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Massart F.,University of Pisa | Massart F.,Pediatric Endocrine Unit | Saggese G.,University of Pisa
Sexual Development | Year: 2010

Although important advances in testicular physiology have been achieved, the aetiology of human cryptorchidism remains mostly unknown. Next to sex steroidal signaling pathways, morphogenetic genes are specifically involved in the testicular descent via gubernacular development. Mutations in the human genes encoding insulin-like factor 3 (INSL3) and its Leu-rich repeat-containing G protein-coupled receptor 8 (LGR8), homeobox A10 (HOXA10), zinc finger 214 (ZNF214) and 215 (ZNF215) have occasionally been identified but do not seem to be a frequent cause of cryptorchidism. On the other hand, common polymorphisms in these genes have recently been investigated as contributing risk factors for idiopathic isolated (nonsyndromic) cryptorchidism. Copyright © 2010 S. Karger AG, Basel.


Ackerman K.E.,Harvard University | Skrinar G.S.,Boston University | Medvedova E.,Harvard University | Misra M.,Harvard University | And 2 more authors.
Clinical Endocrinology | Year: 2012

Objective Strenuous training commonly results in amenorrhoea, which contributes to bone loss in some female collegiate athletes. However, the impact of athletic training on endocrine function and bone mineral density (BMD) in male collegiate athletes is less well understood. The objective of the study was to investigate the specific endocrine determinants of BMD in male collegiate runners and wrestlers, including the potential impact of gonadal steroid levels. Design Cross-sectional study. Patients Twenty-six division I collegiate male athletes (wrestlers, runners and golfers). Measurements Main outcome measures included (i) BMD endpoints measured by dual energy x-ray absorptiometry (DXA); (ii) endocrine end-points: total and free oestradiol, total and free testosterone; (iii) body composition end-points: lean and fat mass, measured by DXA; and (iv) exercise end-points: maximal oxygen uptake (VO 2 max), number of miles run weekly and grip strength. Results Free and total oestradiol levels were important positive determinants of BMD. In contrast, total and free testosterone levels were not significant predictors of BMD at any skeletal site (except for free testosterone at the radius). In addition, lean body mass, % ideal body weight, total body weight, body mass index (BMI) and hours per week of resistance training were positive predictors of BMD. VO 2 max was a negative predictor of BMD. Mean BMD was higher at all skeletal sites in the wrestlers compared with the runners and a comparison group (golfers). Conclusions Our data suggest that oestradiol levels, BMI, and resistance training are more important determinants of BMD in male collegiate athletes than testosterone. © 2012 Blackwell Publishing Ltd.


Bhutta H.Y.,Harvard University | Bhutta H.Y.,Imperial College London | Deelman T.E.,Harvard University | Ashley S.W.,Harvard University | And 3 more authors.
Digestive Diseases and Sciences | Year: 2013

Background: Intestinal absorptive capacity shows a circadian rhythm synchronized with eating patterns. Disrupting these coordinated rhythms, e.g., with shift work, may contribute to metabolic disease. Circadian expression of nutrient transporters has not been studied in metabolic disease. We studied the circadian rhythm of intestinal transporter sodium glucose co-transporter type 1 (SGLT1) in an obese diabetic rat. Methods: We compared obese Zucker diabetic fatty (ZDF) rats to lean ZDF littermates. Temporal feeding patterns were assessed, then rats were harvested at Zeitgeber (ZT, ZT0 = 7:00 a.m.) 3, 9, or 15 to measure insulin resistance, SGLT1 expression and intestinal glucose absorption capacity. Regulators of SGLT1 (sweet taste receptor T1R2/3; clock genes) were measured to elucidate underlying mechanisms. Results: Both groups exhibited altered circadian food intake. Obese ZDF rats lost circadian rhythmicity of SGLT1 mRNA expression and functional activity. Lean ZDF rats maintained rhythmicity of SGLT1 mRNA expression but that of functional glucose absorption was blunted. Circadian rhythms of intestinal clock genes were maintained in both groups. Neither group had discernible rhythms of intestinal GLUT2 (glucose transporter) or T1R2 (sweet taste receptor component) mRNA expression. In summary, lean and obese ZDF rats exhibited similar disruptions in circadian feeding. Glucose intolerance was evident in lean rats, but only obese rats further developed diabetes and exhibited disrupted circadian rhythmicity of both SGLT1 mRNA expression and function. Conclusions: Our findings suggest that disrupted circadian feeding rhythms contribute to glucose intolerance, but additional factors (genetics, changes in nutrient sensing/transport) are needed to lead to full diabetes. © 2013 Springer Science+Business Media New York.


