Gonadorelin

The flush revisited.

A nadir of LH precedes the onset of the flush and a flush is never seen without an LH pulse. However, after surgical and medical (GnRH agonist) hypophysectomy flushing occurs while LH is absent, thus LH itself is not the cause of the flush. GnRH agonist treatment induces low LH, whereas flushes remain, even when oestrogens are supplemented, suggesting that GnRH itself is the mediator. As flushes are preceded by a spike of LH-RH, GnRH involvement is most likely. Pulsatile administration of GnRH does not induce flushes, whereas continuous administration does. Thus it is the interference with the pulsatile pattern of GnRH that causes flushes. Even high doses of oestradiol during GnRH agonist treatment do not abolish flushes, whereas the alpha 2-adrenergic agonists such as clonidine and alpha-methyldopa abolish flushes during treatment with GnRH agonists. Thus, dysregulation of the GnRH releasing clock center in the nucleus arcuatus in the mediobasal hypothalamus is associated with altered central alpha-receptor activity which results in lowering of the set point of the central thermostat and the circulatory changes. The balance of evidence indicates that interference with the pulsatile pattern of GnRH causes the flush.

Reproductive performance of goats treated with free gonadorelin or nanoconjugated gonadorelin at estrus.

The reproductive performance of goats that received a GnRH analog (gonadorelin) fabricated with or without chitosan-sodium tripolyphosphate (TPP) nanoparticles on the day of estrus (day 0) was evaluated. The chitosan-TPP polymer was conjugated with gonadorelin using an ionic gelation method. Thirty-three multiparous Zaraiebi goats were synchronized for estrus with 2 intramuscular (im) injections of 125 μg prostaglandin F2α 14 d apart. Goats showing signs of estrus were divided equally into 3 experimental groups and received a single im injection of 1 mL physiological saline (placebo; control), 50 μg/mL gonadorelin (GnRH), or 12.5 μg (quarter of GnRH dose)/mL chitosan-TPP-conjugated gonadorelin nanoparticles (NGnRH). Each goat underwent ultrasound imaging of their ovaries at day 0 and at day 10 after mating, and pregnancy was diagnosed 28 and 45 d after mating. The concentrations of estradiol (E2) and progesterone (P4) were determined at day 0 and at days 7, 14, 21, and 42 after mating. NGnRH size, polydispersity, and zeta potential were 93.91 nm, 0.302, and 11.6 mV, respectively. Chitosan-TPP nanoparticles showed 91.2% entrapment efficiency for GnRH. No differences in estrus rate, interval to estrus, or ovarian structure at day 0 were observed among the experimental groups, but the GnRH and NGnRH treatments significantly decreased the duration of estrus compared with the control. At day 10 after mating, both GnRH and NGnRH increased (P = 0.011) the number of corpora lutea compared with the control. Treatment with GnRH increased (P = 0.023) serum E2 concentrations from day 7 to 42 after mating compared with NGnRH and control treatments. The highest (P = 0.043) serum P4 concentration was observed in the GnRH group, followed by the NGnRH and control groups. The increase in serum P4 concentration started earlier a on day 7 in the GnRH group but later on day 14 in the NGnRH group. Compared with the control, GnRH resulted in a higher (P = 0.041) P4-to-E2 ratio, followed by NGnRH. Both gonadorelin treatments significantly increased the twinning rate, the number of embryos at days 28 and 42, and prolificacy and decreased pregnancy losses compared with the control. In conclusion, the administration of GnRH at the time of estrus improved the prolificacy of goats by increasing both the ovulation rate and the number of embryos. In addition, the nanoformulation developed in this study allowed a 75% reduction in the conventional dose of gonadorelin without affecting the fertility and prolificacy of goats, indicating the bioavailability of the reduced GnRH dose after conjugation with developed nanoformula.

GnRH and steroids in cancer.

Gonadotropin-releasing-hormone (GnRH) analogues are synthetic compounds derived from decapeptide neurohormones (LHRH; LH/FSH-RH). They have a key role in hormone dependent cancer, particularly breast and prostate cancer. GnRH analogues produce an efficient inhibition of gonadotropins and sex steroid hormones. Their use in cancer therapy result in a, pharmacological castration (i.e. ovariectomy and orchiectomy), providing an androgen and estrogen ablation. GnRH exert an inhibitory action on the growth of hormone-dependent human and canine mammary tumor. Mammary tumors can produce growth factor that potentially could modulate their own proliferation in an autocrine fashion (i.e. TGF-alpha and TGF-beta or with a paracrine mechanism (i.e. EGF, IGF, FGF). The expression of EGF receptors is related in mammary tissues to the action of oestrogen and progesteron and to the presence of functional receptors for oestrogen (ER) and progesteron (PR). The present review elucidate the role of GnRH receptors in cancer and their connection with steroid hormones. Besides we showed the link between GnRH and signal transductions pathways: Estrogen-receptors, GnRH-receptors, EGF-receptors signal transduction pathways. A very tight link exists between steroid hormones and GnRH analogues both on central pituitary gonadal axis and on tumor receptors peripherically. This last mechanism could be explained either locally activating GnRH receptors or locally interacting with EGF receptor-Intracellular NitricOxide system.

Bovine reproductive immunoinfertility: pathogenesis and immunotherapy.

Infertility is one of the primary factors for cattle reproduction in the present scenario. Reproduction-related immunoinfertility mainly involves immunization against the antigens related to reproductive hormones (LHRH, GnRH, Gonadal steroids, PGF2α and oxytocin), spermatozoa, seminal plasma and ovum. Anovulation, delayed ovulation, sperm immobilization, failure of fertilization, prolonged uterine involution, extended calving interval, prolonged post-partum estrus and reduced conception rate could be a result of immunoinfertility that occur due to the blockage of receptor site by antibodies formed against hormones, sperm and ovum. Immunoinfertility can be treated in the animal by giving sexual rest to females, by using various reproductive technologies such as in-vitro fertilization, gamete intra fallopian tube transfer, and intracytoplasmic sperm injection, sperm washing and by treating the animals with immunomodulators such as LPS, Oyster glycogen, etc. This review summarizes the different causes of bovine reproductive immunoinfertility and amelioration strategies to overcome it.

Non-peptidic GnRH receptor antagonists.

Gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) hypothalamic hormone that acts upon 7-trans membrane spanning GnRH receptors in the pituitary. This action leads to the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) that in turn act on the reproductive organs regulating gonadal steroid production, spermatogenesis and follicular development. Peptidic agonists of the GnRH receptor have been known for many years and are currently employed therapeutically in the treatment of prostate and breast tumours, uterine fibroids, precocious puberty, endometriosis, premenstrual syndrome, contraception and infertility. Peptidic antagonists to date have only been employed commercially in the treatment of infertility during assisted reproductive therapy; however, many peptidic antagonists are currently in late stage development for many of the aforementioned indications. Whilst peptidic agonists and antagonists of the GnRH receptor have been discovered and exploited clinically, they are limited to predominantly parenteral administration due to their poor oral bioavailability. Recently, several small molecule GnRH antagonist series have been discovered offering the prospect of orally active therapeutics based on GnRH receptor antagonism. This article will review the current medicinal chemistry literature and structure activity relationships known for non-peptidic GnRH receptor antagonists.

Identification of the FSH-RH as the other gonadotropin-releasing hormone.

In vertebrates, folliculogenesis and ovulation are regulated by two distinct pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Currently, there is an intriguing consensus that a single hypothalamic neurohormone, gonadotropin-releasing hormone (GnRH), regulates the secretion of both FSH and LH, although the required timing and functions of FSH and LH are different. However, recent studies in many non-mammalian vertebrates indicated that GnRH is dispensable for FSH function. Here, by using medaka as a model teleost, we successfully identify cholecystokinin as the other gonadotropin regulator, FSH-releasing hormone (FSH-RH). Our histological and in vitro analyses demonstrate that hypothalamic cholecystokinin-expressing neurons directly affect FSH cells through the cholecystokinin receptor, Cck2rb, thereby increasing the expression and release of FSH. Remarkably, the knockout of this pathway minimizes FSH expression and results in a failure of folliculogenesis. Here, we propose the existence of the "dual GnRH model" in vertebrates that utilize both FSH-RH and LH-RH.

