Pituitary Luteinizing Hormone Secretion Research Articles

Androgen inhibition of reproductive neuroendocrine function in females and transgender males.

Ovarian function is controlled by pituitary secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which in turn are governed by gonadotropin releasing hormone (GnRH) secreted from the brain. A fundamental principle of reproductive axis regulation is negative feedback signaling by gonadal sex steroids back to the brain to fine-tune GnRH and gonadotropin secretion. Endogenous negative feedback effects can be mimicked by exogenous steroid treatments, including androgens, in both sexes. Indeed, a growing number of clinical and animal studies indicate that high levels of exogenous androgens, in the typically male physiological range, can inhibit LH secretion in females, as occurs in males. However, the mechanisms by which male-level androgens inhibit GnRH and LH secretion still remain poorly understood, and this knowledge gap is particularly pronounced in transgender men (individuals designated female at birth but identifying as male). Indeed, many transgender men take long-term gender-affirming hormone therapy that mimics male-level testosterone levels. The impact of such gender-affirming testosterone on the reproductive axis, both at the ovarian and neuroendocrine level, is a long-understudied area that still requires further investigation. Importantly, the few concepts of androgen actions in females mostly come from studies of polycystic ovary syndrome which does not recapitulate a similar androgen milieu or a pathophysiology of inhibited LH secretion as occurs in testosterone-treated transgender men. This review summarizes clinical evidence indicating that exogenous androgens can impair neuroendocrine reproductive function in both females and transgender men and highlights emerging experimental data supporting this in recently-developed transgender rodent models.

Ethanolamine plasmalogens derived from scallops stimulate both follicle-stimulating hormone and luteinizing hormone secretion by bovine gonadotrophs

Brain ethanolamine plasmalogens (EPls) are the only known ligands of G-protein-coupled receptor 61, a novel receptor that stimulates follicle-stimulating hormone (FSH), but not luteinizing hormone (LH), secretion by bovine gonadotrophs. We hypothesized that the recently developed neuroprotective EPls extracted from scallop (Pecten yessoensis) (scallop EPls) could stimulate FSH secretion by gonadotrophs. To test this hypothesis, bovine gonadotrophs were cultured for 3.5 days and treated with increasing concentrations of scallop EPls. FSH secretion was stimulated by all tested concentrations of scallop EPls (P < 0.05). Surprisingly, LH secretion was stimulated by both 0.5 (P < 0.05) and 5 (P < 0.01) ng/mL of scallop EPls. To clarify the important differences between bovine brain and scallop EPls, we utilized two-dimensional liquid chromatography–mass spectrometry, which revealed 44 peaks, including 10 large peaks. Among them, eight were scallop-specific EPl molecular species, occupying approximately 58% of the total area percentage of scallop EPls. Almost all large peaks contained 4, 5, or 6 unsaturated double bonds in the carbon chain at the sn-2 position of the glycerol backbone. Our results showed that EPls from scallops, lacking pituitary glands, stimulated both FSH and LH secretion by bovine gonadotrophs.

Ovarian Sensitivity Decreased Significantly in Patients With Insulin Resistance Undergoing in vitro Fertilization and Embryo Transfer.

Ovarian sensitivity could affect the outcome of in vitro fertilization and embryo transfer (IVF-ET). The objective of this study was to explore the relationship between the ovarian sensitivity index (OSI) and traditional ovarian response makers and observe the relationship between OSI and insulin resistance (IR). The patients enrolled in this study included 131 patients with polycystic ovary syndrome (PCOS) with IR (PCOS-IR), 52 patients with PCOS without IR (PCOS-N), 164 patients with control with IR (control-IR), 133 patients with control without IR (control-N), 295 patients with IR, 184 patients with non-IR, 183 patients with PCOS, and 297 patients with control (patients with non-PCOS). All patients received standard long protocol or the gonadotropin-releasing hormone (GnRH) antagonist protocol to induce follicular development. The two protocols downregulated the pituitary function or blocked the pituitary luteinizing hormone (LH) secretion with a GnRH antagonist. Both protocols can block premature LH surges because premature luteinization is not conducive to follicular development. All patients underwent IVF or intracytoplasmic sperm injection (ICSI). Embryo transfer was carried out according to the specific situation of each patient. The OSI was significantly reduced in patients with IR. The OSI had a significant positive relationship with anti-Müllerian hormone (AMH), antral follicle count (AFC), basal LH/follicle-stimulating hormone (FSH), dominant follicle number on trigger day, retrieved oocytes, embryo number, and high-quality embryo number. OSI had a significant negative relationship with age, body mass index (BMI), basal FSH, initial dose of Gn, and total dose of Gn. The receiver operating characteristic (ROC) curve of OSI demonstrated a better accuracy in distinguishing patients with positive pregnancy and clinical pregnancy, with an area under the curve (AUC) of 0.662 (95% CI, 0.598–0.727) and 0.636 (95% CI, 0.577–0.695), respectively. Patients could get a higher rate of dominant follicle count (p < 0.0001) through the treatment of standard long protocol when compared with GnRH antagonist protocol. The OSI has a significant correlation with traditional ovarian response markers and could be a good predictor of positive pregnancy and clinical pregnancy for patients with IR.

