Gonadotropin-releasing Hormone Research Articles

Diagnostic Value of Single LH and LH/FSH Ratio at 60-minute after GnRHa Stimulation Test for Central Precocious Puberty.

To evaluate the diagnostic value of luteinizing hormone (LH) and LH/follicle stimulating hormone (FSH) ratio at 60 min after gonadotropin-releasing hormone analogs (GnRHa) stimulation test for central precocious puberty (CPP) in girls. Two hundred and fifty-seven girls, aged 3 to 7.5 y, suspected of precocious puberty at authors' hospital from April 2020 through November 2023 were enrolled in the study. The blood was taken at 0, 30, 60 min after GnRHa stimulation test, and LH and LH/FSH were detected by chemiluminescence assay. The diagnostic efficacy was analysed by Mann-Whitney U test, spearman's correlation analysis and receiver operating characteristic (ROC) analysis. The proportion of obesity was analysed by Chi-square test. LH and LH/FSH at different times were statistically significantly different (P <0.05) between the CPP and non-CPP groups. Spearman's correlation analysis showed that the level of LH and LH/FSH at 60 min had the strongest consistency with the peak of LH (r = 0.9988, P <0.001) and LH/FSH (r = 0.9981, P <0.001). ROC curve analysis showed that the area under the ROC curves at 60 min of LH and LH/FSH were 0.975 and 0.997 with a cut-off value of 5.70 IU/L and 0.609, respectively. The peak of LH and LH/FSH in the diagnosis of CPP can be determined by LH and LH/FSH at 60 min after the triptorelin acetate is injected. This will reduce the number of blood draws required compared with the traditional stimulation test, which is more effective and acceptable for children.

GnRH peripherally modulates nociceptor functions, exacerbating mechanical pain

The function of peripheral nociceptors, the neurons that relay pain signals to the brain, are frequently tuned by local and systemic modulator substances. In this context, neurohormonal effects are emerging as an important modulatory mechanism, but many aspects remain to be elucidated. Here we report that gonadotropin-releasing hormone (GnRH), a brain-specific neurohormone, can aggravate pain by acting on nociceptors in mice. GnRH and GnRHR, the receptor for GnRH, are expressed in a nociceptor subpopulation. Administration of GnRH and its analogue, localized for selectively affecting the peripheral neurons, deteriorated mechanical pain, which was reproducible in neuropathic conditions. Nociceptor function was promoted by GnRH treatment in vitro, which appears to involve specific sensory transient receptor potential ion channels. These data suggest that peripheral GnRH can positively modulate nociceptor activities in its receptor-specific manner, contributing to pain exacerbation. Our study indicates that GnRH plays an important role in neurohormonal pain modulation via a peripheral mechanism.

Advancing Age May Decrease Mitochondrial Activity in Cumulus Cells

Background: The goal of this study was to compare mitochondrial activity in cumulus cells (CCs) between young and advancing-aged women, the factors that affect mitochondrial activity, and their association with blastocyst quality. Materials and methods: This prospective study included 80 infertile women who underwent ICSI between May and October 2023. Participants were divided into two groups: older and younger than 38. The oocyte mitochondrial activity from CCs was evaluated using MitoTracker, and the mean fluorescence intensity (MFI) was also evaluated. Results: The univariate and multivariate analyses revealed a significant difference in the MFI between the woman ≥ 38 age group and the lower age group (162.68 ± 79.87 vs. 228.39 ± 121.38; p-value = 0.005; 95%CI 19.97, 111.45). The factors that affected the MFI were women ≥ 38 years of age (p-value = 0.005; 95%CI −111.45, −19.91), total gonadotropin dosages (p-value = 0.006; 95%CI −0.08, 0.01), and gonadotropin-releasing hormone agonist (GnRHa) triggering (p-value = 0.006; 95%CI 36.46, 210.06). However, only women aged ≥38 years remained statistically significant after a multivariable regression analysis (p-value = 0.014; 95%CI −121.00, −14.30). In addition, only male age (mean age ± SD = 38.26 ± 5.13) was associated with high blastocyst quality in univariate and mixed multivariate analyses (OR 0.91; 95%CI 0.56, 3.04). The chemical pregnancy rate was not significantly different between the two age groups (34.5% vs. 56.7%; p-value = 0.162; 95%CI 0.2, 1.30). Conclusion: Advancing age decreased mitochondrial activity in CCs but did not affect blastocyst quality. By contrast, male age may be a predictor of high-grade blastocyst quality.

Gonadotropin-releasing hormone antagonist (relugolix) for treatment of uterine adenomyosis with symptomatic endometriosis

