Pituitary Gonadotropin Research Articles

Obesity‐Related Stressors Repress Gonadotropin‐releasing Hormone Gene Expression via the Transcription Factor c‐Fos

In obesity, endoplasmic reticulum (ER) stress is a well‐characterized mediator of hormonal dysfunction in multiple tissues, including liver, pancreas, and adipose tissue. In the brain, ER stress induced by excess nutrients and inflammatory cytokines disrupts insulin and leptin sensitivity in hypothalamic neurons controlling food intake. Obesity‐related cellular stressors may also disrupt hypothalamic control of the reproductive system, as obesity is a risk factor for infertility in both men and women. Thus, we sought to determine how ER stress and nutrient excess directly affect production of gonadotropin‐releasing hormone (GnRH) by hypothalamic neurons. GnRH controls pituitary gonadotropin release and subsequent gonadal function, and expression of the Gnrh1 gene is regulated by multiple transcription factors and signaling pathways. Using an immortalized mouse hypothalamic cell line (GT1‐7), we determined that ER stress induced by tunicamycin or thapsigargin repressed expression of the Gnrh1 gene as measured by qRT‐PCR. We also exposed cells to a saturated fatty acid (palmitic acid) to mimic excess nutrients in obesity and observed similar Gnrh1 repression. Both ER stress and palmitic acid promoted inflammation in GT1‐7 cells, as measured by NFκB and JNK activation and IL‐6 production. Repression of Gnrh1 by ER stress was partially rescued by PKC and JNK inhibitors. Because ER stress and palmitic acid upregulated expression of Fos, and because c‐Fos is a known repressor of Gnrh1, we asked whether inhibition of c‐Fos transcriptional activity could rescue Gnrh1 repression. The c‐Fos/AP‐1 inhibitor T5224 was able to completely reverse repression of Gnrh1 by ER stress and palmitic acid, indicating a pivotal role for c‐Fos induction in Gnrh1 repression by obesity‐related stressors. Thus, our work suggests that obesity‐related stressors can directly impact GnRH neurons, and that dysregulation of Gnrh1 expression may contribute to obesity‐related infertility.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Constitutively active follicle-stimulating hormone receptor enables androgen-independent spermatogenesis.

Spermatogenesis is regulated by the 2 pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This process is considered impossible without the absolute requirement of LH-stimulated testicular testosterone (T) production. The role of FSH remains unclear because men and mice with inactivating FSH receptor (FSHR) mutations are fertile. We revisited the role of FSH in spermatogenesis using transgenic mice expressing a constitutively strongly active FSHR mutant in a LH receptor–null (LHR-null) background. The mutant FSHR reversed the azoospermia and partially restored fertility of Lhr–/– mice. The finding was initially ascribed to the residual Leydig cell T production. However, when T action was completely blocked with the potent antiandrogen flutamide, spermatogenesis persisted. Hence, completely T-independent spermatogenesis is possible through strong FSHR activation, and the dogma of T being a sine qua non for spermatogenesis may need modification. The mechanism for the finding appeared to be that FSHR activation maintained the expression of Sertoli cell genes considered androgen dependent. The translational message of our findings is the possibility of developing a new strategy of high-dose FSH treatment for spermatogenic failure. Our findings also provide an explanation of molecular pathogenesis for Pasqualini syndrome (fertile eunuchs; LH/T deficiency with persistent spermatogenesis) and explain how the hormonal regulation of spermatogenesis has shifted from FSH to T dominance during evolution.

Role of granulosa cell mitogen-activated protein kinase 3/1 in gonadotropin-mediated meiotic resumption from diplotene arrest of mammalian oocytes

In mammals, preovulatory oocytes are encircled by several layers of granulosa cells (GCs) in follicular microenvironment. These follicular oocytes are arrested at diplotene arrest due to high level of cyclic nucleotides from encircling GCs. Pituitary gonadotropin acts at the level of encircling GCs and increases adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP) and activates mitogen-activated protein kinase 3/1 (MAPK3/1) signaling pathway. The MAPK3/1 disrupts the gap junctions between encircling GCs and oocyte. The disruption of gap junctions interrupts the transfer of cyclic nucleotides to the oocyte that results a drop in intraoocyte cAMP level. A transient decrease in oocyte cAMP level triggers maturation promoting factor (MPF) destabilization. The destabilized MPF finally triggers meiotic resumption from diplotene arrest in follicular oocyte. Thus, MAPK3/1 from GCs origin plays important role in gonadotropin-mediated meiotic resumption from diplotene arrest in follicular oocyte of mammals.

