Gonadal Dysfunction Research Articles

PMON193 Reactive oxygen species in the development of gonadal failure in late-onset transaldolase deficiency

Abstract Background Deficiency in Transaldolase, an essential enzyme in regulating NADPH and ribose 5-phosphate production, has been reported in only 39 patients to date. Most patients present already prenatally/neonatally with intra uterine growth retardation, hepato(spleno)megaly and consequent liver failure, anemia, thrombocytopenia, dysmorphic facial features, cardiac and skin abnormalities and hypergonadotropic hypogonadism in cases of late-onset presentation. The mechanism underlying gonadal dysfunction is not fully understood. Clinical case, methods and results A 15y old male from an Indian-Jewish background, with atrial-septal-defect, renal tubulopathy, mild facial dysmorphism and transient liver enzymes abnormalities presented with absence of pubertal development. His gonadotropins levels were elevated (LH – 22 IU/L, FSH 103 IU/L) while testosterone was low. Whole exome sequencing revealed homozygous variant in a novel T167M missense mutation in TALDO1 (transaldolase) gene whereas both parents were heterozygote carriers. Proteine structure analysis indicate that Threonine 167 is part of transaldolase catalytic site and critical for its function. As transaldolase activity is required for nucleic acids production, NADPH synthesis and reduction of cellular Reactive Oxygen Species (ROS) we measured the ROS accumulation using 2′,7′-dichlorodihydrofluorescein diacetate, in fibroblasts derived from the patient and normal controls. The affected patient's fibroblasts showed a significantly increased accumulation of ROS (207%, P=0.007), compared to controls indicating an increased susceptibility to oxidative stress. Conclusion The novel T167M missense mutation in the transaldolase (TALDO1) gene causes a unique clinical presentation including a relative mild liver involvement and hypergonadotrophic hypogonadism. The compromised TALDO1 activity in preventing cellular ROS accumulation in actual patient's fibroblasts is shown here for the first time and may indicate the therapeutic use of antioxidants in all patients with TALDO1 dysfunction. The high expression of TALDO1 in the testis and the gonadal failure suggests its tissue specific requirement in preventing the accumulation of ROS during steroidogenesis. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

NGF and the Male Reproductive System: Potential Clinical Applications in Infertility.

Infertility is a worldwide health issue defined by the World Health Organization (WHO) as the inability to establish a pregnancy after 12 months or more of regular and unprotected sexual intercourse. Male infertility etiology can be related to either congenital or acquired factors. The therapeutical approach to male infertility depends on the underlying causes and includes medical and surgical treatments. In recent studies, the potential role of nerve growth factor (NGF) in male reproductive physiology has been proposed. It has been hypothesized that neurotrophins might be involved in testis morphogenesis and regulation of several aspects of spermatogenesis. Moreover, it has been shown that NGF exerts its role on gonadotropin-releasing hormone (GnRH) neurons through the activation of the PKC/p-ERK1/2/p-CREB cascade, which leads to the activation of hypothalamic cells and the consequent activation of hypothalamus-pituitary-gonadal axis (HPG) with the secretion of GnRH. Lastly, it has been shown that the physiology of mature sperm is affected by both exogenous and endogenous NGF. The NGF impact on the HPG axis and its effect on GnRH neurons might be exploited in the therapy of male hypogonadism or used as a protective strategy against gonadal dysfunction related to chemotherapeutic agents. Moreover, the improving effect of NGF on sperm motility and vitality could be useful to enhance assisted reproduction outcomes. NGF could be supplemented to cryopreserved sperm samples to counteract the oxidative stress induced by the frozen and thawing processes. Indeed, the potential clinical applications of NGF in male infertility treatment have been discussed.

Endocrine Disorders in Children with Brain Tumors: At Diagnosis, after Surgery, Radiotherapy and Chemotherapy.