Objective: To determine the effects of relugolix administration for uterine adenomyosis on uterine volume and subjective symptoms. Methods: This retrospective observational study included 30 patients with clinical symptoms of endometriosis complicated with uterine adenomyosis who were treated with 40 mg/day of relugolix orally for &gt;16 weeks. The uterine volume was calculated pre- and post-administration, and the volume percentage post-administration. Furthermore, the presence or absence of subjective post-administration symptoms and adverse effects were also examined. Results: The median (interquartile range) long diameter, short diameter, width, and volume of the patients’ uteri pre- and post-administration of relugolix significantly decreased from 9.63 (9.02–11.00) to 8.00 (6.84–9.12) cm, 6.47 (5.58–8.02) to 5.00 (4.26–5.63) cm, 6.91 (5.68–8.46) to 5.49 (4.58–6.00) cm, and 221.04 (146.52–390.26) to 111.90 (71.59–165.84) cm3, respectively ( p &lt; 0.001 for all four items). Additionally, the uterus volume post-administration was 48.30% (33.88–62.54%) of that pre-administration. Heavy menstrual bleeding, dysmenorrhea, and chronic pelvic pain occurred in 23 (76.7%), 21 (70.0%), and 13 (43.3%) of the 30 patients, respectively; however, all patients experienced resolution of all symptoms. Nine, three, and one patients had hot flashes, mild arthralgia, and a mild headache, respectively. No cases of persistent irregular or heavy bleeding were observed during treatment. Conclusions: Relugolix contributes to volume reduction and eliminates subjective symptoms of uterine adenomyosis, suggesting that it is an effective treatment for uterine adenomyosis.

Serum Metabolomic Analysis of Synchronous Estrus in Yaks Based on UPLC-Q-TOF MS Technology

The yak is a unique species of livestock found in the Qinghai-Tibet Plateau and its surrounding areas. Due to factors such as late sexual maturity and a low rate of estrus, its reproductive efficiency is relatively low. The process of estrus synchronization in yaks plays a crucial role in enhancing their reproductive success and ensuring the continuation of their species. In order to clarify the characteristics of the serum metabolites of yak estrus synchronization, the yaks with inactive ovaries were compared with the estrus synchronization yaks. In this study, yaks were divided into the inactive ovaries group (IO), gonarelin-induced yak estrus group (GnRH), and chloprostenol sodium-induced yak estrus group (PGF). After the completion of the estrus synchronization treatment, blood samples were collected from the jugular veins of the non-estrus yaks in the control group and the yaks with obvious estrus characteristics in the GnRH and PGF groups. Metabolites were detected by ultra-high performance liquid chromatography-mass spectrometry, and differential metabolites were screened by multivariate statistical analysis. The results showed that a total of 70 significant differential metabolites were screened and identified in the GnRH vs. IO group, and 77 significant differential metabolites were screened and identified in the PGF vs. IO group. Compared with non-estrus yaks, 36 common significant differential metabolites were screened out after the induction of yak estrus by gonarelin (GnRH) and cloprostenol sodium (PGF), which were significantly enriched in signaling pathways such as the beta oxidation of very long chain fatty acids, bile acid biosynthesis, oxidation of branched chain fatty acids, steroidogenesis, steroid biosynthesis, and arginine and proline metabolism. This study analyzed the effects of gonadotropin releasing hormone (GnRH) and prostaglandin F (PGF) on the reproductive performance of yaks treated with estrus synchronization, which provides a theoretical basis for the optimization and application of yak estrus synchronization technology and promotes the healthy development of the yak industry.

The comparision among euploidy of preimplantation blastocysts in different controlled ovary stimulation (COH) protocols.

To compare differences in euploidy rates for blastocysts in preimplantation genetic testing for aneuploidy (PGT-A) cycles after gonadotropin-releasing hormone agonist (GnRH-a) long and short protocols, GnRH-antagonist (GnRH-ant) protocol, progestin-primed ovarian stimulation and mild stimulation protocols, and other ovary stimulation protocols. This was a retrospective cohort study from the Assisted Reproductive Medicine Department of Shanghai First Maternity and Infant Hospital. A total of 1657 PGT-A cycles with intracytoplasmic sperm injection after different controlled ovary hyperstimulation protocols were analyzed, and a total of 3154 embryos were biopsied. Differences in euploidy rate per embryo biopsied, embryo euploidy rate per oocyte retrieved and cycle cancellation rate were compared. For the PGT-A cycles, the euploidy rate per embryo biopsied was lower in the GnRH-ant protocol than in the GnRH-a long protocol (53.26 vs. 58.68%, respectively). Multiple linear regression showed that the GnRH-ant protocol was associated with a lower euploidy rate per embryo biopsied (β =  -0.079, p = 0.011). The euploidy rate per embryo biopsied was not affected by total gonadotropin dosage, duration of stimulation and number of oocytes retrieved. The embryo euploidy rate per oocyte retrieved was similar in all protocols and was negatively correlated with the total number of oocytes retrieved (β =  -0.003, p = 0.003). Compared with the GnRH-a long protocol, the GnRH-ant protocol was associated with a lower euploidy rate per embryo biopsied. The total gonadotropin dosage, duration of stimulation and number of oocytes retrieved did not appear to significantly influence euploidy rates.

Effectiveness of gonadotropin-releasing hormone agonists for ovarian function suppression in premenopausal patients with hormone receptor-positive breast cancer: a retrospective single-center real-world study.

This study evaluated the effectiveness of ovarian function suppression (OFS) of various gonadotropin-releasing hormone agonists (GnRHa) combined with aromatase inhibitors (AI) in premenopausal patients with hormone receptor-positive (HR-positive) breast cancer. Potential risk factors associated with insufficient OFS were analyzed. Premenopausal HR-positive breast cancer patients who had received AI with GnRHa were studied retrospectively. Patients were divided into different groups according to monthly or trimonthly GnRHa schedules they received, and the effectiveness of OFS was compared between groups. Insufficient OFS was defined as at least one instance of estradiol ≥ 30pg/ml. Patient data was gathered from medical records for this comparison. Of the 264 patients enrolled in this study, 117 were administered 3.6mg of goserelin monthly (goserelin 1M group), 63 received 3.75mg of leuprorelin monthly (leuprorelin 1M group) and 84 were given 11.25mg of leuprorelin every three months (leuprorelin 3M group). Overall, 7.20% experienced insufficient OFS. The incidence rates in the three GnRHa depot groups were 7.69%, 6.35%, and 7.14%, respectively, without a significant statistical difference (P = 0.900). Notably, younger patients exhibited a higher likelihood of insufficient OFS [OR = 0.900, 95%CI (0.824-0.982), P = 0.018]. Insufficient OFS remains a concern during GnRHa and AI treatment. The effectiveness of the three GnRHa depots commonly used in China seems comparable. Younger patients face a heightened risk of insufficient OFS.

