Use Of Gonadotropin-releasing Hormone Agonists Research Articles

Chronic use of a GnRH agonist (deslorelin) or immunization against GnRH: effects on testicular function and sperm quality of bucks

Chronic use of GnRH agonists and immunization against GnRH have been used as reversible contraceptive methods. The aim of this study was to compare the effectiveness of both treatments to inhibit reproductive function of adult bucks, in terms of strength and duration of the effects. We used 9 control untreated bucks (CON), 7 bucks treated chronically with a GnRH agonist (subcutaneous implants with 7.4 mg of deslorelin, Suprelorin, Virbac) (AGO), and another 7 bucks were immunized against GnRH (dose of 2 mL of Improvac-Zoetis with 300 μg of a synthetic incomplete analog of natural GnRH; 300 mg of diethylaminoethyl-dextran; and 2.0 mg of chlorocresol) (IMM). Testicular and sperm evaluations, testosterone concentrations, and male odor were determined from 4 wk before applying the treatments until 17 mo of their application. Scrotal circumference of CON (21.0 ± 0.1 cm) and IMM (21.2 ± 0.2 cm) was greater than that of AGO bucks (19.9 ± 0.2 cm) (P < 0.05 for each), without difference between CON and IMM bucks. Pixels' color intensity of testicular ultrasound images was not affected by treatment (general mean ± SEM: 116.0 ± 1.8). Testosterone concentration was greater in CON than AGO and IMM in months 3 and 4, greater in CON and IMM than AGO bucks in months 15 and 16, and greater in IMM than CON and AGO bucks in month 17 (P < 0.05 for all comparisons). Male odor was greater in CON (1.5 ± 0.0) than IMM bucks (1.3 ± 0.0) and greater in IMM than AGO (1.1 ± 0.0) bucks (P < 0.05 for each). Treatment negatively affected all the sperm variables: the total number of sperm in the ejaculate, sperm motility, sperm with normal morphology and sperm with integral membrane function. It was concluded that both treatments were effective in inhibiting the reproductive axis; however, neither of them produced azoospermia or decreased testosterone concentrations to undetectable levels. With both treatments, there were individual males exhibiting characteristics of fertility in all periods of the study. However, chronic use of a GnRH agonist seemed to be the most effective treatment in terms of duration and strength.

Utilization of gonadotropin-releasing hormone agonists for preservation of ovarian function in women with breast cancer receiving chemotherapy

To determine the use and predictors of GnRH (gonadotropin-releasing hormone) agonists for ovarian conservation in young, reproductive age women with newly diagnosed breast cancer undergoing chemotherapy. Retrospective cohort study. The MarketScan database was used to identify women 15-45 years of age with newly diagnosed breast cancer from 2008-2017. All patients underwent cancer directed surgery (lumpectomy, mastectomy, biopsy or lymph node evaluation) and received cytotoxic chemotherapy within three months before or after surgery. Patients were considered to have received GnRH agonist therapy if they had one claim for a GnRH agonist in the same period. All women with history of oophorectomy before or during the study period were excluded from the study. Trends and predictors of GnRH agonist use were described and compared using Cochran-Armitage trend test and Chi-square tests. We identified a total of 13,634 women with breast cancer who underwent treatment with chemotherapy. The median age was 39 years with 755 women <30 (5.5%) years of age and 12,879 >30 (94.5%) years old. GnRH agonists were administered to 112 (0.8%, 95% CI 0.7-1.0%) women. The rate of GnRH agonist use was higher in women age 15-30 years compared to women age 30-45 (2.8% vs 0.7%) (P< 0.001). During the study period, the utilization of GnRH agonists increased from 0.3% in 2008 to 1.3% in 2017 (P<0.001). Use of GnRH agonists was higher in the Northeast (2.0%) compared to the north central (0.7%), southern (0.6%) and western (0.5%) U.S. (P<0.001). The utilization of GnRH agonists among reproductive age women with breast cancer undergoing chemotherapy is extremely low.

