Effect of androgen on Kiss1 expression and luteinizing hormone release in female rats

Abstract

Hyperandrogenic women have various grades of ovulatory dysfunction, which lead to infertility. The purpose of this study was to determine whether chronic exposure to androgen affects the expression of kisspeptin (ovulation and follicle development regulator) or release of luteinizing hormone (LH) in female rats. Weaned females were subcutaneously implanted with 90-day continuous-release pellets of 5α-dihydrotestosterone (DHT) and studied after 10 weeks of age. Number of -expressing cells in both the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) was significantly decreased in ovary-intact DHT rats. Further, an estradiol-induced LH surge was not detected in DHT rats, even though significant differences were not observed between DHT and non-DHT rats with regard to number of AVPV-expressing cells or gonadotrophin-releasing hormone (GnRH)-immunoreactive (ir) cells in the presence of high estradiol. -expressing and neurokinin B-ir cells were significantly decreased in the ARC of ovariectomized (OVX) DHT rats compared with OVX non-DHT rats; pulsatile LH secretion was also suppressed in these animals. Central injection of kisspeptin-10 or intravenous injection of a GnRH agonist did not affect the LH release in DHT rats. Notably, ARC-expressing cells expressed androgen receptors (ARs) in female rats, whereas only a few -expressing cells expressed ARs in the AVPV. Collectively, our results suggest excessive androgen suppresses LH surge and pulsatile LH secretion by inhibiting kisspeptin expression in the ARC and disruption at the pituitary level, whereas AVPV kisspeptin neurons appear to be directly unaffected by androgen. Hence, hyperandrogenemia may adversely affect ARC kisspeptin neurons, resulting in anovulation and menstrual irregularities.

Gonadotrope androgen receptor mediates pituitary responsiveness to hormones and androgen-induced subfertility

“…When we used 10 nM DHT ex vivo, levels used by Foecking et al (41,42), we also observed reduced basal LH secretion in control mice. Further, testosterone has been shown to suppress LH and FSH secretion independently of peripheral aromatization in both men (43)(44)(45) and women (9,43). Although LH is often elevated in women with PCOS and in nonrodent animal models of PCOS, this could be due to the timing of androgen exposure, adult vs. gestational androgen exposure, and not the species differences.…”

Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition

“…In this highly coordinated system, both E 2 and T act as feedback signals. GnRH neurons lack estrogen receptor α receptors, in contrast to kisspeptin neurons that mediate such feedback [22]. Feedback on LH secretion has been studied in men with central hypogonadism lacking GnRH signaling [23, 24].…”

The Correlation between Hormonal Disturbance in PCOS Women and Serum Level of Kisspeptin

“…Similarly, Kondo et al [28] who studied ARC kisspeptin immune reactivity by using antiprogestin R4486 found that besides the increase in the LH level, there was also an increase in the number of kisspeptin-positive cells in the hypothalamus. On the contrary, Marcondes et al [29,30] did not agree with this. ey suggested that low kisspeptin expression in testosterone-treated rats might contribute to anovulation and decrease in LH secretion.…”

“…Peripheral administration of kisspeptin in adult mice caused a dramatic increase in free testosterone level [6]. On the contrary, Iwata et al [30] found that hyperandrogenism in adult rats caused a decrease in the number of KISS1expressing cells in both AVPV and ARC nucleus. Additionally, they argued that the ARC nucleus (containing estrogen receptor) also has an androgen receptor which can be affected by excess androgen and so cause negative feedback to kisspeptin.…”

“…Many pieces of evidence in humans and animals found that the hyperandrogenism leads to an increase of LH/GnRH secretion [32][33][34][35]. In Iwata et al study [30], dihydrotestosterone was used, which may act through the estrogen negative pathway, not through the androgen pathway.…”