Effect of different gonadorelin (GnRH) products used for the first or resynchronized timed artificial insemination on pregnancy rates in postpartum dairy cows.

Different GnRH products are used for timed artificial insemination (AI) in postpartum dairy cows. Previous studies reported greater LH release and increased ovulation percentage for gonadorelin diacetate tetrahydrate compared with gonadorelin hydrochloride but pregnancies per AI (P/AI) were not evaluated. The objective, therefore, was to compare P/AI for cows treated with either gonadorelin hydrochloride or gonadorelin diacetate tetrahydrate before the first timed AI or resynchronized timed AI. Holstein cows (n&#xa0;=&#xa0;3938) in a confinement dairy in northeast Missouri were assigned to weekly cohorts (n&#xa0;=&#xa0;22) on the basis of calving date. Cows were treated with "Presynch Ovsynch" (PGF2&#x3b1;, 14&#xa0;days; PGF2&#x3b1;, 14&#xa0;days; GnRH, 7&#xa0;days; PGF2&#x3b1;, 56&#xa0;hours; GnRH, 16&#xa0;hours; timed AI) so that the first timed AI was 70 to 76&#xa0;days postpartum. The PGF2&#x3b1; was Lutalyse (5&#xa0;mL; 25&#xa0;mg; Zoetis). The GnRH product was either gonadorelin hydrochloride (2&#xa0;mL; 100&#xa0;&#x3bc;g; n&#xa0;=&#xa0;1945) or gonadorelin diacetate tetrahydrate (2&#xa0;mL; 100&#xa0;&#x3bc;g; n&#xa0;=&#xa0;1993) and alternated weekly for cows assigned to cohorts. There were first timed AI (n&#xa0;=&#xa0;1790) and resynchronized timed AI (n&#xa0;=&#xa0;2148) cows within each cohort. The resynchronization began 32&#xa0;days after timed AI (GnRH, 6 days; ultrasound pregnancy diagnosis, 1&#xa0;day; and then for nonpregnant cows: PGF2&#x3b1;, 56&#xa0;hours; GnRH, 16&#xa0;hours; timed AI). The trial was conducted from January to February 2012 (n&#xa0;=&#xa0;1203) and July to October 2012 (n&#xa0;=&#xa0;2735). Cows were fed a total mixed ration, milked thrice daily, and milk tested monthly for volume, somatic cell count (SCC), fat percentage, protein percentage, and milk urea nitrogen. Data were analyzed by fitting the binary response data to a generalized linear mixed model for repeated measures. There was no effect of the GnRH product (treatment) on P/AI (38.4&#xa0;&#xb1;&#xa0;1.2 vs. 35.7&#xa0;&#xb1;&#xa0;1.3; gonadorelin diacetate tetrahydrate vs. gonadorelin hydrochloride). Treatment interactions with parity, month of breeding, or insemination number were not significant. The first-service P/AI (38.8&#xa0;&#xb1;&#xa0;1.4%) was greater (P&#xa0;<&#xa0;0.05) than the resynchronized P/AI (35.3&#xa0;&#xb1;&#xa0;1.3%). Cows inseminated in the summer had lesser P/AI (effect of month; P&#xa0;<&#xa0;0.001) compared with cows inseminated in the winter. There was a decrease (P&#xa0;<&#xa0;0.002) in timed AI conception for cows with a greater milk SCC and an increase (P&#xa0;<&#xa0;0.003) in P/AI for cows with a greater milk protein percentage. In conclusion, the GnRH product did not affect P/AI for the first or resynchronized timed AI in an Ovsynch-based program. Other factors affected P/AI including service number (lesser for the second service or greater), month (lesser in summer months), SCC (lesser for cows with greater SCC), and milk protein percentage (greater for cows with greater protein percentage).

Diagnostic accuracy of the triptorelin stimulation test for central precocious puberty in girls.

Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis. The GnRH stimulation test remains the diagnostic gold standard, especially in girls with undetectable basal LH levels. However, native GnRH is expensive and often unavailable. Rapid-acting subcutaneous triptorelin has been proposed as a reliable alternative. This retrospective study evaluated the diagnostic accuracy of subcutaneous triptorelin compared with intravenous gonadorelin and investigated the optimal timing for LH peak assessment. A total of 341 girls referred for suspected precocious puberty were evaluated: 102 underwent the triptorelin test and 239 the gonadorelin test, with gonadotropins measured by electrochemiluminescence assay at baseline and after stimulation. Based on clinical, radiological, and laboratory criteria, 143 girls were diagnosed with CPP and 198 with non-progressive thelarche (NPT). Triptorelin elicited significantly higher FSH peaks than gonadorelin, while LH peaks were comparable; consequently, FSH/LH ratios were higher after triptorelin. ROC analysis identified an optimal diagnostic LH peak cut-off of 7.14 IU/L following triptorelin administration (sensitivity 94%, specificity 96%; AUC 0.985), while a threshold of 4.7 IU/L was observed after gonadorelin (sensitivity 100%, specificity 87%; AUC 0.982). Peak LH occurred predominantly at 180 min after triptorelin in both CPP and NPT groups (78 and 90%, respectively). Despite the limitations of its retrospective and non-parallel design, this large cohort study demonstrates that subcutaneous triptorelin provides excellent diagnostic accuracy, comparable to gonadorelin. These findings support triptorelin as a reliable and accessible alternative for CPP diagnosis and contribute to the standardization of diagnostic protocols in clinical practice. This study tested triptorelin stimulation as an alternative to the standard gonadorelin test to diagnose precocious puberty in girls. Triptorelin proved equally accurate and reliable, especially when hormone levels are measured 3 h after injection, offering a practical diagnostic tool in clinical practice.

Neuroendocrinology of the pituitary gland.

The hypophysial-portal chemotransmitter hypothesis of control of the anterior pituitary was first set forth in the 1940s on the basis of physiological studies of the effects of lesions of the hypothalamus, and of section of the pituitary stalk on pituitary function. Morphological demonstration of specific neuropeptide pathways in the hypothalamus, which project to the median eminence, and the chemical identification of releasing hormones in the hypothalamus have fully established this theory. Specific neuropeptides have been isolated which stimulate the secretion of ACTH (CRF, corticotrophin releasing hormone), TSH (TRH, thyrotropin releasing hormone), GH (GHRH, growth hormone releasing hormone), and the gonadotropins (LHRH, luteinizing hormone releasing hormone; GnRH, gonadotropin releasing hormone). Prolactin secretion is regulated by both an inhibitory hormone (dopamine), and by one or more releasing factors. A factor inhibitory to GH and TSH secretion has also been identified. All factors except for the prolactin inhibitory hormone (which is a biogenic amine) are peptides, all synthesized as part of large prohormones. These substances have all been introduced into medical and veterinary practice where they are useful for regulation of pituitary abnormalities, and study of normal physiology.

An Expert Review on the Combination of Relugolix With Definitive Radiation Therapy for Prostate Cancer.