A novel potential role of pituitary gonadotropins in the pathogenesis of human colorectal cancer.

BackgroundColorectal cancer (CRC) is a leading cause of death in the western world, and its incidence increases with patient age. It is also known that with age there occur changes in the levels of certain hormones, including an increase in the secretion of pituitary gonadotropins (PtGs) as a result of the loss of gonadal hormone feedback. We recently reported that functional PtG receptors are expressed in human lung cancer cells, rhabdomyosarcoma cells, and malignant hematopoietic stem cells.FindingsHere we report for the first time that the receptors for follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are expressed in primary tumor samples isolated from CRC patients as well as in the established human CRC cell lines HTC116 and HTB37. Moreover, we also report that PtGs stimulate chemotaxis, adhesion, and proliferation of these cell lines.ConclusionsOur results suggest that PtGs play an important and underappreciated role in CRC pathogenesis, and we call for further studies to better define their role in gastrointestinal malignancies and their direct effect on putative CRC cancer stem cells.

Modulation of bone morphogenetic protein activity by melatonin in ovarian steroidogenesis.

BackgroundMelatonin regulates circadian and seasonal rhythms and the activities of hormones and cytokines that are expressed in various tissues, including the ovary, in which melatonin receptors are expressed. In the ovary, follicular growth occurs as a result of complex interactions between pituitary gonadotropins and autocrine and paracrine factors, including bone morphogenetic proteins (BMPs) that are expressed in the ovary.MethodsThe effects of melatonin and BMPs on steroidogenesis were examined by using the primary cultures of rat granulosa cells.Main findings (Results)It was shown that melatonin has antagonistic effects on BMP‐6 actions in the granulosa cells, suggesting that melatonin is likely to contribute to balancing the biological activity of endogenous BMPs that maintain progesterone production and luteinization in the growing follicles. Similar interactions between melatonin and BMP–smad signaling also were shown in the mechanism of controlling ovarian steroidogenesis by other ligands.ConclusionA new role of melatonin in the regulation of endocrine homeostasis in relation to BMP activity is introduced in this review.

Seasonal variation of pituitary gonadotropin subunit, brain-type aromatase and sex steroid receptor mRNAs, and plasma steroids during gametogenesis in wild sablefish

Pituitary-hormone signaling plays critical roles in the onset and progression of gametogenesis in vertebrates. This study characterized expression patterns of pituitary gonadotropin beta-subunits (fshb and lhb), brain-type aromatase (cyp19a1b), androgen (ar1, ar2) and estrogen receptors (esr1, esr2a, esr2b), and changes in plasma steroid levels by liquid chromatography/tandem mass spectrometry in wild sablefish (Anoplopoma fimbria, order Scorpaeniformes) during a complete reproductive cycle. Transcripts for fshb increased during early gametogenesis and peaked in late vitellogenic females and late recrudescent males, while expression of lhb reached maximum levels in periovulatory and spermiating fish. Pituitary levels of cyp19a1b and ar1 were strongly correlated with those of lhb in females and males, increasing during gametogenesis and reaching maximum levels prior to spawning. By contrast, expression of ar2, and the three estrogen receptors differed between female and male sablefish. 17β-estradiol (E2) was the dominant steroid in females during vitellogenesis, while a range of at least 6 steroids (11β-hydroxyandrostenedione, testosterone [T], E2, 11-ketotestosterone [11KT], 11-deoxycortisol, and 17α,20β,21-trihydroxyprogesterone) were detected at similar levels in males during testicular development. Prior to spawning, a marked increase in 4-androstenedione, T, 11KT and E2 was found in both periovulatory females and spermiating males. In conclusion, the concomitant changes in plasma androgen levels and pituitary ar1 expression during gametogenesis suggest a specific role for androgens in pituitary hormone regulation of reproduction in sablefish. Further, our data highlight the importance of E2 during final stages of maturation in this species, which may regulate the transcription of pituitary lhb in a paracrine fashion.

