Discovery of gonadotropin-inhibitory hormone (GnIH), progress in GnIH research on reproductive physiology and behavior and perspective of GnIH research on neuroendocrine regulation of reproduction.

Based on extensive studies on gonadotropin-releasing hormone (GnRH) it was assumed that GnRH is the only hypothalamic neurohormone regulating gonadotropin release in vertebrates. In 2000, however, Tsutsui's group discovered gonadotropin-inhibitory hormone (GnIH), a novel hypothalamic neuropeptide that inhibits gonadotropin release, in quail. Subsequent studies by Tsutsui's group demonstrated that GnIH is conserved among vertebrates, acting as a new key neurohormone regulating reproduction. GnIH inhibits gonadotropin synthesis and release through actions on gonadotropes and GnRH neurons via GnIH receptor, GPR147. Thus, GnRH is not the sole hypothalamic neurohormone controlling vertebrate reproduction. The following studies by Tsutsui's group have further demonstrated that GnIH has several important functions in addition to the control of reproduction. Accordingly, GnIH has drastically changed our understanding about reproductive neuroendocrinology. This review summarizes the discovery of GnIH, progress in GnIH research on reproductive physiology and behavior and perspective of GnIH research on neuroendocrine regulation of reproduction.

Elagolix: el primer antagonista de la hormona liberadora de gonadotropina por vía oral / No disponible

No disponible

Gonadotropin Surge-Attenuating Factor: A Nonsteroidal Ovarian Hormone Controlling GnRH-Induced LH Secretion in the Normal Menstrual Cycle.

Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian substance, which attenuates the endogenous LH surge in superovulated women. Different molecular sequences have been found, but only one of them has shown substantial homology to a known substance of the human genome. A molecular mass of 12.5kDa showing identity to the carboxyl-terminal fragment of human serum albumin and expressing GnSAF bioactivity in vitro has been identified. It has been suggested that in the normal menstrual cycle the in vivo bioactivity of GnSAF increases under the influence of the intercycle rise of FSH. GnSAF is considered the "missing link" between the ovaries and the hypothalamo-pituitary system, maintaining the pituitary in a state of low responsiveness to GnRH in the early- to midfollicular phase of the cycle. A marked decline in GnSAF bioactivity in the late follicular phase facilitates the onset and the full expression of the midcycle LH surge.

Discovery of GnIH and Its Role in Hypothyroidism-Induced Delayed Puberty.

It is known that hypothyroidism delays puberty in mammals. Interaction between the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-gonadal (HPG) axes may be important processes in delayed puberty. Gonadotropin-inhibitory hormone (GnIH) is a newly discovered hypothalamic neuropeptide that inhibits gonadotropin synthesis and release in quail. It now appears that GnIH is conserved across various mammals and primates, including humans, and inhibits reproduction. We have further demonstrated that GnIH is involved in pubertal delay induced by thyroid dysfunction in female mice. Hypothyroidism delays pubertal onset with the increase in hypothalamic GnIH expression and the decrease in circulating gonadotropin and estradiol levels. Thyroid status regulates GnIH expression by epigenetic modification of the GnIH promoter region. Furthermore, knockout of GnIH gene abolishes the effect of hypothyroidism on delayed pubertal onset. Accordingly, it is considered that GnIH is a mediator of pubertal disorder induced by thyroid dysfunction. This is a novel function of GnIH that interacts between the HPT-HPG axes in pubertal onset delay. This mini-review summarizes the structure, expression, and function of GnIH and highlights the action of GnIH in pubertal disorder induced by thyroid dysfunction.

Submaximal doses of ghrelin do not inhibit gonadotrophin levels but stimulate prolactin secretion in postmenopausal women.

