GnRH Analogue Therapy Research Articles

A phase 1/2a, open-label, multicenter study of intramuscular (IM) abiraterone decanoate (PRL-02) depot in patients with advanced prostate cancer (NCT04729114).

TPS5090 Background: PRL-02 is a long-acting IM formulation of a lipophilic abiraterone prodrug being developed for the treatment of patients with metastatic castration-sensitive (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). In nonclinical models, PRL-02 has a longer effective half-life and duration of action compared to oral abiraterone acetate (AA), due to slow release of the prodrug into circulation. PRL-02 is expected to provide greater abiraterone bioavailability and less variability in pharmacokinetics than oral AA. Based upon results in non-human primate models, PRL-02 should provide efficacy (e.g., testosterone [T] suppression) comparable to oral AA, but with lower abiraterone peak plasma concentrations and overall exposures, potentially leading to a superior therapeutic index and safety profile. The current trial is a phase 1/2a, open-label, dose escalation and subsequent dose expansion study of PRL-02 in men with metastatic prostate cancer. Study Objectives: The primary objective of this study is to determine a recommended phase 2 dose (RP2D) of PRL-02 that provides adequate T suppression up to 84 days. The secondary objectives of this study include the evaluation of safety and tolerability, the pharmacokinetic profile following IM administration and the pharmacodynamic effects of PRL-02. Methods: The phase 1 portion (Dose Escalation) is a standard 3+3 design intended to identify a RP2D that adequately suppresses T up to 84 days. The phase 2a portion (Dose Expansion) will confirm the safety, tolerability and pharmacodynamic effects of the RP2D. Main inclusion criteria are orchiectomy or ongoing GnRH analogue therapy for at least 3 months and a screening T level <50 ng/dL but >2 ng/dL. Prior treatment with abiraterone (or any other CYP17 inhibitor) and current treatment with enzalutamide or any other AR blocking agents are excluded. Patients will undergo scheduled periodic assessments of T levels. Patients may remain on study unless their T is >1 ng/dL on two sequential determinations starting on Day 28 through Day 77 of the first dosing cycle. In phase 1, three patients will initially be enrolled at each dose. The starting dose is 180 mg (i.e., 1.0 mL of PRL-02) and dose escalation will proceed with a modified Fibonacci sequence. If none of the patients in a cohort experience a dose-limiting toxicity (DLT), the dose will be escalated in the next cohort of 3 patients. A DLT is defined as a drug-related Grade 3 or higher toxicity on the Common Terminology Criteria for Adverse Events v5.0, or meets drug-induced liver injury criteria, occurring during the first 28 days following the first dose. In phase 2a, 12 mCSPC and 12 mCRPC patients will be enrolled to receive up to 4 cycles of PRL-02 at the RP2D. The results of this phase 1/2a study will be presented at a future ASCO conference. Clinical trial information: NCT04729114.

Ovarian Hyperandrogenism and Response to Gonadotropin-releasing Hormone Analogues in Primary Severe Insulin Resistance.

ContextInsulin resistance (IR) is associated with polycystic ovaries and hyperandrogenism, but underpinning mechanisms are poorly understood and therapeutic options are limited.ObjectiveTo characterize hyperandrogenemia and ovarian pathology in primary severe IR (SIR), using IR of defined molecular etiology to interrogate disease mechanism. To extend evaluation of gonadotropin-releasing hormone (GnRH) analogue therapy in SIR.MethodsRetrospective case note review in 2 SIR national referral centers. Female patients with SIR with documented serum total testosterone (TT) concentration.ResultsAmong 185 patients with lipodystrophy, 65 with primary insulin signaling disorders, and 29 with idiopathic SIR, serum TT ranged from undetectable to 1562 ng/dL (54.2 nmol/L; median 40.3 ng/dL [1.40 nmol/L]; n = 279) and free testosterone (FT) from undetectable to 18.0 ng/dL (0.625 nmol/L; median 0.705 ng/dL [0.0244 nmol/L]; n = 233). Higher TT but not FT in the insulin signaling subgroup was attributable to higher serum sex hormone–binding globulin (SHBG) concentration. Insulin correlated positively with SHBG in the insulin signaling subgroup, but negatively in lipodystrophy. In 8/9 patients with available ovarian tissue, histology was consistent with polycystic ovary syndrome (PCOS). In 6/6 patients treated with GnRH analogue therapy, gonadotropin suppression improved hyperandrogenic symptoms and reduced serum TT irrespective of SIR etiology.ConclusionSIR causes severe hyperandrogenemia and PCOS-like ovarian changes whether due to proximal insulin signaling or adipose development defects. A distinct relationship between IR and FT between the groups is mediated by SHBG. GnRH analogues are beneficial in a range of SIR subphenotypes.

