Exposure to testosterone (T) during d 30-90 of fetal life results in low-birth-weight offspring, hypergonadotropism, multifollicular ovaries, and early cessation of cyclicity. The multifollicular phenotype may result from failure of follicles to regress and consequent follicular persistence or, alternatively, increased follicular recruitment. We tested the hypothesis that prenatal exposure to excess T causes intrauterine growth retardation and increases ovarian follicular recruitment. Time-mated pregnant ewes were treated with 100 mg T propionate in cottonseed oil or vehicle twice weekly from d 30-90 of gestation. Ewes were euthanized near term, from d 139-141 of gestation (term is 147 d). After determining fetal measures and organ weights, ovaries were removed from fetuses of control and T-treated dams, and follicular distribution in each ovary was determined by morphometric quantification. Total number and percentage distribution of the various classes of follicles (primordial, primary, preantral, and antral follicles) were compared between treatment groups. Prenatally T-treated female fetuses were smaller in size, had an increased head circumference to fetal weight ratio (P < 0.01), increased adrenal to fetal weight ratio (P < 0.05), decreased number of follicles (P < 0.05), a decrease in percentage of primordial follicles (P < 0.001), and a corresponding increase in the remaining classes of follicles (P < 0.05). Ovarian findings support decreased ovarian reserve and enhanced follicular recruitment, potential contributors of early reproductive failure. The extent to which metabolic changes associated with intrauterine growth retardation contribute toward altered trajectory of ovarian folliculogenesis remains to be determined.
Prenatal testosterone excess programs an array of adult reproductive disorders including luteinizing hormone excess, functional hyperandrogenism, neuroendocrine defects, polycystic ovarian morphology, and corpus luteum dysfunction, culminating in early reproductive failure. Polycystic ovarian morphology originates from enhanced follicular recruitment and follicular persistence. We tested to determine whether prenatal testosterone treatment, by its androgenic actions, enhances follicular recruitment, causes early depletion of follicular reserve, and disrupts the ovarian architecture. Pregnant sheep were given twice-weekly injections of testosterone or dihydrotestosterone (DHT), a nonaromatizable androgen, from Days 30 to 90 of gestation. Ovaries were obtained from Day-90 and Day-140 fetuses, and from 10-mo-old females during a synchronized follicular phase (n = 5-9 per treatment). Stereological techniques were used to quantify changes in ovarian follicle/germ cell populations. Results revealed no differences in numbers of oocytes and follicles between the three groups on Fetal Day 90. Greater numbers of early growing follicles were found in prenatal testosterone- and DHT-treated fetuses on Day 140. Increased numbers of growing follicles and reduced numbers of primordial follicles were found in 10-mo-old, prenatal testosterone-treated females, but not in those treated with DHT. Antral follicles of prenatal testosterone-treated females, but not those treated with DHT, manifested several abnormalities, which included the appearance of hemorrhagic and luteinized follicles and abnormal early antrum formation. Both treatment groups showed morphological differences in the rete ovarii. These findings suggest that increased follicular recruitment and morphologic changes in the rete ovarii of prenatal testosterone-treated females are facilitated by androgenic programming, but that postpubertal follicular growth, antral follicular disruptions, and follicular depletion largely occur through estrogenic programming.
