Native Gonadotropin-releasing Hormone Research Articles

Update on the management of endometriosis-associated pain in France

The French National College of Obstetricians and Gynecologists (CNGOF) published guidelines for managing endometriosis-associated pain in 2018. Given the development of new pharmacological therapies and a review that was published in 2021, most national and international guidelines now suggest a new therapeutic approach.In addition, a novel validated screening method based on patient questionnaires and analysis of 109-miRNA saliva signatures, which combines biomarkers and artificial intelligence, opens up new avenues for overcoming diagnostic challenges in patients with pelvic pain and for avoiding laparoscopic surgery when sonography and MRI are not conclusive.Dienogest (DNG) 2 mg has been a reimbursable healthcare expense in France since 2020, and, according to recent studies, it is at least as effective as combined hormonal contraception (CHC) and can be used as an alternative to CHC for first-line treatment of endometriosis-associated pain. Since 2018, the literature concerning the use of DNG has grown considerably, and the French guidelines should be modified accordingly.The levonorgestrel intrauterine system (LNG IUS) and other available progestins per os, including DNG, or the subcutaneous implant, can be offered as first-line therapy, gonadotropin-releasing hormone (GnRH) agonists with add-back therapy (ABT) as second-line therapy.Oral GnRH antagonists are promising new medical treatments for women with endometriosis-associated pain. They competitively bind to GnRH receptors in the anterior pituitary, preventing native GnRH from binding to GnRH receptors and from stimulating the secretion of luteinizing hormone and follicle-stimulating hormone. Consequently, estradiol and progesterone production is reduced. Oral GnRH antagonists will soon be on the market in France. Given their mode of action, their efficacy is comparable to that of GnRH agonists, with the advantage of oral administration and rapid action with no flare-up effect. Combination therapy with ABT is likely to allow long-term treatment with minimal impact on bone mass. GnRH antagonists with ABT may thus be offered as second-line treatment as an alternative to GnRH agonists with ABT.This article presents an update on the management of endometriosis-associated pain in women who do not have an immediate desire for pregnancy.

Role of GnRH Isoforms in Paracrine/Autocrine Control of Zebrafish (Danio rerio) Spermatogenesis.

Abstract It is well established that hypothalamic GnRH (gonadotropin-releasing hormone) is one of the key peptides involved in the neuroendocrine control of testicular development and spermatogenesis. However, the role of GnRH as a paracrine regulator of testicular function has not been fully investigated. The present study demonstrates the presence of GnRH and its receptors in the zebrafish (Danio rerio) testis, and provides information on direct action of native GnRH isoforms (GnRH2 and GnRH3) on different stages of spermatogenesis in this model. Both GnRH2 and GnRH3 stimulated basal spermatogenesis by increasing numbers of type Aund spermatogonia, spermatozoa, and testosterone release, and in this study GnRH2 exerted higher relative activity than GnRH3. Next, we evaluated the effects of GnRH isoforms on human chorionic gonadotropin (hCG)- and follicle-stimulating hormone (Fsh)-induced spermatogenesis. The 2 GnRH isoforms were found to have different effects on Fsh- and hCG-induced response depending on the stage of spermatogenesis and concentration of the peptides. The results provide strong support for the hypothesis that locally produced GnRH2 and GnRH3 are important components of the complex multifactorial system that regulates testicular germinal cell development and function in adult zebrafish.