Gonadotropin releasing hormone analogue therapy in girls with idiopathic precocious puberty/early-fast puberty: dynamics in adiposity indices, eating habits and quality of life.

The impact of gonadotropin-releasing-hormone-analogue (GnRHa) treatment on weight and body composition is controversial. Exploring the nutritional, psychological patterns of this population may aid to clarify this propensity to gain weight. This prospective observational study aimed to evaluate longitudinal changes in adiposity, nutrition and quality of life in girls with central precocious/early-fast puberty (CPP/EFP) during GnRHa treatment. Thirty-two GnRHa-treated girls with CPP/EFP and 27 prepubertal girls (7-10years) were included in theanalysis. Outcome measures assessed at baseline forCPP/EFP and the control groups and during up to two yearsof GnRHa treatment for the CPP/EFP group, included anthropometrics, body-composition, basal-metabolic-rate (BMR), 3-day food-diaries, child eating-behavior questionnaire, and pediatric quality-of-life questionnaire (PedsQL). Girls with CPP/EFP had higher pretreatment BMI-SDS, fat percentages, waist circumference and waist-per-height (p<0.01 for all), and lower psychosocial functioning than controls (p<0.05). Changes in anthropometric and body composition measurements indicated a gradual increase in adiposity and a decrease in muscle mass (p<0.001 for all). Dynamics in body composition could not be explained by the participants' self-reported dietary patterns and physical activity levels or by themeasured BMR, which revealed an adequate and relatively low energy intake as compared to energy requirements. A gradual decline in physical functioning (PedsQL) after one and twoyears of GnRHa treatment was observed (p<0.001). Our findings highlight the need for comprehensive surveillance in girls with CPP/EFP. Dynamics in weight status and body composition during GnRHa treatment indicate the need for tailored nutritional and physical activity counseling aimed at preventing obesity.

Perils of prolonged ovarian suppression and hypoestrogenism in the treatment of breast cancer: Is the risk of treatment worse than the risk of recurrence?

Premenopausal breast cancer is usually estrogen receptor positive, and hence, prolonged ovarian suppression by medical or surgical means to prevent recurrence has become standard of management to improve disease-free survival. Ten-year adjuvant tamoxifen therapy is associated with 3.5% fewer recurrences compared to five years. The SOFT trial demonstrated small but statistically significant incremental improvements in long-term disease-free survival by the addition of gonadotropin-releasing hormone analog treatment (triptorelin) to an aromatase inhibitor (exemestane). Profound hypoestrogenism in the premenopausal age group may not be well tolerated due to a host of bothersome side effects (primarily vasomotor symptoms, musculoskeletal complaints, genitourinary syndrome of menopause, and mood disorders). Prolonged hypoestrogenism in younger women is associated with premature development of cardiovascular disease, bone loss, cognitive decline, and all-cause mortality. This paper explores multi-system consequences of prolonged hypoestrogenism in premenopausal women derived from studies of women with and without breast cancer. Pretreatment counseling in estrogen receptor positive breast cancer should emphasize the benefit of prolonged estrogen suppression on breast cancer recurrence and established risks of lifelong hypoestrogenism on quality of life and all-cause mortality. Future genomic research may help identify the best candidates for extended ovarian suppression to avoid treating many women when only a minority benefit.

Fertility preservation in patients receiving gonadotoxic therapies for systemic autoimmune diseases in Japan

Objectives Gonadotoxic therapies, mainly cyclophosphamide, are used for the treatment of various systemic autoimmune diseases. In Japan, the number of patients who undergo gonadotoxic therapy for autoimmune diseases, fertility preservation procedures performed in these patients, and problems associated with performing such procedures have not been reported. This study was performed to address these issues. Methods A questionnaire was sent to Certified Educational Facilities of the Japanese Society of Rheumatology, and a single rheumatologist at each center completed the questionnaire. Results A total of 63 facilities completed the questionnaire. Between April 2014 and March 2019, a total of 1302 men and premenopausal women had received gonadotoxic therapies for systemic autoimmune disease. Nearly half of the respondents reported that gonadotropin releasing hormone analog therapy was available in their area. However, the availability of other fertility preservation procedures was limited, and the number of patients undergoing fertility preservation procedures was limited. 85.7% of the respondents responded that measures to preserve fertility in patients receiving gonadotoxic therapies for autoimmune diseases were inadequate. Conclusions A substantial number of patients are receiving gonadotoxic therapies for the treatment of autoimmune diseases in Japan, and those patients may not be receiving adequate care regarding their fertility.