Vasoactive Intestinal Peptide Indirectly Elicits Pituitary LH Secretion Independent of GnRH in Female Zebrafish

Vasoactive intestinal peptide (Vip) regulates luteinizing hormone (LH) release through the direct regulation of gonadotropin-releasing hormone (GnRH) neurons at the level of the brain in female rodents. However, little is known regarding the roles of Vip in teleost reproduction. Although GnRH is critical for fertility through the regulation of LH secretion in vertebrates, the exact role of the hypophysiotropic GnRH (GnRH3) in zebrafish is unclear since GnRH3 null fish are reproductively fertile. This phenomenon raises the possibility of a redundant regulatory pathway(s) for LH secretion in zebrafish. Here, we demonstrate that VipA (homologues of mammalian Vip) both inhibits and induces LH secretion in zebrafish. Despite the observation that VipA axons may reach the pituitary proximal pars distalis including LH cells, pituitary incubation with VipA in vitro, and intraperitoneal injection of VipA, did not induce LH secretion and lhβ mRNA expression in sexually mature females, respectively. On the other hand, intracerebroventricular administration of VipA augmented plasma LH levels in both wild-type and gnrh3-/- females at 1 hour posttreatment, with no observed changes in pituitary GnRH2 and GnRH3 contents and gnrh3 mRNA levels in the brains. While VipA's manner of inhibition of LH secretion has yet to be explored, the stimulation seems to occur via a different pathway than GnRH3, dopamine, and 17β-estradiol in regulating LH secretion. The results indicate that VipA induces LH release possibly by acting with or through a non-GnRH factor(s), providing proof for the existence of functional redundancy of LH release in sexually mature female zebrafish.

The Hippo Pathway Effectors YAP and TAZ Regulate LH Release by Pituitary Gonadotrope Cells in Mice.

The Hippo transcriptional coactivators YAP and TAZ exert critical roles in morphogenesis, organ size determination and tumorigenesis in many tissues. Although Hippo kinase cascade activity was recently reported in the anterior pituitary gland in mice, the role of the Hippo effectors in regulating gonadotropin production remains unknown. The objective of this study was therefore to characterize the roles of YAP and TAZ in gonadotropin synthesis and secretion. Using a conditional gene targeting approach (cKO), we found that gonadotrope-specific inactivation of Yap and Taz resulted in increased circulating levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in adult male mice, along with increased testosterone levels and testis weight. Female cKO mice had increased circulating LH (but not FSH) levels, which were associated with a hyperfertility phenotype characterized by higher ovulation rates and larger litter sizes. Unexpectedly, the loss of YAP/TAZ did not appear to affect the expression of gonadotropin subunit genes, yet both basal and GnRH-induced LH secretion were increased in cultured pituitary cells from cKO mice. Likewise, pharmacologic inhibition of YAP binding to the TEAD family of transcription factors increased both basal and GnRH-induced LH secretion in LβT2 gonadotrope-like cells in vitro without affecting Lhb expression. Conversely, mRNA levels of ChgA and SgII, which encode key secretory granule cargo proteins, were decreased following pharmacologic inhibition of YAP/TAZ, suggesting a mechanism whereby YAP/TAZ regulate the LH secretion machinery in gonadotrope cells. Together, these findings represent the first evidence that Hippo signaling may play a role in regulating pituitary LH secretion.

Reproductive Regulation of PrRPs in Teleost: The Link Between Feeding and Reproduction.

