Use Of GnRH Analogues Research Articles

Paediatric endocrinology: Treatment of girls with central precocious puberty.

Gonadotropin-releasing hormone analogues (GnRHa) can improve adult height prospects in children with central precocious puberty (CPP). A recent report demonstrates that 50 mg histrelin subcutaneous implants are safe and effective when used yearly. However, questions remain regarding the use of GnRHa in girls with idiopathic CPP, who experience a slow progressive form of puberty.

Diagnosis, pathophysiology and management of premenstrual syndrome

Key content An overview of current information available on premenstrual syndrome (PMS), which is in accordance with the new RCOG Green‐top Guideline. Definition of PMS and explanation about the different types of premenstrual disorders. How to accurately diagnose PMS. Discussion about various treatment options available in accordance with the current literature. Learning objectives Develop an understanding of the pathophysiology behind PMS. How to diagnose PMS accurately and understand the different classifications of PMS. How to treat PMS, including the different treatment options available and discussion about side effects and benefits. Ethical issues Discussion about the long‐term risks of GnRH analogue use, and the impact of long‐term estrogen deficiency following a bilateral salpingoophorectomy. Misdiagnosed PMS in patients with underlying psychiatric and medical conditions.

The use of gonadotrophin-releasing hormone analogues in ART programs (clinical lecture)

The use of gonadotrophin-releasing hormone analogues in ART programs (clinical lecture)

Safety and five-year re-intervention following magnetic resonance-guided focused ultrasound (MRgFUS) for uterine fibroids

ObjectiveTo examine the safety and re-intervention rates following magnetic resonance-guided focused ultrasound (MRgFUS) for uterine fibroids at 5 years. To assess how the non-perfused volume (NPV), fibroid signal intensity and use of gonadotrophin-releasing hormone analogues (GnRHa) affect the re-intervention rates. Study designCohort study of women undergoing MRgFUS for treatment of their uterine fibroids between 2003 and 2010. ResultsOf 280 women undergoing MRgFUS the rate of minor complications was 3.9% and there were 3 serious complications (1.1%) including one skin burn, a fibroid expulsion and one case of persistent neuropathy. The NPVs achieved following MRgFUS have increased as the experience with this treatment has grown. In a 5-year follow-up study of 162 women, the overall re-intervention rate was 58.64%, but in those treatments with greater than 50% NPV the re-intervention rate was 50%. ConclusionMRgFUS treatment of uterine fibroids is a safe treatment for uterine fibroids. The re-intervention rate at 5 years is high, but the improvements in NPVs achieved may further improve the long term results.

Gonadotropin-releasing hormone analogs: Understanding advantages and limitations.

Pituitary stimulation with pulsatile gonadotropin-releasing hormone (GnRH) analogs induces both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Pituitary gonadotropin secretions are blocked upon desensitization when a continuous GnRH stimulus is provided by means of an agonist or when the pituitary receptors are occupied with a competitive antagonist. GnRH antagonists were not available originally; therefore, prolonged daily injections of agonist with its desensitizing effect were used. Today, single- and multiple-dose injectable antagonists are also available to block the LH surge and thus to cause desensitization. This review provides an overview of the use of GnRH analogs which is potent therapeutic agents that are considerably useful in a variety of clinical indications from the past to the future with some limitations. These indications include management of endometriosis, uterine leiomyomas, hirsutism, dysfunctional uterine bleeding, premenstrual syndrome, assisted reproduction, and some hormone-dependent tumours, other than ovulation induction.

Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice

The main objective of individualization of treatment in IVF is to offer every single woman the best treatment tailored to her own unique characteristics, thus maximizing the chances of pregnancy and eliminating the iatrogenic and avoidable risks resulting from ovarian stimulation. Personalization of treatment in IVF should be based on the prediction of ovarian response for every individual. The starting point is to identify if a woman is likely to have a normal, poor or a hyper response and choose the ideal treatment protocol tailored to this prediction. The objective of this review is to summarize the predictive ability of ovarian reserve markers, such as antral follicle count (AFC) and anti-Mullerian hormone (AMH), and the therapeutic strategies that have been proposed in IVF after this prediction. A systematic review of the existing literature was performed by searching Medline, EMBASE, Cochrane library and Web of Science for publications in the English language related to AFC, AMH and their incorporation into controlled ovarian stimulation (COS) protocols in IVF. Literature available to May 2013 was included. The search generated 305 citations of which 41 and 25 studies, respectively, reporting the ability of AMH and AFC to predict response to COS were included in this review. The literature review demonstrated that AFC and AMH, the most sensitive markers of ovarian reserve identified to date, are ideal in planning personalized COS protocols. These sensitive markers permit prediction of the whole spectrum of ovarian response with reliable accuracy and clinicians may use either of the two markers as they can be considered interchangeable. Following the categorization of expected ovarian response to stimulation clinicians can adopt tailored therapeutic strategies for each patient. Current scientific trend suggests the elective use of the GnRH antagonist based regimen for hyper-responders, and probably also poor responders, as likely to be beneficial. The selection of the appropriate and individualized gonadotrophin dose is also of paramount importance for effective COS and subsequent IVF outcomes. Personalized IVF offers several benefits; it enables clinicians to give women more accurate information on their prognosis thus facilitating counselling especially in cases of extremes of ovarian response. The deployment of therapeutic strategies based on selective use of GnRH analogues and the fine tuning of the gonadotrophin dose on the basis of potential ovarian response in every single woman can allow for a safer and more effective IVF practice.

Bioethics in reproduction

Giuseppe Benagiano speaks to Claire Attwood, Commissioning EditorProfessor Giuseppe Benagiano’s scientific interests have been in reproductive medicine, obstetrics and gynecology and public health. His early work focused on placental enzymes and the feto-placental unit. Then, for years, he focused his attention on contraception. More recently, his research activities have expanded to gynecological disorders of endocrine origin, such as endometriosis, adenomyosis and leiomyomata, and he has pioneered the use of GnRH analogues for these conditions. Over the last decade, he has dedicated himself to the issue of bioethics, published a number of essays on bioethics of reproduction and became coeditor of a special supplement of Reproductive BioMedicine Online called ‘Ethics, Bioscience and Life’. In recognition of his scientific achievements, he has been appointed Visiting Professor at the Ohio State University (OH, USA) and at the Peking Union Medical College University, Honorary Professor at the Health Scienc...

GnRH-Analogues for Ovarian Protection in Childhood Cancer Patients: How Adult Hypotheses are Relevant in Prepubertal Females

Systemic chemotherapy frequently causes primary ovarian insufficiency. In prepubertal girls, currently the only option to preserve ovarian function is ovarian tissue preservation. The use of gonadotropin-releasing hormone analogues given in combination with chemotherapy has been studied in reproductive age women. The exact mechanism is unknown, but some of the proposed protective mechanisms could theoretically protect the prepubertal ovary as it has been theorized in many of the studies on reproductive age women. None of the studies implies an adverse affect of GnRH analogue administration in terms of worsening health or cancer status. As 83% of children diagnosed with cancer will survive into adulthood, GnRH analogue administration to female childhood cancer patients in combination with chemotherapy might represent a valuable attempt to preserve future ovarian function and fertility when ovarian tissue preservation is not an option.

Stress‐induced changes in gene expression associated with prostate cancer

Prostate cancer is common among men in the U.S., and stress is prevalent in our society, but the relationship between stress and prostate cancer is not well defined. Stress modulation of the gonadotropin‐releasing hormone (GnRH) system, and the use of GnRH analogs in prostate cancer treatment, suggests this endocrine pathway as a possible link between these two conditions. In this study, our hypothesis was that stress would suppress GnRH and increase the expression of proliferation‐associated genes in prostate tissue. Adult male rats were acutely (30min × 1d) or repeatedly (30min × 21d) restrained and prostate tissues analyzed by PCR array to determine changes in cancer‐related gene expression. Acute and repeated stress caused significant (p<0.05) downregulation of different genes associated with cellular proliferation. Angiopoeitin‐2 and cadherin‐2 were reduced by acute stress, while caspase‐2 and ‐7, IGF binding protein‐3 and ‐7, and MAPKK1 were decreased following repeated stress. Telomerase‐associated protein‐1 was significantly decreased by both stress treatments. These data demonstrate that expression of genes involved in proliferation is downregulated in prostate tissue from stressed animals. Our findings may help identify biomarkers for prostate cancer, and mechanisms through which stress may contribute to prostate cancer progression.Support: 5U54RR022762–03S1, 8G12MD007592

Oocyte Donation and Endometriosis: What Are the Lessons?

