Efficacy and Safety of Triptorelin 3-Month Formulation in Chinese Children with Central Precocious Puberty: A Phase 3, Open-Label, Single-Arm Study.

INTRODUCTION: Triptorelin is available as 1- and 3-month prolonged-release (PR) formulations; at the time of the study, only the former was approved for central precocious puberty (CPP) in China. This study assessed the efficacy and safety of the triptorelin 3-month PR formulation in Chinese children with CPP. METHODS: In this 12-month, prospective, open-label, multicentre, single-arm study (NCT04736602), Chinese children (mean age [standard deviation (SD)], 7.6 ± 0.8 years) with CPP received triptorelin pamoate 15 mg on day 1 and at months 3, 6 and 9. The primary endpoint was the proportion with luteinizing hormone (LH) suppression (stimulated peak LH ≤ 3 IU/L after gonadotropin-releasing hormone [GnRH] stimulation) at month 3. Secondary endpoints included changes from baseline in hormone levels and clinical parameters, as well as safety assessments. RESULTS: Overall, 32 children were enrolled, including three boys. LH suppression to prepubertal levels (≤ 3 IU/L) after GnRH stimulation was observed in 100%, 93.5% and 93.5% of participants at months 3, 6 and 12, respectively. Basal and peak LH and follicle-stimulating hormone levels were substantially suppressed at months 3, 6 and 12, and most participants showed sex hormone suppression. At months 6 and 12 respectively 92.9% and 89.3% of girls had stable breast development, and all boys had stable genital development. There was a decrease in mean growth velocity from baseline (8.96 cm/year) to months 3, 6 and 12 (8.07, 5.24 and 6.94 cm/year, respectively). The mean difference between bone and chronological age decreased from baseline (2.85 years) to month 12 (2.39 years). In girls, uterine length was stable or reduced at month 12; in boys, testicular volume was reduced. Triptorelin was well tolerated. CONCLUSION: The triptorelin 3-month PR formulation demonstrated similar efficacy to that previously reported in non-Chinese patients with CPP and had an acceptable safety profile. This supports triptorelin 3-month PR as a viable option for Chinese children with CPP.

Central precocious puberty (CPP) occurs when the reproductive organs and secondary sexual characteristics develop too early in children (before 8 years old in girls or 9 years old in boys). It can cause significant psychological harm and may lead to health problems later in life. Triptorelin is a type of treatment designed to suppress the hormonal activity responsible for CPP and therefore slow down early pubertal development. Triptorelin can be given as an injection into muscle every month or every 3 months; the 3-monthly formulation is commonly used in many countries but at the time of this study it was not licensed for patients with CPP in China. Our trial assessed the effect of triptorelin treatment every 3 months for 1 year in 32 Chinese children with CPP. For all patients who had measurements available, 3-monthly triptorelin suppressed luteinizing hormone­a key hormone involved in CPP­to below typical prepubertal levels. Other hormones involved in puberty were also suppressed. Children experienced a slowing down of the development of secondary sexual characteristics (breasts, genitals and pubic hair), and stabilization or reduction in the size of internal sexual organs (uterine length in girls and testicular volume in boys). Their height also increased less rapidly than previously. There were no concerning side effects of triptorelin treatment, and the safety profile matched that seen in other countries where triptorelin is widely used for CPP. Overall, our study findings suggest that the 3-monthly triptorelin formulation may be a good option for Chinese children with CPP.

Sustained-release deslorelin acetate implants disrupt oestrous cyclicity in the mare.