HCG trigger versus GnRH agonist trigger in PCOS undergoing IVF cycles: frozen embryo transfer outcome

The use of Gonadotrophin releasing hormone agonist (GnRHa), with freeze-all strategy followed by frozen embryo transfer (FET) has been found to eliminate the risk of ovarian hyperstimulation syndrome (OHSS) in women with polycystic ovarian syndrome (PCOS) undergoing IVF cycles. However, there still has been hesitations with the use of GnRHa as a routine trigger replacing Human chorionic gonadotrophin (hCG), for concerns of compromised cycle outcome. We aimed to evaluate the outcome following transfer of embryos in FET cycles obtained from GnRHa trigger in comparison with hCG trigger in PCOS of Asian origin. Prospective observational cohort study. 210 PCOS undergoing IVF in an antagonist protocol who were randomized in the previous study (to evaluate if GnRHa trigger is a better alternative than hCG in PCOS for prevention of OHSS; Group A: GnRHa trigger (n=92)] and Group B: hCG trigger (n=101)], were followed up in FET cycles to assess the outcome. A prospective, observational study was conducted in a tertiary care center- Milann, The fertility center, Bangalore to assess the frozen- thawed embryo transfer cycle outcome following GnRHa trigger and hCG trigger in PCOS. In the previous randomized controlled trial conducted between May 2013 and November 2015, [comparing GnRH agonist with hCG trigger in an antagonist protocol for prevention of OHSS with freeze-all strategy; 210 PCOS patients were randomized; 92 subjects in Group A: GnRHa trigger (n=92) and Group B: hCG trigger (n=101) included for the final analysis (Deepika et al., 2016)], were followed up prospectively over a period of three years. All participants underwent subsequent frozen-thawed embryo transfer cycles and the treatment outcome of these subjects is reported herein. The odds of cumulative live birth rate per stimulation cycle favours GnRHa trigger as against hCG trigger [OR= 2.15; (CI 1.2–3.83); P=0.008]. A significantly higher number of mature oocytes (19.1±11.7 versus 14.1±4.3; P<0.001) and blastocysts (4.2±1.63 versus 3.26±1.22; P<0.001) were available in GnRHa group as compared to hCG group. The cumulative live birth rate is better following transfer of frozen-thawed embryos generated from GnRHa triggered cycles compared to hCG trigger. Hence, in PCOS undergoing IVF, as a good practice point, hCG trigger should be replaced by GnRHa trigger with vitrification of all embryos followed by FET later.

Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer.

This review paper is a comprehensive look at the cardiovascular disease (CVD) risk that is associated with the use of androgen deprivation therapy in prostate cancer. It summarizes when certain cancer therapies are indicated and should guide physicians in identifying patients at increased risk for CVD during prostate cancer therapy. GnRH agonist use and maximal androgen blockade (MAB) are associated with increased CVD. This association is not observed in patients on GnRH antagonists. One example is the novel agent abiraterone, which is associated with hypertension whose mechanisms are likely driven by mineralocorticoid excess. Incidence of cardiovascular disease events is greatest when using MAB, especially in patients with pre-existing CVD. There is significant confounding that exists given patients with more aggressive cancers tend to be older and have more co-existing CVD. Given the lower CVD event rates with GnRH antagonists, future studies and strategies should focus on high-risk cancer patients with co-existing CVD receiving antagonists over agonists.

Effect of Gonadotrophin-Releasing Hormone Agonist Addition for Luteal Support on Pregnancy Outcome in vitro Fertilization/Intracytoplasmic Sperm Injection Cycles: A Meta-Analysis Based on Randomized Controlled Trials

Purpose: The meta-analysis aimed to evaluate the effect of gonadotrophin-releasing hormone agonist (GnRH-a) addition for luteal support on pregnancy outcome in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Methods: Meta-analysis. Results: A total of 3,584 cycles were identified from 13 randomized controlled trials. The cumulative analysis showed that GnRH-a addition for luteal supports significantly improved live birth rate (relative risk [RR] = 1.52; 95% CI 1.20–1.94; p = 0.0006), the clinical pregnancy rate (RR 1.21; 95% CI 1.11–1.33; p < 0.0001), ongoing pregnancy rate (RR 1.18; 95% CI 1.06–1.32; p = 0.004), pregnancy rate (RR 1.36; 95% CI 1.01–1.82; p = 0.04), implantation rate (RR 1.44; 95% CI 1.17–1.77; p = 0.0007), and multiple pregnancy rate (RR 1.40; 95% CI 1.04–1.88; p = 0.03) in comparison with control, but not for the incidence of ovarian hyperstimulation syndrome (RR 0.96; 95% CI 0.32–2.89; p = 0.94). We also found that GnRH-a addition for luteal support had a tendency to decrease the abortion rate (RR 0.72; 95% CI 0.56–0.93; p = 0.01). Conclusions: Overall, the current meta-analysis showed a substantial efficacy of GnRH-a addition for luteal support on pregnancy outcomes in women undergoing IVF/ICSI and support the use of GnRH-a in luteal phase to improve the success of IVF/ICSI.