Brain tumors are the second most frequent type of all pediatric malignancies. Depending on their localization, patients with brain tumors may present neurological or ophthalmological symptoms, but also weight anomalies and endocrine disorders ranging from growth hormone deficiency, anomalies of puberty, diabetes insipidus to panhypopituitarism. Immediately at diagnosis, all patients with brain tumors require a complete assessment of the hypothalamic-pituitary function in order to address eventual endocrine disorders. Moreover, children and adolescents undergoing brain surgery must receive peri- and postoperative hydrocortisone stress therapy. Post-operative disorders of water homeostasis are frequent, ranging from transient diabetes insipidus, as well as syndrome of inappropriate antidiuretic hormone secretion to persistent diabetes insipidus. Late endocrine disorders may result from surgery near or within the hypothalamic-pituitary region. Pituitary deficits are frequent after radiotherapy, especially growth hormone deficiency. Thyroid nodules or secondary thyroid cancers may arise years after radiotherapy. Gonadal dysfunction is frequent after chemotherapy especially with alkylating agents. Early detection and treatment of specific endocrine disorders at diagnosis, perioperatively, and during long-term follow-up result in improved general and metabolic health and quality of life.

Endocrine complications after hematopoietic stem cell transplantation during childhood-Results from a close follow-up in a cohort of 152 patients.

Haematopoietic stem cell transplantation (HSCT) is a therapeutic option for numerous haematologic diseases and solid tumours. Increasing indications for HSCT and reduction in associated mortality have been raising the number of paediatric HSCT survivors and their long-term toxicities. To characterize the endocrine disorders developed after HSCT. Retrospective analysis of 152 patients submitted to HSCT in paediatric age with at least 24 months of follow-up at our endocrine late-effects clinics. Patients were followed up for 9.9 (interquartile range [IQR]: 12.2) years. The median age at HSCT was 7.5 (IQR: 9) years. At least one endocrine complication was observed in 65.1% of the patients. Primary hypogonadism was detected in 34.2%. Female gender (p < .001), HSCT > 10 years old (p = .01) and chemotherapy before HSCT (p < .001) were identified as risk factors for developing gonadal dysfunction. Growth hormone deficiency (GHD) occurred in 23.0% with a mean stature Z-score at diagnosis of -1.8 ± 1.4. GHD was associated with cranial (p < .001) and HSCT < 10 years old (p ≤ 0.001). Patients who were exposed to total body irradiation (TBI) were at higher risk for primary hypothyroidism (22.3%) (p = .01), thyroid nodules (17.1%) (p < .001), thyroid carcinoma (5.3%) (p < .001), dyslipidaemia (19.1%) (p < .001) and disturbance of carbohydrate metabolism (19.1%) (p < .001). At least one endocrine complication was diagnosed in 65.1% of patients, with gonadal dysfunction being the most prevalent. The conditioning regimen with TBI was a risk factor for the development of several endocrine disorders. This study is one of the largest series evaluating the endocrine disorders among survivors of paediatric HSCT and intends to reinforce the importance of routine follow-up of these patients.

Pathological variants in genes associated with disorders of sex development and central causes of hypogonadism in a whole-genome reference panel of 8380 Japanese individuals

Disorders of sex development (DSD) comprises a congenital condition in which chromosomal, gonadal, or anatomical sex development is atypical. In this study, we screened for pathogenic variants in 32 genes associated with DSDs and central causes of hypogonadism (CHG) in a whole-genome reference panel including 8380 Japanese individuals constructed by Tohoku Medical Megabank Organization. Candidate pathogenic (P) or likely pathogenic (LP) variants were extracted from the ClinVar, InterVar, and Human Gene Mutation databases. Ninety-one candidate pathological variants were found in 25 genes; 28 novel candidate variants were identified. Nearly 1 in 40 (either ClinVar or InterVar P or LP) to 157 (both ClinVar and InterVar P or LP) individuals were found to be carriers of recessive DSD and CHG alleles. In these data, genes implicated in gonadal dysfunction did not show loss-of-function variants, with a relatively high tendency of intolerance for haploinsufficiency based on pLI and Episcore, both of which can be used for estimating haploinsufficiency. We report the types and frequencies of causative variants for DSD and CHG in the general Japanese population. This study furthers our understanding of the genetic causes and helps to refine genetic counseling of DSD and CHG.

