Use Of Gonadotropin-releasing Hormone Research Articles

Locally advanced prostate cancer: Biochemical results from a prospective phase II study of intermittent androgen suppression for men with evidence of prostate‐specific antigen recurrence after radiotherapy

In the article by Bruchovsky et al.,1 intermittent androgen suppression was evaluated in patients with clinically locally advanced prostate cancer who developed biochemical disease recurrence after radiotherapy. We consider it to be of utmost important to improve currently existing knowledge regarding intermittent androgen suppression, which could be a feasible approach as adjuvant or salvage therapy for prostate cancer in selected patients. The authors concluded that the baseline and nadir levels of prostate-specific antigen are major predictors of response to androgen suppression. Nevertheless, it was not clear whether patients suspected of having local disease recurrence rather than systemic disease recurrence2 (and who therefore had disease that was amenable to local salvage treatment with curative intent rather than androgen suppression) were excluded from this analysis.3 Furthermore, it is unclear which definition of biochemical disease recurrence after radiotherapy was considered by the authors because false diagnoses of biochemical disease recurrence are not infrequent in prostate cancer patients who are treated with radiotherapy.4 We believe that including patients with local disease recurrence or a false diagnosis of biochemical disease recurrence could have biased the results of the study by Bruchovsky et al. Finally, it is important to remember that the combination of cyproterone acetate and gonadotropin-releasing hormone (Gn-RH) analogue is reported to have a significantly more unfavorable outcome compared with the use of Gn-RH alone and an even worse outcome compared with maximum androgen blockade with nilutamide or flutamide.5

The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study

To determine whether there are any differences in the incidence of ovarian hyperstimulation syndrome (OHSS) and implantation rates in high-risk patients undergoing IVF using a protocol consisting of GnRH agonist trigger after cotreatment with GnRH antagonist or hCG trigger after dual pituitary suppression protocol. Prospective randomized controlled trial. University-based tertiary fertility center. Sixty-six patients under 40 years of age with polycystic ovarian syndrome, polycystic ovarian morphology, or previous high response undergoing IVF. Patients were randomized to an ovarian stimulation protocol consisting of either GnRH agonist trigger after cotreatment with GnRH antagonist (study group) or hCG trigger after dual pituitary suppression with a GnRH agonist (control group). Both groups received luteal phase and early pregnancy supplementation with IM progesterone (P), and patients in the study group also received E(2) patches and their doses were adjusted according to the serum levels. Incidence of OHSS and implantation rate. None of the patients in the study group developed any form of OHSS compared with 31% (10/32) of the patients in the control group. There were no significant differences in the implantation (22/61 [36.0%] vs. 20/64 [31.0%]), clinical pregnancy (17/30 [56.7%] vs. 15/29 [51.7%]), and ongoing pregnancy rates (16/30 [53.3%] vs. 14/29 [48.3%]) between the study and control groups, respectively. The use of a protocol consisting of GnRH agonist trigger after GnRH antagonist cotreatment combined with adequate luteal phase and early pregnancy E(2) and P supplementation reduces the risk of OHSS in high-risk patients undergoing IVF without affecting implantation rate.

Gonadotropin-Releasing Hormone Antagonist in in Vitro Fertilization Superovulation

The use of gonadotropin-releasing hormone (GnRH) antagonists in in vitro fertilization superovulation remains controversial. The GnRH agonist 'long protocol' has been seen as the gold standard for many years. Comparisons and meta-analyses of the efficacy of GnRH antagonists and agonists have been largely inconclusive, with the dataset being contaminated with outdated reports of poorer efficacy with GnRH antagonists, which have stemmed from studies of their use as a second-line drug in older women and women who were poor responders. This work cannot reflect the actual clinical effectiveness of GnRH antagonist and must be interpreted with care. The major advantages of GnRH antagonists use in superovulation include a gentler and more patient-friendly stimulation cycle with less hypoestrogenic side effects, with the potential to lower the risk of ovarian hyperstimulation and enhanced embryo growth. Our current clinical experience with GnRH antagonists in in vitro fertilization is limited, although there are a growing number of in vitro fertilization centers embracing this new technology. There is a clear need for a modern, suitably powered clinical trial to demonstrate the place of GnRH antagonist-based superovulation protocols and in subgroups of patients, such as polycystic ovary syndrome or poor responders.