Regulation of gonadotrophin-releasing hormone secretion by testosterone in male sheep

In males, including the ram, testosterone, acting via its primary metabolites oestradiol and dihydrotestosterone (DHT), suppresses circulating LH concentrations. This effect is due primarily, although not totally, to decreased frequency of gonadotrophin-releasing hormone (GnRH) pulses. The arcuate-ventromedial region (ARC-VMR) of the mediobasal hypothalamus and possibly the medial preoptic area (mPOA) are sites at which oestradiol acts to suppress GnRH, but the site of DHT action is not known. Given that native GnRH neurones appear to contain few or no oestrogen or androgen receptors, the effects of testosterone metabolites probably are exerted by modulating activity of inhibitory interneurone systems such as beta-endorphin, dopamine, and gamma-aminobutyric acid (GABA). Although beta-endorphin clearly inhibits GnRH secretion, the observation that testosterone treatment during a long-day photoperiod reduced proopiomelanocortin (POMC) mRNA in the arcuate nucleus while coincidentally suppressing GnRH release indicates that beta-endorphin does not mediate the inhibitory effect of testosterone on GnRH. Activation of GABAA receptors in either the mPOA or ARC-VMR suppressed LH, whereas activation of GABAB receptors in the ARC-VMR increased LH pulse amplitude. Therefore, it is suggested that GABA acts in both regions to regulate LH. Whereas testosterone affects GABA metabolism in the rat hypothalamus, its effect in the ram hypothalamus is yet to be determined. Testosterone treatment activated dopaminergic cells in the retrochiasmatic A15 area in the same animals in which it suppressed POMC mRNA in the arcuate nucleus. This dopaminergic system may partially mediate the negative feedback effect of testosterone in the ram analogous to its role in partially mediating the negative effect of oestrogen in the ewe. Future studies must concentrate on determining how these and other putative inhibitory neuronal systems interact and how they in turn are regulated by environmental factors such as photoperiod.

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

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

Synthesis, Stability and Direct Antiproliferative Effect of New Cysteine Modified GnRH Analogs

It is demonstrated that gonadotropin-releasing hormone (GnRH) analogs can directly inhibit the proliferation of reproductive tissue cancer cells, but the poor pharmacokinetic properties still restrict their application in treating hormone-dependent diseases. Modifications in position 6 and 10 of natural GnRH can improve the metabolic stability. In order to study the effect of incorporation Cys6 substitution with C-terminal Pro9-NHEt modification and dimerization of linear peptides on metabolic stability and antiproliferative activity of GnRH analogs, two new GnRH analogs [l-Cys6, desGly10, Pro9-NHEt]-GnRH (1) and [d-Cys6, desGly10, Pro9-NHEt]-GnRH (2), and their corresponding dimer derivatives ([l-Cys6, desGly10, Pro9-NHEt]-GnRH)2 (3) and ([d-Cys6, desGly10, Pro9-NHEt]-GnRH)2 (4) were synthesized. Incubation of these analogs with human serum was carried out to evaluate their metabolic stability, and direct growth inhibitory effect of the two dimer derivatives 3 and 4 on MCF-7 human breast cancer cell line was examined by MTT assay. The metabolic stability of dimer derivatives 3 and 4 was remarkably improved in comparison with natural GnRH. The d-Cys6 substituted dimer derivative 4 exhibited higher inhibitory effect (29.6–39.7% growth reduction) on cell growth than its corresponding counterpart 3 (21.8–26.2% growth reduction) at concentration range of 50, 100 and 200 μΜ. The cell growth inhibition of leuprolide was 16.4–27.2% at the tested concentrations. The dimer derivative 4 was the most stable and active GnRH analog in this study and has the potential for future preclinical investigations as promising antitumor drug candidate.

Development and optimization of in-situ forming microparticles for long term controlled delivery of deslorelin acetate

Deslorelin is a nonapeptide analogue of the natural gonadotropin releasing hormone or luteinizing hormone releasing hormone used in the treatment of prostate cancer, endometriosis and uterine fibroids. In-situ forming microparticles were developed for deslorelin using smart, biodegradable polymer i.e. PLGA. Different formulations were designed, prepared and evaluated by employing response surface, I-optimal design. To determine the optimized formulation, numerical and graphical optimization techniques were employed. The resulting optimized formulation was evaluated for other physicochemical parameters viz., rheology, particle size distribution, surface morphology of the particles, peptide conformation stability in the formulation and stability study at different environmental conditions. It was concluded that the optimized deslorelin acetate ISFM formulation effectively extended the peptide release for 30 days while maintaining its conformational stability during the period of study. The optimized ISFM formulation was found to be stable at 5°C ± 2°C and 25°C ± 2°C during 6 months stability studies.

