Use Of GnRH Analogues Research Articles

Puberty suppression in gender identity disorder: the Amsterdam experience

The use of gonadotropin-releasing hormone analogs (GnRHa) to suppress puberty in adolescents with gender dysphoria is a fairly new intervention in the field of gender identity disorders or transsexualism. GnRHa are used to give adolescents time to make balanced decisions on any further treatment steps, and to obtain improved results in the physical appearance of those who opt to continue with sex reassignment. The effects of GnRHa are reversible. However, concerns have been raised about the risk of making the wrong treatment decisions, as gender identity could fluctuate during adolescence, adolescents in general might have poor decision-making abilities, and there are potential adverse effects on health and on psychological and psychosexual functioning. Proponents of puberty suppression emphasize the beneficial effects of GnRHa on the adolescents' mental health, quality of life and of having a physical appearance that makes it possible for the patients to live unobtrusively in their desired gender role. In this Review, we discuss the evidence pertaining to the debate on the effects of GnRHa treatment. From the studies that have been published thus far, it seems that the benefits outweigh the risks. However, more systematic research in this area is needed to determine the safety of this approach.

Laparoscopic salpingo-oophorectomy for ovarian ablation in women with hormone-sensitive breast cancer

Objective To evaluate institutional experiences regarding laparoscopic salpingo-oophorectomy in breast cancer patients and to compare the technique with gonadotropin-releasing hormone (GnRH) analogs among premenopausal women with hormone-sensitive breast cancer. Methods Between 2004 and 2009, 103 women with breast cancer underwent laparoscopic salpingo-oophorectomy at Addenbrooke's Hospital, Cambridge, UK. All relevant medical records—including reasons for salpingo-oophorectomy, peri-operative events, and subsequent follow-up—were reviewed. Results In the study period, 3 (2.9%) women experienced a recurrence of breast cancer but none had primary peritoneal/ovarian cancer within a median follow-up interval of 34 months (range, 0–70 months). No operative complications were noted among these women and all of them went home on the day of their operation. Conclusion Laparoscopic salpingo-oophorectomy seems to be a safe, permanent, and cost-effective method of ovarian ablation compared with the use of GnRH analogs. Salpingo-oophorectomy also considerably reduces the risk of subsequent ovarian/fallopian tube malignancy in this high-risk population.

Pubertad precoz central: aspectos epidemiológicos, etiológicos y diagnóstico-terapéuticos

Central precocious puberty (CPP) is a rare disease with female predominance and a higher incidence among adopted children. Of idiopathic aetiology in most cases, in the past few years the first mutations in patients with CPP have been described. The prevalence of organic disease is notably lower among girls with CPP. However, no predictors have been described to select which kind of girls should undergo an imaging tests. Although the sensitivity of the determination of basal LH as a marker of CPP has improved with the new techniques, to date, the LH peak after LHRH stimulation test remains the gold standard for the diagnosis of CPP. Finally, the use of GnRH analogues has shown to be particularly effective in the treatment of CPP patients less than 6 years-old.

Emerging gonadotropin-releasing hormone agonists

Introduction: Gonadotropin-releasing hormone agonist analogs (GnRHa) are peptides that mimic the action of gonadotropin-releasing hormone (GnRH) and are used to suppress subsequent sex steroid production. Although the analogs are a rather defined group of drugs, there have been developments in the past decades and there is still ample room for improvement. New therapeutic strategies in the use of GnRHs are discussed.Areas covered: Major points of discussion include: i) the use of concomitant treatment of early breast cancer in premenopausal estrogen-positive and -negative patients, ii) the use of GnRHa for fertility preservation in young female patients with malignant diseases and iii) the use of GnRH analogs in assisted reproduction. The manuscript provides a better understanding of GnRH agonists as well as an explanation of their major indications, biochemical pathways and concluding therapeutic strategies. Recent results from international meetings and debates are described to explain current controversies.Expert opinion: This paper highlights the need for more complex GnRH analogs. In the next few years, there will be longer acting GnRHas that may improve adherence. New therapeutic targets in oncological concepts may go beyond fertility preservation and focus on the antiproliferative effects of GnRH analogs.

