Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?

Abstract

The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.

Maternal testosterone levels during pregnancy are associated with offspring size at birth

“…This supports the concept that fetal growth retardation, an early marker of adult diseases, can be initiated through prenatal excess exposure to sex steroids. Studies in nonhuman primates and other animals have shown that prenatal exposure to testosterone led to female hyperandrogenism (19), infertility (22,23), behavior modifications (24) abdominal adiposity (25) and insulin resistance (17) during adulthood in the offspring. In all these studies, testosterone was administered to otherwise normal pregnant female animals and hence the increase in circulating maternal testosterone was of exogenous origin and not caused by any maternal disease.…”

“…Accordingly, maternal testosterone may only be a biomarker for fetal growth. However, assisted by the available animal data on the effect of the exertion of exogenously administered testosterone on otherwise normal pregnancies (19), we hypothesize that the association between maternal testosterone levels and reduced birth size is a direct effect of increased maternal androgen levels. Probably, it is mediated by one or more of the above possible mechanisms and is not just a chance-coincidental phenomenon.…”

“…In ewes, prenatal testosterone exposure caused intrauterine growth retardation (18). A recent review of animal data indicates that excess fetal androgen exposure can induce metabolic and endocrine deficits in females, possibly by an adverse, permanent programming of the metabolic pathways (19).…”

The influence of antenatal exposure to phthalates on subsequent female reproductive development in adolescence: a pilot study

“…In females, antenatal exposure of sheep and monkeys to androgens has been shown to cause a polycystic ovarian syndrome (PCOS)-like phenotype, although this as a potential cause of PCOS and is highly speculative (Abbott et al 2005). Furthermore, there is evidence for a direct effect of some pesticides on ovarian function.…”

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.…”