Prenatal testosterone (T) excess during midgestation leads to estrous cycle defects and polycystic ovaries in sheep. We hypothesized that follicular persistence causes polycystic ovaries and that cyclic progesterone (P) treatment would overcome follicular persistence and restore cyclicity. Twice-weekly blood samples for P measurements were taken from control (C; n = 16) and prenatally T-treated (T60; n = 14; 100 mg T, im, twice weekly from d 30-90 of gestation) Suffolk sheep starting before the onset of puberty and continuing through the second breeding season. A subset of C and T60 sheep were treated cyclically with a modified controlled internal drug-releasing device for 13-14 d every 17 d during the first anestrus (CP, 7; TP, 6). Transrectal ovarian ultrasonography was performed for 8 d in the first and 21 d in the second breeding season. Prenatal T excess reduced the number, but increased the duration of progestogenic cycles, reduced the proportion of ewes with normal cycles, increased the proportion of ewes with subluteal cycles, decreased the proportion of ewes with ovulatory cycles, induced the occurrence of persistent follicles, and reduced the number of corpora lutea in those that cycled. Cyclic P treatment in anestrus, which produced one third the P concentration seen during luteal phase of cycle, did not reduce the number of persistent follicles, but increased the number of progestogenic cycles while reducing their duration. These findings suggested that follicular persistence might contribute to the polycystic ovarian morphology. Cyclic P treatment was able to only partially restore follicular dynamics, but this may be related to the low replacement concentrations of P achieved.
Prenatal testosterone excess in sheep leads to reproductive and metabolic disruptions that mimic those seen in women with polycystic ovary syndrome. Comparison of prenatal testosterone-treated sheep with prenatal dihydrotestosterone-treated sheep suggests facilitation of defects by androgenic as well as androgen-independent effects of testosterone. We hypothesized that the disruptive impact of prenatal testosterone on adult pathology may partially depend on its conversion to estrogen and consequent changes in maternal and fetal endocrine environments. Pregnant Suffolk sheep were administered either cottonseed oil (control) or testosterone propionate in cottonseed oil (100 mg, i.m. twice weekly), from Day 30 to Day 90 of gestation (term is ~147 d). Maternal (uterine) and fetal (umbilical) arterial samples were collected at Days 64-66, 87-90, and 139-140 (range; referred to as D65, D90, and D140, respectively) of gestation. Concentrations of gonadal and metabolic hormones, as well as differentiation factors, were measured using liquid chromatography/mass spectrometer, radioimmunoassay, or ELISA. Findings indicate that testosterone treatment produced maternal and fetal testosterone levels comparable to adult males and D65 control male fetuses, respectively. Testosterone treatment increased fetal estradiol and estrone levels during the treatment period in both sexes, supportive of placental aromatization of testosterone. These steroidal changes were followed by a reduction in maternal estradiol levels at term, a reduction in activin A availability, and induction of intrauterine growth restriction in D140 female fetuses. Overall, our findings provide the first direct evidence in support of the potential for both androgenic as well as estrogenic contribution in the development of adult reproductive and metabolic pathology in prenatal testosterone-treated sheep.
Testosterone (T) treatment during early-midgestation (30-90 d; term is 147 d) leads to reproductive cycle defects. Daily ultrasonography in prenatal T-treated female sheep during the first two breeding seasons revealed an increase in the number of large follicles and follicular persistence. The objective of this study was to determine whether follicular persistence in prenatal T-treated females was programmed by the androgenic actions of T. Pregnant Suffolk ewes were injected with 100 mg (im; twice weekly) of T propionate or dihydrotestosterone (DHT, a nonaromatizable androgen) in cottonseed oil from d 30 to d 90 of gestation. Prior to daily transrectal ovarian ultrasonography, estrus was synchronized with two injections of 20 mg of prostaglandin F2alpha (PGF2alpha) given 11 d apart in two consecutive years. In yr 1 ultrasonography began 14 d after PGF2alpha, during the presumptive luteal phase, and continued until subsequent ovulation and corpora lutea were detected (10-13 d). In yr 2, ultrasonography began 2 d before the last PGF2alpha injection and concluded 25 d after the last PGF2alpha injection. Daily changes in appearance and disappearance of ovarian follicles and follicular sizes were assessed. Prenatal DHT, but not prenatal T, treatment increased the total number of follicles by increasing the number of small follicles. Prenatal T, but not DHT, treatment increased (P<0.05) the number of large follicles with the majority of prenatal T-treated females manifesting follicular persistence. The data indicate that occurrence of large-sized follicles and follicular persistence in prenatal T-treated females are not programmed by androgenic actions but likely are programmed by estrogenic actions stemming from aromatization of T to estradiol.
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