Orexins/hypocretins and sex

The neuropeptides orexin A and orexin B, also referred to as hypocretin 1 and hypocretin 2, are selectively produced by specific neurons of the lateral hypothalamic area. Orexin neurons project to various brain areas and are involved in the regulation of a variety of physiological functions including sleep and wakefulness, arousal, energy homeostasis, reward related behavior, and also neuroendocrine functions.

Shortly after the discovery of orexins and their G-protein coupled receptor subtypes OX1 and OX2 by two independent groups in 1998 [1], [2], Pu et al. revealed that orexins can stimulate or inhibit pituitary luteinizing hormone (LH) secretion dependent on the presence of ovarian steroid hormones, as already known at this time for other neuropeptides involved in regulation of food intake and energy homeostasis [3]. In addition, a sexually dimorphic expression of orexins/prepro-orexin in the hypothalamus and in gonads as well as of orexin receptors in the hypothalamus, pituitary, and adrenal glands was found. Orexin A levels were shown to be higher in the lateral and posterior hypothalamus of female rats compared to male rats [4]. Accordingly, hypothalamic prepro-orexin mRNA levels were higher in female rats compared to males [5]. Moreover, prepro-orexin expression was also detected in testes but not in ovaries and the expression of OX1 receptors in the pituitary as well as OX2 receptors in adrenal glands was found to be higher in male rats than in female rats while in the hypothalamus OX1 receptor expression was higher in female rats [6].

Various studies have confirmed and extended the initial observation by Pu et al. on the regulation of the hypothalamo-pituitary-gonadal axis by orexins showing that gonadotropin-releasing hormone (GnRH) synthesizing neurons are innervated by orexin containing axonal terminals, express OX1 receptors, and release GnRH after direct stimulation with orexins [7], [8], [9], [10]. Thus, it can be assumed that orexins regulate plasma LH mainly via regulating the release of GnRH from hypothalamus although a direct pituitary effect of orexins on LH secretion was also observed in dispersed anterior pituitaries from proestrous female, but not male rats [10], suggesting a role of gonadal steroids and, in addition, also a direct effect of orexins at the pituitary. Indeed, orexin receptors, mainly OX1 receptors, are expressed in the pituitary and could mediate this direct effect on the LH release. Furthermore, estrogens influence the effect of orexins on LH release. In ovarectomized rats, plasma LH concentrations were reduced by intracerebroventricularly injected orexins, while in estradiol-treated rats, orexin increased LH concentrations [3], [11], [12]. Thus, apparently the orexin system has not only an influence on the activity of the hypothalamic-pituitary-gonadal (HPG) axis that regulates reproductive functions including gonadal steroid hormone production but, in turn, this effect is controlled by estrogens and the expression of components of the orexin system is also regulated in a sex-dependent manner. Such a dimorphic expression could be caused by the action of sex hormones. Indeed, in adult male rats gonadectomy led to an increased expression of OX1 receptors in the pituitary and testosterone replacement reversed this effect [13]. A similar, even more pronounced effect was observed in ovariectomized rat and by estradiol replacement [13]. On the other hand, no effect of gonadectomy and steroid replacement could be found on the expression of components of the orexin system in the hypothalamus of male and female rats [13] although hypothalamic expression of prepro-orexin and OX1 receptor is higher in female rats compared to males [5]. Thus, the expression of prepro-orexin and OX1 receptors in the hypothalamus appears to be insensitive to long-term hormonal changes in adults while the gender differences in the expression of orexin receptors in the pituitary gland are due to the effect of gonadal steroids. On the other hand, rapid changes of prepro-orexin as well as orexin receptor expression were observed in the hypothalamus and pituitary of adult cycling female rats with an increased expression at the evening of proestrus [14].

In this issue of Peptides, Cataldi et al. confirmed the sexually dimorphic expression of the orexin system in the hypothalamus and pituitary and, more importantly, demonstrate that the increased expression of prepro-orexin and orexin receptors associated with the LH surge in proestrous rats was abolished in neonatally androgenized female rats [15]. In demasculinized adult male rats no regulation of prepro-orexin and orexin receptors was observed when treated with an estradiol/progesterone (E2/P4) regimen similar to proestrous females. In contrast, in male rats which were perinatally demasculinized, E2/P4 treatment increased the expression of prepro-orexin and orexin receptors in the hypothalamus and pituitary. In conclusion, perinatal testosterone not only imprints the sex-specific control of the GnRH/LH surge in rats but also the synchronized expression of prepro-orexin and orexin receptors. The exact molecular mechanisms, e.g. by epigenetic modifications, of this regulation remain unclear.

The importance of a sexually dimorphic expression and regulation of the orexin system cannot be underestimated. Orexins not only regulate the HPG axis but also motivational sexual behavior in males [16], [17], the sexually dimorphic development of obesity [18], [19] and gender specific responses to stress and related disorders such as depression as recent data suggest [20], [21]. Thus, the elucidation of the mechanisms causing sex specific functions of orexins may also help to better understand the pathophysiology of a variety of orexin-related disorders.