Prolactin-releasing peptide (PrRP), a sort of vital hypothalamic neuropeptide, has been found to exert an enormous function on the food intake of mammals. However, little is known about the functional role of PrRP in teleost. In the present study, two PrRP isoforms and four PrRP receptors were isolated from grass carp. Ligand-receptor selectivity displayed that PrRP1 preferentially binds with PrRP-R1a and PrRP-R1b, while PrRP-R2a and PrRP-R2b were special receptors for PrRP2. Tissue distribution indicated that both PrRPs and PrRP-Rs were highly expressed in the hypothalamus-pituitary-gonad axis and intestine, suggesting a latent function on food intake and reproduction. Using grass carp as a model, we found that food intake could significantly induce hypothalamus PrRP mRNA expression, which suggested that PrRP should be also an anorexigenic peptide in teleost. Interestingly, intraperitoneal (IP) injection of PrRPs could significantly induce serum luteinizing hormone (LH) secretion and pituitary LHβ and GtHα mRNA expression in grass carp. Moreover, using primary culture grass carp pituitary cells as a model, we further found that PrRPs could directly induce pituitary LH secretion and synthesis mediated by AC/PKA, PLC/IP3/PKC, and Ca2+/CaM/CaMK-II pathways. Finally, estrogen treatment of prepubertal fish elicited increases in PrRPs and PrPR receptors expression in primary cultured grass carp hypothalamus cells, which further confirmed that the PrRP/PrRPR system may participate in the neuroendocrine control of fish reproduction. These results, taken together, suggest that PrRPs might act as a coupling factor in feeding metabolism and reproductive activities in teleost.

Gonadotropin-Releasing Hormone (GnRH) Neuron Potassium Currents and Excitability in Both Sexes Exhibit Minimal Changes upon Removal of Negative Feedback.

Gonadotropin-releasing hormone (GnRH) drives pituitary secretion of luteinizing hormone and follicle-stimulating hormone, which in turn regulate gonadal functions including steroidogenesis. The pattern of GnRH release and thus fertility depend on gonadal steroid feedback. Under homeostatic (negative) feedback conditions, removal of the gonads from either females or males increases the amplitude and frequency of GnRH release and alters the long-term firing pattern of these neurons in brain slices. The neurobiological mechanisms intrinsic to GnRH neurons that are altered by homeostatic feedback are not well studied and have not been compared between sexes. During estradiol-positive feedback, which is unique to females, there are correlated changes in voltage-gated potassium currents and neuronal excitability. We thus hypothesized that these same mechanisms would be engaged in homeostatic negative feedback. Voltage-gated potassium channels play a direct role in setting excitability and action potential properties. Whole-cell patch-clamp recordings of GFP-identified GnRH neurons in brain slices from sham-operated and castrated adult female and male mice were made to assess fast and slow inactivating potassium currents as well as action potential properties. Surprisingly, no changes were observed among groups in most potassium current properties, input resistance, or capacitance, and this was reflected in a lack of differences in excitability and specific action potential properties. These results support the concept that, in contrast to positive feedback, steroid-negative feedback regulation of GnRH neurons in both sexes is likely conveyed to GnRH neurons via mechanisms that do not induce major changes in the biophysical properties of these cells.

Dissecting the Involvement of Arcuate Nucleus Kisspeptin Neurons in Puberty Onset and LH Secretion

Puberty is a crucial period of transition to adulthood, marked by an increased activation of gonadotropin-releasing hormone (GnRH) neurons that drives increased pulsatile secretion of pituitary luteinizing hormone (LH). The mechanisms governing GnRH neuron activation at puberty remain unclear but are likely due to enhanced signaling from upstream neuron populations, including kisspeptin neurons. Kisspeptin (encoded by Kiss1) directly stimulates GnRH neurons to drive GnRH release and downstream LH secretion. Humans and animals with Kiss1 mutations fail to reach puberty, demonstrating kisspeptin’s importance in puberty onset. Nonetheless, the specific brain area(s) from where kisspeptin signaling arises to trigger puberty remain undetermined. Kisspeptin is primarily expressed in two hypothalamic areas, the arcuate nucleus (ARC) and anteroventral periventricular (AVPV) region. ARC Kiss1 neurons are known to drive pulsatile GnRH/LH secretion in both sexes whereas AVPV Kiss1 neurons are sexually dimorphic and mediate the preovulatory GnRH/LH surge in females. We previously showed that Kiss1 gene expression increases in both the ARC and AVPV across the peri-pubertal period, yet it still remains to be determined whether just one or both of these populations is essential for proper pubertal timing. Indeed, the relative involvement of either ARC or AVPV Kiss1 neurons in the pubertal process still remains unknown. Here, we hypothesized that ARC Kiss1 neurons are required for normal puberty timing in both sexes and, conversely, AVPV Kiss1 neurons are not sufficient on their own to trigger normal puberty. To test this hypothesis, we used transgenic mice expressing diphtheria toxin receptor (DTR) exclusively in Kiss1 cells (Kiss Cre/iDTR flox) and took advantage of the differential ontogeny of ARC and AVPV Kiss1 neurons to selectively ablate ARC kisspeptin neurons before puberty, while leaving AVPV neurons intact. We found that targeted deletion of just ARC Kiss1 neurons during the juvenile period (which does not alter AVPV Kiss1 cell number) significantly delays puberty onset in both sexes, as measured by vaginal opening, first estrous, and preputial separation. In addition, these mice also exhibit decreased basal and pulsatile LH secretion in adulthood, further supporting a role for ARC kisspeptin neurons in GnRH pulse generation. By contrast, females with ablated ARC Kiss1 cells still exhibit full estradiol-induced LH surges, ruling out a necessary role of ARC kisspeptin neurons in that process and further supporting AVPV kisspeptin as the primary regulator of the surge. Collectively, our findings demonstrate that ARC Kiss1 neurons are required for both properly timed activation of the reproductive axis during puberty and proper pulsatile LH secretion in adulthood, while AVPV Kiss1 neurons are not sufficient to drive normal puberty onset but are sufficient for the preovulatory LH surge.

