Gonadal dysfunction and beyond: Clinical challenges in children, adolescents, and adults with 47,XXY Klinefelter syndrome.

Klinefelter syndrome (KS) is the most frequent sex chromosomal aneuploidy. The karyotype 47,XXY originates from either paternal or maternal meiotic nondisjunction during gametogenesis. KS males are very likely to exhibit marked gonadal dysfunctions, presenting both in severely attenuated spermatogenesis as well as hypergonadotropic hypogonadism. In addition, neurocognitive and psychosocial impairments, as well as cardiovascular, metabolic and bone disorders are often found in KS and might explain for an increased morbidity/mortality. All conditions in KS are likely to be induced by both gene overdosage effects resulting from supernumerary X-chromosomal genes as well as testosterone deficiency. Notwithstanding, the clinical features are highly variable between KS men. Symptoms can become obvious at infancy, childhood, or adolescence. However, the majority of KS subjects is diagnosed during adulthood. KS adolescents require specific attention regarding pubertal development, in order to exploit their remaining fertility potential and allow for timely and tailored testosterone replacement. The chances for sperm retrieval might decline with age and could be hampered by testosterone replacement; therefore, cryostorage of spermatozoa is an option during adolescence, before the decompensation of endocrine and exocrine testicular functions becomes more overt. Sperm from semen or surgically retrieved, in combination with intracytoplasmic sperm injection enables KS males to become biological fathers of healthy children. The aim of this article is to present the current knowledge on KS, to guide clinical care and to highlight research needs.

Effects of treatments on gonadal function in long-term survivors of pediatric hematologic malignancies: A cohort study.

BACKGROUND: Potentially gonadotoxic protocols are currently used for the treatment of childhood hematologic malignancies. This study aims to evaluate the prevalence of gonadal dysfunction and the most important associated risk factors in a cohort of hematologic malignancy survivors. PROCEDURE: We considered all patients referred to our long-term follow-up clinic for childhood cancer survivors, between November 2001 and December 2017. Inclusion criteria were: (a) previous diagnosis of hematologic malignancy; (b) age at hematologic malignancy diagnosis < 18 years; (c) at least five years after the end of anticancer treatments; (d) at least one evaluation of gonadal function after the 18th birthday. Patients diagnosed before January 1, 1990, were excluded. RESULTS: Three hundred twenty-seven survivors (males = 196) were included. Isolated spermatogenesis damage was found in 58/196 (29.6%) of males, whereas 18/196 (9.2%) had Leydig cell failure. In females, 35/131 (26.7%) experienced premature ovarian insufficiency. In both sexes, abdominopelvic irradiation and hematopoietic stem cell transplantation were strongly associated with the risk of gonadal dysfunction. For every 1000 mg/m2 increase in cyclophosphamide-equivalent dose exposure, the risk of spermatogenesis damage increased 1.52-fold and that of Leydig cell failure increased 1.34-fold, whereas the risk of premature ovarian insufficiency increased 1.80-fold. About 30% of those males who developed Leydig cell failure did so more than five years after the end of treatments. CONCLUSIONS: Gonadal dysfunction is still a significant late effect of therapies for pediatric hematologic malignancies. In males, the reevaluation of Leydig cell function may be useful even several years after the exposure to gonadotoxic treatments.

Saponin-rich extract of Tribulus terrestris alleviates systemic inflammation and insulin resistance in dietary obese female rats: Impact on adipokine/hormonal disturbances.

Tribulus terrestris saponins (TTS) have been longley used as an overall tonic and recent studies showed they influence inflammatory conditions. We examined the ameliorative effect of a commercial formula of a saponin-rich extract of TT in a model of dietary obesity in female rats focusing on their ability to control the inflammatory burden, insulin resistance (IR), adipokine expression and the related reproductive system pathologies. Female rats were fed with high fat diet (HFD) for 14 weeks to launch diet-induced obesity; they were assigned as: the obese control female rats (OFR) which received no treatment and TTS (5 and 10 mg/kg/day) treated rats; they were compared to a normal rat group. We determined the IR index, serum/tissue inflammatory cytokines, and adipose tissue adipokine expression and examined the secondary ovarian pathologies. Body weight gain, serum triglycerides and IR (>5-fold) in the OFR group were greater than the normal group; TTS lessened these parameters compared with the OFR group. TTS, at 10 mg/kg dose, ameliorated mRNA expression of leptin and visfatin genes in addition to serum inflammatory cytokine levels. Moreover, TTS corrected the hyperprolactinemia and other hormonal disturbances and ameliorated the ovarian pathologies. This study highlighted that the anti-inflammatory properties of TTS helped in alleviation of IR and body weight gain in OFR. Upon correction of obesity manifestations, the gonadal hormone dysregulations and ovarian pathologies were subsequently ameliorated. We can consider TTS as a promising candidate that may alleviate the inflammatory burden, IR and adipokine expression in obesity and hence prevent the secondary gonadal complications in female subjects if appropriate clinical studies are available.