Effect of Testicular Boost in Children With Leukemia Receiving Total Body Irradiation and Stem Cell Transplant: A Single-Institution Experience

Children with leukemia who receive fractionated total body irradiation (fTBI) with 12 to 13.2 Gy as part of conditioning for hematopoietic stem cell transplant are frequently treated with an additional 4 Gy testicular boost to reduce the risk of testicular relapse. While institutional practices vary, limited data exists regarding whether the 4-Gy testicular boost reduces the risk of relapse and whether it causes toxicity beyond that imparted by TBI. This study compared the survival and endocrine outcomes among the patients who were treated with and without a testicular boost as part of fTBI from 1990 to 2019 at our center. We retrospectively reviewed charts of male children with leukemia treated with fTBI as part of a conditioning regimen for stem cell transplant from 1990 to 2019. Reported outcomes included progression-free survival, testicular relapse rate, and overall survival. Gonadal dysfunction and fertility were assessed by comparing the rate of abnormally low testosterone or high luteinizing hormone or follicular stimulating hormone, number of offspring, fertility service use, and abnormal sperm count in the subsequent follow-up period between the testicular boost and nonboost subset. Ninety-three male patients (63 acute lymphoblastic leukemia, 30 acute myeloid leukemia) with a median age of 9 years (range, 1-22) and follow-up of 3.3 years were included. In addition to 12- to 13.2-Gy fTBI, 51 male patients (54%) received a testicular boost to 4 Gy. There was 1 testicular relapse in the boost subset and none in the nonboost subset. Five-year progression-free survival for the boost and nonboost subset was 74% and 66%, respectively (P=.31). On multivariable analysis, boost was not associated with improved relapse-free survival or overall survival. More patients in the boost subset (35 of 51, 69%) had abnormal serum gonadal blood work compared with the nonboost subset (18 of 42, 43%) (P=.03). Omission of testicular boost may be associated with comparable oncologic but improved gonadal endocrine outcomes and should be further studied.

Sellar and parasellar lesions in the transition age: a retrospective Italian multi-centre study

BackgroundSellar/parasellar lesions have been studied in the adult and paediatric age range, but during the transition age their epidemiology, clinical manifestations, management and treatment outcomes have been poorly investigated.Materials and methodsAn Italian multicentre cohort study, in which hospital records of patients with diagnosis of sellar/parasellar lesions during the transition age and young adulthood (15–25 years), were reviewed in terms of prevalence, clinical and hormonal features at diagnosis, and outcomes where available. Both pituitary neuroendocrine tumours (pituitary tumours, Group A) and non-endocrine lesions (Group B) were included.ResultsAmong Group A (n = 170, 46.5% macroadenomas), the most frequent were prolactin and GH-secreting tumours, with a female predominance. Among Group B (n = 28), germinomas and Rathke cells cysts were the most common. In Group A, the most frequent hormonal deficiency was gonadal dysfunction. Galactorrhoea and amenorrhoea were relatively common in female patients with prolactinomas. Pre-surgical diabetes insipidus was only seen in Group B, in which also hormone deficiencies were more frequent and numerous. Larger lesions were more likely to be seen in Group B. Patients in Group B were more frequently male, younger, and leaner than those of Group A, whereas at last follow-up they showed more obesity and dyslipidaemia. In our cohort, the percentage of patients with at least one pituitary deficiency increased slightly after surgery.ConclusionsThe management of sellar/parasellar lesions is challenging in the transition age, requiring an integrated and multidisciplinary approach. Hormone and metabolic disorders can occur many years after treatment, therefore long-term follow-up is mandatory.