27 Standardized ileal digestible lysine to metabolizable energy ratio equations for 12 to 127 kg boars, gilts, immunocastrated gilts and boars

Abstract We aimed to determine the standardized ileal digestible (SID) lysine (Lys) to metabolizable energy (ME) ratio equations for 12 to 127 kg boars, gilts, immunocastred gilts (IC gilts), and barrows (IC barrows). An average of 3,545 split-gender pigs (PIC 337×Camborough, initially 11.98 ± 1.26 kg) were used in a 21-d trial followed by a 21-d wash-out period in 2 replicates, totaling six feeding periods. In feeding phase 6, both genders were immunized against gonadotropin-releasing hormone (administrated with Vivax, Zoetis, São Paulo, SP, Brazil). Pens of pigs were weighed, blocked by body weight, and randomly allotted to 1 of 5 treatments consisting of 80, 90, 100, 110, and 120% of PIC SID Lys:Mcal of ME recommendations for mixed gender between boars, barrows, and gilts for each phase. The treatment diets were corn-soybean-meal-based and contained 3,300 Kcal of ME/kg. There were six split-gender pens•treatment-1•replicate-1 •phase-1 and 30 pigs/pen. Data were analyzed using generalized linear and nonlinear mixed models with a pen as the experimental unit. Competing models included linear, quadratic polynomial (QP), broken-line linear (BLL), and broken-line quadratic (BLQ) for average daily gain (ADG) and gain to feed ratio (G:F). There was no significant gender by quadratic coefficient interactions in all phases of this study (P &amp;gt; 0.05), then the mixed gender equation was determined, and the intact boars and gilts equation was estimated by the PIC overall difference in efficiency between genders. In the immunocastrated phase, after second dose, the mixed gender optimum level was determined and the equations for IC gilts and barrows was estimated by the differences in efficiency observed in the phase 6 of the two replicates. The SID Lys to calorie ratio recommended is based on the average for ADG and G:F (Table 1). Approximately 98.4% and 99.2% of maximum ADG and G:F were achieved at these levels, respectively, and these equations were similar compared with previous PIC biological requirements (Orlando et al., 2021).

PSIII-7 7&amp;7 Synch improved pregnancy rates in beef cows experiencing estrus over 24 h before fixed-time insemination

Abstract Our objectives were to compare estrus response and pregnancy rates between two different estrus synchronization protocols and between cows that experienced estrus more than 24 h before appointment breeding and those that experienced estrus less than 24 h before breeding. Over each of 2 yr, postpartum beef cows (n = 1,108) from two different locations were ranked by days postpartum and randomly selected to receive either; 1) 7-d CO-Synch + CIDR (CO-Synch, n = 547), or; 2) 7 &amp; 7 Synch (7&amp;7, n = 561). For the CO-Synch treatment, cows received a controlled internal drug release insert (CIDR; 1.38g progesterone) and 100 µg gonadotropin-releasing hormone (GnRH) i.m., followed in 7 d by CIDR removal and 25 mg prostaglandin F2alpha (PGF) i.m., followed in 60 to 66 h with AI and 100 µg GnRH i.m. For the 7&amp;7 Synch protocol, cows received a CIDR (1.38g progesterone) and 25 mg PGF i.m., followed in 7 d by 100 µg GnRH i.m., followed in 7 d by CIDR removal and 25 mg PGF i.m., followed in 60 to 66 h with AI and 100 µg GnRH i.m. Heat detection patches were applied at the time of CIDR removal to determine estrus response by the time of AI, with cows having patches ≥ 50% activated defined as being in estrus and cows with patches &amp;lt; 50% activated defined as not experiencing estrus. In yr 2, an additional heat detection was performed 24 h before breeding, at which time cows with ≥ 50% activated heat detection patches were defined as having an early estrus (i.e., estrus more than 24 h before breeding) and cows with activated patches first observed at the time of AI were defined as having an on-time estrus. Pregnancy status was determined via transrectal ultrasonography 35 d after AI. Data were analyzed using the GLIMMIX procedure of SAS. As expected, cows in the 7&amp;7 treatment had greater (P ≤ 0.005) estrus response and pregnancy rates than those in the CO-Synch treatment (83% vs. 62% and 65% vs. 55%, respectively). The proportion of cows experiencing early estrus was similar (P &amp;gt; 0.60) between treatments (20.4 and 22.9 for Co-Synch and 7&amp;7, respectively). Interestingly, pregnancy rate was impacted by a treatment × estrus timing interaction (P = 0.04), where cows in the Co-Synch treatment that experienced an early estrus (52.9%) had reduced pregnancy rates compared with 7&amp;7 cows that experienced early estrus (74.0%), Co-Synch cows that experienced on-time estrus (73.7%) and 7&amp;7 cows that experienced on-time estrus (70.5%). Our results indicate the 7&amp;7 Synch protocol can effectively increase pregnancy rates to fixed-time AI, and that pregnancy rates of cows experiencing early estrus are influenced by synchronization protocol.

