GnRH agonist trigger in poor prognosis patients undergoing a multicycle approach through DuoStim or consecutive stimulations: a SWOT analysis.

PURPOSE OF REVIEW: Identify the most recent and significant evidence regarding the ovulation trigger within the framework of a multicycle approach through DuoStim, providing valuable insights for improving treatment strategies in patients with a poor prognosis. RECENT FINDINGS: The trigger method plays a pivotal role in optimizing in-vitro fertilization (IVF) stimulation, influencing oocyte retrieval and maturation rates, as well as follicle recruitment in consecutive ovarian stimulations such as double stimulation. Decision-making involves multiple factors and, while guidelines exist for conventional stimulation, specific recommendations for the multicycle approach are not well established. SUMMARY: The different methods for inducing oocyte maturation underscore the need for personalization of IVF protocols. The GnRH agonist trigger induces rapid luteolysis and establishes favorable hormonal conditions that do not adversely affect the recruitment of consecutive follicular waves in the context of DuoStim. It serves as a valid alternative to hCG in freeze-all cycles. This strategy might enhance the safety and flexibility of ovarian stimulations with no impact on oocyte competence and IVF efficacy.

GnRH analogue triptorelin acetate induces ovulation in jennies during oestrus.

Most of the northern hemisphere donkey breeds are faced with the risk of extinction, thus donkey reproduction is considered an emerging branch of theriogenology, and the management of artificial insemination and induction of ovulation is a crucial point in setting up preservation protocols. For four consecutive cycles, six jennies' ovarian activity was routinely monitored; an ultrasound examination was performed daily from the evidence of a follicle diameter ≥27 mm until ovulation. Upon reaching a follicular diameter ≥32 ± 2 mm (Hour 0), oestrous jennies were treated alternatively with 0.1 mg triptorelin acetate, sc, (TRIP), 0.4 mg/sc of buserelin acetate (BUS) or saline, sc, (CTRL) and examined ultrasonographically at Hours 14, 24, 38, 42, 48, 62 and every 24 h until ovulation. Induction of ovulation was considered successful if ovulation occurred from 24 to 48 h after treatment. 11/12 cycles resulted in ovulation for TRIP and 12/12 for BUS and CTRL groups, respectively. Mean ± SD ovulation time after treatment was 37.3 ± 8.3, 47.1 ± 21.0 and 66.8 ± 25.9 h for BUS, TRIP and CTRL, respectively (p = .0032). Ovulation rates between h24 and h48 were 10/12 (83.3%) for both TRIP/BUS and 2/12 (16.7%) for CTRL, respectively (p = .003). Buserelin and triptorelin-treated jennies had a 25 times higher probability to ovulate between Hours 24 and 48 than controls (p = .003), while there were no jenny and cycle effects on the ovulatory rate. The results of this study show how triptorelin successfully induced ovulation in jennies, like other GnRH analogues previously evaluated.

Peak serum luteinising hormone cut-off during gonadotropin-releasing hormone analogue test for diagnosing central precocious puberty was lower in girls with obesity as compared with girls with normal weight.

OBJECTIVE: Serum luteinising hormone (LH) concentration has been reported to be lower in girls with overweight and obesity (OW/OB) as compared with girls with normal weight (NW). This study aimed to evaluate peak serum LH concentration during gonadotropin-releasing hormone analogue (GnRHa) test in girls with OW/OB and NW who had central precocious puberty (CPP) and to determine peak serum LH cut-off for diagnosing CPP in girls with OW/OB. DESIGN, PATIENTS AND MEASUREMENTS: Medical records of 971 girls with premature breast development who underwent subcutaneous GnRHa (100 µg of triptorelin acetate) test were reviewed. All girls were classified as either CPP or premature thelarche. All of them were further classified into two groups according to their body mass index as NW and OW/OB groups for each Tanner stage. RESULTS: There were 634 and 337 girls in NW and OW/OB groups, respectively. CPP was diagnosed in 600 girls (249 had Tanner stage II and 351 had Tanner stage III). There were no differences in peak serum LH concentrations between CPP girls with NW and OW/OB. Peak serum LH cut-off of 5 IU/L (the current widely used cut-off) had a sensitivity and a specificity of 75% and 90%, respectively in NW group. Peak serum LH cut-off for CPP diagnosis was lower at 4 IU/L in the OW/OB group with greater sensitivity and specificity of 86% and 93%, respectively. The results were reproducible for each Tanner stage of breasts. CONCLUSION: Lower peak serum LH cut-off to 4 IU/L for diagnosing CPP in girls with OW/OB should be considered to avoid underdiagnosis of the condition.