Comparison of Anti-Mullerian Hormone Levels Pre- and Post-Hematopoietic Cell Transplantation in Pediatric and Adolescent Females with Sickle Cell Disease

Allogeneic hematopoietic cell therapy (HCT) is an established cure for sickle cell disease (SCD); however, HCT conditioning regimens are known to be gonadotoxic. Anti-mullerian hormone (AMH) measures ovarian reserve, and follicle-stimulating hormone (FSH) defines premature ovarian insufficiency (POI) at values >40 mIU/mL in pubertal females. The present study was conducted to assess ovarian reserve and function before and after transplantation in pediatric and adolescent females with SCD treated with allogeneic HCT between January 2015 and June 2020 at Children's Healthcare of Atlanta. In this retrospective review of 17 females age <21 years with SCD who had AMH levels measured at baseline and at 2 years post-HCT, AMH levels were categorized as normal, low, or undetectable, and FSH levels were measured and used to identify pubertal females who had developed POI. Demographic and treatment data were abstracted from the institutional database and medical records, and a descriptive statistical analysis was conducted. Of the 17 patients in the study cohort, 14 had been treated with hydroxyurea and 3 had chronic transfusions but with no significant iron overload. AMH levels were normal in 15 patients (88%) and low in 2 patients (12%) at baseline. The median age at HCT was 7.5 years (range, 3.7 to 20.3 years), and 14 patients (82%) underwent matched related donor HCT. After HCT, 15 patients (88%) had undetectable AMH and 2 (12%) had low AMH, with no apparent differences by HCT conditioning regimen. No pubertal patients had POI at baseline, whereas 55% of pubertal patients had progressed to POI by 2 years post-HCT. In this cohort, the majority of females had normal AMH levels at baseline but undetectable levels after HCT. Females with SCD considering HCT should be counseled about the treatment-related risk of gonadal dysfunction. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Late endocrine effects after hematopoietic stem cell transplantation in children with nonmalignant diseases.

The number of children undergoing hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases has increased in recent years. Endocrine complications are common after HSCT for malignant diseases, while little is known about long-term prevalence and risk factors in children transplanted for nonmalignant diseases. We retrospectively evaluated gonadal function, near adult height and thyroid function in 197 survivors of pediatric HSCT for hemoglobinopathies (n = 66), inborn errors of immunity/metabolism (n = 74) and bone marrow failure disorders (n = 57); median follow-up was 6.2 years (range 3.0-10.5). Gonadal dysfunction occurred in 55% of (post)pubertal females, was still present at last assessment in 43% and was more common after busulfan- than treosulfan-based conditioning (HR 10.6, CI 2.2-52.7; adjusted for HSCT indication). Gonadal dysfunction occurred in 39% of (post)pubertal males, was still present at last assessment in 32% and was less common in those who were prepubertal compared to (post)pubertal at HSCT (HR 0.11; CI 0.05-0.21). Near adult height was more than 2 SDS below mean parental height in 21% of males and 8% of females. Hypothyroidism occurred in 16% of patients; 4% received thyroxin treatment. In conclusion, endocrine complications, especially gonadal dysfunction, are common after pediatric HSCT for nonmalignant conditions. In females, treosulfan seems less gonadotoxic than busulfan. Careful long-term endocrine follow-up is indicated.