OBJECTIVE: An inhibitory effect of ghrelin on gonadotrophin secretion has been reported in normally menstruating women possibly modulated by endogenous oestrogen. The aim of this study was to examine the effect of ghrelin on gonadotrophin and prolactin (PRL) secretion in oestrogen-deprived postmenopausal women. DESIGN: Prospective intervention study. PATIENTS AND MEASUREMENTS: Ten healthy postmenopausal volunteer women were studied during two 15-days periods of oestrogen treatment (A and B) a month apart. Four experiments (Exp) were performed in total, two on day 1 (Exp 1A and Exp 1B) and two on day 15 (Exp 15A and Exp 15B) of the two periods. The women received in Exp 1A and in Exp 15A two iv injections of ghrelin (0.15 µg/kg at time 0 minute and 0.30 µg/kg at time 90 minutes) and in Exp1B and in Exp 15B normal saline (2 mL), respectively. Blood samples were taken at -15, 0, 30, 60, 90, 120, 150 and 180 minutes. RESULTS: After oestrogen treatment, late follicular phase serum oestradiol levels were attained on day 15 of periods A and B. Ghrelin administration did not affect serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), whereas it increased significantly those of growth hormone (GH) and PRL. In Exp 15A, serum PRL increment in response to ghrelin (area under the curve, net increment) was significantly greater than in Exp 1A (P<.05). CONCLUSIONS: This study demonstrates for the first time that in oestrogen-deprived postmenopausal women, ghrelin administration affects neither FSH nor LH levels but stimulates PRL secretion, that is amplified by exogenous oestrogen administration.

Gonadotropin-inhibitory hormone (GnIH) in the amphibian brain and its relationship with the gonadotropin releasing hormone (GnRH) system: An overview.

It is well known that the hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) plays an important role as a primary factor regulating gonadotropin secretion in reproductive processes in vertebrates. The discovery of the presence of a gonadotropin-inhibitory hormone (GnIH) in the brains of birds has further contributed to our understanding of the reproduction control by the brain. GnIH plays a key role in inhibition of reproduction and acts on the pituitary gland and GnRH neurons via a novel G protein-coupled receptor (GPR147). GnIH decreases gonadotropin synthesis and release, thus inhibiting gonadal development and maintenance. The GnRH and GnIH neuronal peptidergic systems are well reported in mammals and birds, but limited information is available regarding their presence and localization in the brains of other vertebrate species, such as reptiles, amphibians and fishes. The aim of this review is to compile and update information on the localization of GnRH and GnIH neuronal systems, with a particular focus on amphibians, summarizing the neuroanatomical distribution of GnIH and GnRH and emphasizing the discovery of GnIH based on RFamide peptides and GnIH orthologous peptides found in other vertebrates and their functional significance.

[Spontaneous ovulation in in vitro fertilization-embryo transfer cycles using gonadotropin-releasing hormone antagonist: a large-sample retrospective study].

OBJECTIVE: To investigate the premature spontaneous ovulation rates in in vitro fertilization-embryo transfer (IVF-ET) cycles using gonadotropin-releasing hormone antagonist (GnRH-ant) and gonadotropin-releasing hormone agonist (GnRH-a), as well as the risk factors for premature spontaneous ovulation. METHODS: The rates of premature spontaneous ovulation in a total of 10 612 cycles using GnRH-ant or GnRH-a were compared. Matched case-controlled study and binary logistic regression model were conducted to analyze the risk factors for premature spontaneous ovulation. RESULTS: The spontaneous ovulation rate in the whole for GnRH-a cycles was 0.15% (13/8 514), compared with a 1.62% (34/2 098) in GnRH-ant cycles (P<0.01). Further matched controlled study and regression analyze found out that higher basal FSH level was a predominant risk and prediction factor for spontaneous ovulation (OR=1.20, P=0.009). CONCLUSIONS: In GnRH-ant cycles, spontaneous ovulation rate is about 10 times than which in GnRH-a cycles. Diminished ovarian function is a predominate risk factor for premature spontaneous ovulation.

Evolution of gonadotropin-inhibitory hormone receptor and its ligand.

