intervals) exceeds 1 ng/ml [3]. Other authors define puberty as when ovulation is accompanied by visual signs of estrus with subsequent normal luteal function as evidenced by serum progesterone concentration above baseline for over two consecutive weeks [4]. Puberty involves a complex series of interactions between genetic, nutritional, and environmental factors that direct endocrine events that culminate in the attainment of reproductive capacity. In heifers, puberty is triggered when the hypothalamic–pituitary–gonadal axis first loses its sensitivity to the negative feedback effects of estradiol‐17β, allowing a surge of luteinizing hormone (LH) to occur [5]. It is now accepted that puberty and first ovulation are not necessarily coincident since in most heifers “silent” ovulations and short luteal phases may occur during the peripubertal phase [5].
Endocrine Events
Puberty encompasses the transition from the anovular state to one of regular recurring ovulations. The mechanism by which the hypothalamic–pituitary–gonadal axis loses its sensitivity to the negative feedback effects of estradiol‐17β has been the subject of research efforts for many years. The classical “gonadostat” theory, originally developed in a rodent model, appears applicable to cattle [6]. Ramirez et al. proposed that first ovulation results when sensitivity to steroid negative feedback diminishes, allowing sufficient gonadotropin output to drive follicular maturation, ovulation, and formation of a corpus luteum [6]. The hypothalamic–pituitary–gonadal axis of female cattle goes through several changes during its development. In utero, the fetus secretes gonadotropins for the first seven months of gestation. After this period, circulating gonadotropins are substantially reduced due to stimulation of the fetal central nervous system (CNS) [7]. In sheep, it has been demonstrated that the CNS‐stimulated reduction in gonadotropin release that occurs in late gestation is mediated through inhibition of N‐methyl‐D‐aspartate (NMDA) receptors, which have been demonstrated to be stimulatory to the gonadotropin‐releasing hormone (GnRH) pulse generator nucleus in the fetal hypothalamus [8]. It has become well established that kisspeptin‐1 (kiss‐1) neurons are the final common pathway regulating GnRH neurons [9]. However, NMDA may also act directly on GnRH cell bodies in a kisspeptin‐independent fashion [10]. Postnatally, mean plasma LH concentrations reach a maximum around three months of age, then slowly decline, before rising again and culminating in ovulation – typically around 10–11 months of age [11]. This transient increase in the circulating concentration of LH is associated with early follicular development and is thought to play a role in the timing of puberty.
In an attempt to hasten the onset of sexual maturity, Madgwick et al. [12] noted that the early rise in LH concentration was advanced by injecting heifer calves with GnRH twice daily from four to eight weeks of age. Treatment with GnRH increased mean circulating concentrations of LH at eight weeks of age, increased LH pulse frequency at four and eight weeks of age, and reduced the mean age at puberty by six weeks. Body weight gain was greater in GnRH‐treated calves than in control calves and the rate of weight gain was shown to be a significant covariate with age at puberty. This early transient rise in circulating LH stimulates ovarian follicular development, resulting in estradiol‐17β synthesis that has a negative feedback effect on gonadotropin secretion [13].
Although an increase in circulating estradiol‐17β has not been consistently demonstrated during this time period [14, 15], it is assumed the decline in LH is due to increased sensitivity to negative feedback by estradiol‐17β on the hypothalamus–pituitary [14, 15]. From this point until just prior to puberty, estradiol‐17β continues to exert negative feedback, after which sensitivity to the negative feedback effect of estradiol‐17β gradually declines. This period is known as the peripubertal period and begins about 50 days before puberty [13, 16]. The decline in sensitivity to negative feedback by estradiol‐17β has been associated with a reduction in the number of cytosolic estradiol‐17β receptors in the anterior and medial‐basal hypothalamus [16]. The result is that estradiol‐17β becomes ineffective at suppressing LH secretion and an ovulatory surge of LH is released [17]. Progesterone levels are very low (300 pg/ml) in the peripubertal period, but there are two distinct elevations of progesterone prior to the first preovulatory peak of LH [18]. The return to baseline levels subsequent to the first elevation in progesterone is always followed by the priming peak of LH, while the second elevation in progesterone precedes the pubertal peak of LH [18]. The profile of concentrations of LH between the two major LH peaks, coincident with the second progesterone elevation, appears as a transition between prepubertal and postpubertal LH baseline concentrations. This suggests that progesterone plays a key role in the changes leading to the establishment of the phasic LH release characteristic of the postpubertal heifer by priming the hypothalamus to respond to E2 positive feedback [18]. During the peripuberal period, growth‐related cues are monitored and regulate the activity of the GnRH pulse generator. When sufficient body size/composition is attained, the frequency of LH pulses increases because sensitivity to estradiol‐17β inhibitory feedback decreases [14]. The high‐frequency LH pulses stimulate follicular maturation and estradiol‐17β accelerates the GnRH pulse generator, resulting in the ovulatory surge of LH [19].
Pro‐opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) comprise a critical metabolic‐sensing pathway controlling the reproductive neuroendocrine axis. The POMC–kisspeptin pathway may be important in mediating the nutritional acceleration of puberty in heifers [20].
The first ovulation is not synonymous with puberty and the first luteal phase is typically of shorter than normal duration. Prostaglandin (PGF2α) released from the endometrium is responsible for the reduction in luteal lifespan (premature luteolysis) following first ovulation in heifers [21, 22]. Presumably, this occurs because of an abundance of endometrial oxytocin receptors that mediate release of PGF2α [23]. Subsequently, endometrial oxytocin receptor concentration is downregulated by exposure to progesterone for 12–14 days [24]. Frequency of LH pulses increases during the 50 days preceding first ovulation and reach about one per hour around the time of first ovulation [17]. Amplitude of LH pulses also increases during this time, but increased pulse frequency appears to be critical for initial ovulation [17]. Follicle‐stimulating hormone (FSH) concentrations in blood do not fluctuate as much as LH in the peripubertal period, suggesting that FSH may play more of a permissive role in the initiation of puberty [18]. Other hormones undoubtedly play a role in initiation of puberty, but LH appears to be of paramount significance. Prolactin may play a role in heifer puberty, but blood concentrations do not change at puberty as they do in bulls. There is abundant evidence to suggest that heifers are actually capable of ovulating from early on in life but fail to do so because of insufficient gonadotropic stimulation. In fact, McLeod et al. [25] were able to induce preovulatory gonadotropin surges in GnRH‐treated five‐month‐old heifers. Even more impressive was the research of Seidel et al. [26] who induced ovulations in one‐month‐old heifers with gonadotropin administration. Although ovulations can be artificially induced with gonadotropins, it is notable that the hypothalamus–pituitary becomes increasingly sensitive to GnRH stimulation as the time of puberty approaches. It has been shown that the positive feedback effect of estradiol‐17β on surge LH release becomes functional between three and five months of age [27]. Collectively, available data indicate heifers are capable of ovulating long before puberty but fail to do so spontaneously until the inhibitory effect of estradion‐17β on GnRH release wanes.
Development of the Female Reproductive Tract
Overall, body growth and development of the reproductive tract occur in an asynchronous pattern. For example, the ovaries grow at a rate 2.7 times faster than the body until puberty, whereas the tubular reproductive tract grows at about the same rate as body growth until about six months of age, and then enters a period of accelerated development until puberty [28]. No ovarian follicles are macroscopically visible at birth, but their numbers increase to maximal at four months, decrease through eight months of age, and remain relatively constant thereafter [28]. Growing and antral follicles increase in number during the first three to four months of age, which corresponds to the transient increase in circulating LH concentrations observed during that time period [29].
Height
