Developmental programming: prenatal steroid excess disrupts key members of intra-ovarian steroidogenic pathway

PADMANABHAN V; SALVETTI NR; MATILLER V; ORTEGA HH

ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2014 vol. 155 p. 3649 - 3660

0013-7227

Prenatal testosterone (T) excess disrupts ovarian cyclicity, increases circulating estradiol levels as well as follicular recruitment and persistence culminating in multifollicular ovarian morphology similar to women with PCOS. We tested whether prenatal T excess, by androgenic or estrogenic action, disrupts the steroid biosynthetic machinery in a cell, follicle stage, age and treatment-specific manner consistent with the ovarian disruptions and increased estradiol release. Impact of T / dihydrotestosterone (DHT) treatments from days 30-90 of gestation on STAR, HSD3B, CYP17A1 and CYP19A1 were examined on fetal day 90, 140, 10 months (postpubertal) and 21 months (adult, no DHT group) of age by immunohistochemistry. All 4 markers changed in a cell, follicle stage, and age-specific manner. Both treatments increased STAR expression in preantral follicles of postpubertal and adult females. Effects of prenatal T and DHT on HSD3B differed in a follicle and age-specifc manner. CYP17A1 was reduced in the theca interna of antral follicles by T, but not DHT in 10 and 21 month old females. CYP19A1 was reduced by both T and DHT at all ages barring an increase on fetal day140. Reduced granulosa cell CYP19A1 and thecal CYP17A1 in adults likely disrupt the intrafollicular androgen / estrogen balance contributing to follicular persistence. The reduced thecal CYP17A1 expression suggest the hyperandrogenic ovarian phenotype may originate from increased enzyme activity or alternatively via a diferent isoform of CYP17.  The reduced CYP19A1 in antral follicles of adults indicates that the increased circulating estradiol release likely arises from the increased number of persisting follicles.