotrophin tests. The mean basal serum levels for LH, FSH and testosterone in MS patients were significantly lower than the mean for normal controls (P = 0.01). The injection of GnRH analogue did not yield a significant increase in FSH and LH levels in the MS patients compared to normal controls (P = 0.001). Total sperm count, sperm motility and percent normal sperm morphology were lower in MS patients compared to controls. MS subjects with progressive disease had higher and more severe HPT axis abnormalities than that for patients with relapsing remitting MS. Most subjects with MS have hypogonadotrophic hypogonadism state and fertility impairment. It appears that the damage to HPT axis is both in pituitary and testicular levels. Further studies are needed to better elucidate the underlying pathophysiology of HPT axis dysregulation.

Lansoprazole increases testosterone metabolism and clearance in male Sprague-Dawley rats: implications for leydig cell carcinogenesis

Leydig cell tumours (LCTs) are frequently observed during rodent carcinogenicity studies, however, the significance of this effect to humans remains a matter of debate. Many chemicals that produce LCTs also induce hepatic cytochromes P450 (CYPs), but it is unknown whether these two phenomena are causally related. Our aim was to investigate the existence of a liver–testis axis wherein microsomal enzyme inducers enhance testosterone metabolic clearance, resulting in a drop in circulating hormone levels and a consequent hypertrophic response from the hypothalamic–pituitary–testis axis. Lansoprazole was selected as the model compound as it induces hepatic CYPs and produces LCTs in rats. Male Sprague-Dawley rats were dosed with lansoprazole (150 mg/kg/day) or vehicle for 14 days. Lansoprazole treatment produced effects on the liver consistent with an enhanced metabolic capacity, including significant increases in relative liver weights, total microsomal CYP content, individual CYP protein levels, and enhanced CYP-dependent testosterone metabolism in vitro. Following intravenous administration of [ 14C]testosterone, lansoprazole-treated rats exhibited a significantly smaller area under the curve and significantly higher plasma clearance. Significant reductions in plasma and testicular testosterone levels were observed, confirming the ability of this compound to perturb androgen homeostasis. No significant changes in plasma LH, FSH, or prolactin levels were detected under our experimental conditions. Lansoprazole treatment exerted no marked effects on testicular testosterone metabolism. In summary, lansoprazole treatment induced hepatic CYP-dependent testosterone metabolism in vitro and enhanced plasma clearance of radiolabelled testosterone in vivo. These effects may contribute to depletion of circulating testosterone levels and hence play a role in the mode of LCT induction in lansoprazole-treated rats.