O-276: The use of gonadotropin releasing hormone (GnRH) agonist to induce oocyte maturation in high-risk patients undergoing IVF reduces the risk of ovarian hyperstimulation syndrome (OHSS) - a prospective randomized controlled study

O-276: The use of gonadotropin releasing hormone (GnRH) agonist to induce oocyte maturation in high-risk patients undergoing IVF reduces the risk of ovarian hyperstimulation syndrome (OHSS) - a prospective randomized controlled study

GnRH antagonists in ovarian stimulation for IVF

The present review describes, on the basis of the currently available evidence, the consensus reached by a group of experts on the use of gonadotropin-releasing hormone (GnRH) antagonists in ovarian stimulation for IVF. The single or multiple low-dose administration of GnRH antagonist during the late-follicular phase effectively prevents a premature rise in serum luteinizing hormone (LH) levels in most women. Although controversy remains, most comparative studies suggest a slight, not significant reduction in the probability of pregnancy after IVF using GnRH antagonist versus GnRH agonist co-treatment. Published meta-analyses suggest that this slight difference in pregnancy rates is not attributed to chance. Further studies applying varying treatment regimens and outcome measures are required. Data are not in favour of a need to modify the starting dose of gonadotropins. Data are not in favour of increasing gonadotropin dose at GnRH antagonist initiation. The addition of LH from the initiation of ovarian stimulation or from GnRH antagonist administration does not appear to be necessary. Replacement of human chorionic gonadotropin (HCG) by GnRH agonist for triggering final oocyte maturation is associated with a lower probability of pregnancy. The optimal timing for HCG administration needs to be explored further. GnRH antagonist initiation on day 6 of stimulation appears to be superior to flexible initiation by a follicle of 14-16 mm, although earlier GnRH antagonist administration is worth further evaluation. Luteal phase supplementation in GnRH antagonist protocols remains mandatory in IVF. Effects of GnRH antagonist co-treatment on the incidence of ovarian hyperstimulation syndrome remains uncertain, although a trend is present in favour of the GnRH antagonists. The role of GnRH antagonists in ovarian stimulation for IVF appears to be promising, although many questions regarding preferred dose regimens and effects on clinical outcomes remain.

GnRH agonist therapy before myomectomy or hysterectomy

Uterine leiomyomata, also known as fibroids or myomas, are the most common pelvic tumor, found in at least 20% to 25% of women by the age of 35 1 and in more than 50% of all women. 2 Though the majority of myomas (50%‐ 80%) are asymptomatic, they can be the cause of pelvic pressure and pain, excessive menstrual bleeding, spontaneous abortion, and infertility. 3 The standard treatment for symptomatic myomas has been surgical; approximately 40% of abdominal hysterectomies are performed for the treatment of myomas. 4 In those women who wish to preserve fertility, myomectomy is performed. The purpose of this manuscript is to review the use of gonadotropin-releasing hormone (GnRH) agonist therapy before myomectomy and hysterectomy.