Androgen deprivation therapy (ADT) is an integral component in the management of prostate cancer across multiple disease states. Traditionally, luteinizing hormone-releasing hormone (LHRH) agonists constituted the backbone of ADT. However, gonadotropin-releasing hormone receptor hormone (GnRH) antagonists also are available, which offer faster testosterone suppression and reduced likelihood of ADT-related adverse effects compared with LHRH agonists, including the potential for fewer ADT-associated major cardiac events. Until recently, all forms of LHRH agonists and GnRH antagonist formulations were of parenteral administration. However, recently relugolix gained Food and Drug Administration approval as the first oral GnRH antagonist. Relugolix achieves faster and more complete testosterone suppression compared with an LHRH agonist. This translates to more rapid prostate-specific antigen response compared with LHRH agonists. After discontinuation of relugolix, testosterone recovers faster than after GnRH agonists or injectable GnRH antagonist therapy. Overall, these factors provide opportunities for more precisely defined ADT duration when combined with radiation therapy. The rapid onset and offset of testosterone suppression with relugolix may require physicians to rethink the mechanism and goals of ADT when prescribing. As an oral formulation, relugolix enables patients to avoid pain and injection site reactions, limit extra office visits for injections, and achieve a shorter duration of experiencing the side effects of castrate testosterone levels. This convenience and tolerability may enhance physicians' willingness to prescribe ADT and patients' feeling of control during their ADT course, but the potential advantages are accompanied by the risks of patients choosing to discontinue therapy to escape side effects of ADT. This article focuses on different aspects of what is known and unknown regarding the optimal use of ADT and radiation therapy, and how relugolix, due to its properties, fit into our current treatment paradigms for localized prostate cancer.

99mTc-LHRH in tumor receptor imaging.

Detection of gonadotropin-releasing hormone (GnRH) also known as luteinizing hormone-releasing hormone (LHRH) in the relevant tumor tissue and normal tissues and organs in vivo expression was investigated. To examine the method of direct radio labeling of LHRH by 99mTc with relatively high radiochemical purity and stability, screening the best labeling conditions, to establish a simple and reliable method of preparation of 99mTc-LHRH was undertaken. The detection of radioisotope-labeled LHRH distribution in mice, LHRH receptor imaging for the study and treatment of cancer basis were evaluated. i) Immunohistochemical staining test was used in 23 patients with hepatocellular carcinoma (HCC), 20 patients with breast cancer, 10 patients with prostate cancer, 20 patients with lung cancer, 20 patients with endometrial cancer tumor cells and normal tissue LHRH-R De Biaoda levels; ii) pre-tin method use direct labeling of LHRH, marking completion of saline or human serum were added at room temperature, the chromatography was measured at different times, to calculate the rate of labeled product and the radiochemical purity of the label, in vivo observation of its stability, and comparative analysis of selected optimal condition; iii) rat pituitary cell membrane protein, the product of in vitro radio-receptor marker analysis, through the saturation and inhibition experiments, was used to test its receptor binding activity; iv) Ch-T method labeled 125I-LHRH, tail vein injection of normal mice at different times were sacrificed, blood and major organs were determined and calculated per gram organization percentage injected dose rate (%, ID/g). Detected by immunohistochemistry in 23 cases of HCC in the LHRH-positive rate was 82.61%, in the corresponding normal tissues, the positive rate was 15%; 20 cases of breast cancer positive rate of 95%, the corresponding normal tissues, the positive rate was 20%; 10 cases of prostate cancer positive rate of 70%, the corresponding normal tissues, the positive rate of 40%; 20 cases of lung cancer positive rate of 85%, the corresponding normal tissues, the positive rate of 15.79%; 20 cases of endometrial cancer positive rate of 80% in the corresponding normal tissues was 16.67% positive. 99mTc-LHRH mark was 97.9-100.0%, the radiochemical purity of 93.9-96.4%, marking the reaction gel content of <5%. Great product receptor marker analysis showed 99mTc-LHRH with saturable receptor binding characteristics and inhibition, and high affinity, RT = 23.2174 pmol, KD = 0.4348 nmol; intravenous injection of 131I-LHRH within 72 h after the mice rapidly cleared the blood radioactivity, the major radioactive accumulation in the liver and kidneys and by the liver, renal clearance, and other tissues and organs of the radioactivity gradually decreased with time. In conclusion, i) the liver, lung, breast, prostate, endometrial cancer exist in both LHRHR; ii) 99mTc-LHRH preparation is simple, rapid, radiochemical purity product obtained higher marks, better stability, no further purification; and iii) LHRH 99mTc labeled, still has a high receptor binding ability, biological activity; and has an ideal and realistic dynamics in animals, there is hope, as with the clinical value of imaging agent of GnRH receptors.

Role of Gonadotropin-Releasing Hormone (GnRH) in Ovarian Cancer.

The hypothalamus-pituitary-gonadal (HPG) axis is the endocrine regulation system that controls the woman's cycle. The gonadotropin-releasing hormone (GnRH) plays the central role. In addition to the gonadotrophic cells of the pituitary, GnRH receptors are expressed in other reproductive organs, such as the ovary and in tumors originating from the ovary. In ovarian cancer, GnRH is involved in the regulation of proliferation and metastasis. The effects on ovarian tumors can be indirect or direct. GnRH acts indirectly via the HPG axis and directly via GnRH receptors on the surface of ovarian cancer cells. In this systematic review, we will give an overview of the role of GnRH in ovarian cancer development, progression and therapy.

Induction of ovulation after gnRH antagonists.

The gonadotrophin-releasing hormone (GnRH) antagonist binds competitively to the receptors and thereby prevents endogenous GnRH from exerting its stimulatory effect on the pituitary cells. This causes suppression of gonadotrophin secretion which occurs immediately after administration of the antagonist. When using GnRH antagonist in controlled ovarian stimulation, ovulation or maturation of the oocyte can, therefore, be induced by a variety of drugs, e.g. native GnRH, recombinant LH or short-acting GnRH agonists. Short-acting GnRH agonists were recommended for triggering ovulation in cases with a high risk of developing ovarian hyperstimulation syndrome (OHSS). Since it is evident that GnRH is required to initiate the LH surge and the oestradiol rise, a single administration of GnRH antagonist during the late follicular phase delays the LH surge. Studies showed that a single s.c. administration of 3 or 5 mg of Cetrorelix in the late follicular stage was sufficient to prevent the LH surge for 617 days. This phenomenon can be used in high responder patients who are prone to OHSS. The question whether this delay has any effect on oocyte quality and maturation still remains unanswered. Overall, there are four uses for GnRH antagonist: (i) using short-acting GnRH agonists for triggering ovulation in cases in which the GnRH antagonist is part of the protocol for ovarian stimulation. Recombinant LH and native LHRH could also be used as triggers of LH surge; (ii) delaying the LH surge in cases prone to OHSS by treatment with GnRH antagonist; (iii) to administer GnRH antagonist during the luteal phase to decrease the activity of corpora lutea; (iv) in polycystic ovarian disease with elevated LH the LH/FSH ratio can be corrected with the injection of GnRH antagonist prior to and during ovarian stimulation.

[Pharmacokinetics and pharmacodynamics of triptorelin].

GnRH agonists are derived from the native molecule by substitution of a D-amino acid in position 6 which increases their resistance to enzymatic breakdown and their affinity for LH-RH receptors in comparison with the native hormone. Because of this improved resistance which increases their half-life they have a super-agonistic effect. In 1973, two years only after he characterized LH-RH, A.V. Schally synthesized several GnRH analogs, including D-TRP6-LHRH obtained by substituting the glycine-6 with a D-tryptophan. The biological half life of this agonist injected by the subcutaneous route is 10 times greater than that observed after intravenous injection because of the progressive release of the peptide from the injection site. Pharmaceutical research has led to the development of delayed-release formulations allowing doses to be spaced by intervals of several weeks, or even three months when needed in some indications (Decapeptyl slow release). Triptorelin, as the other GnRH agonists, strongly reduces LH secretion, by preventing the production of the LH-beta subunit. On the opposite, the production of LH-alpha subunit is markedly increased and remains responsive to exogenous GnRH injection, demonstrating that the agonist does not induce actual pituitary desensitization. Compared with LH-RH antagonists which inhibit both LH-alpha and LH-beta subunit secretion, agonists offer the advantage of a sustained efficacy even after one or two days of withdrawal, while the effect of the agonist disappeared as soon as the administration is stopped. On the other hand, GnRH antagonists do not induce the initial hyperstimulation of the gonadotrophs, the so-called flare up, characteristic of the superagonistic effect.

Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer.