There is a need for a safe, effective and practical method of oestrus suppression in the mare. The aim of this study was to monitor ovarian activity in mares exposed to either 9.4 or 28.2 mg deslorelin acetate, a GnRH agonist, in the form of a sustained-release implant. Following oestrus synchronisation, mares were randomly assigned to one of three groups (n = 4 per group) and administered either one (Des1 group; 9.4 mg) or three (Des3 group; 28.2 mg) implants of deslorelin acetate (Suprelorin-12, Virbac Australia) or one blank implant (Control group; Virbac Australia). Mares underwent weekly blood sampling for 12 weeks following implant placement (Day 0-Day 84), with transrectal palpation and ultrasonography of the reproductive tract at all sampling timepoints except Days 56, 70 and 77. All mares showed baseline serum progesterone concentrations (SPC; ≤1.3 nmol/L or 0.4 ng/ml) on Day 0. Cycling Control mares showed typical oestrous cyclicity characterised by peaks and troughs in SPC over time. Four of eight treated mares demonstrated a sustained elevation in SPC after the initial ovulation after implant placement; SPC declined to baseline levels (Des1 group; 2 mares) or remained elevated (Des3 group; 2 mares) at the final sampling timepoint on Day 84. Oestrous cyclicity was erratic in three of the remaining four treated mares. In total, 87.5% (7 of 8) of treated mares showed atypical oestrous cyclicity after implant placement. These results suggest that deslorelin acetate disrupts oestrous cyclicity in the mare, which warrants further research.

Cardiovascular adverse events-related to GnRH agonists and GnRH antagonists: analysis of real-life data from Eudra-Vigilance and Food and Drug Administration databases entries.

INTRODUCTION AND OBJECTIVES: GnRH agonists and GnRH antagonists are two of the mainstays of hormonal therapy (HT) for prostate cancer (PCa). These drugs are at increased risk of cardiovascular (CV) adverse events (AEs). Aim of our study was to compare real-life data on AEs associated with GnRH agonists and GnRH antagonists based on Eudra-Vigilance (EV) and Food and Drug Administration (FDA) reported AEs. MATERIALS AND METHODS: EV and FDA databases were queried and the number of CV adverse events (AEs) for degarelix, buserelin, goserelin, leuprorelin, triptorelin until September 2021 were recorded. Specific CV AEs were recorded and data were analyzed per age and severity. pooled relative risk (PRR) was used to compare data between drugs. RESULTS: CV events were reported in 315/5128 (6%) for Degarelix, in 55/628 for Buserelin (9%), in 843/12,145 (7%) for Goserelin, in 3395/71,160 (5%) for Leuprorelin and in 214/4969 (5%) for Triptorelin. In terms of specific CV disorders, Degarelix presented lower risk of hypertension (PRR 0.60 (95% CI 0.37-0.98), p = 0.04), of myocardial infarction (PRR 0.05 (95% CI 0.01-0.39), p < 0.01) and thrombosis (PRR 0.14 (0.02-1.07), p = 0.06) when compared to GnRH agonists. Overall, younger patients (<65 years) presented a very low risk of CV AEs. Side effects were classified as serious in 90-96% of the cases. Fatal AEs were 5-20% over the CV AEs and 0.2-1% over the total AEs. CONCLUSIONS: Real-life data are consistent with registry studies regarding side effects related to HT. Real-life data suggest GnRH agonists are associated with higher CV AEs when compared to GnRH antagonists. Clinicians should consider these data when prescribing HT especially in patients with CV comorbidities.

The efficacy and safety of triptorelin-therapy following conservative surgery for deep infiltrating endometriosis: A multicenter, prospective, non-interventional study in China.

ABSTRACT: Triptorelin is one of the most commonly used gonadotropin-releasing hormone agonists and has been used in the treatment of deep infiltrating endometriosis (DIE). This study aimed to evaluate the efficacy and safety of up to 24 weeks of triptorelin treatment after conservative surgery for DIE.This prospective, non-interventional study was performed in 18 tertiary hospitals in China. Premenopausal women aged ≥18 years treated with triptorelin 3.75 mg once every 28 days for up to 24 weeks after conservative surgery for DIE were included. Endometriosis symptoms were assessed, using a visual analogue scale (0-10 cm) or numerical range (0-10), at baseline (pre-surgery) and routine visits 3, 6, 9, 12, 18, and 24 months after surgery. Changes in symptom intensity over time were primary outcome measures.A total of 384 women (mean [standard deviation] age, 33.4 [6.2] years) were analyzed. Scores for all symptoms (pelvic pain, dysmenorrhea, ovulation pain, dyspareunia, menorrhagia, metrorrhagia, and gastrointestinal and urinary symptoms) assessed decreased from baseline over 24 months. Cumulative improvement rates in pelvic pain, dysmenorrhoa, ovulation pain, and dyspareunia were 74.4%, 83.6%, 55.1%, and 66.9%, respectively. The 24-month cumulative recurrence rate (≥1 symptom) was 22.2%. The risk of symptom recurrence was higher in patients with ≥2 versus 1 lesion (odds ratio [OR] 2.539; 95% CI: 1.458-4.423; P = .001) and patients with moderate (OR 5.733; 95% CI: 1.623-20.248; P = .007) or severe (OR 8.259; 95% CI: 2.449-27.851; P = .001) pain versus none/mild pain. Triptorelin was well tolerated without serious adverse events.Triptorelin after conservative surgery for DIE improved symptoms over 24 months of follow up. The recurrence rate of symptoms was low and triptorelin was generally well tolerated.Trial registration number: ClinicalTrials.gov, NCT01942369.

