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De novo onset of Graves' disease (GD) after controlled ovarian stimulation (OS) is exceptional. Only one case of progression to GD after OS in a patient with pre‐existing subclinical hyperthyroidism has been reported. We describe the case of a patient with neither previous thyroid disorders nor autoimmunity who developed GD after OS for primary infertility. A 40‐year‐old woman with primary infertility underwent four cycles of OS. Her thyroid function performed before the last cycle was unremarkable (thyroid stimulating hormone [TSH] 1.9 mU/L, fT4 1.3 ng/dL, fT3 2.4 pg/mL), and thyroid autoimmunity was negative (anti‐thyroperoxidase antibodies and anti‐thyroglobuline antibodies). Six weeks after the last cycle she developed overt thyrotoxicosis (TSH < 0.005 mU/L, fT4 4.79 ng/dL, fT3 15.6 pg/mL) with anti‐thyrotropin receptor antibodies (TRAb) positivity (9.2 IU/L). She was diagnosed with GD and anti‐thyroid therapy was instituted. After 1 year of treatment, thyroid function was still suboptimal (TSH 0.2 mU/L, fT4 1.04 ng/dL, fT3 2.2 pg/mL), and TRAb titer still elevated (8.75 IU/L). Despite her desire to achieve pregnancy, a further cycle of OS was postponed until complete remission of thyroid dysfunction and withdrawal of anti‐thyroid therapy. Although TSH assay after OS is not recommended in euthyroid women without autoimmunity, in the presence of hyperthyroid symptoms throughout OS it is advisable to evaluate thyroid function and TRAb. It is advisable to carefully evaluate the course of GD before proceeding with further courses of OS that could lead to its exacerbation or recurrence. In cases where a strong desire for pregnancy persists, thyroidectomy may be proposed. [ABSTRACT FROM AUTHOR]

Abstract Background In response to the imperative need for standardized support for adolescent Gender Dysphoria (GD), the Italian Academy of Pediatrics, in collaboration with the Italian Society of Pediatrics, the Italian Society for Pediatric Endocrinology and Diabetes, Italian Society of Adolescent Medicine and Italian Society of Child and Adolescent Neuropsychiatry is drafting a position paper. The purpose of this paper is to convey the author's opinion on the topic, offering foundational information on potential aspects of gender-affirming care and emphasizing the care and protection of children and adolescents with GD. Main body Recognizing that adolescents may choose interventions based on their unique needs and goals and understanding that every individual within this group has a distinct trajectory, it is crucial to ensure that each one is welcomed and supported. The approach to managing individuals with GD is a multi-stage process involving a multidisciplinary team throughout all phases. Decisions regarding treatment should be reached collaboratively by healthcare professionals and the family, while considering the unique needs and circumstances of the individual and be guided by scientific evidence rather than biases or ideologies. Politicians and high court judges should address discrimination based on gender identity in legislation and support service development that aligns with the needs of young people. It is essential to establish accredited multidisciplinary centers equipped with the requisite skills and experience to effectively manage adolescents with GD, thereby ensuring the delivery of high-quality care. Conclusion Maintaining an evidence-based approach is essential to safeguard the well-being of transgender and gender diverse adolescents.

Introduction: Breast cancer affects almost 1.5 million women worldwide below the age of 45 years each year. Many of these women will be advised to undergo adjuvant chemotherapy to minimize the risk of death or recurrence of the tumor. For these patients, chemotherapy is a known cause of infertility, as it can damage primordial follicles, which can lead to early menopause or premature ovarian insufficiency. This systematic review aims to synthesize the current evidence of the most suitable treatments for fertility preservation. Methodology: This review was performed following the PRISMA guidelines. The authors conducted an extensive search from the last 15 years. Relevant studies were pursued in PubMed, Embase, and the Cochrane Library up until 31 July 2023. A total of seven eligible studies were identified. Results: From the reviewed literature, ovarian suppression with gonadotropin-releasing hormone agonists showed promising results in preserving fertility for breast cancer patients undergoing chemotherapy. Additionally, oocyte and embryo cryopreservation demonstrated successful outcomes, with embryo cryopreservation being the most effective option. Notably, the slow-freezing and vitrification methods were both effective in preserving embryos, with vitrification showing superior results in clinical-assisted reproductive technologies. Ovarian tissue cryopreservation emerged as a viable option for prepubertal girls and those unable to undergo conventional ovarian stimulation. The potential of in vitro maturation (IVM) as an alternative method presents a promising avenue for future fertility preservation research. Discussion: The most suitable treatments for fertility preservation in young patients is the temporary suppression with luteinizing hormone-releasing analogs, while the patient undergoes chemotherapy and cryopreservation. For cryopreservation, the physicians might deem it necessary to either cryopreserve ovarian tissue taken from the patient before any treatment or cryopreserve embryos/oocytes. Cryopreservation of oocytes and/or embryos is the most effective solution for fertility preservation in women of reproductive age, who have a sufficient ovarian reserve and are diagnosed with breast cancer, regardless of the histological type of the tumor. Because approximately 50% of young breast cancer patients are interested in becoming pregnant right after completion of therapy, the evolution and development of fertility preservation techniques promise to be very exciting. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer affects almost 1.5 million women worldwide below the age of 45 years each year. Many of these women will be advised to undergo adjuvant chemotherapy to minimize the risk of death or recurrence of the tumor. For these patients, chemotherapy is a known cause of infertility, as it can damage primordial follicles, which can lead to early menopause or premature ovarian insufficiency. This systematic review aims to synthesize the current evidence of the most suitable treatments for fertility preservation. Methodology: This review was performed following the PRISMA guidelines. The authors conducted an extensive search from the last 15 years. Relevant studies were pursued in PubMed, Embase, and the Cochrane Library up until 31 July 2023. A total of seven eligible studies were identified. Results: From the reviewed literature, ovarian suppression with gonadotropin-releasing hormone agonists showed promising results in preserving fertility for breast cancer patients undergoing chemotherapy. Additionally, oocyte and embryo cryopreservation demonstrated successful outcomes, with embryo cryopreservation being the most effective option. Notably, the slow-freezing and vitrification methods were both effective in preserving embryos, with vitrification showing superior results in clinical-assisted reproductive technologies. Ovarian tissue cryopreservation emerged as a viable option for prepubertal girls and those unable to undergo conventional ovarian stimulation. The potential of in vitro maturation (IVM) as an alternative method presents a promising avenue for future fertility preservation research. Discussion: The most suitable treatments for fertility preservation in young patients is the temporary suppression with luteinizing hormone-releasing analogs, while the patient undergoes chemotherapy and cryopreservation. For cryopreservation, the physicians might deem it necessary to either cryopreserve ovarian tissue taken from the patient before any treatment or cryopreserve embryos/oocytes. Cryopreservation of oocytes and/or embryos is the most effective solution for fertility preservation in women of reproductive age, who have a sufficient ovarian reserve and are diagnosed with breast cancer, regardless of the histological type of the tumor. Because approximately 50% of young breast cancer patients are interested in becoming pregnant right after completion of therapy, the evolution and development of fertility preservation techniques promise to be very exciting.