The expression of GnRH (GnRH-I, LHRH) and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the ovary. The proliferation of human ovarian cancer cell lines is time- and dose-dependently reduced by GnRH and its superagonistic analogs. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in these cancer cells. The GnRH receptor rather interacts with the mitogenic signal transduction of growth-factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in downregulation of cancer cell proliferation. In addition GnRH activates nucleus factor kappaB (NFkappaB) and protects the cancer cells from apoptosis. Furthermore GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (JNK/AP-1) pathway independent of the known AP-1 activators, protein kinase (PKC) or mitogen activated protein kinase (MAPK/ERK). Recently it was shown that human ovarian cancer cells express a putative second GnRH receptor specific for GnRH type II (GnRH-II). The proliferation of these cells is dose- and time-dependently reduced by GnRH-II in a greater extent than by GnRH-I (GnRH, LHRH) superagonists. In previous studies we have demonstrated that in ovarian cancer cell lines except for the EFO-27 cell line GnRH-I antagonist Cetrorelix has comparable antiproliferative effects as GnRH-I agonists indicating that the dichotomy of GnRH-I agonists and antagonists might not apply to the GnRH-I system in cancer cells. After GnRH-I receptor knock down the antiproliferative effects of GnRH-I agonist Triptorelin were abrogated while the effects of GnRH-I antagonist Cetrorelix and GnRH-II were still existing. In addition, in the ovarian cancer cell line EFO-27 GnRH-I receptor but not putative GnRH-II receptor expression was found. These data suggest that in ovarian cancer cells the antiproliferative effects of GnRH-I antagonist Cetrorelix and GnRH-II are not mediated through the GnRH-I receptor.

Quantitation of endogenous GnRH by validated nano-HPLC-HRMS method: a pilot study on ewe plasma.

Gonadotropin-releasing hormone isoform I (GnRH), a neuro-deca-peptide, plays a fundamental role in development and maintenance of the reproductive system in vertebrates. The anomalous release of GnRH is observed in reproductive disorder such as hypogonadotropic hypogonadism, polycystic ovary syndrome (PCOS), or following prenatal exposure to elevated androgen levels. Quantitation of GnRH plasma levels could help to diagnose and better understand these pathologies. Here, a validated nano-high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS) method to quantify GnRH in ewe plasma samples is presented. Protein precipitation and solid-phase extraction (SPE) pre-treatment steps were required to purify and enrich GnRH and internal standard (lamprey-luteinizing hormone-releasing hormone-III, l-LHRH-III). For the validation process, a surrogate matrix approach was chosen following the International Council for Harmonisation (ICH) and FDA guidelines. Before the validation study, the validation model using the surrogate matrix was compared with those using a real matrix such as human plasma. All the tested parameters were analogous confirming the use of the surrogate matrix as a standard calibration medium. From the validation study, limit of detection (LOD) and limit of quantitation (LOQ) values of 0.008 and 0.024&#xa0;ng/mL were obtained, respectively. Selectivity, accuracy, precision, recovery, and matrix effect were assessed with quality control samples in human plasma and all values were acceptable. Sixteen samples belonging to healthy and prenatal androgen (PNA) exposed ewes were collected and analyzed, and the GnRH levels ranged between 0.05 and 3.26&#xa0;ng/mL. The nano-HPLC-HRMS developed here was successful in measuring GnRH, representing therefore a suitable technique to quantify GnRH in ewe plasma and to detect it in other matrices and species.

The Role of Gonadotropin-Releasing Hormone (GnRH) in Endometrial Cancer.

Endometrial cancer (EC) is one of the most common gynecological malignancies. Gonadotropin releasing hormone (GnRH) is a decapeptide first described to be secreted by the hypothalamus to regulate pituitary gonadotropin secretion. In this systematic review, we analyze and summarize the data indicating that most EC express GnRH and its receptor (GnRH-R) as part of an autocrine system regulating proliferation, the cell cycle, and apoptosis. We analyze the available data on the expression and function of GnRH-II, its putative receptor, and its signal transduction. GnRH-I and GnRH-II agonists, and antagonists as well as cytotoxic GnRH-I analogs, have been shown to inhibit proliferation and to induce apoptosis in human EC cell lines in pre-clinical models. Treatment with conventional doses of GnRH-agonists that suppress pituitary gonadotropin secretion and ovarian estrogen production has become part of fertility preserving therapy of early EC or its pre-cancer (atypical endometrial hyperplasia). Conventional doses of GnRH-agonists had marginal activity in advanced or recurrent EC. Higher doses or more potent analogs including GnRH-II antagonists have not yet been used clinically. The cytotoxic GnRH-analog Zoptarelin Doxorubicin has shown encouraging activity in a phase II trial in patients with advanced or recurrent EC, which expressed GnRH-R. In a phase III trial in patients with EC of unknown GnRH-R expression, the cytotoxic GnRH doxorubicin conjugate was not superior to free doxorubicin. Further well-designed clinical trials exploiting the GnRH-system in EC might be useful.

Evolution of gonadotropin-releasing hormone (GnRH) neuronal systems.

The neuropeptide gonadotropin-releasing hormone (GnRH, LHRH) serves as both a hormone and a neurotransmitter, and it has multiple actions on reproductive physiology and behavior. At least seven different molecular forms of GnRH have evolved, and nearly all vertebrates studied express at least two different forms of GnRH: chicken GnRH II, and a second form that varies across classes. The GnRH cell bodies span a broad region of the forebrain and midbrain, and processes project to virtually every region of the CNS, to the vasculature, and to the cerebrospinal fluid. Comparative evidence supports the model that gnathostomic vertebrates possess two principle GnRH systems, with different embryonic and, probably, evolutionary origins, expressing different molecular forms of GnRH and projecting to different targets. The terminal nerve-septo-preoptic system serves as the principle regulator of gonadotropin release in most vertebrates. Neurons originate in the embryonic olfactory placode and migrate centrally during development, and it is proposed that ontogeny of the TN-septo-preoptic system reflects its evolutionary origins as a peripheral endocrine organ associated with the olfactory system. The second GnRH system, which arises from non-placodal precursors, comprises cell bodies in periventricular regions of the posterior diencephalon and/or midbrain. Although much less is known about the posterior GnRH system, evidence suggests that these cells served as the ancestral brain GnRH system and are the cellular locus of the chicken GnRH peptide. The GnRH system of lampreys does not appear to be homologous to either the TN-septo-preoptic or posterior GnRH system, and it is suggested that GnRH in agnathans represents a third evolutionary event.

Gonadotropin-releasing hormone genes: phylogeny, structure, and functions.

Gonadotropin-releasing hormone (GnRH, previously called leutinizing hormone-releasing hormone, LHRH) is the final common signaling molecule used by the brain to regulate reproduction in all vertebrates. Recently, genes encoding two other GnRH forms have been discovered. Here we present a phylogenetic analysis that shows that the GnRH genes fall naturally into three distinct branches, each of which shares not only a molecular signature but also characteristic expression sites in the brain. The GnRH genes appear to have arisen through gene duplication from a single ancestral GnRH whose origin predates vertebrates. Several lines of data support this suggestion, including the fact that all three genes share an identical exonic structure. The existence of three distinct GnRH families suggests a new, natural nomenclature for the genes, and in addition, we present a logical proposal for naming the peptide sequences. The two recently discovered GnRH genes are unusual because they encode decapeptides that are identical in all the species in which they have been found. The control of gene expression also differs among the three gene families as might be expected since they have had separate evolutionary trajectories for perhaps 500 million years.

The neuroendocrinology of human puberty revisited.