A Case of Nonalcoholic Steatohepatitis in Central Precocious Puberty Aggravated by Gonadotropin-releasing Hormone Analog

We report the case of a girl with central precocious puberty (CPP) and nonalcoholic steatohepatitis (NASH) aggravated by gonadotropin-releasing hormone analog (GnRHa). She was diagnosed with CCP and began treatment with GnRHa at the age of 8 years and 9 months. She already had mild liver dysfunction and was obese at that time; however, liver dysfunction was aggravated during GnRHa initiation. Her liver dysfunction improved after the discontinuation of GnRHa. Liver biopsy was performed twice during GnRHa initiation and findings suggested NASH. In this case, NASH may have been aggravated by the mechanism of estrogen suppression by GnRHa besides obesity. In conclusion, NASH should be ruled out in obese CPP patients with abnormal liver function before starting GnRHa therapy. CPP patients treated with GnRHa require close examination for the early diagnosis of NASH or its progression.

Aromatase Inhibitor Increases the Height of Patients with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Patients with 21-hydroxylase deficiency (21OHD) typically suffer from short stature due to early exposure to adrenal-derived androgen. The aim of this study was to investigate whether adding aromatase inhibitor (AI) to gonadotropin-releasing hormone (GnRH) analogue (GnRHa) and recombinant human growth hormone (rhGH) therapy would increase the height of patients with 21OHD. This retrospective study included 15 patients with 21OHD. The AI/GnRHa/rhGH group consisted of 9 patients, who were treated with AI for at least 12 months in addition to GnRHa/rhGH therapy. The other 6 patients, who received GnRHa/rhGH therapy only, were defined as the GnRHa/rhGH group. Patients were 6.3±1.7 years old, and 7/15 of patients were male. Among them, 12 patients exhibited simple virilization type, and 3 patients were salt-wasting type. In the AI/GnRHa/rhGH group, patients were 6.6±2.0 years old when AI therapy was initiated. Their bone age was 5.9±2.2 years ahead of their chronological age. They received the AI letrizole for an average of 25.1 months (range, 12 to 37 months). In the GnRHa/rhGH group, the patients were 5.9±0.9 years old when they started GnRHa/rhGH therapy, and their bone age was 6.2±1.7 years ahead of their chronological age. Patients received GnRHa/rhGH therapy for an average of 24.5 months (range, 12 to 41 months). The predicted final height increased from 145.9±7.9 to 158.0±8.4 cm in the AI/GnRHa/rhGH group (P = .001, compared with the baseline) and from 141.7±2.7 to 150.7±4.7 cm in the GnRHa/rhGH group (P = .001, compared with the baseline). Bone age progression was 0.15±0.05 per year versus 0.44±0.13 per year in the two groups, respectively (P = .032). Addition of letrizole to GnRHa/rhGH therapy significantly delays bone maturation and may increase the final height.

OR27-04 Risk Factors For Low Baseline Bone Mineral Density In Gender Diverse Youth