Gonadotropin-Releasing Hormone Agonist Versus Human Chorionic Gonadotropin for Ovulation Induction in Polycystic Ovary Syndrome Patients Undergoing Intrauterine Insemination: A Randomised Controlled Trial

Background: Gonadotropins have been recommended to improve ovulation, pregnancy and live birth rates in polycystic ovary syndrome (PCOS) patients with anovulatory infertility and clomiphene citrate (CC) resistance. However, this could increase the risk of ovarian hyperstimulation syndrome (OHSS). Gonadotropin-releasing hormone agonist (GnRHa) triggering could significantly reduce the risk of OHSS in patients undergoing in vitro fertilisation. However, data on the use of GnRHa in intrauterine insemination (IUI) is limited. This study compared the effectiveness of GnRHa and human chorionic gonadotropin (hCG) for ovulation induction in PCOS patients undergoing IUI. Methods: This non-inferiority, single-centre, randomised controlled trial was conducted at IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam between April 2016 and May 2018. PCOS patients aged 18–37 years with CC resistance and [Formula: see text] 3 developing ([Formula: see text] 16 mm) follicles on trigger day after stimulation with gonadotropins were eligible. Those with uterine abnormalities or tubal damage or inseminated with frozen semen were excluded. Triptorelin 0.1 mg or hCG 5000 IU was used when there was [Formula: see text] 1 follicle of [Formula: see text] 17 mm. IUI was performed at 36 hours after triggering. Primary outcome was ongoing pregnancy. Secondary outcomes were clinical pregnancy, multiple pregnancy, miscarriage and OHSS. Results: A total of 380 patients were randomised (190 per group). Treatment groups had similar characteristics at baseline. Ongoing pregnancy rate was 23.7% in the GnRHa group versus 25.3% in the hCG group (Relative risk 0.94; 95% confidence interval, 0.66–1.34; p [Formula: see text] 0.81). Secondary outcome parameters were also not significantly different between the two groups. There were two cases of mild OHSS in the hCG group and none in the GnRHa group. Conclusion: 0.1 mg triptorelin was non-inferior to 5000 IU hCG IU in PCOS patients undergoing ovulation induction by hMG followed by IUI with respect to pregnancy outcomes.

Influence of Different Gonadotropin-releasing Hormone Agonist Administration Methods on Pregnancy Outcomes of Patients Undergoing In-vitro Fertilization-embryo Transfer

This study aimed to investigate the effect of different gonadotropin-releasing hormone agonist (GnRH-a) administration methods on pregnancy outcomes of patients undergoing in-vitro fertilization-embryo transfer (IVF-ET). Clinical data of 5217 patients who underwent IVF-ET were retrospectively analyzed. Patients were divided into the long-acting GnRH-a group (n=1330) and the short-acting GnRH-a group (n=3887) based on their various treatment plans. The clinical and laboratory embryo data and clinical pregnancy outcomes were compared between the two groups. The results showed that there were no significant differences in the age, infertility, primary/secondary infertility rate, IVF rate, body mass index (BMI), antral follicle counting (AFC), follicle-stimulating hormone (FSH) level, and the number of transplanted embryos between the two groups (P>0.05). There were no significant differences in the oocyte numbers, MII rate, fertilization rate, cleavage rate and blastocyst formation rate (P>0.05) between the two groups. The gonadotropin (Gn) using days, Gn dose and endometrial thickness were significantly greater in the long-acting GnRH-a group than those in the short-acting GnRH-a group (P<0.01). Additionally, the estradiol (E2) levels, blastocyst freezing rate, embryo utilization rate, transplant cancellation rate and abortion rate were significantly lower in the long-acting GnRH-a group than those in the short-acting GnRH-a group (P<0.01). The clinical pregnancy rate and embryo implantation rate were significantly higher in the long-acting GnRH-a group than in the short-acting GnRH-a group (P<0.01). It was concluded that use of long-acting GnRH-a can effectively reduce the transplant cancellation rate and improve the clinical pregnancy rate of the fresh cycle.

