Iron overload disorders: Growth and gonadal dysfunction in childhood and adolescence.

Hemochromatosis (HC) is characterized by the progressive accumulation of iron in the body, resulting in organ damage. Endocrine complications are particularly common, especially when the condition manifests in childhood or adolescence, when HC can adversely affect linear growth or pubertal development, with significant repercussions on quality of life even into adulthood. Therefore, a timely and accurate diagnosis of these disorders is mandatory, but sometimes complex for hematologists without endocrinological support. This is a narrative review focused on puberty and growth disorders during infancy and adolescence aiming to offer guidance for diagnosis, treatment, and proper follow-up. Additionally, it aims to highlight gaps in the existing literature and emphasizes the importance of collaboration among specialists, which is essential in the era of precision medicine.

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.

Menstrual and Gonadal Function Alterations in Women with Systemic Lupus Erythematosus.

PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune disorder and may affect the reproductive health status of the women. Objective is to analyze the types, incidence of various menstrual disturbances in these women, to identify risk factors and to assess the gonadal function. METHODS: The prospective cohort study was conducted in the SLE clinic of the Rheumatology Department of IPGMEandR, Kolkata from April 2010 to April 2011. Out of 152 females attending clinic, 110 patients fulfilling criteria were included in the study. RESULTS: Mean age of the study population was 27.25±3.4 years. Sixty six cases had menstrual abnormalities (12.72% amenorrhea, 44.45% oligomenorrhea, 2.7% premature ovarian failure, 10.9% menorrhogia). When comparative analysis of demographic, hormonal, ovarian Doppler and therapeutic variables of normal and abnormal cycles was carried out, following parameters were significantly more related to patients with abnormal cycle ; SLEDAI score (12.48±5.53 vs 8.69±4.9; p=0.00), disease duration (6.46±3.08 vs 4.3±1.36; p< 0.05), TSH (7.73±8.64 vs 3.07±2.06; p=0.00.), LH (6.55±4.38 vs 4.56±3.29; p=0.02), a high normal prolactin (12.57±7.75 vs 8.73±3.07; p=0.02), peak systolic velocity (6.53±2.17 vs 9.12±2.1; p=0.00), end-diastolic volume (4.21±2.9 vs 9.35±2.32; p=0.00) and cumulative dose of steroid (24.02±41.44 vs 9.32±9.96; p=0.01).Cyclophosphamide with cumulative dose ≥10 gm was related to amenorrhea and affected gonadal function. Gonadal insufficiency was evident in 33.63% and 2.72% had ovarian failure. CONCLUSIONS: Reduced menstruation is a major health concern in women with SLE as it is frequent and can result in depressed and failed gonadal function later. Doppler study of ovaries is a novel way of depiction of gonadal status in these women. Certain risk factors and revolving treatment part can be preventable.

Evaluating the patients with thalassemia major for long-term endocrinological complications after bone marrow transplantation.

The aim of this study was to evaluate the endocrinological complications of the patients with thalassemia major (TM) who underwent bone marrow transplantation (BMT) and followed-up more than two years in our center, prospectively. "BMT group" consisted of 41 patients with TM. The mean age was 12.4 ± 5.4 years and transplantation age was mean 7.5 ± 4.9 years. Post-BMT follow-up lasted from 24 to 122 months (mean 65.07 months). Also, 32 TM patients with similar age group and same history of transfusion and chelation therapy were recruited for the study as "control (C) group". The weight SDS score after transplantation was found better than before transplantation (p = 0.010). There was a negative correlation between height SDS and BMT age (p = 0.008). The height SDS scores were better in patients whose BMT age was under seven years old compared to those older than seven years old (p = 0.02). Z-scores of femur neck and L2-4 vertebrae DEXA were decreased (p = 0.032, p = 0.0001) and incidence of insulin resistance increased (p = 0.01) in patients with increased BMT age. The risk of gonadal insufficiency was significantly lower in the patients who underwent BMT <7 years of age (p = 0.009). There was no statistically significant relationship between BMT age and complications such as hypothyroidism, hypoparathyroidism, and adrenal insufficiency. The patients with TM should be evaluated for transplantation in early stage of the disease, especially before the age of seven years. Because the BMT cannot correct the endocrinological complications of TM completely, the patients should be followed up regularly after the transplantation.

Gonadal dysfunction in women with diabetes mellitus.