Gonadotrophin-releasing hormone receptor autoantibodies induce polycystic ovary syndrome-like features in a rat model.

What is the central question of this study? Is there a causal relationship between gonadotrophin-releasing hormone (GnRH) receptor-activating autoantibodies and polycystic ovary syndrome (PCOS)? What is the main finding and its importance? Induction of GnRH receptor-activating autoantibodies in rats resulted in increased luteinizing hormone pulsatility and testosterone concentrations, disrupted oestrous cycles, increased atretic follicles, and activation of insulin signalling in the pituitary and ovary. These changes replicate those seen in humans with PCOS, suggesting that GnRH receptor-activating autoantibodies might be involved in the pathogenesis of PCOS. Gonadotrophin-releasing hormone receptor-activating autoantibodies (GnRHR-AAb) are associated with polycystic ovary syndrome (PCOS). In the present study, we examined the impact of GnRHR-AAb on reproductive function in GnRHR-immunized female rats. All immunized rats produced high titres of GnRHR-AAb targeting a dominant epitope located in the central region of the second extracellular loop of the GnRHR. Increased pulsatile luteinizing hormone secretion and testosterone concentrations were found in immunized rats. These rats exhibited disrupted oestrous cycles, increased ovarian follicular atresia, and activation of insulin signalling in the pituitary and ovary, as indicated by increased mRNA expressions of insulin receptor substrate, phosphatidylinositol 3-kinase and glucose transporter1. No significant changes in inflammatory cytokines were detected in the ovarian tissue. These features mimic those observed in humans with PCOS. Our findings support the concept that chronic stimulation of the GnRHR by GnRHR-AAb, with an associated increase in pituitary luteinizing hormone secretion and ovarian androgen overproduction, might represent a new aetiological mechanism for PCOS.

Luteal Phase in Assisted Reproductive Technology.

Luteal phase (LP) is the period of time beginning shortly after ovulation and ending either with luteolysis, shortly before menstrual bleeding, or with the establishment of pregnancy. During the LP, the corpus luteum (CL) secretes progesterone and some other hormones that are essential to prepare the uterus for implantation and further development of the embryo, the function known as uterine receptivity. LP deficiency (LPD) can occur when the secretory activity of the CL is deficient, but also in cases of normal CL function, where it is caused by a defective endometrial response to normal levels of progesterone. LPD is particularly frequent in treatments using assisted reproductive technology (ART). Controlled ovarian stimulation usually aims to obtain the highest number possible of good-quality oocytes and requires the use of gonadotropin-releasing hormone (GnRH) analogs, to prevent premature ovulation, as well as an ovulation trigger to achieve timed final oocyte maturation. Altogether, these treatments suppress pituitary secretion of luteinizing hormone (LH), required for the formation and early activity of the CL. In addition to problems of endometrial receptivity for embryos, LPD also leads to dysfunction of the local uterine immune system, with an increased risk of embryo rejection, abnormally high uterine contractility, and restriction of uterine blood flow. There are two alternatives of LPD prevention: a direct administration of exogenous progesterone to restore the physiological progesterone serum concentration independently of the CL function, on the one hand, and treatments aimed to stimulate the CL activity so as to increase endogenous progesterone production, on the other hand. In case of pregnancy, some kind of LP support is often needed until the luteal–placental shift occurs. If LPD is caused by defective response of the endometrium and uterine immune cells to normal concentrations of progesterone, a still poorly defined condition, symptomatic treatments are the only available solution currently available.