Effect of GnRH agonist and letrozole treatment in women with recurrent implantation failure

To compare the influence of dual suppression with the use of GnRH agonist plus aromatase inhibitor compared with suppression with the use of GnRH agonist alone or no suppression at all in patients with idiopathic recurrent implantation failure (RIF). Retrospective cohort study. University-affiliated reproductive center. A total of 523 infertile women who failed two blastocyst transfers underwent a third frozen blastocyst transfer. Women with known endometriosis were excluded. A total of 204 subjects were not pretreated, 143 received 2months of GnRH agonist (3.75mg intramuscular leuprolide acetate monthly) only, and 176 received GnRH agonist and aromatase inhibitor (5mg oral letrozole daily for 60days). Demographic and stimulation information was collected and cycle outcomes reported. Clinical pregnancy rates. Age, antral follicle count, basal FSH levels, duration of infertility, previous pregnancies, and full-term deliveries were similar (P>.05). Clinical pregnancy rates were higher among women who received GnRH agonist plus letrozole compared with women who received GnRH agonist only or women without pretreatment (63%, 42%, and 40%, respectively; P<.0001). Live birth rates were higher among women who received GnRH agonist plus letrozole compared with the other groups (56%, 36%, and 34%; P<.0001). No differences in pregnancy outcomes were noted between patients who did not receive pretreatment and those in the GnRH agonist only group. In patients with RIF, treatment with a GnRH agonist plus letrozole may improve live birth rates in subsequent cycles. We hypothesize that this improvement is due to alterations in the endometrium receptivity or treatment of undiagnosed endometriosis.

SAT-210 Autoimmune Progesterone Dermatitis: A Rare Case Report in a Young Woman with Chronic Dermatitis

Back ground: Autoimmune progesterone dermatitis (APD) or progesterone hypersensitivity (PH) is a rare hypersensitivity reaction to progestogen that exclusively occur in women of childbearing age of which is the underlying mechanism remains not well understood. Clinical case: A 44 years old lady was referred to our endocrine outpatient clinic by her dermatologist for treatment of a recently diagnosed autoimmune progesterone dermatitis. She was initially evaluated for a skin rash that started during the second trimester of her second pregnancy in 2009. Her initial diagnosis was pregnancy induced eczema which was treated with topical steroid with no significant improvement. Her rash worsens after delivery and had persisted since then. She failed chronic systemic steroid treatment and multiple immunosuppressive medications over the years. She had regular menstrual period since her menarche at age of 11 years old. She was on oral contraceptive medication prior to her second pregnancy which she resumed after delivery. She then switched to IUD. Her rash typically gets worse 7-10 days before the onset of her menstrual period with some improvement after her period. Her initial clinical exam showed erythematous papules over her extensor elbows, thighs and genital area with scattered eczematous excoriated plaques over her extremities and trunk. She underwent skin patch test which showed that she is allergic to class A, B, and D1 steroids PH was suspected based on her history and confirmed by a positive progesterone skin test. She was referred to reproductive endocrinology for consideration of ovulation suppression using GnRH agonist. Conclusion: APD is a rare hypersensitivity reaction that can be triggered by endogenous progesterone (menses, pregnancy) or exogenous progestin (OCP, IUD, IVF) exposure. Women between menarche and menopause can be affected with the average age of onset to be in the third decade of life. The underlying mechanism is not well known with several hypotheses being postulated (e.g hypersensitivity reaction type I and IV, hormone cross reactivity and autoimmunity) Clinical presentation is variable and can range from mild dermatitis to life threatening anaphylaxis with some extra dermal manifestations have been described. Detailed history taking is the key to diagnosis as the most consistent features is the presentation of symptoms during the luteal phase of the menstrual cycle. The goal of treating APD is to suppress ovulation which can be achieved by the use of GnRH agonist, selective estrogen receptor modulator or oophorectomy. Progesterone desensitization has been tried in women desiring pregnancy.

Wild ungulate vontraception: Use of GnRH agonist or GnRH vaccine to control reproduction in captive and free-ranging female elk (Cervus elaphus nelsoni)

Wild ungulate vontraception: Use of GnRH agonist or GnRH vaccine to control reproduction in captive and free-ranging female elk (Cervus elaphus nelsoni)

GnRH agonist treatment of luteal phase deficiency in HCG-triggered IVF cycles: a matched case-control study.

