Analysis of the incidence of central precocious puberty treated with gonadotropin-releasing hormone analogs. Impact of the COVID-19 pandemic / Análisis de la incidencia de pubertad precoz central tratada con análogos de hormona liberadora de gonadotrofina. Impacto de la pandemia por COVID-19

Introducción. Desde inicios de la pandemia por coronavirus 2019 (COVID-19), fue comunicado en varios países un incremento de las consultas de niñas con pubertad precoz central idiopática (PPCI), sin que contáramos con datos argentinos. Este aumento estaría vinculado con los cambios en el estilo de vida y los niveles de estrés resultantes del aislamiento que afectó particularmente a la población infantil. Objetivos. 1) Describir la evolución de la incidencia de PPCI con requerimiento de inhibición del eje hipotálamo-hipófiso-gonadal (EHHG) en niñas entre 2010 y 2021 en una cohorte del Área Metropolitana de Buenos Aires. 2) Comparar las características de las niñas, con dicho diagnóstico realizado durante la pandemia, con las de un grupo control. Métodos. Serie de tiempo interrumpida y estudio de casos y controles. Resultados. La incidencia anual fue estable entre 2010 y 2017. Desde 2017 hubo un ascenso anual que promedió el 59,9 % (IC95 % 18,6-115,5) y pareciera haberse acelerado durante la pandemia. Constatamos asociación entre haber desarrollado PPCI y haber requerido tratamiento inhibitorio entre el 01 de junio de 2020 y el 31 de mayo de 2021, y dos variables: edad de menarca materna (OR 0,46; IC95 % 0,28-0,77) y antecedente familiar de PPCI (OR 4,42; IC95 % 1,16-16,86). Conclusión. Evidenciamos desde 2017 un aumento significativo en la incidencia de PPCI con requerimiento de inhibición del EHHG. El incremento en la exposición a diversos desencadenantes ambientales durante la pandemia por COVID-19 podría haber ejercido mayor influencia en las niñas con alguna predisposición genética.

Introduction. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, consultations of girls with idiopathic central precocious puberty (ICPP) increased in several countries, but there were no data from Argentina. This increase may be related to changes in lifestyle and stress levels resulting from the lockdown, which particularly affected the child population. Objectives. 1) To describe the progression of the incidence of ICPP requiring inhibition of the hypothalamic- pituitary-gonadal (HPG) axis in girls between 2010 and 2021 in a cohort from the Metropolitan Area of Buenos Aires. 2) To compare the characteristics of girls diagnosed with ICPP during the pandemic with those of a control group. Methods. Interrupted time-series and case-control study. Results. The annual incidence remained stable between 2010 and 2017. Since 2017, it increased to an average of 59.9% (95% CI: 18.6­115.5) and appears to have accelerated during the pandemic. We found an association between ICPP and requiring inhibitory treatment between June 1 st, 2020 andMay 31 st, 2021 and 2 variables: maternal age at menarche (OR: 0.46, 95% CI: 0.28­0.77) and family history of ICPP (OR: 4.42, 95% CI: 1.16­16.86). Conclusion. We evidenced a significant increase in the incidence of ICPP with requirement of HPG axis inhibition since 2017. Increased exposure to various environmental triggers during the COVID-19 pandemic may have had a greater influence in girls with some genetic predisposition.

Differential diagnosis of precocious puberty in girls during the COVID-19 pandemic: a pilot study.