Kousta E.,P and A Kyriakou Childrens Hospital | Papathanasiou A.,P and A Kyriakou Childrens Hospital | Skordis N.,Pediatric Endocrine Unit
Hormones | Year: 2010

There have been considerable advances concerning understanding of the early and later stages of ovarian development; a number of genes have been implicated and their mutations have been associated with developmental abnormalities. The most important genes controlling the initial phase of gonadal development, identical in females and males, are Wilms' tumor suppressor 1 (WT1) and steroidogenic factor 1 (SF1). Four genes are likely to be involved in the subsequent stages of ovarian development (WNT4, DAX1, FOXL2 and RSPO1), but none is yet proven to be the ovarian determining factor. changes in nomenclature and classification were recently proposed in order to incorporate genetic advances and substitute gender-based diagnostic labels in terminology. The term "disorders of sex development" (DsD) is proposed to substitute the previous term "intersex disorders". Three main categories have been used to describe DsD in the 46,XX individual: 1) disorders of gonadal (ovarian) development: ovotesticular DsD, previously named true hermaphroditism, testicular DsD, previously named XX males, and gonadal dysgenesis; 2) disorders related to androgen excess (congenital adrenal hyperplasia, aromatase deficiency and P450 oxidoreductase deficiency); and 3) other rare disorders. In this mini-review, recent advances concerning development of the genital system in 46,XX individuals and related abnormalities are discussed. basic embryology of the ovary and molecular pathways determining ovarian development are reviewed, focusing on mutations disrupting normal ovarian development. Disorders of sex development according to the revised nomenclature and classification in 46,XX individuals are summarized, including genetic progress in the field.


Ackerman K.E.,Harvard University | Putman M.,Harvard University | Guereca G.,Harvard University | Taylor A.P.,Harvard University | And 6 more authors.
Bone | Year: 2012

Context: Lower bone density in young amenorrheic athletes (AA) compared to eumenorrheic athletes (EA) and non-athletes may increase fracture risk during a critical time of bone accrual. Finite element analysis (FEA) is a unique tool to estimate bone strength in vivo, and the contribution of cortical microstructure to bone strength in young athletes is not well understood. Objective: We hypothesized that FEA-estimated stiffness and failure load are impaired in AA at the distal radius and tibia compared to EA and non-athletes despite weight-bearing exercise. Design and setting: Cross-sectional study; Clinical Research Center. Subjects: 34 female endurance athletes involved in weight-bearing sports (17 AA, 17 EA) and 16 non-athletes (14-21. years) of comparable age, maturity and BMI. Outcome measures: We used HR-pQCT images to assess cortical microarchitecture and FEA to estimate bone stiffness and failure load. Results: Cortical perimeter, porosity and trabecular area at the weight-bearing tibia were greater in both groups of athletes than non-athletes, whereas the ratio (%) of cortical to total area was lowest in AA. Despite greater cortical porosity in EA, estimated tibial stiffness and failure load was higher than in non-athletes. However, this advantage was lost in AA. At the non-weight-bearing radius, failure load and stiffness were lower in AA than non-athletes. After controlling for lean mass and menarchal age, athletic status accounted for 5-9% of the variability in stiffness and failure load, menarchal age for 8-23%, and lean mass for 12-37%. Conclusion: AA have lower FEA-estimated bone strength at the distal radius than non-athletes, and lose the advantage of weight-bearing exercise seen in EA at the distal tibia. © 2012 Elsevier Inc.

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