Testicular steroids during midgestation sexually differentiate the steroid feedback mechanisms controlling GnRH secretion in sheep. To date, the actions of the estrogenic metabolites in programming neuroendocrine function have been difficult to study because exogenous estrogens disrupt maternal uterine function. We developed an approach to study the prenatal actions of estrogens by coadministering testosterone (T) and the androgen receptor antagonist flutamide, and tested the hypothesis that prenatal androgens program estradiol inhibitory feedback control of GnRH secretion to defeminize (advance) the timing of the pubertal increase in LH. Pregnant sheep were either untreated or treated with T, dihydrotestosterone (DHT) (a nonaromatizable androgen), or T plus flutamide from d 30-90 of gestation. To study the postnatal response to steroid negative feedback, lambs were gonadectomized and estradiol-replaced, and concentrations of LH were monitored in twice-weekly blood samples. Although T and DHT produced penile and scrotal development in females, the external genitalia of T plus flutamide offspring remained phenotypically female, regardless of genetic sex. Untreated females and females and males treated with T plus flutamide exhibited a pubertal increase in circulating LH at 26.4+/-0.5, 26.0+/-0.7, and 22.4+/-1.6 wk of age, respectively. In females exposed to prenatal androgens, the LH increase was advanced (T: 12.0+/-2.6 wk; DHT: 15.0+/-2.6 wk). These results demonstrate the usefulness of combining T and antiandrogen treatments as an approach to increasing prenatal exposure to estradiol. Importantly, the findings support our hypothesis that prenatal androgens program sensitivity to the negative feedback actions of estradiol and the timing of neuroendocrine puberty.
The dimensions and volume of the anterior ventral cochlear nucleus (AVCN), the density and number of AVCN neurons, and the size of neuronal somata nuclei (in Nissl-stained tissue) were determined in two mouse models of age-related hearing loss: the C57BL/6J strain, which undergoes progressive chronic sensorineural hearing loss with onset during young adulthood, and the CBA/J, which demonstrates only moderate hearing loss with onset late in life. Frontal and horizontal AVCN sections, as well as cochleas, were analyzed in 4 C57 age-groups (1, 7, 12, 19+ months) and in 3 CBA groups (1, 10, 22 months). Within each strain no significant changes in AVCN dimensions or volume occur with aging. In C57 mice, packing density and cell number decrease between 1 and 7 months, but remain stable thereafter, despite chronic severe hearing impairment. CBA mice show a reduction in AVCN cell number and packing density only during the second year of life. In aging C57 mice, the size of spherical and perhaps globular cells increases, whereas the size of multipolar cells tends to decrease slightly. In CBA mice, all three AVCN cell types tend to decrease in size with aging. The early cell loss and cell size increases in C57 mice are most consistent in the dorsal (high frequency) region of the AVCN. Likewise, loss of cochlear spiral ganglion cells is most pronounced in the base of the cochlea, which provides input to this region. The data indicate that aging is associated with rather different central effects, depending on AVCN cell type, cochleotopic organization, genotype, and/or the type of peripheral hearing loss involved. The C57 and CBA AVCNs also differ in several aspects irrespective of age. The volume of AVCN and number of AVCN neurons are significantly greater in C57 mice.
In female sheep, estradiol (E2) stimulates the preovulatory GnRH/LH surge and receptive behavior, whereas progesterone blocks these effects. Prenatal exposure to testosterone disrupts both the positive feedback action of E2 and sexual behavior although the mechanisms remain unknown. The current study tested the hypothesis that both prenatal and postnatal steroids are required to organize the surge and sex differences in reproductive behavior. Our approach was to characterize the LH surge and mating behavior in prenatally untreated (Control) and testosterone-treated (T) female sheep subsequently exposed to one of three postnatal steroid manipulations: endogenous E2, excess E2 from a chronic implant, or no E2 due to neonatal ovariectomy (OVX). All females were then perfused at the time of the expected surge and brains processed for estrogen receptor and Fos immunoreactivity. None of the T females exposed postnatally to E2 exhibited an E2-induced LH surge, but a surge was produced in five of six T/OVX and all Control females. No surges were produced when progesterone was administered concomitantly with E2. All Control females were mounted by males, but significantly fewer T females were mounted by a male, including the T/OVX females that exhibited LH surges. The percentage of estrogen receptor neurons containing Fos was significantly influenced in a brain region-, developmental stage-, and steroid-specific fashion by testosterone and E2 treatments. These findings support the hypothesis that the feedback controls of the GnRH surge are sensitive to programming by prenatal and postnatal steroids in a precocial species.
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