Efficacy of Triptorelin 3-Month Depot Compared to 1-Month Depot for the Treatment of Korean Girls with Central Precocious Puberty in Single Tertiary Center.

BACKGROUND: Triptorelin depot is largely used to treat central precocious puberty (CPP) in children, and a 3-month depot has been introduced. However, data about the 3-month gonadotropin-releasing hormone use for treatment of CPP in Korean girls are not available. This study was conducted to compare the efficacy of a triptorelin 11.25 mg 3-month depot with that of a 3.75 mg 1-month depot in suppressing pubertal development for the treatment of CPP. METHODS: A retrospective study, including 106 girls with CPP treated with triptorelin, was conducted. Fifty patients were treated with a triptorelin 3-month depot, and 56 were treated with a triptorelin 1-month depot. Serum luteinizing hormone (LH), follicle-stimulating hormone, and estradiol levels were analysed every 6 months after the visit. The height and bone age of each patient was evaluated at the beginning of treatment, after 6 months, and one year after therapy. RESULTS: The baseline characteristics of the girls treated with a 3-month depot were similar to those of the girls treated with a 1-month depot. A suppressed levels of LH to the triptorelin injection (serum LH < 2.5 IU/L) at 6 months was seen in 90.0% and 98.2% of the girls treated with the 3-month and 1-month depots, respectively (P = 0.160). After 1 year of treatment, a suppressed levels of LH was seen in 93.5% and 100% of the girls treated with the 3-month and 1-month depots, respectively (P = 0.226). Height velocity showed no significant difference between the two groups. Degree of bone age advancement decreased from 1.22 ± 0.07 and 1.22 ± 0.08 years at baseline (P = 0.914) to 1.16 ± 0.07 and 1.17 ± 0.08 in the girls treated with the 3-month and 1-month depots after 1 year, respectively (P = 0.481). CONCLUSION: This study showed that the efficacy of long-acting triptorelin 3-month was comparable to 1-month depot regarding hormonal suppression and inhibition of bone maturation. The triptorelin 11.25 mg 3-month depot is an effective treatment for girls with CPP.

[Development of a large intraprostatic cyst following the use of a GnRH agonist-implant in a male dog with benign prostatic hyperplasia]. / Entwicklung einer großen intraprostatischen Zyste nach Einsatz eines GnRH-Agonist-Implantats bei einem Rüden mit benigner Prostatahyperplasie.

A male dog with benign prostatic hyperplasia and several small intraprostatic cysts was treated with a GnRH-agonist implant containing 4,7 mg deslorelin (Suprelorin®). Within 2 weeks after the implantation, the prior urethral bleeding worsened. A large intraprostatic cyst was detected sonographically. The patient was subsequently treated with osaterone acetate (0.4 mg/kg p. o. once a day for 7 days) and enrofloxacin (5 mg/kg p. o. once a day for 21 days). The clinical symptoms receded within 10 days. Within one month, the cyst regressed completely. The mechanisms of cyst enlargement are discussed.

Addition of Antiestrogen Treatment in Patients with Malignant PEComa Progressing to mTOR Inhibitors.