Outcomes of in vitro fertilization cycles in women with endometriosis are significantly worse than in patients without this condition. The impact of endometriosis on ovarian reserve and the quality of retrieved oocytes seems evident. Lower implantation rates, however, raise the question whether this finding is purely the consequence of lower number and poorer quality of embryos, or whether it also reflects compromised endometrial receptivity. Oocyte donation provides an interesting model to investigate reproductive outcome because factors affecting the oocytes are excluded, especially if cycles using oocytes derived from the same donor are analyzed. These studies have shown lower implantation rates in nonendometriotic patients who received oocytes from women with endometriosis, whereas healthy donated oocytes have proven to contribute to a pregnancy with similar chances in women without the disease. The question still to be answered is whether this situation applies for natural cycles or whether it is the use of gonadotropin-releasing hormone analogs and hormonal replacement therapy used for endometrial priming in oocyte recipients that reestablishes an adequate uterine environment. Using a genomic tool based on microarray technology (endometrial receptivity array), the study of differential gene expression in the eutopic endometrium of endometriosis patients undergoing oocyte donation treatment is still underway.

Fertility preservation in women with cancer: update and perspectives

With the increased number of cancer diagnoses among young women and the advances in treatment, many patients who may have had their fertility compromised by chemotherapy express desire to become pregnant in the future. Freezing embryos for later IVF so as to preserve fertility is a well established process. Oocyte cryopreservation by vitrification has evolved greatly in recent years and is no longer considered experimental. By 2009 more than 900 children were born from cryopreserved oocytes, without increased risk of congenital anomalies. The preventive use of GnRH analogues for ovarian suppression during chemotherapy to avoid premature ovarian failure has uncertain outcomes. Other techniques such as cryopreservation of ovarian tissue for later autograft are still considered experimental. Although use has already been reported in 24 births, doubts still persist and motivate further study. In vitro maturation of ovarian follicles is a promising alternative for preserving patient fertility and has shown positive results in rodents, monkeys, and humans. Caution should be used with experimental techniques, especially when offered to emotionally fragile patients. Therefore it is important to thoroughly convey information on the chances of pregnancy with existing treatments and the limitations of experimental techniques.

Treatment of high risk Sertoli–Leydig cell tumors of the ovary using a gonadotropin releasing hormone (GnRH) analog

Sertoli–Leydig cell tumors are rare ovarian neoplasms. We report two unusual cases with bilateral SLCTs suggesting evidence of genetic predisposition and at high risk of recurrence. To reduce this risk, we exploited the use of GnRH analog to lower gondadotropin and potentially directly inhibit the tumors through expressed GnRH receptors. We used it as maintenance antitumor therapy for 2 years after completion of chemotherapy, to cover the period of risk for recurrence. Both patients remain in complete remission at >2 years after completing leuprorelin therapy. Of note, both patients carry DICER1 mutations, frequently found in pleuropulmonary blastoma syndrome. Pediatr Blood Cancer 2013; 60: E16–E18. © 2012 Wiley Periodicals, Inc.

Chemotherapy-Induced Amenorrhea - An Update.

Because of the heterogeneity in the definition of chemotherapy-induced amenorrhea (CIA) there are distinct differences in the literature with regard to its incidence as well as its dependence on various influencing factors. The occurrence of CIA varies greatly depending on the applied chemotherapy. The pathogenesis of CIA is especially based on a reduction of ovarian reserves. Various sonographic and biochemical factors can be used to exclude or confirm CIA. This is particularly important when an endocrine therapy with tamoxifen is not possible and the use of aromatase inhibitors is under consideration. CIA and especially the frequently thereby resulting early menopause can lead to pronounced restrictions in the quality of life of the affected patients, not least due to the resulting infertility. On the other hand, various studies have shown that CIA may have a positive prognostic significance. Thus, the identification of measures to prevent CIA (for example, through the use of GnRH analogues) is of particular importance.