BackgroundSex steroids such as testosterone and estrogen are necessary for accumulation of bone mass. Transgender youth treated with gonadotropin releasing hormone analogues (GnRHa) to block natal puberty for gender-affirming care are at risk of low bone mineral density (BMD). Previous studies indicate that transfemale patients assigned male at birth (AMAB) have low BMD at baseline, during and after GnRHa treatment despite cross hormone treatment. Transmales assigned female at birth (AFAB), however, have normal BMD at baseline that decreases upon GnRHa treatment, with normalization upon cross hormone therapy. The reason(s) for the low baseline BMD in transfemales is unclear. We aimed to assess the baseline characteristics of transgender youth at a single multidisciplinary gender clinic prior to medical intervention and determine factors associated with BMD.MethodsThis is a retrospective chart review of patients <19 years old evaluated in the gender clinic. Dual-energy x-ray absorptiometry (DXA) scans were obtained prior to initiation of GnRHa or cross-hormone therapy per Endocrine Society guidelines for the treatment of gender dysphoria. We included patients with DXA scans completed prior to initiation of treatment with GnRHa or cross gender hormones and excluded those with concurrent medical diagnoses that may affect bone density. Data collected were bone mineral density (BMD) Z-scores, anthropometric data, vitamin D and calcium levels, and calcium intake. Multivariable linear regression models were used to assess the impact of vitamin D levels, height Z-score, weight Z-score, and BMI Z-score on subtotal body BMD Z-score, adjusted for sex assigned at birth and age.ResultsSixty-four patients were included in our analysis. Of these, 73% were AMAB and 27% AFAB. Gender identity was male in 14%, female in 44%, and non-binary in 42%. Average height Z-score was 0.12, weight Z-score 0.27, and BMI Z-score 0.22 (using sex assigned at birth). Subtotal body BMD Z-scores were greater than zero in 11%, between zero and greater than -2 in 59%, and less than or equal to -2 in 30% of tested patients. AMAB patients had lower BMD Z-scores compared to those AFAB (p<0.05 for all Z-scores). There was a positive association with BMI, height, and weight Z-scores and increasing BMD Z-scores after adjusting for sex assigned at birth and age (p<0.05 for all Z-scores). Patients who consumed <2 servings of calcium per day had lower BMD Z-scores (p<0.05 for all Z-scores). Average vitamin D level was 24 ng/ml (+/- 9.5 SD) with no significant association with BMD Z-scores (adjusted for sex assigned at birth).ConclusionsPatients AMAB and patients with calcium intake of < 2 servings/day are associated with lower baseline BMD in a cohort of adolescents seen in a multidisciplinary gender clinic. Height, weight, and BMI are associated linearly with BMD Z-score, following patterns previously described in other populations.

Efecto sobre la talla en niñas con pubertad precoz central de diagnóstico tardío tratadas con análogos de GnRH

Objetivo: evaluar el efecto de los análogos de GnRH sobre la predicción de talla final adulta en niñas con pubertad precoz central de diagnóstico tardío. Materiales y métodos: estudio descriptivo, retrospectivo. Se incluyeron niñas atendidas entre 2012 y 2018 en la Unidad de Endocrinología Pediátrica del Hospital Cayetano Heredia con diagnóstico de pubertad precoz central idiopática de diagnóstico tardío. Se realizó evaluación antropométrica, evaluación de estadío Tanner y determinación de edad ósea con el método de Greulich y Pyle, estimando la predicción de talla final adulta mediante el método de Bayley Pinneau antes y después del tratamiento con análogos de GnRH. Se realizó t de student para comparar la predicción de talla antes y después del tratamiento. Se consideró significativo un p&lt; 0,05. Resultados: se incluyeron 23 niñas con edad cronológica media de 8,4 ± 0,4 años y una edad ósea de 10,7 ± 0,8 años al ingreso. El 83,9% de las pacientes tuvieron exceso de peso y el 74,0% estadio Tanner 3 al diagnóstico. El tiempo promedio de tratamiento con análogos de GnRH fue de 20,5 ± 8,4 meses. El efecto del tratamiento calculado con la diferencia de predicción de talla final adulta menos predicción de talla inicial fue de 2,5 ± 4,1 cm (p&lt;0,01). Conclusión: las niñas con diagnóstico de pubertad precoz central de diagnóstico tardío muestran un discreto beneficio sobre la predicción de talla final adulta, por lo que la terapia a esta edad debe ser individualizada.

Effect of gonadotropin-releasing hormone analog on ovarian reserve in children with central precocious puberty.