242 Comparison of GnRH administration day in the 7&amp;7 Synch versus 8&amp;6 Synch Protocol for fixed-timed artificial insemination in beef heifers

Abstract The research aimed to investigate the impact of reducing the time interval for progesterone exposure on the ovulatory follicle just before performing fixed-timed artificial insemination (FTAI). This was achieved by adjusting the timing of administering a gonadotropin-releasing hormone agonist (GnRH; specifically, 100 µg gonadorelin, known as Cystorelin). The study assessed the effectiveness of two estrous synchronization protocols, the “7 &amp; 7 Synch” and a modified protocol, by examining estrus expression (EE) and the resulting pregnancy rates (PR) following FTAI. The research utilized frozen conventional Angus semen from Select Sires, Inc. (Plain City, OH), and involved 66 Angus-cross heifers from the beef cattle research unit near Fayetteville at the University of Arkansas. To ensure consistency, the heifers were divided into two treatment groups based on their cyclicity status (CYC) and age. CYC status was determined by assessing a reproductive tract score (RTS) 1 wk before the synchronization process. RTS scores ranged from 1 to 5, with RTS 1-3 indicating pre- or peripubertal status and scores of 4 and 5 indicating cycling. Heifers with an RTS of 1 and 2 were excluded from the study before synchronization commenced. Both treatment groups involved the insertion of a controlled internal drug-releasing device (CIDR; specifically, Eazi-breed, containing 1.38 g of progesterone) into the vagina on d -14. Simultaneously, a prostaglandin F2α analogue (PGF; 500 µg cloprostenol sodium, known as Synchsure) was administered. In the first treatment group (7&amp;7), GnRH was administered on d -7, while in the second group (8&amp;6), GnRH was given on d -6. In both cases, PGF was administered on d 0 when the CIDR was removed, precisely 72 ± 1 h before FTAI, along with another dose of GnRH. Estrus expression (EE) was assessed during FTAI by examining Estrotect patches (Rockway Inc., Spring Valley, WI). EE was considered present when a patch had 50% or more of its color rubbed off, and it was deemed absent when less than 50% of the color had worn off. Pregnancy rates (PR) were determined through ultrasound examination on d 55. EE and PR were analyzed by treatment using the GLIMMIX procedure on SAS 9.4 (SAS Institute Inc., Cary, NC). Statistical differences were declared at α ≤ 0.05 and tendencies declared between 0.05 &amp;lt; P ≤ 0.1. Heifers on the 8&amp;6-d protocol had greater rectal temperatures at breeding compared with 7&amp;7-d heifers (P &amp;lt; 0.0001). AI pregnancy rates were greater in heifers on the 8&amp;6-d protocol compared with the heifers on 7&amp;7-d protocol (P = 0.625) with average pregnancy rates of 39.4% and 30.3%, respectively. Overall, pregnancy rate was greater as well for the 8&amp;6-d heifers compared with the 7&amp;7-d heifers (P = 0.044), with mean overall pregnancy rates of 78.8% and 54.5%, respectively.

Raphe glucose-sensing serotonergic neurons stimulate KNDy neurons to enhance LH pulses via 5HT2CR: rat and goat studies

Dysfunction of central serotonergic neurons is known to cause depressive disorders in humans, who often show reproductive and/or glucose metabolism disorders. This study examined whether dorsal raphe (DR) serotonergic neurons sense high glucose availability to upregulate reproductive function via activating hypothalamic arcuate (ARC) kisspeptin neurons (= KNDy neurons), a dominant stimulator of gonadotropin-releasing hormone (GnRH)/gonadotropin pulses, using female rats and goats. RNA-seq and histological analysis revealed that stimulatory serotonin-2C receptor (5HT2CR) was mainly expressed in the KNDy neurons in female rats. The serotonergic reuptake inhibitor administration into the mediobasal hypothalamus (MBH), including the ARC, significantly blocked glucoprivic suppression of luteinizing hormone (LH) pulses and hyperglycemia induced by intravenous 2-deoxy-D-glucose (2DG) administration in female rats. A local infusion of glucose into the DR significantly increased in vivo serotonin release in the MBH and partly restored LH pulses and hyperglycemia in the 2DG-treated female rats. Furthermore, central administration of serotonin or a 5HT2CR agonist immediately evoked GnRH pulse generator activity, and central 5HT2CR antagonism blocked the serotonin-induced facilitation of GnRH pulse generator activity in ovariectomized goats. These results suggest that DR serotonergic neurons sense high glucose availability to reduce gluconeogenesis and upregulate reproductive function by activating GnRH/LH pulse generator activity in mammals.

