Gonadal Function in Male Patients With Metastatic Renal Cell Cancer Treated With Sunitinib.

BACKGROUND/AIM: Single-agent tyrosine kinase inhibitors are still prescribed as first-line treatment to a relevant subgroup of patients with metastatic renal cell carcinoma (mRCC). These agents are known to cause disfunction of many endocrine glands (e.g., thyroid). In this two-step trial, we aimed to assess gonadal function among male patients with mRCC treated with sunitinib. PATIENTS AND METHODS: We enrolled a first cross-sectional cohort of pre-treated (>6 months) patients and a subsequent cohort of treatment-naïve patients who were prospectively followed-up. All patients were screened for hypogonadism and received a Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire at study entry and after 6 months of therapy. Patients who were candidates for testosterone replacement therapy (TRT) also received a FACT-G questionnaire at baseline and 3 months after supplementation. RESULTS: Among the 30 enrolled patients, the prevalence of hypogonadism was found to be higher in those receiving sunitinib for a longer period (27.3% at baseline, 41.7% in the first 6 months, and 68.4% after 9 months of therapy). The testosterone level of patients correlated with quality of life (R=0.32). A total of six patients received TRT, with a significant improvement in their global quality of life after the first 3 months of treatment. CONCLUSION: An increasing prevalence of hypogonadism was seen among male patients who received long-term treatment with sunitinib. TRT was associated with relevant improvements in quality of life. These findings corroborate similar published observations and encourage the assessment of gonadal function in male patients with mRCC under treatment with sunitinib.

Is there impact of the SARS-CoV-2 pandemic on steroidogenesis and fertility?

In December of 2019, several cases of unknown atypical respiratory diseases emerged in Wuhan, Hubei Province in China. After preliminary research, it was stated that the disease is transmittable between humans and was named COVID-19. Over the course of next months, it spread all over the world by air and sea transport and caused a global pandemic which affects life of everyone now-a-days. A large number of countries, have since been forced to take precautions such as curfews, lockdowns, wearing facemasks etc. Even with vaccines being produced in mass numbers, lack of targeted therapy continues to be a major problem. According to studies so far it seems that elderly people are more vulnerable to severe symptoms while children tend to by asymptomatic or have milder form the disease. In our review, we focused on gathering data about the virus itself, its characteristics, paths of transmission, and its effect on hormone production and secretion. In such, there is insufficient information in the literature worldwide, especially the ones that focus on the effect of COVID-19 on individual organs systems within the human body. Hence, the present evidence-based study focused on the possible effects of COVID-19 on adrenal gland and gonads i.e. on the process of steroidogenesis and fertility.

Immune checkpoint inhibitor-related hypogonadism and infertility: a neglected issue in immuno-oncology.

Despite a significant amount of data on incidence and therapy of immune-related adverse events affecting virtually all organ systems, the potential impact of immune checkpoint inhibitors (ICIs) on gonadal function has not been sufficiently studied. The limited evidence available suggests that ICI-related primary hypogonadism due to orchitis as well as secondary hypogonadism due to hypophysitis are a potential risk for infertility. A systematic investigation of gonadal function under ICIs is warranted given the increasing application of ICIs in the adjuvant setting, among young adults and children and the possible influence of sex hormone levels on the efficacy and toxicity of ICIs.

Hypertension and reproductive dysfunction: a possible role of inflammation and inflammation-associated lymphangiogenesis in gonads.

Hypertension is one of the most prevalent diseases that leads to end organ damage especially affecting the heart, kidney, brain, and eyes. Numerous studies have evaluated the association between hypertension and impaired sexual health, in both men and women. The detrimental effects of hypertension in men includes erectile dysfunction, decrease in semen volume, sperm count and motility, and abnormal sperm morphology. Similarly, hypertensive females exhibit decreased vaginal lubrication, reduced orgasm, and several complications in pregnancy leading to fetal and maternal morbidity and mortality. The adverse effect of hypertension on male and female fertility is attributed to hormonal imbalance and changes in the gonadal vasculature. However, mechanistic studies investigating the impact of hypertension on gonads in more detail on a molecular basis remain scarce. Hence, the aim of the current review is to address and summarize the effects of hypertension on reproductive health, and highlight the importance of research on the effects of hypertension on gonadal inflammation and lymphatics.

Opioids and the Hypothalamic-Pituitary-Gonadal (HPG) Axis.