Infertility treatment strategy involving combined freeze-all embryos and single vitrified-warmed embryo transfer during hormonal replacement cycle for in vitro fertilization of women with hypogonadotropic hypogonadism.

Hypogonadotropic hypogonadism (HH) is a condition caused by the deficient secretion of pituitary gonadotropins, leading to diminished ovarian function. Several studies of in vitro fertilization (IVF) in women with HH revealed acceptable clinical pregnancy outcomes but high multiple pregnancy rates after multiple fresh embryo transfer (ET). The purpose of this study was to analyze the outcomes of combined freeze-all embryos and single vitrified-warmed ET in women with HH. Of 91 infertile women with HH (basal luteinizing hormone and follicle-stimulating hormone levels <2.0 mIU/mL), we excluded patients aged ≥40 years (n = 2) and women who preferred fresh ET (n = 10). Seventy-nine women underwent 117 oocyte retrieval cycles and 135 vitrified-warmed ET during hormone replacement (HR) cycles from 2008 to 2014 at the Kato Ladies Clinic and Juntendo University Hospital. In 26 single cleavage ET cycles, the rates of clinical pregnancy and live birth were 34.6% (9/26 ET) and 26.9% (7/26 ET), respectively. Regarding the outcomes after single vitrified-warmed blastocyst transfer, clinical pregnancy and live birth rates were 65.1% (71/109 ET) and 50.5% (55/109 ET), respectively. Multiple conceptions and ovarian hyperstimulation syndrome did not occur in any of the women with HH. Our results demonstrated that IVF followed by single vitrified-warmed ET in adjusted endocrine milieu during the HR cycle is an effective fertility treatment for women with HH and decreases the incidence of complications, including multiple conceptions.

107 Preservation of Normal Concentration of Pituitary Gonadotropins Despite Achievement of Normal Serum Testosterone Levels in Hypogonadal Men Treated with 4.5% Nasal Testosterone Gel (Natesto)

One well-recognized limitation of standard testosterone treatments is impaired spermatogenesis via suppression of the pituitary hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). We report here the results of treatment with a 4.5% intranasal testosterone gel (Natesto®), on serum total testosterone (TT), LH, and FSH in hypogonadal men. Hypogonadal men were randomized into a 90-day, open-label, dose-ranging study. 4.5% intranasal testosterone gel (125 uL/nostril, 11.0mg testosterone/dose) was self-administered using a multiple-dose dispenser either twice daily (BID, n=122) or 3 times a day (TID, n=151) for a total dose of 22.0mg or 33.0mg, respectively. Titration was performed based on blood levels so as to achieve the eugonadal range (300 -1050 ng/dL). Serum samples were obtained at baseline and after 90 days of treatment to determine relevant hormone levels. Total serum testosterone increased from a mean Cavg 200.8 ng/dL at baseline to a mean Cmax 818.49 ng/dL at ∼40 minutes. After 90 days, 90% (95% CI = 83-97%) of men in the TID group, and 71% (95% CI = 62-79%) of men in the BID group reached normal T levels, and a mean total testosterone Cavg 421 ng/dL and 375 ng/dL, respectively. Baseline FSH (BID) was 8.49 IU/L, mean at Day 90 was 5.99 IU/L. Baseline FSH (TID) was 6.42 IU/L, mean at Day 90 was 3.12 IU/L. Baseline LH (BID) was 5.42 IU/L, mean at Day 90 was 3.56 IU/L. Baseline LH (TID) was 5.25 IU/L, mean at Day 90 was 2.20 IU/L.

Elevated Expression of follistatin Gene in the Pituitaries of Allotriploid Crucian Carp

AbstractAs a paracrine factor, Follistatin (Fst) plays an important role in regulating biosynthesis and release of pituitary gonadotropin (GTH), gonadal development, and ovulation cycle. In this study, full‐length complementary DNAs (cDNAs) of the follistatin gene in diploid red crucian carp, Carassius auratus red var., allotriploid crucian carp, and allotetraploid hybrids were obtained. Our data showed that the cDNAs of follistatin of all three fish encoded 322 amino acids. Referring to the structural characteristics of Fst in other species, we found that the Fst protein of these three fish had four domains, respectively. Reverse transcriptase polymerase chain reaction (PCR) indicated that the follistatin gene was widely expressed in all tested tissues, except spleens, in these three fish. Real‐time quantitative PCR analysis of different seasonal profiles showed that allotriploids had significantly higher expression of follistatin messenger RNA in pituitaries during both the prespawning and spawning periods. These results suggest that the elevated expression of the follistatin gene in the pituitaries of allotriploids might lead to sterility of allotriploids by blocking the inhibitory effect of activin on luteinizing hormone β subunit. Furthermore, the results may improve our understanding of reproduction characteristics in triploids, which benefits polyploidy breeding.