Doppler of the uterine arteries combined with endometrial thickness correlate well with the degree of pituitary suppression in women treated with long-acting GnRH agonists

The aim of this study was to evaluate the use of Doppler velocimetry of the uterine arteries and its association to endometrial thickness as a method to confirm pituitary suppression after administration of gonadotropin-releasing hormone analogues in assisted reproduction treatment cycles. A total of 70 patients using gonadotropin-releasing hormone analogues for pituitary suppression for in vitro fertilization treatment were studied. To confirm down-regulation, serum estradiol levels and endometrial thickness were evaluated 10 days after gonadotropin-releasing hormone analogues administration. When estradiol was <30 pg/ml and endometrial thickness was <3 mm, pituitary suppression was confirmed. Doppler velocimetric measurements were performed at the same day to study the pulsatility index of the uterine arteries, until pituitary suppression was confirmed. All 70 patients had normal ovarian morphology. For the patients who had estradiol levels ≤30 pg/ml, the mean pulsatility index of the uterine arteries was 2.95 ± 0.79 and for those who had levels >30 pg/ml the mean PI was 2.22 ± 0.8 (p = 0.005). For the patients who had endometrial thickness ≤5 mm the mean PI was 2.86 ± 0.82 and for those with endometrial thickness >5 mm the mean PI was 2.17 ± 0.79 (p = 0.004). Using a cut-off point of 2.51 for the pulsatility index, to compare to estradiol levels, we observed a sensitivity of 72.7 % and specificity of 71 %. The combination of Doppler velocimetric and endometrial thickness showed a sensitivity of 94 % and specificity of 82.3 %. Doppler velocimetric analysis of the uterine arteries can be an important tool in the diagnosis of the down-regulation after the use of gonadotropin-releasing hormone analogues and might help simplify assisted reproduction programmes.

1551PD - Role of Temporary Ovarian Suppression Obtained with GNRH Analog in Reducing Premature Ovarian Failure (POF) Induced By Chemotherapy in Premenopausal Cancer Patients: a Meta-Analysis of Randomized Studies

ABSTRACT Background premenopausal cancer patients treated with chemotherapy (CT) are at risk of POF. The role of GnRHa in the prevention of CT-induced POF is still controversial. We performed a pooled analysis of randomized studies that evaluated the role of GnRHa as strategy to prevent POF. Methods studies were retrieved by searching the PubMed database and the proceedings of major conferences. Odds ratios (OR) and 95% CIs for CT induced POF were extracted from each trial and averaged to obtain pooled estimates using an inverse-variance model. Results we included in the meta-analysis 7 randomized trials involving 745 premenopausal women randomly assigned to receive chemotherapy or chemotherapy + GnRHa: five trials were carried out in breast cancer patients and two trials in patients with lymphoma. The pooled OR estimate for CT induced POF was 0.46 (95% CI, 0.3-0.72). Conclusion temporary ovarian suppression obtained with the use of GnRH analogues reduces the incidence of chemotherapy induced POF in premenopausal cancer patients. Disclosure All authors have declared no conflicts of interest.

Chemotherapy-induced amenorrhea in premenopausal breast cancer patients treated with adjuvant anthracycline and taxane based chemotherapy within the SUCCESS study.