CONTEXT: Hypogonadism is a well-established consequence of opioid use. It has been reported in both men and women, although more widely studied in men. EVIDENCE ACQUISITION: PubMed was searched for articles in English until December 2019 for opioids and hypogonadism. Bibliography of retrieved articles was searched for relevant articles. EVIDENCE SYNTHESIS: The prevalence of opioid-induced hypogonadism (OIH) varies between studies but was reported to be 69% in a recent systematic review. There is large heterogeneity in the studies, with different factors shown to have stronger association with hypogonadism such as specific types of opioids, higher doses, and longer durations of use. The consequences of OIH include sexual dysfunction, depression, decreased quality of life, and low bone density. There is paucity of randomized controlled trials assessing the efficacy of testosterone replacement therapy (TRT) for OIH in men, and even less studies on treating OIH in women. TRT studies in men reported varying outcomes with some studies favoring and others showing no clear benefit of TRT on different measures. CONCLUSIONS: Despite the high prevalence of OIH, it remains underrecognized and undertreated with multiple endocrine and metabolic consequences. A reasonable approach in patients using opioids includes informing them of this complication and its potential consequences, screening for signs and symptoms of hypogonadism then sex hormone levels if prolonged opioid use > 3 months, and treating patients diagnosed with hypogonadism, if and when clinically indicated, with sex hormones if chronic opioids are planned to be continued for ≥ 6 months.

Opioid-induced hypogonadism: Pathophysiology, clinical and therapeutics review.

Opioids are pivotal therapeutics in the management of escalated chronic pain (moderate-severe). In the last two decades, the increased prescription rate and the prolonged usage of opioids shed light on opioid-induced endocrinopathy. Opioid-induced hypogonadism (OHG) results upon long-term opioid therapy. Clinically, patients with OHG are presented mainly by sexual dysfunction and infertility. Opioid clinical use in pain therapy is indispensable. However, the resultant sexual endocrinopathy cannot be overlooked and hence hormonal replacement therapy with regular monitoring of the patients represents a potential therapeutic strategy while avoiding opioids in patients with guaranteed long therapeutic exposure and switching to using low-dose naltrexone as alternative represents a possible prophylactic measure to ensure therapeutic compliance and secure a good life quality of patients.

The impact of childhood cancer and its treatment on puberty and subsequent hypothalamic pituitary and gonadal function, in both boys and girls.

Childhood cancer survivors (CCS) are at an increased risk of endocrine disorders. Disorders of the hypothalamic-pituitary-gonadal (HPG) axis are a particular concern because of their impact on pubertal development and future fertility and may be of central (hypothalamic or pituitary damage) or primary (gonadal) origin. Hypogonadism may present as pubertal disorders during adolescence and subsequent infertility in adulthood but should be anticipated to ensure appropriate surveillance is in place to address these issues at an appropriate age. Those at risk of HPG axis dysfunction include those with tumours primarily affecting the hypothalamus, pituitary or gonads themselves or due to their treatment with surgery, radiotherapy and chemotherapy. CCS who have had cranial irradiation of more than 30 Gy are at risk of gonadotrophin deficiency. Those who have had gonadotoxic chemotherapy, especially alkylating agents or radiotherapy to the gonads are at risk of primary gonadal failure. HSCT survivors who have had chemotherapy and total body irradiation are at risk of primary gonadal failure but may also have gonadotrophin deficiency. Understanding those at risk is essential to appropriate counselling and long-term follow-up. This chapter gives an overview on the impact of childhood cancer and its treatment on puberty, gonadal function and fertility in childhood cancer survivors.

Apoptosis contributes to protect germ cells from the oogenic germline starvation response but is not essential for the gonad shrinking or recovery observed during adult reproductive diapause in C. elegans.