Endocrine profile of the kisspeptin receptor agonist MVT-602 in healthy premenopausal women with and without ovarian stimulation: results from 2 randomized, placebo-controlled clinical tricals.

BACKGROUND: Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 can induce oocyte maturation during in vitro fertilization treatment, including in women who are at high risk of ovarian hyperstimulation syndrome. MVT-602 is a potent kisspeptin receptor agonist with prospective utility to treat anovulatory disorders by triggering oocyte maturation and ovulation during medically assisted reproduction (MAR). Currently, the endocrine profile of MVT-602 during ovarian stimulation is unreported. OBJECTIVE: To determine the endocrine profile of MVT-602 in the follicular phase of healthy premenopausal women (phase-1 trial), and after minimal ovarian stimulation to more closely reflect the endocrine milieu encountered during MAR (phase-2a trial). DESIGN: Two randomized, placebo-controlled, parallel-group, dose-finding trials. SETTING: Clinical trials unit. PATIENTS: Healthy women aged 18-35 years, either without (phase-1; n = 24), or with ovarian stimulation (phase-2a; n = 75). INTERVENTIONS: Phase-1: single subcutaneous dose of MVT-602 (0.3, 1.0, or 3.0 µg) or placebo, (n = 6 per dose). Phase-2a: single subcutaneous dose of MVT-602 (0.1, 0.3, 1.0, or 3.0 µg; n = 16-17 per dose), triptorelin 0.2 mg (n = 5; active comparator), or placebo (n = 5). MAIN OUTCOME MEASURES: Phase-1: safety/tolerability; pharmacokinetics; and pharmacodynamics (luteinizing hormone [LH] and other reproductive hormones). Phase-2a: safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones); and time to ovulation assessed by transvaginal ultrasound. RESULTS: In both the trials, MVT-602 was safe and well tolerated across the entire dose range. It was rapidly absorbed and eliminated, with a mean elimination half-life of 1.3-2.2 hours. In the phase-2a trial, LH concentrations increased dose dependently; mean maximum change from baseline of 82.4 IU/L at 24.8 hours was observed after administration of 3 µg MVT-602 and remained >15 IU/L for 33 hours. Time to ovulation after drug administration was 3.3-3.9 days (MVT-602), 3.4 days (triptorelin), and 5.5 days (placebo). Ovulation occurred within 5 days of administration in 100% (3 µg), 88% (1 µg), 82% (0.3 µg), and 75% (0.1 µg), of women after MVT-602, 100% after triptorelin and 60% after placebo. CONCLUSIONS: MVT-602 induces LH concentrations of similar amplitude and duration as the physiological midcycle LH surge with potential utility for induction of oocyte maturation and ovulation during MAR. CLINICAL TRIAL REGISTRATION NUMBER: EUDRA-CT: 2017-003812-38, 2018-001379-20.

Oral dydrogesterone versus micronized vaginal progesterone for luteal phase support: a double-blind crossover study investigating pharmacokinetics and impact on the endometrium.