Gonadotropin-inhibitory hormone (GnIH) is a neuropeptide inhibitor of gonadotropin secretion, which was first identified in the Japanese quail hypothalamus. GnIH peptides share a C-terminal LPXRFamide (X=L or Q) motif in most vertebrates. The receptor for GnIH (GnIHR) is the seven-transmembrane G protein-coupled receptor 147 (GPR147) that inhibits cAMP production. GPR147 is also named neuropeptide FF (NPFF) receptor 1 (NPFFR1), because it also binds NPFF that has a C-terminal PQRFamide motif. To understand the evolutionary history of the GnIH system in the animal kingdom, we searched for receptors structurally similar to GnIHR in the genome of six mammals (human, mouse, rat, cattle, cat, and rabbit), five birds (pigeon, chicken, turkey, budgerigar, and zebra finch), one reptile (green anole), one amphibian (Western clawed flog), six fishes (zebrafish, Nile tilapia, Fugu, coelacanth, spotted gar, and lamprey), one hemichordate (acorn worm), one echinoderm (purple sea urchin), one mollusk (California sea hare), seven insects (pea aphid, African malaria mosquito, honey bee, buff-tailed bumblebee, fruit fly, jewel wasp, and red flour beetle), one cnidarian (hydra), and constructed phylogenetic trees by neighbor joining (NJ) and maximum likelihood (ML) methods. A multiple sequence alignment of the receptors showed highly conserved seven-transmembrane domains as well as disulfide bridge sites between the first and second extracellular loops, including the receptor of hydra. Both NJ and ML analyses grouped the receptors of vertebrates into NPFFR1 and NPFFR2 (GPR74), and the receptors of insects into the receptor for SIFamide peptides that share a C-terminal YRKPPFNGSIFamide motif. Although human, quail and zebrafish GnIHR (NPFFR1) were most structurally similar to SIFamide receptor of fruit fly in the Famide peptide (FMRFamide, neuropeptide F, short neuropeptide F, drosulfakinin, myosuppressin, SIFamide) receptor families, the amino acid sequences and the peptide coding regions of GnIH precursors were most similar to FMRFamide precursor of fruit fly in the precursors of Famide peptide families. Chromosome synteny analysis of the precursor genes of human, quail and zebrafish GnIH and fruit fly Famide peptides further identified conserved synteny in vertebrate GnIH and fruit fly FMRFa precursor genes as well as other Famide peptide precursor genes. These results suggest that GnIH and its receptor pair and SIFamide and its receptor pair may have diverged and co-evolved independently in vertebrates and insects, respectively, from their ancestral Famide peptide and its receptor pair, during diversification and evolution of deuterostomian and protostomian species.

"Mild" vs. "long" protocol for controlled ovarian hyperstimulation in patients with expected poor ovarian responsiveness undergoing in vitro fertilization (IVF): a large prospective randomized trial.

BACKGROUND: This large prospective, randomized study was designed to compare the "mild" protocol with clomiphene citrate, low-dose gonadotropins and a GnRH-antagonist (CC/Gn/GnRH-ant protocol) with the "long" protocol with a GnRH-agonist and high-dose Gn for the controlled ovarian hyperstimulation (COH) of patients with expected poor ovarian responsiveness undergoing IVF. MATERIALS AND METHODS: A total of 695 women with clinical, endocrine and ultrasound characteristics suggesting a low ovarian reserve and a poor responsiveness to COH were recruited and randomly assigned to receive the CC/Gn/GnRH-ant "mild" protocol (mild group, n = 355) or the "long" protocol with high-dose Gn (long group, n = 340). RESULTS: The "mild" stimulation led to significantly shorter follicular phase, lower consumption of exogenous Gn and lower peak estradiol level than the "long" regimen. With the "long" protocol, significantly less cycles were cancelled due to the lack of ovarian response; further, it obtained significantly more oocytes, more mature oocytes, more embryos, and a thicker endometrium. As for the final IVF outcome, however, the two stimulation regimens obtained comparable implantation rate, clinical pregnancy rate, and ongoing pregnancy rate at 12 weeks. CONCLUSIONS: In conclusion, the "mild" CC/Gn/GnRH-ant stimulation protocol is a valid alternative to the long protocol with high Gn dose as it obtains a comparable success rate and requires significantly less medications, with an obvious economical advantage.

Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception.

