Disordered follicle development in ovaries of prenatally androgenized ewes

Forsdike, R.; Hardy, Kate; Bull, Lauren; Stark, Jaroslav; Webber, Lisa; Stubbs, S; Robinson, Jane E.; Franks, Stephen

doi:10.1677/joe.1.07097

Cited by 81 publications

(51 citation statements)

References 44 publications

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“…Animal models have shown that prenatal androgen treatment induce accelerations of LH pulsatile release in primates (Abbott et al 2009), sheep (Forsdike et al 2007, Steckler et al 2009), and rodents (Foecking et al 2005), in accordance with the present results. Our observations confirm the concept that an early disturbance due to intrauterine androgen excess reprograms nervous tissue development of the fetus and irreversibly alters neuroendocrine function in female offspring.…”

Section: Discussionsupporting

confidence: 92%

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats

Yan¹,

Yuan²,

Zhao³

et al. 2014

Journal of Endocrinology

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In adolescent girls with polycystic ovary syndrome (PCOS), neuroendocrine derangements manifest after the onset of puberty, characterized by rapid LH pulse frequency. The early mechanism underlying the pubertal regulation of the GNRH/LH pulsatile release in adolescents with PCOS remains uncertain. To determine the effects of prenatal androgen exposure on the activation of GNRH neurons and generation of LH pulse at puberty, we administrated 5a-dihydrotestosterone to pregnant rats and observed serum LH levels and expression of hypothalamic genes in female offspring from postnatal 4 to 8 weeks. The 6-week-old prenatally androgenized (PNA) female rats exhibited an increase in LH pulse frequency. The hypothalamic expression of neurokinin B (Nkb (Tac2)) and Lepr mRNA levels in PNA rats increased remarkably before puberty and remained high during puberty, whereas elevated Kiss1 mRNA levels were detected only after the onset of puberty. Exogenous kisspeptin, NK3R agonist, and leptin triggered tonic stimulation of GNRH neurons and increased LH secretion in 6-week-old PNA rats. Leptin upregulated Kiss1 mRNA levels in the hypothalamus of pubertal PNA rats; however, pretreatment with a kisspeptin antagonist failed to suppress the elevated serum LH stimulated by leptin, indicating that the stimulatory effects of leptin may be conveyed indirectly to GNRH neurons via other neural components within the GNRH neuronal network, rather than through the kisspeptin-GPR54 pathway. These findings validate the hypotheses that NKB and leptin play an essential role in the activation of GNRH neurons and initiation of increased LH pulse frequency in PNA female rats at puberty and that kisspeptin may coordinate their stimulatory effects on LH release.

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Section: Discussionsupporting

confidence: 92%

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats

Yan¹,

Yuan²,

Zhao³

et al. 2014

Journal of Endocrinology

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“…For example, in vivo treatment with testosterone increases androgen receptor mRNA in granulosal and thecal cells in small antral follicles of primates, and the expression of androgen receptor mRNA is positively correlated with FSH receptor (FSHR) mRNA expression (Weil et al 1999). In addition, dihydrotestosterone (DHT) increases FSHR expression in preovulatory follicles in gilts (Cardenas et al 2002), and administration of testosterone or DHT to female rhesus monkeys and pregnant ewes (prenatally treated fetuses) stimulates primordial follicle initiation and increases growing follicle numbers and overall follicle survival , Steckler et al 2005, Forsdike et al 2007. During oocyte maturation and ovulation, androgens increase abundance of FSHR mRNA and number of preovulatory follicles and corpora lutea (Walters et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Evidence that high variation in antral follicle count during follicular waves is linked to alterations in ovarian androgen production in cattle

Mossa¹,

Jimenez-Krassel²,

Folger³

et al. 2010

Reproduction

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Androgens have an important role in ovarian follicular growth and function, but circulating androgen concentrations are also associated with ovarian dysfunction, cardiovascular disease, and metabolic disorders in women. The extent and causes of the variation in androgen production in individuals, however, are unknown. Because thecal cells of follicles synthesize androstenedione and testosterone, variation in production of these androgens is hypothesized to be directly related to the inherently high variation in number of healthy growing follicles in ovaries of individuals. To test this hypothesis, we determined whether thecal CYP17A1 mRNA (codes for a cytochrome P450 enzyme involved in androgen synthesis), LH-induced thecal androstenedione production, androstenedione concentrations in follicular fluid, and circulating testosterone concentrations were lower in cattle with relatively low versus high number of follicles growing during follicular waves and whether ovariectomy reduced serum testosterone concentrations. Results demonstrated that cattle with a low follicle number had lower (P!0.05) abundance of CYP17A1 mRNA in thecal cells, reduced (P!0.01) capacity of thecal cells to produce androstenedione in response to LH, lower (P!0.01) androstenedione concentrations in ovulatory follicles, and lower (P!0.02) circulating testosterone concentrations during estrous cycles compared with animals with high follicle number. Also, serum testosterone in cattle with low or high follicle number was reduced by 63 and 70%, respectively, following ovariectomy. In conclusion, circulating androgen concentrations are lower in cattle with low versus high number of follicles growing during follicular waves, possibly because of a reduced responsiveness of thecal cells to LH.

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“…Srinivasan [27]. Prenatal exposure to androgen excess can lead to, as adults, disrupted ovarian cycles and abnormalities of early follicle development that mimic those observed in women with polycystic ovary syndrome [28][29][30][31]. It was reported that environmental factors can affect spermatogenesis at the level of germ and Stertoli cells and the composition of seminal fluid [32,33].…”

Section: Discussionmentioning

confidence: 99%

The long-term effects of superovulation on fertility and sexual behavior of male offspring in mice

Wei

Zhang

et al. 2014

J Assist Reprod Genet

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Purpose To evaluate the long-term effects of superovulation on fertility and sexual behavior of male offspring in mice. Method The mice were superovaluted, and the fertility of male offspring (F1 generation and F2 generation) were evaluated in terms of the percentage of plugs and pregnancies, serum testosterone concentrations, and sperm motility. Furthermore, the sexual behavior of male offspring and sex ratio (F1 generation and F2 generation) were measured. Results There were no significant differences in the percentage of plug and pregnancies, serum testosterone concentrations, sperm motilities and sex ratio between the offspring in naturally conceived group and superovulation groups (both F1 generation and F2 generation). The sperm hyperactivity at 90 min after incubation of F1 generation in naturally conceived group were higher than that of F1 generation in superovulation group, but the differences did not reach statistical significance. The offspring produced by superovaluted oocytes (both F1 generation and F2 generation) did not exhibit significant alterations in sexual behavior. Conclusions No significant alterations were found in fertility and sexual behavior of male offspring in mice produced by superovaluted oocytes compared with those of naturally conceived offspring.

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Disordered follicle development in ovaries of prenatally androgenized ewes

Cited by 81 publications

References 44 publications

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats

Evidence that high variation in antral follicle count during follicular waves is linked to alterations in ovarian androgen production in cattle

The long-term effects of superovulation on fertility and sexual behavior of male offspring in mice

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