STUDY QUESTION: How do plasma progesterone (P) and dydrogesterone (D) concentrations together with endometrial histology, transcriptomic signatures, and immune cell composition differ when oral dydrogesterone (O-DYD) or micronized vaginal progesterone (MVP) is used for luteal phase support (LPS)? SUMMARY ANSWER: Although after O-DYD intake, even at steady-state, plasma D and 20αdihydrodydrogesterone (DHD) concentrations spiked in comparison to P concentrations, a similar endometrial signature was observed by histological and transcriptomic analysis of the endometrium. WHAT IS KNOWN ALREADY: O-DYD for LPS has been proven to be noninferior compared to MVP in two phase III randomized controlled trials. Additionally, a combined individual participant data and aggregate data meta-analysis indicated that a higher pregnancy rate and live birth rate may be obtained in women receiving O-DYD versus MVP for LPS in fresh IVF/ICSI cycles. Little data are available on the pharmacokinetic (PK) profiles of O-DYD versus MVP and their potential molecular differences at the level of the reproductive organs, particularly at the endometrial level. STUDY DESIGN, SIZE, DURATION: Thirty oocyte donors were planned to undergo two ovarian stimulation (OS) cycles with dual triggering (1.000 IU hCG + 0.2 mg triptorelin), each followed by 1 week of LPS: O-DYD or MVP, in a randomized, cross-over, double-blind, double-dummy fashion. On both the first and eighth days of LPS, serial blood samples upon first dosing were harvested for plasma D, DHD, and P concentration analyses. On Day 8 of LPS, an endometrial biopsy was collected for histologic examination, transcriptomics, and immune cell analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: All oocyte donors were <35 years old, had regular menstrual cycles, no intrauterine contraceptive device, anti-Müllerian hormone within normal range and a BMI ≤29 kg/m2. OS was performed on a GnRH antagonist protocol followed by dual triggering (1.000 IU hCG + 0.2 mg triptorelin) as soon as ≥3 follicles of 20 mm were present. Following oocyte retrieval, subjects initiated LPS consisting of MVP 200 mg or O-DYD 10 mg, both three times daily. D, DHD, and P plasma levels were measured using liquid chromatography-tandem mass spectrometry. Histological assessment was carried out using the Noyes criteria. Endometrial RNA-sequencing was performed for individual biopsies and differential gene expression was analyzed. Endometrial single-cell suspensions were created followed by flow cytometry for immune cell typing. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 21 women completed the entire study protocol. Subjects and stimulation characteristics were found to be similar between groups. Following the first dose of O-DYD, the average observed maximal plasma concentrations (Cmax) for D and DHD were 2.9 and 77 ng/ml, respectively. The Cmax for D and DHD was reached after 1.5 and 1.6 h (=Tmax), respectively. On the eighth day of LPS, the first administration of that day gave rise to a Cmax of 3.6 and 88 ng/ml for D and DHD, respectively. For both, the observed Tmax was 1.5 h. Following the first dose of MVP, the Cmax for P was 16 ng/ml with a Tmax of 4.2 h. On the eighth day of LPS, the first administration of that day showed a Cmax for P of 21 ng/ml with a Tmax of 7.3 h. All 42 biopsies showed endometrium in the secretory phase. The mean cycle day was 23.9 (±1.2) in the O-DYD group versus 24.0 (±1.3) in the MVP group. RNA-sequencing did not reveal significantly differentially expressed genes between samples of both study groups. The average Euclidean distance between samples following O-DYD was significantly lower than following MVP (respectively 12.1 versus 18.8, Mann-Whitney P = 6.98e-14). Immune cell profiling showed a decrease of CD3 T-cell, γδ T-cell, and B-cell frequencies after MVP treatment compared to O-DYD, while the frequency of natural killer (NK) cells was significantly increased. LIMITATIONS, REASONS FOR CAUTION: The main reason for caution is the small sample size, given the basic research nature of the project. The plasma concentrations are best estimates as this was not a formal PK study. Whole tissue bulk RNA-sequencing has been performed not correcting for bias caused by different tissue compositions across biopsies. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study comparing O-DYD/MVP, head-to-head, in a randomized design on a molecular level in IVF/ICSI. Plasma serum concentrations suggest that administration frequency is important, in addition to dose, specifically for O-DYD showing a rapid clearance. The molecular endometrial data are overall comparable and thus support the previously reported noninferior reproductive outcomes for O-DYD as compared to MVP. Further research is needed to explore the smaller intersample distance following O-DYD and the subtle changes detected in endometrial immune cells. STUDY FUNDING/COMPETING INTEREST(S): Not related to this work, C.Bl. has received honoraria for lectures, presentations, manuscript writing, educational events, or scientific advice from Abbott, Ferring, Organon, Cooper Surgical, Gedeon-Richter, IBSA, and Merck. H.T. has received honoraria for lectures, presentations, manuscript writing, educational events, or scientific advice from Abbott, Ferring, Cooper Surgical, Gedeon-Richter, Cook, and Goodlife. S.M. has received honoraria for lectures, presentations, educational events, or scientific advice from Abbott, Cooper Surgical, Gedeon-Richter, IBSA, and Merck and Oxolife. G.G. has received honoraria for lectures, presentations, educational events, or scientific advice from Merck, MSD, Organon, Ferring, Theramex, Gedeon-Richter, Abbott, Biosilu, ReprodWissen, Obseva, PregLem, Guerbet, Cooper, Igyxos, and OxoLife. S.V.-S. is listed as inventor on two patents (WO2019115755A1 and WO2022073973A1), which are not related to this work. TRIAL REGISTRATION NUMBER: EUDRACT 2018-000105-23.