The fundamental aspects of the hypothalamic luteinizing hormone-releasing hormone (LHRH)(1) [1]pulse generator-pituitary gonadotrophin-gonadal apparatus in mammals have striking commonalities. There are, however, critical, substantive differences in the neuroendocrinology of puberty among species. The onset of puberty in the human is marked by an increase in the amplitude of LH pulses, an indirect indicator of the increase in amplitude of LHRH pulses. The hypothalamic LHRH-pituitary gonadotrophin complex is functional by at least 0.3 gestation in the human foetus; the sex difference in the fetal and neonatal pattern of LH and FSH secretion is an apparent consequence of imprinting of the fetal hypothalamus-pituitary-gonadotropin apparatus by fetal testosterone. Until about 6 months of age in boys and 12-24 months in girls, the testes and ovaries respond to the increased LH in boys and follicle-stimulating hormone (FSH) in girls by secreting testosterone and oestradiol, respectively, reaching levels that are not again achieved before the onset of puberty. Striking features of the ontogeny of the human hypothalamic pulse generator are: (1) its development and function in the foetus; (2) the continued function of the hypothalamic LHRH pulse generator-pituitary gonadotrophin-gonadal axis in infancy; (3) the gradual damping of hypothalamic LHRH oscillator activity during late infancy; (4) its quiescence during childhood - the so-called juvenile pause; (5) during late childhood the gradual disinhibition and reactivation of the LHRH pulse generator, mainly at night; (6) the increasing amplitude of the LHRH pulses, which are reflected in the progressively increased and changing pattern of circulating LH pulses, with the approach of and during puberty. The intrinsic central nervous system (CNS) mechanisms responsible for the inhibition of the LHRH pulse generator during childhood (the juvenile phase) involve the major role of an inhibitory neuronal system - the CNS inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and GABAergic neurons, as revealed by studies in the rhesus monkey by Terasawa and her associates. With the onset of puberty, the disinhibition and reactivation of the LHRH pulse generator is associated with a fall in GABAergic neurotransmission and a concomitant increase in the input of excitatory amino acid neurotransmitters (including glutamate) and possibly astroglial-derived growth factors. Despite remarkable progress over the past three decades, large gaps remain in our understanding of the neurobiological, genetic and environmental mechanisms involved in the control of the onset of puberty. The role of leptin in the control of the onset of puberty is reviewed. Severe leptin deficiency is associated with hypogonadotrophic hypogonadism; it appears that a critical level of leptin and a leptin signal is required to achieve puberty. The weight of evidence supports the hypothesis that leptin acts as one of several permissive factors and not a trigger in the onset of human puberty. The application of these advances provides a framework for the described classification of sexual precocity and delayed puberty.1 GnRH is synonymous with LHRH.

Relugolix for the treatment of uterine fibroids.

Uterine leiomyomas represent the most common form of benign gynecological tumors affecting 20-40% of women during their life. Several therapeutic options are available for treating these patients. The use of medical treatment for myomas has largely grown in the last years, in particular for women who would refuse, postpone or are not candidates for surgery. In the last years, the clinical investigation of gonadotropin-releasing hormone (GnRH) antagonists (GnRH-ants) has emerged. This class of drugs exerts pure competitive antagonistic activity on the GnRH receptor at the pituitary gland, producing an immediate stop in the release of gonadotropins and sex steroids. Relugolix is an orally active nonpeptide GnRH-ant, recently licensed for marketing in Japan for the treatment of symptoms related to uterine myomas. Currently, several phase III clinical trials are ongoing to evaluate this molecule in this setting in the U.S. and Europe.

LHRF, LHRH, GnRH: what controls the secretion of this hormone?

In the present study, the possible direct effects of opioids on the release of LHRH have been studied utilizing the GT1-1 cell model. It has been shown that only opioid agonists which bind to delta receptors bring about a significant inhibition of the release of LHRH, when this is stimulated by forskolin- or PGE2. The effects of delta opioid agonists are dose-dependent, and are reversed by the delta specific antagonist naltrindole. If one assumes that the GT1-1 cells represent a good model for the study of LHRH-secreting neurons, the obvious conclusion from these data is that endogenous opioid peptides may influence LHRH secretion also by acting directly on LHRH-secreting neurons. In another study it has been shown that GT1-1 cells possess high affinity-low capacity binding sites for estradiol and androgens. Moreover, a two-fold induction of androgen-binding sites has been observed after treatment of GT1-1 cells with estradiol, indicating that estrogen receptors are functional. The present observations suggest that gonadal steroids might influence LHRH release acting directly on the cells which manufacture and release the hypothalamic hormone. In order to evaluate the possible existence of a humoral communication between glial cells and LHRH-secreting neurons, two different approaches have been used: (a) GT1-1 cells were co-incubated with purified cultures of type 1 astrocytes; (b) GT1-1 cells were exposed to the conditioned medium (CM, untreated or submitted to different experimental procedures) where type 1 astrocytes were grown for 24 h. In both sets of experiments LHRH was measured by RIA in the incubation media of GT1-1 cells. The data show that short periods of either co-culture or exposure to previously frozen or heated CM significantly increase the release of LHRH from the GT1-1 cells. The stimulatory effect on LHRH release appears to be specific for type 1 astrocytes. Surprisingly, fresh CM proved to be inactive; this suggested that the factor(s) involved needed to be 'activated'. Since it is known that TGF beta may be liberated from its supporting proteins by freezing or heating, the effects of TGF beta and of a TGF beta-neutralizing antibody were analyzed. The stimulatory effect exerted by the frozen CM was completely abolished by the antibody, while TGF beta 1 proved able to significantly increase LHRH release from GT1-1 cells. The present data unequivocally show that type 1 astrocytes in culture release some principle(s), probably TGF beta, able to stimulate LHRH release from the LHRH-producing GT1-1 cell line. To the authors' knowledge, the present data provide the first clear-cut demonstration that the glia may directly intervene in the control of LHRH release via the secretion of humoral factors.

Is the metalloendopeptidase EC 3.4.24.15 (EP24.15), the enzyme that cleaves luteinizing hormone-releasing hormone (LHRH), an activating enzyme?

LHRH (GNRH) was first isolated in the mammalian hypothalamus and shown to be the primary regulator of the reproductive neuroendocrine axis comprising of the hypothalamus, pituitary and gonads. LHRH acts centrally through its initiation of pituitary gonadotrophin release. Since its discovery, this form of LHRH (LHRH-I) has been shown to be one of over 20 structural variants with a variety of roles in both the brain and peripheral tissues. LHRH-I is processed by a zinc metalloendopeptidase EC 3.4.24.15 (EP24.15) that cleaves the hormone at the fifth and sixth bond of the decapeptide (Tyr(5)-Gly(6)) to form LHRH-(1-5). We have previously reported that the auto-regulation of LHRH-I (GNRH1) gene expression and secretion can also be mediated by itself and its processed peptide, LHRH-(1-5), centrally and in peripheral tissues. In this review, we present the evidence that EP24.15 is the main enzyme of LHRH metabolism. Following this, we look at the metabolism of other neuropeptides where an active peptide fragments is formed during degradation and use this as a platform to postulate that EP24.15 may also produce an active peptide fragment in the process of breaking down LHRH. We close this review by the role EP24.15 may have in regulation of the complex LHRH system.

Effect of the GnRH stimulation test on Canine Prostatic-Specific Esterase (CPSE).

The gonadotropin-releasing hormone (GnRH) stimulation test is used to investigate testicular production of testosterone (T) when performing a breeding soundness examination. In male dogs with fertility problems, the prostate should also be investigated as prostatic conditions may frequently lower semen quality. Serum concentrations of canine prostatic-specific esterase (CPSE) increase in dogs with benign prostatic hyperplasia (BPH). When performing a breeding soundness examination in a male dog, GnRH administration is frequently done at the beginning of the process and then both T and CPSE are assayed on the same serum sample collected 1&#x2009;h following the GnRH injection. The aim of this study was to assess whether or not the administration of GnRH may alter CPSE concentrations in dogs with a healthy prostate. Twenty-eight client-owned intact adult male dogs were included in the study. Following a 7-day sexual rest all male dogs underwent a clinical examination and an ultrasonographic examination of the prostatic gland. Prostatic size and parenchyma of every tested dog were evaluated by ultrasonography to assess prostatic conditions. Two different GnRH stimulation protocols were used, A&#x2009;=&#x2009;gonadorelin 50&#x3bc;g/dog SC (n&#x2009;=&#x2009;15) and B&#x2009;=&#x2009;buserelin 0.12&#x2009;&#x3bc;g/kg IV (n&#x2009;=&#x2009;13). T and CPSE concentrations were measured before and 1&#x2009;h after GnRH administration by a laser-induced fluorescence analysis. Buserelin and gonadorelin were equally effective in causing a significant increase in serum T concentrations in the post GnRH sample. When considering the 28 dogs together, CPSE concentrations did not change following the stimulation test with either GnRH compound; however, in 4/28 cases, the post GnRH value was markedly increased to values compatible with a diagnosis of BPH. There was no difference in the action of buserelin or gonadorelin in causing an increase in serum T concentrations. CPSE secretion was increased in approximately 15% of dogs treated with either buserelin or gonadorelin. Therefore, whenever performing diagnostic testing in intact male dogs, CPSE should not be assayed on a post-GnRH serum sample.

