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

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

Back to the Future: Is GnRHa Treatment in Transgender and Gender Diverse Adolescents Only an Extended Evaluation Phase?

CONTEXT: The role of body modifications induced by gonadal suppression in transgender and gender diverse adolescents on psychological functioning has not yet been evaluated. OBJECTIVE: The main aim of the present study was to explore several hormone, physical and psychological functioning changes during gonadotropin-releasing hormone analog (GnRHa) treatment in transgender and gender diverse adolescents (TGDAs). The potential relationship between the physical and hormone effects of GnRHa and psychological well-being, along with its magnitude, was assessed for the first time. METHODS: This prospective multidisciplinary study included 36 TGDA (22 assigned female at birth, and 14 assigned male at birth) who received psychological assessment followed by triptorelin prescription after referring to the Florence Gender Clinic. This study consisted of 3 time points: first referral (T0), psychological assessment (T1); and treatment with intramuscular injections of triptorelin for 3 up to 12 months (T2). Psychometric questionnaires were administered at each time point, and clinical and biochemical evaluations were performed at T1 and T2. RESULTS: The following results were found: (1) GnRHa showed efficacy in inhibiting puberty progression in TGDAs; (2) an increase in psychopathology was observed before starting GnRHa (T1) compared with baseline levels; (3) during GnRHa treatment (T2), a significant improvement in psychological functioning, as well as decrease in suicidality, body uneasiness, depression, and anxiety levels were observed; (4) hormone and physical changes (in terms of gonadotropin and sex steroid levels, height and body mass index percentiles, waist-hip ratio, and acne severity) observed during triptorelin treatment significantly correlated with a reduction in suicidal ideation, anxiety, and body image concerns. CONCLUSION: Psychological improvement in TGDA on GnRHa seems to be related to the objective body changes induced by a GnRHa. Therefore, the rationale for treatment with a GnRHa may not only be considered an extension of the evaluation phase, but also the start of a medical (even if reversible) gender-affirming path, especially in TGDAs whose puberty has already progressed.

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

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

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

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

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

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

A single blood sample for stimulated LH assayed by ICMA is useful for monitoring the treatment efficacy of triptorelin depot in girls.

BACKGROUND: There is still no consensus on the optimal monitoring method to evaluate the hypothalamic-pituitary-gonadal axis (HPGA) inhibition. METHODS: There were 124 girls treated with triptorelin depot due to puberty disorders, including 77 central precocious puberty and 47 early puberty. After treatment, triptorelin stimulation tests were performed, and blood samples were collected at 0, 20, 40 and 60 min. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured by immunochemiluminometric assay (ICMA). RESULTS: Peak LH (PLH), peak FSH and estradiol in 124 girls were significantly decreased after treatment, while 2 cases had inadequate treatment efficacy. Areas under the receiver operating characteristic curves (AUC) of PLH and peak FSH after stimulation for the diagnosis of HPGA suppression were 0.984 and 0.121. When the cut-off value of PLH was ≤ 2.25 IU/L, the sensitivity was 96.7% and specificity was 100.0%. There was no difference in AUC between PLH and a single LH at 20, 40, or 60 min (p > 0.05). When LH were ≤ 2.34 IU/L, ≤ 2.21 IU/L and ≤ 2.00 IU/L at 20, 40 and 60 min, respectively, the sensitivity were 99.1%, 96.7% and 98.4%, and the specificity were all 100.0%. The correlation coefficients between PLH and LH at 20, 40 or 60 min were 0.947, 0.975 and 0.961. CONCLUSION: A single blood sample for stimulated LH at 20 min, 40 min, or 60 min assayed by ICMA during triptorelin stimulation test is useful for monitoring the treatment efficacy of triptorelin depot in girls with puberty disorders.

Long-Term Treatment With Letrozole in a Boy With Familial Male-Limited Precocious Puberty.