Effects of Deslorelin on Testosterone Secretion and Testicular Volume in Male Rhesus Macaques (Macaca mulatta).

Sterility in male NHP has long been achieved through surgical castration or vasectomy. However, these techniques are irreversible, require a surgical procedure, and have potential consequences such as sperm granulomas and long recovery time. Deslorelin is a gonadotropin-releasing hormone agonist that temporarily and reversibly suppresses sex hormone secretion. Our goal in this study was to investigate the effects of deslorelin on testosterone secretion and testicular volume in male rhesus macaques (Macaca mulatta). Male macaques (n = 4) each received two, 4.7-mg deslorelin implants subcutaneously in the interscapular region. Serum testosterone and testicular volume were then monitored at specific time points until 10 mo after treatment. Testosterone suppression was defined as testosterone levels lower than 0.6 ng/mL for a sustained period of at least 30 d. After implantation, mean testicular volume was significantly reduced by day 121. Testosterone suppression was observed in all subjects. However, the time from implantation to testosterone suppression and duration of suppression varied. Two macaques were hormonally suppressed by day 26 after implantation and remained suppressed for at least 6 mo. The other 2 macaques were hormonally suppressed by 2 mo after implantation; of these two, one remained suppressed for 70 days while the other was suppressed for at least 245 days. We conclude that deslorelin can safely suppress testosterone secretion in male rhesus macaques, but individual variation in onset and duration of action should be considered when establishing reimplantation time points and potential return to reproductive activity.

Ameliorative effects of aerobic training in girls with precocious puberty: role of leptin and ghrelin.

This study was an attempt to examine the changes in serum levels of ghrelin and leptin after 12-weeks of aerobic training and gonadotropin releasing hormone agonist (GnRH) treatment in girls with central precocious puberty. Thirty girls (6-8 years old) with precocious puberty who had received Triptorelin were randomly divided in two groups (medication and medication + training). Fifteen age-matched healthy girls (without precocious puberty) were also included as the control group. The medication + training group submitted an aerobic training program for 3 days/week with 20-75 min per day and 45-75% of maximum heart rate for 12-weeks. Serum levels of leptin, ghrelin, cholesterol, triglycerides and body mass index (BMI) were determined at baseline and 48 h after the last training session. The results indicated that leptin significantly decreased (p = 0.001) and ghrelin significantly increased (p = 0.001) in the medication + training group but no significant difference was observed in the ghrelin (p = 1) and leptin (p = 0.78) in the medication group. Leptin to ghrelin ratio indicated a decrease in medicine + training group (p = 0.028). Ghrelin were negatively correlated with leptin and BMI. The data indicated that aerobic training increased ghrelin and reduced leptin and leptin to ghrelin ratio but GnRH agonist treatment had no effect on plasma leptin and ghrelin levels.