This study aimed to identify women with IVF failure associated with low serum progesterone levels after embryo transfer in HCG-triggered cycles and to evaluate the effects of gonadotrophin-releasing hormone (GnRH) agonist, administered after embryo transfer, on serum progesterone and pregnancy outcomes in these cases. Fifty women who failed to achieve an ongoing clinical pregnancy and had abnormally low luteal-phase serum progesterone concentrations in their first IVF attempt were assigned to two matched groups in their subsequent attempt. Twenty-five women were treated with the original protocol plus14 daily injections of GnRH agonist, beginning on the day of oocyte recovery, in their second IVF attempt (group 1). These women were matched to 25 women with the same characteristics and outcomes in their first IVF attempt who underwent the second IVF attempt without the use of GnRH agonist after embryo transfer (group 2). In both groups, the two sequential attempts were compared for serum progesterone concentration 14 days after oocyte recovery and pregnancy outcome. The patients in group 1 had significantly higher progesterone levels 14 days after oocyte recovery in the second attempt compared with the first attempt (P < 0.001), and 12 (48%) of them achieved clinical pregnancy and birth. No significant differences in pregnancy outcome or in the serum progesterone concentration were observed between the first and the second attempt in group 2. In patients with luteal phase deficiency, the administration of GnRH agonist after embryo transfer increases serum progesterone concentration and improves the chance of pregnancy and birth.

Use of repeat-dose GnRH agonist, hCG, and co-trigger for final follicular maturation have similar rates oocyte maturity

Use of GnRH agonists with or without hCG for final follicular maturation has become increasingly common in high responders as well as in patients with normal ovarian reserve. However, studies investigating the effect of trigger type on IVF outcomes have been inconsistent and the majority studies have looked at patients triggered with single-dose rather than repeat-dose GnRH. (1-3) The objective of this study was to determine if rate of oocyte maturity differs between patients triggered with repeat-dose GnRH agonist, hCG, and GnRH agonist + hCG co-trigger. All IVF stimulation cycles at a single academic center between December 2016 and February 2018 were included in the study. Cycles were categorized by type of trigger: repeat-dose GnRH agonist trigger (leuprolide acetate 4mg q 12 hours x 2 doses), hCG trigger (purified hCG 5,000-10,000IU), or co-trigger (leuprolide acetate 4mg q 12 hours x 2 doses + hCG 1,500-2,000IU). Retrieval was performed 36 hours after trigger injection. Cycles were evaluated for patient age, antral follicle count (AFC), days of gonadotropin stimulation, oocyte maturity rate (# MII oocytes/# follicles > 12 mm at time of trigger) and fertilization rate. Statistical analysis was performed using analysis of variance and multivariate logistic regression. A total of 132 women underwent 152 cycles during the study period. All cycles were GnRH antagonist protocol. Of the 152 IVF cycles included, hCG trigger was used in 93 cycles (61%), repeat-dose GnRH agonist was used in 43 cycles (28%), and GnRH agonist + hCG co-trigger was used in 16 cycles (11%). The groups did not differ by BMI or number of days of gonadotropin stimulation. Age was significantly higher and AFC lower in the hCG compared to the GnRH and co-trigger groups (Table 1). In a multivariate regression model, after controlling for age and AFC, no difference was observed between trigger type and maturity rate (p=0.669) or fertilization rate (p=0.181).Table 1IVF outcomes by trigger type: Repeat-dose GnRH agonist vs hCG vs GnRH agonist + hCG co-triggerhCG (n = 93)GnRH agonist (n = 43)Co-trigger (n=16)p-valueDays of stimulation9.9 (1.4)9.5 (0.9)9.4 (1.2)0.078Peak E2 (pg/mL)2095.9 (794)4932.4 (1145.9)3735.2 (530.1)<0.001Follicles > 12mm9.6 (1.4)9.5 (0.9)9.4 (1.2)0.078Oocytes retrieved11.8 (6.7)20.9 (6.2)20.6 (6.9)<0.001MII oocytes8.8 (5.3)15.8 (5.6)14.6 (5.4)<0.001Maturity rate (%)83.5 (19.4)83.7 (16.5)85.8 (19.8)0.9Fertilization rate (%)77.5 (22.4)82.3 (21.2)89.7 (11.8)0.079Data presented as mean +/- standard deviation, unless otherwise noted Open table in a new tab Data presented as mean +/- standard deviation, unless otherwise noted Cycles triggered with repeat-dose GnRH agonist, hCG, and GnRH agonist + hCG co-trigger have equivalent oocyte maturity and fertilization rates in our cohort. These findings are reassuring that choice of trigger does not appear to impact oocyte maturity, even after controlling for ovarian reserve and patient age. However, further investigation into the impact of trigger type, including optimal dosage of GnRH agonist, on embryo development, clinical outcomes, and live birth rate is warranted.