The LHRH antagonist cetrorelix: a review.

In those clinical situations in which an immediate and profound suppression of gonadotrophins is desired, LHRH agonists have the disadvantage of producing an initial stimulatory effect on hormone secretion. Therefore, the use of GnRH antagonists which cause an immediate and dose-related inhibition of LH and FSH by competitive blockade of the receptors is much more advantageous. One of the most advanced antagonist produced to date is Cetrorelix, a decapeptide which has been shown to be safe and effective in inhibiting LH and sex-steroid secretion in a variety of animal species and in clinical studies as well. Clinical trials in patients suffering from advanced carcinoma of the prostate, benign prostate hyperplasia, and ovarian cancer are currently in progress and have already shown the usefulness of this new treatment modality. In particular, the concept that a complete suppression of sex-steroids may not be necessary in indications such as uterine fibroma, endometriosis and benign prostatic hyperplasia represents a promising novel perspective for treatment of these diseases. Following completion of phase III trials in controlled ovarian stimulation for IVF regimens, Cetrorelix was given marketing approval and, thus, became the first LHRH antagonist available clinically.

GnRH agonists: gonadorelin, leuprolide and nafarelin.

Gonadotropin-releasing hormone (GnRH), a decapeptide synthesized and released by the hypothalamus, regulates production and release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the adenohypophysis. Parenterally administered GnRH was initially used diagnostically as a test of adenohypophyseal reserve of LH and FSH. Subsequently, native GnRH was used therapeutically to treat hypothalamic hypogonadal and infertility states in both men and women. Because of the low potency and short half-life of native GnRH, long-acting, potent analogs have been developed that suppress secretion of native pituitary gonadotropins, resulting in medical gonadectomy. When administered parenterally and, more recently, intranasally, these compounds are useful in the management of prostate and breast carcinoma, endometriosis and uterine leiomyomata, precocious puberty and nontumorous ovarian hyperandrogenic syndromes.

Luteinizing Hormone-Releasing Hormone (LHRH)-Targeted Treatment in Ovarian Cancer.

Ovarian cancer remains one of the most lethal gynecologic malignancies and requires more effective and targeted treatment strategies. Luteinizing hormone-releasing hormone (LHRH), or gonadotropin-releasing hormone (GnRH), receptors are expressed in approximately 80% of ovarian tumors, representing a promising target for targeted drug delivery. This narrative review aimed to explore the development and advancements of LHRH-receptor targeted therapies in ovarian cancer. A bibliographic search was performed using PubMed, Scopus, Google Scholar, and Web of Science. The search strategy included studies on LHRH-peptide drug delivery systems and LHRH-conjugate nanosystems. Literature search covered in vitro studies, preclinical models, and ongoing clinical trials from 2000 to 2025. A total of 19 studies were included for peptide-drug delivery, and 30 studies were included for LHRH-conjugated nanosystems. Overall findings demonstrated enhanced preclinical efficacy, achieving ~50-80% tumor-growth inhibition and 2-4-fold higher cellular uptake, alongside reduced systemic toxicity. Early clinical studies, although limited, reported an overall response/disease-control rate of approximately 50%, supporting improved tumor accumulation of drugs, small interfering RNA (siRNA), and diagnostic agents. Ovarian cancer-specific therapy, targeting LHRH receptors, represents a promising strategy to enhance therapeutic outcomes. Further efforts in preclinical and clinical research are essential to refine personalized treatments and integrate them with a combination of therapies.

A New Bihormonal Model for the Brain Regulation of Gonadotropins in Teleosts.

The brain-pituitary-gonadal tissues play a key role in the neuroendocrine regulation of reproduction in vertebrates. Brain hormones, especially gonadotropin-releasing hormone (GnRH) is considered an important stimulant of gonadotropins (luteinizing hormone and follicle-stimulating hormone) released from the anterior pituitary. The current concept proposes a single brain hormone (GnRH) stimulating the release of both gonadotropins in fish and mammals. However, two articles published in 2024 proposed a dual-hormone concept in the brain regulation of gonadotropins in female medaka and zebrafish. The emerging concept proposes GnRH as the LH releasing hormone (LH-RH), and a second hormone, cholecystokinin (Cck), as the FSH-releasing hormone (FSH-RH) in these species. The two studies discussed here found that Cck is a potent FSH-RH. The line of evidence from the first study to support this notion includes the abundance of Cck receptors in the anterior pituitary Fsh-producing gonadotrophs, and severe reproductive defects in female medaka that genetically lacks Cck receptor 2. The second study used zebrafish, and found hypothalamic expression of Cck, anterior pituitary abundance of Cck receptors, and an all-male phenotype when Cck receptor 2 was knocked out. In both studies, Cck was found to be a more potent stimulant of intracellular Ca2+, when compared to GnRH effects. These evidence from two independent studies indicate that Cck is a potent FSH-RH, and GnRH is the LH-RH, and supports a bihormonal model for the regulation of gonadotropin secretion from teleost pituitary. However, whether Cck elicits FSH-RH effects in other fish species remains unknown. In addition, the role of other hormones in the diverse endocrine milieu that regulate reproduction in modulating the phenotype seen in Cck receptor deficient fish warrants further consideration.

Efficacy of methods to synchronize follicular wave emergence in pregnant heifers.

The objective of the present study was to evaluate the efficacy of various methods for synchronization of follicular wave emergence (FWE) in pregnant heifers. Pregnant (60 d of gestation) Holstein heifers (n = 86) arranged in cohorts were randomly assigned to be administered 172 &#xb5;g of gonadorelin acetate (GnRH), 3,300 IU of human chorionic gonadotropin (hCG), follicular ablation of follicles >5 mm (FA), or saline (control). Ultrasonography was performed to determine ovulation and emergence of a new follicular wave. Data were analyzed using generalized linear mixed models with treatment as a fixed effect and cohort as a random effect. Ovulatory response was greater for hCG (81.0%; 95% CI: 58.0-92.9) than GnRH-treated (50.0%; 95% CI: 28.8-71.2) heifers, whereas ovulation was not observed for heifers in the FA or control groups. Heifers in the FA group had a shorter (34.8 &#xb1; 1.7 h) interval from treatment to FWE compared with heifers in the hCG (51.8 &#xb1; 5.3 h), GnRH (56.8 &#xb1; 5.3 h), and control (61.4 &#xb1; 9.8 h) groups. Furthermore, treatments differed in variability of time to FWE, whereby FA-treated heifers had less variable, more consistent responses than hCG and GnRH heifers. These groups were, in turn, less variable in time to FWE than heifers in the control group. Synchronization of FWE efficacy was greater in FA (97.6%; 95% CI: 69.8%-99.9%) and hCG-treated (75.0%; 95% CI: 52.8%-89.0%) heifers than control (27.5%; 95% CI: 12.2%-50.9%) heifers, with marginal evidence for a difference between GnRH (69.1%; 95% CI: 46.4%-85.2%) and control heifers. Overall, we found no evidence for differences in FWE synchronization efficacy between hCG, GnRH, and FA. Nevertheless, FA resulted in a shorter and less variable interval from treatment to FWE, thus providing a more precise control of follicular development.

Improved fertility following a gonadotropin-releasing hormone treatment on day 2 of an estradiol and progesterone-based timed-artificial insemination protocol in lactating dairy cows.