554 Background: Chemotherapy induced amenorrhea (CIA) is often used as a surrogate marker for cytotoxic gonadal damage. The aim of this analysis was to identify predicitve factors for CIA in premenopausal breast cancer patients treated with adjuvant chemotherapy. Methods: The German multicenter, phase III SUCCESS trial compared 3 cycles of FEC q3w followed by 3x docetaxel q3w vs. FEC followed by Doc+gemcitabine as adjuvant treatment in patients with node positive or high risk node negative primary breast cancer. Premenopausal patients with hormone receptor positive tumors underwent endocrine treatment with tamoxifen (Tam) for 5 years. Additional goserelin (GnRH) for 2 years was given in the following cases: Age &lt;40 years at study entry, premenopausal hormone status or regular menses within 6 months after chemotherapy. We retrospectively investigated CIA rates of 1.189 initially premenopausal patients during disease-free follow-up. Results: Median age at diagnosis was 44 years (range 21-50). The median follow up time was 44 months (range 1-62). 791 patients (66.5%) received endocrine treatment. Tam intake was reported in 370 patients, GnRH in 29 patients, Tam+GnRH in 392 patients. In 963 patients (81.0%) CIA occurred for ≥3 months after chemotherapy. In 22.7% of initially amenorrheic patients CIA was temporary. 192 patients (16.2%) had continuous menstrual bleeding. In multivariate analysis the risk of CIA was significantly higher in older patients, increasing by factor 1.32 per life year (p&lt;0.0001). Tam intake was also associated with increased CIA rates (p=0.0032). Patients with combined Tam+GnRH were more likely to resume menses compared to patients without endocrine therapy (p=0.0056). Factors like the cytotoxic regimen, tumor stage, grading, the patient`s BMI or the use of GnRH analogues as ovarian protectants during chemotherapy did not correlate with CIA rates. Conclusions: Age was the strongest predictor for CIA. Tam administered alone increased CIA rates. Opposite effects were observed for patients who received Tam+GnRH. The addition of gemcitabine to sequential anthracyline-taxane based chemotherapy did not influence CIA.

GnRH analogue use in postmenopausal hyperandrogenism: long-term remission

To the Editor, The medical therapy of postmenopausal hyperandrogenism remains poorly described. The effectiveness of short-term GnRH analogues in suppressing androgens is generally indicative of the ovarian origin of the androgen production, and its benign nature [1–3], although very rarely adrenal tumours secreting androgen responsive to GnRH agonist have been reported [4]. Here we report a rare case of longterm GnRH analogue-induced suppression of androgens of ovarian origin. A 78-year-old woman was referred for investigation of severe hyperandrogenism. She had noticed the progressive appearance of hirsuties over her face and body over a period of 3–4 years, her face becoming plethoric, with concomitant deepening of her voice which became more husky, and increasing temporal recession. She had gained around 10 kg in weight, and reported increased libido for 2 years. She was treated for hypertension with agents not considered to be causative of hirsutism. Clinical examination confirmed significant hirsutism: both her serum testosterone and androstenedione levels were markedly elevated at 21.3 nmol/l (NR \ 2.9) and 17.8 nmol/l (normal 3–8), respectively, with a normal serum DHEAS. Serum testosterone failed to suppress on a low-dose dexamethasone suppression test (16.8 nmol/l at 48 h, with normal suppression of cortisol). Her serum gonadotrophins were appropriately elevated for the menopause (FSH 40.2 U/l, NR [ 25; LH 21.9 U/l, NR [ 16), and her estradiol appropriately low (157 pmol/L, NR 18.4–201). Basal 17-hydroxyprogesterone was normal, excluding the common form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Imaging (CT scanning, MRI) did not show any adrenal or ovarian abnormality, while a transvaginal US scan showed a slightly bulky uterus without thickening of the endometrium. The most likely diagnosis at this stage was either bilateral ovarian hilar cell hyperplasia or hyperthecosis, or a small Leydig cell tumour in one or both ovaries. Ovarian venous catheterisation was not considered as we have previously noticed the lack of utility of this procedure in this situation [5]. A single longacting 10.8 mg subcutaneous injection of goserelin (Zoladex LA, AstraZeneca) was given which induced the suppression of the serum testosterone level to 0.7 nmol/l 2 months later. The GnRH dependence of androgen secretion was taken to be indicative of an ovarian origin. Treatment with the GnRH agonist was continued for 17 months (subcutaneous injections every 3 months), and her serum testosterone levels remained within the normal range (0.9 and 1.6 nmol/l) for a further 27 months off treatment. Significant improvement of her symptoms was noticed; 11 months later the patient died from overwhelming sepsis due to methicillin-resistant S. aureus unrelated to her endocrine condition. In this case, in addition to representing a functional diagnostic tool, the use of GnRH analogues offers a valuable therapeutic approach which is a particularly useful mode of therapy in patients for whom surgical intervention is not appropriate for diverse reasons. Indeed, only rare M. Gueorguiev Department of Endocrinology, St Bartholomew’s Hospital, London EC1A 7BE, UK

