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Background Endometriosis is the major cause of progressive pelvic pain and subfertility. Up to 50% of reproductive-age women suffer from pelvic pain. Endometriosis is a classic indication for IVF. Compared with women whose inability to procreate is caused by simple tubal infertility, women with endometriosis often have lower pregnancy rates following in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). The administration of gonadotrophin-releasing hormone (GnRH) agonists prior to IVF/ICSI can improve the successful pregnancy rate. Whether a briefer treatment interval would be efficacious has not been studied. Methods/design Eligible and consenting women will be randomly assigned to one of two treatments (one cycle of a GnRH agonist or two cycles of a GnRH agonist) prior to IVF/ICSI using a table of random numbers. The primary outcome of this trial is clinical pregnancy rate. Other outcomes include gonadotrophin (Gn) duration, the total dose of follicle-stimulating hormone (FSH) used, number of oocytes retrieved, number of embryos available for transfer, implantation rate, the abortion rate, live birth rate, and incidence of moderate-to-severe ovarian hyperstimulation. The sample size of this trial is estimated to be 421 participants for each of the two arms. Appropriate interim analyses will be conducted by a data monitoring and ethics committee (DMEC), and the final test will be an intention-to-treat analysis. Trial registration This trial has been assigned the following registry number: NCT03006406 .

Triptorelin, a gonadotropin-releasing hormone agonist, has been used in the treatment of hormone-responsive prostate cancer by inducing testosterone suppression. Research on the relationship between the time courses of triptorelin and testosterone is very important, but accurate quantification of triptorelin and testosterone simultaneously in biological specimens is a challenging analytical problem. In the present study, a rapid, sensitive, and selective method for simultaneous determination of triptorelin and testosterone in rat plasma by solid-phase extraction and liquid chromatography–tandem mass spectrometry was developed using a ZORBAX RRHD Eclipse Plus C8 column (2.1 × 50 mm, 1.8 μm) with a 0.05 % propionic acid/methanol gradient. In view of the polarity difference between the two analytes, two internal standards, i.e., leuprolide and testosterone- 13 C 3 , were used for individual quantitation of triptorelin and testosterone. Endogenous testosterone was determined by reference to a calibration curve prepared using testosterone-D 3 as a surrogate analyte. The method exhibits excellent linearity over three orders of magnitude for each analyte. The lower limit of quantification was 0.01 ng/mL for triptorelin and 0.05 ng/mL for testosterone, with consumption of 100 μL of plasma. The method was successfully applied to characterize the pharmacokinetics and pharmacodynamics of slow-release 28-day form triptorelin acetate biodegradable microspheres in rats after intramuscular injections of three consecutive doses of 0.6 mg/kg per 28 days. The results revealed that the pharmacokinetic profile of triptorelin produced an initial flare-up in testosterone levels, rapid castration within 5 days after injection, and long-term castration until the next dose. Figure Analytical strategy to characterize the PK/PD properties of triptorelin

Background. Few data are available on quarterly 11.25 mg GnRH analog treatment in central precocious puberty (CPP). Aim. To assess the efficacy of triptorelin 11.25 mg in children with CPP. Patients. 17 patients (16 females) with CPP (7.9±0.9 years) were treated with triptorelin 11.25 mg/90 days. Methods. Gonadotropins, basal-, and GnRH-stimulated peak, gonadal steroids, and pubertal signs were assessed at preinclusion and at inclusion visit, 3 months, 6 months, and 12 months of treatment. Results. At 3, 6, and 12 months, all patients had suppressed LH peak (<3 IU/L after GnRH stimulation), as well as prepubertal oestradiol levels. Mean LH peak values after GnRH test significantly decreased from 25.7±16.5 IU/L at baseline to 0.9±0.5 IU/L at M3 (P<0.0001); they did not significantly changed at M6 and M12. Conclusions. Triptorelin 11.25 mg/90 days efficiently suppressed the pituitary-gonadal axis in children with CPP from first administration.