The present study evaluated the addition of gonadotropin-releasing hormone (GnRH) concomitant or 2 d after the beginning of protocols initiated with estradiol benzoate (EB). A total of 459 multiparous and 371 primiparous lactating Holstein cows were enrolled in the study. Weekly cohorts of cows were randomly assigned to 1 of 3 experimental groups that differed in the strategy to initiate the timed AI (TAI protocol. On d 0, all cows received a 1.55-g progesterone (P4) implant. Additionally, cows in the EBd0 group received 2 mg of EB i.m.; cows in the EBd0-GnRHd0 group were treated simultaneously on d 0 with 2 mg of EB plus 100 &#xb5;g of gonadorelin diacetate tetrahydrate (GnRH) i.m.; and cows in the EBd0-GnRHd2 group received 2 mg of EB on d 0 and 100 &#xb5;g of GnRH 48 h later (d 2). The remaining treatments in the protocol were similar among groups and included 0.53 mg (i.m.) of cloprostenol sodium (PGF2&#x3b1;) on d 7, followed by a second PGF2&#x3b1; treatment on d 9 (at the time of P4 implant withdrawal) and 1 mg of estradiol cypionate i.m. Then, TAI was performed on d 11 (48 h after P4 removal) in all experimental groups. We detected an effect of treatment on pregnancy per AI (P/AI) on d 30, in which cows from the EBd0-GnRHd2 group demonstrated greater fertility than EBd0 cows, whereas cows in the EBd0-GnRHd0 group did not differ among EBd0 and EBd0-GnRHd0 (40.5 vs. 30.4 vs. 34.4%, respectively). In summary, GnRH treatment at the beginning of an estradiol and P4-based TAI protocol increased fertility only when GnRH was given on d 2. Moreover, a more pronounced positive effect of this strategy was observed in particular classes of cows: multiparous cows, cows with greater milk production, and those receiving the first service.

A biomimetic enzyme-linked immunosorbent assay (BELISA) for the analysis of gonadorelin by using molecularly imprinted polymer-coated microplates.

An original biomimetic enzyme-linked immunoassay (BELISA) to target the small peptide hormone gonadorelin is presented. This peptide has been recently listed among the substances banned in sports by the World Antidoping Agency (WADA) since its misuse by male athletes triggers testosterone increase. Hence, in response to this emerging issue in anti-doping controls, we proposed BELISA which involves the growth of a polynorepinephrine (PNE)-based molecularly imprinted polymer (MIP) directly on microwells. PNE, a polydopamine (PDA) analog, has recently displayed impressive performances when it was exploited for MIP preparation, giving even better results than PDA. Gonadorelin quantification was accomplished via a colorimetric indirect competitive bioassay involving the competition between biotinylated gonadorelin linked to the signal reporter and the unlabeled analyte. These compete for the same MIP binding sites resulting in an inverse correlation between gonadorelin concentration and the output color signal (&#x3bb; = 450 nm). A detection limit of 277 pmol L-1 was achieved with very good reproducibility in standard solutions (avCV% = 4.07%) and in urine samples (avCV% = 5.24%). The selectivity of the assay resulted adequate for biological specimens and non-specific control peptides. In addition, the analytical figures of merit were successfully validated by mass spectrometry, the reference anti-doping benchtop platform for the analyte. BELISA was aimed to open real perspectives for PNE-based MIPs as alternatives to antibodies, especially when the target analyte is a poorly or non-immunogenic small molecule, such as gonadorelin. Biomimetic enzyme-linked immunosorbent assay (BELISA).

Gonadorelin and erythropoiesis.

Recent advances in the understanding and management of delayed puberty.

Delayed puberty, especially in boys, is a common presentation in paediatrics. Recent advances have improved our understanding of the neuroendocrine, genetic and environmental factors controlling pubertal development, and hence inform the pathophysiology of delayed puberty. The discovery of kisspeptin signalling through its receptor identified neuroendocrine mechanisms controlling the gonadotrophin-releasing hormone (GnRH) pulse generator at the onset of puberty. Genetic mechanisms from single gene mutations to single nucleotide polymorphism associated with delayed puberty are being identified. Environmental factors, including nutritional factors and endocrine disruptors, have also been implicated in changes in secular trends and abnormal timing of puberty. Despite these advances, the key clinical question is to distinguish delayed puberty associated with an underlying pathology or hypogonadism from constitutional delay in growth and puberty, which remains challenging as biochemical tests are not always discriminatory. The diagnostic accuracies of newer investigations, including 36-hour luteinising hormone releasing hormone (LHRH) tests, GnRH-agonist tests, antimullerian hormone and inhibin-B, require further evaluation. Sex hormone replacement remains the main available treatment for delayed puberty, the choice of which is largely dictated by clinical practice and availability of the various sex steroid preparations. Spontaneous reversal of hypogonadism has been reported in boys with idiopathic hypogonadotrophic hypogonadism after a period of sex steroid treatment, highlighting the importance of reassessment at the end of pubertal induction. Novel therapies with a more physiological basis such as gonadotrophins or kisspeptin-agonist are being investigated for the management of hypogonadotrophic hypogonadism. Careful clinical assessment and appreciation of the normal physiology remain the key approach to patients with delayed puberty.

Degarelix versus luteinizing hormone-releasing hormone agonists for the treatment of prostate cancer.

Androgen deprivation therapy (ADT) is the mainstay for advanced, hormone-sensitive prostate cancer, and options include surgical castration, luteinizing hormone-releasing hormone (LHRH) agonist, and more recently, gonadotropin releasing hormone (GnRH) antagonist therapy. Our understanding of the mechanisms and adverse effects of ADT has increased substantially, including the class-specific adverse effects of ADT. Areas covered: This review will summarize the pharmacodynamic and pharmacokinetic properties of the GnRH antagonist degarelix and its role in the management of advanced prostate cancer, the clinical evidence supporting its regulatory approval, as well as potential benefits and disadvantages over traditional LHRH agonist therapy. Expert opinion: Degarelix represents a newer class of ADT that results in a rapid and reliable decline in serum testosterone, a quality that makes it particularly advantageous in men presenting with symptomatic, hormone-sensitive prostate cancer. Due to differences in mechanism of action, there is observational data suggesting a potential cardiovascular and even oncologic benefit over traditional LHRH agonist therapy. Further research is ongoing to more clearly define this potential benefit.

Recent advances in contraceptive vaccine development: a mini-review.

Contraceptive vaccines (CV) may provide viable and valuable alternatives to the presently available methods of contraception. The molecules that are being explored for CV development either target gamete production [luteinizing hormone-releasing hormone (LHRH)/GnRH, FSH], gamete function [sperm antigens and oocyte zona pellucida (ZP)], and gamete outcome (HCG). CV targeting gamete production have shown varied degrees of efficacy; however, they either affect sex steroids causing impotency and/or show only a partial rather than a complete effect in inhibiting gametogenesis. However, vaccines based on LHRH/GnRH are being developed by several pharmaceutical companies as substitutes for castration of domestic pets, farm and wild animals, and for therapeutic anticancer purposes such as in prostatic hypertrophy and carcinoma. These vaccines may also find applications in clinical situations that require the inhibition of increased secretions of sex steroids, such as in uterine fibroids, polycystic ovary syndrome, endometriosis and precocious puberty. CV targeting molecules involved in gamete function such as sperm antigens and ZP proteins are exciting choices. Sperm constitute the most promising and exciting target for CV. Several sperm-specific antigens have been delineated in several laboratories and are being actively explored for CV development. Studies are focused on delineating appropriate sperm-specific epitopes, and increasing the immunogenicity (specifically in the local genital tract) and efficacy on the vaccines. Anti-sperm antibody (ASA)-mediated immunoinfertility provides a naturally occurring model to indicate how a vaccine might work in humans. Vaccines based on ZP proteins are quite efficacious in producing contraceptive effects, but may induce oophoritis, affecting sex steroids. They are being successfully tested to control feral populations of dogs, deer, horses and elephants, and populations of several species of zoo animals. The current research for human applicability is focused on delineating infertility-related epitopes (B-cell epitopes) from oophoritis-inducing epitopes (T-cell epitopes). Vaccines targeting gamete outcome primarily focus on the HCG molecule. The HCG vaccine is the first vaccine to undergo Phase I and II clinical trials in humans. Both efficacy and lack of immunopathology have been reasonably well demonstrated for this vaccine. At the present time, studies are focused on increasing the immunogenicity and efficacy of the birth control vaccine, and examining its clinical applications in various HCG-producing cancers. The present article will focus on the current status of the anti-sperm, anti-ZP, anti-LHRH/GnRH and anti-HCG vaccines.