Background: The long-term follow-up in children with familial male-limited precocious puberty (FMPP) who were treated with letrozole, triptorelin, and spironolactone is limited, especially considering the efficiency and safety. Objective: We describe the clinical characteristics and long-term treatment with letrozole on adult height of a boy diagnosed with FMPP, confirmed by analysis of the LHCGR gene. Methods: Physical examinations, bone age (BA), testosterone, and gonadotropin levels were measured as well as gene sequencing of the proband and parents. Results: The boy was referred to the hospital at 3.1 years of age due to peripheral precocious puberty. His height was 116.8cm (+5.1SD) and BA was 9 years. Genetic analysis revealed a patrilineal c.1703C>T.(p.Ala568Val) mutation of the LHCGR gene. After treating with letrozole for 1.6 years, the height according to BA went from -3.52SD to -2.82SD. Triptorelin was added at age 4.7 years based on both the evidence of central puberty and his growth velocity according to BA. During the 6.9 years of treatment, he had a height gain of 51.9cm, and BA increased 5.2 years. At age 10, his present height is 168.7cm (0.05SD) and BA is 14.7 years. No adverse effects of treatment were encountered. Conclusion: A patrilineal mutation of the LHCGR gene has been identified in a boy with FMPP. His height is 168.7cm (-0.05SD) which is approaching his adult height after long-term treatment with letrozole, triptorelin, and spironolactone.

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

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

Tratamiento con análogos de la hormona liberadora de gonadotrofinas (aGnRH) en niñas, niños y adolescentes / Treatment with gonadotropin-releasing hormone analogs (GnRHa) in childhood and adolescence

Desde hace varias décadas, los análogos de la hormona liberadora de gonadotrofinas (aGnRH) son el tratamiento de elección en la pubertad precoz central (PPC) en niñas y en niños. Causan una inhibición del eje hipotálamo-hipófiso-gonadal, disminuyen la secreción de gonadotrofinas, estradiol y testosterona; como consecuencia, producen una regresión de los caracteres sexuales secundarios durante el tratamiento. En los últimos años, estos análogos también se utilizan en adolescentes transgénero, en adolescentes y adultas jóvenes con enfermedades oncológicas, en algunas situaciones muy particulares en niños y niñas con talla baja, y en pacientes con trastornos del neurodesarrollo. En Argentina, los más utilizados son el acetato de triptorelina y el acetato de leuprolide en sus formas de depósito. Estos medicamentos han demostrado eficacia y seguridad. El objetivo de esta publicación es realizar una revisión y actualización del uso de los aGnRH en niños, niñas y adolescentes.

For several decades, gonadotropin releasing hormone analogs (GnRHa) are the medical treatment selected for central precocious puberty (CPP) in girls and boys. They generate an inhibition of the hypothalamus-pituitarygonadal axis decreasing LH, FSH, estradiol and testosterone secretion and, in this way, they produce a regression of secondary sexual characters under treatment. In the last years, these analogs are also used in trans adolescents, in adolescents and young adults with oncological diseases, in some very particular situations in children with short stature and in patients with neurodevelopmental disorders. In Argentina the most commonly used formulations are triptorelin and leuprolide acetate depot forms. These analogs have proven both their efficacy and their safety. The aim of this paper is to review and update about the use of GnRHa in children and adolescents.

Embonato de triptorrelina 22, 5 mg para o tratamento da puberdade precoce central / Triptorelin Embonate 22. 5 mg for the treatment of central precocious puberty