Androgen-Secreting Ovarian Tumors.

About 1% of ovarian tumors that comprise testicular cell types can cause hyperandrogenism followed by characteristic virilization. Androgenic group of tumors originated mainly from sex-cord stromal ovarian tumors are including steroid cell tumors, Leydig tumors, granulosa cell tumors, Sertoli cell tumors, Sertoli-Leydig cell tumors, gonadoblastomas, and some other rare forms as ovarian metastases from neuroendocrine tumors. Germline or somatic mutations in some genes like DICER1, STK11, and FOXL2 are associated with the development of some sex cord-stromal ovarian tumors. Basal serum testosterone concentrations above 7 nmol/L could indicate an androgen-secreting tumor. Other ovarian and adrenal androgens should be determined and functional endocrine testing including low-dose dexamethasone suppression test, gonadotrophin-releasing hormone (GnRH) agonist test, imaging methods, and selective venous sampling should be performed. Surgery is the first-line treatment for most of the tumors. Women who are not good surgical candidates could benefit from use of GnRH agonist to control hyperandrogenism. In some cases, chemotherapy and/or radiation therapy is required while some tumors respond on antiangiogenic agents used alone or in combination with chemotherapy. Metabolic implications and long-term outcomes of ovarian androgen-secreting tumors are unknown and require more detailed follow-up in multicentric and longitudinal clinical studies.

Fertility Preservation Using GnRH Agonists: Rationale, Possible Mechanisms, and Explanation of Controversy.

The only clinically accepted method of fertility preservation in young women facing gonadotoxic chemo- and/or radiotherapy for malignant or autoimmune diseases is cryopreservation of embryos or unfertilized ova, whereas cryopreservation of ovarian tissue for future reimplantation, or in vitro maturation of follicles, and the use of gonadotropin-releasing hormone agonists (GnRHa) are still considered investigational, by several authorities. Whereas previous publications have raised the fear of GnRHa’s possible detrimental effects in patients with hormone receptor-positive breast cancers, recent randomized controlled trials (RCTs) have shown that it either improves or does not affect disease-free survival (DFS) in such patients. This review summarizes the pros and cons of GnRHa co-treatment for fertility preservation, suggesting 5 theoretical mechanisms for GnRHa action: (1) simulating the prepubertal hypogonadotropic milieu, (2) direct effect on GnRH receptors, (3) decreased ovarian perfusion, (4) upregulation of an ovarian-protecting molecule such as sphingosine-1-phosphate, and (5) protecting a possible germinative stem cell. We try to explain the reasons for the discrepancy between most publications that support the use of GnRHa for fertility preservation and the minority of publications that did not support its efficiency.

Continuous oral contraceptives versus long-term pituitary desensitization prior to IVF/ICSI in moderate to severe endometriosis: study protocol of a non-inferiority randomized controlled trial.