BACKGROUND: To investigate the differential diagnosis of girls aged 6 to 8 years with idiopathic premature thelarche (IPT) and central precocious puberty (CPP) during the COVID-19 pandemic. We explored predicted adult height (PAH) discrepancy to guide appropriate diagnosis and treatment. METHODS: From January 2020 to December 2021, Chinese girls aged 6 to 8 years with precocious puberty were recruited. They were divided into IPT and CPP groups. Clinical characteristics, including height, weight, body mass index (BMI), basal luteinizing hormone (LH), oestradiol, uterine length and volume, follicle numbers (d > 4 mm) and bone age (BA) were recorded. We analysed differential diagnosis and PAH discrepancy in both groups. Binary logistic regression analysis was used to explore risk factors for CPP, and receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic value of related indexes. RESULTS: Sixty patients, including 40 girls with IPT and 20 girls with CPP, were recruited. The prevalence of overweight and obesity in the entire cohort was 25% (15/60) and was significantly higher in IPT than CPP, 32.5% (13/40) vs. 10% (2/20), respectively (P=0.045). There were significant differences in LH, uterine volume, follicle numbers and BA (P<0.05). The impaired PAH of IPT and CPP was 0.01 ± 1.19 SD and 0.62 ± 0.94 SD with significant differences (P=0.047). Logistic regression analysis showed that LH and follicle numbers were independent risk factors for CPP. The ROC curve showed that the area under the curve (AUC) of LH and follicle numbers were 0.823 and 0.697. The sensitivity and specificity of LH with a cut off of 0.285 IU/L were 78.9% and 77.8%. The sensitivity and specificity of follicle numbers with a cut off of 3.5 were 89.5% and 52.8%. CONCLUSION: The prevalence of overweight and obesity in 6- to 8-year-old girls with precocious puberty was high. Auxological data should not be used in the differential diagnosis of IPT and CPP. Basal LH above 0.285 IU/L and follicle numbers greater than 4 were important features suggestive of CPP. PAH was impaired in individuals with CPP, but it was not impaired in individuals with IPT.

Analysis of the incidence of central precocious puberty treated with gonadotropin-releasing hormone analogs. Impact of the COVID-19 pandemic. / Análisis de la incidencia de pubertad precoz central tratada con análogos de hormona liberadora de gonadotrofina. Impacto de la pandemia por COVID-19.

Introduction. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, consultations of girls with idiopathic central precocious puberty (ICPP) increased in several countries, but there were no data from Argentina. This increase may be related to changes in lifestyle and stress levels resulting from the lockdown, which particularly affected the child population. Objectives. 1) To describe the progression of the incidence of ICPP requiring inhibition of the hypothalamic-pituitary-gonadal (HPG) axis in girls between 2010 and 2021 in a cohort from the Metropolitan Area of Buenos Aires. 2) To compare the characteristics of girls diagnosed with ICPP during the pandemic with those of a control group. Methods. Interrupted time-series and case-control study. Results. The annual incidence remained stable between 2010 and 2017. Since 2017, it increased to an average of 59.9% (95% CI: 18.6-115.5) and appears to have accelerated during the pandemic. We found an association between ICPP and requiring inhibitory treatment between June 1st, 2020 and May 31st, 2021 and 2 variables: maternal age at menarche (OR: 0.46, 95% CI: 0.28-0.77) and family history of ICPP (OR: 4.42, 95% CI: 1.16-16.86). Conclusion. We evidenced a significant increase in the incidence of ICPP with requirement of HPG axis inhibition since 2017. Increased exposure to various environmental triggers during the COVID-19 pandemic may have had a greater influence in girls with some genetic predisposition.

Introducción. Desde inicios de la pandemia por coronavirus 2019 (COVID-19), fue comunicado en varios países un incremento de las consultas de niñas con pubertad precoz central idiopática (PPCI), sin que contáramos con datos argentinos. Este aumento estaría vinculado con los cambios en el estilo de vida y los niveles de estrés resultantes del aislamiento que afectó particularmente a la población infantil. Objetivos. 1) Describir la evolución de la incidencia de PPCI con requerimiento de inhibición del eje hipotálamo-hipófiso-gonadal (EHHG) en niñas entre 2010 y 2021 en una cohorte del Área Metropolitana de Buenos Aires. 2) Comparar las características de las niñas, con dicho diagnóstico realizado durante la pandemia, con las de un grupo control. Métodos. Serie de tiempo interrumpida y estudio de casos y controles. Resultados. La incidencia anual fue estable entre 2010 y 2017. Desde 2017 hubo un ascenso anual que promedió el 59,9 % (IC95 % 18,6-115,5) y pareciera haberse acelerado durante la pandemia. Constatamos asociación entre haber desarrollado PPCI y haber requerido tratamiento inhibitorio entre el 01 de junio de 2020 y el 31 de mayo de 2021, y dos variables: edad de menarca materna (OR 0,46; IC95 % 0,28-0,77) y antecedente familiar de PPCI (OR 4,42; IC95 % 1,16-16,86). Conclusión. Evidenciamos desde 2017 un aumento significativo en la incidencia de PPCI con requerimiento de inhibición del EHHG. El incremento en la exposición a diversos desencadenantes ambientales durante la pandemia por COVID-19 podría haber ejercido mayor influencia en las niñas con alguna predisposición genética.

