Gonadotropin-releasing Hormone Agonist Therapy Research Articles

Disseminated Peritoneal Leiomyomatosis: A Case Report

Disseminated peritoneal leiomyomatosis is a benign disease with unknown etiology and an indolent course. The site of origin can be mesentery, omentum, or peritoneum. Diagnosis is challenging and more often lead to misdiagnosis. It can be managed both surgically or by nonsurgical options. The nonsurgical modalities include limiting hormonal exposure which has shown to decrease tumor size. Avoiding Oral contraceptive pills (OCP) and hormonal replacement therapy (HRT), and giving the patient gonadotrophin-releasing hormone agonist and aromatase inhibitor therapy have been found effective. However, there are no firm guidelines in the literature regarding the management of this condition. If left untreated, it can cause complications such as pain, bleeding, chronic constipation, and infertility. Prognosis is good but recurrence is possible after tumor resection. There is little evidence regarding the follow up of this condition.

Combined Androgen Blockade in Localized Prostate Cancer Treated With Definitive Radiation Therapy.

The addition of androgen deprivation therapy to radiation therapy (RT) improves survival in patients with intermediate- and high-risk prostate cancer (PCa), but it is not known whether combined androgen blockade (CAB) with a gonadotropin-releasing hormone agonist (GnRH-A) and a nonsteroidal antiandrogen improves survival over GnRH-A monotherapy. This study evaluated patients with intermediate- and high-risk PCa diagnosed in 2001 through 2015 who underwent RT with either GnRH-A alone or CAB using the Veterans Affairs Informatics and Computing Infrastructure. Associations between CAB and prostate cancer-specific mortality (PCSM) and overall survival (OS) were determined using multivariable regression with Fine-Gray and multivariable Cox proportional hazards models, respectively. For a positive control, the effect of long-term versus short-term GnRH-A therapy was tested. The cohort included 8,423 men (GnRH-A, 4,529; CAB, 3,894) with a median follow-up of 5.9 years. There were 1,861 deaths, including 349 resulting from PCa. The unadjusted cumulative incidences of PCSM at 10 years were 5.9% and 6.9% for those receiving GnRH-A and CAB, respectively (P=.16). Compared with GnRH-A alone, CAB was not associated with a significant difference in covariate-adjusted PCSM (subdistribution hazard ratio [SHR], 1.05; 95% CI, 0.85-1.30) or OS (hazard ratio, 1.02; 95% CI, 0.93-1.12). For high-risk patients, long-term versus short-term GnRH-A therapy was associated with improved PCSM (SHR, 0.74; 95% CI, 0.57-0.95) and OS (SHR, 0.82; 95% CI, 0.73-0.93). In men receiving definitive RT for intermediate- or high-risk PCa, CAB was not associated with improved PCSM or OS compared with GnRH alone.

Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis.