Aromatase inhibitors are somewhat more effective than tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer. This benefit was extended to premenopausal women when they also received ovarian suppression to prevent ovarian compensation for aromatase inhibition. The most effective adjuvant endocrine therapy for premenopausal women with hormone-receptor (estrogen, progesterone, or both)–positive breast cancer is uncertain. Tamoxifen for at least 5 years is a standard of care. 1 – 3 Adjuvant suppression of ovarian function (hereafter, ovarian suppression) may be recommended in addition. For postmenopausal women, adjuvant therapy with an aromatase inhibitor, as compared with tamoxifen, improves outcomes. 2 – 9 In 2003, the International Breast Cancer Study Group (IBCSG) initiated two randomized, phase 3 trials, the Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT), involving premenopausal women with hormone-receptor–positive early breast cancer, through collaboration with . . .

Triptorelin is an established treatment for central precocious puberty (CPP) as 1- and 3-month formulations. The current triptorelin 22.5 mg 6-month formulation is approved for prostate cancer therapy. This is the first study in patients with CPP. The efficacy and safety of the triptorelin 6-month formulation in CPP were investigated. The primary objective was to evaluate the efficacy in achieving luteinizing hormone (LH) suppression to pre-pubertal levels at month 6. This was an international, non-comparative phase III study over 48 weeks. Eighteen medical centers in the US, Chile and Mexico participated. Forty-four treatment naïve patients (39 girls and five boys) aged at treatment start 2–8 years for girls and 2–9 years for boys with an advancement of bone age over chronological age ≥1 year were to be included. Triptorelin was administered im twice at an interval of 24 weeks. LH, follicle stimulating hormone (FSH) (basal and stimulated), estradiol (girls), testosterone (boys), auxological parameters, clinical signs of puberty and safety were assessed. Forty-one patients (93.2%) showed pre-pubertal LH levels (stimulated LH ≤5 IU/L) at month 6 and maintained LH suppression through month 12. The percentage of patients with LH suppression exceeded 93% at each time point and reached 97.7% at month 12. No unexpected drug-related adverse events were reported. The triptorelin 6-month formulation was safe and effective in suppressing the pituitary-gonadal axis in children with CPP. The extended injection interval may improve compliance and increase comfort in the management of CPP.

Treatment with a luteinizing hormone–releasing hormone (LHRH) agonist increases adult height in children with precocious puberty. This study was designed to determine whether LHRH-agonist therapy would increase adult height in short adolescents with normally timed puberty. The adolescents had an increase of 0.6 in the standard-deviation score for height, as compared with the initially predicted adult height; however, bone mineral density was decreased. An LHRH agonist cannot be recommended. Puberty first accelerates the rate of growth and then induces epiphyseal fusion, terminating the growth of long bones. 1 In the 1970s, long-acting agonists of luteinizing hormone–releasing hormone (LHRH) were shown to suppress gonadotropin secretion. In children with LHRH-dependent precocious puberty, treatment with LHRH agonists slows bone maturation, delays epiphyseal fusion, and increases adult height. 2 – 7 Studies of patients with hypogonadotropic hypogonadism, 8 estrogen insensitivity, 9 or estrogen deficiency 10 have suggested that prolonging the period of growth by delaying senescence of the growth plate 11 can increase adult height. However, changes in the tempo of puberty within the normal range do not influence adult . . .