CONTEXTO: Considera-se puberdade precoce o aparecimento de caracteres sexuais secundários antes dos 8 anos, em meninas, e antes dos 9 anos, em meninos. Em 80% dos casos, a precocidade sexual é dependente de gonadotrofinas, sendo chamada de puberdade precoce central (PPC) ou verdadeira. Neste caso, há uma ativação precoce do eixo hipotálamo-hipófise-gônadas. A secreção prematura dos hormônios sexuais leva à aceleração do crescimento e à fusão precoce das epífises ósseas, antecipando o final do crescimento e comprometendo a estatura final. Trata-se de uma condição rara, com incidência estimada de 1:5.000 a 1:10.000, acometendo mais frequentemente as meninas (10 a 23 vezes mais). O diagnóstico é baseado em exame físico, laboratorial e de imagem. No diagnóstico laboratorial utiliza-se a dosagem de LH. O tratamento é feito com agonistas de GnRH com o objetivo de bloquear a evolução puberal, retardar os caracteres sexuais secundários, diminuir a velocidade de crescimento e a progressão da idade óssea. Os agonistas de GnRH suprimem a secreção de gonadotrofinas hipofisárias, evitando a produção de esteroides sexuais. TECNOLOGIA: Embonato de triptorrelina. PERGUNTA: A triptorrelina de 22,5 mg é eficaz e segura para o tratamento de puberdade precoce central? EVIDÊNCIAS CLÍNICAS: A busca por evidência científica retornou apenas um estudo clínico multicêntrico (18 locais em 3 países), braço único, aberto, com o objetivo de avaliar a eficácia e segurança de triptorrelina formulação semestral no tratamento de pacientes com PPC. Foram incluídos 44 participantes (39 meninas e 5 meninos) com puberdade precoce central sem tratamento prévio com análogo do hormônio liberador de gonadotrofina (GnRHa); idade média de 7,41 ± 1,28 anos. Os participantes receberam duas injeções intramuscular contendo 22,5 mg de triptorrelina em um intervalo de 6 meses. O nível sérico de LH, FSH, estradiol (nas meninas) e testosterona (nos meninos) foi medido na etapa de triagem e em 6 diferentes momentos ao longo de 12 meses. Os eventos adversos foram monitorados e registrados pelo investigador a cada consulta. Os exames laboratoriais para avaliação dos parâmetros de segurança (hematológico, bioquímico e urinário) foram realizados no 6º e 12º mês do estudo, sendo analisados centralmente. O desfecho primário analisado foi a supressão de LH a níveis pré-puberal, avaliado no 6º mês após administração de triptorrelina 22,5 mg. Em 41 participantes foi observado resultados compatíveis com os níveis normais de LH na fase pré-puberal (93,2%; 95% IC 81,3%;98,6%). A supressão de LH foi mantida até o 12º mês do estudo. Os desfechos secundários também foram atingidos. A porcentagem de participantes com redução na relação idade óssea/idade cronológica (BA/CA) foi de 63,6% no 6º mês e 95,5% no 12º mês. A média (DP) foi de 1,40 (0,24) no 6º mês e 1,34 (0,20) no 12 º mês. A velocidade média de crescimento foi de 6,8 cm/ano no 6º mês e 6,1 cm/ano no 12º mês. No gráfico de avaliação da curva de crescimento de escore Z, a alteração média em relação ao valor basal foi de 0,1 no 6º mês e 0,0 no 12º mês. No gráfico de avaliação da curva de crescimento de percentis as médias foram 1,0 no 6º mês e 0,9 no 12º mês, sugerindo que a aceleração no crescimento foi desacelerando. Em relação ao estágio puberal, a comparação entre o valor basal e o 6º mês, o estágio de Tanner estabilizou ou reduziu em 90,9% dos participantes do estudo. Ao término das 48 semanas do estudo, um total de 82 (89,0%) eventos adversos leves emergentes do tratamento foram reportados por 33 (75,0%) dos 44 participantes incluídos. Os eventos adversos mais frequentes, reportados em >5% dos pacientes, foram nasofaringite (13,6%), dor de cabeça (13,6%), infecção no trato respiratório superior (9,1%), gastroenterite (6,8%), tosse (6,8%). Um evento adverso grave, avaliado como não associado ao tratamento, foi relatado durante o estudo. Para avaliação da qualidade metodológica do estudo, aplicou-se a ferramenta ROBINS-I, e concluiu-se que há sério risco de viés no estudo apresentado. Para avaliação do nível de evidência dos desfechos, adotou-se o sistema GRADE e considerou-se baixa ou muito baixa a certeza na evidência de que triptorrelina 22,5 mg é eficaz e segura no tratamento da PPC. AVALIAÇÃO ECONÔMICA: Foi apresentada análise de custo-minimização baseada no pressuposto que os comparadores são equivalentes em termos de eficácia, no entanto, não foi apresentada a evidência para sustentar esse pressuposto, bem como não foi localizada na literatura científica nenhum estudo. Com base nos dados apresentados pelo demandante, com valore obtidos no SIGTAP, a triptorrelina 22,5 mg apresenta custo inferior à ciproterona e triptorrelina 11,25 mg. Com dados obtidos no banco de preços em saúde, triptorrelina 22,5 mg com administração semestral tem custo inferior à leuprorrelina 11,25 mg, gosserrelina (3,60 e 10,80 mg), e triptorrelina 11,25 mg. O custo incremental é observado em relação à ciproterona 50 mg, acetato de medroxiprogesterona e triptorrelina 3,75 mg. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A análise realizada pelo demandante se baseou nos resultados do modelo de custominimização e valores obtidos no SIGTAP. Em um horizonte temporal de cinco anos(2021-2025), os resultados mostraram custo incremental no valor de R$ 639,52. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Não foram identificados medicamentos em desenvolvimento ou estudos clínicos em andamento com novos medicamentos para o tratamento da puberdade precoce central. CONSIDERAÇÕES FINAIS: A respeito da evidência clínica, o único estudo clínico com triptorrelina 22,5 mg encontrado, obteve respostas favoráveis nos desfechos de eficácia, com redução nos níveis séricos dos principais hormônios marcadores da doença (LH, FSH, estradiol e testosterona) e também nos parâmetros clínicos (velocidade de crescimento). O estudo não foi conduzido com grupo controle, favorecendo a introdução riscos de viés no domínio "confundimento". Na avaliação econômica elaborada pelo demandante, a incorporação da tecnologia resultaria em custo superior frente aos medicamentos já incorporados: medroxiprogesterona, leuprorrelina, gosserrelina, e triptorrelina 3,75 mg. Na avaliação do impacto orçamentário apresentada pelo demandante haveria impacto incremental no valor de R$ 639,52 ao término de 5 anos. Em ambas as análises, recálculos foram feitos pelo parecerista e há limitações a serem consideradas. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Diante do exposto, os membros do plenário, em sua 102ª reunião realizada no dia 07 de outubro de 2021, deliberaram por unanimidade encaminhar o tema para consulta pública com recomendação preliminar favorável à incorporação da triptorrelina 22,5 mg administração semestral para o tratamento da puberdade precoce central no SUS. CONSULTA PÚBLICA: Foi realizada entre os dias 22 de novembro de 2021 e 13 de dezembro de 2021. Foram recebidas 189 contribuições, sendo 156 enviadas pelo formulário de experiência ou opinião de pacientes, familiares, amigos, cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema, e 33 enviadas pelo formulário de contribuições técnico-científicas. Após apreciação, o Plenário considerou que não houve nenhuma informação adicional para mudança de entendimento acerca de sua recomendação preliminar. RECOMENDAÇÃO FINAL DA CONITEC: Os membros presentes na 105ª Reunião Ordinária da Conitec, realizada no dia 10/02/2022, deliberaram por unanimidade recomendar a incorporação de triptorrelina 22,5 mg administração semestral para o tratamento da puberdade precoce central no SUS. Foi assinado o registro de deliberação nº 713/2022. DECISÃO: Incorporar o embonato de triptorrelina 22,5 mg administração semestral para o tratamento de puberdade precoce central, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 27, publicada no Diário Oficial da União nº 52, seção 1, página 74, em 17 de março de 2022.