Endometriosis is known to have an impact on fertility and it is common for women affected by endometriosis to require fertility treatments, including in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI), to improve the chance of pregnancy. It has been postulated that long-term gonadotrophin-releasing hormone (GnRH) agonist therapy prior to IVF or ICSI can improve pregnancy outcomes. This systematic review supersedes the previous Cochrane Review on this topic (Sallam 2006). To determine the effectiveness and safety of long-term gonadotrophin-releasing hormone (GnRH) agonist therapy (minimum 3 months) versus no pretreatment or other pretreatment modalities, such as long-term continuous combined oral contraception (COC) or surgical therapy of endometrioma, before standard in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) in women with endometriosis. We searched the following electronic databases from their inception to 8 January 2019: Cochrane Gynaecology and Fertility Specialised Register of Controlled Trials, CENTRAL via the Cochrane CENTRAL Register of Studies ONLINE (CRSO), MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL). We searched trial registries to identify unpublished and ongoing trials. We also searched DARE (Database of Abstracts of Reviews of Effects), Web of Knowledge, OpenGrey, Latin American and Caribbean Health Science Information Database (LILACS), PubMed, Google and reference lists from relevant papers for any other relevant trials. Randomised controlled trials (RCTs) involving women with surgically diagnosed endometriosis that compared use of any type of GnRH agonist for at least three months before an IVF/ICSI protocol to no pretreatment or other pretreatment modalities, specifically use of long-term continuous COC (minimum of 6 weeks) or surgical excision of endometrioma within six months prior to standard IVF/ICSI. The primary outcomes were live birth rate and complication rate per woman randomised. Two independent review authors assessed studies against the inclusion criteria, extracted data and assessed risk of bias. A third review author was consulted, if required. We contacted the study authors, as required. We analysed dichotomous outcomes using Mantel-Haenszel risk ratios (RRs), 95% confidence intervals (CIs) and a fixed-effect model. For small numbers of events, we used a Peto odds ratio (OR) with 95% CI instead. We analysed continuous outcomes using the mean difference (MD) between groups and presented with 95% CIs. We studied heterogeneity of the studies via the I2 statistic. We assessed the quality of evidence using GRADE criteria. We included eight parallel-design RCTs, involving a total of 640 participants. We did not assess any of the studies as being at low risk of bias across all domains, with the main limitation being lack of blinding. Using GRADE methodology, the quality of the evidence ranged from very low to low quality. Long-term GnRH agonist therapy versus no pretreatment We are uncertain whether long-term GnRH agonist therapy affects the live birth rate (RR 0.48, 95% CI 0.26 to 0.87; 1 RCT, n = 147; I2 not calculable; very low-quality evidence) or the overall complication rate (Peto OR 1.23, 95% CI 0.37; to 4.14; 3 RCTs, n = 318; I2 = 73%; very low-quality evidence) compared to standard IVF/ICSI. Further, we are uncertain whether this intervention affects the clinical pregnancy rate (RR 1.13, 95% CI 0.91 to 1.41; 6 RCTs, n = 552, I2 = 66%; very low-quality evidence), multiple pregnancy rate (Peto OR 0.14, 95% CI 0.03 to 0.56; 2 RCTs, n = 208, I2 = 0%; very low-quality evidence), miscarriage rate (Peto OR 0.45, 95% CI 0.10 to 2.00; 2 RCTs, n = 208; I2 = 0%; very low-quality evidence), mean number of oocytes (MD 0.72, 95% CI 0.06 to 1.38; 4 RCTs, n = 385; I2 = 81%; very low-quality evidence) or mean number of embryos (MD -0.76, 95% CI -1.33 to -0.19; 2 RCTs, n = 267; I2 = 0%; very low-quality evidence). Long-term GnRH agonist therapy versus long-term continuous COC No studies reported on this comparison. Long-term GnRH agonist therapy versus surgical therapy of endometrioma No studies reported on this comparison. This review raises important questions regarding the merit of long-term GnRH agonist therapy compared to no pretreatment prior to standard IVF/ICSI in women with endometriosis. Contrary to previous findings, we are uncertain as to whether long-term GnRH agonist therapy impacts on the live birth rate or indeed the complication rate compared to standard IVF/ICSI. Further, we are uncertain whether this intervention impacts on the clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, mean number of oocytes and mean number of embryos. In light of the paucity and very low quality of existing data, particularly for the primary outcomes examined, further high-quality trials are required to definitively determine the impact of long-term GnRH agonist therapy on IVF/ICSI outcomes, not only compared to no pretreatment, but also compared to other proposed alternatives to endometriosis management.

Retrospective SHI (Statutory Health Insurances) real-world study on initial GnRH antagonist and agonist therapy for advanced prostate cancer: prescription patterns and hospital costs in Germany

Androgen deprivation therapy (ADT) plays a pivotal role in the treatment of advanced or metastasised prostate cancer (PCa). The aim of this health services research was to compare real-world data on the initial use of different GnRH agonists and antagonists (GnRHa) with regard to prescription patterns, hospitalisation rates and costs. Anonymised claims data from > 70 German health insurance funds between 2010 and 2015 (n = 4 205 227) were analysed (1 year pre-observation period, 1 index quarter with initial GnRHa prescription, ≥ 2 years of follow-up (FU)). The study population included 2382 PCa patients (mean age 75 years). Leuprolide (Leu) was prescribed most frequently (56.6 %). At initial GnRHa administration, 70 % of patients neither had lymph node nor distant metastases. Around 11.2 % of all patients stopped GnRHa treatment after the first prescription, 17.6 % switched their initial therapy to another substance after a mean of 457 days (median: 399 days); in the hybrid (hyb) group 100 days earlier on average than in the agonist group (p = 0.016). The prevalence ranking of the most common comorbidities was consistent over time: hypertension, hyperlipidaemia, cardiovascular disease (CVD) and diabetes. The prevalence of hypertension increased significantly in the agonist group (16.4 %) compared with the antagonist (6.9 %, p = 0.022) and hyb group (11.6 %, p = 0.006). With regard to CVD, there were no significant differences in the relative growth rate between the 3 combined therapy classes. In total, 23.9 % of all patients died within the 3-year FU. The mortality rate was lowest for triptorelin (Trp, 22.1 %) and highest for goserelin (Gos, 29.4 %, n.s.). In the index quarter, 26.4 % of patients had at least one inpatient hospitalisation [min-max: Trp 22.4 %; Gos 30.3 %], with an average length of hospital stay/patient of 3 days [Trp 2.4; Gos 4.5]. The annual hospitalisation rate was between 36.2 and 40.7 %, the average length of hospital stay in the entire FU was between 17.6 (Trp) and 20.8 days (hyb). The average hospital costs in the index quarter were approx. EUR 1200 [Trp 988; Gos 1803] and per FU year approx. EUR 3000. In the Trp cohort, total costs (index quarter + 3 years) were more than EUR 1000 below the average costs of EUR 9476 [Trp 8116; Leu 9779; n.s.]. This comparative retrospective analysis provides real-world information on initial GnRHa treatment for advanced prostate cancer, revealing differences in treatment patterns, hospitalisation rates and hospital costs in Germany.

GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression.

Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer. Degarelix (Firmagon), a gonadotropin-releasing hormone (GnRH) receptor antagonist differs from luteinizing hormone-releasing hormone (LHRH) agonists by avoiding "testosterone flare" and lower follicle-stimulating hormone (FSH) levels. The direct effect of degarelix and leuprolide on human prostate cancer cells was evaluated. In LNCaP, C4-2BMDVR, and CWR22Rv1 cells, degarelix significantly reduced cell viability compared with the controls (P ≤ 0.01). Leuprolide was stimulatory in the same cell lines. In C4-2B MDVR cells, degarelix alone or combined with abiraterone or enzalutamide reduced the AR-V7 protein expression compared with the control group. SCID mice bearing VCaP xenograft tumors were divided into 4 groups and treated with surgical castration, degarelix, leuprolide, or buffer alone for 4 weeks. Leuprolide slightly suppressed tumor growth compared with the vehicle control group (P > 0.05). Tumors in degarelix-treated mice were 67% of those in the leuprolide-treatment group but 170% larger than in surgically castrated ones. Measurements of intratumoral steroids in serum, tumor samples, or treated cell pellets by LC/MS confirmed that degarelix better decreased the levels of testosterone and steroidogenesis pathway intermediates, comparable to surgical castration, whereas leuprolide had no inhibitory effect. Collectively, our results suggested a selective mechanism of action of degarelix against androgen steroidogenesis and AR-variants. This study provides additional molecular insights regarding the mechanism of degarelix compared with GnRH agonist therapy, which may have clinical implications.

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.

Changes in body mass index in children on gonadotropin-releasing hormone agonist therapy with precocious puberty, early puberty or short stature.

Background The use of gonadotropin-releasing hormone agonists (GnRHa) for pubertal suppression has been associated with increased body mass index (BMI) in female subjects with central precocious puberty (CPP), although results have been so far conflicting. This study examined the effects of GnRHa therapy in both genders and in subjects treated for CPP, early puberty or short stature. Methods This was a longitudinal retrospective study of subjects followed at outpatient pediatric endocrinology clinics of an academic medical center from 2005 to 2014 receiving GnRHa therapy. Results At 12 months, subjects on depot GnRHa had a statistically significant increase in BMI standard deviation score (SDS) from baseline (0.13 ± 0.35, p < 0.02). Subjects with short stature (0.17 ± 0.34, p < 0.02) but not early or precocious puberty, and subjects with normal baseline BMI (0.18 ± 0.38, p < 0.02) had significant increases in BMI SDS; no significance was noted at 24 months. Male subjects did not have a significant increase in BMI SDS, whereas female subjects did (0.11 ± 0.36, p < 0.01). Conclusions Subjects with short stature, normal BMI at baseline and female sex had significant increases in BMI SDS at 12 months. This is the first study to show an increase in BMI SDS in children treated with GnRHa for short stature, and is one of the few studies to assess BMI changes in males.

Psychological effects of gonadotropin-releasing hormone agonist treatment in girls with central precocious puberty.

Objective This study was done to evaluate the emotional and behavioral status of precocious puberty patients and analyze the effect of gonadotropin-releasing hormone agonist (GnRHa) treatment. Methods Sixty-six female precocious puberty patients were enrolled prospectively for the study at Kangdong Sacred Heart Hospital of Hallym University Medical Center from September 2011 to December 2012 and self-administered questionnaire was completed during the GnRHa treatment initiation period and after 12 months from the first injection. The patients were evaluated using the Korean version of Child Behavior Checklist (K-CBCL) and Children's Depression Inventory (CDI). Results A total of 30.3% (n = 20) of the patients scored within the clinical range for one or more scales of K-CBCL at the initiation of GnRHa treatment, but only 10.6% (seven patients) were within the clinical range after 1 year of treatment. Average CDI scores of the patients decreased from baseline 6.5 ± 6.0 to 4.9 ± 4.7 after GnRHa therapy. Conclusions This study shows that both K-CBCL and CDI scores improved from baseline score ranges after 1 year of GnRHa treatment in female central precocious puberty patients while significant psychological problems of clinical range amongst them were not noted.