Development of New Gonadotropin-Releasing Hormone-Modified Dendrimer Platforms with Direct Antiproliferative and Gonadotropin Releasing Activity.

Gonadotropin-releasing hormone (GnRH) agonists (e.g., triptorelin) are used for androgen suppression therapy. They possess improved stability as compared to the natural GnRH, yet they suffer from a poor pharmacokinetic profile. To address this, we used a GnRH peptide-modified dendrimer platform with and without lipidation strategy. Dendrimers were synthesized on a polylysine core and bore either native GnRH (1, 2, and 5) or lipid-modified GnRH (3 and 4). Compound 3, which bore a lipidic moiety in a branched tetramer structure, showed approximately 10-fold higher permeability and metabolic stability and 39 times higher antitumor activity against hormone-resistant prostate cancer cells (DU145) relative to triptorelin. In gonadotropin-release experiments, dendrimer 3 was shown to be the most potent construct. Dendrimer 3 showed similar luteinizing hormone (LH)-release activity to triptorelin in mice. Our findings indicate that dendrimer 3 is a promising analog with higher potency for the treatment of hormone-resistant prostate cancer than the currently available GnRH agonists.

Synthesis and Biological Evaluation of Two New Analogues of Gonadotropin Releasing Hormone (GnRH)D-alanine8 and D-alanine

So far synthesis of Gonadotropin Releasing Hormone (GnRH) analogues reported in the literature has clarified some aspects of structural activity of the naturally released GnRH. As a part of continuing efforts for further understanding of this relationship, the present investigation was undertaken which involved synthesis and biological evaluation of two GnRH analogues, firstly, by replacement of the amino acid L-Argenine in the 8th position at the backbone structure of the natural hormone by the amino acid D-Alanine; and secondly, by replacement of the amino acid L-Glycine in the 10th position by D-Alanine also at the backbone structure of the nature hormone, to obtain the following analogues respectively:&#x0D; PGlu-His-Trp-Ser-Tyr-Gly-Leu-DAla-Pro-Gly-NH2 (Analogue I: D-Alanine8 GnRH),&#x0D; PGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-DAla-NH2 (Analogue II: D-Alanine10 GnRH), which were synthesized by applying conventional solution method. Peptides were purified by several recrystallization using appropriate solvent and proved to be homogenous. Conformity of the synthetic procedure was achieved by applying different physico-chemical analyses including Melting Point (mp), Thin Layer Chromatography (Tlc.), Infrared Spectroscopy (IR), Elemental Analysis (CHN), Amino Acid Analysis (AAA), and Nuclear Magnetic Resonance (H1NMR).Preliminary biological activity of the two analogues was determined by testing their effects of parenteral administration on ascorbic acid depletion from the ovary of pseudopregnant mice and compared with that of natural GnRH hormone. Analogue II showed significant ascorbic acid depletion as compared to the native hormone while the percentage in ascorbic acid depletion after administration of analogue I were not significant as compared to the native hormone.&#x0D; Key Words: Gonadotropine releasing hormone, Peptide synthesis, Biological activity of GnRH