Abstract PO1-13-02: Circulating tumor DNA mutation landscape in HR+/HER2− patients with mBC treated with cyclin-dependent kinase 4/6 inhibitors in the SCRUM-Japan MONSTAR-SCREEN study

Abstract Introduction: Combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6i) + endocrine therapy (ET) is recommended as first- or second-line treatment (1L or 2L Tx) for hormone receptor-positive, human epidermal growth factor receptor-2-negative metastatic breast cancer (HR+/HER2− mBC). In this study, we assessed cancer-specific genetic alterations in circulating tumor DNA (ctDNA) and tissues in abemaciclib-treated patients with HR+/HER2− mBC in Japan. Methods: MONSTAR-SCREEN is a multicenter study and part of a nation-wide cancer genome screening project for patients with advanced solid tumors (SCRUM Japan). Regardless of the Tx line, the current analysis included abemaciclib-treated patients with HR+/HER2− mBC (N=97). Data were collected between Jan 2020 and Dec 2021. Blood samples collected at ≤21 days before abemaciclib initiation (baseline; n=77) and at disease progression or Tx discontinuation (paired post-Tx; n=33) were tested with the FoundationOne® Liquid Companion Diagnostic panel. Additionally, archival or fresh tissue biopsy samples (n=79) were tested with the FoundationOne® Companion Diagnostic panel. Patient characteristics, baseline genetic alterations, neoplastic burden (measured by shedding rate and maximum variant allele frequency [VAF]), and alterations at clinical progression were reported. Results: The total population (N=97) included patients with next generation sequencing ctDNA and/or tissue data. All were female with median age of 57 years (interquartile range 50, 67). Bone, either alone or with other sites, was the most common metastatic site (61%). 78% of patients received abemaciclib in the first or second line of Tx (LoT). Fulvestrant with or without gonadotropin-releasing hormone (55%), letrozole (24%), and anastrozole (11%) were the most common concomitant drugs. Among patients with baseline ctDNA data (n=77), 30% and 21% had received prior ET and prior chemotherapy, respectively. In baseline ctDNA samples, PIK3CA (37%) and TP53 (28%) alterations were detected most frequently across all LoT; while ESR1 (16%), GATA3 (11%), and FGF3/4/19 (9%) were more frequently detected in samples from later LoT. The frequency of ESR1 alterations (p&amp;lt; 0.01), shedding rate, and maximum VAF (both p&amp;lt; 0.05) were significantly higher in prior ET recipients than those who did not receive prior ET. Frequency of post-Tx ESR1 alterations numerically decreased from baseline in patients on fulvestrant (23% to 18%) and numerically increased in patients on aromatase inhibitors (27% to 45%). Other genes showed either a numeric increase or similar alteration frequency between the baseline and post-tx. Newly acquired post-Tx alterations were detected in FGF3/4/19 (18%); PIK3CA, TP53, and RB1 (all 15%) and ESR1 (12%). The table shows PIK3CA and ESR1 alterations detected at baseline and post-Tx. In the tissue samples (n=79), TP53 (32% vs 20%) and ESR1 (14% vs 7%) alterations were numerically more frequent in metastatic versus primary lesions. Other gene alteration frequencies were similar. Conclusion: PIK3CA alterations were the most frequently detected genetic alterations in both pre- and post- abemaciclib Tx patients with HR+/HER2− mBC. Patients with prior ET had more frequent ESR1 alterations and higher neoplastic burden. Evidence from this study provides insight into the ctDNA dynamics and potential resistance mechanisms in patients with HR+/HER2− mBC. PIK3CA and ESR1 alterations detected in circulating tumor DNA at baseline and post abemaciclib treatment Citation Format: Masaya Hattori, Victoria Serelli-Lee, Yoichi Naito, Takashi Yamanaka, Hiroyuki Yasojima, Rikiya Nakamura, Takao Fujisawa, Mitsuho Imai, Yoshiaki Nakamura, Hideaki Bando, Tsutomu Kawaguchi, Takayuki Yoshino, Hiroji Iwata. Circulating tumor DNA mutation landscape in HR+/HER2− patients with mBC treated with cyclin-dependent kinase 4/6 inhibitors in the SCRUM-Japan MONSTAR-SCREEN study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-13-02.

Abstract PO4-19-09: Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20)