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.

Short-term clinical and hormonal effects of a deslorelin implant on late-prepubertal bitches - Based on flare-up signs.

Gonadotropin-releasing hormone (GnRH) agonists offer an alternative to surgical sterilization in prepubertal dogs, preserving ovarian and uterine functions. However, the clinical and hormonal effects of GnRH agonist application during the late-prepubertal stage remain insufficiently understood. This study aimed to investigate the clinical effect (flare-up) and hormonal changes, specifically serum progesterone (P4) and estradiol (E2) levels, in bitches treated with 4.7 mg deslorelin acetate (DA) implants (Suprelorin®, Virbac, F) during the late prepubertal period. Sixteen clinically healthy kangal cross-breed bitches, aged 7-8 months, with a mean body weight of 20.5 ± 0.8 kg, were implanted with DA. Estrus signs were monitored daily, and blood and vaginal cytological samples were collected every other day for four weeks. Cytological changes were analyzed for overall and superficial cell index. Six out of sixteen DA-treated bitches (EST group; n = 6) exhibited clinical proestrus 8.6 ± 0.6 days after implant insertion. The mean serum concentrations of P4 and E2 at the onset of estrus were 1.38 ± 0.32 ng/ml and 37.38 ± 10.07 pg/ml, respectively. Notably, all non-estrus (N-EST group; n = 10) bitches demonstrated an increase in superficial cell index, in addition to expected cytological changes observed in the EST group. On the 18th day post-implantation, the EST group exhibited a significantly higher number of superficial cells compared to the N-EST group (p < 0.001). DA implantation resulted in cytological profile alterations accompanied by a slight increase in estrogen concentrations in all dogs. However, the flare-up response exhibited significant variability, differing from that observed in adult dogs. This study highlights the importance of meticulous timing and breed-specific considerations when utilizing DA for puberty manipulation in late-prepubertal bitches. The observed cytological and hormonal changes in response to DA implants provide valuable insights, but the variability in flare-up responses warrants further investigation.

Sex Steroids Regulate Liver Fat Content and Body Fat Distribution in Both Men and Women: A Study in Transgender Persons.

CONTEXT: Liver fat content and visceral fat volume are associated with insulin resistance and cardiovascular disease and are higher in men than in women. OBJECTIVE: To determine the effect of estradiol and testosterone treatment on liver fat and visceral fat in transgender persons. DESIGN: Open-label intervention study (SHAMVA) with a 1-year follow-up. SETTING: Gender clinic in a hospital. PATIENTS: 8 trans women and 18 trans men receiving hormone treatment. INTERVENTIONS: Trans women received an antiandrogen and after 6 weeks estradiol was added. Trans men were randomized to receive triptorelin, testosterone, and anastrozole for 12 weeks or triptorelin and testosterone for 12 weeks, followed by only testosterone until week 52. MAIN OUTCOME MEASURES: Liver fat content, visceral and abdominal subcutaneous fat volume, measured by magnetic resonance spectrometry or imaging at baseline, 6, 8, 18, and 58 weeks in transwomen or at baseline; at 6 and 12 weeks in trans men with anastrozole; and at 52 weeks in trans men without anastrozole. RESULTS: In trans women, liver fat content decreased by 1.55% (-2.99 to -0.12) after 58 weeks, compared to week 6. Visceral fat did not change. In trans men with anastrozole, the liver fat content and visceral fat volume did not change. In trans men without anastrozole, after 52 weeks, liver fat content increased by 0.83% (0.14 to 1.52) and visceral fat volume increased by 34% (16 to 51). CONCLUSIONS: Sex hormones regulate liver fat content and visceral fat in men and women.