Background The prevalence of precocious puberty is increasing. Obesity has been demonstrated to be associated with changes in the adipokine profile and incidence of early puberty in girls. This study assessed the pubertal signs, the levels of adiponectin, resistin, and tumor necrosis factor-alpha (TNF-α) after 12 weeks of combined exercise and 4 weeks of detraining in overweight and obese girls with precocious puberty. Methods Thirty overweight and obese girls (aged 7–9) with precocious puberty, who had received Triptorelin, were randomly divided into two groups (15 exercise and 15 control). Initially, serum levels of adiponectin, resistin, TNF-α, luteinising hormone (LH), and follicle-stimulating hormone (FSH) and the signs of puberty progression (bone age, uterine length, and ovarian volume) were measured. The exercise group performed 60 min of combined (aerobic and resistance) exercise three times/week for 12 weeks. The control group did not receive any exercise. 48 h after the last training session and after 4 weeks of detraining, all research variables were measured (also in the control group). The statistical method used for data analysis was repeated measures ANOVA. Results In the exercise group, adiponectin significantly increased and resistin significantly decreased after 12 weeks. After 4 weeks of detraining, adiponectin significantly decreased, but resistin significantly increased. TNF-α levels did not change significantly during the study. There was no significant difference in all of the factors in the control group. Throughout the 16-week study period, the rate of puberty and LH significantly decreased in both exercise and control groups, but FSH, LH/FSH and ovarian volume significantly decreased in the exercise group alone ( P <0.05). Conclusions Combined exercise increased adiponectin and decreased resistin and the rate of puberty. However, after 4 weeks of detraining, these effects diminished but did not disappear. Trial registration IRCT, IRCT56471. Registered 25 may 2021 - Retrospectively registered, https://fa.irct.ir/user/profile

Background Breast cancer is the most common malignancy among females. The Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT) were two landmark studies, which showed adjuvant therapy with the aromatase inhibitor (AI), exemestane, or tamoxifen combined with ovarian function suppression (OFS) improved disease-free survival (DFS) among premenopausal women (Pagani et al. in N Engl J Med 371(2):107–118, 2014). However, data has since emerged regarding incomplete OFS with Gonadotropin-releasing hormone (GnRH) agonists in some premenopausal patients. The SOFT Estrogen Substudy (SOFT-EST) was a prospective substudy of SOFT, which evaluated estradiol (E2) levels to determine if patients on exemestane and triptorelin experienced suboptimal ovarian function suppression. In this study, 17% of patients had an E2 level greater than 2.72 pg/mL at each time point, which was determined to be incomplete OFS. This study called into question whether E2 levels should routinely be monitored in women on GnRH agonists (Bellet et al. in J Clin Oncol 34(14):1584–1593, 2016). The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) provide recommendations to monitor E2 levels in premenopausal patients on an aromatase inhibitor (AI) due to the concern of incomplete OFS for patients receiving GnRH agonist therapy (Burstein et al. in J Clin Oncol 37(5):423–438, 2019, National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2024. www.nccn.org ). The purpose of our study is to develop and implement a protocol for monitoring E2 levels at Froedtert & MCW based on the NCCN and ASCO recommendations. Methods This study implemented an OFS monitoring guideline in combination with a collaborative practice agreement at Froedtert & MCW. Pharmacists were responsible for ordering and monitoring E2 levels monthly on eligible patients based on a specified protocol. An E2 level ≤ 2.72 pg/mL while receiving an AI or ≤ 21 pg/mL while receiving tamoxifen in addition to a GnRH agonist injection was defined as complete OFS. E2 levels were retrospectively analyzed to evaluate if patients had incomplete OFS and if clinical management changed based on those levels. The primary outcome was proportion of patients identified per the E2 monitoring protocol that fail to achieve OFS for two consecutive levels over an 18-month period. Nominal data were compared using the chi-squared or Fisher’s exact test, and continuous data using the Mann Whitney U or student’s t-test, where appropriate. Results A total of 85 patients were reviewed at the time of analysis. Fifty-three patients (62.4%) achieved complete OFS (three consecutive E2 levels within goal), compared to 17 patients (20%) demonstrating incomplete OFS. Seven patients (8.2%) did not have enough consecutive levels demonstrating complete or incomplete OFS and E2 lab monitoring continues. Eight patients (9.4%) declined lab monitoring. Out of the 17 patients with incomplete OFS, 14 underwent a change in their GnRH agonist as an intervention aimed at achieving complete OFS. Among these 14 patients, 7 successfully attained OFS, 5 continued to experience incomplete OFS, and 2 opted to decline future monitoring. . More patients were chemotherapy naïve in the continued incomplete OFS group compared to those who had complete OFS after intervention ( p  = 0.010). Conclusion Our study has shown a trend toward the need for checking E2 levels to assess for incomplete OFS and that changing GnRH agonist agent can improve rates of complete OFS for some patients. Additionally, our study has shown that chemotherapy naïve patients experience more incomplete OFS; however, further data is needed to validate these results.