PURPOSE: Perivascular epithelioid cell tumors (PEComa) are rare mesenchymal neoplasms. mTOR inhibitors are the most active agents in PEComa and in patients progressing to mTOR inhibitors, other available therapies have limited benefit. Preclinical evidences showed a cross-talk between the mTOR pathway and estrogen receptor signaling. This provided a rationale for adding an antiestrogen treatment in female patients becoming resistant to mTOR inhibitors. EXPERIMENTAL DESIGN: Since April 2018, female patients with advanced/metastatic PEComa progressing to mTOR inhibitors were treated with a combination of sirolimus and exemestane with or without LHRH analogue (based on menopausal status). This case series was retrospectively reviewed. Survival analyses were performed using the Kaplan-Meier method. RESULTS: A total of seven consecutive patients treated with the combination of sirolimus and antiestrogen treatment were retrospectively reviewed. Six (86%) received a combination of sirolimus and exemestane, whereas one patient (14%) received a combination of sirolimus, exemestane, and triptorelin since in premenopausal status. After a median follow-up of 13.1 months, three patients (43%) experienced a partial response, three patients (43%) experienced a stabilization of disease, and one patient (14%) had disease progression with an overall response rate of 43% and a disease control rate of 86%. CONCLUSIONS: In this small retrospective case series, the addition of antiestrogen treatment in female patients with advanced PEComa progressing to mTOR inhibitors resulted in a remarkable clinical benefit in a setting where no other options are available.

Management of Systemic Hypersensitivity Reactions to Gonadotropin-Releasing Hormone Analogues during Treatment of Central Precocious Puberty.

BACKGROUND: Besides local reactions, systemic hypersensitivity reactions such as urticaria, anaphylaxis, serum sickness and Henoch-Schönlein purpura (HSP) have been reported during gonadotropin-releasing hormone (GnRH) analogue treatment. AIM: To present the clinical presentation of 9 cases with systemic hypersensitivity reactions to GnRH analogues and discuss the management of such reactions based on our experience. PATIENTS AND METHODS: Nine of 232 (3.8%) patients with central precocious puberty receiving GnRH analogue treatment had systemic hypersensitivity reactions in 4 years' period. Six patients had a type 1 hypersensitivity reaction (generalized hives, pruritus, and/or edema) to triptorelin acetate (TA), 2 patients to leuprolide acetate (LA), and 1 patient to both medications who also developed anaphylaxis to LA during intradermal test (IDT). Another patient on TA had skin lesions suggestive of HSP. GnRH analogue treatment was discontinued in 2 patients after discussion with the parents. Treatment was changed to another GnRH analogue preparation in 6 patients and was maintained with the same medication with antihistamines and corticosteroid premedication in 1 patient. None of the patients developed new reactions after these precautions. CONCLUSION: Systemic hypersensitivity reactions should be carefully evaluated and cross-reaction to the other GnRH analogues should be kept in mind. Discontinuation of GnRH analogue is always an option. However, if continuation of GnRH analogue is elected, we recommend switching to an alternative GnRH analogue, which should be considered only after a skin prick test (SPT) and IDT. In the lack of the possibility to perform SPT and IDT, injections may be administered under strict medical supervision in a well-equipped facility to manage anaphylaxis. We discuss additional options in situations where alternative GnRH analogues are unavailable, which enabled us to continue treatment in most cases without further problems.

Fertility of Women Treated during Childhood with Triptorelin (Depot Formulation) for Central Precocious Puberty: The PREFER Study.

BACKGROUND: Gonadotropin-releasing hormone analogues (GnRHa) administered as depot formulations are the standard of care for children with central precocious puberty (CPP). Puberty resumes after treatment discontinuation, but little is known concerning fertility in women who have been treated with GnRHa for CPP during childhood. METHODS: The PREFER (PREcocious puberty, FERtility) study prospectively analysed fertility, via a series of questionnaires, in women treated during childhood with triptorelin (depot formulation) for CPP. Co-primary endpoints were the proportion of women wanting a pregnancy any time before study inclusion and during the follow-up period but not pregnant 6 and 12 months after stopping contraception and the waiting time to pregnancy (WTP). RESULTS: A total of 574 women were identified, and 194 women were included in the analysis. Although there were not enough data for primary endpoint assessment, few women (1.7%) reported issues with fertility or were unable to become pregnant despite trying to conceive. Most pregnancies (84.4%, 95% CI [67.2-94.7%]) occurred within 1 year of trying to conceive, in line with the WTP for women without previous CPP. CONCLUSION: The results, based on a limited sample of patients, suggest that CPP treated with triptorelin does not negatively impact women's fertility in adulthood. These results need to be consolidated with a subsequent study performed when these women will have reached their mid-thirties.