Gonadotropin-releasing hormone analog (GnRHa) is the mainstream treatment for central precocious puberty (CPP). However, its effect on the ovarian reserve in CPP girls remains unclear. This study was designed to analyze the changes of ovarian reserve in CPP girls during and after GnRHa therapy, with an attempt to achieve the early prediction of the effect of GnRHa treatment on the reproductive function of CPP girls, eliminate the concerns of girls and their parents on the potential toxicities of GnRHa treatment, and improve the patients' adherence to treatment. The clinical data of 383 CPP girls who had been treated with GnRHa for more than half a year in our hospital within the past 10 years were retrospectively analyzed. The serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), FSH/LH, estradiol (E2), and anti-Müllerian hormone (AMH) levels, as well as uterine and ovarian volumes, were measured before treatment, at various time points during treatment, and after menarche or resumption of menses (ROM) after treatment discontinuation. GnRHa treatment had similar effects on uterine/ovarian volumes, LH, FSH, and E2: these indicators were significantly inhibited during the treatment (compared with the pre-treatment levels), gradually returned normal after drug withdrawal, and became significantly higher than the pre-treatment levels after menarche or ROM (both P<0.05 for LH and FSH levels and P>0.05 for E2 and uterine/ovarian volumes). AMH level transiently decreased 6 months after GnRHa treatment (2.70±1.76 vs. 3.56±2.21, t=3.227, P=0.001); however, the AMH levels after 12, 18, and 24 months of treatment were similar to the pre-treatment level (P>0.05). The FSH/LH ratio significantly increased after 12 months of treatment compared with the pre-treatment (P<0.05), and the FSH/LH ratio after menarche or ROM was significantly lower than the pre-treatment value (1.34±0.66 vs. 5.69± 6.85, t=3.068, P=0.006). When FSH/LH and FSH level were used to reflect the ovarian reserve, the proportion of CPP girls with normal ovarian reserve after menarche or ROM was higher than at pre-treatment (FSH/LH ratio: 100% vs. 46%, χ2=27.586, P<0.05; FSH level: 100% vs. 99%, P>0.05). When AMH level was used to reflect the ovarian reserve, the proportion of CPP girls with normal ovarian reserve after menarche or ROM was slightly lower than at pre-treatment (87% vs. 93%, P>0.05). The ovarian reserve of CPP girls is somehow inhibited during GnRHa treatment but is gradually restored after drug discontinuation. Thus, GnRHa treatment does not affect ovarian reserve in CPP children after the treatment stops.

The alteration of IGF-1 levels and relationship between IGF-1 levels and growth velocity during GnRH analogue therapy

Background Some studies have examined the effect of gonadal suppression on insulin-like growth factor-1 (IGF-1) levels and the growth velocity (GV) with conflicting results. Methods Forty-four girls treated with gonadotropin-releasing hormone analogue (GnRHa) for central precocious puberty (CPP) were included in the study. IGF-1 levels were examined at the beginning and after 12 months of treatment. Results IGF-1 and IGF-1 standard deviation score (SDS) according to chronological age (CA-IGF-1 SDS) at diagnosis were positively correlated with chronological age (CA), anthropometric measurements, stage of puberty, bone age (BA), BA-CA, follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, uterus length, endometrium thickness and ovarian volume (OV) at diagnosis (p < 0.05). There was no significant difference in IGF-1 levels after treatment. However, there was a negative correlation between ΔIGF-1 SDS and IGF-1 level, CA-IGF-1 SDS and BA-IGF-1 SDS at diagnosis (p < 0.05). There was no correlation between GV and IGF-1, ΔIGF-1. GV was negatively correlated with basal LH level at diagnosis (p = 0.008, r = -0.397). Peak LH levels of the patients who had GV-SDS < 0 were more suppressive than those of the patients who had GV-SDS > 0 after 12 months of treatment. Conclusions It was determined that the IGF-1 level and CA-IGF-1 SDS at baseline were correlated with more advanced pubertal stage prior to treatment. Initiation of treatment with a relatively high level of IGF-1 increased the risk of a decrease in the IGF-1 level. Likewise, the initiation of treatment with a relatively high LH level may increase the risk of low GV, but low GV was not related to the IGF-1 level. Increased sex steroid suppression may increase the risk of low GV.

Final height in growth hormone-deficient childhood cancer survivors after growth hormone therapy.