Hydroxysteroid (17β) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility.

The pituitary gonadotrophins and testosterone are the main hormonal regulators of spermatogenesis, but estradiol is also known to play a role in the process. The hormonal responses in the testis are partially mediated by somatic Sertoli cells that provide nutritional and physical support for differentiating male germ cells. Hydroxysteroid (17β) dehydrogenase 1 (HSD17B1) is a steroidogenic enzyme that especially catalyzes the conversion of low potent 17keto-steroids to highly potent 17β-hydroxysteroids. In this study, we show that Hsd17b1 is highly expressed in Sertoli cells of fetal and newborn mice, and HSD17B1 knockout males present with disrupted spermatogenesis with major defects, particularly in the head shape of elongating spermatids. The cell-cell junctions between Sertoli cells and germ cells were disrupted in the HSD17B1 knockout mice. This resulted in complications in the orientation of elongating spermatids in the seminiferous epithelium, reduced sperm production, and morphologically abnormal spermatozoa. We also showed that the Sertoli cell-expressed HSD17B1 participates in testicular steroid synthesis, evidenced by a compensatory up-regulation of HSD17B3 in Leydig cells. These results revealed a novel role for HSD17B1 in the control of spermatogenesis and male fertility, and that Sertoli cells significantly contribute to steroid synthesis in the testis.-Hakkarainen, J., Zhang, F.-P., Jokela, H., Mayerhofer, A., Behr, R., Cisneros-Montalvo, S., Nurmio, M., Toppari, J., Ohlsson, C., Kotaja, N., Sipilä, P., Poutanen, M. Hydroxysteroid (17β) dehydrogenase 1 expressed by Sertoli cells contributes to steroid synthesis and is required for male fertility.

Reproductive stage- and sex-dependant effects of neurohypophyseal nonapeptides on gonadotropin subunit mRNA expression in the catfish Heteropneustes fossilis: An in vitro study

In the present study, in vitro effects of synthetic vasotocin (VT), isotocin (4Ser, 8Ile- oxytocin; ITb) and the recently cloned IT gene paralog product (8Val-Isotocin, ITa) were studied on the expression of pituitary gonadotropin (GtH) subunit mRNA levels. In male pituitaries of early (preparatory phase) and late (prespawning phase) recrudescing catfish, Heteropneustes fossilis, VT (10 nM, 100 nM and 1000 nM) stimulated fshβ expression dose-dependently. But in females, the dose-dependent effect was found only in the preparatory phase. In males, VT stimulated lhβ expression only at higher doses. In females, VT produced a significant dose-dependent increase of the lhβ expression only in the prespawning phase. VT stimulated the expression of gpα, dose-dependently in the preparatory phase in males and in the prespawning phase in females. The incubation of the pituitaries with ITb did not alter the fshβ expression in either sex in both preparatory and prespawning phases. In males, ITb stimulated the expression of lhβ and gpα only at the highest concentration (1000 nM) in both phases. In females, ITb stimulated both lhβ and gpα expression only at 1000 nM in the preparatory phase and dose-dependently in the prespawning phase. The incubation of the pituitaries with ITa produced effects similar to ITb on the expression of fshβ, lhβ, and gpα. The results show that the basic peptide VT modulates both fshβ and lhβ expressions, which are influenced by the sex and reproductive stage. The neutral peptide ITA/ITb exerts an insignificant effect on the fshβ expression regardless of sex or season. Both VT and ITa/ITb elicit a significant effect on the lhβ expression in late recrudescent phase especially in females.