Overview of elagolix for the treatment of endometriosis

ABSTRACTIntroduction: Suppression of sex-steroid secretion is required in a variety of gynecological conditions. This can be achieved using gonadotropin releasing hormone (GnRH) agonists that bind pituitary gonadotropin receptors and antagonize the link-receptor of endogenous GnRH, inhibiting the mechanism of GnRH pulsatility. On the other hand, GnRH antagonists immediately reduce gonadal steroid levels, avoiding the initial stimulatory phase of the agonists. Potential benefits of GnRH antagonists over GnRH agonists include a rapid onset and reversibility of action. Older GnRH antagonists are synthetic peptides, obtained by modifications of certain amino acids in the native GnRH sequence. They require subcutaneous injections, implantation of long-acting depots. The peptide structure is responsible for histamine-related adverse events and the tendency to elicit hypersensitivity reactions.Areas covered: Research has worked towards the development of non-peptidic molecules exerting antagonist action on GnRH. They are available for oral administration and may have a more beneficial safety profile in comparison with peptide GnRH antagonists. This article focuses on the data of the literature about elagolix, a novel non-peptidic GnRHantagonist, in the treatment of endometriosis.Expert opinion: Elagolix demonstrated efficacy in the management of endometriosis-associated pain and had an acceptable safety and tolerability profile. However, further studies are necessary to evaluate its non-inferiority in comparison with other endometriosis’s treatments.

Returning of cyclicity in infertile Corriedale sheep with natural progesterone and GnRH based strategies

Abstract Objective To evaluate the return of ovarian cyclicity with four hormone based protocols during non-breeding season in infertile Corriedale sheep. Methods The return to ovarian cyclicity was considered in terms of percent estrus response rate (ERR). The time of exhibition of estrus after either sponge removal or last PGF2α injection, was considered as time to onset of estrus. Infertile Corriedale ewes were randomly selected and distributed into four groups corresponding to four hormonal protocols such as PsE (intravaginal progesterone sponges for 12 days and eCG (equine chorionic gonadotropin) at 24 h before sponge removal; n = 6), GP (GnRH on day 0 and PGF2α on day 5; n = 7), GPG (GnRH on day 0, PGF2α on day 5 and second injection of GnRH on day 7; n = 7) and PsPG (Intravaginal progesterone sponges for 12 days, PGF2α and gonadotropin-releasing hormone (GnRH) respectively, at 24 h before and after sponge removal; n = 8). Results PsPG protocol produced significantly (P 0.05) higher than GP (85.71%) and PsE (66%). Estrus was compact and more synchronized in PsPG group because 75% of ewes exhibited estrus during the first 48 h. The collective incidence of estrus (78.94%) was also maximum during the first 48 h. Conclusion PsPG estrus induction strategy has a potential to replace eCG based protocols for returning of ovarian cyclicity in infertile Corriedale sheep.

Clinical use of deslorelin (GnRH agonist) in companion animals: a review.

Over the years, many contraceptive medications have been developed for companion animals, but many secondary adverse effects have limited their use. A major advancement was achieved with the use of gonadotropin-releasing hormone (GnRH) analogues, mainly GnRH agonists, which mimic the effects of native GnRH. The development of effective low-dose, slow-release implants with potent agonists such as deslorelin (Suprelorin®, Virbac) have allowed their use to become widespread in recent years, with many potential benefits in companion animals. While the major application of deslorelin was initially male contraception, due to its two differing actions, either the stimulation of oestrus or the sterilization of fertility, its use has been increasing in the bitch as well. The aim of this study is to review the applications of deslorelin GnRH agonist implants in companion animal, such as dogs, cats and some exotic pets.

Synthesis of Leuprorelin Acetate

A method for preparing leuprorelin acetate – a synthetic agonist of natural gonadotropin-releasing hormone - was developed, using liquid-phase peptide synthesis. The new method yields target peptide with a main substance content of > 99% on a semi-industrial scale.

Синтез ацетата лейпрорелина

Разработана технология получения ацетата лейпрорелина — синтетического агониста природного гонадотропин-рилизинг гормона с использованием методов жидкофазного пептидного синтеза. Новый метод позволяет получать целевой пептид с содержанием основного вещества &gt; 99 % в полупромышленном масштабе.

