Variable: Cultura tributaria.

The hypothalamus-pituitary-ovarian (HPO) axis is comprised by the anatomic and functional relationships existing among the hypothalamus, pituitary gland, and ovaries, thus allowing these endocrine glands to act as a single entity. The hormones involved in the control of this axis include gonadotropin-releasing hormone (GnRH, produced by the hypothalamus), luteinizing hormone and follicle-stimulating hormone (LH and FSH, respectively; produced by the anterior pituitary), and estradiol, inhibin and progesterone (synthetized in the ovaries). However, numerous other factors and hormones have been linked to the control of the HPO axis in mammals. Furthermore, the neuroendocrine nature of the HPO axis integrates external factors such as stress, nutrition, and photoperiod, in the control of the reproductive physiology [41].

The hypothalamus is located in the ventral brain and comprises groups of cell bodies known as hypothalamic nuclei (namely, the paraventricular nucleus, the surge center and the tonic or pulsatile center) [41, 42]. The neurons located in the surge and tonic centers secrete GnRH, while the neurons of the paraventricular nucleus synthetize oxytocin. Anatomic arrangements are of special importance for the communication between the hypothalamus and pituitary gland. GnRH-producing neurons release their secretion through long axons located in vicinity to the pituitary stalk [43]. Within the pituitary stalk there is highly complex capillary network, the hypothalamo-hypophyseal portal system, which allows GnRH to reach the anterior portion of the pituitary, the adenohypophysis. It is believed that the main function of this capillary system is to

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prevent the very small amount of GnRH produced by the hypothalamus from getting diluted in the general circulation [42]. Once GnRH binds to its receptors on the gonadotroph cells, LH and FSH are produced and secreted into the blood stream in order to reach their target organ, the ovaries [43].

The gonadotropins (FSH and LH) play an important role in communicating with the ovaries. Gonadotropins activate the ovaries to produce different steroid hormones such as estrogen, androgens and progesterone which are linked to the regulation the estrous cycle. Positive and negative feedback loops are involved in the communication between the ovaries and the hypothalamus and pituitary [10, 44-46]. Estrogen receptors (ER) are present in the hypothalamus, pituitary and in the ovaries of many species, including cattle [47-50]. Hence, alteration in estradiol concentration could have direct and independent effects on all the endocrine glands that comprise the HOP axis. Details of the interactions between gonadotropins and ovarian sex steroids in cattle will be discussed in later sections of this literature review.

Non-steroidal ovarian products have also been related to the control of gonadotropin secretions [51, 52]. Inhibin is a protein produced by the granulosa cell of growing follicles under the influence of FSH. It comprises α and β sub-units and it is known to suppress FSH secretion by acting at hypothalamic and pituitary levels [43, 53-55]. The combination of two β sub-units results in a related protein, known as activin, which counteracts the effect of inhibin by stimulating FSH release [43]. Other factors present in the follicular fluid include follistatin, oxytocin, insulin-like growth factor (IGF), epidermal growth factor (EGF) and plasminogen activator (reviewed in [56]).

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Kisspeptins (Kps) are a family of peptide hormones which bind to protein G-coupled receptor 54 (GPR54) and integrates nutritional and hormonal information which is critical to metabolism and regulation of reproduction [57]. All Kps are the product of the KISS-1 gene and contain, at the C- terminal region, a common deca-peptide sequence (Kp-10) that confers to them biological activity [57, 58]. Although Kp receptors (GPR54) have been described in the hypothalamus, pituitary, ovaries and placenta, its major role has been postulated as being the neuroendocrine regulator of GnRH release [58, 59]. Kisspeptin and hypothalamic GPR54 have been associated with the onset of pulsatile GnRH secretion observed at puberty and in seasonal breeders, like sheep [57-59].

Kisspeptin-secreting neurons contain ER and other sex steroid receptors and are located in close vicinity to GnRH-secreting cells in the hypothalamus [59, 60]. Two sub-populations of Kp- secreting cells have been identified: one is located in the arcuate nucleus (ARC) and the other is located in the anteroventral periventricular area (AVPV) [59, 60]. This differentiation of these two sub-populations of cells is relevant since the regulatory effects of estrogens are nucleus- specific. Thus, estrogens inhibit the expression of Kp at the ARC, causing a negative-feedback effect on gonadotropin secretion. As expected, reducing circulating E2 concentrations resulted in higher Kp mRNA levels and increased GnRH output [58]. In contrast, estrogens enhance Kiss1 expression at the AVPV in rodents mediated by ERα, which suggests that this population of neurons may be involved in the positive-feedback actions of estradiol to generate the preovulatory surge of gonadotropins [57, 59]. In cattle, administration of 100 pmole/kg of Kp during diestrus, proestrus and estrus resulted in increased circulating LH concentrations during diestrous and proestrus, but not during estrous [61].

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It is important to highlight that, although estrogen plays a key role in the regulation of GnRH pulsatile secretion pattern, GnRH-releasing neurons seem to lack ER thus making the Kp/GPR54 system pivotal for the normal development of the reproductive functions [59].