Association between body mass index and oocyte maturation in patients triggered with GnRH agonist who are at high risk for severe ovarian hyperstimulation syndrome: an observational cohort study.

RESEARCH QUESTION: Is body-mass index (BMI) associated with oocyte maturation in women at high risk for developing severe ovarian hyperstimulation syndrome (OHSS) who are triggered with gonadotrophin releasing hormone (GnRH) agonist? DESIGN: Prospective observational cohort study. A total of 113 patients at high risk for severe OHSS (presence of at least 19 follicles ≥11 mm) pre-treated with gonadotrophin releasing hormone (GnRH) antagonists and recombinant FSH were administered 0.2 mg triptorelin to trigger final oocyte maturation. Patients were classified in two groups depending on their BMI: ΒΜΙ less than 25 kg/m2 (n = 72) and ΒΜΙ 25 kg/m2 or over (n = 41). Baseline, ovarian stimulation and embryological characteristics, as well as luteal-phase hormone profiles, were compared in patients classified into the two BMI groups. The main outcome measure was the number of mature oocytes. RESULTS: A significantly higher number of mature (metaphase II) oocytes (19 [18-21] versus 16 [13-20], P = 0.029) was present in women with BMI less than 25 kg/m2 compared with those with BMI 25 kg/m2 or greater. The number of retrieved oocytes, the number of fertilized oocytes, oocyte retrieval, maturation and fertilization rates were similar in the two groups. A significantly higher dose of recombinant FSH was required for patients with BMI 25 kg/m2 or greater compared with patients with BMI less than 25 kg/m2 (1875 [1650-2150] IU versus 1650 [1600-1750] IU, P = 0.003) and the two groups displayed different luteal phase hormonal profiles. CONCLUSIONS: Among women at high risk for developing severe OHSS who are triggered with a standard dose (0.2 mg) of the GnRH agonist triptorelin, women with BMI 25 kg/m2 or greater had significantly fewer mature oocytes, required a higher total dose of recombinant FSH compared with women with BMI less than 25 kg/m2.

Pituitary adenoma and apoplexy during GnRH agonist treatment for IVF - case report.

In vitro fertilization is commonly used for treating infertility. One stage of this process is controlled hyperstimulation of the ovaries, achieved by administering gonadotropins. There are several stimulation protocols utilized that increase the number of ovarian follicles during IVF. The most common protocol employs desensitization - the inhibition of follicle-stimulating hormone and luteinizing hormone secretion by the pituitary gland. This is achieved by administering a gonadotropin-releasing hormone (GnRH) analog that is agonistic for the GnRH receptor. However the use of a this drug during therapy carries a risk of complications. This case report deals with a rare case of a woman who underwent pituitary tumor growth as a result of the treatment of GnRH analog.

Is oocyte maturation rate associated with triptorelin dose used for triggering final oocyte maturation in patients at high risk for severe ovarian hyperstimulation syndrome?