Use of goserelin in the treatment of breast cancer

Gonadotropin-releasing hormone analogs are, alongside tamoxifen, one of the most commonly used drugs in the treatment of pre-/perimenopausal endocrine-responsive breast cancer. Goserelin, as a principal agent of this class of drugs, is mainly investigated in clinical trials. The indirect comparison of goserelin with tamoxifen as a single drug in the adjuvant setting showed similar efficacy. Furthermore, goserelin is as effective as cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy, and total endocrine blockade as a combination of gonadotropin-releasing hormone analog and tamoxifen showed a comparable benefit with anthracycline-containing adjuvant chemotherapy. Goserelin administered after cessation of chemotherapy leads to a further improvement and may be equieffective as tamoxifen or a combination of both. Data concerning taxane-based and dose-dense chemotherapy as well as combination of gonadotropin-releasing hormone analogs with third-generation aromatase inhibitors are still lacking (ongoing suppression of ovarian function, tamoxifen and exemestane, and premenopausal endocrine-responsive chemotherapy trials). Moreover, duration of therapy with gonadotropin-releasing hormone analogs (2–3 years or longer) is still a matter of debate. Palliative endocrine treatment is standard in the first-line therapy of patients without life-threatening disease and endocrine-responsive breast cancer. Treatment decisions depend upon adjuvant endocrine pretreatment. Clinical data regarding ovarian protection by synchronous use of gonadotropin-releasing hormone in young breast cancer patients receiving chemotherapy are incoherent.

Using gonadotropin-releasing hormone (GnRH) and GnRH analogs to modulate testis function and enhance the productivity of domestic animals

Gonadotropin releasing hormone (GnRH) controls the activity of the gonadotrope cells of the pituitary gland and, as a consequence, is a critical component of the endocrine cascade that determines the growth, development, and functional activity of testicular tissue. The use of GnRH and GnRH analogs is common in domestic animal production systems. Although GnRH and GnRH analogs are most commonly used to control the fertility and reproductive events in female animals, GnRH agonists and antagonists are increasingly used to modulate the fertility, behavior, and productivity of male animals as well. This review will focus on recent advances in this use of GnRH agonists and antagonists.

GnRH antagonists in IVF

The present review summarizes existing knowledge on the use of gonadotropin releasing hormone (GnRH) antagonists based on experience gathered after the completion of phase III comparative trials with GnRH agonists. Available data suggest that prolongation of the follicular phase significantly decreases the probability of pregnancy. Moreover, patients with elevated progesterone at initiation of stimulation have significantly fewer chances of achieving an ongoing pregnancy. Luteal support remains mandatory, while the replacement of human chorionic gonadotrophin by GnRH agonist does not appear to be feasible. Although not conclusive, existing data are not in favour of increasing the starting dose of gonadotrophins, of LH supplementation or of using a flexible antagonist protocol.

Recruitment prior to ovarian stimulation: ways of improving follicular recruitment

Modulation of follicle profiles prior to FSH in cycles of assisted reproduction is an important part of current practice, but perhaps with wider applications in the future. The conventional use of gonadotrophin-releasing hormone (GnRH) antagonists has employed the perimenstrual rise in FSH to initiate follicular development from antral stages, leading to two stages of follicular development, endogenously stimulated followed by the exogenously stimulated. This contrasts with GnRH agonists, where there is a single and continuous induction of growth. In theory, it may prove possible to modulate the source material, the antral follicle pool by using LH to sensitize follicles to FSH. However, in polycystic ovary syndrome, with its excessive follicle pool, short-term reduction of insulin promoted LH action by metformin treatment has failed to influence follicle responses to exogenous FSH. On the other hand, there is now evidence that long-term metformin treatment may lead to a reduction in the size of the antral follicle pool, potentially leading to lower risk of ovarian hyperstimulation.

Strategic use of gonadotrophin-releasing hormone (GnRH) to increase pregnancy rate and reduce pregnancy loss in lactating dairy cows subjected to synchronization of ovulation and timed insemination

