Response to the gonadotropin releasing hormone agonist leuprolide in immature female sheep androgenized in utero

Abstract

Similar to women with Polycystic Ovary Syndrome (PCOS), female sheep treated prenatally with testosterone (T-females) are hypergonadotropic, exhibit neuroendocrine defects, multifollicular ovarian morphology, hyperinsulinemia and cycle defects. Hypergonadotropism and multifollicular morphology may in part be due to developmentally regulated increase in pituitary responsiveness to GnRH and may culminate in increased ovarian estradiol production. In this study, we utilized a GnRH agonist, leuprolide, to determine the developmental impact of prenatal testosterone exposure on pituitary-gonadal function and to establish if prenatal exposure produces changes in the reproductive axis similar to those described for women with PCOS. Eight control and eight T-females were injected intravenously with 0.1 µg of leuprolide acetate per kilogram of body weight at 5, 10 and 20 weeks of age. Blood samples were collected by means of an indwelling jugular vein catheter at 0, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 hours after leuprolide. Area under the curve (AUC) of LH response to leuprolide increased progressively between the three ages studied (P<0.05). AUC of LH in Tfemales was higher than in control females of the same age at 5 and 10 weeks of age (P<0.05), but similar at 20 weeks of age. AUC of estradiol response was lower at 10 but higher at 20 weeks of age in T-females compared to controls of the same age (P<0.05). Our findings suggest that prenatal T treatment alters the pituitary and ovarian responsiveness in a manner comparable to that observed in women with PCOS.

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

“…Prenatally T-treated males of this study had similar birth weights to the control males. This differs from findings of reduced birth weight in prenatally T-treated females born in the same flock around the same time (Recabarren et al 2005b), which also exhibit compensatory growth during the first few months after birth (Manikkam et al 2004, Recabarren et al 2005b. Similarly, infants born to mothers with polycystic ovary syndrome, another source of fetal T excess (Sir-Petermann et al 2002) had lower birth weight compared to those born to mothers without PCOS (Sir-Petermann et al 2005).…”

La exposición prenatal a andrógenos como factor de reprogramación fetal

“…Adicionalmente, estudios en modelos animales (monas y ovejas) establecen que las hembras androgenizadas por una exposición prenatal a andrógenos durante la vida intrauterina, como consecuencia de la administración exógena de testosterona a las madres, presentan cambios neuroendocrinos, gonadales y metabólicos, que en su conjunto asemejan a lo descrito en el síndrome de ovario poliquístico 26,[38][39][40] , lo que sugiere que este síndrome pudiera tener, en parte, un origen prenatal, como consecuencia del ambiente esteroidal anormal. Previamente, desde un punto de vista clínico, los primeros indicios que vincularon un posible papel de una exposición excesiva de andrógenos en la vida fetal con el desarrollo ulterior del SOP en la vida postnatal, derivaron de observaciones en mujeres portadoras de un déficit clásico de la 21-hidroxilasa, que fueron adecuadamente tratadas y que por ende presentaron una normalización de sus andróge-nos.…”

Epigenética del síndrome de ovario poliquístico

“…En los últimos años se ha propuesto que la programación fetal podría estar implicada en la patogenia del SOP. En este contexto la exposición prenatal a andrógenos (EPA) podría ser uno de los principales candidatos como factor reprogramador [13][14][15][16][17][18][19][20] . Independiente de la fuente del exceso de andrógenos prenatal, estas observaciones sugieren que el SOP podría ser programado in utero por la influencia del aumento de andrógenos e insulina, posiblemente mediante la alteración de la expresión génica durante la vida pre y post-natal.…”