Attenuin: What It Is, How It Works and What It Does

Abstract

The reproductive function in female mammals, unlike that of males, is cyclical in nature. Whilst testosterone exerts a wholly negative control, regulation of the ovarian cycle is effected through a complex series of positive and negative feedback mechanisms involving the ovary, the pituitary and the hypothalamus. Although the role of these feedback mechanisms has been known for many years, our knowledge of the detailed workings involved continues to expand. Reproductive-axis hormones have proved to be similar in all the mammalian species studied to date. The female cycle can generally be divided into the follicular, periovulatory (preovulatory and ovulatory) and luteal phases. The pituitary hormones – the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) – remain at basal levels throughout most of the reproductive cycle, due to negative regulation by ovarian hormones (mainly estradiol and progesterone; see fig. 1 for additional details). The physiological capacity of steroids to control gonadotropin secretion is evident in a marked increase in plasma LH and FSH levels after the menopause or following ovariectomy. During the preovulatory phase, the estradiol negative feedback switches to positive. Major positive actions by estrogens include: a 20- to 50-fold increase in pituitary sensitivity to gonadotropin-releasing hormone (GnRH) (Speight et al., 1981); an increase in pituitary GnRH receptors, in concert with GnRH (Clayton et al., 1980); an increase in progesterone receptors (PR) in both pituitary and hypothalamus (Conneely et al., 1989); stimulation of GnRH synthesis and release, resulting in preovulatory GnRH secretion (Sarkar et al., 1976); and a drop in GnRH metabolism by pituitary cells (Danforth et al., 1990). These positive actions of estradiol lead to the appearance of GnRH self-priming. GnRH self-priming is an event with a twofold effect: it prompts an exponential increase in pituitary responsiveness to GnRH, and it coordinates increased responsiveness with enhanced GnRH release, ensuring that both occur at the same time and thus guaranteeing preovulatory LH secretion (Fink, 1995). In rats, this self-priming effect has been found to be more effective when GnRH pulses occur at hourly intervals (Fink, 1995), a frequency also reported to be optimal in monkeys with hypothalamic lesions (Knobil, 1980) and in women with idiopathic hypogonadotropic hypogonadism (Crowley et al., 1985). How does GnRH come to possess this unique property? Probably because the preovulatory LH surge is indispensable for species reproduction, and the fact that a very small amount of GnRH induces a disproportionate release of LH makes the process both economic and efficient