Testosterone (T), alone or in combination with progestin, provides a promising approach to hormonal male contraception. Its principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the testicular T production needed for spermatogenesis, while simultaneously maintaining the extragonadal androgen actions, such as potency and libido, to avoid hypogonadism. A serious drawback of the treatment is that a significant proportion of men do not reach azoospermia or severe oligozoospermia, commensurate with contraceptive efficacy. We tested here, using hypogonadal luteinizing hormone/choriongonadotropin receptor (LHCGR) knockout (LHR(-/-)) mice, the basic principle of the T-based male contraceptive method, that a specific T dose could maintain extragonadal androgen actions without simultaneously activating spermatogenesis. LHR(-/-) mice were treated with increasing T doses, and the responses of their spermatogenesis and extragonadal androgen actions (including gonadotropin suppression and sexual behavior) were assessed. Conspicuously, all dose responses to T were practically superimposable, and no dose of T could be defined that would maintain sexual function and suppress gonadotropins without simultaneously activating spermatogenesis. This finding, never addressed in clinical contraceptive trials, is not unexpected in light of the same androgen receptor mediating androgen actions in all organs. When extrapolated to humans, our findings may jeopardize the current approach to hormonal male contraception and call for more effective means of inhibiting intratesticular T production or action, to achieve consistent spermatogenic suppression.

Differential expression of RFamide-related peptide, a mammalian gonadotrophin-inhibitory hormone orthologue, and kisspeptin in the hypothalamus of Abadeh ecotype does during breeding and anoestrous seasons.

Gonadotrophin-inhibitory hormone (GnIH) is a novel hypothalamic neuropeptide that was discovered in birds as an inhibitory factor for gonadotrophin release. RFamide-related peptide (RFRP) is a mammalian GnIH orthologue that inhibits gonadotrophin synthesis and release in mammals through actions on gonadotrophin-releasing hormone (GnRH) neurones and gonadotrophs, mediated via the GnIH receptor (GnIH-R), GPR147. On the other hand, hypothalamic kisspeptin provokes the release of GnRH from the hypothalamus. The present study aimed to compare the expression of RFRP in the dorsomedial hypothalamus and paraventricular nucleus (DMH/PVN) and that of kisspeptin in the arcuate nucleus (ARC) of the female goat hypothalamus during anoestrous and breeding seasons. Mature female Abadeh does were used during anoestrus, as well as the follicular and luteal phases of the cycle. The number of RFRP-immunoreactive (-IR) neurones in the follicular phase was lower than in the luteal and anoestrous stages. Irrespective of the ovarian stage, the number of RFRP-IR neurones in the rostral and middle regions of the DMH/PVN was higher than in the caudal region. By contrast, the number of kisspeptin-IR neurones in the follicular stage was greater than in the luteal stage and during the anoestrous stage. Irrespective of the stage of the ovarian cycle, the number of kisspeptin-IR neurones in the caudal region of the ARC was greater than in the middle and rostral regions. In conclusion, RFRP-IR cells were more abundant in the rostral region of the DMH/PVN nuclei of the hypothalamus, with a greater number being found during the luteal and anoestrous stages compared to the follicular stage. On the other hand, kisspeptin-IR neurones were more abundant in the caudal part of the ARC, with a greater number recorded in the follicular stage compared to the luteal and anoestrous stages.

Coadministration of anastrozole sustains therapeutic testosterone levels in hypogonadal men undergoing testosterone pellet insertion.

INTRODUCTION: Current U.S. Food and Drug Administration-approved therapies for hypogonadism involve testosterone (T) replacement. Testosterone pellets (TP) require a minor office procedure every 3 to 4 months. The need for repeated insertions increases the likelihood of a complication. Anastrozole (AZ) is an aromatase inhibitor that has been used off-label for the treatment of male hypogonadism. AZ increases T levels by lowering serum estradiol (E2) levels and increasing gonadotropin (GTP) levels. AIM: We hypothesized that the concomitant use of AZ with TP insertions would sustain therapeutic T levels and increase the interval between TP insertions. METHODS: Men treated with TP for hypogonadism at an academic center were offered AZ (1 mg/day) at the time of TP reinsertion as a way of potentially decreasing the frequency of TP insertions. Total T (TT), free T (FT), sex hormone binding globulin, E2, luteinizing hormone (LH), and follicle-stimulating hormone FSH levels were obtained prior to T replacement and at 6 and 15 weeks from TP insertion. Men were re-implanted at 16 weeks if their TT levels were less than 350 ng/dL and their symptoms recurred. We retrospectively reviewed our records of men who underwent TP, TP, and AZ from 2011 to 2012. Demographics, TT, FT, LH, FSH, and E2 levels were recorded. Data were analyzed with anova and a Tukey's test. MAIN OUTCOME MEASURE: TT level at 6, 15, or >15 weeks from TP insertion. RESULTS: Thirty-eight men with 65 insertions were analyzed. The TP AZ group had significantly higher TT and FT levels than the TP group at >120 days (P < 0.05). The TP group had significantly higher E2 levels at all time points (P < 0.01). GTP levels remained stable in the TP AZ group. Average time to reinsertion in TP AZ was 198 days vs. 128 days in the TP group. CONCLUSION: Men on TP AZ maintain therapeutic T levels longer than men on TP alone and have significantly less GTP suppression.