When C. elegans hermaphrodites are deprived of food during the mid-L4 larval stage and throughout adulthood, they enter an alternative stage termed "adult reproductive diapause (ARD)" in which they halt reproduction and extend their lifespan. During ARD, germ cell proliferation stops; oogenesis is slowed; and the gonad shrinks progressively, which has been described as the "oogenic germline starvation response". Upon refeeding, the shrunken gonad is regenerated, and animals recover fertility and live out their remaining lifespan. Little is known about the effects of ARD on oocyte quality after ARD. Thus, the aim of this study was to determine how oocyte quality is affected after ARD by measuring brood size and embryonic lethality as a reflection of defective oocyte production. We found that ARD affects reproductive capacity. The oogenic germline starvation response protects oogenic germ cells by slowing oogenesis to prevent prolonged arrest in diakinesis. In contrast to a previous report, we found that germ cell apoptosis is not the cause of gonad shrinkage; instead, we propose that ovulation contributes to gonad shrinkage during the oogenic germline starvation response. We show that germ cell apoptosis increases and continues during ARD via lin-35/Rb and an unknown mechanism. Although apoptosis contributes to maintain germ cell quality during ARD, we demonstrated that apoptosis is not essential to preserve animal fertility. Finally, we show that IIS signaling inactivation partially participates in the oogenic germline starvation response.

Sex differences in health and aging: a dialog between the brain and gonad?

Women live longer than men in virtually all circumstances. However, a more common pattern among animals is that one sex lives longer under some conditions, the other lives longer under other conditions. In laboratory mice, interventions that extend longevity are surprisingly often sex-specific in their effects. Understanding these conditional sex differences could provide mechanistic insight into how longevity could be modulated in humans. One way that longevity can be consistently enhanced is by inhibiting reproduction or eliminating the capacity to reproduce. Thus, there appears to be a mechanistic link between gonadal activity and longevity. There also appears to be a mechanistic link between some types of neuroendocrine signaling and longevity. Combining these two observations suggest that communication between the brain and gonad is a ripe avenue for further exploring longevity-assurance mechanisms. Also, because the timing and activity of specific brain-gonad endocrine differs between the sexes, neuroendocrine linkages between the brain and gonad, particularly among the less obvious hormones such as activin and inhibin, could provide additional insight into mechanisms of sex differences in aging.

Puberty: Onset and Progression.

Puberty is an important process that providers of health care to children and adolescents should be comfortable discussing. The normal process of puberty is complex and involves many different hormonal pathways. A clear understanding of these pathways will help providers counsel patients on what to expect as they anticipate and progress through puberty as well as be alerted when puberty is not progressing normally. Both early and late puberty can have physical and psychological implications for the pediatric population. Being familiar with the common causes and initial testing of abnormal puberty will allow the primary care provider to monitor appropriately and initiate further investigation if warranted. This article reviews both the typical pubertal pathway as well as delayed and premature puberty and their common causes. [Pediatr Ann. 2019;48(4):e141-e145.].

Hypothalamic-pituitary-gonadal axis dysfunction: An innate pathophysiology of schizophrenia?

The female hormone 17ß-estradiol is postulated to be protective against schizophrenia onset and severity. Hypoestrogenism is a common phenomenon in women with schizophrenia that has serious effects that adds to the burden of an already very onerous disease. The cause of hypoestrogenism is largely attributed to antipsychotic-induced hyperprolactinemia. Evidence suggest however that a significant portion of female schizophrenia patients develop hypoestrogenism either before antipsychotic treatment or without regard to the level of prolactin, suggesting that for a sizeable segment of female patients, gonadal abnormality may be an innate and early aspect of the disease. This review aims to summarise the available literature that examines gonadal dysfunction in schizophrenia through this prism as well as to outline some recent developments in treatment strategies that may provide feasible ways to successfully tackle hypoestrogenism in schizophrenia.

Feminization, altered gonadal development, and liver damage in least killifish (Heterandria formosa) exposed to sublethal concentrations of 17α-ethinylestradiol.

The widespread use of the synthetic estrogen 17 α-ethinylestradiol (EE2) has resulted in elevated levels in aquatic environments, where it is known to act as an endocrine disrupting chemical affecting fish and other aquatic organisms. Examining changes in the structure of the fish' gonads and liver has proven to be an effective approach for assessing these impacts. While changes have been reported for various fish species, it is not clear whether impacts are equally severe in live-bearing fishes. The present study looked at gonadal and liver development in EE2-exposed least killifish (Heterandria formosa), a live-bearing Poeciliid. Exposures to 0, 5, or 25 ng/L EE2 began within six days of birth and continued until fish became sexually mature 12-23 weeks later. Exposure to 5 ng/L EE2 resulted in severe intersex in fish with external male characteristics, a slowdown of spermatogenesis in these intersex fish and a slowdown of oogenesis in the female fish. Moreover, these fish had a variety of liver injuries. Fish exposed to 25 ng/L EE2 exhibited intersex but at a lower frequency than occurred at 5 ng/L. In contrast, liver damage and slowdown of both oogenesis and spermatogenesis exhibited the typical dose-dependence. These findings illustrate the importance of including histological analyses when assessing endocrine disruption in fish, demonstrate that the live-bearing mode of reproduction appears to provide limited protection from the effects of waterborne EE2, and provide further evidence that EE2 has multiple impacts on fish health and reproduction that are severe enough to potentially affect fish populations.