Effects of allopregnanolone on central reproductive functions in sheep under natural and stressful conditions

Reproductive functions may be affected by internal and external factors that are integrated in the central nervous system (CNS). Stressful stimuli induce the neuroendocrine response of the hypothalamic-pituitary-adrenal axis, as well as the synthesis of the neurosteroid allopregnanolone (AL) in the brain. This study tested the hypothesis that centrally administered AL could affect the expression of certain genes involved in reproductive functions at the hypothalamus and pituitary levels, as well as pulsatile gonadotropin secretion in sheep under both natural and stressful conditions. Luteal-phase sheep (n = 24) were subjected to a three-day (day 12–14 of the estrous cycle) series of control or AL (4 × 15 μg/60 μL/30 min, at 30 min intervals) infusions into the third ventricle. Acute stressful stimuli (isolation from other sheep and partial movement restriction) were used in the third day of infusion. Stressful stimuli reduced kisspeptin-1 mRNA levels in both the mediobasal hypothalamus (MBH) and the preoptic area (POA), while pro-dynorphin (PDYN) mRNA level only in the MBH. AL alone decreased the abundances of these transcripts in both structures. Stress increased the expression of gonadotropin-releasing hormone (GnRH) mRNA in the MBH and POA, luteinizing hormone (LH) β subunit (LHβ) mRNA in the anterior pituitary (AP) and pulsatile LH secretion. In contrast, mRNA level of follicle stimulating hormone (FSH) β subunit (FSHβ) was decreased in the AP, with no effect of stress on pulsatile FSH secretion. In stressed sheep, AL counteracted the increase in GnRH mRNA expression only in the POA, but it decreased the level of this transcript in both hypothalamic tissues when infused alone. AL prevented the stress-induced increase in LHβ mRNA expression in the AP and pulsatile LH secretion, as well as inhibited almost all aspects of FSH secretion when administered alone. The suppressive effect of AL on GnRH receptor mRNA expression was also observed in both MBH and AP. We concluded that acute stress and AL exerted multidirectional effects on hypothalamic centers that regulate reproductive functions and secretory activity of AP gonadotrophs in sheep. However, we indicated the dominant inhibitory effect of AL under natural and stressful conditions.

SUN-LB57 Assessing the Requirement of Arcuate Nucleus Kisspeptin Neurons in Puberty Onset and Adult LH Secretion

Puberty is a critical developmental period marking the transition to adulthood and attainment of reproductive capability. A hallmark of puberty is increased pulsatile secretion of pituitary luteinizing hormone (LH) which is itself driven by increased gonadotropin-releasing hormone (GnRH) from the forebrain. The mechanisms governing GnRH neuron activation at puberty still remain unclear, but likely include enhanced stimulation from upstream reproductive neural circuits, including kisspeptin neurons. Kisspeptin is a potent stimulator of GnRH and is required for proper puberty onset. However, the specific brain site(s) from where kisspeptin signaling arises to trigger puberty remain unclarified. Kisspeptin is expressed in two primary nuclei in the hypothalamus, the arcuate nucleus (ARC) and anteroventral periventricular (AVPV) region. Studies suggest that, in adulthood, ARC Kiss1 neurons are involved in driving pulsatile secretion of GnRH (and hence, LH) in both sexes whereas AVPV Kiss1 neurons participate in the preovulatory GnRH/LH surge in females. However, the specific role of either kisspeptin neuron population in puberty onset still remains unknown. We previously showed that both kisspeptin populations show increased Kiss1 gene expression across the pubertal period, yet whether just one or both (or neither) population is needed for puberty to occur has not been determined. Here, we sought to tease out the role—if any—of ARC and AVPV Kiss1 neurons in the pubertal onset process. Since ARC Kiss1 neurons are abundant in both sexes and drive pulsatile GnRH secretion in adulthood, we hypothesized that ARC Kiss1 neurons are necessary for normal puberty onset and, conversely, that AVPV Kiss1 neurons are not sufficient on their own to induce normal puberty. To test this hypothesis, we used a Cre-specific diphtheria toxin approach to ablate just ARC Kiss1 neurons in juvenile mice (~ 2 weeks old) while leaving AVPV Kiss1 neurons intact. Preliminary data thus far indicates that site specific ablation of just ARC Kiss1 neurons during the juvenile period significantly delays puberty onset in both sexes, as measured by vaginal opening, first estrous, and preputial separation. In addition, selective ARC Kiss1 neuron ablation in juvenile life diminishes pulsatile LH secretion levels measured in adulthood, but does not alter LH surge generation in adult females. These preliminary findings empirically demonstrate that, in mice, ARC Kiss1 neurons are required for proper activation of the reproductive axis during puberty but not the LH surge in adulthood, and AVPV Kiss1 neurons are not sufficient to trigger normal pubertal onset.