Puberty identifies the transition from childhood to adulthood. Precocious puberty is the onset of signs of pubertal development before age eight in girls and before age nine in boys, it has an incidence of 1/5000–1/10,000 with an F:M ratio ranging from 3:1 to 20:1. Precocious puberty can be divided into central, also known as gonadotropin-dependent precocious puberty or true precocious puberty, and peripheral, also recognized as gonadotropin-independent precocious puberty or precocious pseudopuberty. Thus, the main aim of this narrative report is to describe the standard clinical management and therapy of precocious puberty according to the experience and expertise of pediatricians and pediatric endocrinologists at Policlinico Umberto I, Sapienza University of Rome, Italy. In the suspicion of early sexual maturation, it is important to collect information regarding the age of onset, the speed of maturation of secondary sexual features, exposure to exogenous sex steroids and the presence of neurological symptoms. The objective examination, in addition to the evaluation of secondary sexual characteristics, must also include the evaluation of auxological parameters. Initial laboratory investigations should include serum gonadotropin levels (LH and FSH) and serum levels of the sex steroids. Brain MRI should be performed as indicated by the 2009 Consensus Statement in all boys regardless of chronological age and in all girls with onset of pubertal signs before 6 years of age. The gold standard in the treatment of central precocious puberty is represented by GnRH analogs, whereas, as far as peripheral forms are concerned, the triggering cause must be identified and treated. At the moment there are no reliable data establishing the criteria for discontinuation of GnRH analog therapy. However, numerous pieces of evidence suggest that the therapy should be suspended at the physiological age at which puberty occurs. [ABSTRACT FROM AUTHOR]

Central precocious puberty (CPP) classically refers to premature activation of the hypothalamic–pituitary–gonadal axis with onset of sexual development before the age of 8 years in girls and 9 years in boys. A decrease in the age of thelarche has been reported over the past several decades; however, the tempo of pubertal progression can be slower and adult height may not be adversely affected in many of the girls who experience thelarche at 6-8 years. Outside of this secular trend in the development itself, the past several decades have also brought about advances in diagnosis and management. This includes the widespread use of an ultrasensitive luteinizing hormone assay, decreasing the need for stimulation testing and a better understanding of the genetics that govern the onset of puberty. Additionally, management of CPP using gonadotropin-releasing hormone analogs (GnRHas) has changed with the advent of new longer-acting formulations. Emerging long-term outcomes of GnRHa administration with regards to obesity, cardiovascular risk factors and fertility are reassuring. Despite these advancements, clinical care in CPP is hampered by the lack of well-designed controlled studies, and management decisions are frequently not supported by clear practice guidelines. Data in boys with CPP are limited and this article focuses on the diagnosis and management of CPP in girls, particularly, in those who present with thelarche at the age of 6-8 years. [ABSTRACT FROM AUTHOR]

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

Puberty identifies the transition from childhood to adulthood. Precocious puberty is the onset of signs of pubertal development before age eight in girls and before age nine in boys, it has an incidence of 1/5000–1/10,000 with an F:M ratio ranging from 3:1 to 20:1. Precocious puberty can be divided into central, also known as gonadotropin-dependent precocious puberty or true precocious puberty, and peripheral, also recognized as gonadotropin-independent precocious puberty or precocious pseudopuberty. Thus, the main aim of this narrative report is to describe the standard clinical management and therapy of precocious puberty according to the experience and expertise of pediatricians and pediatric endocrinologists at Policlinico Umberto I, Sapienza University of Rome, Italy. In the suspicion of early sexual maturation, it is important to collect information regarding the age of onset, the speed of maturation of secondary sexual features, exposure to exogenous sex steroids and the presence of neurological symptoms. The objective examination, in addition to the evaluation of secondary sexual characteristics, must also include the evaluation of auxological parameters. Initial laboratory investigations should include serum gonadotropin levels (LH and FSH) and serum levels of the sex steroids. Brain MRI should be performed as indicated by the 2009 Consensus Statement in all boys regardless of chronological age and in all girls with onset of pubertal signs before 6 years of age. The gold standard in the treatment of central precocious puberty is represented by GnRH analogs, whereas, as far as peripheral forms are concerned, the triggering cause must be identified and treated. At the moment there are no reliable data establishing the criteria for discontinuation of GnRH analog therapy. However, numerous pieces of evidence suggest that the therapy should be suspended at the physiological age at which puberty occurs.