The endocrine effects of multiple folliculogenesis

Abstract Induction of multiple follicular development is a common practice in IVF programmes. Nevertheless, such an approach is not without implications. Apart from the high multiple pregnancy rate, marked changes in the secretion of pituitary and ovarian hormones take place. Estradiol and inhibin are produced in high amounts during the follicular phase and as a result the negative feedback mechanism is potentiated leading to the marked suppression of gonadotropin secretion from the pituitary. The secretion of LH is also reduced in down-regulated cycles as well as in women receiving a GnRH antagonist, while LH levels are maintained stable when a GnRH agonist is used in a short protocol. The suppression of LH secretion is also evident at midcycle with the endogenous LH surge being blocked or markedly attenuated due to the production of gonadotropin surge attenuating factor (GnSAF). Under these conditions, the LH surge is usually premature in relation to the size of the leading follicle resulting in premature luteinization, but can be prevented by the use of GnRH analogs. In IVF cycles, the luteal phase is disrupted due to the suppression of LH levels. Mild protocols might provide a better approach to the ovarian stimulation than conventional protocols resulting in a reasonable success rate of IVF treatment.

Biological and technological background of estrus synchronization and fixed-time ovulation induction in the pig

A technology that allows for manipulating of estrus and ovulation, and would then also allow for fixed-time insemination, can be of great benefit for swine farms that operate using sow batch management. Such technology at least in part, saves labor and permits the production of large batches of evenly developed pigs. Thanks to the current knowledge on endocrine regulation of follicle development and ovulation, and the availability of numerous reproductively active substances such a technology is now available. This 'biotechnology of reproduction' will be reviewed. It covers procedures for synchronizing estrus based on the use of altrenogest in gilts and of batch-wise weaning in sows, for stimulating follicle development using eCG and for inducing of ovulation using hCG or LH as well as GnRH analogues. While the procedures for estrus synchronization stand alone, other procedures require additional treatments. If fixed-time insemination is the goal, estrus needs to be synchronized and follicular development and ovulation induced by the use of GnRH analogues and hCG with ovulation occurring within 36-42 hrs. It is a general recommendation to inseminate those animals twice, i.e. 24 and 40 hrs after ovulation induction. However, the aforementioned technology requires healthy animals and a solid management and cannot be used to compensate for poor management.

No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group

Background: The reduction of treatment-related toxic effects is the main goal in the current trials of the German Hodgkin Study Group (GHSG). In this regard, the protection of the ovarian reserve in young women is very important. Therefore, the GHSG investigated the use of gonadotropin-releasing hormone-analogues (GnRH-a) and oral contraceptives (OC) in young women with advanced-stage Hodgkin lymphoma (HL).Patients and methods: Women (18–40 years) were randomly assigned either to receive daily OC or monthly GnRH-a during escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). Hormonal levels were determined at baseline, during therapy, and at follow-up.Results: The study was closed prematurely after an interim analysis of 12 patients in arm A (OC) and 11 in arm B (GnRH-a), 9 and 10 are assessable for the primary end point. Women’s median age was 25 years in both arms. The anti-Mullerian hormone level after at least 12 months was reduced in all patients. For the entire study cohort, the respective ovarian follicle preservation rate was 0% (95% confidence interval 0% to 12%).Conclusion: We observed no protection of the ovarian reserve with hormonal co-treatment during BEACOPPesc. This result supports efforts of ongoing trials to reduce chemotherapy intensity and toxicity. Alternative strategies for the protection of fertility must be offered to young female HL patients before the start of BEACOPPesc therapy.

Combination of gonadotropin-releasing hormone (GnRH) agonists with GnRH antagonists before chemotherapy reduce but does not completely prevent a follicle-stimulating hormone flare-up

Increasing evidence supports GnRH agonists to be an effective treatment to preserve ovarian function during chemotherapy, but the initial flare-up of FSH during the first week after GnRH agonist application still limits its use. The combination of GnRH agonists with GnRH antagonists might solve this problem to some extent as the addition of GnRH antagonists at least significantly reduces the FSH flare-up.