The Finding of New In Vivo Metabolite Triptorelin (5-10) in Human Urine Using Liquid Chromatography Coupled with Ion Trap/Time-of-Flight Mass Spectrometry with Dimethyl Sulfoxide Additives in the Mobile Phase.

Triptorelin and leuprorelin are synthetic gonadotrophin-releasing hormones (GnRH) that are on the World Anti-Doping Agency (WADA) list of prohibited substances. To investigate the possible in vivo metabolites of triptorelin and leuprorelin in humans compared to previously reported in vitro metabolites, excreted urine from five patients treated with either triptorelin or leuprorelin was analyzed by liquid chromatography coupled with ion trap/time-of-flight mass spectrometry (LC/MS-IT-TOF). The addition of dimethyl sulfoxide (DMSO) to the mobile phase was found to enhance the detection sensitivity of certain GnRH analogs. The method was validated, and the limit of detection (LOD) was found at 0.02-0.08 ng/mL. Using this method, a novel new metabolite of triptorelin was discovered in the urine of all subjects up to 1 month after triptorelin administration, but it was not observed in the urine of subjects before drug administration. The limit of detection was estimated to be 0.05 ng/mL. The structure of the metabolite, triptorelin (5-10), is proposed from bottom-up mass spectrometry analysis. The discovery of in vivo triptorelin (5-10) can possibly be used as supporting evidence of triptorelin misuse in athletes.

Triptorelin nanoparticle-loaded microneedles for use in assisted reproductive technology.

Triptorelin is a first-line drug for assisted reproductive technology (ART), but the low bioavailability and frequent subcutaneous injection of triptorelin impair the quality of life of women preparing to become pregnant. We report silk fibroin (SF)-based microneedles (MNs) for transdermal delivery of triptorelin-loaded nanoparticles (NPs) to improve bioavailability and achieve safe and efficacious self-administration of triptorelin. Triptorelin was mixed into an aqueous solution of SF with shear force to prepare NPs to control the release and avoid the degradation of triptorelin by enzymes in the skin. Two-step pouring and centrifugation were employed to prepare nanoparticles-encapsulated polymeric microneedles (NPs-MNs). An increased ß-sheet content in the conformation ensured that NPs-MNs had good mechanical properties to pierce the stratum corneum. Transdermal release of triptorelin from NPs-MNs was increased to ∼65%. The NPs-MNs exhibited a prolonged drug half-life and increased relative bioavailability after administration to rats. Surging levels of luteinizing hormone and estradiol in plasma and their subsequent prolonged downregulation indicate the potential therapeutic role of NPs-MNs in ART regimens. The triptorelin-loaded NPs-MNs developed in this study may reduce the physical and psychological burden of pregnant women using ART regimens.

Effects of water-soluble additive on the release profile and pharmacodynamics of triptorelin loaded in PLGA microspheres.

A satisfactory drug release profile for gonadotropin-releasing hormone (GnRH) agonist drugs is high initial release followed by small amount of drug release per day. In the present study, three water-soluble additives (NaCl, CaCl2 and glucose) were selected to improve the drug release profile of a model GnRH agonist drug-triptorelin from PLGA microspheres. The pore manufacturing efficiency of the three additives was similar. The effects of three additives on drug release were evaluated. Under the optimal initial porosity, the initial release amount of microspheres containing different additives was comparable, this ensured a good inhibitory effect on testosterone secretion in the early stage. For NaCl or CaCl2 containing microspheres, the drug remaining in the microsphere depleted rapidly after the initial release. The testosterone concentration gradually returned to an uncontrolled level. However, for glucose containing microspheres, it was found that the addition of glucose could not only increase the initial release of the drug but also assist in the subsequent controlled drug release. A good and long-time inhibitory effect on testosterone secretion was observed in this formulation. The underlying cause why the incorporation of glucose delayed the subsequent drug release was investigated. SEM results showed that considerable pores in glucose containing microspheres were healed during the microspheres incubation. After thermal analysis, an obvious glass transition temperature (Tg) depression was observed in this formulation. As Tg decreased, polymer chains are able to rearrange at lower temperatures. This, morphologic change was reflected in the gradual closure of the pores, and is the likely reason that drug release slowed down after the initial release.HIGHLIGHTSThe addition of glucose could not only increase the burst release of the drug but also delay the subsequent drug release.High initial burst and a sustained drug release helped obtain a good inhibitory effect on testosterone secretion.As Tg decreased, polymer chain was prone to rearrange. Morphologic change was reflected in the gradual closure of the pores. This was the reason that drug release slowed down after the initial burst.