A novel HPLC-ESI-MS/MS method for simultaneous gonadotropin-releasing hormone (GnRH) analogs and somatostatin analog quantitation was developed and validated. The developed method was successfully applied to pharmacokinetic studies. The sample preparation process included solid-phase extraction (SPE). Effective chromatographic separation of the analytes and internal standard (dalargin) was achieved with a C18 column, using a gradient elution with two mobile phases: 0.1% v/v formic acid (aqueous solution) and 0.1% v/v formic acid (acetonitrile solution). The linearity of the method was demonstrated within a concentration range of 0.5–20 ng/mL, with correlation coefficients between 0.998–0.999 for goserelin, buserelin, triptorelin, and octreotide, respectively. The relative standard deviation (RSD, %) values for method accuracy and precision did not exceed 20% at the lower level of quantitation (LLOQ) or 15% at other concentration levels. [ABSTRACT FROM AUTHOR]

Introduction: Requests for hormonal transition in minors are increasing. To date, there is no national recommendation to guide these practices in France. Therefore, the SFEDP (French Society of Pediatric Endocrinology and Diabetology) has commissioned a group of experts to draft the first national consensus on this topic., Method: Each chapter was prepared by one to three authors who conducted a literature review, and it was then reviewed and revised by the group as many times as necessary to achieve a consensus position. The final document was reviewed by a group of external experts., Results: A consensus position was reached regarding the multi-professional nature of support for trans youth, the prescription of molecules aimed at inhibiting endogenous hormone secretion, and the use of gender-affirming hormone therapies, as well as the importance of offering gamete preservation. Non-hormonal aspects of support and various considerations, including ethical ones, were also discussed., Conclusion: This work constitutes an initial set of recommendations for professionals involved in the hormonal transition of trans youth. Additional recommendations under the auspices of the French High Authority for Health would be worthy of being drafted, involving all relevant stakeholders to establish comprehensive official national guidelines that would secure the support and rights of these young individuals, especially those under 16 years old, as well as the professionals involved in their care., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

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

Central precocious puberty (CPP) is a rare disease. The mean annual incidence in girls is 0.8-1.1/100,000 and in boys 0-0.1/100,000. Intracranial arachnoid cysts (ICACs) are usually congenital and represent 1% of intracranial masses in newborns. Intraventricular location is rare. The objective of this work is to carry out a literature updated review of the coexistence of CPP and intraventricular arachnoid cyst (IVAC). ICACs are usually asymptomatic but can present with CPP in 10-40% of patients. IVACs represents only 0.3-1.4% of ICACs, and most seemed originate from the velum interpositum cistern. CPP in girls is usually idiopathic, while in 30-70% of boys are due to an intracranial lesion. Therefore, the coexistence of PPC and IVAC is very rare in boys and exceptional in girls. The exact mechanism of a cyst´s influence on the hypothalamic-pituitary axis is not completely understood. Theories include increased ventricular volume, associated mass effect on the hypothalamus, and direct compression of portions of the hypothalamic-pituitary axis. Analysis of LH peaks after GnRH testing is the gold standard for the diagnosis of CPP. Brain MRI should be part of the assessment in boys and also in girls since clinical features, including age and sex, are not helpful in predicting those with underlying brain pathology. In cases of CPP with IVAC, surgery does not have any effect on the course of pubertal development. The indication for surgery is the onset of neurological symptoms. The medical treatment selected, safe and effective, is GnRH analog depot preparations. In conclusion, there seems to be a consensus for the diagnosis and management of the coexistence of CPP and IVAC, but the etiopathogenesis is not yet well recognized.

Poly(lactide-co-glycolide) PLGA microparticles represent an efficient and modern tool to encapsulate peptide drugs, which enables their administration to live organisms with the benefit of prolongedrelease. One area that could make the best of this opportunity is fish breeding in aquaculture. The presented study was centered on the formulation of gonadotropin-releasing hormone (GnRH) analog loaded PLGA microparticles intended for fish breeding augmentation, using the double emulsion evaporation method. In this initial experiment, the influence of several input variables (drug, PLGA type, emulsifier concentration, gelatine concentration in internal phase) on observed parameters (morphology, particle size, drug content, drug release, resuspension index) was evaluated. It was found that at lower emulsifier concentration, the particle size is apparently lower (8.54 ± 6.13-10.36 ± 4.65 vs. 25.56 ± 18.86), which is more advantageous in injection administration. Encapsulation efficiency ranged from 39.13 ± 8.85 to 75.30 ± 8.83, favoring lower emulsifier concentration, while resuspension index (70.99 ± 6.47%) suggested the possibility of longer-term administration. Dissolution tests revealed prolonged release for ten days, with most of the drug released in 72-96 hrs. A follow-up study discerning polymer type/gelatine concentration was suggested. Accompanying studies of imaging agent coumarin-6 encapsulation for eventual distribution imaging and metoclopramide base drug release for potential adjuvant use were also successfully realized. [ABSTRACT FROM AUTHOR]

A novel HPLC-ESI-MS/MS method for simultaneous gonadotropin-releasing hormone (GnRH) analogs and somatostatin analog quantitation was developed and validated. The developed method was successfully applied to pharmacokinetic studies. The sample preparation process included solid-phase extraction (SPE). Effective chromatographic separation of the analytes and internal standard (dalargin) was achieved with a C18 column, using a gradient elution with two mobile phases: 0.1% v/v formic acid (aqueous solution) and 0.1% v/v formic acid (acetonitrile solution). The linearity of the method was demonstrated within a concentration range of 0.5–20 ng/mL, with correlation coefficients between 0.998–0.999 for goserelin, buserelin, triptorelin, and octreotide, respectively. The relative standard deviation (RSD, %) values for method accuracy and precision did not exceed 20% at the lower level of quantitation (LLOQ) or 15% at other concentration levels.