Paradoxical effect of gonadotrophin-inhibiting hormone to negatively regulate neuropeptide Y neurones in mouse arcuate nucleus.

Regulation of reproduction and energy homeostasis are linked, although our understanding of the central neural mechanisms subserving this connection is incomplete. Gonadotrophin-inhibiting hormone (GnIH) is a neuropeptide that negatively regulates reproduction and stimulates food intake. Neuropeptide Y (NPY) and products of the pro-opiomelanocortin (POMC) precursor (ß-endorphin melanocortins) are appetite regulating peptides produced in the neurones of the arcuate nucleus; these peptides also regulate reproduction. In the present study, we determined the effects of GnIH on NPY and POMC neurones. Using brain slices from mice with transgenes for fluorescent tags in the two types of neurone and patch clamp electrophysiology, a predominant inhibitory effect of GnIH was observed. GnIH (100 nM) inhibited the firing rate in POMC cells, confirming the results of previous studies and consistent with the stimulatory effect of GnIH on food intake. Paradoxically (i.e. because both GnIH and NPY stimulate food intake), GnIH also had a predominantly inhibitory effect on action potential activity in NPY cells. GnIH also inhibited the secretion of NPY and α-melanocyte-stimulating hormone secretion in incubated hypothalamic blocks. GnIH (100 ng) injected into the cerebral ventricles of mice did not increase the number of NPY cells that were positively immunostained for c-Fos. Finally, dual label immunocytochemistry showed that 20% of NPY neurones had close contacts from GnIH fibres/varicosities. In conclusion, we confirm a negative effect of GnIH on POMC cells and demonstrate a paradoxical reduction of electrophysiological and functional activity in NPY cells.

Gonadotropin-inhibitory hormone reduces sexual motivation but not lordosis behavior in female Syrian hamsters (Mesocricetus auratus).

Reproductive success is maximized when female sexual motivation and behavior coincide with the time of optimal fertility. Both processes depend upon coordinated hormonal events, beginning with signaling by the gonadotropin-releasing hormone (GnRH) neuronal system. Two neuropeptidergic systems that lie upstream of GnRH, gonadotropin-inhibitory hormone (GnIH; also known as RFamide related peptide-3) and kisspeptin, are potent inhibitory and excitatory modulators of GnRH, respectively, that participate in the timing of the preovulatory luteinizing hormone (LH) surge and ovulation. Whether these neuropeptides serve as neuromodulators to coordinate female sexual behavior with the limited window of fertility has not been thoroughly explored. In the present study, either intact or ovariectomized, hormone-treated female hamsters were implanted for fifteen days with chronic release osmotic pumps filled with GnIH or saline. The effect of GnIH on sexual motivation, vaginal scent marking, and lordosis was examined. Following mating, FOS activation was quantified in brain regions implicated in the regulation of female sexual behavior. Intracerebroventricular administration of GnIH reduced sexual motivation and vaginal scent marking, but not lordosis behavior. GnIH administration altered FOS expression in key neural loci implicated in female reproductive behavior, including the medial preoptic area, medial amygdala and bed nucleus of the stria terminalis, independent of changes in circulating gonadal steroids and kisspeptin cell activation. Together, these data point to GnIH as an important modulator of female proceptive sexual behavior and motivation, independent of downstream alterations in sex steroid production.