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.

Impact of 6-month triptorelin formulation on predicted adult height and basal gonadotropin levels in patients with central precocious puberty.

Background: Triptorelin, a long-acting gonadotropin-releasing hormone (GnRH) agonist, is available in 1-, 3-, and 6-month formulations to treat central precocious puberty (CPP). The triptorelin pamoate 22.5-mg 6-month formulation recently approved for CPP offers greater convenience to children by reducing the injection frequency. However, worldwide research on using the 6-month formulation to treat CPP is scarce. This study aimed to determine the impact of the 6-month formulation on predicted adult height (PAH), changes in gonadotropin levels, and related variables. Methods: We included 42 patients (33 girls and nine boys) with idiopathic CPP treated with a 6-month triptorelin (6-mo TP) formulation for over 12 months. Auxological parameters, including chronological age, bone age, height (cm and standard deviation score [SDS]), weight (kg and SDS), target height (TH), and Tanner stage, were evaluated at baseline, and after 6, 12, and 18 months of treatment. Hormonal parameters, including serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol for girls or testosterone for boys, were analyzed concurrently. Results: The mean age at treatment initiation was 8.6 ± 0.83 (8.3 ± 0.62 for girls, 9.6 ± 0.68 for boys). The peak LH level following intravenous GnRH stimulation at diagnosis was 15.47 ± 9.94 IU/L. No progression of the modified Tanner stage was observed during treatment. Compared to baseline, LH, FSH, estradiol, and testosterone were significantly reduced. In particular, the basal LH levels were well suppressed to less than l.0 IU/L, and the LH/FSH ratio was less than 0.66. The bone age/chronological age ratio remained stable with a decreasing trend (1.15 at the start of treatment, 1.13 at 12 months, 1.11 at 18 months). PAH SDS increased during treatment (0.77 ± 0.79 at baseline, 0.87 ± 0.84 at the start of treatment, 1.01 ± 0.93 at six months, and 0.91 ± 0.79 at 12 months). No adverse effects were observed during treatment. Conclusion: The 6-mo TP suppressed the pituitary-gonadal axis stably and improved the PAH during treatment. Considering its convenience and effectiveness, a significant shift to long-acting formulations can be expected.

EFFECTS OF A GNRH VACCINE AND DESLORELIN ACETATE IMPLANTS IN MALE FRESHWATER STINGRAYS (POTAMOTRYGON SP.).

Very little information is available in veterinary literature concerning chemical contraception in elasmobranchs. To decrease breeding and adverse reproductive behaviors, male Potamotrygon sp., housed in two zoologic institutions, were treated using methods used in other elasmobranchs. Four animals received deslorelin acetate implants (Suprelorin 4.7 mg and 9.4 mg), four animals received a gonadotropin-releasing hormone vaccine (Improvac 50-100 µg) twice separated by 1 mon, and two animals were not treated to serve as controls. Health checks, including blood sampling, coelomic ultrasound, and sperm analysis, were performed bimonthly and then monthly over almost 2 yr. Microscopic examination of sperm never revealed any significant change in concentration or motility. Size of testes and seminal vesicles glands did not change significantly after treatment. Plasma testosterone concentrations were stable (∼1 ng/ml) in intact and vaccinated animals throughout the study period. Plasma testosterone level increased significantly after deslorelin implantation and remained very high for at least 13 mon, never returning to initial values. Peak concentration varied according to the deslorelin acetate concentration used. Aggression toward females continued despite the use of contraception. Histopathologic examination on dead stingrays revealed active testicular tissue. These results suggest that deslorelin acetate implants and GnRH vaccine are ineffective at dosages used in our cases. Implants caused a continuous stimulation of the hypothalamic-pituitary-gonadal axis that could be harmful for the animals.