Gonadotropin-releasing hormone (GnRH) analogs (e.g., triptorelin) are developed to treat hormone-dependent reproductive cancers. However, these analogs lack a significant direct antitumor activity to make them suitable for hormone-refractory reproductive cancers. In this study, we examined different biological properties of lipid-modified GnRH analogs, with/without D-amino acid substitution at position 6 in prostate and ovarian cancer cells. We revealed that the improved metabolic stability due to lipid-modification and D-amino acid substitution played a pivotal role in enhancing GnRH receptor-mediated direct antiproliferative activity up to 4.5-fold higher than triptorelin. Furthermore, a comparable FSH release and higher LH release activity in pituitary cells than triptorelin was observed, indicating an improved specificity and/or binding affinity to GnRH receptors. We confirmed the important role of sex steroids in the antitumor activity of the lipopeptides, which were contrasting in prostate and ovarian cancer cells. The superior activity of these GnRH analogs over commercial peptides renders promises for developing new GnRH receptor ligands to treat hormone-dependent and -refractory cancers, as well as emerging new targeting moieties for the delivery of anticancer agents in GnRH receptor-overexpressing cancers. [ABSTRACT FROM AUTHOR]

Jian-wei Li,1,2,* Guang-yu Liu,1,2,* Ya-jie Ji,3,* Xia Yan,1,2 Da Pang,4 Ze-fei Jiang,5 De-dian Chen,6 Bin Zhang,7 Bing-he Xu,8 Zhi-ming Shao1,2 1Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Breast Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Department of Breast Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 5Department of Oncology, 307 Hospital of People’s Liberation Army, Beijing, People’s Republic of China; 6Department of Breast Diseases, Cancer Hospital of Yunnan Province, Kunming, People’s Republic of China; 7Department of Breast Surgery, Cancer Hospital of Liaoning Province, Shenyang, People’s Republic of China; 8Department of Oncology, Cancer Hospital of Chinese Academy of Medical Sciences, Beijing, People’s Republic of China *These authors contributed equally to this work Purpose: To assess the efficacy, safety, and quality-of-life impact of switching adjuvant treatment in hormone receptor-positive primary breast cancer patients who are still premenopausal after 2–3 years of tamoxifen therapy to anastrozole plus goserelin as compared with continuing tamoxifen over a total period of 5 years. Patients and methods: Hormone receptor-positive, premenopausal, lymph node-positive, or tumor size ≥4 cm breast cancer patients who had received tamoxifen for 2–3 years were randomly assigned to continue tamoxifen treatment (TAM group) or switch to adjuvant anastrozole plus goserelin (ADD group) and continue treatment for another 2–3 years (total treatment duration 5 years). Endpoints evaluated were adverse events (AEs), changes in bone mineral density, quality of life, and disease-free survival-related events. Results: A total of 62 patients (33 in the ADD group and 29 in the TAM group) were evaluated. Grade 3–4 drug-related AEs occurred in five patients (15.2%) in the ADD group vs none in the TAM group. In the ADD group, arthralgias were the most common AEs (5/33 patients; 15.2%), and three patients in this group were discontinued because of AEs. Treatment was temporarily suspended due to AEs in three patients (9.1%) in the ADD group and one patient (3.4%) in the TAM group. Compared with continuing TAM therapy, switching to anastrozole plus goserelin did not result in any worsening of bone mineral density or quality of life. During a median follow-up of 34 months, five patients (15.2%) in the ADD group had disease-free survival events vs four patients (13.8%) in the TAM group. Conclusion: For early-stage breast cancer patients who remain premenopausal following 2–3 years of adjuvant tamoxifen therapy, switching to anastrozole plus goserelin therapy was safe with tolerable adverse effects. However, it did not show superior efficacy compared to remaining on tamoxifen treatment. Trial Registration: ClinicalTrials.gov (identifier NCT01352091). Keywords: breast cancer, adjuvant therapy, anastrozole, tamoxifen, GnRH analogs, aromatase inhibitors

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Although significant progress has been made in the implementation of new breast cancer treatments over the last three decades, this neoplasm annually continues to show high worldwide rates of morbidity and mortality. In consequence, the search for novel therapies with greater effectiveness and specificity has not come to a stop. Among the alternative therapeutic targets, the human gonadotropin-releasing hormone type I and type II (hGnRH-I and hGnRH–II, respectively) and its receptor, the human gonadotropin-releasing hormone receptor type I (hGnRHR-I), have shown to be powerful therapeutic targets to decrease the adverse effects of this disease. In the present review, we describe how the administration of GnRH analogs is able to reduce circulating concentrations of estrogen in premenopausal women through their action on the hypothalamus–pituitary–ovarian axis, consequently reducing the growth of breast tumors and disease recurrence. Also, it has been mentioned that, regardless of the suppression of synthesis and secretion of ovarian steroids, GnRH agonists exert direct anticancer action, such as the reduction of tumor growth and cell invasion. In addition, we discuss the effects on breast cancer of the hGnRH-I and hGnRH-II agonist and antagonist, non-peptide GnRH antagonists, and cytotoxic analogs of GnRH and their implication as novel adjuvant therapies as antitumor agents for reducing the adverse effects of breast cancer. In conclusion, we suggest that the hGnRH/hGnRHR system is a promising target for pharmaceutical development in the treatment of breast cancer, especially for the treatment of advanced states of this disease.