Increased use of 6-monthly gonadotropin-releasing hormone agonist therapy for prostate cancer: a capacity and cost-minimization analysis for England.

AIMS: The National Health Service (NHS) in England is facing extreme capacity pressures. The backbone of prostate cancer care is gonadotropin-releasing hormone agonist (GnRHa) therapy, commonly administered every month or 3 months. We estimated the cost and capacity savings associated with increased use of 6-monthly GnRHa therapy in England. METHODS: A capacity and cost-minimization model including a societal perspective was developed (in Microsoft Excel) to generate cost and capacity estimates for GnRHa drug acquisition and administration for "Current practice" and for a "Base case" scenario. In the "Base case" scenario, 50% of patients who were receiving monthly or 3-monthly GnRHa therapy in "Current practice" switched/transitioned to a 6-monthly formulation. Cost/capacity estimates were calculated per patient per administration and scaled to annualized population levels. Sensitivity analyses were conducted to assess the impact of individual model assumptions: 1 tested the impact of drug acquisition costs; 2 and 3 tested the level of nurse grade and the time associated with treatment administration, respectively; 4 tested the rate of switch/transition to 6-monthly GnRHa therapy; and 5 tested differing diagnostic patterns following the coronavirus disease 2019 pandemic. RESULTS: Compared with "Current practice", the "Base case" scenario was associated with annual cost savings of £5,164,296 (148,478 fewer appointments/year and 37,119 fewer appointment-hours/year). The largest savings were in drug administration (£2.2 million) and acquisition (£1.6 million) costs. Annual societal cost savings totaled £1.4 million, mainly in reduced appointment-related travel, productivity and leisure time opportunity losses. Increased use of 6-monthly versus monthly or 3-monthly GnRHa therapy consistently achieved system-wide annual cost and capacity savings across all sensitivity analysis scenarios. CONCLUSIONS: Our holistic model suggests that switching/transitioning men from monthly or 3- monthly GnRHa therapy to a 6-monthly formulation can reduce NHS cost and capacity pressures and the societal and environmental costs associated with prostate cancer care.

Men with prostate cancer often receive hormone injections to slow their cancer progression and relieve their symptoms. In England, most men who are prescribed hormone injections receive them once every month or 3 months; however, a 6-monthly option would reduce the number of injection appointments required each year. If some men who are receiving hormone injections every month or every 3 months switched to treatment once every 6 months, it could reduce the impact of prostate cancer treatment on their lives. It might also reduce the demands of prostate cancer treatment on the National Health Service (NHS). We developed a computer-based model to assess how NHS costs and nursing would be affected if half of the men in England who are receiving hormone injections every month or 3 months switched to injections every 6 months. According to our model, this change could save the NHS about £5.2 million each year. The main cost savings would be in reduced nursing costs. The change would also benefit the NHS because nurses would have almost 150,000 fewer injections to give, meaning that they could spend their time providing care elsewhere. Given that men would have to attend fewer appointments, they would also benefit from reduced time traveling, which would benefit the environment as well. Overall, these benefits to society would contribute about £1.4 million of savings per year. Given how stretched the NHS is in England, particularly after the COVID-19 pandemic, opportunities to reduce time and staffing pressures are very important.

Early onset of puberty during COVID-19 pandemic lockdown: experience from two Pediatric Endocrinology Italian Centers.

OBJECTIVES: During COVID-19 pandemic lockdown, reports of evaluations for suspected precocious puberty significantly raised. We aimed to assess the increase of precocious puberty in patients referred to Pediatric Endocrinology Units of Brescia (Italy), to determine clinical characteristics of patients undergoing a GnRH stimulation test before and during lockdown and evaluate the role of environmental factors in pubertal development. METHODS: Clinical and biochemical data of patients undergoing GnRH stimulation test were collected and stratified in two groups: March 2019 - February 2020 (Period 1) and March 2020 - February 2021 (Period 2). RESULTS: A total number of 391 evaluations for suspected precocious puberty were identified in the two study periods: 183 (46.8%) first visits during Period 1, and 208 (53.2%) in Period 2. Sixty-one patients underwent a GnRH stimulation test (4.1% of first consultations) before the SARS-CoV2 pandemic, and 93 children (8.7%) after the lockdown. Thirty-four new diagnoses of central precocious puberty were registered during Period 1 (2.3%), vs. 45 new cases (4.2%) in Period 2. During lockdown patients evaluated for suspected precocious puberty underwent a stimulation test at younger age than those evaluated before pandemic (median age of 8.2 years vs. 8.4, p=0.04). In Period 2, children showed a median bone age advancement of 0.61 years vs. 1.06 of Period 1 (p=0.03). CONCLUSIONS: During the COVID-19 pandemic, we observed an increased proportion of consultations for suspected precocious puberty. These children showed lower bone age advancement than observed in pre-lockdown suggesting the influence of pandemic-related lifestyle changes on pubertal development.