Adenine-induced chronic kidney disease in rats.

Many animal models have been developed to study the causes and treatments of chronic kidney disease (CKD) in humans, an insidious disease resulting from kidney injury and characterized by persistent functional decline for more than 3 months, with or without evidence of structural deficit. The eventual outcome of CKD may be end-stage kidney disease (ESKD), where patients need dialysis or transplantation to survive. Cardiovascular disease is accelerated in patients with CKD and contributes to increased mortality, with the relationship between CKD and cardiovascular disease being bi-directional. Most animal models do not mimic the complexity of the human disease as many do not develop CKD-associated cardiovascular disease. The adenine diet model of CKD in rodents is an exception. The original adenine diet model produced rapid-onset kidney disease with extensive tubulointerstitial fibrosis, tubular atrophy, crystal formation and marked vessel calcification. Since then, lower adenine intake in rats has been found to induce slowly progressive kidney damage and cardiovascular disease. These chronic adenine diet models allow the characterization of relatively stable kidney and cardiovascular disease, similar to CKD in humans. In addition, interventions for reversal can be tested. Here the key features of the adenine diet model of CKD are noted, along with some limitations of other available models. In summary, the data presented here support the use of chronic low-dose adenine diet in rats as an easy and effective model for understanding human CKD, especially the links with cardiovascular disease, and developing potential therapeutic interventions.

A practical guide for evaluating gonadal germ cell tumor predisposition in differences of sex development.

Differences of Sex Development (DSD) includes a wide spectrum of etiologies and phenotypes. A subset of individuals with DSDs are predisposed to gonadal germ cell tumor (GCT). In this setting, GCT risk varies widely, depending on the DSD molecular etiology and penetrance. Prognostication based on molecular diagnosis remains challenging, as natural history data specific to recently identified molecular causes of DSD is lacking. In this review, we provide a framework for the clinical geneticist to consider GCT tumor risk in the patient with DSD. We discuss germ cell development and etiology of GCT growth, along with parameters to consider when recommending prophylactic gonadectomy including fertility, hormonal output, and malignant GTC treatment outcomes. Shortly after the 2006 reorganization of DSD nomenclature, literature reviews of natural history publications stratified GCT risk by a chromosomal, pathological, and hormonal taxonomy. Our 2017 literature review reveals a larger body of publications. However, the broad DSD GCT risk stratification within the 2006 taxonomy remains stable. We discuss precise GCT risk assessment for specific diagnoses, including androgen insensitivity, Smith-Lemli-Opitz, and 46,XY with MAP3K1 mutations and gonadal dysgenesis, as examples. We also examine the GCT risk in non-DSD syndromes, in addition to the cancer risks in DSD patients with dimorphic gonads and genitalia. This review is intended to provide a nuanced assessment of relative germ cell tumor risk in the DSD patient, including modern precise molecular diagnosis, for use by the clinical geneticist.

Gonadal and Sexual Dysfunction in Childhood Cancer Survivors.

PURPOSE: Few studies have addressed gonadal and sexual dysfunctions in childhood cancer survivors. We evaluated the prevalence rates and risk factors for gonadal failure among adolescent/young adult childhood cancer survivors and their sexual function. MATERIALS AND METHODS: Subjects were childhood cancer survivors aged 15-29 years who had completed therapy more than 2 years ago. Demographic and medical characteristics were obtained from the patients' medical records. In addition, hormonal evaluation and semen analysis were performed and sexual function was evaluated via questionnaire. RESULTS: The study included 105 survivors (57 males, 48 females), of which 61 were adults (age > 19 years) and 44 were adolescents. In both males and females, the proportion of survivors with low sex hormone levels did not differ among age groups or follow-up period. Thirteen female subjects (27.1%) needed sex hormone replacement, while five males subjects (8.8%) were suspected of having hypogonadism, but none were receiving sex hormone replacement. Of 27 semen samples, 14 showed azospermia or oligospermia. The proportion of normospermia was lower in the high cyclophosphamide equivalent dose (CED) group (CED ≥ 8,000 mg/m2) than the low CED group (27.3% vs. 62.5%, p=0.047). Among adults, none were married and only 10 men (35.7%) and eight women (34.3%) were in a romantic relationship. Though a significant proportion (12.0% of males and 5.3% of females) of adolescent survivors had experienced sexual activity, 13.6% had not experienced sex education. CONCLUSION: The childhood cancer survivors in this study showed a high prevalence of gonadal/sexual dysfunction; accordingly, proper strategies are needed to manage these complications.