Fertility and Reproductive Considerations in Premenopausal Patients with Breast Cancer

Approximately 10% of all new breast cancer diagnoses occur in young women. Although lacking medical comorbidities, these patients often have unique issues with regard to their reproductive health that merit special consideration. As breast cancer outcomes continue to improve, quality of life for patients and their families after breast cancer treatment has come to the forefront of cancer research, particularly in the growing field of oncofertility. This article reviews the literature on the singular situations and controversies faced by premenopausal breast cancer patients. Data on amenorrhea and the effects of modern chemotherapeutic agents on amenorrhea are limited, although the role of tamoxifen in amenorrhea is more clearly defined as increasing the rate of amenorrhea across several studies. At the forefront of studies on fertility and premenopausal breast cancer patients are investigations on fertility preservation via ovarian protection and on assisted reproductive technologies. The use of gonadotropin-releasing hormone analogs for ovarian protection remains controversial and continues to be investigated. Early integration of assessment and counseling regarding fertility preservation is part of the multidisciplinary approach in the care of the premenopausal breast cancer patient and is key to optimizing both cancer treatment and fertility plans for the future. Because of the many ongoing biological, practical, and ethical controversies surrounding oncofertility, eligible patients should be strongly encouraged to participate in clinical trials and studies to further increase our knowledge in this growing field.

Factors Affecting Conversion of Laparoscopic Myomectomy to Laparotomy

Objectives: The purpose of our study was to evaluate cases that required conversion to laparotomy and its predisposing factors. Design: This was a retrospective study. Methods: We examined the medical records of women who underwent laparoscopic myomectomy during the period 2000–2008. Results: Of 67 patients, 9 required conversion of laparoscopy to laparotomy (conversion rate of 13.4%). The median diameter of the dominant myoma in the conversion group (group I) was 9 cm (range 6–17 cm) and in the laparoscopic myomectomy group (group II was 7.4 cm [range 4–21 cm; p: 0.03, CI 0–4.5]). Group I had more intramural myoma (n = 8; 88.9%) than group II (n = 28, 48.3%; p < 0.03), and two thirds of patients in group I had had posterior intramural myoma. Preoperative gonadotropin-releasing hormone analog (GnRHa) was used by all patients in group I and by 67.2% of patients in group II. There was no difference in the blood loss between both groups. The weight of myomas in group I (387.1 ± 86.0 g) was higher than in group II (196.7 ± 33.9 g, p < 0.04). Conclusions: Factors related to conversion of laparoscopic myomectomy to laparotomy are posterior intramural location, the use of preoperative GnRHa, the diameter of the dominant myoma, and the weight of the myoma. (J GYNECOL SURG 26:115)

Clinical application of gonadotropin-releasing hormone analogs in children and adolescents

= Abstract = Although the increasing incidence of central precocious puberty (CPP) in Korea has recently raised public concerns about health and growth problems, there are many areas of uncertainty regarding the pathogenesis, diagnosis, and management of CPP. In this paper, we review the definition of precocity, the assessment of CPP, and the hormonal abnormalities that support the diagnosis. In addition, we review the practical guidelines regarding the clinical use of gonadotropin-releasing hormone analogs in children with CPP. Indications for treatment, determination of dosage, monitoring during treatment, and discontinuation of therapy are discussed. (Korean J Pediatr 2010;53:294-299)

No Reduction of Ovarian Failure with the Use of GnRH-Analogues or Oral Contraceptives in Young Women Treated with Escalated BEACOPP for Advanced-Stage Hodgkin Lymphoma (HL). Final Results of the PROFE Trial, German Hodgkin Study Group (GHSG).