Although significant progress has been made in the implementation of new breast cancer treatments over the last three decades, this neoplasm annually continues to show high worldwide rates of morbidity and mortality. In consequence, the search for novel therapies with greater effectiveness and specificity has not come to a stop. Among the alternative therapeutic targets, the human gonadotropin-releasing hormone type I and type II (hGnRH-I and hGnRH–II, respectively) and its receptor, the human gonadotropin-releasing hormone receptor type I (hGnRHR-I), have shown to be powerful therapeutic targets to decrease the adverse effects of this disease. In the present review, we describe how the administration of GnRH analogs is able to reduce circulating concentrations of estrogen in premenopausal women through their action on the hypothalamus–pituitary–ovarian axis, consequently reducing the growth of breast tumors and disease recurrence. Also, it has been mentioned that, regardless of the suppression of synthesis and secretion of ovarian steroids, GnRH agonists exert direct anticancer action, such as the reduction of tumor growth and cell invasion. In addition, we discuss the effects on breast cancer of the hGnRH-I and hGnRH-II agonist and antagonist, non-peptide GnRH antagonists, and cytotoxic analogs of GnRH and their implication as novel adjuvant therapies as antitumor agents for reducing the adverse effects of breast cancer. In conclusion, we suggest that the hGnRH/hGnRHR system is a promising target for pharmaceutical development in the treatment of breast cancer, especially for the treatment of advanced states of this disease. [ABSTRACT FROM AUTHOR]

Long-acting analogs of GnRH (GnRHas) have been the gold-standard treatment of central precocious puberty (CPP) worldwide and have an enviable track record of safety and efficacy. Recent years have witnessed much growth in the availability of longer-acting and sustained-release forms of GnRHas. Although all available agents appear promising, limited long-term follow-up and/or comparative data are available. In this review, important issues pertaining to the treatment of children with CPP are discussed. In addition to an assessment of the newer extended-release GnRHa formulations, a delineation of factors essential in determining which children should be treated is offered. Outstanding uncertainties in clinical management are highlighted and areas in need of future research identified. Literature searches for this review were performed in PubMed and OVID, with a focus on English-language publications using the terms "central precocious puberty" and "treatment." [ABSTRACT FROM AUTHOR]

Catamenial precipitation of attacks of acute intermittent porphyria (AIP) is commonly treated with gonadotropin-releasing hormone analogues (GnRHas). However, this leads to various adverse effects that might necessitate "add-back" therapy with estrogen. The literature on the efficacy and safety of such therapy is scarce. A 15-year-old girl presented to us with recurrent catamenial attacks of AIP. GnRHa therapy led to near-complete amelioration of the episodes but her bone density worsened as an adverse effect. To circumvent this, low-dose estrogen was added to her regimen as an "add-back" therapy, which was later coupled with cyclical progesterone. She continues to do well using this regimen, with no new episodes. GnRHa therapy with estrogen "add-back" is an attractive option for treating catamenial AIP episodes. [ABSTRACT FROM AUTHOR]

In vitro fertilization is commonly used for treating infertility. One stage of this process is controlled hyperstimulation of the ovaries, achieved by administering gonadotropins. There are several stimulation protocols utilized that increase the number of ovarian follicles during IVF. The most common protocol employs desensitization - the inhibition of follicle-stimulating hormone and luteinizing hormone secretion by the pituitary gland. This is achieved by administering a gonadotropin-releasing hormone (GnRH) analog that is agonistic for the GnRH receptor. However the use of a this drug during therapy carries a risk of complications. This case report deals with a rare case of a woman who underwent pituitary tumor growth as a result of the treatment of GnRH analog. [ABSTRACT FROM AUTHOR]

Over ablasyonu meme kanserinin temel hedeflerinden biridir. Premenopozal kadınlarda overler östrojen sentezinin ana kaynağıdır ve bu nedenle tedavi seçenekleri olarak ooferektomi, over radyoterapisi veya hipotalamik- pituiter-overyan aksın baskılayıcı luteinize hormone analogları (löprolid asetat, goseralin asetat gibi) bilinmektedir. Çok nadiren bu ajanlar etkili olmayarak LHRH analogları kullananlarda gebelik gözlenebilir. Biz löprolid asetat (LA) kullanırken gebe kalan meme kanserli bir vaka sunduk. Otuz dört yaşında kadın hasta kemik metastatik meme kanser tanılı tamoksifen 10 mg günde 2 kez ve 28 günde bir LA 3.75 mg cilt altı ve zolendronik asit 4 mg intravenöz uygulama ile takip edilmekteydi. MAyıs 2013'te 7 aydır LA asit kullanmakta iken hastada 3-4 kg kilo artışı, karnında hareket hissi tarifledi ve gebelik tanısı konuldu. Bugüne kadar LHRH analogları ile tedavi altında iken toplam 4 gebelik vakası bildirilmiştir ancak bu vakaların hepsi GA kullanmakta idi. Tüm vakalar en az 15 aydır GA kullanmakta olup bizim vakamız en erken dönemde LHRH kullanırken gözlenen gebelik vakasıydı. Klinisyenler LHRH kullanan hastalarda gebelik açısından dikkatli olmalı ve hastaları olası riskler için bilgilendirmeliler.