STUDY QUESTIONSThe primary objective is to investigate if continuous use of oral contraceptives is non-inferior compared to long-term pituitary desensitization with a GnRH agonist prior to IVF/ICSI in patients with moderate to severe endometriosis with regard to treatment efficacy. Secondary objectives concern treatment safety and cost-effectiveness.WHAT IS KNOWN ALREADYLong-term pituitary desensitization with a GnRH agonist for 3–6 months prior to IVF/ICSI improves clinical pregnancy rates in women suffering from endometriosis. However, discussion about this treatment strategy exists because of its uncomfortable side effects. Alternatively, IVF/ICSI pre-treatment with continuously administered oral contraceptives may offer fewer side-effects and lower (in)direct costs, as well as encouraging IVF outcomes in women with endometriosis. To date, these two different IVF/ICSI pre-treatment strategies in women with endometriosis have not been directly compared.STUDY DESIGN, SIZE, DURATIONAn open-label, parallel two-arm randomized controlled multicenter trial is planned, including patients with moderate to severe endometriosis. To demonstrate an absolute difference of 13% (delta of 10% with non-inferiority margin of 3%) with a power of 80% 137 patients per group are sufficient. Taking into account a withdrawal of patients of 10% and a cancelation rate of embryo transfer after ovarian pick up of 10% (for instance due to fertilization failure), the sample size calculation is rounded off to 165 patients per group; 330 patients in total will be included. After informed consent, eligible patients will be randomly allocated to the intervention or reference group by using web based block randomization stratified per centre. Study inclusion is expected to be complete in 3–5 years.PARTICIPANTS/MATERIALS, SETTING, METHODSThe research population consists of patients with moderate to severe endometriosis (ASRM III/IV) who are scheduled for their first, second or third IVF/ICSI treatment attempt. Women aged over 41 years, younger than 18 years, with a known contraindication for the use of oral contraceptives and/or GnRH agonists or with severe male factor infertility will be excluded from participation. After informed consent patients are allocated to the intervention group (one-phase oral contraceptive continuously during three subsequent months) or the reference group (three Leuprorelin 3.75 mg i.m./s.c. depot injections during three subsequent months). Tibolon 2.5 mg can be given daily as add-back therapy in the reference group. After 3 months of pre-treatment the IVF/ICSI stimulation phase will be started. The primary outcome is live birth rate after fresh embryo transfer. Secondary outcomes are cumulative live birth rate after one IVF/ICSI treatment cycle (including fresh and frozen embryo transfers up to 15 months after randomization), ongoing pregnancy rate and time to pregnancy. In addition, treatment outcome parameters, adverse events, side-effects during the first 3 months, complications, recurrence of endometriosis (complaints), quality of life, patient preferences, safety and costs effectiveness will be reported. Measurements will be performed at baseline and at 3, 6, 9, 12 and 15 months after randomization.STUDY FUNDING/COMPETING INTEREST(s)All authors have no conflict of interest related to this manuscript. The department of reproductive medicine of the Amsterdam UMC location VUmc has received several research and educational grants from Guerbet, Merck and Ferring not related to the submitted work.TRIAL REGISTRATION NUMBERThe trial is registered as the COPIE trial (Continuous use of Oral contraceptives as an alternative for long-term Pituitary desensitization with a GnRH agonist prior to IVF/ICSI in Endometriosis patients) in the Dutch Trial Register (Ref. No. NTR6357, http://www.trialregister.nl).TRIAL REGISTRATION DATE16 March 2017.DATE OF FIRST PATIENT’S ENROLMENTEnrollment is planned for November 2018.

Preventing ovarian failure associated with chemotherapy.

Alkylating chemotherapy is often used to treat pre-menopausal women for various malignancies and autoimmune diseases. Chemotherapy-associated ovarian failure is a potential consequence of this treatment which can cause infertility, and increases the risk of other long term adverse health sequelae. Randomised trials, predominantly of women undergoing alkylating chemotherapy for breast cancer, have shown evidence for the efficacy of gonadotropin-releasing hormone agonists (GnRHa) in preventing chemotherapy-associated ovarian failure. The European St Gallen and United States National Comprehensive Cancer Network guidelines recommend the use of concurrent GnRHa to reduce the risk of ovarian failure for pre-menopausal women undergoing chemotherapy for breast cancer. The GnRHa goserelin, a monthly 3.6 mg depot subcutaneous injection, has recently been listed on the Australian Pharmaceutical Benefits Scheme to reduce risk of ovarian failure for pre-menopausal women receiving alkylating therapies for malignancy or autoimmune disease. The first dose of goserelin should ideally be administered at least 1 week before commencement of alkylating treatment and continued 4-weekly during chemotherapy. Concurrent goserelin use should now be considered for all pre-menopausal women due to commence alkylating chemotherapy (except those with incurable cancer), regardless of their childbearing status, in an effort to preserve their ovarian function. For women who have not completed childbearing, consideration of other fertility preservation options, such as cryopreservation of embryos or oocytes, is also important.

Effect of gonadotropin-releasing hormone agonist used before surgery on natural pregnancy rates in patients with ovarian endometriomas