P1085: EVALUATION OF GONADAL FUNCTION IN YOUNG WOMEN DIAGNOSED WITH HODGKIN AND NON-HODGKIN LYMPHOMA

Background: ABVD chemotherapy (CT) is the standard treatment approach for Hodgkin lymphoma (HL), with a negative interim PET. R-DA-EPOCH and R-CHOP are the most frequently used regimens used in primary mediastinal/high grade B-NHL and DLBCL, respectively. Young women are often affected by these types of lymphoma and may be cured in >80% of the cases. Thus, treatment-related complications are being increasingly recognized, among which, gonadal insufficiency with its major psychological consequences. This is more prevalent in female patients, in whom collection and cryopreservation of oocytes/ovarian tissue are not applied in everyday clinical practice. Published data are scarce on this subject. Moreover, little is known about the kinetics of gonadal function and sex hormones during chemotherapy to safely guide contraceptive measures. Aims: The aim of this study is the prospective evaluation of gonadal function in young women with malignant lymphoma who are receiving CT. We here present our preliminary results on 50 patients with HL and B-NHL. Methods: This is a prospective study of gonadal function in female patients≤40 years. Hormonal measurements were performed at pre-specified time points: before treatment (t0), during CT(t1), at the end of CT(t2) and every six months(t6,t12) thereafter. The following hormones were measured: follicle-stimulating hormone (FSH), lutenizing hormone (LH), progesterone (PG), estradiol (Ε2), anti-Mullerian hormone (ΑΜΗ). The study included:32 HL [median age: 29 years, 32 ABVD] and 18 B-NHL patients [median age:27 years, 9 RDAEPOCH, 7 RCHOP, 2 other]. FSH reflects gonadal function in women (increased levels indicate gonadal dysfunction). AMH is considered to be the most sensitive biomarker for gonadal reserve (decreasing values correlate with ovarian insufficiency). E2 and progesterone are the major sex hormones. Results: HL-ABVD: FSH constantly increased from the beginning, peaking in the middle (fsh0-1 p<0.0001), remaining high until the end (fsh0-2 p<0.0001), without reaching normal levels at 6 months (fsh0-6 p=0.002), finally normalizing at 12 months after the end of treatment. Consistently with FSH, AMH sharply decreased during treatment: [median values: 2,85IU/mL(t0), 0,45IU/mL(t1), 0,62IU/mL(t2), p<0.0001 for both]. A rebound increase was observed at 6 months and slowly decreased again to normal values at 12 months after the end of CT. Estradiol and progesterone were not affected throughout the treatment. B-NHL: Gonadal damage, reflected by the increase in FSH, was evident, though with slightly different kinetics compared to HL: [median values: 4,1IU/mL(t0), 8,3IU/mL(t2), fsh0-2 p=0,035]. FSH gradually increased during treatment, reaching a peak towards the end. FSH slowly reached normal values after six months from the end of treatment. In parallel to HL, AMH values sharply decreased during CT: [median values: 7,3IU/mL(t0), 0,17IU/mL(t1), 1,57IU/mL(t2), amh0-1 p=0.002, amh0-2 p=0,043). However, in contrast to HL, no clear rebound was seen and AMH values remained extremely low, even at 18 months after the end of treatment (median values: 0,23IU/mL), highlighting the gonadotoxic effect of CT. Estradiol and progesterone did not change significantly. Image:Summary/Conclusion: Gonadal function in female patients with malignant lymphomas is affected during CT in both HL and B-NHL, though with different kinetics. In HL patients treated with ABVD, gonadal function normalized at 6 months, whereas, in B-NHL gonadal dysfunction remained even at 18 months after the end of CT, possibly indicating a chemotherapy-dependent genotoxic effect.

Hypertension induces gonadal macrophage imbalance, inflammation, lymphangiogenesis, and dysfunction.

Hypertension (HTN) is associated with gonadal dysfunction and impaired reproductive health in both men and women. An imbalance in the systemic and renal proinflammatory (M1)/anti-inflammatory (M2) macrophage ratio, increased inflammation, and inflammation-associated lymphangiogenesis have been observed in animals with HTN. However, the impact of HTN on gonadal macrophages, inflammation, and lymphatics remains obscure. We hypothesized that salt-sensitive HTN (SSHTN) and HTN alters gonadal macrophage polarization, which is associated with inflammation, inflammation-associated lymphangiogenesis, and reproductive dysfunction. Flow cytometry analyses revealed a significant increase in M1 macrophages in the testes of SSHTN and nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced HTN (LHTN) mice, with a concurrent decrease in M2 macrophages in SSHTN mice yet an increase in M2 macrophages in LHTN mice. Ovaries from SSHTN mice exhibited an increase in M1 and a decrease in M2 macrophages, while ovaries from LHTN mice had a significant increase in M2 and a decrease in M1 macrophages. Gene expression patterns of proinflammatory cytokines revealed gonadal inflammation in all hypertensive mice. Increased lymphatic vessel density in the gonads of both male and female hypertensive mice was confirmed by immunofluorescence staining for lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). HTN adversely affected the expression pattern of steroidogenic enzymes, hormone receptors, and secretory proteins in both the testes and ovaries. In line with these results, male hypertensive mice also presented with decreased sperm concentration, and increased percentage of sperm with abnormal morphology, damaged acrosome, and nonfunctional mitochondrial activity. These data demonstrate that HTN alters gonadal macrophage polarization, which is associated with gonadal inflammation, inflammation-associated lymphangiogenesis, and dysfunction.

