Long-term testosterone treatment during pregnancy does not alter insulin or glucose profile in a sheep model of polycystic ovary syndrome

© 2017, © 2017 Informa UK Limited, trading as Taylor & Francis Group.The administration of testosterone to pregnant sheep to resemble fetal programming of the polycystic ovary syndrome could alter other hormones/factors of maternal origin with known effects on fetal growth. Hence, we studied the weekly profile of insulin, progesterone and glucose during a treatment with testosterone propionate given biweekly from weeks 5 to 17 of pregnancy (term at 21 weeks) and checked the outcome of their fetuses at 17 weeks of gestation after C-section. Control dams were only exposed to the vehicle of the hormone. The testosterone administration did not cause any significant change in the maternal weekly profile of insulin, progesterone or glucose concentration, although the plasma levels of testosterone in the treated dams were inversely correlated to the levels of progesterone. Testosterone treatment also induced an inverse correlation between mean maternal insulin levels and fetal insulin levels

Prenatal testosterone exposure disrupts Insulin secretion and promotes insulin resistance

Hyperandrogenemia and metabolic disturbances during postnatal life are strongly linked both to polycystic ovary syndrome and other conditions that arise from prenatal exposure to androgen excess. In an animal model of this condition, we reported that insulin sensitivity (IS) was lower in young female sheep born to testosterone-treated mothers versus sheep born to non-exposed mothers (control). This lower insulin sensitivity remains throughout reproductive life. However, it is unknown whether abnormal postnatal levels of testosterone (T) further decrease IS derived from prenatal exposure to testosterone. Therefore, we assessed the effects of an acute testosterone administration (40 mg) on IS and insulin secretion during an intravenous glucose tolerance test performed at 40 weeks of age (adulthood) in previously ovariectomized sheep at 26 weeks of age (prepuberty), that were either prenatally exposed to testosterone (T-females, n = 6) or not (C-females, n = 6). The incremental area under the curve of insulin was greater in C-females both with or without the acute testosterone treatment (P < 0.05). The ISI-Composite was lower after an acute testosterone treatment, only in T-females. We conclude that prenatal exposure to testosterone disrupts pancreatic insulin secretion in response to glucose and that in this setting further hyperandrogenemia may predispose to lower insulin sensitivity.Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) CONICYT FONDECYT 114043

Epigenetics of polycystic ovary syndrome

Polycystic ovarian syndrome (PCOS) is an endocrine and metabolic dysfunction, highly prevalent in women in their reproductive years. Hyperandrogenism, oligo-ovulation, polycystic ovarian morphology are the main features of this syndrome. PCOS is a genetic disorder with a multifactorial etiology and has a strong link with environmental components. It is frequently associated with obesity and insulin resistance. Recently, epigenetic mechanisms have been involved in the pathogenesis of PCOS. Several studies showed that methylation in DNA and miRNAs is altered in women with PCOS in blood, serum, adipose tissue, granulose cells and theca. This evidence indicates that women with PCOS have a different epigenetic regulation, which might be triggered by an adverse intrauterine environment or by postnatal environmental elements such as diet and or obesity.Fondecyt 1151531 Fondecyt 1130240 Fondecyt 114043

Secretory patterns of leptin and luteinizing hormone in food-restricted young female sheep

Leptin, the product of the ob gene, has been proposed as a metabolic signal that regulates the secretion of GnRH/LH. This may be critical during prepubertal development to synchronize information about energy stores and the secretion of GnRH/LH. This study aimed to assess the effect of food restriction on the episodic secretion of leptin and LH in young female sheep. Five 20-week-old prepubertal females were fed a low-level diet for 10 weeks to maintain the body weight. Control females of the same age received food ad libitum. Blood samples were collected at 10-min intervals for six hours at 20, 26, and 30 weeks of age, and plasma leptin, LH, insulin and cortisol concentrations were measured. In the control group, no changes were found in pulsatile LH secretion characteristics. Mean LH concentrations and LH amplitude were lower in the food-restricted group than in the control group at 26 and 30 weeks of age. In the control group, pulsatile Ieptin secretion did not change. When compare

Altered testicular development as a consequence of increase number of sertoli cell in male lambs exposed prenatally to excess testosterone