[Treatment with gonadotropin-releasing hormone analogs (GnRHa) in childhood and adolescence]. / Tratamiento con análogos de la hormona liberadora de gonadotrofinas (aGnRH) en niñas, niños y adolescentes.

For several decades, gonadotropin releasing hormone analogs (GnRHa) are the medical treatment selected for central precocious puberty (CPP) in girls and boys. They generate an inhibition of the hypothalamus-pituitary-gonadal axis decreasing LH, FSH, estradiol and testosterone secretion and, in this way, they produce a regression of secondary sexual characters under treatment. In the last years, these analogs are also used in trans adolescents, in adolescents and young adults with oncological diseases, in some very particular situations in children with short stature and in patients with neurodevelopmental disorders. In Argentina the most commonly used formulations are triptorelin and leuprolide acetate depot forms. These analogs have proven both their efficacy and their safety. The aim of this paper is to review and update about the use of GnRHa in children and adolescents.

Desde hace varias décadas, los análogos de la hormona liberadora de gonadotrofinas (aGnRH) son el tratamiento de elección en la pubertad precoz central (PPC) en niñas y en niños. Causan una inhibición del eje hipotálamo-hipófiso-gonadal, disminuyen la secreción de gonadotrofinas, estradiol y testosterona; como consecuencia, producen una regresión de los caracteres sexuales secundarios durante el tratamiento. En los últimos años, estos análogos también se utilizan en adolescentes transgénero, en adolescentes y adultas jóvenes con enfermedades oncológicas, en algunas situaciones muy particulares en niños y niñas con talla baja, y en pacientes con trastornos del neurodesarrollo. En Argentina, los más utilizados son el acetato de triptorelina y el acetato de leuprolide en sus formas de depósito. Estos medicamentos han demostrado eficacia y seguridad. El objetivo de esta publicación es realizar una revisión y actualización del uso de los aGnRH en niños, niñas y adolescentes.

Positive effect of combined exercise on adipokines levels and pubertal signs in overweight and obese girls with central precocious puberty.

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.

Acetato de leuprorrelina subcutânea 45mg para tratamento de puberdade precoce central / Subcutaneous Leuprorelin Acetate 45mg for central precocious puberty treatment