Follicular atresia in granulosa and theca cells occurs by apoptosis through weak hormonal stimulation. We have previously proposed an in vitro model to study this process by inducing apoptosis in BGC-1, a bovine granulosa cell line, and in primary cultures from ovaries with or without corpus luteum (CPGB+ and CPGB−, respectively), with different doses of gonadotropin releasing hormone (GnRH) analogs (leuprolide acetate (LA) as agonist and antide as antagonist). BGC-1 represent immature granulosa cells, whereas CPGB represent different degrees of luteinization. Our aim was to evaluate the intracellular pathways involved in the GnRH regulation of apoptosis in BGC-1. Treatment with LA 100 nM but not with antide led to an increase in BAX over BCL-2 expression, showing antagonism of antide. All treatments inhibited phospholipase-D (PLD) activity compared to control, implying agonist behavior of antide. Progesterone in vitro production and 3β-hydroxysteroid dehydrogenase (3β-HSD) expression revealed different degrees of luteinization: BGC-1 were immature, whereas CPGB+ were less differentiated than CPGB−. We concluded that LA-induced apoptosis in BGC-1 occurs by activation of the mitochondrial pathway and by inhibition of PLD activity and that antide might work both as an antagonist of the intrinsic pathway and as an agonist of the extrinsic protection pathway by inhibiting PLD activity. [ABSTRACT FROM AUTHOR]

Résumé La dysphorie de genre est caractérisée par une inadéquation entre le genre exprimé d’un individu et le genre assigné à la naissance, entraînant une détresse clinique. Depuis une dizaine d’années, la dysphorie de genre est prise en charge chez les enfants et adolescents conjointement par les pédopsychiatres et les endocrinologues pédiatres. Des recommandations ont été publiées récemment sur le plan international pour la prise en charge précoce de la dysphorie de genre chez les adolescents dès les premiers stades de développement pubertaire. Cette prise en charge selon un protocole développé par les équipes des Pays-Bas, avec un recul d’une quinzaine d’années maintenant, fait intervenir successivement un blocage du développement pubertaire du sexe natal par les analogues de la GnRH, puis une induction de la puberté dans le sexe désiré par les androgènes ou les estrogènes. Cet article reprend les différentes étapes de l’évaluation et de la prise en charge médicale de la dysphorie de genre sur le plan endocrinologique, telle qu’elle est proposée actuellement en France, reposant sur les recommandations internationales. Gender dysphoria is characterized by the dissociation between one's expressed gender and the gender of rearing as assigned at birth, which generates significant clinical distress with social, academic, and other important forms of isolation. For the last 15 years, the management of gender dysphoria in children and adolescents has developed internationally. Since 2013, several pediatric psychiatry and endocrinology departments have initiated a multidisciplinary evaluation and management approach for these patients in France. This management includes early recognition of gender dysphoria and after a thorough combined evaluation, the discussion of starting from early pubertal developmental stages a treatment by GnRH analogs. This treatment allows the suppression of further development of the secondary sexual characteristics of the natal gender, followed after several years, by the induction of puberty in the desired gender by androgens or estrogens. This article reviews the different steps of evaluation and hormonal management of gender dysphoria in adolescents as it is currently proposed in France, based on the international recommandations. [ABSTRACT FROM AUTHOR]

Induction of multiple follicular development is a common practice in IVF programmes. Nevertheless, such an approach is not without implications. Apart from the high multiple pregnancy rate, marked changes in the secretion of pituitary and ovarian hormones take place. Estradiol and inhibin are produced in high amounts during the follicular phase and as a result the negative feedback mechanism is potentiated leading to the marked suppression of gonadotropin secretion from the pituitary. The secretion of LH is also reduced in down-regulated cycles as well as in women receiving a GnRH antagonist, while LH levels are maintained stable when a GnRH agonist is used in a short protocol. The suppression of LH secretion is also evident at midcycle with the endogenous LH surge being blocked or markedly attenuated due to the production of gonadotropin surge attenuating factor (GnSAF). Under these conditions, the LH surge is usually premature in relation to the size of the leading follicle resulting in premature luteinization, but can be prevented by the use of GnRH analogs. In IVF cycles, the luteal phase is disrupted due to the suppression of LH levels. Mild protocols might provide a better approach to the ovarian stimulation than conventional protocols resulting in a reasonable success rate of IVF treatment.

In the past, the primary approach for the treatment of endometriosis was represented by surgery; however, after the introduction of non-invasive diagnosis of endometriosis with the development of imaging technologies, medical treatment became the preferred approach, particularly in young patients. Hormonal drugs, by blocking menstruation, are the most effective for the treatment of endometriosis-related pain, independently of phenotype (ovarian, deep, or superficial endometriosis). Gonadotropin-releasing hormone analogs and oral antagonists act on hypothalamus-pituitary-ovary axis inducing iatrogenic menopause, thus reducing dysmenorrhea and all pain symptoms. The side effects, such as hot flushes and bone loss, may be reduced by an add-back therapy. However, the cost in terms of women's health remains high in view of a long-term treatment. Progestins are considered the first-line treatment, highly effective, and with reduced side effects. In addition to the well-known and largely used Norethisterone acetate and Medroxyprogesterone acetate, recently Dienogest has become one of the most used drugs in all endometriosis phenotypes for long-term treatment. Besides, Intrauterine levornogestrel or subcutaneous etonogestrel are valid alternative for long-term treatment. [ABSTRACT FROM AUTHOR]