Abstract 3710Poster Board III-646 PurposeFor ongoing trials of the German Hodgkin Study Group (GHSG), the reduction of treatment-related toxicities is the main goal. In this respect, the prevention of ovarian failure in young women is of major importance. This might be achieved with oral contraceptives and Gonadotropin-releasing hormone agonistic analoges (GnRH-a) by inhibiting follicular growth in the ovary. Unfortunately, only contradictory, mostly retrospective or non-controlled results on these protective effects have been published, Thus, the GHSG started a randomised phase-II trial (PROFE) for the reduction of ovarian failure with the use of GnRH-analogues and oral contraceptives in young women treated with intensive chemotherapy for advanced-stage HL. The aim of the trial was to develop a standard co-treatment for the reduction of infertility rates. MethodsThe study was designed for young female patients (18-40 years) with advanced-stage HL, including stage II with B symptoms and one of the following risk factors: extranodal disease and/or large mediastinal mass, stage III, and IV. The patients were randomly assigned either to receive daily oral contraceptive or to receive the GnRH-analogue given monthly during 8 cycles of polychemotherapy with escalated BEACOPP. Blood samples were drawn for determination of hormonal levels once before the beginning of therapy, monthly during therapy, and 6, 12, and 18 months after therapy. Hormonal profiles including follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, Anti-Müllerian Hormone (AMH), prolactin, testosterone, DHEAS, SHBG, Inhibin A, Inhibin B, and progesterone were measured to document fertility status. The primary endpoint according to study protocol was the FSH level 6 months after the end of therapy. Because in the meantime AMH has been established as more valid indicator for ovarian function, we finally used AMH levels after minimally 12 months (<.46 μg/l) as more conclusive criterion for infertility. Individual courses for FSH, AMH and oestradiol in the 2 experimental groups will be presented. ResultsThe recruitment started in 2004 and was prematurely stopped in 2007 because of the following hindrances to participation: first, the application of the more intensive 8 cycles of escalated BEACOPP instead of less toxic treatment alternatives in the competing HD15 study (6 cycles of escalated BEACOPP or 8 cycles of BEACOPP-14). Second, to date, mostly all female patients in advanced stages already receive GnRH-analogue co-treatment, as recommended by their gynaecologists, and could therefore not be included into the PROFE trial. Consequently, a total of 23 patients are now evaluable for the final analysis of blood samples. Twelve patients were enrolled into arm A (oral contraceptive) and 11 into arm B (GnRH-analogue). At randomisation, women's mean age was 28 years in arm A and it was 26 years in arm B. FSH and AMH levels were correlated but also showed remarkable differences. In 8 cases FSH levels finally returned to normal values after therapy, whereas AMH levels remained reduced with exception of one woman receiving co-treatment with oral contraceptives (arm A). The respective infertility rates and 95% confidence intervals were 90% in arm A (62%-99%) and 100% in arm B (76%-100%). Combining arm A and arm B, the infertility rate in all 19 patients determined by AMH after minimally 12 months was 95% (78%-99%). ConclusionIn this prospectively randomised study in HL patients, no meaningful ovarian protection with hormonal co-treatment during HL therapy consisting of 8 cycles of escalated BEACOPP has been achieved. Though the confidence interval in this study is large due to the limited number of patients, the results do certainly not support the use of oral contraceptives or GnRH analogues to prevent ovarian failure in young women during this intensive chemotherapy regimen. Thus, alternative strategies for the protection of ovarian function should be offered to young women before the start of treatment. Disclosures:Off Label Use: Gonadotropin-releasing hormone agonistic analoges inhibiting follicular growth in the ovary with purpose to reduce infertility.

Luteal support: Progestogens for pregnancy protection

Following ovulation, the granulosa cells undergo luteinization and form part of the corpus luteum; this then secretes progesterone that causes secretory transformation of the endometrium so that implantation can occur. The ideal time for implantation is 6–10 days after the luteinizing hormone (LH) surge; implantation occurring outside this optimal window is associated with a higher likelihood of miscarriage. Before the placenta takes over progesterone production, the progesterone produced by the corpus luteum also provides the necessary support to early pregnancy. A defect in corpus luteum function is not only associated with implantation failure but also with miscarriage. In assisted reproduction, both the use of gonadotropin-releasing hormone analogues to prevent the LH surge and aspiration of granulosa cells during the oocyte retrieval may impair the ability of the corpus luteum to produce sufficient progesterone. This may be treated effectively with progestational agents such as progesterone or dydrogesterone, which have a very similar pharmacological profile. Studies indicate that an estrogen may be given during the luteal phase to optimise the estrogen:progestogen ratio to facilitate implantation, although the available evidence is inconsistent in its strength for this hypothesis. In addition to assisted reproduction, progestational agents have shown beneficial effects in the management of patients with recurrent spontaneous miscarriage of unknown cause. In conclusion, despite the wide-spread use and many years of clinical experience, the amount of data from well-controlled clinical trials is currently limited. Further studies are therefore required to establish the optimal treatment situation and type and dose of progestational agent.