Abstract 1018: GnRH antagonists have direct inhibitory effects on castration-resistant prostate cancer via intracrine androgen and AR-V7 expression

Abstract Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer (PCa). Degarelix (Firmagon, Deg), a GnRH receptor antagonist demonstrated some advantages over the LHRH agonist Leuprolide (Leup) by avoiding “testosterone flare” and lower FSH levels. We compared the effect of Deg and Leup on prostate cancer (PC) cell progression in vitro and in vivo. GnRHR2 was readily detectable in PC cells. AR transcriptional activity reported by PSA-Luc assay was modulated by both Leup and Deg. In LNCaP and C4-2B MDVR cells, 20µM Deg significantly reduced the cell viability (p&amp;lt;0.01). GnRH-antagonist (alone or in combination with AA or Enza) counteracted the transactivation activity of AR by reducing AR-FL and AR variants at the protein level. In C4-2BMDVR cells, Deg reduced AR-V7 protein expression by 26 to 40% alone or combined with AA and Enza compared to control. Leup, however, enhanced variant expression. Deg reduced AR-variant levels from 17 to 41% in monotherapy or combinations compared to control. In mice, Leup slightly suppressed tumor growth compared to controls (p&amp;gt;0.05). However, tumors in Deg-treated group were 1.5-fold smaller than Leup-treated group but 1.7-fold bigger than surgical castration-group. Ki67 IHC staining confirmed the difference in tumor proliferation among groups. Measurements of intratumoral steroids by LC-MS from tumors, serum samples or cell pellets confirmed that Deg decreased the levels of testosterone and steroidogenesis pathway intermediates, comparable to surgical castration; while Leup had no inhibitory effect. Our results suggest a selective mechanism of action of Deg against AR-variants. The present study provides additional molecular insights regarding the mechanism of Deg compared to GnRH agonist therapy which may have clinical implications. Citation Format: Vito Cucchiara, Joy C. Yang, Chengfei Liu, Hans Adomat, Emma Guns, Martin E. Gleave, Allen C. Gao, Christopher P. Evans. GnRH antagonists have direct inhibitory effects on castration-resistant prostate cancer via intracrine androgen and AR-V7 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1018.

Comparing adult height gain and menarcheal age between girls with central precocious puberty treated with gonadotropin-releasing hormone agonist alone and those treated with combined growth hormone therapy.

PurposeThis study aimed to investigate the outcomes of gonadotropin-releasing hormone agonist (GnRHa) therapy with or without growth hormone (GH) therapy for girls with idiopathic central precocious puberty (CPP).MethodsThe medical records of 166 girls diagnosed with CPP from 2002 to 2017 were retrospectively reviewed. All included patients were treated with GnRHa for ≥36 months. Changes in height standard deviation score (SDS) for bone age, chronological age (CA), and predicted adult height (PAH) were assessed for the first three years of treatment. The final height gain SDS was calculated as the difference between the initial PAH SDS and adult height (AH) SDS; these were then compared between the GnRHa group (group A, n=135) and the combined GnRHa/GH group (group B, n=31).ResultsThe initial mean CA was 7.89 years. The mean menarcheal age was 13.12 years (group A, 13.1±0.99; group B, 13.18±0.58 years; P=0.755). PAH SDS at the start of GnRHa treatment and AH SDS were significantly lower in group B than in group A (PAH SDS: -2.20±0.83 vs. -3.19±0.84, P<0.001; AH SDS: 0.18±084 vs. -0.30±0.66, P=0.021). The increase in PAH SDS was higher in group B than in group A for the first three years of GnRHa treatment (1.66±0.66 vs. 2.35±0.93, P<0.001). The height gain SDS was significantly higher in group B than in group A (2.5±0.75 vs. 2.93±1.02, P=0.048). Younger age, higher PAH at the start of treatment, and a greater increase in PAH SDS during the first year of GnRHa treatment positively affected AH.ConclusionsThe combined GH group had more additional height gain than the GnRHa-alone group.