Has the Frequency of Precocious Puberty and Rapidly Progressive Early Puberty Increased in Girls During the COVID-19 Pandemic?

Objective: Early puberty is development of secondary sex characteristics earlier than the expected normal age range. We subjectively observed an increased frequency of early puberty during the Coronavirus disease-2019 (COVID-19) lockdown and aimed to show the clinical, demographic characteristics of the cases and the change in its incidence. Methods: Female patients with central precocious puberty (CPP, n=28) and rapidly progressive early puberty (RPEP, n=61), presenting to our clinic before (January 2019-March 2020) and during the COVID-19 pandemic (April 2020-June 2021) were included. Results: Among 28 CPP cases, six (21%) presented before the pandemic lockdown, whereas 22 (79%) were diagnosed during the COVID-19 pandemic lockdown. While RPEP was seen in 16 (26%) patients before the pandemic, 45 (74%) patients were diagnosed during the lockdown period. Presentation with menarche was seen in 15 RPEP patients; two (13%) were in the prepandemic period and 13 (87%) were in the lockdown period. Chronological age, bone age, bone age to chronological age ratio, height, weight, and body mass index standard deviation scores of patients with RPEP and CPP were similar between the prepandemic and pandemic period. Conclusion: In this cohort, the frequency of CPP and RPP cases were significantly (p<0.001) increased during the COVID-19 pandemic, possibly due to environmental changes.

DeepHisCoM: deep learning pathway analysis using hierarchical structural component models.

Many statistical methods for pathway analysis have been used to identify pathways associated with the disease along with biological factors such as genes and proteins. However, most pathway analysis methods neglect the complex nonlinear relationship between biological factors and pathways. In this study, we propose a Deep-learning pathway analysis using Hierarchical structured CoMponent models (DeepHisCoM) that utilize deep learning to consider a nonlinear complex contribution of biological factors to pathways by constructing a multilayered model which accounts for hierarchical biological structure. Through simulation studies, DeepHisCoM was shown to have a higher power in the nonlinear pathway effect and comparable power for the linear pathway effect when compared to the conventional pathway methods. Application to hepatocellular carcinoma (HCC) omics datasets, including metabolomic, transcriptomic and metagenomic datasets, demonstrated that DeepHisCoM successfully identified three well-known pathways that are highly associated with HCC, such as lysine degradation, valine, leucine and isoleucine biosynthesis and phenylalanine, tyrosine and tryptophan. Application to the coronavirus disease-2019 (COVID-19) single-nucleotide polymorphism (SNP) dataset also showed that DeepHisCoM identified four pathways that are highly associated with the severity of COVID-19, such as mitogen-activated protein kinase (MAPK) signaling pathway, gonadotropin-releasing hormone (GnRH) signaling pathway, hypertrophic cardiomyopathy and dilated cardiomyopathy. Codes are available at https://github.com/chanwoo-park-official/DeepHisCoM.

Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFS.

After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient's fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male's Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient's symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).

Targeting the androgen receptor signaling pathway in advanced prostate cancer.

PURPOSE: This article summarizes current androgen receptor (AR)-directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC). SUMMARY: PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone-releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR gene overexpression, and mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism, possess a higher affinity for AR, and are postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects. CONCLUSION: Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.

Reduction in pediatric growth hormone deficiency and increase in central precocious puberty diagnoses during COVID 19 pandemics.