Growth hormone deficiency (GHD) is the most prevalent hypothalamic-pituitary (HP) disorder found in childhood cancer survivors (CCS). The published studies assessing GHD in CCS concluded that recombinant human GH (rhGH) does not restore final height (FH) to that predicted from mid-parental height (MPH). Thus, wider analyses on final height outcomes after rhGH in CCS are needed. Retrospective study on final height (FH) in 87 CCS treated with rhGH. Patients were divided into: Group A (n =48) who underwent cranial radiotherapy or had non-irradiated tumours of HP area, and B (n =39) who were treated with craniospinal or total body irradiation (TBI). 19/87 patients with central precocious/early puberty also received GnRH analogues. Height (HT) gain after 1 and 2years of rhGH was 0.38 ± 0.35SDS and 0.18 ± 0.30SDS, respectively (P < 0.0001); mean FH was in the normal range (- 0.85 ± 1.34SDS), though not significantly different from HT SDS at baseline. 67% overall failed to reach MPH especially in Group B (P < 0.0001). However, height loss (HT SDS-MPH SDS) at FH improved or remained stable compared to baseline in 26/45 patients (58%). On stepwise regression analysis, major determinants of FH were HT at baseline (P < 0.0001) and delay before start of rhGH (P = 0.012). There was no significant difference in FH when GnRHa was added to rhGH. rhGH and GnRH analogues therapy, when indicated, though failing to induce catch-up growth, prevented further height loss leading to a FH within the normal range but still below MPH, this latter being statistically significant in children who received craniospinal and TBI.

Comparative Efficacy and Safety of Three Current Clinical Treatments for Girls with Central Precocious Puberty: A Network Meta-Analysis

Objective: The optimal treatment for girls with central precocious puberty (CPP) is unknown. We conducted a network meta-analysis to evaluate the efficacy and safety of existing treatments to provide credible clinical guidelines. Methods: We compared gonadotropin-releasing hormone analogue (GnRHa) therapy, GnRHa plus growth hormone (GH) combination therapy, and no-treatment therapy for girls with CPP by performing an electronic search for studies in PubMed, Embase, Chinese National Knowledge Infrastructure databases, and Wanfang Data from their inception until September 30, 2018. Six outcomes, including bone maturation ratio, final height, final height compared with target height, growth velocity, height gain, and gain in predicted adult height (ΔPAH), were expressed as the mean difference with 95% confidence interval. The surface under the cumulative ranking curve (SUCRA) value illustrated the rank probability of each treatment under different outcomes. Results: Twenty-two studies with 1,268 patients were included. GnRHa plus GH had the best performance on final height, final height compared with target height, growth velocity, height gain, and ΔPAH, with the highest SUCRA values of 0.919, 0.975, 0.909, 0.999, and 0.957, respectively. For bone maturation ratio, GnRHa ranked the highest, with a SUCRA value of 0.663. No severe adverse effects were reported. Conclusion: For girls with CPP, GnRHa plus GH had the highest probability of being the optimal therapy for improving final height, and no severe adverse effects were reported. Abbreviations: BMI = body mass index; CI = confidence interval; CPP = central precocious puberty; GH = growth hormone; GnRHa = gonadotropin-releasing hormone analogue; HPG = hypothalamic-pituitary-gonadal; LH = luteinizing hormone; NMA = network meta-analysis; PAH = predicted adult height; PCOS = polycystic ovary syndrome; RCT = randomized controlled trial; SUCRA = surface under the cumulative ranking curve.

5. Premature Height Deceleration: A Risk in Transmasculine Youth

Increasing numbers of transmasculine (TM) youth (transgender and gender diverse (TGD) youth assigned female at birth) are avoiding puberty with endogenous hormones and utilizing GnRH analogs followed by masculinizing gender affirming hormone therapy (GAHT). Clinicians providing early hormone care must monitor development, including growth. Growth spurts and final adult height are determined by numerous factors including parental heights, timing of puberty, and hormonal factors. We have noted anecdotally that a high percentage of TM youth attain their adult heights early. Few studies have systematically assessed growth variations in TGD youth, and little is known about the effects of therapies on height outcomes. The goal of this study is to assess growth patterns in TM youth before and after GnRH analog therapy and various types of GAHT.

Massive Ovarian Growth in a Woman With Severe Insulin-Resistant Polycystic Ovary Syndrome Receiving GnRH Analogue