021 Short term consequences of childhood cancer

The survival rates of all subtypes of childhood cancer have increased over the last decades thanks to improved treatment regimens. Nowadays, over 80% of children with cancer will survive the disease. Therefore, the childhood cancer survivor population is growing. Because of this increasing number, the consequences or effects of cancer treatment became more apparent. It has been shown that almost 75 percent of the survivors have one or more unwanted side effects of anticancer treatment. One of these effects is gonadal dysfunction.

Male Gonadal Function After Pediatric Hematopoietic Stem Cell Transplantation: A Systematic Review

Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development, sexual dysfunction, and infertility. However, no systematic review exists regarding prevalence and risk factors in relation to different treatment regimens. We aimed to systematically evaluate the current evidence regarding the prevalence of male gonadal dysfunction after pediatric HSCT, related risk factors, and the diagnostic value of surrogate markers of spermatogenesis in this patient group. We searched PubMed and Embase using a combination of text words and subject terms. The eligibility screening was conducted using predefined criteria. Data were extracted corresponding to the Leydig cell compartment involved in testosterone production and the germ cell compartment involved in spermatogenesis, respectively. Subsequently, data synthesis was performed. Of 2369 identified records, 25 studies were eligible. The studies were heterogeneous in terms of included diagnoses, gonadotoxic therapy, follow-up time, and definitions of gonadal dysfunction. The data synthesis revealed a preserved Leydig cell function in patients treated with non-total body irradiation (TBI) regimens, whereas the evidence regarding the impact of TBI conditioning on Leydig cell function was conflicting. Based on surrogate markers of spermatogenesis and only limited data on semen quality, the germ cell compartment was affected in half of the patients treated with non-TBI regimens and in nearly all patients treated with TBI conditioning. Testicular irradiation as part of front-line therapy before referral to HSCT led to complete Leydig cell failure and germ cell failure. Evidence regarding the impact of diagnosis, pubertal stage at HSCT, and chronic graft-versus-host disease is limited, as is the evidence of the diagnostic value of surrogate markers of spermatogenesis. Testicular irradiation as part of front-line therapy and TBI conditioning are the main risk factors associated with male gonadal dysfunction after pediatric HSCT; however, impaired spermatogenesis is also observed in half of the patients treated with non-TBI regimens. Methodological shortcomings limit existing evidence, and future studies should include semen quality analyses, follow-up into late adulthood, and evaluation of the cumulative exposure to gonadotoxic therapy.

Beta Thalassemia and Klinefelter syndrome: a rare occurrence

Backgroundβ-Thalassemia is an inherited haematological blood disorder in the HBB gene, and variations in this HBB gene lead to the absence/deficiency of the Beta chain synthesis of haemoglobin leading to severe anaemia. Klinefelter syndrome is a chromosomal abnormality that affects physical and cognitive development in males. Affected individuals are taller, show gynaecomastia and behavioural problems and have small testes that do not produce much testosterone. We describe a boy with β-Thalassemia major referred for chromosomal analysis due to delayed puberty and short stature. This is a second case reported in the literature that gives information on two different contradicting genetic disorders in a single individual but novel case as he exhibits additional short-stature phenotype.Case presentationA 17-year-old boy with short stature and gonadal dysfunction was referred for chromosomal analysis. He needed blood transfusion every 4 weeks. The GTG banding for chromosomal analysis and standard PCR for variant detection of HBB gene, Bi-directional Sanger sequencing of the PCR products and multiplex PCR for Y microdeletion of the AZF a, b and c regions on the Y chromosome were performed. The cytogenetic analysis revealed a karyotype of 47,XXY. The HBB gene detected two heterozygous variants forming a pathogenic compound heterozygous condition. The multiplex PCR revealed that the AZF a, b and c regions were intact and were not deleted.ConclusionTo our knowledge, this is the second case of a patient with β-Thalassemia associated with Klinefelter syndrome but a novel case with short-stature phenotype association instead of tall stature. The possible association of these two disorders and the unusual phenotypic presentation are discussed. This study highlights the possibility of ruling out Thalassemia while evaluating patients with short stature and delayed puberty.