Background and Objectives: Leiomyoma of uterus forms the most common type of benign tumor of uterus and also the most common pelvic tumor in women. The symptomatology continues to be variable. Surgery has for long been the main mode of therapy for the myomas. For women who wish to retain the uterus for future pregnancies or other reasons, myomectomy is preferred. Recent trend has been toward nonsurgical approaches like GnRH hormone analogs/agonists, RU 486, or selective uterine artery embolization, laparoscopic cryoablation, radiofrequency thermal ablation, and MRGUs. This multicentric study was an attempt to analyze the clinicopathological spectrum in cases of leiomyoma of the uterus at Cheluvamba Hospital, Adichunchanagiri Institute of Medical Sciences, and to know regarding the pattern of presentation, pathological correlation, with type of fibroid, and endometrial and ovarian changes. Methods: A clinical study of 100 cases of fibroid uterus was conducted in the Cheluvamba Hospital, attached to Mysore Medical College and Research Institute, Mysore, and Adichunchanagiri Institute of medical sciences, BG Nagara, Mandya from November 2008 to August 2012. The cases are selected by random allocation. On admission, detailed history, clinical examination, and investigations were recorded. Results: Leiomyoma is the most common benign tumor of the uterus and commonly affects the women of child-bearing age, most commonly in the third decade, 55 %. The most common mode of presentation was menstrual disturbances (76 %), among which menorrhagia was seen in 54 % of the cases. Primary infertility was seen in 15 % of the patients. Intramural fibroids were the most common variety occurring in 60 % of the cases. Endometrial pattern was proliferative in 66.3 %. Cystic ovaries were seen in 8 % of the patients, adenomyosis in 16 % indicating hyperestrogenism. Conclusion: Fibromyoma (leiomyoma) is the most common benign tumor of the pelvis. It commonly affects the women of child-bearing age, mostly in the third decade and is most commonly seen in multipara. The most common mode of presentation is menstrual disturbances. Intramural fibroid is the most common variety. The proliferative and hyperplastic endometrium was commonly reported. The presence of proliferative endometrium, adenomyosis, and cystic ovaries all are indicative of hyperestrogenic state associated with development of fibroids. [ABSTRACT FROM AUTHOR]

Minimizing endogenous estrogen production and activity in women at high risk for breast cancer is a prominent approach to prevention of the disease. A number of clinical trials have shown that the administration of selective-estrogen receptor modulators or aromatase inhibitors significantly reduces the incidence of breast cancer in healthy women. Unfortunately, these drugs often produce adverse effects on the quality of life and are, therefore, poorly accepted by many women, even those who are at high risk for breast cancer. We propose a novel alternative approach to decreasing estrogen production: suppression of ovarian synthesis of the androgen precursors of estrogens by administration of long-acting gonadotropin-releasing hormone analogs to women with ovarian stromal hyperplasia. The specific target population would be elderly postmenopausal women, at increased risk of breast cancer, and with high blood levels of testosterone, marker of ovarian hyperandrogenemia, and recognized factor of risk for breast cancer. Testosterone levels are measured at baseline to identify women at risk and during the follow-up to evaluate the effectiveness of therapy. The postmenopausal ovary is an important source of excessive androgen production which originates from the ovarian interstitial cell hyperplasia frequently present in breast cancer patients. We propose to counter the source of androgen excess in women with ovarian stromal hyperplasia, thus reducing the substrate for estrogen formation without completely inhibiting estrogen synthesis. Available evidence indicates that gonadotropin-releasing hormone analogs can be safely used for breast cancer prevention in postmenopausal women. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the minimum dose of buserelin acetate (buserelin) able to induce ovulation between 24 and 48 h from treatment (positive response) in estrous jennies. Jennies were studied during a total of 172 estrous cycles: ovarian activity was routinely monitored by ultrasound; when the dominant follicle reached a diameter of 33 ± 1 mm, estrous jennies were treated by subcutaneous administration of different doses of buserelin, 3.3 mg ( N = 11), 1.5 mg ( N = 21), 0.8 mg ( N = 12), 0.4 mg ( N = 16), 0.2 mg ( N = 13), 0.1 mg ( N = 16), 0.04 mg ( N = 14), 0.02 mg ( N = 16), or employed as controls ( N = 53). Single jennies ( P = 0.0001) and GnRH dose ( P = 0.003) significantly affected ovulation rates. Ovulation rates between 24 and 48 h of each treated group, except for the 0.02 mg group, was higher than in the control group ( P < 0.05). The minimum dose of buserelin effective to induce ovulation in estrous jennies was 0.04 mg. [ABSTRACT FROM AUTHOR]

Male breast cancer is a rare disease treated as hormone receptor-positive female breast cancer. The characterization of breast cancer at the molecular level has lately revealed gender-related differences. As the androgen receptor is emerging as a potential oncogenic driver in male breast cancer, we analyzed efficacy data from metastatic patients treated with antiandrogens. We evaluated the activity of cyproterone acetate, either as a monotherapy or combined with a GnRH analog, in 36 metastatic male breast cancer patients. Fourteen patients were treated with cyproterone acetate as monotherapy and 22 patients with complete androgen blockade. We recorded 4 complete responses and 15 partial responses, for an overall response rate of 52.8 % (95 % CI, 36.5-69.4). Stable disease was reported in 11 patients. Median PFS was 8.9 months (95 % CI, 6.1-11.7), and median OS was 24.3 months (95 % CI, 22.5-26.1). Data on androgen receptor expression were available for 7 patients. All the 4 patients with androgen receptor-expressing tumors had a clinical benefit, including a patient with an estrogen receptor-negative disease. Conversely, none of the 3 patients with androgen receptor-negative tumors had a tumor response. Antiandrogen-based therapy showed efficacy in metastatic male breast cancer patients. Our results encourage considering antiandrogens in the therapeutic continuum, especially if supported by androgen receptor expression. [ABSTRACT FROM AUTHOR]