Fertility and Gonadal Function After Treatment of Early Unfavorable Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Study Group (GHSG)

Abstract 432 Purpose:Two cycles of BEACOPPescalated followed by two cycles of ABVD (“2+2”) improves the primary outcome in early unfavorable HL patients as shown in the GHSG HD14 trial. Compared to 4xABVD, this benefit might be compromised by more gonadal toxicity in women and men. We thus analyzed gonadal function and fertility of survivors in the HD14 trial. Methods:Women between 18–40 years and men between 18–50 years at diagnosis in ongoing remission at least one year after therapy, treated with either 4xABVD (arm A) or “2+2” (arm B), were included. In women, different hormone parameters (follicle-stimulating hormone (FSH), Anti-Muellerian-Hormone (AMH)) as well as menopausal symptoms, prophylactic measures to preserve fertility, concurrent hormonal treatment, menstrual cycle, pregnancies, and offspring were evaluated. In men, serum levels of FSH, testosterone, and inhibin B were determined as well as symptoms of hypogonadism (aging males symptom scale, AMS) and children after therapy. Results:From a total of 579 women addressed, 331 participated in the present study (57%) and 263 per-protocol treated patients qualified for the comparison of treatment arms (A: 137, B: 126; mean time from end of therapy 42 and 43 months, respectively). The rates of regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. FSH and AMH, reflecting ovarian reserve, were significantly better in arm A and AMH levels were also low after 4xABVD in women >30 years. In contrast, pregnancies after therapy favored arm B (A: 15%, B: 26%, p=0.043) and motherhood rates were equivalent to the German normal population in both arms. A multivariate analysis revealed prophylactic use of GnRH-analogues as highly relevant and significant prognostic factor for preservation of fertility (OR=12.87, p=0.001). Severe menopausal symptoms were reported frequently in women ≥30 years (A: 21%, B: 25%). From a total of 592 men addressed, 322 participated in the present study (54%) and 235 per-protocol treated patients qualified for the comparison of treatment arms (A: 111, B: 124; mean time from end of therapy 43 and 45 months, respectively). Levels of FSH (A: 4.3 U/l, B: 7.7 U/l, p<0.001) and inhibin B (A: 140.7 ng/l, B: 46.9 ng/l, p<0.001) were significantly better in arm A and children after therapy were also more frequently reported after treatment with 4xABVD (A: 12%, B: 5%, p=0.075). However, levels of testosterone and symptoms of hypogonadism were not different between treatment arms. In addition, symptoms of hypogonadism were equivalent as compared to the reference population. Conclusion:With focus on hormonal markers, results of the present study demonstrate higher gonadal toxicity in women and men after the “2+2” regimen compared to 4xABVD. Accordingly, in men, more children after 4xABVD are reported. In women, fertility is not compromised within the evaluated observation time, especially when GnRH-analogues were used. Disclosures:No relevant conflicts of interest to declare.

Prevention of menstrual migraine with perimenstrual transdermal 17-β-estradiol: a randomized, placebo-controlled, double-blind crossover study

The effect of treatment with percutaneous E(2) (100 μg/24 h) during 2 weeks perimenstrually on the number and severity of menstrual migraine attacks was studied in 27 women in a randomized, placebo-controlled, double-blind, crossover trial. We were not able to demonstrate any difference between E(2) supplementation and placebo on the number or severity of migraine attacks, but both regimens showed significant effects compared with before treatment. CLINICAL TRIAL IDENTIFICATION NUMBER: NCT00204074.

Evolução da função pulmonar após tratamento com goserelina em pacientes com linfangioleiomiomatose

In the atypical smooth muscle cells that are characteristic of lymphangioleiomyomatosis (LAM), there are estrogen and progesterone receptors. Therefore, anti-hormonal therapy, despite having produced controversial results, can be considered a treatment option. The objective of this retrospective study was to evaluate hormonal and spirometric data for nine women with LAM after one year of treatment with goserelin. The mean increase in FEV1 and FVC was 80 mL and 130 mL, respectively. There was effective blockage of the hormonal axis. It is still not possible to exclude a potential beneficial effect of the use of gonadotropin-releasing hormone analogues in LAM patients, which underscores the need for randomized trials.