How to manage puberty and prevent fertility disorders in men with CAH?

Gonadal dysfunction is an adverse outcome in patients with congenital adrenal hyperplasia (CAH), which may become apparent already during puberty. In males, gonadal dysfunction can be caused by primary gonadal failure due to testicular adrenal rest tumours (TART), and by secondary gonadal failure due to poor hormonal control. Yearly evaluation for TART using ultrasonography is recommended from the start of puberty or even earlier when poor hormonal control is present. We recommend yearly evaluation of gonadal function by measuring LH, FSH, testosterone, and inhibin B. When TART is present, cryopreservation of semen should be considered as soon as possible.

Gonadal dysfunction in male patients with Budd Chiari syndrome and its reversibility with treatment.

Budd Chiari syndrome (BCS) commonly affects adolescents and adults. With improved survival, important quality-of-life parameters such as sexual life and fertility become more relevant. This study was aimed to assess the gonadal function in male patients with BCS and the effect of treatment on gonadal function. Thirty male patients with newly diagnosed BCS were prospectively assessed for the presence of gonadal dysfunction. Erectile function was assessed using standardized International Index of Erectile Function questionnaire (IIEF). Follicular stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), estradiol, total testosterone (TT), calculated free testosterone (cFT), calculated bioavailable testosterone (cBT), sperm count, and sperm motility were compared at baseline and at 6months of treatment for the assessment of gonadal function. Sixteen (53.3%) out of 30 patients were sexually active at the time of study and 5/16 (31%) had erectile dysfunction. Hypogonadotropic hypogonadism (HH) was the most common pattern seen in 50% cases followed by hypergonadotropic hypogonadism (HyH) in 23% cases. 27% patients had eugonadism. At 6months of treatment, 60% of patients in HH group became eugonadal as compared to only 14% in HyH group. Proportion of patients with erectile dysfunction reduced (5/16 vs 1/16) after 6months of therapy. The improvement in sperm count and sperm motility was not significant. Gonadal dysfunction is common in male patients with BCS. HH remains the most common type of hypogonadism BCS and the type which improves significantly after treatment.

Late Endocrine and Metabolic Sequelae and Long-Term Monitoring of Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma Survivors: A Systematic Review by the Fondazione Italiana Linfomi.

Simple SummaryThe aim of this systematic review, conducted by the researchers of Fondazione Italiana Linfomi (FIL), was to fill a gap in the literature regarding the follow-up of endocrine-metabolic sequelae in lymphoma patients five years and more after the end of treatments. These patients can develop a series of late toxicities, such as thyroid and gonadal dysfunctions, osteoporosis and metabolic syndrome, that contribute to comorbidity burden and could affect quality of life and overall survival. There are currently no specific indications for tailored screening programs and/or tertiary prevention for the subset of long-term lymphoma survivors treated with modern therapeutic approaches. This systematic review also aimed to understand whether there is sufficient evidence to plan modern, tailored screening programs and validated exams for the outcomes of interest based on the real incidence or prevalence of late endocrine and metabolic sequelae.Background: Overall survival after lymphoma has improved in recent years, but the high prevalence of late treatment-related sequelae has been observed as a counterpart. Method: In this systematic review, FIL researchers aimed to: (i) estimate the incidence or prevalence of late endocrine-metabolic sequelae, (ii) evaluate the effects of modern therapeutic approaches on incidence or prevalence of late endocrine-metabolic sequelae, and (iii) determine whether there is evidence of follow-up schemes for their screening/early diagnosis in the subset of long-term classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) survivors treated at adult age. The MEDLINE, Embase and the Cochrane Library databases were searched for relevant articles published up to October, 2020. The study selection process was conducted by three independent reviewers and was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A risk of bias assessment was performed using the Cochrane tool for randomized trials and the Newcastle-Ottawa Scale for observational studies. Results: In the final analysis, eight studies were included, four of which focused on thyroid disease, two on gonadal dysfunction, one on bone disease and one on metabolic syndrome. Hypothyroidism was reported in up to 60% of adult cHL survivors and was frequently recorded even with modern radiotherapy approaches. Menopause occurred in 52–72% of women after chemotherapy. An 86% reduction in vertebral density was reported following R-CHOP-like chemotherapy. Sarcopenia and metabolic syndrome were reported in 37.9% and 60% of patients, respectively. No validated screening protocols were found for the early diagnosis of long-term treatment-related endocrine and metabolic sequelae, thus the authors finally suggest the execution of screening exams according to the risk category which were identified in the epidemiologic studies.