Use of Fertility Drugs and Risk of Uterine Cancer: Results From a Large Danish Population-based Cohort Study

Some epidemiologic studies have indicated that uterine cancer risk may be increased after use of fertility drugs. To further assess this association, the authors used data from a large cohort of 54,362 women diagnosed with infertility who were referred to Danish fertility clinics between 1965 and 1998. In a case-cohort study, rate ratios and 95% confidence intervals were used to assess the effects of 4 groups of fertility drugs on overall risk of uterine cancer after adjustment for potentially confounding factors. Through mid-2006, 83 uterine cancers were identified. Ever use of any fertility drug was not associated with uterine cancer risk (rate ratio (RR) = 1.10, 95% confidence interval (CI): 0.69, 1.76). However, ever use of gonadotropins (follicle-stimulating hormone and human menopausal gonadotropin) increased uterine cancer risk (RR = 2.21, 95% CI: 1.08, 4.50); the risk was primarily observed after 10 years of follow-up. Furthermore, uterine cancer risk increased with number of cycles of use for clomiphene (for > or =6 cycles, RR = 1.96, 95% CI: 1.03, 3.72) and human chorionic gonadotropin (for > or =6 cycles, RR = 2.18, 95% CI: 1.16, 4.08) but not for other gonadotropins. Use of gonadotropin-releasing hormone analogs was not associated with risk. Gonadotropins, and possibly clomiphene and human chorionic gonadotropin, may increase the risk of uterine cancer, with higher doses and longer follow-up leading to greater risk.

Gonadotropin releasing hormone analogs induce apoptosis by extrinsic pathway involving p53 phosphorylation in primary cell cultures of human prostatic adenocarcinomas

Gonadotropin-releasing-hormone (GnRH) analogs are widely used to block hypothalamic-pituitary-gonadal axis and inhibit blood androgen levels in patients with prostate cancer (PCa). In addition, GnRH analogs induce proliferation arrest and apoptosis through GnRH receptors expressed on the membrane of PCa cells. Possible molecular mechanisms involved in GnRH-mediated apoptosis on prostate cancer cells were studied. Primary cultures from PCa and benign prostatic hyperplasia (BPH) (non-malignant control) were derived from samples provided by our Institutional Hospital. Cell cultures were incubated for 24 hr with 20 ng/ml of GnRH agonist Leuprolide (Lp) or antagonist Cetrorelix (Cx). Apoptosis was evaluated by studying the expression of Bax and Bcl-2 and the activation of caspase-9 (intrinsic pathway), caspase-8 (extrinsic pathway), and caspase-3. Also, mRNA level, protein expression and phosphorylation of p53 were studied. Cleaved caspase-8 and -3, but not -9, increased in presence of Lp and Cx in PCa cell cultures. Bax and Bcl-2 mRNA levels showed no changes after GnRH-analog treatments. Only Bax protein showed an increase after Cx treatment in PCa cell cultures. p53 mRNA level was higher in PCa than in BPH cell cultures. Lp and Cx increased p53 expression and phosphorylation in PCa cell cultures. Apoptosis induced by GnRH analogs seems to be mediated by extrinsic pathway involving p53 phosphorylation. Phosphorylated-p53 might be associated with the increase in apoptotic NGF receptor, p75, previously reported by our laboratory. These findings reinforce the concept of clinical use of GnRH analogs for PCa suggesting that intraprostatic treatment may be more effective.