Novel AMH and AMHR2 Mutations in Two Egyptian Families with Persistent Müllerian Duct Syndrome.

Anti-müllerian hormone (AMH) is produced by Sertoli cells and signals through 2 transmembrane receptors (AMHR), specific types I and II, leading to regression of müllerian ducts during fetal male sex differentiation. Mutations in AMH and AMHR2 lead to the persistence of müllerian ducts in males which is transmitted in a recessive pattern. Here, we report 2 Egyptian DSD (disorder of sex development) patients reared as males who presented with bilateral cryptorchidism and otherwise normal male external genitalia and who both had a 46,XY karyotype. The first patient presented at the age of 2 years. Laparoscopic surgery revealed a uterus and fallopian tubes with the presence of 2 gonads, and biopsy and pathology revealed prepubertal testicular tissue showing small-sized tubules with mostly Sertoli cells and very few spermatogonia, edematous stroma, and no detectable ovarian tissue. The second patient presented at the age of 3 years. Laparoscopic surgery revealed a uterus and fallopian tubes, and serum AMH was very low (0.1 ng/mL). Molecular studies revealed a novel missense mutation in the AMHR2 gene in the first patient (c.767A>C; p.H256P) and a novel frameshift mutation in the AMH gene in the second patient (c.203delC; p.L70Cfs*7). We conclude that persistent müllerian ducts should be included in the differential diagnosis of cryptorchidism.

Endocrine Manifestations in a Monocentric Cohort of 64 Patients With Erdheim-Chester Disease.

CONTEXT: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by infiltration of foamy histiocytes in multiple organs. Endocrine involvement has mostly been described in case reports. OBJECTIVE: We performed systematic endocrine evaluation in a large cohort of patients with ECD. DESIGN: This was a single-center observational study conducted between October 2007 and May 2013. SETTING: The evaluation was conducted in Pitié-Salpêtrière Hospital (Paris, France), a tertiary care hospital. PATIENTS: Sixty-four consecutive patients with ECD (sex ratio, 3.6; mean age, 57.6 years [range, 20-80 years]). Thirty-six patients had follow-up assessments. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Clinical, biological, and morphological evaluations of pituitary, gonadal, adrenal, and thyroid functions, as well as metabolic evaluation, were performed. RESULTS: Diabetes insipidus was found in 33.3% of patients, frequently as the first manifestation of ECD. Anterior pituitary dysfunction was found in 91.3% of patients with full anterior pituitary evaluation, including somatotropic deficiency (78.6%), hyperprolactinemia (44.1%), gonadotropic deficiency (22.2%), thyrotropic deficiency (9.5%), and corticotropic deficiency (3.1%). Thirty-five patients (54.7%) had ≥2 anterior pituitary dysfunctional axes, rising to 69.6% (16 of 23) when only patients with complete evaluations were considered. Two patients had panhypopituitarism. Infiltration of the pituitary and stalk was found with magnetic resonance imaging in 24.4% of patients. Testicular insufficiency was found in 53.1% of patients, with sonographic testicular infiltration in 29% of men, mostly bilateral. Computed tomography adrenal infiltration was found in 39.1% of patients, and 1 case of adrenal insufficiency was observed. No patient was free of endocrine hormonal or morphological involvement. Endocrine dysfunctions were most often permanent, and new deficits appeared during follow-up. CONCLUSION: Endocrine involvement is very frequent in ECD and should be evaluated carefully at diagnosis and during follow-up.

Sexual Precocity--Genetic Bases of Central Precocious Puberty and Autonomous Gonadal Activation.