A narrative review on the research progress of gonadal function protection in children with cancer.

Background and ObjectiveThe global incidence of malignant tumors in children (0–14 years) and adolescents (15–19 years) ranges between 95 per 1 million and 255 per 1 million, which seriously affects the survival of patients. In the past 30 years, with the application of comprehensive treatments (including surgery, chemotherapy, radiotherapy, and bone marrow transplantation), great progress has been made in the treatment of malignant tumors in children and adolescents. The 5-year survival rate now exceeds 80%, and most patients can smoothly enter adolescence or the reproductive period. However, due to the particular age of patients with malignant tumors in children and adolescents, treatment may cause abnormal growth of the patient’s height, bones, and some vital organs (such as the pituitary gland and reproductive organs). Treatment may also cause abnormal secretion of growth hormones, thyroid hormones, and sex hormones. These complications seriously affect the quality of life of tumor patients. In the past ten years, countries have established long-term follow-up specifications for children with tumors. These programs have found that, in adulthood, 67% to 75% of children who survived having tumors have at least one treatment-related complication. Among patients receiving chemotherapy, gonadal dysfunction is the most common related endocrine dysfunction.MethodsThis paper reviews the literature on fertility protection services for cancer patients in foreign countries was conducted to provide a reference for developing gonadal protection services for cancer patients and for establishing consensus or guidelines on gonadal protection in China.Key Content and FindingsIn the treatment of childhood cancer, the assistance of reproductive technology can effectively reduce the occurrence of complications from treatment.ConclusionsTherefore, minimizing the effects of radiotherapy and chemotherapy on the growth and endocrine of children and adolescents while treating tumors is a new challenge for oncologists.

A study of gonadal dysfunction in women with thyroid disease

Background: Thyroid diseases are among the commonest endocrine disorders. It effects growth, embryonic development, tissue differentiation, maturation, metabolism, increases chronotropic and inotropic action of heart. The aim was to study gonadal dysfunction in women with thyroid disease; to study levels of FSH, LH, prolactin, estrogen and testosterone in hypothyroid and hyperthyroid.Methods: All participants fulfilling the inclusion criteria were interviewed as per proforma and medical details were recorded in proforma sheet and patients were subjected to necessary blood investigations.Results: Among 80 study subjects, majority were in the age group 26-35 years (60.1%) and majority had overt hypothyroid disease (72.5%). Symptoms of hypothyroid subjects mainly were fatigue, weight gain, hair loss, oligomenorrhea. Hyperthyroid subjects had fatigue, palpitations, oligomenorrhea, polymenorrhea. Prolactin had positive correlation with TSH in hypothyroid subjects, their LH, FSH levels were normal and sex steroid levels were low. In contrary, majority of the hyperthyroid subjects had normal prolactin and FSH, high LH and high sex steroid levels.Conclusions: The study demonstrated that thyroid disease in women causes menstrual abnormalities due to altered gonadotropin patterns which in turn alter ovarian hormone pattern. Hypothyroidism is associated with hyperprolactinemia leading to anovulation and abnormal menstrual cycle. Hyperthyroidism is associated with increased levels of LH, estrogen and testosterone with normal levels of PRL and FSH. Screening, identifying and correcting thyroid disease should be undertaken to prevent infertility as early as possible.

Prevalence of Gonadal Dysfunction in Patients with Chronic Kidney Disease at a Tertiary Care Centre.

Prevalence of Gonadal Dysfunction in Patients with Chronic Kidney Disease at a Tertiary Care Centre.