Gonadal dysfunction in male cancer patients before cytotoxic treatment.

Male patients diagnosed with cancer are often referred for semen cryopreservation before gonadotoxic treatment but often have low semen quality. The aim of this study was to evaluate which type of cancer affects gonadal function and proposes a risk factor for low pre-treatment semen quality. Between January 1983 and August 2006, 764 male cancer patients were referred for semen cryopreservation prior to chemotherapy and radiotherapy. We compared semen characteristics and reproductive hormones between different groups of cancer patients. In addition, we evaluated the role of tumour markers in patients with testicular germ-cell tumours (TGCT) on fertility. Abnormal semen parameters were found in 489 men (64%) before cancer treatment. Patients with TGCT and extragonadal germ-cell tumours had significantly lower sperm concentrations and inhibin B levels than all other patient groups. No semen could be banked in 93 patients (12.2%). Eight hundred and thirty-nine of 927 (90%) produced semen samples were adequate for cryopreservation. Inhibin B in all groups showed to be the best predictor of semen quality. Although pre-treatment raised tumour markers were associated with a decrease in inhibin B and increased follicle stimulating hormone, both predictive for low semen quality; no direct linear association could be found between raised beta-HCG, alfa-fetoprotein and semen quality. Only 1/3 of cancer patients had normal semen parameters prior to cancer treatment. Patients with TGCT and extragonadal GCT have the highest risk for impaired semen quality and gonadal dysfunction at the time of semen cryopreservation.

Male Obesity Associated Gonadal Dysfunction and the Role of Bariatric Surgery.

Obesity is an ever growing pandemic and a prevalent problem among men of reproductive age that can both cause and exacerbate male-factor infertility by means of endocrine abnormalities, associated comorbidities, and direct effects on the precision and throughput of spermatogenesis. Robust epidemiologic, clinical, genetic, epigenetic, and preclinical data support these findings. Clinical studies on the impact of medically induced weight loss on serum testosterone concentrations and spermatogenesis is promising but may show differential and unsustainable results. In contrast, literature has demonstrated that weight loss after bariatric surgery is correlated with an increase in serum testosterone concentrations that is superior than that obtained with only lifestyle modifications, supporting a further metabolic benefit from surgery that may be specific to the male reproductive system. The data on sperm and semen parameters is controversial to date. Emerging evidence in the burgeoning field of genetics and epigenetics has demonstrated that paternal obesity can affect offspring metabolic and reproductive phenotypes by means of epigenetic reprogramming of spermatogonial stem cells. Understanding the impact of this reprogramming is critical to a comprehensive view of the impact of obesity on subsequent generations. Furthermore, conveying the potential impact of these lifestyle changes on future progeny can serve as a powerful tool for obese men to modify their behavior. Healthcare professionals treating male infertility and obesity need to adapt their practice to assimilate these new findings to better counsel men about the importance of paternal preconception health and the impact of novel non-medical therapeutic interventions. Herein, we summarize the pathophysiology of obesity on the male reproductive system and emerging evidence regarding the potential role of bariatric surgery as treatment of male obesity-associated gonadal dysfunction.

Localized solitary left renal vein thrombus complicating nutcracker syndrome: a case report and review of the literature.

Nutcracker syndrome (NCS) refers to compression of the left renal vein (LRV) between the abdominal aorta and the superior mesenteric artery (SMA). The clinical presentation of NCS includes hematuria, abdominal and left flank pain, gonadal varices, and varicocele formation. Theoretically, thrombosis can occur in the LRV in patients with NCS. However, an isolated solitary left renal vein thrombus (LRVT) complicating NCS is rare. In addition, the clinical features of an LRVT complicating NCS remain unclear. We describe a 43-year-old woman presenting with an asymptomatic LRVT complicating NCS. She was referred to our hospital for investigation of dysfunctional uterine bleeding, and detailed examination revealed endometrial cancer. Computed tomography angiography (CTA) and Doppler ultrasonography revealed compression of the LRV between the aorta and the SMA, as well as an LRVT. CTA performed 4 months after the administration of an anticoagulant showed complete disappearance of the LRVT. We have also included a review of published reports describing LRVT complicating NCS and discussed the clinical features of such a presentation.

Endocrine consequences of neuroblastoma treatment in children: 20 years' experience of a single center.