Desmoid Tumor at the Site of Endometriosis Surgery, Coincident with the Use of Oral Contraceptives

Desmoid tumors, which are often estrogen-dependent, frequently develop in surgical wounds. Here we report the case of 33-year-old woman with a 4-cm solid mass detected in her left adnexal area. She had previously undergone a laparoscopic surgery for endometriosis at age 29 years and had been using a combined oral contraceptive (COC) to prevent recurrence. The mass was diagnosed as a uterine myoma on the basis of ultrasonography and magnetic resonance imaging. Gonadotropin-releasing hormone agonist therapy for 3 months resulted in shrinkage of the tumor. Using a second laparoscopy, we identified a tumor originating from the sigmoid colon. The pathological diagnosis was desmoid tumor. Gynecologists should consider the possibility of desmoid tumor in patients who have been using COCs and undergone previous surgeries.

PS6K1 as an efficacy marker of GnRH agonist with premenopausal breast cancer.

Estradiol is a key factor for tumorigenesis and prognosis of hormone receptor-positive breast cancer. Adipocytes are one source of estradiol in patients with breast cancer. Recent studies have shown that phosphorylated ribosomal protein S6 kinase-1 plays a critical role in adipogenesis. Therefore, estrogen depletion therapy might have beneficial effects in phosphorylated ribosomal protein S6 kinase-1-positive breast cancer. This study was conducted to evaluate the value of phosphorylated ribosomal protein S6 kinase-1 as a marker for gonadotropin-releasing hormone agonist treatment, a form of estrogen depletion therapy, for premenopausal patients with HR-positive, human epidermal growth factor receptor 2-negative breast cancer. We reviewed the medical records of 296 premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary invasive breast cancer treated between 2008 and 2015. Phosphorylated ribosomal protein S6 kinase-1 positivity was defined by immunohistochemical staining scores of 1+, 2+ and 3+, whereas a score of 0 was considered negative. Phosphorylated ribosomal protein S6 kinase-1-positive tumors were found in 74.0% of the patients. In the phosphorylated ribosomal protein S6 kinase-1-positive group, disease-free survival of patients treated with a gonadotropin-releasing hormone agonist was significantly longer than that of patients treated without a gonadotropin-releasing hormone agonist (mean 106.7 months vs mean 91.1 months, P = 0.018). Phosphorylated ribosomal protein S6 kinase-1 is a potential biomarker for predicting the efficacy of gonadotropin-releasing hormone agonist therapy in premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.

Switching from a gonadotropin-releasing hormone (GnRH) agonist to a GnRH antagonist in prostate cancer patients: A systematic review and meta-analysis.

We sought to address whether there are clinical responses when patients who are failing gonadotropin-releasing hormone (GnRH) agonist therapy are switched to degarelix. Androgen-deprivation therapy remains the backbone of treatment for disseminated prostate cancer and may be achieved with orchiectomy, GnRH agonists, or degarelix, a GnRH antagonist. We conducted a systematic review and meta-analysis with a search of the BIOSIS Previews, Embase, International Pharmaceutical Abstracts, MEDLINE, and Google Scholar databases using key terms. Quantitative meta-analysis was performed to provide a pooled estimate of prostate specific antigen (PSA) response at three months. Thirteen studies were identified, eight of which were included in the qualitative and quantitative analyses. Patient characteristics were broadly similar between the studies. Out of 155 patients across all included studies, 20 had stable PSA after the switch (12.9%), 14 had a 10-30% decrease in PSA (9.0%), three had a 30-50% decrease (1.9%), and 13 had a more than 50% decrease (8.4%). Random effects meta-analysis of these data demonstrated a pooled response rate of 27.75% (95% confidence interval 18.9-36.5%; I2=7.9%). Changes in testosterone levels following the switch could not be quantitatively assessed due to lack of sufficient data. Our results suggest that a switch to GnRH antagonist following progression on a GnRH agonist may result in a stable or decreased PSA at three months in about 30% of patients. This information should be considered among the potential options to discuss with patients with a rising PSA on GnRH agonist therapy.

SAT-291 Gonadotropin Releasing Hormone Agonist Therapy Improves Hyperandrogenism in an Adolescent with Type A Insulin Resistance Syndrome

