Prenatal Programming of Reproductive Neuroendocrine Function: Fetal Androgen Exposure Produces Progressive Disruption of Reproductive Cycles in Sheep

Abstract

In the agonadal, androgenized ewe testosterone before birth produces a precocious pubertal rise in circulating LH and abolishes the LH surge mechanism. The present study tested two predictions from this model in the ovary-intact female: 1) prenatal androgen exposure produces early ovarian stimulation; and 2) despite early ovarian stimulation, progestogenic cycles would not occur because of the abolition or disruption of the LH surge. Pregnant ewes were injected with testosterone propionate twice per week from either d 30-90 (T60 group; 100 mg/injection) or d 60-90 (T30 group; 80 mg/injection) of gestation (term, 147 d). Control ewes received no injections. At birth, the androgenized and control lambs were divided into two groups: ovary-intact to determine the effects of prenatal androgen on the timing of puberty and subsequent ovarian function, and ovariectomized to assess the timing of the pubertal decrease in sensitivity to estrogen negative feedback and the subsequent increase in LH. Neonatally orchidectomized, estrogen-treated males were included for comparison of the timing of this pubertal rise in LH secretion. Neuroendocrine puberty (determined on the basis of LH increase) was advanced in the androgenized females to a similar age as in males. Repeated progesterone cycles of the same duration and number occurred in the ovary-intact ewes, and they began at the same time as for control females, thus negating both predictions. Differences appeared during the second breeding season, when reproductive cycles were either absent (T60) or disrupted (T30 group). Our findings reveal that exposure to androgens in utero causes a progressive loss of cyclic function in adulthood.

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.…”

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

“…In the absence of fetal imprinting, the pubertal activation of sex-specific mating behaviors never occurs [43,116]. Furthermore, not only is puberty important for activational effects of steroid hormones on neonatally imprinted circuits [12,153,16,116,119], but the brain may be sensitive to the organizational effects of steroid hormones during this developmental stage [119,129,39,144]. Matsumoto and Arai showed substantial neural development, as manifested by neurite outgrowth, in the hypothalamus of pubertal animals, and further, that this process was stimulated by exogenous hormone exposure [96,7].…”

Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: Implications for a common fertility disorder

“…This is postulated to be caused by androgen-induced reprogramming of neural development such that GnRH neurons are desensitized to steroid feedback (13,14). Prenatally androgenized (PNA) adult female sheep and primates exhibit elevated LH pulse frequency (13) and irregular reproductive cycles (15,16), evidence of disrupted regulation of the hypothalamic-pituitarygonadal axis. To test the hypothesis that altered fertility in PNA animals occurs by means of a central mechanism at the GnRH neuron, we created a PNA model by using transgenic mice in which GnRH neurons are identifiable by expression of GFP (17), allowing effects of PNA to be studied directly on GnRH neurons.…”