Effects of GnRH Antagonists vs Agonists in Domestic Carnivores, a Review

Gonadotrophin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinizing and follicle-stimulating hormones, and thus controls the hormonal and reproductive functions of the gonads. GnRH analogs, which include agonists and antagonists, have been produced by amino acid substitutions within the native GnRH molecule resulting in greater potency and a longer duration of effectiveness. While the initial antagonists produced significant side effects, more recent potent, long-acting, water-soluble, low histamine-release third-generation compounds such as cetrorelix, abarelix, azaline B and acyline have appeared. Differently to GnRH agonists, antagonists competitively block and inhibit GnRH-induced GnRH receptor gene expression leading to an immediate, dose-dependent, pituitary suppression without an initial stimulation of the gonadal axis. The aims of this review are to compare the effects of GnRH agonists vs antagonists and to describe the existing literature concerning new antagonists in domestic carnivores. In male dogs, a single subcutaneous dose of acyline safely and reversibly decreased serum gonadotrophins and testosterone concentrations for 9 days and prevented physiological response of gonadal the axis to agonistic challenge for 14 days. The same protocol reversibly impaired spermiogenesis, spermatocytogenesis and semen quality in both cats and dogs. In females, third-generation GnRH antagonists prevented ovulation and interrupted pregnancy in canids but not in felids. During anestrus, a single acyline injection exhibited limited prevention of the 'flare-up' effect in GnRH agonist-implanted bitches. Although GnRH antagonists appear to have a promising future in domestic carnivores reproduction, the information is still scarce and further work is needed before they can be widely recommended.

Kisspeptin-1 directly stimulates LH and GH secretion from goldfish pituitary cells in a Ca2+-dependent manner

It has been established that kisspeptin regulates reproduction via stimulation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion, which then induces pituitary luteinizing hormone (LH) release. Kisspeptin also directly stimulates pituitary hormone release in some mammals. However, in goldfish, whether kisspeptin directly affects pituitary hormone release is controversial. In this study, synthetic goldfish kisspeptin-1(1–10) (gKiss1) enhances LH and growth hormone (GH) release from primary cultures of goldfish pituitary cells in column perifusion. gKiss1 stimulation of LH and GH secretion were still manifested in the presence of the two native goldfish GnRHs, salmon (s)GnRH (goldfish GnRH-3) and chicken (c)GnRH-II (goldfish GnRH-2), but were attenuated by two voltage-sensitive calcium channel blockers, verapamil and nifedipine. gKiss-induced increases in intracellular Ca2+ in Fura-2AM pre-loaded goldfish pars distalis cells were also inhibited by nifedipine. These results indicate that, in goldfish, (1) direct gKiss1 actions on pituitary LH and GH secretion exist, (2) these actions are independent of GnRH and (3) they involve Ca2+ signalling.

A review of the control of reproduction and hormonal manipulations in finfish species

Control of reproductive is essential for the sustainability of commercial aquaculture production. The reasons for breakage of ovulation and spawning is failure of the pituitary to release gonadotropin hormones. Gonadotropin hormones secretion is under a dual control, by gonadotropin releasing hormone (GnRH), and inhibition by dopamine on the actions of GnRH. The inhibitory actions of dopamine on GTH secretion can vary in potency between species. In some fish it is necessary to use dopamine blocker, such as domperidone, results in potentiation of the actions of GnRH analoge, leading to a large release of GTH-II and ovulation. In some other injection of a high dose of GnRH analoge alone is effective. In several marine species GTH-II secretion is not under dopaminergic inhibitory control but sensitive to exogenous analoge hormones (GnRHa). In many fishes, synthetic analoges of lutenizing hormone-releasing hormone (LHRHa) are widely used for inducing spawning. In several tropical freshwater and marine finfishes the human chorionic gonadotropin (HCG), pituitary homogenate and semi-purified fish gonadotropin are used. Rrecently the replacement of natural GnRH are used and had resulted in a centuple increase in the effectiveness of luteinizing hormones secretion induction. Key word: Reproduction induced spawning, dopamine antagonists, GTH-II- HCG

Gonadotropin releasing hormone agonists: Expanding vistas

Gonadotropin-releasing hormone (GnRH) agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as “pseudomenopause” or “medical oophorectomy,” which are both misnomers. GnRH analogues (GnRH-a) work by temporarily “switching off” the ovaries. Ovaries can be “switched off” for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of “add-back” therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women's healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

Rapid actions of oestrogen on gonadotropin‐releasing hormone neurons; from fantasy to physiology?