Background: Type A insulin resistance (IR) is a form of severe IR due to heterozygous mutations in the insulin receptor gene. It presents with acanthosis nigricans, IR, and hyperandrogenism in the absence of obesity or lipodystrophy. Treatment aims to decrease androgens and improve insulin sensitivity. We describe the first adolescent patient with Type A IR having successful resolution of clinical and biochemical hyperandrogenism during GnRH agonist treatment. Clinical Case: An adolescent female was referred for secondary amenorrhea and hirsutism. She had a normal BMI and prominent hirsutism. Laboratories revealed LH 11.6 mIU/mL, FSH 4.2 mIU/mL, elevated total and free testosterone 96 and 2.21 ng/dL, respectively, normal glucose and HbA1c (5.6 %). She was diagnosed with PCOS and referred for OGTT as per standard care in our PCOS program. Fasting glucose was 80 mg/dL with fasting insulin level of 63.1 mIU/mL. The 2-hour glucose was 199 mg/dL with insulin level of 1480 uIU/mL. Pelvic ultrasound showed enlarged ovaries. Due to hyperandrogenism with severe IR, dysglycemia, and normal lipids, Type A IR was entertained. Genetic testing revealed a heterozygous mutation in the insulin receptor gene for a missense variant pointing towards the diagnosis of Type A IR.The patient had been prescribed treatment with metformin and spironolactone although her adherence to taking her medications was sporadic. She was then trialed on an oral contraceptive which led to monthly menstrual cycles. However, her total and free testosterone levels remained elevated at 139 and 3.06 ng/dL respectively. Her hirsutism had not improved which led to prominent depression. Twelve months from her initial presentation, the decision was made to try treatment with leuprolide and she subsequently began 11.25 mg/month intramuscular injections. She continued metformin as well. One month after her first leuprolide injection, follow-up labs showed normalization of total and free testosterone levels, 7.1 and 0.16 ng/dL respectively, and decreased LH of 0.3 mIU/mL. Hirsutism was markedly improved. Five months into leuprolide therapy, repeat OGTT still showed impaired glucose tolerance and severe IR (0-minute glucose of 91 mg/dL, insulin of 90.9 uIU/mL; 2-hour glucose of 181 mg/dL, insulin of 1038 uIU/mL) along with increased HbA1c (6.4%). Conclusion: We describe an adolescent patient with Type A IR who experienced resolution of hyperandrogenism during GnRH agonist treatment. The bidirectional relationship between insulin and hyperandrogenism including insulin having LH-independent effects on steroidogenesis has been debated. Given our patient’s reduction in testosterone and hirsutism despite persistent hyperinsulinism, this case challenges the idea that insulin increases steroidogenesis independently of gonadotropins. GnRH agonist therapy should be considered to improve hyperandrogenism in severe cases of IR.

Comparison of long-term use of combined oral contraceptive after gonadotropin-releasing hormone agonist plus add-back therapy versus dienogest to prevent recurrence of ovarian endometrioma after surgery

ObjectiveThe aim of this study was to compare long-term use of combined oral contraceptive (COC) after gonadotropin-releasing hormone (GnRH) agonist plus add-back therapy with dienogest (DNG) treatment as medical treatments after surgery for ovarian endometrioma. MethodsThis prospective cohort study analyzed 52 reproductive-aged women who underwent surgery for ovarian endometrioma and received postoperative medical treatment with either COC after GnRH agonist (n = 20) or DNG (n = 32) for 24 months. Changes in quality-of-life (QOL) and bone mineral density (BMD) were compared according to treatment. In addition, recurrence of pain and lesions were compared. ResultsBaseline characteristics did not differ in demographic profiles and factors associated with endometriosis or QOL. During 24 months of treatment, no differences in any component of QOL were found between the two groups. BMD at the lumbar spine significantly decreased after the first 6 months of treatment in both COC after GnRH agonist (−3.5%) and DNG (−2.3%) groups, but the groups did not differ statistically. After 6 months, further decrease in BMD was not observed until 24 months in both groups. In addition, no cases of pain or endometrioma recurrence were found. ConclusionOur results suggest that long-term use of COC after GnRH agonist plus add-back therapy is comparable to dienogest as a long-term postoperative medical treatment for endometriosis.

Thermal manipulation and GnRHa therapy applied to the reproduction of lambari-do-rabo-amarelo, Astyanax altiparanae females (Characiformes: Characidae) during the non-breeding season

Lambari-do-rabo-amarelo Astyanax altiparanae in the wild reproduce during spring and summer, but females undergo vitellogenesis throughout the year, including the non-spawning winter period when water temperatures are low. The present study investigated the physiological role of temperature modulation on the hypothalamus-pituitary-gonads axis of lambari during winter, as well as the effects of gonadotropin releasing hormone agonist (GnRHa) therapy. Captive females were exposed to two different temperatures (20 °C and 27 °C) and were injected weekly with GnRHa for 21 days during winter (Control, CTR; Low dose; LD and high dose of GnRHa, HD). At the end of the 21-days period gonadosomatic index (GSI), oocyte stage of development and theoretical fecundity were evaluated, together with plasma levels of 17β-estradiol (E2). Gene expression of the two pituitary gonadotropins follicle-stimulating hormone (fshβ) and luteinizing hormone (lhβ), as well as hepatic vitellogenin-A (vtgA) expression were also analyzed. At the end of the experimental period, females from the six different experimental conditions were induced to spawn using human chorionic gonadotropin (hCG). Spawning performance parameters and plasma levels of the maturation inducing steroid (MIS) were analyzed. Gene expression of fshβ did not change with temperature manipulation, but females exposed to 27 °C and supplemented with a HD of GnRHa exhibited an increased fshβ gene expression, associated with higher E2 levels. The higher water temperature alone was able to increase E2 levels. At both water temperatures GnRHa injections induced a decrease in E2 levels. GnRHa injected females had a lower vtgA gene expression levels at 20 °C. Even with differences in the gene expression of gonadotropins among the various temperature/GnRHa treatments, GSI and oocyte diameter did not change, but GnRHa enhanced the number of vitellogenic oocytes at 20 °C. The reproductive performance of lambari induced to spawn with hCG was better after the combined treatment with GnRHa and summer temperature.