Lower MPV Can Independently Predict Erectile Dysfunction in T2DM

Objectives: To find out the frequency of erectile dysfunction in diabetic patients and the association between erectile dysfunction and various clinical and laboratory parameters such as diabetic neuropathy, diabetes control, and cardiovascular risk factors. Subjects and methods: 91 type 2 diabetic patients were screened for erectile dysfunction. Clinical data were collected and included body mass index (BMI), blood pressure (BP), heart rate, duration of diabetes and diabetes complications mainly peripheral diabetic neuropathy (PDN). Laboratory data included testosterone, pituitary gonadotropins, fasting plasma glucose (FPG), HbA1c, complete blood count (CBC), serum creatinine and lipid profile. Associations of testosterone and erectile dysfunction with various clinical and biochemical parameters were studied. Results: Erectile dysfunction (ED) was present in 56% of our patients. No significant difference in total testosterone level, LH, FSH or Prolactin level between patients with and those without erectile dysfunction. Patients with peripheral diabetic Neuropathy were significantly at higher risk for erectile dysfunction (ED) [p=0.008]. High HbA1c, Low MPV and low MCH were significant and independent predictors for ED (p= 0.033, 0.033, 0.004 respectively, OR= 1.651, 5.562, 9.524 respectively). Testosterone level was negatively and significantly associated with BMI, heart rate and RDW (p= <0.005, 0.047, 0.028 respectively). Conclusion: Erectile dysfunction is very common among type 2 diabetic patients. It is strongly and directly associated with peripheral diabetic neuropathy (PDN) so, questionnaire and patient examination for PDN and further interrogation of patients complaining of PDN for erectile dysfunction (ED) is of utmost significance. This disorder can be easily predicted by the low MPV and low MCV which are found to be independent predictors in our study population. ED in T2DM is not related to serum testosterone level. Proper control of blood glucose and reaching the target HbA1c can protect diabetic patients from development of such disorder as HbA1c is also found to be a significant independent predictor of it.

Characteristic of factors influencing the proper course of folliculogenesis in mammals

Abstract Folliculogenesis is the process of ovarian follicle formation,, taking presence during foetal period. During the follicular development, oogoniums undergo meiosis and oocytes are formed. In the ovaries of new born sows, primary and secondary follicles are present and, 90 days after birth, tertiary follicles appear. During development in the ovarian follicles growth of granulosa cells and differentiation of the thecal cells can be observed. A cavity filled with follicular fluid appears. Granulosa cells are divided into: mural cells and corona radiata, which together with the oocyte form the cumulus oophorus. Corona radiata cells, mural layers and oolemma contact each other by a network of gap junctions. Secreted from the pituitary gland, FSH and LH gonadotropin hormones act on receptors located in granular and follicular cells. In the postnatal life tertiary follicles and Graafian follicles are formed. When the follicle reaches a diameter of 1 mm, further growth depends on the secretion of gonadotropins. Mature ovarian follicles produce: progestins, androgens and oestrogens. The growth, differentiation and steroidogenic activity of ovarian follicles, in addition to FSH and LH, is also affected by prolactin, oxytocin, steroid and protein hormones, numerous proteins from the cytokine and interleukin family, metabolic hormones like insulin, glucocorticoids, leptin, thyroid hormones and growth hormones. Despite numerous studies, many processes related to folliculogenesis have not been discovered Learning the mechanisms regulating reproductive processes would allow to easily distinguish pathological processes and discover more and more genes and mechanisms of their expression in cells that build ovarian follicles.

Pituitary Gonadotropins, Prolactin and Growth Hormone Differentially Regulate AQP1 Expression in the Porcine Ovarian Follicular Cells.

The present in vitro study analyzed whether the hormones that affect the ovarian follicular steroidogenesis process also participate in the regulation of AQP1 mRNA and protein expression. Granulosa (Gc) and theca cells (Tc) of medium and large porcine ovarian follicles were exposed to follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) and growth hormone (GH) for 24 h in separated cells and co-cultures of these cells. Real-time PCR, Western blotting, immunofluorescence and volumetric analysis were then performed. Gonadotropins, PRL and GH had a stimulatory impact on AQP1 mRNA and protein expression in Gc and Tc of medium and large ovarian cells. Moreover, swelling assays, in response to a hypotonic environment, demonstrated the functional presence of AQPs in porcine Gc and Tc. Immunofluorescence analysis showed that AQP1 protein was mainly localized in the perinuclear region of the cytoplasm, endosomes and cell membranes of Gc and Tc from medium and large follicles. It seems possible that AQP1 present in Gc and Tc cells may be implicated not only in the regulation of water homeostasis required for follicle development but also in cell proliferation and migration.