Ovarian hyperandrogenism from polycystic ovary syndrome (PCOS) and hyperinsulinemia from insulin resistance are modulators of ovarian follicle development. We report on a woman with PCOS and hyperandrogenism and severe insulin resistance from metabolic syndrome who received long-term GnRH analogue therapy preceding bilateral salpingo-oophorectomy for massive ovarian enlargement. Ovarian histological examination showed proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas, demonstrating a unique link between hyperinsulinemia and granulosa cell mitogenesis. A 30-year-old woman with PCOS with hyperandrogenism, severe insulin resistance from metabolic syndrome, and nonalcoholic steatohepatitis experienced abdominal pain from bilaterally enlarged ovaries. She had previously experienced a pulmonary embolism while taking oral contraceptives and hepatotoxicity from metformin and spironolactone therapies. Long-term GnRH analogue therapy to induce pituitary desensitization to GnRH successfully decreased gonadotropin-dependent steroidogenesis without improving insulin resistance. Despite GnRH analogue therapy, progressive ovarian enlargement in the presence of hyperinsulinemia from worsening metabolic function eventually required bilateral salpingo-oophorectomy for removal of massively enlarged ovaries. Histological examination showed both ovaries contained proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas. In women with PCOS and hyperinsulinemia from severe insulin resistance due to metabolic syndrome, granulosa cell proliferation within antral follicles can occur despite long-term GnRH analogue therapy, implicating hyperinsulinemia as a granulosa cell mitogen in the absence of gonadotropin-dependent ovarian function.

The Gonadotropin-Releasing Hormone Analogue Therapy May Not Impact Final Height in Precocious Puberty of Girls With Onset of Puberty Aged 6 - 8 Years.

BackgroundThe effect on final height of gonadotropin-releasing hormone analogues (GnRHa) used in the treatment of precocious puberty is controversial. The aim of this study was to determine whether or not GnRHa therapy would make any contribution to final height in precocious puberty of girls with onset of pubertal characteristic development aged 6 - 8 years.MethodsAge at start of puberty, target height standard deviation score (SDS) presentation, follow-up height SDS, body mass index (BMI) SDS, bone age and predicted adult height of 34 female subjects who had reached their final height and with pubertal findings beginning at the ages of 6 - 8 were evaluated. These subjects were divided into two groups: treatment and non-treatment groups. The treatment group was further divided into two subgroups, receiving monthly or three-monthly depot GnRHa.ResultsAge at onset of puberty was 7.2 ± 0.9 years. Twenty-five cases were started on GnRHa and nine were followed-up without treatment. Fourteen cases received monthly 3.75 mg depot triptorelin acetate and 11 received three-monthly 11.25 mg depot. Mean age at start of treatment in the treatment group was 9.1 ± 1.2 years and mean bone age was 9.7 ± 2.3 years. Age at presentation in the non-treatment group was 8.4 ± 1.4 years and bone age was 10.3 ± 2.1 years. Target and final height SDS were similar in all the groups (P > 0.05). No difference was determined between the treatment groups in terms of initial height SDS, bone age, length of treatment, final height SDS or BMI SDS (P > 0.05).ConclusionsGnRHa therapy did not make a positive contribution to final height in precocious puberty of girls with onset of puberty aged 6 - 8 years.

The Effects of Gonadotropin-Releasing Hormone Analog and a Combination of Gonadotropin-Releasing Hormone Analog and Recombinant Human Growth Hormone on Adult Height in Girls with Early Puberty.

Background:Early puberty (EP) is due to the activation of gonadotropin-releasing hormone (GnRH) pulse generator in lower ages; EP may be a potential cause for impairment of adult height, leading to short stature. The aim of this study was to determine the effects of GnRH analog (GnRHa) and GnRHa plus recombinant human growth hormone (rhGH) treatment on final height in healthy girls with EP.Materials and Methods:Fifty EP girls (sexual maturity rating: 2–3) with chronological age (CA) 9.22 ± 0.56 and bone age (BA) 9.74 ± 0.59 years were treated with GnRHa (Triptorelin) at a dose of 100 μg/kg body weight (BW) as intramuscular every 28 days for 2.82 ± 0.57 years; 45 EP girls with CA 9.84 ± 0.57 and BA 10.14 ± 1.02 years were also treated with the same GnRHa plus rhGH (Norditropin) at a dose of 0.1 unit/kg BW daily for 6 days in a week for 2.55 ± 0.6 years. In the control group, 33 EP girls followed for the same period without treatment. Height, weight, and body mass index of girls and parents were assessed. Predicted adult height (PAH) at the start and the end of the study and target height were assessed.Results:PAH at the end of the study in the GnRHa group was not different with untreated girls. PAH at the end of the treatment in GnRHa plus rhGH group was significantly higher than both untreated and GnRHa group. PAH at the end of therapy in GnRHa plus rhGH group was significantly more than their target height.Conclusion:GnRHa therapy has a benefit effect in achievement of target height. Combination therapy with GnRHa plus rhGH increased their PAH more than both untreated and GnRHa groups.