STUDY QUESTION: Are oocyte maturation rates different among 0.1, 0.2 and 0.4 mg triptorelin used for triggering final oocyte maturation in patients at high risk for ovarian hyperstimulation syndrome (OHSS) undergoing ICSI? SUMMARY ANSWER: A dose of 0.1 mg triptorelin results in similar oocyte maturation rates compared to higher doses of 0.2 and 0.4 mg in patients at high risk for OHSS undergoing ICSI. WHAT IS KNOWN ALREADY: The GnRH agonist triptorelin is widely used instead of hCG for triggering final oocyte maturation, in order to eliminate the risk of severe OHSS in patients undergoing ovarian stimulation for IVF/ICSI. However, limited data are currently available regarding its optimal dose use for this purpose in patients at high risk for OHSS. STUDY DESIGN, SIZE, DURATION: A retrospective study was performed between November 2015 and July 2017 in 131 infertile patients at high risk for severe OHSS undergoing ovarian stimulation for ICSI. High risk for severe OHSS was defined as the presence of at least 19 follicles ≥11 mm in diameter on the day of triggering final oocyte maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian stimulation was performed with recombinant FSH and GnRH antagonists. Patients received 0.1 (n = 42), 0.2 (n = 46) or 0.4 mg (n = 43) triptorelin for triggering final oocyte maturation. Hormonal evaluation of FSH, LH, estradiol (E2) and progesterone (PRG) was carried out on the day of triggering final oocyte maturation, 8 and 36 hours post triggering and 3, 5, 7, and 10 days after triptorelin administration. During this period, all patients were assessed for symptoms and signs indicative of severe OHSS development. Primary outcome measure was oocyte maturation rate, defined as the number of metaphase II (MII) oocytes divided by the number of cumulus-oocyte-complexes retrieved per patient. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences in patient baseline characteristics were observed among the 0.1 mg, the 0.2 mg and the 0.4 mg groups. Regarding the primary outcome measure, no differences were observed in oocyte maturation rate among the three groups compared [82.6% (17.8%) versus 83.3% (18.8%) versus 85.1% (17.2%), respectively, P = 0.686].In addition, no significant differences were present among the 0.1 mg, 0.2 mg and 0.4 mg groups, regarding the number of mature (MII) oocytes [21 (13) versus 20 (6) versus 20 (11), respectively; P = 0.582], the number of oocytes retrieved [25.5 (13) versus 24.5 (11) versus 23 (12), respectively; P = 0.452], oocyte retrieval rate [81.0% (17.7%) versus 76.5% (23.5%) versus 75.0% (22.5), respectively; P = 0.088], the number of fertilized (two pronuclei) oocytes [12.5 (9) versus 14.5 (7) versus 14.0 (8), respectively; P = 0.985], fertilization rate [71.7% (22%) versus 77.1% (19.1%) versus 76.6% (23.3%), respectively; P = 0.525] and duration of luteal phase [7 (1) versus 8 (2) versus 7 (1) days, respectively; P = 0.632]. Moreover, no significant differences were present among the three triptorelin groups regarding serum levels of LH, FSH, E2 and PRG at any of the time points assessed following triggering of final oocyte maturation. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study, and although there were no differences in the baseline characteristics of the three groups compared, the presence of bias cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: Based on the results of the current study, it appears that triggering final oocyte maturation with a lower (0.1 mg) or a higher dose (0.4 mg) of triptorelin, as compared to the most commonly used dose of 0.2 mg, does not confer any benefit in terms of oocyte maturation rate in patients at high risk for severe OHSS. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. There are no conflicts of interest.

Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial.

AIM: The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor-positive (HR+) tumours. PATIENTS AND METHODS: In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. RESULTS: With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3-4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. CONCLUSION: HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. (NCT00412022).

Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy: A Randomized Clinical Trial.

IMPORTANCE: Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting. OBJECTIVE: To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used. INTERVENTIONS: Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks [6 cycles]), or ADT alone (1 year). MAIN OUTCOMES AND MEASURES: The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life. RESULTS: Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life. CONCLUSIONS AND RELEVANCE: Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease. TRIAL REGISTRATION: French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166.

Multiple Cervical Root Resorption in a Young Adult Female Previously Treated with Chemotherapy: A Case Report.

Multiple idiopathic cervical root resorption is an aggressive form of external root resorption that occurs at the cementoenamel junction and can affect multiple teeth (a minimum of 3) throughout the entire dentition. Most of the individuals affected are healthy with noncontributory medical histories. The resorption is usually detected as an incidental finding on radiographs or during dental examination. This case report describes an adult female with multiple cervical root resorptions who had been treated with chemotherapy for ovarian cancer at 16 years old. Nine years later, a total of 12 teeth were diagnosed with cervical root resorption. All of the known causative factors for external cervical resorption were discarded. To our knowledge, this is the first case reported of multiple cervical root resorption related to chemotherapy.

Metabolic consequences of gonadotropin-releasing hormone agonists vs orchiectomy: a randomized clinical study.