Differential Regulation of Gonadotropins in Response to Continuous Infusion of Native Gonadotropin-Releasing Hormone in the Winter Anovulatory Mare and Effects of Treatment With Estradiol-17β

We tested the hypotheses that in winter anovulatory mares (1) both chronic daily injections of estradiol-17β (E2) and subcutaneous E2 implants could enhance pituitary secretion of gonadotropins in response to continuous subcutaneous infusion of native gonadotropin-releasing hormone (GnRH); and (2) the secretory pattern of follicle-stimulating hormone (FSH) in response to continuous subcutaneous infusion of native GnRH is similar to that of luteinizing hormone (LH) but differs between mares that develop or fail to develop an estrogen-active, preovulatory follicle. In Experiment 1, 20 winter anovulatory mares (n = 5 per group) in early February received twice-daily injections of corn oil (control) or 5 mg of E2 with or without continuous subcutaneous treatment with native GnRH (100 μg/hr) or received GnRH only for up to 14 days. In Experiment 2, 24 winter anovulatory mares (n = 6 per group) were treated with a full-length (high dose) or quarter-length (low dose) E2 implant (Compudose) in combination with continuous GnRH infusion (100 μg/hr) for up to 28 days or served as sham controls. Mares developing 35-mm follicles were induced to ovulate with human chorionic gonadotropin. Mares not developing a 35-mm follicle within 14 days received a replacement 14-day GnRH pump. In Experiment 1, E2 enhanced the response to GnRH beginning on Day 3, with mean LH greater (P < .001) in GnRH + E2 than in GnRH only and control mares. In Experiment 2, plasma E2 and estrone sulfate were increased in association with the development of a large (35 mm) follicle but did not increase in response to either E2 implant despite marked increases in uterine edema following their insertion. A sustained increase (P < .0001) in plasma LH was observed in all GnRH-treated mares, but this effect was not modified by implant treatment. By Day 28, six of six GnRH, five of six GnRH + low E2, two of six GnRH + high E2, and zero of six control mares developed 35-mm follicles and were induced to ovulate. A marked increase (P < .0001) in plasma FSH was observed within 24 hours in all GnRH-treated mares, returning to baseline by Day 4. In summary, twice-daily injection of 5 mg E2 enhanced pituitary secretion of LH in response to continuous administration of GnRH, but commercial E2 cattle implants failed to duplicate these effects. Continuous infusion of GnRH produced a differential but consistent pattern of FSH secretion (short-term increase) compared with LH (sustained increase). Differences in ovarian responses to GnRH treatment could not be explained by variation in gonadotropin secretion.

So similar and so different: Circulating androgens and androgen origin in bulimic women

Hyper androgen state frequently can be diagnosed in bulimic women. Eating disorder not otherwise specified (EDNOS) recognized as a less severe form of bulimia nervosa (BN). The objective of the study was to determine whether androgen levels and androgen origin differs in bulimic women compared to control subjects.Forty-six women with bulimia nervosa (BN), 31 with eating disorder not otherwise specified, purging type (EDNOS P) and 56 matched healthy controls were studied with respect to serum testosterone (T), 5alpha-dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG), deyhydroepiahndrosterone sulfate (DHEAS) and luteinizing hormone (LH) and to ovarian morphology.Despite all groups had almost identical androgen and SHBG levels; there were differences in the origin of circulating T and DHT. Correlation analysis suggest major differences in the formation of circulating testosterone (T) and 5α-dihydrotestosterone (DHT) with BN being more like the control subjects with peripheral formation from 4-androsterne-3,17-dione (A-4), dehydroepiandrosterone sulfate (DHEAS) and also from T. While in EDNOS group a possible direct ovarian T secretion and a DHEAS modulating action of androgens on pituitary gonadotropin secretion is present.The origin of circulating T and DHT differs between bulimics. Our findings do probably not reflect direct actions of circulating DHT on pituitary LH secretion in the women with EDNOS, but rather the effect of A-4, T via conversion to DHT in the central nervous system, indicating psych/endocrine differences between the two groups of bulimic women.