The objective of this study was to determine the effect of GnRH (100 μg i.m.) treatment 5 and 15 days after timed insemination (TAI) on pregnancy rate and pregnancy loss in lactating dairy cows subjected to synchronization of ovulation. The study included 831 lactating dairy cows subjected to a Presynch–Ovsynch protocol for first service. On the day of TAI (Day 0), cows were randomly assigned to one of four experimental groups. Cows in Group 1 ( n = 214) were treated with GnRH on Day 5; cows in Group 2 ( n = 209) were treated with GnRH on Day 15; cows in Group 3 ( n = 212) were treated with GnRH on both Day 5 and Day 15; cows in Group 4 ( n = 196) were not treated. Pregnancy rate was evaluated at Day 27 and Day 45 after TAI. The interestrus interval and the proportion of cows diagnosed not pregnant based on expression of estrus and insemination before pregnancy diagnosis on Day 27 were determined. The results of this study are: (1) GnRH treatment on Day 5 or Day 15 did not increase pregnancy rate, or reduce pregnancy loss between Day 27 and Day 55 after TAI; (2) cows treated with GnRH on both Day 5 and Day 15 had a lower ( P < 0.01) proportion of cows diagnosed not pregnant based on expression of estrus before ultrasonography on Day 27 (26.5%) compared to control cows (52.9%), and these cows had an extended ( P = 0.05) interestrus interval (23.4 days vs. 21.5 days); and (3) GnRH treatment on both Day 5 and Day 15 after TAI reduced pregnancy rate on Day 27 (36.8% vs. 44.4% for control cows; P < 0.03) and Day 55 (28.3% vs. 36.2% for control cows; P < 0.01). Therefore, strategies to stimulate CL function using multiple doses of GnRH during the luteal phase need to consider potential negative effects.

Ovarian stimulation for in vitro fertilization in patients with endometriosis.

The use of gonadotropin-releasing hormone (GnRH) agonists in a long protocol appears to enhance the probability of conception in the presence of endometriosis. In addition, there is evidence to suggest that the use of prolonged downregulation with GnRH agonists prior to ovarian stimulation for in vitro fertilization (IVF) is beneficial for achieving pregnancy. Until now, GnRH antagonists have not been used in patients with endometriosis. The management of endometriomas prior to stimulation for IVF and its impact on reproductive outcome are still subject to debate.

Recent developments in oestrous synchronization of postpartum dairy cows with and without ovarian disorders.

This report reviews the most recent developments in prostaglandin-based oestrous synchronization programmes for postpartum dairy cows and addresses the efficiency of controlled breeding protocols based on such developments for cows with abnormal ovarian conditions. A double prostaglandin protocol applied 11-14 days apart seems to be capable of bringing most cows to oestrus. Because of varying oestrus onset times, improved conception rates are obtained following artificial insemination (AI) at detected oestrus rather than fixed-time AI in prostaglandin-treated cows. The administration of oestradiol or human chorionic gonadotrophin, or both these hormones, after prostaglandin treatment, improves the synchrony of oestrus yet does not enhance the conception rate. Progesterone-based treatments for oestrous synchronization are considered the most appropriate for non-cyclic or anoestrous postpartum dairy cows; prostaglandin alone being ineffective because of the absence of a mature corpus luteum in these cows. Improved oestrus synchrony and fertility rate have been reported using short-term progesterone treatment regimes (7-9 days) with or without oestradiol benzoate combined with the use of a luteolytic agent given 1 day before, or at the time of, progesterone withdrawal. The ovulation synchronization (Ovsynch) protocol, based on the use of gonadotrophin releasing hormone and prostaglandin, was developed to coordinate follicular recruitment, CL regression and the time of ovulation. This protocol allows fixed time insemination and has proved effective in improving reproductive management in postpartum dairy cows. However, timed AI following Ovsynch seems to have no beneficial effects in heifers, because of an inconsistent follicle wave pattern, and in anoestrous cows, given their lack of prostaglandin responsive CL. To date, there are several prostaglandin based, fixed-time insemination oestrous synchronization protocols for use in early postpartum dairy cows with ovarian disorders such as ovarian cysts and acyclicity.

Ovarian stimulation for in vitro fertilization in patients with endometriosis

The use of gonadotropin-releasing hormone (GnRH) agonists in a long protocol appears to enhance the probability of conception in the presence of endometriosis. In addition, there is evidence to suggest that the use of prolonged downregulation with GnRH agonists prior to ovarian stimulation for in vitro fertilization (IVF) is beneficial for achieving pregnancy. Until now, GnRH antagonists have not been used in patients with endometriosis. The management of endometriomas prior to stimulation for IVF and its impact on reproductive outcome are still subject to debate.