Abstract Background The current standard first-line treatment in advanced or metastatic hormone receptor (HR) positive breast cancer is combination of aromatase inhibitor (AI) and cyclin D kinase-4/6 (CDK4/6) inhibitor. Emergence of ESR1 mutation is a key mechanism of resistance during first-line AI + CDK4/6 inhibitor treatment. Selective estrogen receptor downregulator (SERD) such as elacestrant or fulvestrant is suggested as second-line treatment, but the progression-free survival (PFS) outcome of second-line treatment is reported up to 3.78 months in patients who harbour ESR1 mutation. Recently, early switch of AI + CDK4/6 inhibitor to fulvestrant + CDK4/6 inhibitor at the point of rising ESR1 mutation showed prolongation of PFS up to 6 months, suggesting there may be a new strategy to overcome ESR1 mutation by modifying endocrine treatment. SWOG S0226 suggested that upfront fulvestrant + AI is feasible and associated with prolongation of PFS compared to AI alone. After CDK4/6 inhibitor has been introduced to standard treatment, there were no trials evaluating the role of AI + fulvestrant with CDK4/6 inhibitor. In this trial, we investigated triplet combination of AI + fulvestrant + CDK4/6 inhibitor as a treatment to overcome resistant mechanism such as development of ESR1 mutation when compared to current standard treatment of AI + CDK4/6 inhibitor as the first line treatment in HR positive advanced or metastatic breast cancer. Methods This study is a randomized, multicenter, open-label phase II trial comparing AI plus ribociclib versus AI, fulvestrant plus ribociclib in HR-positive advanced or metastatic breast cancer. De novo patients or patients with treatment-free interval (TFI) over 12 months after completion of adjuvant AI can be enrolled. If patients received adjuvant tamoxifen, patients with TFI less than 12 months can be also enrolled for the study. Prior endocrine treatment or cytotoxic chemotherapy at metastatic setting was not allowed. In cases of premenopausal women, gonadotropin releasing hormone agonist (GnRHa) is administered every 4 weeks with treatment. A total of 202 patients will be enrolled for 30 months, and 30 months of follow-up is planned after last-patient enrolment. Patients are randomized to 1:1, stratified based on the presence of visceral metastasis and previous administration of adjuvant AI. Study treatment of the control arm consists of letrozole 2.5mg daily with ribociclib 600mg (Day 1-Day 21 daily by month, 1 week off) until progression. In the experimental arm fulvestrant 500mg intramuscular injection is added (Day 1, Day 15, Day 29 and every 4 weeks thereafter) until progression. For exploratory analysis of ESR1 mutations, circulating tumor DNA (ctDNA) is collected at baseline, and then every 3 months thereafter. Primary endpoint is to evaluate the difference of 24-months PFS rate. Secondary endpoint included PFS, overall survival (OS), emergence and frequency of ESR1 mutation, overall response rate (ORR) and clinical benefit rate (CBR). The analysis is planned after completion of 30 months of follow-up, which provides approximately 90% power to detect superiority 24 months-PFS rate assumed by Kaplan-Meier curve of letrozole + fulvestrant + ribociclib versus letrozole + ribociclib using a log-rank test, assuming a hazard ratio of 0.64 at a two-sided alpha of 0.2. Citation Format: Jieun Lee, Su-Jin Koh, Jung Hye Kwon, Gun Min Kim, Jee Hung Kim, Ho Young Kim, Hee-Jun Kim, Keon-Uk Park, Kyong Hwa Park, Yeon Hee Park, Mi Sun Ahn, Hee Kyung Ahn, Gyeong-Won Lee, Kyoung Eun Lee, Kyung-Hun Lee, Moon Hee Lee, Sung Sook Lee, Jung Lim Lee, Kyung Hae Jung, Joo Young Jung, In Hae Park. Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-09.

Abstract PO1-09-09: The journey of HR positive, HER2 negative metastatic breast cancer’s patients: heterogeneities and barriers in Brazilian public health system- a national survey

Abstract Background: Breast cancer is the most common neoplasm in Brazilian women, with high percent of patients diagnosed in advanced stages. Metastatic breast cancer (mBC) is a challenge in the country, where 75% of the population is covered by public health system (Sistema Único de Saúde, SUS). We conducted an on-line survey to describe the journey of human epidermal growth factor receptor 2-negative (HER2-), hormone receptor positive (RH+) mBC patients across public scenario in Brazil. Methods: An on-line survey comprised of 39 to 48 (depending on the kind of some questions, which could open another question in case of affirmative answer) objective questions were sent by e-mail to180 oncologists working in public and private health care system. Questions were focused on assessing wait time for first treatment after admission in the hospital in both systems, availability of oncological drugs within SUS according to essential medicines list by World Health Organization, and presence of palliative and multidisciplinary teams in both systems. Continuous variables were measured by median and mean. The level of statistical significance adopted was 5% with Teste p two-sided. Analyses were performed using SAS statistical software (version 25.0). Results: We had 150 respondents working in SUS and private health system, which fulfilled the inclusion criteria to participate in this survey. The other 30 respondents were excluded from the study because they worked exclusively in SUS or exclusively in the private system, and their answers were not analyzed. Median wait time for surgery was 60 days in the SUS (N=150) and 30 days in the private health system (N=150) e (p &amp;lt; 0,0001). Regardless of chemotherapy provided, median waiting time was 30 and 15 days in the SUS (N=150) and the private health system (N=150), respectively (p &amp;lt; 0,0001). Most oncologists in the SUS (N=125, 83.3%) pointed to endocrine therapy as their first-choice treatment in mBC. Concerning endocrine therapy in the SUS, Gonadotropin-Releasing Hormone Agonist (GnRHa) was available, and it was prescribed by 54 (36.0%) and Fulvestrant for 72 (48.0%) of respondents. Considering chemotherapy, weekly paclitaxel alone or combined with platin were available and they were prescribed by 124 (82.6%) and 109 (72.6%) of oncologists respectively. Vinorelbine was available and it was prescribed according to oncologists’ report by 109 (72.6%) and Pegylated liposomal doxorubicin (PLD) by 38 (25.3%) of oncologists. Oncologists answered agree or strongly agree that they had a multidisciplinary care team in SUS 77,3% (N =116) versus 87,3% (N=131) in the private system (p=0.022). Concerning palliative care 66,09% (N= 99) in the SUS versus 82,0% (N=123) in the private system answered that they agreed or strongly agreed that this service was available (p=0.001). Conclusions: The Brazilian government has continuously improved delivery of services and medicines via the public system (SUS), but there are still significant differences within this system and versus the private sector. Unavailability of endocrine therapy agents as GnRHa and Fulvestrant, and some chemotherapy agents as PLD and Vinorelbine for high percentage of patients, raises the existence of disparities within SUS. Also, longer waiting times for treatment in the SUS, lower availability of support teams such multidisciplinary and palliative care, they point out disparities between SUS and private health systems. The lack of a National Cancer Control Program and low health investment by Brazilian government might explain the difference in cancer patients’ access. Citation Format: Heloísa Resende, Igor Soares, Angélica Renó, Ana Cunha, Vinícius Aguiar, Letícia Tureta, Viviane Pereira. The journey of HR positive, HER2 negative metastatic breast cancer’s patients: heterogeneities and barriers in Brazilian public health system- a national survey [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-09-09.