It is well known that both type 1 and type 2 diabetes mellitus (DM) are related to increased risk for cardiovascular (CV) and chronic kidney disease (CKD). However, besides these prominently presented complications, DM has also been associated with reproductive dysfunctions. It seems that these disorders are met in up to 40% of women with DM and consist of delayed menarche, all types of menstrual disorders, such as amenorrhea, oligomenorrhea, menstrual irregularity, as well as menorrhagia, infertility, characteristics of polycystic ovary syndrome (PCOS) and early (or rarely late) menopause. In type 1 DM (T1DM), insulin treatment, although it has reduced the rates of insulinopenic-induced hypogonadotropic hypogonadism, an entity commonly presented in many women with the disease in the past decades, when it is used in excess it can also promote hyperandrogenism. Regarding type 2 DM (T2DM), insulin resistance (IR) and hyperinsulinemia have mainly been implicated in the pathogenesis of reproductive dysfunctions, as insulin can act as gonadotropin on the theca cells of the ovary and can lead to hyperandrogenism and inhibition of proper ovulation. This review aims to detail the reproductive dysfunctions associated with DM and provide scientific data to enlighten the underlying pathogenetic mechanisms.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on gonadal failure and fertility]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: insuffisance gonadique et fertilité

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview gonadal failure, fertility preservation and post-transplant.

The FSH-inhibin axis in prader-willi syndrome: heterogeneity of gonadal dysfunction.

BACKGROUND: We characterized the spectrum and etiology of hypogonadism in a cohort of Prader-Willi syndrome (PWS) adolescents and adults. METHODS: Reproductive hormonal profiles and physical examination were performed on 19 males and 16 females ages 16-34 years with PWS. Gonadotropins, sex-steroids, inhibin B (INB) and anti-Mullerian hormone (AMH) were measured. We defined 4 groups according to the relative contribution of central and gonadal dysfunction based on FSH and INB levels: Group A: primary hypogonadism (FSH >15 IU/l and undetectable INB (<10 pg/ml); Group B: central hypogonadism (FSH <0.5 IU/l, INB <10 pg/ml); Group C: partial gonadal & central dysfunction (FSH 1.5-15 IU/l, INB >20 pg/ml); Group D: mild central and severe gonadal dysfunction (FSH 1.5-15 IU/l, INB < 10 pg/ml. RESULTS: There were 10, 8, 9 and 8 individuals in Groups A-D respectively; significantly more males in group A (9, 4, 4 and 2; P = 0.04). Significant differences between the groups were found in mean testosterone (P = 0.04), AMH (P = 0.003) and pubic hair (P = 0.04) in males and mean LH (P = 0.003) and breast development (P = 0.04) in females. Mean age, height, weight, BMI and the distribution of genetic subtypes were similar within the groups. CONCLUSIONS: Analysis of FSH and inhibin B revealed four distinct phenotypes ranging from primary gonadal to central hypogonadism. Primary gonadal dysfunction was common, while severe gonadotropin deficiency was rare. Longitudinal studies are needed to verify whether the individual phenotypes are consistent.

[Radiation induced side effects]. / Effets indésirables de la radiothérapie.

More than half of all people with cancer are treated with radiation therapy. Over the last decade the technical advances, both in therapy beam precision and imaging, have greatly improved the therapeutic ratio and accuracy of modern radiotherapy. However, damaging healthy tissues near the tumor leads to radiation induced injury that develops immediately and continue to progress long after exposure to radiation. Recently dramatic advances have been made in understanding the determinant of tissue response to radiation exposure.

[Diagnostics and treatment of polyglandular syndrome of adults].

Autoimmune polyendocrine syndromes (APS) are rare endocrinopathies characterized by the coexistence of at least two glandular autoimmune diseases. APS comprise a wide spectrum of autoimmune disorders and are divided into a very rare juvenile (APS type 1) and a more common adult type with (APS 2) or without adrenal failure (APS 3). The first clinical manifestations of APS 1 usually occur in childhood whereas APS 2 mostly occurs during the third and fourth decades of life. The third type has been described in adults that, contrary to types 1 and 2, does not involve the adrenal cortex. No clinical differences between types 2 and 3 have been described except the absence of adrenal failure. Type 4 APS is a rare syndrome characterized by the combination of autoimmune conditions not falling into the above categories. It consists of adrenal failure with one or more minor autoimmune disorders barring major components of type 1 and 2 APS. Usually, autoimmune polyendocrine syndrome of adults manifests itself as one of the major autoimmune diseases (such as adrenal failure, Grave's disease, or type 1 diabetes) and minor autoimmune disorders (vitiligo, alopecia) preceding the development of autoimmune deficiency of major endocrine glands. This article describes a patient with type 3 APS, who developed type 1 diabetes. Grave's disease and vitiligo. The development of the syndrome started from vitiligo in the chidhood. Moreover, the patient suffered primary sterility and presented with progressive diabetic nephropathy of autoimmune origin. It is concluded that patients with a single autoimmune component of polyendocrine syndrome should be screened to exclude other autoimmune endocrine disorders.