Novel roles of neuropeptide processing enzymes: EC3.4.24.15 in the neurome.

Neuropeptide processing metalloenzymes, such as angiotensin converting enzyme, neprilysin, endothelin converting enzyme, neurolysin, and EC3.4.24.15 (EP24.15), are central to the formation and degradation of bioactive peptides. We present EP24.15 as a paradigm for novel functions ascribed to these enzymes in the neurome. Although the neurome typically encompasses proteomes of the brain and central nervous system, exciting new roles of these neuropeptidases have been demonstrated in other organ systems. We discuss the involvement of EP24.15 with clinical sequelae involving the use of gonadotropin-releasing hormone (GnRH; LHRH) analogs that act as enzyme inhibitors, in vascular physiology (blood pressure regulation), and in the hematologic system (immune surveillance). Hemodynamic forces, such as cyclic strain and shear stress, on vascular cells, induce an increase in EP24.15 transcription, suggesting that neuropeptidase-mediated hydrolysis of pressor/depressor peptides is likely regulated by changes in hemodynamic force and blood pressure. Lastly, EP24.15 regulates surface expression of major histocompatibility complex Class I proteins in vivo, suggesting that EP24.15 may play an important role in maintenance of immune privilege in sites of increased endogenous expression. In these extraneural systems, regulation of both neuropeptide and other peptide substrates by neuropeptidases indicates that the influence of these enzymes may be more global than was anticipated previously, and suggests that their attributed role as neuropeptidases underestimates their physiologic actions in the neural system.

A potential new use for gonadotropin-releasing hormone antagonists

Objective To describe a potential new use of gonadotropin-releasing hormone (GnRH) antagonists. Design Case report. Setting Assisted conception unit at a teaching hospital in the United Kingdom. Patient(s) A 37-year-old woman undergoing in vitro fertilization (IVF) who accidentally stopped using GnRH agonists after starting ovarian stimulation. Intervention(s) A GnRH antagonist was used to avoid a luteinizing hormone (LH) surge and hence “rescue” the cycle. Result(s) Successful oocyte retrieval was carried out, two embryos transferred, and a viable twin pregnancy ensued. Conclusion(s) This may be a new indication for the use of GnRH antagonists.

Gonadotropin-releasing hormone antagonists: impact of IVF practice and potential non-assisted reproductive technology applications.

To provide the clinician with updated knowledge of the most recent findings on the clinical use of gonadotropin-releasing hormone antagonists. Gonadotropin-releasing hormone antagonists, which have recently been introduced in clinical practice, cause an immediate suppression of gonadotropin secretion by competitive blocking of pituitary gonadotropin-releasing hormone receptors. Thus, they are effective in preventing the premature luteinizing hormone surges during ovarian stimulation for in-vitro fertilization and may improve the patient's response to lower doses of gonadotropins. Better patient acceptance, shorter treatment cycles and fewer follicles and oocytes are also reported. Data existing so far concerning the necessity of luteal phase support after the use of gonadotropin-releasing hormone antagonists show that it might not be mandatory when used in clomiphene citrate costimulated cycles or in intrauterine insemination cycles. The use of gonadotropin-releasing hormone antagonists seems to be safe for pregnant women and their offspring. All sex-hormone-dependent disorders, currently treated with gonadotropin-releasing hormone agonists, may in future be indications for a gonadotropin-releasing hormone antagonist, including endometriosis, leiomyoma, and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. The vast majority of the available clinical data up till now, however, are in assisted reproduction and prostate cancer. It is expected that the availability of gonadotropin-releasing hormone antagonist will lead to the use of 'softer' ovarian stimulation protocols, which will be shorter, cheaper and safer compared with the conventional protocols.