Abstract PO4-02-04: Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort

Abstract Background: In the PENELOPEB trial, the addition of 1-year of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib to standard endocrine therapy (ET) for women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer at high risk of recurrence after neoadjuvant chemotherapy (NACT) did not improve invasive disease-free survival (iDFS) or overall survival (OS) in the main study analysis. Invasive lobular breast cancer (ILC) accounts for ~15% of all breast cancers (BC) and represents an underinvestigated subtype of BC with typically less sensitivity to (neo)adjuvant chemotherapy, and poor distant disease-free survival (DDFS) irrespective of response to NACT. Here, we report the post-hoc analysis results of iDFS, DDFS and OS in pre- and postmenopausal women enrolled on PENELOPEB and with ILC. Methods: Patients with HR+/HER2-negative BC without pathological complete response (pCR) after taxane-containing NACT and at high risk of relapse (CPS-EG score ≥3, or 2 and ypN+) were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 of a 28-day cycle in addition to standard ET with tamoxifen (TAM) +/- gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) +/- GnRH. Randomization was stratified by nodal status at surgery, age at first diagnosis (&amp;lt; 50 vs. ≥50 years), Ki-67, region, and CPS-EG score. ILC diagnosis was locally assessed and reported by the investigators on the pathology case report form. The primary objective of this post-hoc analysis was to evaluate iDFS, DDFS and OS by treatment arm in patients with high risk ILC. Results: A total of 1,250 patients were randomized, of whom 110 had ILC and were nearly uniformly distributed between both treatment arms (palbociclib n=58 vs. placebo n=52), with a higher proportion of postmenopausal women (58.6% in the palbociclib arm vs. 53.8% in the placebo arm) compared to premenopausal women (41.4% in the palbociclib arm vs. 46.2% in placebo arm). There was no difference in the distribution of AI/TAM use between the treatment arms. An estimated absolute 3-year-iDFS difference of 18.3% with palbociclib compared to placebo (iDFS 88.4% [95% CI 76.0-94.6] vs. 70.1% [95% CI 55.3-80.7]) with a HR of 0.66 [95% CI 0.27 – 1.61, log-rank p=0.354]) was observed. A comparable 3-year-DDFS difference of 16.3% was observed. An estimated 3-year-OS difference of 16.4% (98.0% [95% CI 86.6 – 99.7] vs. 81.6% [95% CI 67.5 – 90.0]) with a hazard ratio (HR) of 0.27 (95% CI 0.05 – 1.43, log-rank p=0.108) was observed. Out of 12 observed deaths (n=2 palbociclib vs. n=10 placebo), 11 (in placebo arm) were related to metastasic BC. Conclusions: In this post-hoc analysis, a trend towards improvement in OS and a trend in favor of iDFS and DDFS for the addition of palbociclib to ET was observed among women with HR+/HER2- ILC at high risk of recurrence after NACT, but these differences were not statistically significant. This could represent a valuable treatment option for patients with high risk ILC. Due to the small sample size of the ILC subgroup, further follow-up evaluation is necessary. Moreover, analyses in the ILC subgroup from other adjuvant CDK4/6 inhibitor trials could substantiate these findings. Table. Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort Results of iDFS, DDFS and OS. Citation Format: Hervé Bonnefoi, Frederik Marmé, Miguel Martín, Michael Untch, Sung-Bae Kim, Harry Bear, Nicole McCarthy, Karen Gelmon, José Ángel García-Sáenz, Catherine M. Kelly, Toralf Reimer, Zhe Zhang, Masakazu Toi, Hope Rugo, Michael Gnant, Andreas Makris, Nader Hirmas, Valentina Nekljudova, Johannes Holtschmidt, Sibylle Loibl. Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-02-04.

Pubertal Suppression in Early Puberty Followed by Testosterone Mildly Increases Final Height in Transmasculine Youth

Abstract Purpose Treatment for transmasculine youth (TMY) can involve testosterone (T) treatment and is sometimes preceded by gonadotropin-releasing hormone agonist (GnRHa) treatment for puberty blockade. GnRHa can increase final height in birth-assigned females with central precocious puberty. Maximizing final adult height (FAH) is an important outcome for many TMY. Our objective was to determine how GnRHa treatment before testosterone impacts FAH. Methods Retrospective cohort study at 5 U.S. transgender health clinics. Participants were 32 TMY treated with GnRHa in early-to-mid-puberty before testosterone (GnRHa+T group) and 62 late/post-pubertal TMY treated with only testosterone (T-only group). Results The difference between FAH minus mid-parental target height (MPTH) was +2.3 ± 5.7cm and -2.2 ± 5.6cm in the GnRHa+T and T-only groups, respectively (p&amp;lt;0.01). In the GnRHa+T group, FAH was 1.8 ± 3.4cm greater than predicted adult height (PAH) (p&amp;lt;0.05) and FAH vs. initial height (IH) z-score was 0.5 ± 1.2 vs. 0.16 ± 1.0 (p&amp;lt;0.05). After adjusting for patient characteristics, each additional month of GnRHa monotherapy increased FAH by 0.59cm (95% CI: 0.31,0.9 cm), stage 3 breast development at start of GnRHa was associated with 6.5cm lower FAH compared to stage 2 (95% CI: -10.43, -2.55), and FAH was 7.95cm greater in the GnRHa+T group compared to T-only group (95% CI: -10.85, -5.06). Conclusions Treatment with GnRHa in TMY in early puberty before testosterone increases FAH compared with MPTH, PAH, IH, and TMY who only received testosterone in late/post-puberty. TMY considering GnRHa should be counseled that GnRHa may mildly increase their FAH if started early.