Background Neuroblastoma (NBL) is a child neoplasia affecting extracranial tissue of neuroectodermal origin. It accounts for 10% of solid malignancies in children and is characterized by a survival rate approaching 70%, confronting physicians with the emergence of an adult survivor population who have been previously exposed to surgery, cytotoxic drugs, radiation therapy or metaiodobenzylguanidine (MIBG) therapy. All these treatments potentially affect the endocrine system. Our study consists in a retrospective review of late endocrine effects arising in survivors treated for NBL during childhood. Methods The medical files of 47 patients (M/F = 26/21) treated for NBL were reviewed. Collected data consisted of age, height, weight and biological hormonal values at diagnosis and at the last follow-up consultation. The incidence of late effects in our sample was compared to the data from the literature. Results Patients were between 0 and 15.8 years of age at diagnosis (median: 1.16 years) and between 1 and 25 years of age at last follow-up (median: 16 years). Twenty-six patients were treated with chemotherapy (CT), 11 underwent CT and radiation therapy and five were treated with CT and MIBG therapy. Ten percent of the patients died before reaching the end of therapy. Late effects occurred in 54% of the patients. Thirty-six percent of patients had non-endocrine complications (musculoskeletal, neurological, hematological or hepatic chronic conditions). Endocrine complications (28%) affected mainly patients treated with CT and consisted of gonadal dysfunction (up to 42% patients of over 12 years of age at follow-up) and hypothyroidism (21%). Our analysis revealed that CT had a significant impact on final height (p < 0.05). Conclusions Treatment for childhood malignancies exposes children to late effects affecting the endocrine system. In children treated for NBL, hypothyroidism, gonadal failure and impaired growth appear to be the main endocrine complications. Close follow-up of survivors is thus appropriate.

The role of glucagon-like peptide-1 in reproduction: from physiology to therapeutic perspective.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) have become firmly established in the treatment of type 2 diabetes and obesity, disorders frequently associated with diminished reproductive health. Understanding of the role of GLP-1 and GLP-1 RAs in reproduction is currently limited and largely unaddressed in clinical studies. OBJECTIVE AND RATIONALE: The purpose of this narrative review is to provide a comprehensive overview of the role of GLP-1 in reproduction and to address a therapeutic perspective that can be derived from these findings. SEARCH METHODS: We performed a series of PubMed database systemic searches, last updated on 1 February 2019, supplemented by the authors' knowledge and research experience in the field. A search algorithm was developed incorporating the terms glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor, GLP-1R, or incretins, and this was combined with terms related to reproductive health. The PICO (Population, Intervention, Comparison, Outcome) framework was used to identify interventional studies including GLP-1 RAs and dipeptidyl peptidase-4 (DPP-4) inhibitors, which prevent the degradation of endogenously released GLP-1. We identified 983 potentially relevant references. At the end of the screening process, we included 6 observational (3 preclinical and 3 human) studies, 24 interventional (9 preclinical and 15 human) studies, 4 case reports, and 1 systematic and 2 narrative reviews. OUTCOMES: The anatomical distribution of GLP-1 receptor throughout the reproductive system and observed effects of GLP-1 in preclinical models and in a few clinical studies indicate that GLP-1 might be one of the important modulating signals connecting the reproductive and metabolic system. The outcomes show that there is mostly stimulating role of GLP-1 and its mimetics in mammalian reproduction that goes beyond mere weight reduction. In addition, GLP-1 seems to have anti-inflammatory and anti-fibrotic effects in the gonads and the endometrium affected by obesity, diabetes, and polycystic ovary syndrome (PCOS). It also seems that GLP-1 RAs and DPP-4 inhibitors can reverse polycystic ovary morphology in preclinical models and decrease serum concentrations of androgens and their bioavailability in women with PCOS. Preliminary data from interventional clinical studies suggest improved menstrual regularity as well as increased fertility rates in overweight and/or obese women with PCOS treated with GLP-1 RAs in the preconception period. WIDER IMPLICATIONS: GLP-1 RAs and DPP-4 inhibitors show promise in the treatment of diabetes and obesity-related subfertility. Larger interventional studies are needed to establish the role of preconception intervention with GLP-1 based therapies, assessing fertility outcomes in obesity, PCOS, and diabetes-related fertility problems. The potential impact of the dose- and exposure time-response of different GLP-1 RAs need further exploration. Future research should also investigate sex-specific variability of GLP-1 on reproductive outcomes, in particular on the gonads where the observations in males are most conflicting.

Morphological abnormalities in gonads of the Baltic herring (Clupea harengus membras): Description of types and prevalence in the northern Baltic Sea.