Evaluation of low-dose letrozole addition to ovulation induction in IVF.

PURPOSE: The aim was to investigate the impact of low-dose letrozole usage along with gonadotropin treatment in vitro fertilization (IVF) cycles in comparison to gonadotropin treatment alone. MATERIALS AND METHODS: Fifty patients were prospectively included in this randomized study and were divided into two groups. Age, demographic features, causes, and period of infertility were adjusted and matched for both groups. Group 1 included 25 patients who received gonadotropin treatment and letrozole along with gonadotropin-releasing hormone (GnRH) antagonist protocol; group 2 included 25 patients who received gonadotropin treatment along with GnRH antagonist protocol. RESULTS: Total follicle-stimulating hormone (FSH) and daily FSH doses were lower in group 1, although not statistically significant (p > 0.05). The period of ovulation induction was significantly shorter in group 2. While numbers of retrieved oocytes and transferred embryos were lower in group 1, they were not statistically significant (p > 0.05). Number of clinical pregnancies per embryo transfer, number of clinical pregnancies per cycle, and number of ongoing pregnancies (> 16 gestational weeks) were similar in both groups (p > 0.05). CONCLUSIONS: Addition of low-dose letrozole to gonadotropin treatment in GnRH antagonist protocols may result in a lower dose of gonadotropin administration. However, routine clinical practice remains questionable due to no evident positive effect on pregnancy rates.

Cholesterol homeostasis in the ovaries of neonatally diethylstilbestrol-treated mice.

In the ovary of neonatally DES-treated mice, lipid droplets accumulation was observed in the hypertrophied interstitial tissues. Our previous results demonstrated that the impaired steroidogenesis in the ovary of neonatally DES-treated mice was caused by altered gonadotropins levels, and resulted in the hypertrophy of ovarian interstitial cells. We speculated that lipid droplets in the ovary mainly consisted of cholesterol. This study was aimed to examine the effects of neonatal DES on cholesterol homeostasis in the ovary. The serum and ovarian total cholesterol concentrations in 3-month-old neonatally DES-treated mice were significantly higher than those in the neonatally oil-treated mice, but triglyceride concentrations were not altered. In the ovary of neonatally DES-treated mice, expression of Hmgcr, a rate-limiting enzyme in de novo cholesterol biosynthesis, was reduced but expression of Ldlr and Scarb1, involved in cholesterol uptake, was not changed. These results suggest that cholesterol uptake is not altered in the ovary of 3-month-old neonatally DES-treated mice. However, the expression of Acat1, the microsomal acyl coenzyme A cholesterol acyltransferase which is involved in cholesterol esterification and storing was increased compared with that in the ovary of neonatally oil-treated mice. Since ovarian steroidogenesis in neonatally DES-treated mice was impaired, synthesized and/or obtained cholesterol from the blood may not be used sufficiently. Thus, in the ovary of neonatally DES-treated mice, cholesterol is esterified by ACAT1 and stored in the interstitial cells.

The clinical ramifications of polycystic ovarian morphology in oocyte donors.

OBJECTIVE: To determine the relationship between Polycystic Ovary (PCO) morphology and In Vitro Fertilization (IVF) outcome in oocyte donation cycles. DESIGN: Cross sectional study SETTING: Private IVF clinic PATIENTS: 164 consecutive ovum donors and their recipients were reviewed, 149 were included in the study where 113 patients had normal ovarian morphology and 36 patients had PCO morphology. INTERVENTIONS: All donors underwent ovarian stimulation in conjunction with GnRH agonist or antagonist in standard fashion. MAIN OUTCOME MEASURES: Baseline donor characteristics were recorded, as well as details of IVF stimulation and embryo data. Recipient data on pregnancy and miscarriage were also collected. RESULTS: Patients with PCO ovaries had significantly higher peak estradiol levels and required less gonadotropins during IVF stimulation. In addition, the baseline characteristics between donor groups did not differ except for ovarian morphology. The number of oocytes retrieved and indicators of embryo quality did not differ between the two groups, and there was no significant difference between pregnancy and miscarriage rates in the recipients. CONCLUSIONS: Oocyte donors with PCO morphology have equivalent pregnancy rates and do not need to be excluded as potential donors.