The use of gonadotrophin-releasing hormone (GnRH) agonists in early and advanced breast cancer in pre- and perimenopausal women

Gonadotrophin-releasing hormone (GnRH) agonists, in particular goserelin (‘Zoladex’), are increasingly being used for the treatment of breast cancer in women with functioning ovaries. They act by downregulating pituitary GnRH receptors, thereby suppressing the release of luteinising hormone (LH) and follicle stimulating hormone (FSH), which, in turn, reduce the main source of oestradiol production in the ovaries. GnRH agonists have been shown to be as effective therapeutically as surgical ovarian ablation in pre- and perimenopausal women with advanced breast cancer. The combination of a GnRH agonist such as goserelin with the peripheral oestrogen antagonist, tamoxifen, may be used to produce ‘combined oestrogen blockade’. In advanced breast cancer, this regimen prolongs progression-free survival and increases both the response rate and duration relative to the use of a GnRH agonist alone. In patients with early breast cancer, the addition of goserelin to ‘standard treatment’ (i.e. surgery±tamoxifen, chemotherapy or radiotherapy) results in a significant benefit in recurrence-free survival and overall survival. This benefit was most apparent in patients with oestrogen receptor (ER) +ve tumours. Goserelin, when used either alone or in combination with tamoxifen as an adjuvant systemic therapy in women with ER +ve tumours, has been shown in clinical trials to produce recurrence-free survival rates equivalent to cytotoxic chemotherapy such as cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Evidence suggests that at least part of the effect of adjuvant cytotoxic chemotherapy in premenopausal women is produced by ovarian ablation. Endocrine therapy with goserelin or goserelin plus tamoxifen should now be considered a treatment option in the management of premenopausal women with ER +ve early breast cancer.

Does the Addition of Luteinizing Hormone in Ovarian Stimulation Protocols Improve the Outcome?

Ovarian stimulation is an integral part of assisted reproductive technologies (ART). Under physiologic conditions, both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) activity is necessary to guarantee follicle growth and maturation. This can be shown in patients with hypogonadotrophic hypogonadism, who have no endogenous FSH or LH activity. The use of FSH alone in these patients does not result in sufficient follicle growth and oocyte quality. Approximately 75IU of LH activity per day is necessary to guarantee optimal success. The use of gonadotropin-releasing hormone (GnRH) agonists in normogonadotrophic patients may result in suppression of LH levels below a certain threshold, resulting in suboptimal outcomes. The question under discussion in this article is the threshold level of LH below which exogenous LH activity should be added to provide optimal ovarian response. Different studies indicate that the endogenous LH level should be 0.5-1.5IU in long-term protocol situations. Patients treated in ultra-long GnRH agonist protocols, as well as older patients, patients with a low response to gonadotropin treatment, and patients treated with a GnRH antagonist protocol may benefit from exogenous LH activity. There are three ways of adding LH activity in ovarian stimulation cycles. Nowadays, lutropin alfa (recombinant LH) may be the optimal choice since it has no chorionic gonadotropin activity and allows individual dosage titration. Every menotropin preparation currently on the market contains some chorionic gonadotropin activity. However, more data are necessary before evidence-based recommendations regarding LH supplementation in ovarian stimulation protocols can be given.

Ovarian hyperstimulation syndrome: strategies for prevention

Ovarian hyperstimulation syndrome (OHSS) is a serious, iatrogenic complication of ovarian stimulation. The following report is a review of traditional and new strategies to prevent the development of OHSS. Techniques such as reducing the ovarian stimulus, coasting and cryopreservation are discussed. Other more investigative strategies are also summarized, including follicular aspiration, in-vitro maturation of immature oocytes, the use of gonadotrophin-releasing hormone (GnRH) agonists to trigger ovulation and the use of volume expanders such as hydroxyethyl starch. In addition, a review of the internal experience with OHSS at the authors’ institution is described. All these preventative approaches are based on current understanding of the physiologic mechanisms involved in the pathogenesis of OHSS.