Due to heavy anthropogenic influence and variation of the environmental conditions in the Baltic Sea, reproductive disorders are becoming a major environmental concern. We show here an increasing prevalence of gonadal malformations in the Baltic herring (Clupea harengus membras), a key species of the Baltic ecosystem and important in commercial fishery. During 1987-2014, the spawning herring population in the Archipelago Sea (AS) (North Baltic Sea, Finland) was monitored annually and analyzed for gross morphology of the gonads [total number (n) of analyzed fish = 38 284]. Four different types of malformations were repeatedly found and named as asymmetric, rudimentary, segmented, and branched gonads, but also hermaphroditic gonads and miscellaneous (unidentified) disorders were recorded. In 2013, additional samplings (n of fish analyzed = 541) showed similar malformations in herring from the Bothnian Sea. In some gonad types, histological examination revealed disintegration of seminiferous tubules and hyperplasia of the interstitial tissue. In 2014, the overall prevalence of malformations was still relatively low in the AS (frequency = 0-3.4 %; n = 750) and had apparently minimal effect on population recruitment. However, an increasing trend in the time-series (GLM; F = 32.65; p < 0.001) and a significantly higher prevalence in the Bothnian Sea (frequency = 0.7-5.0 %; n = 541; χ (2) = 6.24; p < 0.05) suggest that gonadal malformations may become a new threat for fish in the Baltic Sea. The observed gonad atrophies may be due to environmental endocrine disruption; however, also other explanations may exist and potential explanations are discussed.

Pituitary gonadotropins and autoimmunity.

Autoimmune disease occurs when the body produces an inappropriate immune response against its own tissues producing antibodies, called autoantibodies, reacting to specific antigens. Studies regarding the presence of an autoimmune process specifically involving gonadotropins date from over than 20 years ago, when antibodies to gonadotropic-secreting cells were found by immunofluorescence in sera from a group of patients affected by cryptorchidism. Later on, antibodies detected by the same technique, and directed to the same cells were also found at high titer in sera from patients affected by hypogonadotropic hypogonadism, Kallmann's syndrome, lymphocytic hypophysitis with isolated gonadotropin deficiency, as well as autoimmune polyendocrine syndrome. Concerning the autoimmune target/s within the gonadotropic cells, rarely autoantibodies were found labeling gonadotropins while in a large number of cases, auto-antigens remained to be identified. Since pituitary gonadotropins are fundamental for the sexual maturity and reproductive mechanisms, patients with infertility were largely investigated by enzyme-linked immunosorbent assay for the presence of circulating antibodies likely interfering with gonadotropin activity. In infertile women, autoantibodies to gonadotropins were found related to ovarian autoimmunity, ovarian disorders that cause infertility and also associated with in vitro fertilization treatments. In infertile men, autoantibodies to gonadotropins may alter the testicular spermatogenesis and cause apoptosis of the spermatogenic cells. In conclusion, circulating antibodies were found labeling gonadotropic cells and/or gonadotropins, and in both cases they could create dysfunctions in gonadotropin related mechanism. The intriguing question of what can cause the production of such autoantibodies is not clear yet.

Torsion of the gonad in the pediatric population: spectrum of histologic findings with focus on aspects specific to neonates and infants.

Histopathologic findings of gonadal torsion in neonates and infants (GTNI) are poorly defined in the literature. We describe herein the histopathologic spectrum of GT with emphasis on the pediatric population and on features specific for NI (≤1 year of age). Twenty-four cases of GTNI (6 females/18 males), 33 cases of GT in an older pediatric population (OPP) (19 females/14 males), and 43 cases of GT in adults (35 females/8 males) were found in our pathology files between 2003 and 2011. Our findings disclosed 2 categories of GT: 1) the group of NI, and 2) that of OPP and adults who share a similar presentation as acute hemorrhagic necrosis of the gonad. Although findings in NI were rather uniform, a few differences were demonstrated between the 2 genders. All GTNI revealed calcifications, fibrosis, siderophages, and extensive necrosis. However, prominent necrotizing palisaded granulomatas were seen in most (4 of 6) cases of ovarian torsion but not in the testicular counterpart. Furthermore, complete gonad regression was encountered exclusively in neonatal testicular torsion cases. In conclusion, 1) pathologic findings in GT are distinctly different between NI and OPP, the latter being more comparable to adults, presenting with acute hemorrhagic necrosis; 2) the distinctive findings in GTNI of both genders include calcifications, siderophages, and fibrosis, in addition to background necrosis; 3) of particular note, complete gonadal regression is seen only in the testis in GTNI; and 4) necrotizing palisaded granulomatas are unique to the ovarian subgroup and are often extensive, obscuring the nature of the process.