Identification and functional characterization of two Secretogranin II genes in orange-spotted grouper (Epinephelus coioides)

Secretoneurin (SN) is an important stimulator of pituitary luteinizing hormone (LH) synthesis and secretion in goldfish. It is unknown whether this neuropeptide performs the same role in other fish species. In this study, the full-length cDNAs encoding Secretogranin IIa (SgIIa) and b (SgIIb) were cloned from the brain of orange-spotted grouper. Sequence analysis showed that a 34-amino acid SN peptide (SNa) is present in SgIIa proprotein, and a 33-amino acid SN peptide (SNb) is present in SgIIb proprotein. The two SN peptides share a low degree of similarity but contain the signature YTPQ-X-LA-X7-EL sequence. Real-time PCR showed that two SgII genes are mainly expressed in the brain and pituitary. During ovarian development, the expression levels of two SgII genes in the hypothalamus and pituitary were significantly reduced at the stage when the ovary contained full-grown oocytes. The biological functions of the two SN peptides were further investigated in vitro and in vivo. Both SN peptides could significantly elevate the mRNA levels of Gonadotropin-Releasing Hormone 1 (GnRH1) and 3 (GnRH3) in the hypothalamic fragments and upregulated the expression of Follicle-Stimulating Hormone beta (FSHb) and Luteinizing Hormone beta (LHb) in the pituitary cells. The stimulatory effects on the expression of GnRHs and Gonadotropins were also observed after intraperitoneal injection of SN peptides. Our study indicated that the SgII/SN system has stimulatory effects on the reproductive axis of orange-spotted grouper.

High-Frequency Firing Activity of GnRH1 Neurons in Female Medaka Induces the Release of GnRH1 Peptide From Their Nerve Terminals in the Pituitary.

Hypothalamic gonadotropin-releasing hormone (GnRH) neurons play an important role in promoting secretion of pituitary luteinizing hormone (LH) and ovulation by releasing GnRH peptide. The release of GnRH peptide is generally assumed to be mainly modulated according to the firing activity of GnRH neurons. However, the relationship between the firing activity and the release of GnRH peptide has been elusive. We analyzed the relationship using two lines of transgenic medaka (gnrh1:enhanced green fluorescent protein and lhb:inverse-pericam) for the combined electrophysiological and Ca2+ imaging analyses. We show that a high-frequency firing activity induced by an excitatory neurotransmitter, glutamate, strongly increases [Ca2+]i in the cell bodies of GnRH1 neurons, which should lead to stimulation of GnRH release. We examined whether this high-frequency firing actually leads to the release of endogenous GnRH1 peptide from the nerve terminals projecting to the pituitary LH cells using a whole brain-pituitary preparation of a fish generated by crossing the two types of transgenic fish. Ca2+ imaging analyses showed that local glutamate activation of GnRH1 cell bodies, but not their nerve terminals in the pituitary, induced a substantial Ca2+ response in LH cells that was abolished in the presence of a GnRH receptor antagonist, Analog M. These results suggest that such an evoked high-frequency firing activity of GnRH1 cell body stimulates the release of endogenous GnRH1 peptide from the axon terminals to the pituitary LH cells. Thus, the findings of the present study have clearly demonstrated the relationship between the firing activity of hypothalamic GnRH neurons and the release of GnRH peptide.

Metabolic Basis of Polycystic Ovarian Syndrome; Indications for Biochemical Screening.

Polycystic ovary syndrome (PCOS) is a heterogeneous condition with wide range of phenotype the cause of this disorder is unknown, however, increased ovarian androgen production including increased theca cell responsiveness to gonadotropin stimulation, increased pituitary secretion of luteinizing hormone, and hyperinsulinemia have been suggested. Some known risk factors are ethnicity and environmental factors including lifestyle and bodyweight. Relevant English language studies from January 1995 to September 2015 were identified, reviewed, synthesized and discussed extensively. various forms of PCOS, and the underlying mechanisms; and highlights biochemical, morphological and metabolic hallmarks of PCOS, including trends and emerging phenotypes; and presents a simplified synthesis that integrates current understanding of biochemical and metabolic endocrinology of PCOS are summarized. As no generally accepted criteria exist for its diagnosis, some existing diagnostic criteria that cut across different geographical regions are also highlighted. Indeed, emerging evidence points that the severity of menstrual problems could serve as a predictor of the like-hood of insulin resistance in women of reproductive age, suggesting the need for routine metabolic screening and early intervention in PCOS.

Gonadotropin surge-inhibiting/attenuating factors: a review of current evidence, potential applications, and future directions for research.