Seasonal effect of gonadotrophin inhibitory hormone on gonadotrophin-releasing hormone-induced gonadotroph functions in the goldfish pituitary.

We have shown that native goldfish gonadotrophin inhibitory hormone (gGnIH) differentially regulates luteinsing hormone (LH)-ß and follicle-stimulating hormone (FSH)-ß expression. To further understand the functions of gGnIH, we examined its interactions with two native goldfish gonadotrophin-releasing hormones, salmon gonadotrophin-releasing hormone (sGnRH) and chicken (c)GnRH-II in vivo and in vitro. Intraperitoneal injections of gGnIH alone reduced serum LH levels in fish in early and mid gonadal recrudescence; this inhibition was also seen in fish co-injected with either sGnRH or cGnRH-II during early recrudescence. Injection of gGnIH alone elevated pituitary LH-ß and FSH-ß mRNA levels at early and mid recrudescence, and FSH-ß mRNA at late recrudescence. Co-injection of gGnIH attenuated the stimulatory influences of sGnRH on LH-ß in early recrudescence, and LH-ß and FSH-ß mRNA levels in mid and late recrudescence, as well as the cGnRH-II-elicited increase in LH-ß, but not FSH-ß, mRNA expression at mid and late recrudescence. sGnRH and cGnRH-II injection increased pituitary gGnIH-R mRNA expression in mid and late recrudescence but gGnIH reduced gGnIH-R mRNA levels in late recrudescence. gGnIH did not affect basal LH release from perifused pituitary cells and continual exposure to gGnIH did not alter the LH responses to acute applications of GnRH. However, a short 5-min GnIH treatment in the middle of a 60-min GnRH perifusion selectively reduced the cGnRH-II-induced release of LH. These novel results indicate that, in goldfish, gGnIH and GnRH modulate pituitary GnIH-R expression and gGnIH differentially affects sGnRH and cGnRH-II regulation of LH secretion and gonadotrophin subunit mRNA levels. Furthermore, these actions are manifested in a reproductive stage-dependent manner.

Gonadatrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial.

OBJECTIVE: To estimate the effectiveness of gonadotropin-releasing hormone (GnRH) analogues cotreatment in preventing chemotherapy-induced amenorrhea in young breast cancer patients undergoing cyclophosphamide-based chemotherapy. METHODS: One hundred hormone-insensitive breast cancer participants (aged 18-40 years) were recruited from two university-affiliated oncology centers in Egypt. Opting for type of cotreatment was based on available timeframe until start of chemotherapy. Fifty women ready for early chemotherapy were randomized to receive either chemotherapy alone (arm I) or chemotherapy after downregulation (estradiol less than 50 pg/mL) by GnRH antagonist and agonist (arm II). Then, GnRH antagonist was discontinued and agonist was continued until the end of chemotherapy. When chemotherapy was to start later than 10 days after study inclusion, 50 women were randomized to receive either chemotherapy alone (arm III) or chemotherapy after downregulation with GnRH agonist (arm IV). Resumption of menstruation at 12 months after end of chemotherapy was the primary outcome. Postchemotherapy hormonal and ultrasound changes were secondary outcomes. RESULTS: Twelve months after termination of chemotherapy, there were no differences in menstruation resumption rates between GnRH-treated patients and control group individuals in either early (80% in arms I and II, risk ratio 1, 95% confidence interval 0.7-.32; P=1.00) or delayed chemotherapy groups (80% and 84% in arms III and IV, risk ratio 0.95, 95% confidence interval 0.73-1.235; P=.71). There were no differences in hormonal and ultrasound markers between GnRH analogue users and control group individuals. The use of GnRH analogue cotreatment did not predict independently the odds of menstruating at 12 months. CONCLUSION: GnRH analogue cotreatment does not offer a significant protective effect on ovarian function in patients treated by cyclophosphamide-based chemotherapy. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. www.anzctr.org.au, ACTRN12609001059257. LEVEL OF EVIDENCE: I.