Objective: To evaluate the impact of gonadotropin-releasing hormone agonist (GnRH-a) used before surgery on natural pregnancy rates in patients with ovarian endometriomas. Methods: In this retrospective study, 57 patients with ovarian endometriomas who had a consecutive laparoscopic surgery between June, 2010 to September, 2015 in Peking Union Medical College Hospital were included. Those patients were divided into preoperative GnRH-a treatment group (n=31) and non-GnRH-a treatment group (n=26) . There were no differences in patients' characteristics between the two groups. All of them had a desire for natural pregnancy postoperatively. GnRH-a was no longer used after surgery. After the surgical procedure, the patients were observed over a period of 12 months, during which the frequency of natural pregnancy was assessed. The two groups were compared in terms of natural pregnancy rates. Results: Totally 33 patients had natural pregnancy after surgery. The univariate analysis showed that the pregnancy rates of age, r-AFS stage, infertility, preoperative use of GnRH-a, tumor size, tumor side, deep infiltrating endometriosis and adenomyosis did not have statistically significant differences (all P>0.05) . The two classified logistic regression showed that OR for preoperative use of GnRH-a was 0.250 (95%CI: 0.064-0.978) with a statistical difference (P=0.046) . Conclusion: The use of GnRH-a preoperatively may have a negative effect on natural pregnancy rates of patients after surgery with ovarian endometriomas.

Transgender medicine - puberty suppression.

Puberty suppression is the reversible first step of endocrine medical treatment in transgender youth, and allows for two very important aspects of transgender management. Firstly, it buys the patient, family and their medical team time to fully evaluate the presence and persistence of gender dysphoria. Secondly, it successfully prevents the development of cis-gender unwanted secondary sexual characteristics. The latter, when present, almost certainly increase the burden of psychological co-morbidity for any transgender person. This management is modelled from treatment of gonadotropin-dependent precious puberty, with use of GnRH agonists at its core. With the increasing number of transgender youth treated, and the changing demographics of patients seeking medical care, providers are faced with the decision to start puberty blockade at younger ages than previous decades. This article will review the rationale behind puberty blockade for transgender children, the providers' options for achieving this goal, the emerging literature for potential adverse effects on such an approach, as well as identify directions of potential future research.

Trends in the "Off-Label" Use of GnRH Agonists Among Pediatric Patients in the United States.

Gonadotropin-releasing hormone (GnRH) agonists are FDA approved for the treatment of precocious puberty. The therapy consists of histrelin acetate (Supprelin), a surgically implanted device, or Lupron injections. In recent years, the use of these agents has been extended to include the off-label treatment of children with normally timed puberty. Trends in the off-label use of GnRH agonists in children across the U.S. have not been previously described in the literature. We analyzed data on the use of Supprelin and Lupron reported to the Pediatric Health Information System (PHIS) from 2013 to 2016 to determine the trends in both the FDA-approved and off-label uses of these medications. We identified a stable cohort of 39 children's hospitals administering GnRH agonist therapies from 2013 to 2016. During this period, the annual number of children treated with these medications for precocious puberty increased modestly, from 283 to 303; meanwhile, the fraction of children receiving therapy for an off-label indication more than doubled, from 12% (39 of 322 total patients) to 29% (125 of 428 total patients). Privately insured patients were more likely to be treated for an off-label indication (13%; 119 out of 883 patients) than Medicaid patients (8%; 58 out of 706 patients; χ2[1] = 10.97, P = .00093). From 2013 to 2016, the proportion of children treated with GnRH agonists for an off-label indication notably increased. The number of children treated for precocious puberty modestly increased. Private insurance coverage was associated with higher rates of off-label use.

Novel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment.

Infertility affects one in six of the population and increasingly couples require treatment with assisted reproductive techniques. In vitro fertilization (IVF) treatment is most commonly conducted using exogenous FSH to induce follicular growth and human chorionic gonadotropin (hCG) to induce final oocyte maturation. However, hCG may cause the potentially life-threatening iatrogenic complication “ovarian hyperstimulation syndrome” (OHSS), which can cause considerable morbidity and, rarely, even mortality in otherwise healthy women. The use of GnRH agonists (GnRHas) has been pioneered during the last two decades to provide a safer option to induce final oocyte maturation. More recently, the neuropeptide kisspeptin, a hypothalamic regulator of GnRH release, has been investigated as a novel inductor of oocyte maturation. The hormonal stimulus used to induce oocyte maturation has a major impact on the success (retrieval of oocytes and chance of implantation) and safety (risk of OHSS) of IVF treatment. This review aims to appraise experimental and clinical data of hormonal approaches used to induce final oocyte maturation by hCG, GnRHa, both GnRHa and hCG administered in combination, recombinant LH, or kisspeptin. We also examine evidence for the timing of administration of the inductor of final oocyte maturation in relationship to parameters of follicular growth and the subsequent interval to oocyte retrieval. In summary, we review data on the efficacy and safety of the major hormonal approaches used to induce final oocyte maturation in clinical practice, as well as some novel approaches that may offer fresh alternatives in future.