BACKGROUND: While several studies have been published so far on the effect of COVID-19 pandemic on health care for non-COVID-19 diseases, to date no study evaluated the impact of the COVID-19 pandemic on the entire field of pediatric endocrinology. This study aimed to evaluate differences in pediatric endocrine stimulation tests after the advent of COVID-19 pandemics. METHODS: Retrospective study with data collection for pediatric endocrine stimulation tests performed in 2019 and 2020 in a tertiary center. RESULTS: Overall, 251 tests were performed on 190 patients in 2020, compared to 278 tests on 206 patients in 2019 (- 10% tests; - 8% children evaluated). A significant reduction was found in tests to diagnose growth hormone deficiency (GHD) (- 35%), while LHRH tests increased (+ 22%). A reduction of 30% in GHD diagnosis was observed. Central precocious puberty (CPP) diagnosis increased by 38% compared to 2019, mainly in females. CONCLUSION: This study found a significant reduction of tests investigating GHD during COVID-19 pandemics. It also showed a clinically meaningful increase in cases of CPP in girls. These results suggest the need for families and pediatricians to monitor children's growth during isolation and enlighten new perspectives towards conditions associated with lockdown restrictions as increased screen time, social isolation, and children's anxiety as possible triggers of CPP.

An antagonist of growth hormone-releasing hormone protects against LPS-induced increase of bronchoalveolar lavage fluid protein concentration.

Growth Hormone-Releasing Hormone (GHRH) is a neuropeptide regulating the release of Growth Hormone (GH) from the anterior pituitary gland, and acts as a growth factor in a diverse variety of tissues. GHRH antagonists (GHRHAnt) have been developed to counteract those events, and the beneficial effects of those peptides toward homeostasis have been associated with anti-inflammatory activities. Our lab is interested in delineating the mechanisms governing endothelial barrier function. Our goal is to establish new grounds on the development of efficient countermeasures against Acute Respiratory Distress Syndrome (ARDS), which has been associated with thousands of deaths worldwide due to COVID-19. Herein we demonstrate in vivo that GHRHAnt suppresses LPS-induced increase in bronchoalveolar lavage fluid (BALF) protein concentration, thus protecting the lungs against edema and inflammation.

Willingness of Women with Endometriosis Planning to Undergo IVF to Participate in a Randomized Clinical Trial and the Effects of the COVID-19 Pandemic on Potential Participation.

The Pre-IVF Treatment with a GnRH Antagonist in Women with Endometriosis (PREGnant) Trial (clinicaltrials.gov no. NCT04173169) was designed to test the hypothesis that 60-day pre-treatment with an oral GnRH antagonist in women with documented endometriosis and planning an IVF cycle will result in a superior live birth rate to placebo. Eight hundred fourteen women are required from 4 national sites. To determine the feasibility of using an electronic medical record (EMR)-based strategy to recruit 204 participants at the Colorado site, we conducted a survey of women within the UCHealth system. Eligible women, identified using relevant ICD-10 codes, were invited to complete a 6-question survey to assess planned utilization of IVF, potential interest in participation, and whether delays in treatment due to COVID-19 would influence their decision to participate. Of 6354 age-eligible women with an endometriosis diagnosis, 421 had a concurrent infertility diagnosis. After eliminating duplicates, 212 were emailed a survey; 76 (36%) responded, 6 of whom reported no endometriosis diagnosis. Of the remaining 70, 29 (41%) were planning fertility treatment; only 19 planned IVF. All 19 expressed interest in participation. COVID-19 delays in treatment were not considered as a factor affecting participation by 8/19; the remaining 11 felt that it would "somewhat" affect their decision. None reported that they would not consider participation because of COVID-19. EMR-based recruitment for an endometriosis clinical trial is feasible although the overall yield of participants is low. Delays in treatment due to COVID-19 did not appear to overly influence potential recruitment.

Cardiovascular Toxicities of Androgen Deprivation Therapy.

OPINION STATEMENT: Prostate cancer is the second leading cause of cancer death in men, and cardiovascular disease is the number one cause of death in patients with prostate cancer. Androgen deprivation therapy, the cornerstone of prostate cancer treatment, has been associated with adverse cardiovascular events. Emerging data supports decreased cardiovascular risk of gonadotropin releasing hormone (GnRH) antagonists compared to agonists. Ongoing clinical trials are assessing the relative safety of different modalities of androgen deprivation therapy. Racial disparities in cardiovascular outcomes in prostate cancer patients are starting to be explored. An intriguing inquiry connects androgen deprivation therapy with reduced risk of COVID-19 infection susceptibility and severity. Recognition of the cardiotoxicity of androgen deprivation therapy and aggressive risk factor modification are crucial for optimal patient care.