The Effect of Gonadotropin-Releasing Hormone Analogue on Final Adult Height in Children with Idiopathic Short Stature

Objective: To assess final adult height (FAH) in children with short stature treated with gonadotropin-releasing hormone analogue (GnRHa). Methods: All patients with idiopathic short stature (ISS) with normally timed puberty and a Tanner stage between 2 and 3, who achieved their FAH between 2005 and 2015, were included in this clinical historical cohort study. Height gain, FAH, and mid-parental height of 28 children with ISS who received GnRHa treatment for 1.8 ± 1.0 years to delay their puberty were compared to 31 untreated children. Results: The FAHs of the treated and the untreated girls were 151.3 ± 5.1 and 146.8 ± 3.8 cm (p = 0.01), respectively. The FAHs of the treated and the untreated boys were 156.4 ± 4.7 and 152.3 ± 5.7 cm (p = 0.111), respectively. The height gain in the treated and the untreated girls was 1.6 ± 7.8 and –3.6 ± 5.7 cm (p = 0.036), respectively. Height gain in the treated and the untreated boys was –5.1 ± 13.6 and –11.5 ± 8.4 cm (p = 0.171), respectively. Conclusion: GnRHa therapy has a modest effect in improving FAH in adolescent females with ISS but not in boys.

Apalutamide: a better option for the treatment of non-metastatic castration resistant prostatic carcinoma

Prostate cancer is cancer of the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, some grow relatively quickly. The cancer cells may spread from the prostate to other area of the body, particularly the bones and lymph nodes. Factors that increase the risk of prostate cancer include older age, a family history of the disease, and race. About 99% of cases occur in males over the age of 50. Clinical features include hematuria, dysuria (painful urination),nocturia(urination at night). Lower blood levels of vitami D may increase the risk of developing prostate cancer. Infection with the sexually transmitted diseases, chlamydia, gonorrhea, syphilis and prostatitis seem to increase risk of prostate cancer. Diagnosis can be confirmed by digital rectal examination (DRE) with prostate-specific antigen (PSA) blood test, cystoscopy, transrectal ultrasonography and biopsy (The removal of small pieces of the prostate for microscopic examination). Medicines like 5-alpha-reductase inhibitors (finasteride and dutasteride) reduce the overall risk of prostate cancer. Apalutamide, sold under the brand name Erleada, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC). It is taken by mouth. Apalutamide was first described in 2007 and was approved for the treatment of prostate cancer in February 2018. Apalutamide is used in conjunction with castration, either via bilateral orchiectomy or gonadotropin-releasing hormone analogue (GnRH analogue) therapy, as a method of androgen deprivation therapy in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC).

Subnormal Growth Velocity and Related Factors During GnRH Analog Therapy for Idiopathic Central Precocious Puberty

Objective:Data concerning subnormal growth velocity (GV) and factors that influence this during gonadotropin-releasing hormone analog (GnRHa) therapy for idiopathic central precocious puberty (ICPP) are scarce. We investigated the incidence of subnormal GV and associated factors in patients receiving GnRHa therapy for ICPP.Methods:In this retrospective cohort study, the records of 50 girls who had been diagnosed with ICPP and started on GnRHa treatment before the age of eight years were investigated. Subnormal GV frequency, related factors during GnRHa therapy and the effect on final height were examined.Results:During the treatment, a significant decrease in the annual GV and GV standard deviation score (SDS) of the patients was observed. In 16 (32%) patients GV never declined below -1 SDS, while a decline was noted once and twice in 19 (38%) and 15 (30%) patients respectively. The median age of detection of subnormal GV was 9.9 (4.9-10.9) years. Patients with pubic hair at diagnosis were found to have an increased risk of subnormal GV (p=0.016). There was a significant negative correlation between diagnostic basal luteinizing hormone (LH) level and the first and second year GV SDS (p=0.012 and 0.017 respectively). A significant negative correlation between bone age at diagnosis and 3rd year GV SDS, and 4th year GV SDS (p=0.002 and p=0.038) was also observed. LH suppression significantly increased during treatment (p=0.001).Conclusion:In girls with ICPP the risk of subnormal GV appears highest at the 3rd year of GnRHa treatment, particularly in those patients with, at the time of diagnosis, pubic hair in conjunction with high baseline and peak LH and advanced BA and excessive LH suppression on follow-up.