Pelvic Ultrasound in Diagnosing and Evaluating the Efficacy of Gonadotropin-Releasing Hormone Agonist Therapy in Girls With Idiopathic Central Precocious Puberty.

Background and Objective: Idiopathic central precocious puberty (ICPP) is characterized by early pubertal changes, the acceleration of growth velocity, and rapid bone maturation that often results in reduced adult height. Gonadotrophin-releasing hormone agonist (GnRHa) is currently considered to be an effective therapeutic agent. At present, GnRH stimulation test is adopted as a gold standard for the diagnosis of ICPP and the efficacy evaluation of GnRHa therapy. However, it is difficult to operate in practice due to the cumbersome procedures and multiple blood samples required. This study was conducted to establish the value of pelvic ultrasound in diagnosing ICPP and evaluating the efficacy of GnRHa therapy.Materials and Methods: One hundred and twenty-two girls with ICPP (ICPP group) were enrolled in the study. Pelvic ultrasound and levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were examined before and after GnRHa therapy for 3 months. Eighty normal prepubertal girls were enrolled as the control group. The difference in pelvic ultrasound parameters between the ICPP group before GnRHa therapy and the control group was compared by independent-sample t-test, while paired t-test for ICPP group before and after GnRHa therapy. Receiver operating characteristic (ROC) curve was used to explore the optimal pelvic ultrasound parameters for diagnosing ICPP. Pearson correlation analysis was performed between the pelvic ultrasound parameters and serum sexual hormone level.Results: The pelvic ultrasound parameters (length of the uterine body, anteroposterior diameter of the uterine body, transverse diameter of the uterine body, volume of the uterine body, uterine body-cervix ratio, length of the ovary, transverse diameter of the ovary, anteroposterior diameter of the ovary, volume of the ovary, number of increased follicles and maximum diameter of the follicle) in the ICPP group before GnRHa therapy were significantly larger than those of the control group (P < 0.05). All the above pelvic ultrasound parameters in the ICPP group were significantly decreased after GnRHa therapy compared with those before treatment (P < 0.05). The volume of the uterine body had the largest area under the ROC curve in differentiating between patients with ICCP and the control group. Pelvic ultrasound parameters were significantly correlated with serum sexual hormone levels (P < 0.05).Conclusion: This study indicates pelvic ultrasound is a simple and reliable tool to diagnose ICPP and evaluates the efficacy of GnRHa therapy by dynamically observing the morphology of internal genitalia. The volume of uterine body was the best ultrasound parameter to distinguish patients with ICPP from normal girls.

Long-term GnRH agonist therapy before in vitro fertilization (IVF) for improving fertility outcomes in women with endometriosis

Long-term GnRH agonist therapy before in vitro fertilization (IVF) for improving fertility outcomes in women with endometriosis

GONADOTROPIN-RELEASING HORMONE AGONISTS IN ENDOMETRIOSIS TREATMENT AND IN VITRO FERTILIZATION

Endometriosis is a chronic disease of unknown etiology defined as the presence of ectopic endometrial and it affects approximately 10% of women in reproductive age. Sequelae of endometriosis are represented by infertility and chronic pelvic pain. GnRHa (gonadotropin releasing hormone) represent one of one medical approaches that were tried for endometriosis treatment.Choosing between agonists and antagonists means to compare risks and benefits. The antagonists of GnRH are less used because of their many side effects. GnRH agonists have many advantages such as: lower cost, less side effects and shorter treatment. The GnRH therapy is not only useful in the treatment of endometriosis but also in IVF. Nowadays, researches shows that the laparoscopic ablation is as efficient as the GnRH agonists therapy, but also a postoperative therapy with GnRH is indicated. Several protocols are actually available for IVF and Embrio Transfer. Also recent researches proved that a postoperative therapy with GnRH agonists in patients with endometriosis associated infertility raised the pregnancy rate and reduced pelvic pain.GnRH agonists can be considered as a first line therapy when severe pain is involved or second-line treatment in endometriosis in case of failure of therapy with oral contraceptives or progestins. GnRH is more efficient in the protocol of FIV than in the treatment of endometriosis.