OBJECTIVES: To compare the metabolic changes between men with advanced prostate cancer commenced on a gonadotropin-releasing hormone (GnRH) agonist and those treated with orchiectomy. PATIENTS AND METHODS: Fifty-eight hormone-naive men with advanced prostate cancer were randomly assigned (1:1) to either subcapsular orchiectomy or triptorelin 22.5 mg/24 week depot injections. The participants were followed for 48 weeks, with study visits at baseline, 12, 24 and 48 weeks. The primary endpoint was changes in fasting plasma glucose. Secondary endpoints included changes in body composition (i.e. weight, fat mass, visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], lean body mass [LBM] and android/gynoid fat [AG] ratio) assessed with dual X-ray absorptiometry, serum lipid profiles, and insulin resistance evaluated during an oral glucose tolerance test. Linear mixed models were used to analyse the between-group differences. RESULTS: No treatment differences in the changes in fasting plasma glucose (0.2 mmol/L, 95% confidence interval [CI] -0.1, 0.4; P = 0.32) were observed. The orchiectomy group experienced greater increases in total fat mass (+2.06 kg, 95% CI 0.55, 3.56), SAT (+133 cm3 , 95% CI 22, 243) and weight (+3.30 kg, 95% CI 0.74, 5.87) at 48 weeks than did the triptorelin group (all P < 0.05), with the increases in fat mass being moderately correlated with increases in insulin resistance (P < 0.001). No differences in changed VAT, LBM or AG ratio were observed between the groups. The pooled analyses, combining data from both groups, showed androgen deprivation therapy (ADT) to significantly increase fat mass, SAT, VAT, serum cholesterols (total, high-density lipoprotein and low-density lipoprotein) and all measures of insulin resistance over time, while LBM decreased as compared with baseline values (all P < 0.05). These changes were apparent after only 12-24 weeks of ADT. CONCLUSIONS: Androgen deprivation therapy leads to adverse changes in body composition and increased insulin resistance and serum cholesterols, with changes already observed after only 12-24 weeks of treatment. This study further demonstrates that orchiectomy causes greater increases in fat accumulation compared with GnRH agonists and that these increases are associated with an increase in insulin resistance.

Neoadjuvant Degarelix Versus Triptorelin in Premenopausal Patients Who Receive Letrozole for Locally Advanced Endocrine-Responsive Breast Cancer: A Randomized Phase II Trial.

PURPOSE: To evaluate endocrine activity in terms of ovarian function suppression (OFS) of degarelix (a gonadotropin-releasing hormone [GnRH] antagonist) versus triptorelin (a GnRH agonist) in premenopausal patients receiving letrozole as neoadjuvant endocrine therapy for breast cancer. PATIENTS AND METHODS: Premenopausal women with stage cT2 to 4b, any N, M0; estrogen receptor and progesterone receptor greater than 50%; human epidermal growth factor receptor 2-negative breast cancer were randomly assigned to triptorelin 3.75 mg administered intramuscularly on day 1 of every cycle or degarelix 240 mg administered subcutaneously (SC) on day 1 of cycle 1 then 80 mg SC on day 1 of cycles 2 through 6, both with letrozole 2.5 mg/day for six 28-day cycles. Surgery was performed 2 to 3 weeks after the last injection. Serum was collected at baseline, after 24 and 72 hours, at 7 and 14 days, and then before injections on cycles 2 through 6. The primary end point was time to optimal OFS (time from the first injection to first assessment of centrally assessed estradiol level ≤ 2.72 pg/mL [≤ 10 pmol/L] during neoadjuvant therapy). The trial had 90% power to detect a difference using a log-rank test with a two-sided α of .05. Secondary end points included response, tolerability, and patient-reported endocrine symptoms. RESULTS: Between February 2014 and January 2017, 51 patients were enrolled (n = 26 received triptorelin plus letrozole; n = 25 received degarelix plus letrozole). Time to optimal OFS was three times faster for patients assigned to degarelix and letrozole than to triptorelin and letrozole (median, 3 v 14 days; hazard ratio, 3.05; 95% CI, 1.65 to 5.65; P < .001). Furthermore, OFS was maintained during subsequent cycles for all patients assigned to receive degarelix and letrozole, whereas 15.4% of patients assigned to receive triptorelin and letrozole had suboptimal OFS after cycle 1 (six events during 127 measurements). Adverse events as a result of both degarelix plus letrozole and triptorelin plus letrozole were as expected. CONCLUSION: In premenopausal women receiving letrozole for neoadjuvant endocrine therapy, OFS was achieved more quickly and maintained more effectively with degarelix than with triptorelin.