Genetic variants of KISS1 gene in association with polycystic ovary syndrome– A meta-analysis

Polycystic ovary syndrome (PCOS) is a widely diagnosed syndrome associated with clinical and metabolic manifestations and even many cases of infertility. Sexual hormone imbalance can be considered as PCOS causal factor. Thus, kisspeptin (KISS1) regulating gonadotropin-releasing hormone (GnRH) levels plays a critical role in this syndrome. This study aimed to investigate the association of KISS1 genetic polymorphisms with PCOS using meta-analysis protocols. In accordance with PRISMA guidelines, systematic search of scientific databases was conducted to find included articles and then meta-analysis was performed using Review Manager 5.4 in dominant, recessive, and allelic models of inheritance. This meta-analysis included 2165 PCOS patients and 2301 healthy reproductive-aged female genotyped for five different polymorphisms of KISS1. In recessive and allelic models, three genetic variations specifically showed significant association with PCOS. This concerns rs12998 (G → A) which was proved as associated with higher risk of PCOS in recessive (p = 0.0002) and allelic models (P = 0.02). In addition, rs372790354 despite the small number of studies was associated with this syndrome in allelic model (P = 0.03). In additive model, rs4889 was shown as associated with higher PCOS risk (P = 0.02). This meta-analysis suggests rs4889, rs12998 and rs372790354 genetic variations in KISS1 as risk factors of PCOS. Results will improve our knowledge about PCOS and form a basis for future trials trying to find new markers for its prognosis and therapy.

Adding Letrozole to Growth Hormone and Gonadotropin-Releasing Hormone analogous May Further Increase Height in Girls with Short Stature: a hospital record-based retrospective study

BackgroundThere have been rare data in Letrozole for height promotion in girls.This study aims to clarify the efficacy and safety of combination therapy with human recombinant growth hormone, GnRHa and letrozole in improving the height of girls with short stature and advanced bone age. MethodsThis is a retrospective record-based study. Follow-up was conducted on girls with short stature who received rhGH,GnRHa and letrozole treatment at outpatient clinics in our hospital.The treatment group included a total of 29 participants. Prior to treatment, the average age of the patients was 11.17 years, and an average treatment duration of 17.31 months.The control group consisted of 29 short-statured girls who received rhGH/GnRHa treatment, with an average age of 12.43 years, and an average treatment duration of 16.59 months. ResultsThe predicted adult height(PAH) before treatment was 155.38 cm, and the PAH after treatment was 161.32cm ( p<0.001). The ΔPAH in the treatment group is 4 cm higher than that of the control group (5.85cm VS 1.82cm, P<0.001). There was a significant difference in the height SDS of Bone age before and after treatment ( P<0.001).And there was a significant difference in the height SDS of chronological age (P=0.003).There was a increasing BMI during therapy (P=0.039). The height gain was 8.71±4.46 cm, and the growth rate was 6.78±3.84cm per year. ConclusionsCombined treatment with GH,GnRHa and letrozole can enhance the adult height(AH)and PAH in short-stature girls and no significant side effects were reported.

Brown adipose tissue metabolism in women is dependent on ovarian status.

In rodents, loss of estradiol (E2) reduces brown adipose tissue (BAT) metabolic activity. Whether E2 impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (n = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m2) and postmenopausal (n = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m2) women at room temperature and during acute cold exposure using [11C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[18F]fluoro-d-glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (n = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m2) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min-1) and postmenopausal women (0.63 ± 0.28 min-1). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min-1, P = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g-1·min-1, P < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min-1 to 0.91 ± 0.41 min-1) to that observed in postmenopausal women (0.91 ± 0.63 min-1). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women.NEW & NOTEWORTHY In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age.

Diagnosis and treatment of hypogonadism in men seeking to preserve fertility - what are the options?

Male hypogonadism is a clinical syndrome that results in low testosterone levels and frequently leads to infertility. The syndrome occurs due to disruption at one or more levels of the hypothalamic-pituitary-gonadal axis. Testosterone replacement therapy (TRT) is the most common treatment utilised for male hypogonadism. However, long-acting forms of TRT leads to infertility and so is inappropriate for patients wishing to conceive. For patients who wish to remain fertile, nasal TRT, clomiphene citrate, exogenous gonadotropins, gonadotropin releasing hormone and aromatase inhibitors have been used as alternative treatment options with different degrees of success. A review of the literature was performed to identify the safety and efficacy of alternative treatment options. Gonadotropin releasing hormone can successfully induce spermatogenesis but is impractical to administer. Likewise, aromatase inhibitors have limited use due to inducing osteopenia. Nasal TRT may be a good treatment option for these patients, but its efficacy has so far only been demonstrated in small sample sizes. However, clomiphene citrate and exogenous gonadotropins are safe, offer good symptom control and can successfully induce fertility in hypogonadism patients.