Estudio comparativo de la miomectomía laparotómica frente a laparoscópica

ObjectiveTo compare the outcomes of laparotomic versus laparoscopic myomectomy in the gynecology service of a Spanish hospital. Material and methodsWe performed a retrospective, comparative study of myomectomies performed between January 2005 and December 2007. The variables analyzed were demographic data, preoperative use of GnRH analogues, mean operating time, reconversion rate, postoperative pain, variations in the hemoglobin count, mean length of hospital stay, maximum myoma weight, the overall complications rate, and postoperative fertility. ResultsDuring the study period, 35 myomectomies (19 laparotomic and 16 laparoscopic) were performed. The mean operating time was 88 minutes in the laparotomic group and 104 minutes in the laparoscopic group (P<.05). In the laparotomic group, hemoglobin loss was 2.87 g/dl, rescue analgesia was required in 52.6% of the women and the mean length of hospital stay was 3.1 days. In the laparoscopic group these values were 3.26 g/dl, 6.22% and 1.7 days, respectively. ConclusionsIn well-trained and experienced hands, laparoscopic myomectomy is an effective alternative to the laparotomic route in well-selected patients.

Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children

Gonadotropin-releasing hormone analogs revolutionized the treatment of central precocious puberty. However, questions remain regarding their optimal use in central precocious puberty and other conditions. The Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology convened a consensus conference to review the clinical use of gonadotropin-releasing hormone analogs in children and adolescents. When selecting the 30 participants, consideration was given to equal representation from North America (United States and Canada) and Europe, an equal male/female ratio, and a balanced spectrum of professional seniority and expertise. Preference was given to articles written in English with long-term outcome data. The US Public Health grading system was used to grade evidence and rate the strength of conclusions. When evidence was insufficient, conclusions were based on expert opinion. Participants were put into working groups with assigned topics and specific questions. Written materials were prepared and distributed before the conference, revised on the basis of input during the meeting, and presented to the full assembly for final review. If consensus could not be reached, conclusions were based on majority vote. All participants approved the final statement. The efficacy of gonadotropin-releasing hormone analogs in increasing adult height is undisputed only in early-onset (girls <6 years old) central precocious puberty. Other key areas, such as the psychosocial effects of central precocious puberty and their alteration by gonadotropin-releasing hormone analogs, need additional study. Few controlled prospective studies have been performed with gonadotropin-releasing hormone analogs in children, and many conclusions rely in part on collective expert opinion. The conference did not endorse commonly voiced concerns regarding the use of gonadotropin-releasing hormone analogs, such as promotion of weight gain or long-term diminution of bone mineral density. Use of gonadotropin-releasing hormone analogs for conditions other than central precocious puberty requires additional investigation and cannot be suggested routinely.

Circonstances de prescription de l’hormonothérapie chez des patients atteints de cancer de la prostate

Although screening has improved the diagnosis of prostate cancer, hormone therapy still plays an important role in its treatment. This article aims to evaluate the circumstances for the use of hormone therapy in 2007.Observational study, with no intervention, carried out between October 2006 and March 2007, on 208 urologists and radiotherapists. This study allowed for the analysis of the circumstances and reasons for the prescription of hormone therapy for four to eight consecutive patients.The 1187 patients included had an average age of 73.5+/-8 years (median: 75 years). The cancer had been diagnosed for 1.1+/-2.3 years. The diagnosis had generally been made at localized stage, less often at local advanced stage (37.2%, n=442) or metastasis (15.4%, n=183). The prescription of GnRH analogues was principally motivated by a biological recurrence (22.2%, n=263), the presence of bone or visceral metastasis at time of diagnosis (22.1%, n=262) or a contraindication of local treatment at localized stage (16.6%). The decision to use hormone therapy was taken jointly by the doctor and the patient in 57% of cases. The majority of patients (92%) benefited from an injection every three months.Hormone therapy by GnRH analogues remains established for cases of cancer metastasis or in cases of recurrence. This observation corroborates scientific recommendations regarding the use of GnRH analogues.

Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children

Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children

Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children

Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children