Introduction: Endometriosis is an estrogen-dependent disease on the background of progesterone resistance. Increased estrogen production, low estrogen metabolization, and altered estrogen receptors (ERs) expression contribute to the hyperestrogenic milieu within endometriotic lesions. Since estrogens play a crucial role in the pathogenesis of the disease, inhibition of estrogen production is one of the main targets of available and emerging drugs., Areas Covered: Firstly, we described the molecular alterations responsible for estrogen dependence. Secondly, we reviewed available and emerging treatments that interfere, through central (gonadotropin-releasing hormone analogs (GnRH-a), GnRH antagonists) or local mechanisms (aromatase inhibitors (AIs), inhibitors of steroid sulfatase (STS) and hydroxysteroid dehydrogenase type 1 (17β-HSD1)), with estrogen dependence. Finally, we focused on emerging treatments targeting ERs (selective estrogen receptor modulators (SERMs), estrogen receptors agonists, and antagonists)., Expert Opinion: Available treatments interfering with estrogen pathways exert a contraceptive effect, have hypoestrogenic side effects, and cannot prevent or definitively treat the disease. Preclinical and animal studies are focusing on emerging drugs targeting ERs in order to overcome limitations of available treatments. These treatments may represent a promising option, as they may produce a more specific inhibition of disease activity within endometriotic implants, avoiding prolonged hypoestrogenic status and limiting systemic side effects.

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Our research was concentrated about physiological and structural aspects of metal complexes with GnRH, which were synthetized by Professor Henryk Kozłowski from the Uniwersity of Wrocław. We found that copper, nickel, zinc and cobalt complexes with GnRH stimulated the release of LH and FSH both in vivo and in vitro. The most stable and active was Cu-GnRH. It also exhibited the higher affinity to specific receptor than GnRH, had higher releasing power for LH and FSH and stimulated differently the intracellular signaling. We suggest, that this complex in highly promissive as a new analog of GnRH with possible application to further research. [ABSTRACT FROM AUTHOR]

Copyright of Der Gynäkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The aim of this study was to describe the effects of a single dose of the gonadotrophin releasing hormone (GnRH) antagonist acyline on testicular characteristics of the domestic cat. Twelve mature cats were orchidectomised unilaterally (right testis) on Day -7 (n = 7) or Day 15 (n = 5). On Day 0, 330 µg/kg acyline was administered SC to all the animals. Left orchidectomy was carried out on Day 15 (n = 2), Day 30 (n = 4) and Day 60 (n = 6). Sperm were recovered from the epididymis and the testes were evaluated grossly, histologically and immunohistochemically. Significant differences (P < 0.05) were found between days for epididymal sperm motility, vigor, abnormal morphology, germinal epithelium height, spermatocytes, spermatids, spermatozoa, lumen and cellular debris. Conversely, no significant differences were found for gross testicular and tubular characteristics, spermatogonia, Sertoli and Leydig cells and intertubular compartments. It was concluded that a single dose of acyline reversibly impaired spermiogenesis, spermatocytogenesis and sperm motility for 2 weeks. [ABSTRACT FROM AUTHOR]

Abstract: Androgen deprivation therapy (ADT) is considered an effective strategy in sexual offender treatment. However, the evidence base concerning its effects on sexual arousal control is limited. Past research has focused almost exclusively on men in forensic contexts. The present retrospective observational study provided data on ADT in a sample of self-identifying, help-seeking pedohebephilic men applying for a one-year group therapy program. Factors possibly influencing the readiness to take up or discontinue ADT were presented. Effects of a combination of ADT and group psychotherapy program on changes in paraphilic sexual behavior and associated psychological factors were examined. The proportion of men having taken up ADT was rather small (n=15). Greater awareness of potentially risky situations to commit child sexual offenses and self-rated uncontrollability of sexual urges were identified as characterizing men resorting to ADT. Additionally, these men were initially more open to include medical treatment. Examination of the effects of ADT and psychotherapy was limited to a sample of six men providing complete data sets. Descriptive data demonstrated a reduction of paraphilic sexual behaviors, an increase of risk-awareness and self-efficacy, and a decrease of offense-supportive cognitions and self-esteem. The present study underlined the importance of careful education and monitoring of self-identifying, help-seeking pedohebephilic patients interested in ADT concerning the effects and side effects of the treatment in a clinical context. [Copyright &y& Elsevier]

Abstract: The aim of this article is to argue the usefulness of the systematic administration of medical treatment in women managed for endometriosis, either alone or associated with the surgery. The authors dispute seven frequent objections against the medical treatment: the lack of curative effect, the lack of primary prevention and the risk of delaying the diagnostic, the contraceptive effect in women wishing to conceive, the adverse effects, the risk of occurence of new lesions following the arrest of the treatment, the lack of proof favourable to the efficient prevention of recurrences and the cost of the treatment. The authors conclude that to date the therapeutic amenorrhea represents an indispensable tool in the management of the endometriosis, in women both benefiting or not from surgical procedures. [Copyright &y& Elsevier]