Precocious puberty has been classically defined as the onset of sexual secondary characteristics in girls younger than 8 years and in boys younger than 9 years. The discovery of potential factors which trigger human puberty is one of the central mysteries of reproductive biology. Several approaches, including mutational analysis of candidate genes, large-scale genome-wide association studies, and (more recently) whole-exome sequencing, have been performed in attempt to identify novel genetic factors that modulate the human hypothalamic-pituitary-gonadal axis, resulting in premature sexual development. In the last two decades, it has been well established that autonomous gonadal activation can be caused by somatic (GNAS) or germline (LHCGR)-activating mutations of genes that encode essential elements for signal transduction of G protein-coupled receptors, resulting in peripheral precocious puberty in McCune-Albright syndrome and testotoxicosis, respectively. More recently, dominant activating and inactivating mutations of excitatory (KISS1/KISS1R) and inhibitory (MKRN3) modulators of gonadotropin-releasing hormone secretion, respectively, were associated with central precocious puberty phenotype. Indeed, loss-of-function mutations of MKRN3, a maternal imprinted gene located at chromosome 15q, currently represent a frequent cause of central precocious puberty diagnosed in families from distinct geographic origins. Here, we review the known genetic defects in central and peripheral precocious puberty.

Prenatal stress-immune programming of sex differences in comorbidity of depression and obesity/metabolic syndrome.

Major depressive disorder (MDD) is the number one cause of disability worldwide and is comorbid with many chronic diseases, including obesity/metabolic syndrome (MetS). Women have twice as much risk for MDD and comorbidity with obesity/MetS as men, although pathways for understanding this association remain unclear. On the basis of clinical and preclinical studies, we argue that prenatal maternal stress (ie, excess glucocorticoid expression and associated immune responses) that occurs during the sexual differentiation of the fetal brain has sex-dependent effects on brain development within highly sexually dimorphic regions that regulate mood, stress, metabolic function, the autonomic nervous system, and the vasculature. Furthermore, these effects have lifelong consequences for shared sex-dependent risk of MDD and obesity/MetS. Thus, we propose that there are shared biologic substrates at the anatomical, molecular, and/or genetic levels that produce the comorbid risk for MDD-MetS through sex-dependent fetal origins.

El trastorno depresivo mayor (TDM) es la causa número uno de incapacidad en el mundo y es comórbido con muchas enfermedades crónicas, incluyendo la obesidad y el síndrome metabólico (SMet). Si bien las mujeres tienen el doble de riesgo que los hombres para el TDM y para la comorbilidad con obesidad y SMet, aun no se han aclarado las bases para comprender esta asociación. En base a estudios clínicos y preclínicos, se argumenta que el estrés materno prenatal (como la expresión excesiva de glucocorticoides y las respuestas inmunes asociadas) que ocurre durante la diferenciación sexual del cerebro fetal tiene efectos dependientes del sexo sobre el desarrollo cerebral en las regiones con alto dimorfismo sexual que regulan el ánimo, el estrés, la función metabólica, el sistema nervioso autónomo y la vascularización. Además, estos efectos tienen consecuencias a lo largo de la vida para el riesgo compartido sexo-dependiente para TDM y obesidad/SMet. Por lo tanto, se propone que hay sustratos biológicos compartidos a niveles anatómicos, moleculares y/o genéticos que producirían el riesgo comórbido para el TDM-SMet a través de orígenes fetales sexo-dependientes.

Le trouble dépressif caractérisé (TDC) est la première cause d'invalidité dans le monde et il existe une comorbidité avec de nombreuses maladies chroniques, dont le syndrome métabolique/obésité (SMet). Le risque de TDC est deux fois plus élevé chez les femmes ayant un SMet que chez les hommes, mais les tenants et les aboutissants de cette association sont encore mal compris. Au vu des études cliniques et précliniques existantes, nous soutenons que le stress maternel prénatal (c'est-à-dire l'excès de libération de glucocorticoïdes et les réponses immunes associées) qui survient pendant la différentiation sexuelle du cerveau du foetus a des effets dépendant du sexe sur le développement cérébral dans des régions très dimorphiques sexuellement, régulant l'humeur, le stress, la fonction métabolique, le système nerveux autonome et la vascularisation. De plus, les conséquences de ces effets pour le risque partagé de TDC et de SMet/obésité en fonction du sexe durent toute la vie. Nous pensons donc qu'il existerait des substrats biologiques partagés aux niveaux anatomique, moléculaire et/ou génétique qui seraient responsables du risque comorbide de TDC-SMet selon le sexe du foetus.