Animal studies in the 1980s suggested the existence of an ovarian hormone, termed gonadotropin surge-inhibiting/attenuating factor (GnSIF/AF), that modulates pituitary secretion of luteinizing hormone (LH). Given the importance of identifying regulatory factors of the hypothalamic-pituitary-ovarian axis and the accumulating data suggesting its existence, we conducted a comprehensive literature search using PubMed, Web of Science, Scopus, and Embase to identify articles related to GnSIF/AF. The search generated 161 publications, of which 97 were included in this study. Several attempts have been made to identify and characterize this hormone and several candidates have been identified, but the protein sequences of these putative GnSIF/AF factors differ widely from one study to another. In addition, while the RF-amide RFRP-3 is known foremost as a neuropeptide, some research supports an ovarian origin for this non-steroidal hormone, thereby suggesting a role for RFRP-3 either as a co-modulator of GnSIF/AF or as a gonadotropin-inhibiting factor in the hypothalamus (GnIH). Discovery of the KNDy neurons that modulate GnRH secretion, on the other hand, further encourages the search for substance(s) that modulate their activity and that indirectly affect LH secretion and the hypothalamic-pituitary-ovarian axis. While it has remained an elusive hormone, GnSIF/AF holds many potential applications for contraception, in vitro fertilization, and/or cancer as well as for understanding polycystic ovary syndrome, metabolic diseases, and/or pubertal development. In this review, we rigorously examine the available evidence regarding the existence of GnSIF/AF, previous attempts at its identification, limitations to its discovery, future directions of research, and potential clinical applications.

Caffeine stimulates in vitro pituitary LH secretion in lipopolysaccharide-treated ewes

The study was designed to determine the effects of caffeine on luteinizing hormone (LH) secretion and gene expression of caffeine-associated receptors in anterior pituitary (AP) explants obtained from saline- and lipopolysaccharide (LPS)-treated ewes. Animals had been treated with LPS or saline daily for seven days. Three hours after the last injection of LPS/saline, the AP were collected and divided into four explants. The explants were incubated with: 1/medium-199 (control explants), 2/gonadotropin-releasing hormone (GnRH; 100pmol/mL; a positive control), 3/caffeine (10mmol/L), or 4/GnRH+caffeine. Caffeine stimulated (p<0.05) LH release by explants from both saline (19.7 vs. control 12.6ng/mg) and LPS (28.3 vs. control 13.9ng/mg) treated animals. The effect of caffeine on LH secretion was stronger in the LPS-treated group than in saline-treated group, and the observed LH release was similar to that induced by GnRH alone (27.2ng/mg). Caffeine increased (p<0.05) LHβ gene expression only in explants from LPS-treated animals. In conclusion, the results of the present study demonstrated a stimulatory in vitro effect of caffeine on LH secretion by ovine pituitary explants. The potency of the caffeine-induced LH secretion was affected by in vivo treatment of the animals with endotoxin.

Elevated Insulin in Obese Women Relates to Low Endogenous Luteinizing Hormone

INTRODUCTION: Obesity is a state of insulin resistance as it is also a state of relative hypogonadotropic hypogonadism. The physiology behind this is still unclear and may be the result of hypothalamic or pituitary factors or pharmacokinetics of gonadotropins. We sought to investigate if insulin, directly or indirectly, suppresses pituitary luteinizing hormone (LH) secretion. METHODS: A luteal phase frequent blood sampling study was undertaken in regularly menstruating obese (n=10) and normal-weight women (n=10). The study included 12 hours of unstimulated monitoring (to evaluate endogenous hypothalamic–pituitary function) with subsequent administration of intravenous bolus of gonadotropin-releasing hormone (to evaluate pituitary sensitivity). Luteinizing hormone was measured with an immunofluorometric assay. Luteinizing hormone pulsatility was evaluated using an objective, widely accepted method. RESULTS: All women were ovulatory. The obese group was significantly older than the normal weight group (32.5±4.7 compared with 27.3±2.6 years, P=.006). Insulin was significantly higher in the obese group than the normal-weight group (21.5 [14.3–28.7] compared with 11.7 [8.9–14.5] mU/L, P=.01). In the 2-hour postprandial period, there was a rise in insulin that was significantly higher (35.6 [17.1–54.1] compared with 16.5 [8.4–24.7] mU/L, P=.04) and LH that trended lower in the obese women (8.1 [3.5–12.7] compared with 4.2 [2.8–5.6] IU/L) (Figure 1).CONCLUSIONS: Higher insulin in obese women may be associated with lower endogenous LH output. A direct role of insulin in suppressing pituitary LH secretion should be further investigated.