The reprograming effects of prenatal testosterone (T) treatment on postnatal reproductive parameters have been studied extensively in females of several species but similar studies in males are limited. We recently found that prenatal T treatment increases Sertoli cell number and reduced spermatogenesis in adult rams. If such disruptions are manifested early in life and involve changes in testicular paracrine environment remain to be explored. This study addresses the impact of prenatal T excess on testicular parameters in infant males, including Sertoli cell number and expression of critical genes [FSH receptor (FSHR), androgen receptor (AR), transforming growth factor beta 1 (TGFB1), 3 (TGFB3), transforming growth factor beta type 1 receptor, (TGFBR1), and anti-Mullerian hormone (AMH)] modulating testicular function. At 4 week of age, male lambs born to dams treated with 30 mg of T propionate twice weekly from day 30 to 90, followed by 40 mg of T propionate from day 90 to 120 of pregnancy (T-males), had a higher number of Sertoli cells/ testis compared to C-males. Expression level of AMH, TGFB1, and AR also tended to be lower in T-males. These findings provide evidence that impact of fetal exposure to T excess is evident early in postnatal life, mainly characterized by an increase in Sertoli cell number. This could explain the testicular dysfunction observed in adult rams.Fil: Rojas García, Pedro P.. Universidad de Concepción; ChileFil: Recabarren, Mónica P.. Universidad de Concepción; ChileFil: Sir Petermann, Teresa. Universidad de Santiago de Chile; ChileFil: Rey, Rodolfo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Palma, Sergio. Universidad de Concepción; ChileFil: Carrasco, Albert. Universidad de Concepción; ChileFil: Pérez Marín, Carlos C.. Universidad de Córdoba; ArgentinaFil: Padmanabhan, Vasantha. University Of Michigan; Estados UnidosFil: Recabarren, Sergio E.. Universidad de Concepción; Chil

Prenatal exposure to androgens as a factor of fetal programming La exposición prenatal a andrógenos como factor de reprogramación fetal

Both epidemiological and clinical evidence suggest a relationship between the prenatal environment and the risk of developing diseases during adulthood. The first observations about this relationship showed that prenatal growth retardation or stress conditions during fetal life were associated to cardiovascular, metabolic and other diseases in later life. However, not only those conditions may have lasting effects after birth. Growing evidence suggests that prenatal exposure to steroids (either of fetal or maternal origin) could be another source of prenatal programming with detrimental consequences during adulthood. We have recently demonstrated that pregnant women with polycystic ovary syndrome exhibit elevated androgen levels compared to normal pregnant women, which could provide an androgen excess for both female or male fetuses. We have further tested this hypothesis in an animal model of prenatal androgenization, finding that females born from androgenized mothers have a low bir

Prenatal testosterone excess alters Sertoli and germ cell number and testicular FSH receptor expression in rams

Exposure to excess testosterone (T) during fetal life has a profound impact on the metabolic and reproductive functions in the female's postnatal life. However, less is known about the effects of excess testosterone in males. The aim of the present study was to evaluate the impact (consequences) of an excess of T during fetal development on mature male testis. The testicular evaluation was by histological analysis and by determination of mRNA expression of the FSH receptor (FSH-R), transforming growth factor-β type I receptor (TβR-I), and two members of the TGF-β superfamily, transforming growth factor-β3 (TGFβ3) and anti-Müllerian hormone (AMH) in males born to mothers receiving an excess of T during pregnancy. At 42 wk of age, postpubertal males born to mothers treated with 30 mg of T propionate twice weekly from day 30 to 90, followed by 40 mg of T propionate from day 90 to 120 of pregnancy (T males), showed higher concentrations of FSH in response to a GnRH analog, a higher number of Sertoli cells/seminiferous tubule cross-section, and a lower number of germ cells/tubules (P < 0.05) than control males (C males) born to mothers treated with the vehicle. The mRNA expression of FSH-R and of TβR-I was higher in T males compared with C males (P < 0.05). Moreover, in T males, AMH expression level correlated negatively with the expression level of TGFβ3. In C males, this latter correlation was not observed. These results suggest that prenatal exposure to an excess of T can negatively modify some histological and molecular characteristics of the mature testis.Fil: Rojas García, Pedro P.. Universidad de Concepción; ChileFil: Recabarren, Mónica. Universidad de Concepción; ChileFil: Sarabia, Luis. Universidad de Chile; ChileFil: Schön, Jennifer. Freie Universität; AlemaniaFil: Gabler, Christoph. Freie Universität; AlemaniaFil: Einspanier, Ralf. Freie Universität; AlemaniaFil: Maliqueo, Manuel. Universidad de Chile; ChileFil: Sir Petermann, Teresa. Universidad de Chile; ChileFil: Rey, Rodolfo Alberto. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Biología Celular e Histología; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Recabarren, Sergio E.. Universidad de Concepción; Chil

Prenatal testosterone treatment alters LH and testosterone responsiveness to GnRH agonist in male sheep

Although evidence is accumulating that prenatal testosterone (T) compromises reproductive function in the female, the effects of excess T in utero on the postnatal development of male reproductive function has not been studied. The aim of this study was to assess the influence of prenatal T excess on age-related changes in pituitary and gonadal responsiveness to GnRH in the male sheep. We used the GnRH agonist, leuprolide (10 μg/kg), as a pharmacologic challenge at 5, 10, 20 and 30 weeks of age. These time points correspond to early and late juvenile periods and the prepubertal and postpubertal periods of sexual development, respectively. LH and T were measured in blood samples collected before and after GnRH agonist administration. The area under the response curve (AUC) of LH increased progressively in both controls and prenatal T-treated males from 5 to 20 weeks of age (P&lt;0.01). The LH responses in prenatal T-treated males were lower at 20 and 30 weeks of age compared to controls (