Protección gonadal de pacientes con malignidades hematológicas durante la quimioterapia: uso del acetato de leuprolide / Gonadal protection in patients with hematological malignancies during chemotherapy: use of leuprolide acetate

Demostrar el papel de los análogos agonistas de hormona liberadora de gonadotropinas en la reserva ovárica de pacientes hemato-oncológicas del Servicio de Hematología del Hospital Universitario de Caracas durante el año 2010, en tratamiento con regímenes de quimioterapia. Estudio de la variable reserva ovárica, mediante la cuantificación periódica de: ritmo menstrual, concentraciones de FSH, volumen ovárico, número de folículos antrales e incidencia de embarazo. Se administró acetato de leuprolide (11,25 mg) cada 3 meses vía intramuscular; se realizaron mediciones trimestrales de las concentraciones de FSH y se practicaron ecosonogramas pélvico o transvaginal cada 6 meses. Posterior al cumplimiento de los análogos de la hormona liberadora de gonadotropinas, se observó la aparición de amenorrea en las pacientes. Las concentraciones de FSH se mantuvieron estables, y siguieron la misma distribución (prueba de Levene p 0,2466) los volúmenes ováricos y el número de folículos antrales se mantienen estables, se rechaza la hipótesis de normalidad del grupo de diferencias al 5 por ciento de significancia. No se registraron embarazos. La reserva ovárica se preserva durante el tratamiento continuo con análogos

To demonstrate the role gonadotropin releasing hormone analogues in ovarian reserve in hematology patients in the hematology service at the Hospital Universitario de Caracas in 2010, treated with chemotherapy regimens. Study of ovarian reserve variable by periodic quantification of: menstrual rhythm, concentrations of FSH, ovarian volume, antral follicle number and incidence of pregnancy. Leuprolide acetate was administered (11.25 mg) intramuscularly every 3 months, were measured quarterly and FSH concentrations were performed pelvic or transvaginal ecosonograms every 6 months. After aGnRH administration, we observed the occurrence of amenorrhea in patients. FSH concentrations were stable, and followed the same distribution (Levene test p 0.2466) ovarian volume and antral follicle numbers were stable, we reject the hypothesis of normality of group differences at 5 percent significance. There were no pregnancies. Ovarian reserve is preserved during continuous treatment with analogs

Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide.

A recent case of iatrogenic Cushing's syndrome and complete suppression of the pituitary-adrenal-axis in a patient with cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis treated with itraconazole as an antifungal agent, and budesonide as an anti-inflammatory agent led to a systematic assessment of this axis and gonadal function in all patients treated with itraconazole in the authors' CF centre. Itraconazole can inhibit CYP3A, thus interfering with synthesis of gluco- and mineralocorticoids, androgens and oestradiol as well as the metabolism of budesonide. The aim of this study was to evaluate adrenal and gonadal function in patients treated with itraconazole with or without budesonide. An adrenocorticotrophic hormone (ACTH) test (250 microg tetracosactid) was performed in 25 CF patients treated with both itraconazole and budesonide, and in 12 patients treated with itraconazole alone (six patients with CF and six with chronic granulomateous disease). Mineralocorticoid and gonadal steroid function were evaluated by measurements of plasma-renin, follicle stimulating hormone, luteinising hormone, progesterone, oestradiol, testosterone, serum-inhibin A and B. ACTH tests performed as part of a pretransplantation programme in an additional 30 CF patients were used as controls. Eleven of the 25 patients treated with both itraconazole and budesonide had adrenal insufficiency. None of the patients on itraconazole therapy alone nor the control CF patients had a pathological ACTH test. Mineralocorticoid and gonadal insufficiency was not observed in any of the patients. Only one patient with an initial pathological ACTH-test subsequently normalised, the other 10 patients improved but had not achieved normalised adrenal function 2-10 months after itraconazole treatment had been discontinued. Suppression of the adrenal glucocorticoid synthesis was observed in 11 of 25 cystic fibrosis patients treated with both itraconazole and budesonide. The pathogenesis is most likely an itraconazole caused increase in systemic budesonide concentration through a reduced/inhibited metabolism leading to inhibition of adrenocorticotrophic hormone secretion along with a direct inhibition of steroidogenesis. In patients treated with this combination, screening for adrenal insufficiency at regular intervals is suggested.

Síndrome del déficit androgenico del anciano o andropausia / No disponible

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Aportación del laboratorio clínico en las disfunciones gonadales / No disponible

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Técnicas de laboratorio y pruebas hormonales para el diagnóstico de disfunciones gonadales / No disponible

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