Assessment of ovarian reserve after cystectomy versus 'one-step' laser vaporization in the treatment of ovarian endometrioma: a small randomized clinical trial.

STUDY QUESTIONDoes CO2 laser vaporization offer better results in treating endometrioma in terms of ovarian reserve preservation compared to traditional cystectomy?SUMMARY ANSWERAssessing both antral follicle count (AFC) and serum anti-Müllerian hormone (AMH) levels as measures of ovarian reserve, the results suggest that CO2 technology may be an alternative treatment for endometrioma, causing minimal damage to adjacent healthy ovarian tissue.WHAT IS KNOWN ALREADYExcisional surgery has been questioned as an ideal surgical approach for endometriomas because it is associated with potential reduction of ovarian reserve. Recently, vaporization with CO2 laser in-line-of-sight, according to the ‘three-step procedure’, has been proposed as the best method to preserve ovarian function. However, no randomized controlled trials have been conducted to compare cystectomy and ‘one-step’ CO2 fiber laser vaporization (without GnRH agonist therapy) with respect to the ovarian reserve.STUDY DESIGN, SIZE, DURATIONA multicentre randomized clinical trial including 60 patients was performed between July 2017 and February 2018. Computerized randomization was conducted to allocate them in a proportion of 1:1 either to Group 1 (laparoscopic stripping: cystectomy) or Group 2 (CO2 laser vaporization). Patients in Group 1 underwent a standardized laparoscopic stripping technique; patients in Group 2 underwent drainage of the cyst content, biopsy and vaporization of the internal wall with a CO2 fiber laser. Patients underwent pelvic ultrasound examination to determine the AFC and blood sampling to determine AMH levels before surgery and at 1- and 3-month follow-up.PARTICIPANTS/MATERIALS, SETTING, METHODSPatients undergoing surgery for symptomatic endometriomas (infertility and/or pelvic pain) larger than 3 cm were randomized in two groups according to the surgical technique. Patients aged ≥40 years, or with deep infiltrating endometriosis/adenomyosis, or previously submitted to surgical procedures on the ovaries or to hysterectomy were excluded from the study. The primary endpoint was the comparison of intra-group AFC changes before and after surgery (ΔAFC) between the two groups (ΔAFC Group 1 versus ΔAFC Group 2). The secondary endpoint was the modification of serum AMH before and after surgery (ΔAMH) between the two groups (ΔAMH Group 1 versus ΔAMH Group 2).MAIN RESULTS AND THE ROLE OF CHANCEThe AFC of the operated ovary was significantly increased in Group 2 (laser vaporization) compared with Group 1 (cystectomy) after surgery (Group 1: from 4.1 ± 2.2 [mean ± SD] at baseline to 6.3 ± 3.5 at 3-month follow-up; 95% CI: 0.9–4; Group 2: from 3.6 ± 1.9 at baseline to 8.6 ± 4.2 at 3-month follow-up; 95% CI: 2.8–7.1; P = 0.016); serum AMH levels were significantly reduced at 3 months in Group 1 (from 2.6 ± 1.4 ng/mL at baseline to 1.8 ± 0.8 ng/mL at 3-month follow-up; 95% CI: −1.3 to −0.2; P = 0.012) compared with no reduction in Group 2 (from 2.3 ± 1.1 ng/mL at baseline to 1.9 ± 0.9 ng/mL at 3-month follow-up; 95% CI: −1 to −0.2; P = 0.09).LIMITATIONS, REASON FOR CAUTIONThe key limitations of the trial were the low accuracy of AFC in estimating the ovarian reserve in ovaries with endometriomas, the limited study size and the relatively short follow-up, which do not allow us to draw definitive conclusions.WIDER IMPLICATIONS OF THE FINDINGSThe present study suggests that CO2 technology may treat endometrioma with minimal damage to the adjacent healthy ovarian tissue; however, this study should be considered as a preliminary clinical trial, intended to stimulate future larger trials to address this clinically relevant issue.STUDY FUNDING/COMPETING INTEREST(S)None.TRIAL REGISTRATION NUMBERClinicalTrials.gov NCT03227640.TRIAL REGISTRATION DATE9 July 2017.DATE OF FIRST PATIENT’S ENROLLMENT24 July 2017.