INTRODUÇÃO: A puberdade precoce se refere ao desenvolvimento de características sexuais secundárias antes dos oito anos, no sexo feminino, ou antes dos nove anos de idade, no sexo masculino, sendo classificada como puberdade precoce central quando as características sexuais se desenvolvem por ativação precoce do eixo hipotálamo-hipófise-gonadal (HHG). Considerada uma condição rara, sua incidência é comumente relatada em torno de 1:5.000 a 1:10.000, sendo mais frequente no sexo feminino em uma proporção de 3 a 23 meninas: 1 menino, com o diagnóstico baseado no exame físico, exames laboratoriais e de imagem. Valores de pico do LH maiores que 5 UI/L após estímulo hormonal confirmam o diagnóstico. A antecipação da puberdade tem implicações psicossociais e na saúde a longo prazo substanciais, incluindo aumento de riscos de obesidade, hipertensão, diabetes tipo 2, doença isquêmica do coração, acidente vascular cerebral, câncer de mama e mortalidade cardiovascular. O uso de agonistas do hormônio liberador de gonadotrofina (GnRH) de longa ação com o objetivo de regredir ou estabilizar os sintomas da puberdade, reduzir a velocidade de crescimento para valores normais pré-púberes e diminuir o avanço da idade óssea é o tratamento de referência. De acordo com o Protocolo Clínico e Diretrizes Terapêuticas (PCDT) de Puberdade Precoce Central, os esquemas de tratamentos com agonistas de GnRH recomendados no SUS são: gosserrelina 3,6 mg subcutâneo (SC) a cada mês ou 10,8 mg a cada 3 meses; leuprorrelina 3,75 mg intramuscular (IM) a cada mês ou 11,25 mg a cada 3 meses, 7,5 mg IM a cada mês em caso de controle clínico e/ou laboratorial insatisfatórios, 3,75 mg IM para o teste diagnóstico; ou triptorrelina 3,75 mg IM a cada mês ou 11,25 mg a cada 3 meses; 7,5 mg IM a cada mês em caso de controle clínico e/ou laboratorial insatisfatórios. O documento vigente do PCDT brasileiro ressalta que não há superioridade terapêutica do uso trimestral sobre o mensal e, assim, o tratamento com triptorrelina ou leuprorrelina pode ser feito com qualquer uma das posologias. PERGUNTA: Os diferentes regimes de leuprorrelina apresentam equivalência em relação à eficácia e segurança no tratamento de pacientes com puberdade precoce central, com ênfase no regime de 45 mg subcutâneo a cada 6 meses? Evidências clínicas: A principal evidência disponível provém de um estudo clínico multicêntrico (25 locais em 6 países), não randomizado, aberto, de braço único com o objetivo de avaliar a eficácia e segurança do tratamento da puberdade precoce central com uso de acetato de leuprorrelina na dose de 45 mg por via subcutânea a cada 6 meses durante o seguimento de aproximadamente 1 ano (48 semanas). Ao todo, 64 crianças (60 do sexo feminino), idade média de 7,5 ± 0,1 anos, diagnosticadas com puberdade precoce central e sem tratamento prévio com GnRHa participaram do estudo. Como desfecho primário, no período de 6 meses, 87,1% (IC95%: 76,5% a 93,3%; n = 54; N = 62) das crianças alcançaram o critério de resposta de se atender a níveis de LH < 4 UI/L 30 minutos após a estimulação com GnRHa. No período de 12 meses, observou-se que 86,2% (IC95%: 75,5% a 93,4%; n = 50; N = 58) das crianças atingiram também o objetivo. Tanto a supressão de LH, como a redução da taxa média de crescimento foi persistente ao longo das 48 semanas de acompanhamento, saindo de 8,9 ± 1,7 cm/ano na semana 4 para 5,4 ± 0,5 cm/ano na semana 24 e 6,0 ± 0,5 cm/ano na semana 48. Os eventos adversos relacionados ao tratamento mais frequentes foram: dor no local da injeção (31%), nasofaringite (22%), pirexia (17%), dor de cabeça (16%), tosse (13%), dor abdominal (9%), eritema no local da injeção (9%), náusea (8%), constipação (6%), vômito (6%), infecção do trato respiratório superior (6%), broncoespasmo (6%), tosse produtiva (6%) e fogacho (5%). Após a análise do risco de viés com a ferramenta ROBINS-I e do nível de evidência dos desfechos críticos pelo sistema GRADE, considerou-se MODERADA (⊕⊕⊕⊝) a certeza na evidência de que o regime de 6 meses de leuprorrelina é eficaz e seguro no tratamento da puberdade precoce central em pacientes com idade igual ou superior a 2 anos. As principais limitações