The reproductive physiology of canines is unique from other mammals because oocyte maturation occurs about 48-72 hours after ovulation. This study aimed to evaluate the blood serum protein profile in canines during the periovulatory period by using shotgun proteomics to identify potential biomarkers of oocyte maturation. Anestrus female dogs (  = 9) were implanted subcutaneously with 4.7 mg of deslorelin to induce estrus and ovulation. After implantation, ovariectomy was performed based on the level of progesterone and vaginal cytology evaluations conducted every 48 hours. Simultaneously, serum samples were collected for proteomic analysis. The oocytes were flushed from the oviduct, and the oocyte maturation stage was identified. Based on oocyte staging, all samples were categorized into three groups (  = 3 dogs per group): pre-ovulation, ovulation with immature oocytes, and ovulation with mature oocytes. All serum samples were analyzed in triplicate (27 independent injections) using liquid chromatography-tandem mass spectrometry to investigate the protein profile. Proteomics analysis showed 11 proteins upregulated from three different groups: tubulin-specific chaperone D (TBCD); coiled-coil domain-containing protein 93 (CCDC93); WDFY family member 4 (WDFY4); calcium and integrin-binding protein 1 (CIB1); IQ motif containing E (IQCE); large ribosomal subunit protein uL23 N-terminal domain-containing protein (RPL23A); neuraminidase 4 (NEU4); G protein-coupled receptor kinase (GRK3); NF-keppaB inhibitor delta (NFKBID); leucine rich repeat containing 4B (LRRC4B); and Rho family-interacting cell polarization regulator 2 (RIPOR2). Among these proteins, NFKDIB, which are oocyte maturation markers in other mammalian species, was upregulated in the ovulation with mature oocyte group (  < 0.01). Therefore, NFKBID is a possible to be an oocyte maturation marker in canines, but further studies on larger populations are needed to confirm its potential.

Introduction Precocious puberty (PP) in girls is defined by thelarche before age 8. The diagnostic gold standard is an increased LH level following gonadotropin-releasing hormone (GnRH) stimulation. Alternatively, GnRH analogues like triptorelin can be used, though their interpretation varies. Since 2000, we have used a triptorelin-induced LH cut-off of 15 IU/L, 4 h post-stimulus. However, many girls showed LH values below this threshold despite evident pubertal progression. Purpose To establish a new LH threshold post-triptorelin stimulation for earlier diagnosis of central precocious puberty (CPP) in girls showing pubertal progression and to evaluate additional parameters for diagnostic accuracy. Methods We enrolled 186 girls with thelarche onset between ages 1–8 and a GnRH analogue assay performed between 2015–2019 without signs of axis activation. Within this cohort, 62 patients repeated the triptorelin test due to rapid pubertal progression. The assay involved administering 100 mcg/m² of triptorelin and measuring LH, FSH, and estradiol levels before and four hours post-injection. Results Patients with axis activation at the second test had significantly higher post-stimulus LH levels at the first test compared to those below 15 IU/L. They also had higher basal LH levels, elevated LH/FSH ratio, and increased growth velocity. Statistical analysis identified a new post-stimulus LH threshold of 5 IU/L. Conclusion We propose a LH value of 5 IU/L after triptorelin administration as a new threshold for early CPP diagnosis. While the LH/FSH ratio and growth velocity are associated with axis activation, they did not significantly enhance diagnostic accuracy when combined with the LH value.