Oestradiol (E2) exerts critical homeostatic feedback effects upon gonadotropin-releasing hormone (GnRH) neurons to maintain fertility. In the female, E2 has both negative and positive feedback actions to suppress and stimulate GnRH neuron activity at different times of the ovarian cycle. This review summarizes reported rapid E2 effects on native embryonic and adult GnRH neurons and attempts to put them into a physiological perspective. Oestrogen has been shown to rapidly modulate multiple processes in embryonic and adult GnRH neurons including intracellular calcium levels, electrical activity and specific second messenger pathways, as well as GnRH secretion itself. Evaluation of in vivo data suggests that there is no essential role for rapid E2 actions in the positive feedback mechanism but that they may comprise part of the negative feedback pathway. Adult GnRH neurons are only likely to be exposed to E2 from the gonads via the circulation with appropriate physiological E2 concentrations in the rodent being 10-50 pM for negative feedback ranging up to 400 pM for positive feedback. Although most studies to date have examined the effects of supraphysiological E2 levels on GnRH neurons, there is accumulating evidence that rapid E2 actions may have a physiological role in suppressing GnRH neuron activity.

Aromatase inhibitors prevent the estrogen rise associated with the flare effect of gonadotropins in patients treated with GnRH agonists

This was a preliminary study to determine the effect of aromatase inhibitors in preventing the flare induced by GnRH agonist (GnRH-a) in women with endometriosis (n = 9) or leiomyomata (n = 4) who were given letrozole on the first 5 days of the GnRH-a therapy. Serum LH and FSH levels showed the typical flare 1 day after the injection of the GnRH-a; however, E(2) declined immediately after letrozole administration and was notably suppressed at 1, 2, and 4 days after GnRH-a. No patients complained of clinical symptoms typical of the GnRH-a flare phenomenon.

New Derivatives of GnRH as Potential Anticancer Therapeutic Agents

GnRH (gonadotropin-releasing hormone), a decapeptide produced by the hypothalamus, plays an important role in the reproduction by regulating the pituitary-gonadal axis. Continuous high doses of GnRH or its superactive agonists result in desensitization of the pituitary gonadotropes and a suppression of sex steroid production by the gonads (chemical castration). Based on these effects, the treatment with GnRH agonists has become a widely used hormonal therapy of the sex-steroid dependent tumors. It was also demonstrated that most tumor cells contain GnRH receptors, and the direct antiproliferative effect of GnRH analogs on cancer cells might be mediated by these receptors. Development of new GnRH derivatives is focused on the decrease of their hormonal potency resulting in higher selectivity of the antitumor activity. One of the most promising natural GnRH analogs, lamprey (l) lGnRH-III, was isolated from see lamprey. This variant of GnRH binds to GnRH receptors and inhibits proliferation of various cancer cells. However, its endocrine effect is insignificant in mammals. lGnRH-III dimers and conjugates were prepared and were shown to have increased antiproliferative effects on various cancer cells, while their hormonal activity was lower than that of the native hormone. lGnRH-III was applied as targeting moiety to deliver anticancer agents to tumor cells. Research data concerning lGnRH-III and its analogs represent a new outlook for research trends of the application of GnRH compounds in cancer chemotherapy. Studies on the effects of lGnRH-III derivatives including antiproliferative effects, cytotoxicity, hormonal actions, and enzymatic stability are reviewed in this article.