da evidência disponível dizem respeito à ausência de um grupo comparador em um estudo randomizado, fator igualmente limitante nas demais apresentações já disponíveis no SUS. Apesar de não haver um grupo controle e uma comparação direta ou indireta, os níveis de resposta são observados logo nas primeiras semanas de tratamento e foram mantidos ao longo do período de seguimento do estudo (48 semanas), com amplitude de intervalos de confiança de 95% de suas respostas semelhantes aos esquemas disponíveis no SUS. O nível de certeza para o desfecho de eventos adversos foi BAIXA (⊕⊕⊝⊝) por se tratar de um estudo com uma pequena amostra e eventos raros podem não ter sido identificados, o que reforça a necessidade do monitoramento do uso numa eventual disponibilização do tratamento a um número maior de pacientes. AVALIAÇÃO ECONÔMICA: Foi construído um modelo de custo-minimização baseado no pressuposto que os comparadores possuem a mesma efetividade. O estudo que baseou essa premissa não possui comparador e tem uma qualidade limitada. O resultado da avaliação econômica foi de uma economia média anual por paciente de R$ 2.598 e R$200,00 ao substituir a leuprorrelina de 11,25mg e 3,75mg respectivamente. Os valores da leuprorrelina de 3,75mg foram atualizados pelos valores de negociação no SIASG. Análise de impacto orçamentário: O impacto orçamentário foi construído com os resultados do modelo de custominimização. A população e os preços das alternativas propostas pelo demandante foram atualizados e adequados a realidade brasileira. Os resultados do modelo do demandante e das adequações fizeram o impacto orçamentário em cinco anos variar de uma economia de R$ 275.955.428,77 a R$153.746.138. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Não foram identificados medicamentos em desenvolvimento clínico para a indicação clínica. CONSIDERAÇÕES FINAIS: Quanto a evidência clínica, o estudo observou respostas favoráveis nos desfechos de eficácia com destaque para a supressão do hormônio luteinizante (LH). Não houve comparação a um grupo controle, tampouco foi construída uma indireta entre estudos. O risco de viés das evidências disponíveis é uma condição inerente ao contexto de condição rara e está também presente nas evidências das apresentações de leuprorrelina já incorporadas no SUS de (3,75 mg mensal e 11,25 trimestral), onde também não há ensaios clínicos de comparação direta. Tanto a avaliação econômica quanto o impacto orçamentário resultaram em economia de recursos para o SUS. CONSULTA PÚBLICA: realizada entre os dias 20/07/2021 e 09/08/2021, a Consulta Pública recebeu um total de 353 contribuições, sendo 66 pelo formulário para contribuições técnico-científicas e 287 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Das 66 contribuições de cunho técnico-científico recebidas, 41 foram analisadas, já que as demais não apresentaram informação alguma (em branco) ou argumentação técnica sobre as evidências. Das 287 contribuições recebidas sobre experiência com a tecnologia ou opinião sobre o tema, 268 foram analisadas, já que as demais não apresentaram informação alguma (em branco). No total, 286 concordaram com a recomendação inicial da Conitec e 1 discordou. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do plenário da Conitec, presentes na 101ª reunião ordinária da Conitec, no dia 01 de setembro de 2021, deliberaram por unanimidade, recomendar a incorporação no SUS do acetato de leuprorrelina subcutânea 45mg para tratamento de puberdade precoce central em pacientes com idade igual ou superior a 2 anos de idade. Além de ressaltados os benefícios acerca da vantagem posológica, que possibilitam maior adesão ao tratamento, não foram adicionadas informações durante a Consulta Pública que alterassem a recomendação preliminar. Foi assinado o Registro de Deliberação nº 662/2021. DECISÃO: Incorporar nova apresentação do acetato de leuprorrelina subcutânea 45mg para tratamento de puberdade precoce central em pacientes com idade igual ou superior a 2 anos de idade, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 69, publicada no Diário Oficial da União nº 206, seção 1, página 76, em 03 de novembro de 2021.