Effect of long-term food restriction on reproductive performances in female yellowtail, Seriola quinqueradiata

In aquaculture of species with a large body size, such as tuna and yellowtail, a major profitability concern is that broodstock management for egg collection incurs high feeding costs and labor. In order to reduce feeding costs, development of restricted feeding techniques without affecting the reproductive performance may be useful. To gain a better understanding of the potential significance of capital energy in reproduction of large fish with income breeding patterns, we examined the effects of long-term restricted feeding prior to the onset of oocyte development on reproductive performance in female yellowtail (Seriola quinqueradiata). A control group was fed to satiety, while experimental groups were restricted to 50 and 25% of the ration administered to the control group from July to December. The females subjected to restricted feeding had lower ovary weight and smaller ovarian follicles than did the control females in February. Moreover, plasma 17β-estradiol levels in food-restricted females were significantly lower than those in normally fed females in January and February. Furthermore, we found that food-restricted females had lower pituitary gene expression levels of gonadotropins (follicle-stimulating hormone and luteinizing hormone) in January. These results suggest that severe food restriction during the immature phase delays initiation of oocyte development via an alteration in pituitary gonadotropin production in yellowtail females. Once food intake was sufficient after switching to the satiation feeding regime, however, oocyte development rapidly advanced, resulting in the production of fully functional eggs. Overall, these findings demonstrate that the yellowtail displays a mixed strategy of capital-breeding patterns at the onset of sexual maturation, but stronger income-breeding patterns with its progression in reproduction with energy acquired during the vitellogenic phase. Additionally, food deprivation over 6months by 50% of the amount of food required for satiation during the immature phase did not change reproductive performance in female yellowtail, although the females in the 25% feeding group showed a lower percentage of normally hatching eggs. Therefore, a 50% restricted feeding regime before the onset of sexual maturation is acceptable for reducing feeding costs in broodstock management without affecting reproductive performance.

Mitogen- and stress-activated protein kinase 1 is required for gonadotropin-releasing hormone–mediated activation of gonadotropin α-subunit expression

Pituitary gonadotropin hormones are regulated by gonadotropin-releasing hormone (GnRH) via MAPK signaling pathways that stimulate gene transcription of the common α-subunit (Cga) and the hormone-specific β-subunits of gonadotropin. We have reported previously that GnRH-induced activities at these genes include various histone modifications, but we did not examine histone phosphorylation. This modification adds a negative charge to residues of the histone tails that interact with the negatively charged DNA, is associated with closed chromatin during mitosis, but is increased at certain genes for transcriptional activation. Thus, the functions of this modification are unclear. We initially hypothesized that GnRH might induce phosphorylation of Ser-10 in histone 3 (H3S10p) as part of its regulation of gonadotropin gene expression, possibly involving cross-talk with H3K9 acetylation. We found that GnRH increases the levels of both modifications around the Cga gene transcriptional start site and that JNK inhibition dramatically reduces H3S10p levels. However, this modification had only a minor effect on Cga expression and no effect on H3K9ac. GnRH also increased H3S28p and H3K27ac levels and also those of activated mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 inhibition dramatically reduced H3S28p levels in untreated and GnRH-treated cells and also affected H3K27ac levels. Although not affecting basal Cga expression, MSK1/2 inhibition repressed GnRH activation of Cga expression. Moreover, ChIP analysis revealed that GnRH-activated MSK1 targets the first nucleosome just downstream from the TSS. Given that the elongating RNA polymerase II (RNAPII) stalls at this well positioned nucleosome, GnRH-induced H3S28p, possibly in association with H3K27ac, would facilitate the progression of RNAPII.

Pyrethroid Insecticide Cypermethrin Modulates Gonadotropin Synthesis via Calcium Homeostasis and ERK1/2 Signaling in LβT2 Mouse Pituitary Cells.