Inhibin B and anti-Müllerian hormone as markers of gonadal function after treatment for medulloblastoma or posterior fossa ependymoma during childhood.

OBJECTIVE: To evaluate the roles of hypothalamic-pituitary and spinal irradiations and chemotherapy in gonadal deficiency after treatment for medulloblastoma or posterior fossa ependymoma by measuring levels of plasma inhibin B and antimüllerian hormone (AMH). STUDY DESIGN: A total of 34 boys and 22 girls were classified as having normal levels of plasma follicle-stimulating hormone (FSH; <9 IU/L), or abnormal levels of FSH (>9 IU/L) and luteinizing hormone (LH; <5 or >5 IUL). RESULTS: Two boys had partial gonadotropin deficiency, combined with testicular deficiency in one boy. Six boys had increased levels of FSH, indicating tubular deficiency, combined with Leydig cell deficiency in 5 boys. The 7 boys with inhibin B levels <100 ng/mL included the one with combined deficiencies and the 6 with testicular deficiency. Puberty did not progress in 7 girls; 3 had gonadotropin deficiency, combined with ovarian deficiency in one, and 4 had increased FSH levels, indicating ovarian deficiency. Inhibin B and AMH levels were low in the girl with combined deficiencies, in the 4 girls with ovarian deficiency, and in 4 girls with normal clinical-biological ovarian function, including 2 who underwent ovarian transposition before irradiation. CONCLUSION: The plasma concentrations of inhibin B and AMH are useful means of detecting primary gonad deficiency in patients with no increase in their plasma gonadotropin levels because of radiation-induced gonadotropin deficiency.

Inhibin B and anti-Müllerian hormone as markers of gonadal function after hematopoietic cell transplantation during childhood.

BACKGROUND: It is difficult to predict the reproductive capacity of children given hematopoietic cell transplantation (HCT) before pubertal age because the plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are not informative and no spermogram can be done. METHODS: We classified the gonadal function of 38 boys and 34 girls given HCT during childhood who had reached pubertal age according to their pubertal development and FSH and LH and compared this to their plasma inhibin B and anti-Müllerian hormone (AMH). RESULTS: Ten (26%) boys had normal testicular function, 16 (42%) had isolated tubular failure and 12 (32%) also had Leydig cell failure. All 16 boys given melphalan had tubular failure. AMH were normal in 25 patients and decreased in 6, all of whom had increased FSH and low inhibin B.Seven (21%) girls had normal ovarian function, 11 (32%) had partial and 16 (47%) complete ovarian failure. 7/8 girls given busulfan had increased FSH and LH and 7/8 had low inhibin B. AMH indicated that ovarian function was impaired in all girls.FSH and inhibin B were negatively correlated in boys (P < 0.0001) and girls (P = 0.0006). Neither the age at HCT nor the interval between HCT and evaluation influenced gonadal function. CONCLUSION: The concordance between FSH and inhibin B suggests that inhibin B may help in counselling at pubertal age. In boys, AMH were difficult to use as they normally decrease when testosterone increases at puberty. In girls, low AMH suggest that there is major loss of primordial follicles.

COVID-19 pandemic: what about the gonads?

The novel SARS-CoV-2 has spread to virtually all countries of the world infecting millions of people, the medical burden of this disease obviously being enormous. The gonads of both sexes are among the organs that may be affected by COVID-19 and/or may affect the severity of the disease. The clinical spectrum of SARS-CoV-2 infection clearly differs between genders. The current evidence indicates that the underlying mechanism of such an interaction could be associated with genetic, hormonal, and immunological differences, as well as with gender differences in such habits as smoking and alcohol use. On the other hand, there are controversies as to how and to what extent the gonads could be affected by COVID-19, possibly impacting upon sex steroids, fertility, and other functions. This review underlines the possible mechanisms that could clarify these questions concerning COVID-19 and the gonads. In addition, reference is made to potential new treatment modalities presently under investigation, these supported by accumulating data published in the recent literature.

Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for sickle cell disease.

We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease.

Endocrine late effects after hematopoietic stem cell transplantation.

The long-term quality of life of patients after hematopoietic stem cell transplantation (HSCT) represents a multidisciplinary problem. HSCT can induce damage of various organs and tissues-from minimal potentially progressive subclinical changes to life-threatening conditions. Endocrine complications are among the most common late effects observed in survivors after HSCT. The relative risk of these complications is likely to be influenced by the underlying disease, type of therapy, and age at HSCT. Understanding the pathogenetic mechanisms of late complications that can occur after HSCT provides a basis for optimal surveillance and early intervention. Further research is needed for improved risk stratification of patients who are at low and high risk of developing late toxicity. Through collaboration between pathophysiologists, clinicians, and patient associations we can enhance the implementation of prospective studies and set forth effective preventive programs for survivors after HSCT.

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.

Alterations in pubertal timing following therapy for childhood malignancies.

The onset of puberty marks a time of rapid linear growth, sexual development, and transition from childhood to maturity. The diagnosis and treatment of a childhood malignancy prior to the onset of puberty has the potential to profoundly affect the timing and the tempo of puberty. CNS tumors located in the hypothalamic-pituitary (H-P) region, surgical resection in this location, and exposure to CNS radiotherapy are all associated with both precocious and delayed puberty. Also, chemotherapy and radiation can directly damage the gonads, which can result in absent, arrested, or delayed puberty. As a consequence of these alterations of pubertal timing, both male and female survivors of childhood cancer may be at risk of adult short-stature, decreased bone-mineral density, absent or incomplete sexual development, and ultimately, reduced rates of fertility. Appropriate and timely assessment of survivors at high risk of alterations in pubertal development will enable the identification of patients who would benefit from early medical intervention.

Endocrine complications after hematopoietic stem cell transplantation during childhood and adolescence.

Long-term survivors of hematopoietic stem cell transplantation (HSCT) during childhood and adolescence are at risk of developing endocrine complications. The purpose of this study was to evaluate the long-term endocrine complications and their associated risk factors among such patients. We reviewed the data from 111 patients (59 males and 52 females) who underwent HSCT at the mean age of 8.3+/-4.1 yr. Thirty patients (27.0%) had growth impairment, and seven (21.2%) out of 33 patients who attained final height reached final height below 2 standard deviation (SD). The final height SD score of the patients conditioned with total body irradiation (TBI) was significantly lower than that of the patients conditioned without TBI (-1.18+/-1.14 vs. -0.19+/-0.78, P=0.011). Thirteen patients (11.7%) developed hypothyroidism (11 subclinical, 2 central) 3.8+/-1.8 (range 1.6-6.2) yr after HSCT. Nineteen (65.5%) out of 29 females had evidence of gonadal dysfunction, and 18 (64.3%) out of 28 males had evidence of gonadal dysfunction. The risk for gonadal dysfunction was significantly higher in females conditioned with busulfan/cyclophosphamide (P=0.003). These results suggest that the majority of patients treated with HSCT during childhood and adolescence have one or more endocrine complications. Therefore, multiple endocrine functions should be monitored periodically after HSCT until they reach adult age.

Setting up a fertility preservation programme.

With improved survival rates from cancer, young people can expect to lead a normal life, including having their own children. However, cancer or other serious disease itself, and more often its treatment, often leads to a significant reduction in fertility or premature gonadal insufficiency. There is increasing acknowledgement for the importance of fertility preservation (FP) options to be discussed and offered to young people whose fertility is at risk, ideally before the gonadotoxic therapy begins. FP options currently include oocyte, embryo and ovarian tissue cryopreservation; ovarian protection during chemotherapy and semen, sperm and testicular tissue cryopreservation. A multidisciplinary team consisting of committed and enthusiastic doctors, scientists, nurses, counsellors, administrators and researchers is required to provide a holistic FP service with rapid response capacity for acute consultation and procedures and a robust system for long-term follow-up. This speciality is developing rapidly with exciting scientific advances that have relevance for the whole spectrum of reproductive medicine.

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.