Cumulative live birth rates between GnRH-agonist long and GnRH-antagonist protocol in one ART cycle when all embryos transferred: real-word data of 18,853 women from China.

BACKGROUND: A consensus has been reached on the preferred primary outcome of all infertility treatment trials, which is the cumulative live birth rate (CLBR). Some recent randomized controlled trials (RCTs) and retrospective studies have compared the effectiveness of GnRH-antagonist and GnRH-agonist protocols but showed inconsistent results. Studies commonly used conservative estimates and optimal estimates to described the CLBR of one incomplete assisted reproductive technology (ART) cycle and there are not many previous studies with data of the complete cycle to compare CLBRs in GnRH-antagonist versus GnRH-agonist protocols. METHODS: A total of 18,853 patients have completed their first IVF cycle including fresh and subsequent frozen-thawed cycles during 2016-2019, 16,827 patients were treated with GnRH-a long and 2026 patients with GnRH-ant protocol. Multivariable logistic analysis was used to evaluate the difference of GnRH-a and GnRH-ant protocol in relation to CLBR. Utilized Propensity Score Matching(PSM) for sampling by up to 1:1 nearest neighbor matching to adjust the numerical difference and balance the confounders between groups. RESULTS: Before PSM, significant differences were observed in baseline characteristics and the CLBR was 50.91% in the GnRH-a and 33.42% in the GnRH-ant (OR = 2.07; 95%CI: 1.88-2.28; P < 0.001). Stratified analysis showed the CLBR of GnRH-ant was lower than GnRH-a in suboptimal responders(46.89 vs 27.42%, OR = 2.34, 95%CI = 1.99-2.74; P < 0.001) and no differences of CLBR were observed in other patients between protocols. After adjusting for potential confounders, multivariable logistic analysis found the CLBR of GnRH-ant group was lower than that of GnRH-a group (OR = 2.11, 95%CI:1.69-2.63, P < 0.001). After PSM balenced the confounders between groups, the CLBR of GnRH-a group was higher than that of GnRH-ant group in suboptimal responders((38.61 vs 28.22%, OR = 1.60, 95%CI = 1.28-1.99; P < 0.001) and the normal fertilization rate and number of available embryo in GnRH-a were higher than these of GnRH-ant groups in suboptimal responders (77.39 vs 75.22%; 2.86 ± 1.26 vs 2.61 ± 1.22; P < 0.05). No significant difference was observed in other patients between different protocols. CONCLUSIONS: It is crucial to optimize the utilization of protocols in different ovarian response patients and reconsider the field of application of GnRH-ant protocols in China.

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

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

The Use of Morning Urinary Gonadotropins and Sex Hormones in the Management of Early Puberty in Chinese Girls.