Pyrethroids are a class of widely used insecticides. Cypermethrin (CP) is one of most commonly used pyrethroid insecticides and its residue has been frequently detected in environmental media. Our recent animal study reported that early postnatal exposure to CP induced an increase in serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as well as the expression of gonadotropin subunit genes (chorionic gonadotropin α [CGα], LHβ and FSHβ) in pituitary tissues. In this study, we further investigated the precise mechanism by which CP at concentrations of 1-100 nM affected the synthesis of gonadotropins using a murine pituitary gonadotropic cell line LβT2. We found that calcium (Ca2+)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) activity was required for CP-regulated transcription of CGαs, LHβ and FSHβ. We provided the novel evidence that CP caused both influx of extracellular Ca2+ through L-type voltage-gated calcium channels (VGCCs) and release of intracellular Ca2+ from endoplasmic reticulum (ER) via inhibition of Ca2+-ATPase. Our results showed that CP disrupted Ca2+ homeostasis via these two separate and independent pathways, thus resulting in the activation of protein kinase C /c-Raf/ERK1/2/immediate-early genes pathways and subsequent increase in the transcription of gonadotropin subunit genes. Our findings would have important implications for understanding the underlying mechanisms of the disrupting effects of some pyrethroids (such as CP) on the synthesis of pituitary gonadotropins.

A Journey through the Gonadotropin-Inhibitory Hormone System of Fish.

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that belongs to the RFamide peptide family and was first identified in the quail brain. From the discovery of avian GnIH, orthologous GnIH peptides have been reported in a variety of vertebrates, including mammals, amphibians, teleosts and agnathans, but also in protochordates. It has been clearly established that GnIH suppresses reproduction in avian and mammalian species through its inhibitory actions on brain GnRH and pituitary gonadotropins. In addition, GnIH also appears to be involved in the regulation of feeding, growth, stress response, heart function and social behavior. These actions are mediated via G protein-coupled GnIH receptors (GnIH-Rs), of which two different subtypes, GPR147 and GPR74, have been described to date. With around 30,000 species, fish represent more than one-half of the total number of recognized living vertebrate species. In addition to this impressive biological diversity, fish are relevant because they include model species with scientific and clinical interest as well as many exploited species with economic importance. In spite of this, the study of GnIH and its physiological effects on reproduction and other physiological processes has only been approached in a few fish species, and results obtained are in some cases conflicting. In this review, we summarize the information available in the literature on GnIH sequences identified in fish, the distribution of GnIH and GnIH-Rs in central and peripheral tissues, the physiological actions of GnIH on the reproductive brain-pituitary-gonadal axis, as well as other reported effects of this neuropeptide, and existing knowledge on the regulatory mechanisms of GnIH in fish.

Síndrome de Klinefelter

This syndrome, originally observed in 1812 and described in 1942 by Klinefelter, Reifenstein, and Albright, is characterized by sterility, small atrophic testes with specific histologic changes, elevated urinary pituitary gonadotropin, and sometimes some degree of eunuchoidism. Generally, the penis is of normal size; the 17 ketosteroids are normal norms. The clinical picture is highly variable; sometimes there is a mental deficiency, feminized obesity and a family incidence has been determined.

Evaluation of Newly Developed Chemical Castration Method: Changes in Hormone Gene Expression of Hypothalamic-Pituitary Axis.

ABSTRACTSurgical castration (also known as orchidectomy, ORX) has been frequently performed to avoid uncontrolled breeding. However, it has some serious disadvantages. Several laboratories have developed chemical castration methods, using bilateral intratesticular injection (BITI) of simple chemical solutions. The present study was undertaken to compare the effects of ORX and of hypertonic saline BITI on the androgen-sensitive tissues such as pituitary and hypothalamus. Serum testosterone (T) levels of ORX animals and hypertonic saline BITI animals (SAL) after 4 weeks of the manipulations exhibited significantly drops as compared with the levels of intact animals (Intact:ORX:SAL = 7.74± 1.31:1.34±0.19:1.28±0.18 ng/ml, p<0.001). Both ORX and BITI method induced similar stimulatory effects on the pituitary gonadotropin subunits and hypothalamic KiSS-1 gene expressions. In contrast, the effects of ORX and hypertonic saline BITI on hypothalamic GnRH gene expression were different from these gene expressions, shown an inverse relationship between the two groups (Intact:ORX:SAL = 1:0.45±0.06:1:2.07±0.41:1.51±0.37 AU; ORX, p<0.001; SAL, p<0.05). In conclusion, we provided evidence that hypertonic saline BITI method has equivalent efficacy of T depletion to surgical castration in rats. The present study suggests the hypertonic saline BITI could be a promising substitute to conventional surgical castration.