Postponement of canine puberty by neonatal administration of a long term release GnRH superagonist.

The objective of this study was to assess the efficiency and clinical safety of postnatal administration of a GnRH agonist on canine puberty postponement. Sexual steroids and histological gonadal changes were also described. Twenty-four littermate puppies were randomly assigned to: Deslorelin acetate 18.8 mg sc (DESLO; n = 12) or Placebo: sc (PLACE; n = 12) postnatally. The dogs were clinically and endocrinologically followed up until puberty when they were gonadectomized and their gonads histomorphometrically studied. Deslorelin postponed the age of puberty (72.7 ±â€¯4.8 vs. 35.8 ±â€¯1.9 weeks; P < 0.01) in these dogs. At the time of this submission, 3 DESLO dogs (108 weeks old) remain non-pubertal. All dogs concluded growing at a similar age (29.75 ±â€¯2.44 vs. 29.25 ±â€¯0.90 weeks; P > 0.1) independently of their group and pubertal status. None of the females had side effects while the 2 non pubertal DESLO males presented bilateral cryptorchydism. All the bitches ovulated at puberty (P > 0.1) and the 2 DESLO that were mated became pregnant. Deslorelin postponed basal serum sexual steroids up to puberty in both genders (P < 0.01). The histomorphometrical study of the testes revealed that the tubular diameter (P < 0.05), germinal epithelium height and composition (P < 0.01) were decreased in DESLO group. Ovarian structures did not differ between treatments (P > 0.05). It was concluded that postnatal deslorelin decreased sexual steroids reversibly postponing puberty in both genders without side effects in bitches and causing 2/6 of cryptorchydism and impairment of testicular histomorphometry in male dogs.

Triptorelin depot for the treatment of children 2 years and older with central precocious puberty.

INTRODUCTION: Triptorelin depot is largely used to treat central precocious puberty (CPP) in children. Areas covered: This review updates triptorelin depot treatment of CPP, focusing on trials that compared 3.75 mg/28 day treated and untreated children till the adult height (AH). Efficacy of the new 11.25 mg/90 days or 22.5 mg/6 month formulations in suppressing pituitary-gonadal axis in short-term trials is also addressed. Short- and long-term safety was summarized. Expert commentary: Long experience on triptorelin depot use in children with CPP is available. Outcome differences on AH are reported; they may be due to heterogenicity of treated patients; some items remain to be optimized. No long term-adverse events on reproductive function are reported; additional studies would clarify if CPP per sè or triptorelin depot administration may increase hyperandrogenism and/or polycystic ovary syndrome risk in adulthood. The quarterly formulation seems to be able to suppress pituitary-gonadal axis and pubertal development and to determine similar end-results as monthly formulation, but additional trials are needed. Few data are available for the 22.5 mg/6 month formulation. Triptorelin depot treatment of CPP should be restricted to tertiary pediatric endocrinology centers, considering that some uncertainties still exist and that rare but serious adverse events may occur.

Development of systemic sclerosis in transgender females: a case series and review of the literature.

OBJECTIVES: Systemic sclerosis (SSc) is a chronic, autoimmune connective tissue disease with a female predominance. The reason for the female predilection in SSc may relate to the difference in hormones between the genders. There are no current data on the influence male-to-female sex transition may have in the development of SSc. We report three patients who developed SSc after initiating the transgender process, and review current literature in regards to transgender patients with connective tissue disease (CTD). METHODS: We describe the clinical features and disease course of three transgender patients who developed SSc after their transition from male-to-female, who presented to our centre. Two additional transgender cases de- scribed in the literature with CTD were included in this review. RESULTS: All three patients developed SSc after having started the hormonal therapy required to transition. Two patients had surgical procedures preceding their diagnosis of SSc. Antibody profile, time of onset and disease features differed among our patients. Hormonal therapies were continued in all patients and they received the standard therapy for SSc. One patient died from complications of her disease. Only two cases describing the development of CTD in transgender patients were identified in the literature and both of these patients were diagnosed with systemic lupus erythematosus (SLE). CONCLUSIONS: This case series suggests that the hormonal modification as part of gender transition may be relevant in development of SSc. No further conclusions can be drawn on the continuation or not of HT.