CONTEXT: Although gonadotropin-releasing hormone stimulation test (GnRHST) is the gold standard in diagnosing central precocious puberty (CPP), it is invasive, expensive, and time-consuming, requiring multiple blood samples to measure gonadotropin levels. OBJECTIVE: We evaluated whether urinary hormones could be potential biomarkers for prepuberty or postpuberty, aiming to simplify the current diagnosis and prognosis procedure. METHODS: We performed a cross-sectional study of a total of 355 girls with CPP in National Clinical Research Center for Child Health in China, including 258 girls with positive and 97 girls with negative results from GnRHST. Twenty patients received GnRH analogue (GnRHa) treatment and completed a 6-month follow up. We measured luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, prolactin, progesterone, testosterone, and human chorionic gonadotropin in the first morning voided urine samples. RESULTS: Their urinary LH levels and the ratios of LH to FSH increased significantly with the advancement in Tanner stages. uLH levels were positively associated with basal and peak LH levels in the serum after GnRH stimulation. A cutoff value of 1.74 IU/L for uLH reached a sensitivity of 69.4% and a specificity of 75.3% in predicting a positive GnRHST result. For the combined threshold (uLH ≥ 1.74 + uLH-to-uFSH ratio > 0.4), the specificity reached 86.6%. After 3 months of GnRHa therapy, the uLH and uFSH levels decreased accordingly. CONCLUSION: uLH could be a reliable biomarker for initial CPP diagnosis and screening; uLH could also be an effective marker for evaluating the efficacy of clinical treatment.

Duplication of the Pituitary Gland (DPG)-Plus Syndrome Associated With Midline Anomalies and Precocious Puberty: A Case Report and Review of the Literature.

Duplication of the pituitary gland (DPG)-plus syndrome is a very rare developmental disorder with few cases described in the literature and characterized by multiple midline and central nervous system malformations. The hypothalamus and hypophysis involvement may be clinically associated with endocrine abnormalities. A 5.9-year-old female child was admitted to our Clinic for premature thelarche and acceleration of growth. DPG-plus syndrome with paired infundibula and pituitary glands was diagnosed after birth, when she appeared small for gestational age and she presented with lingual hypoplasia, cleft palate, right choanal stenosis, nasopharyngeal teratoma, and facial dysmorphisms. Neuroimaging revealed a duplication of the infundibula, the pituitary gland, and the dens of the epistropheus despite surgical removal of a rhino-pharyngeal mass performed at the age of two months. An array-CGH revealed a 2p12 deletion. At our evaluation, bone age assessment resulted advanced and initial pubertal activation was confirmed by Gonadotropin-Releasing Hormone stimulation test. Hormonal suppression treatment was started with satisfactory results. This case shows that DPG-plus syndrome must be considered in presence of midline and craniofacial malformations and endocrinological evaluations should be performed for the prompt and appropriate management of pubertal anomalies.

Ultra-Long GnRH Agonist Protocol During IVF/ICSI Improves Pregnancy Outcomes in Women With Adenomyosis: A Retrospective Cohort Study.

Objective: This study aimed to compare the ultra-long gonadotropin-releasing hormone agonist (GnRH-a) protocol and the long GnRH-a protocol during in vitro fertilization (IVF) or intracytoplasmic sperm (ICSI) treatment on fertility outcomes in women with adenomyosis. Materials and Methods: This study was a retrospective cohort study. From January 2011 to May 2018, a total of 371 fresh IVF/ICSI cycles were included. Among the cycles included, 237 cycles of 212 women underwent the ultra-long GnRH-a protocol, while 134 cycles of 116 women underwent the long GnRH-a protocol. The rates of implantation, clinical pregnancy per embryo transfer, live birth, and early miscarriage were estimated between the compared protocols. Results: In the study, the early miscarriage rate in women undergoing the ultra-long GnRH-a protocol was significantly lower than those undergoing the long GnRH-a protocol (12.0% versus 26.5%, p = 0.045), whereas the differences in the rates of biochemical pregnancy, implantation, clinical pregnancy, and live birth in women between the two groups showed no statistical significance. The pregnancy outcomes were also sub-analyzed according to the adenomyotic region (diffuse and focal). As for diffuse adenomyosis, the rates of clinical pregnancy and live birth in women undergoing the ultra-long GnRH-a protocol were significantly higher than those undergoing the long GnRH-a protocol (55.3% versus 37.9%, p = 0.025; 43.4% versus 25.9%, p = 0.019, respectively). However, pregnancy outcomes showed no difference between the two protocols in women with focal adenomyosis. Conclusions: The ultra-long GnRH-a protocol during IVF/ICSI improves pregnancy outcomes in women with adenomyosis, especially in women with diffuse adenomyosis when compared with the long GnRH-a protocol.