Endocrine Responses to Triptorelin in Healthy Women, Women With Polycystic Ovary Syndrome, and Women With Hypothalamic Amenorrhea.

CONTEXT: Limited data exist regarding whether the endocrine response to the gonadotropin-releasing hormone receptor agonist (GnRHa) triptorelin differs in women with polycystic ovary syndrome (PCOS) compared with healthy women or those with hypothalamic amenorrhea (HA). OBJECTIVE: We compared the gonadotropin response to triptorelin in healthy women, women with PCOS, or those with HA without ovarian stimulation, and in women with or without polycystic ovaries undergoing oocyte donation cycles after ovarian stimulation. METHODS: The change in serum gonadotropin levels was determined in (1) a prospective single-blinded placebo-controlled study to determine the endocrine profile of triptorelin (0.2 mg) or saline-placebo in healthy women, women with PCOS, and those with HA, without ovarian stimulation; and (2) a retrospective analysis from a dose-finding randomized controlled trial of triptorelin (0.2-0.4 mg) in oocyte donation cycles after ovarian stimulation. RESULTS: In Study 1, triptorelin induced an increase in serum luteinizing hormone (LH) of similar amplitude in all women (mean peak LH: healthy, 52.3; PCOS, 46.2; HA, 41.3 IU/L). The AUC of change in serum follicle-stimulating hormone (FSH) was attenuated in women with PCOS compared with healthy women and women with HA (median AUC of change in serum FSH: PCOS, 127.2; healthy, 253.8; HA, 326.7 IU.h/L; P = 0.0005). In Study 2, FSH levels 4 hours after triptorelin were reduced in women with at least one polycystic morphology ovary (n = 60) vs normal morphology ovaries (n = 91) (34.0 vs 42.3 IU/L; P = 0.0003). Serum anti-Müllerian hormone (AMH) was negatively associated with the increase in FSH after triptorelin, both with and without ovarian stimulation. CONCLUSION: FSH response to triptorelin was attenuated in women with polycystic ovaries, both with and without ovarian stimulation, and was negatively related to AMH levels.

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.

Vasculitis-like Palpable Purpuric Rash Induced by Decapeptyl in a Pediatric Patient Diagnosed Central Precocious Puberty

Central precocious puberty (CPP) is defined as the appearance of secondary sexual signs in girls younger than eight years of age or the onset of menarche before the age of 10 years. Gonadotropin-releasing hormone analogs (GnRHa) are the most effective therapy in CPP. Drug-induced hypersensitivity vasculitis is an inflammation of blood vessels, which may be due to the use of a number of pharmacologic agents. This case report describes drug-induced vasculitis in a girl being treated with Decapeptyl. A 7.25 year-old girl was admitted to Pediatric Endocrinology outpatients with premature breast development. She was diagnosed with CPP on the basis of physical examination and laboratory findings and tripoteline acetate (Decapeptyl®) treatment was initiated. She experienced multiple widespread skin rashes and mild abdominal pain with high temperature eight hours after the second dose of Decapeptyl. She was admitted to hospital with the diagnosis of drug-induced vasculitis and a single dose of intravenous methyl-prednisolone (1 mg/kg) and oral cetirizine was given. Her blood and urine analysis revealed no other organ involvement, other than skin. On the third day, the purpuric lesions began to resolve and had completely disappeared by the sixth day. Her treatment for CPP was switched to Depot Leuprolide acetate and she continued her treatment for two years uneventfully. To the best of our knowledge, this is the first report of a child with CPP experiencing drug-induced vasculitis due to tripotelin injection. Effective treatment may be continued by switching to an alternative gonadotropin releasing hormone analog.