Studying the nature of ascending-descending-floating-sinking of Chinese medicines based on gonadotropin-releasing hormone.

to explore the nature of ascending-descending-floating-sinking of Traditional Chinese Medicine on normal rats using gonadotropin-releasing hormone (GnRh). Normal male Sprague-Dawley rats were orally administered six floating Chinese medicines and seven sinking Chinese medicines for 14 d. then, GnRh and relevant indicators were detected. Initially, the different effects of floating and sinking drugs on the body were explored. To verify the effects of floating and sinking drugs on the body, normal rats were orally administered Mahuang (Herba Ephedra Sinica) and Tinglizi (Semen Lepidii Apetali) for 14 d. Then, GnRh antagonists were administered. We observed the changes of relevant indicators and clarified the correlation between GnRh and the laws of floating and sinking. Floating Chinese medicines significantly increased the testicular coefficients; GnRh level in the serum; the protein level of GnRh receptor (GnRhR) in the testis; and the mRNA levels of androgen receptor (AR), small C-terminal domain phosphatase (SCP) 3, SCP2, SYCE1, SMC1B, SMC3, and Rec8 (P < 0.01 or < 0.05). Sinking Chinese medicines did not react similarly, while GnRh antagonists blocked the regulatory effect of Mahuang (Herba Ephedra Sinica) but did not affect Tinglizi (Semen Lepidii Apetali). GnRh may be closely related to the nature of ascending-descending-floating-sinking of Chinese medicine. Floating Chinese medicines may promote their medicinal properties by regulating GnRH level; however, sinking Chinese medicines did not affect GnRh level.

Does Exist a Differential Impact of Degarelix Versus LHRH Agonists on Cardiovascular Safety? Evidences From Randomized and Real-World Studies.

The main systemic therapy for the management of hormone-sensitive prostate cancer (PC) is androgen deprivation therapy (ADT), with the use of long-acting luteinizing hormone releasing-hormone (LHRH) agonists considered the main form of ADT used in clinical practice to obtain castration in PC. The concomitant administration of antiandrogens for the first weeks could reduce the incidence of clinical effects related to the testosterone flare-up in the first injection of LHRH. On the contrary, Gonadotropin Rh (GnRH) antagonists produce a rapid decrease of testosterone levels without the initial flare-up, with degarelix commonly used in clinical practice to induce castration in PC patients. Even if no long-term data are reported in terms of survival to define a superiority of GnRH or LHRH, for oncological efficacy and PC control, data from randomized clinical trials and from real-life experiences, suggest a difference in cardiovascular risk of patients starting ADT. The age-related decline in testosterone levels may represent a factor connected to the increase of cardiovascular disease risk, however, the role of ADT in increasing CV events remains controversial. For these reasons, the aim of the paper is to synthesize the difference in cardiovascular risk between LHRH and degarelix in patients undergoing ADT. A difference in cardiovascular risk could be indeed an important parameter in the evaluation of these two forms of castration therapy. The Randomized trials analyzed in this paper sustain a possible protective role for degarelix versus LHRH agonists in reducing the rate of new CV events and interventions in the short-term period. On the contrary, real-word data are contradictory in different national experiences and are strongly conditioned by huge differences between the LHRH agonists group and the degarelix group.

Endometriosis 1990. Current treatment approaches.

Endometriosis is an extremely common gynaecological disease, affecting between 1 and 5% of women of reproductive age. Women with endometriosis typically present for medical care with one of more of the following problems: pelvic pain, infertility, or a large adnexal mass (an endometrioma). The primary treatment for an endometrioma is surgical. However, long term postoperative hormone therapy may be necessary to prevent new endometriomas from developing. There is no evidence that hormonal therapy of endometriosis will improve fecundability in women with endometriosis and infertility. Pelvic pain due to endometriosis can be successfully treated with hormonal agents in the majority of patients. Four basic hormonal regimens are currently available for the treatment of endometriosis: (a) danazol; (b) gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH); gonadorelin] agonists; (c) progesterones (progestins); and (d) combined estrogens and progesterones. Randomised, controlled, clinical trials suggest that danazol and the GnRH agonists are equally effective in the treatment of endometriosis. However, the side effects caused by danazol and the GnRH agonists are markedly different. Danazol produces androgenic side effects including weight gain, hirsutism, acne, oily skin and deepening of the voice. GnRH agonists produce side effects due to hypoestrogenism, including hot flushes, osteoporosis and dry vagina. The ideal drug regimen for the treatment of endometriosis remains to be developed.

Relugolix: a novel androgen deprivation therapy for management of patients with advanced prostate cancer.

Androgen deprivation therapy (ADT) is the foundation of treatment for patients with locally advanced, recurrent and metastatic prostate cancer, most commonly using luteinizing releasing hormone (LHRH) agonists. More recently, a new approach to ADT has emerged with the development of gonadotropin-releasing hormone (GnRH) antagonists, which aim to overcome some of the potential adverse physiologic effects of LHRH agonists. This article focuses on the newest GnRH antagonist, relugolix - a once-daily treatment and the only oral GnRH antagonist that has now been approved for the treatment of advanced prostate cancer. In phase II and III studies, relugolix achieved rapid and sustained castration without the testosterone surge associated with LHRH agonists, thus avoiding the potential clinical consequences of tumor flare and the necessity for concomitant anti-androgen therapy. Relugolix also achieved rapid testosterone recovery, which may potentially reduce ADT-related adverse events and offer opportunities for combination and intermittent therapy strategies. Cardiovascular safety is a particular concern in men with prostate cancer and ADT further increases cardiovascular risk: indeed, LHRH agonists are required to have a drug label warning about an increased risk of cardiovascular disease. Data from the phase III HERO study demonstrate an improved cardiac safety profile for the GnRH antagonist relugolix compared with the LHRH agonist leuprolide, including a significantly reduced risk for a major adverse cardiovascular event. Taken together, the data indicate that relugolix may mitigate some of the cardiovascular concerns surrounding ADT and has the potential to become a new standard of care for men with prostate cancer. In summary, relugolix represents a novel and recently available prostate cancer management strategy, incorporating the mechanistic advantages of GnRH antagonists and the potential benefits of oral administration.

Elagolix sodium for the treatment of women with moderate to severe endometriosis-associated pain.

First-line medical therapies for treating pain associated with endometriosis mainly consist in combined oral contraceptives and progestins. However, some women, having persistence of symptoms, may require further therapeutic options. Among these, gonadotropin-releasing hormone (GnRH) agonists (GnRH-as) have been widely employed in the last 30 years, despite being characterized by an unfavorable safety profile. Currently, new alternative investigational options are being investigated to treat this benign chronic disease. GnRH antagonists (GnRH-ants) are innovative hormonal drugs that do not induce flare-up effects and present also a limited onset of hypoestrogenic symptoms; in fact, their pharmacological mechanism of action, which consists in pure antagonistic activity, differs from that of traditional GnRH-as. In July 2018, the U.S. Food and Drug Administration (FDA) approved elagolix sodium for the management of moderate to severe pain associated with endometriosis, after the drug showed promising efficacy and safety results in previous phase III trials. This monograph aims to provide a complete overview of the pharmacokinetics, clinical efficacy and safety of this GnRH-ant for treat&#xac;ing patients with endometriosis.