Chapter 22 Charles T. Estill Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, USA Puberty is a critical physiological milestone in a heifer’s reproductive life. In general terms, puberty can be defined as the process whereby animals become capable of reproducing themselves.1 At puberty, plasma progesterone concentrations indicate cyclic ovarian activity before the first observed estrus.2 Thus, puberty is defined as the first day that serum progesterone (determined in blood samples collected at weekly intervals) exceeds 1 ng/mL.3 Regarding heifers, puberty has been defined as the first estrus that is followed by a normal luteal phase.4 This involves a complex series of interactions of genetic and environmental factors that direct endocrine events which culminate in puberty. In heifers, puberty is triggered when the hypothalamic–pituitary–gonadal axis first loses its sensitivity to the negative feedback effects of oestradiol-17β, allowing a surge of luteinizing hormone (LH) to occur.4 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.4 Puberty encompasses the transition from the anovular state to one of regular ovulations. The mechanism of how the hypothalamus–pituitary 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.5 It was proposed that first ovulation results when sensitivity to steroid negative feedback diminishes, allowing sufficient gonadotropin output to drive follicular maturation.5 The hypothalamic–pituitary axis of female cattle goes through several changes during its development. In utero, the fetus secretes gonadotropins for the first 7 months of gestation. After this period, circulating gonadotropins are substantially reduced due to stimulation of the fetal central nervous system (CNS).6 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-dl-aspartate receptors, which have been demonstrated to be stimulatory to the gonadotropin-releasing hormone (GnRH) pulse generator nucleus in the fetal hypothalamus.7 Postnatally, mean plasma LH concentrations reach a maximum around 3 months of age, then slowly decline before again rising and culminating in ovulation typically around 10–11 months of age.8 This early transient increase in circulating concentration of LH is associated with early follicular development and is thought to regulate the timing of puberty. In an attempt to hasten the onset of sexual maturity, Madgwick et al.9 noted that the early rise in LH concentration was advanced by injecting heifer calves with GnRH twice daily from 4 to 8 weeks of age. Treatment with GnRH increased mean circulating concentrations of LH at 8 weeks of age, LH pulse frequency at 4 and 8 weeks of age, and reduced the mean age at puberty by 6 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.10 Although an increase in circulating estradiol-17β has not been consistently demonstrated during this time period,11,12 it is assumed the decline in LH is due to increased sensitivity to negative feedback by estradiol-17β on the hypothalamus–pituitary.11,12 From this point until just prior to puberty, estradiol-17β continues to exert negative feedback after which sensitivity gradually declines. This period is known as the peripubertal period and begins about 50 days before puberty.10,13 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.13 The result is that estradiol-17β becomes ineffective at suppressing LH secretion and an ovulatory surge of LH is released.14 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.15 The return of the first elevation in progesterone to baseline levels is always followed by the priming peak of LH, while the second elevation in progesterone precedes the pubertal peak of LH.15 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 concentration. 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.15 Coincidently, 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.10 The high-frequency LH pulses stimulate follicular maturation and estradiol-17β accelerates the GnRH pulse generator resulting in the ovulatory sure of LH.16 The first ovulation is not synonymous with puberty and the first luteal phase is usually of short duration. Prostaglandin (PG)F2α released from the endometrium is responsible for the reduction in luteal lifespan (premature luteolysis) following the first ovulation in heifers.17,18 Presumably, this occurs because of an abundance of endometrial oxytocin receptors that mediate release of PGF2α.19 Subsequently, endometrial oxytocin receptor concentration is downregulated by exposure to progesterone for 12–14 days.20 Frequency of LH pulses increases during the 50 days preceding first ovulation and reach about one per hour around the time of first ovulation.14 Amplitude of LH pulses also increases during this time but pulse frequency appears to be critical for initial ovulation.14 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.8 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 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.21 were able to induce preovulatory gonadotropin surges in GnRH-treated 5-month-old heifers. Even more impressive was the research of Seidel et al.22 who induced ovulations in 1-month-old heifers with gonadotropin administration. Although ovulations can be artificially induced with gonadotropins, it is also 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 3 and 5 months of age.23 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. 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 6 months of age, then enters a period of accelerated development until puberty.24 No ovarian follicles are macroscopically visible at birth but their numbers increase to maximal at 4 months, decrease to 8 months of age, and remain relatively constant thereafter.24 Growing and antral follicles increase in number during the first 3–4 months of age, which corresponds to the transient increase in circulating LH concentrations.25 Height of the luminal epithelium of the tubular reproductive tract is stimulated at birth but regresses by 1 or 2 months of age. Thereafter, increases in height of epithelia are most rapid after 6 months. From this information it is concluded, at least for Holstein heifers, that rapid peripubertal growth of the reproductive tract commences during the seventh month and is largely terminated by 10 months of age.24 It is generally accepted that puberty in cattle occurs around 9 or 10 months. However, there are reports of puberty occurring any time between 6 and 24 months of age,1 with anecdotal reports of heifers calving at 13 months indicating that puberty can occur as early as 4 months of age. Age at puberty is influenced by body weight and composition, breed, nutrition, genetics, and season. Any adverse factor that decreases prepubertal growth, such as scours, pneumonia, parasitism, or harsh weather conditions, results in delay of the onset of puberty. An early study by Sorensen26 showed that attainment of puberty in heifers was more influenced by weight than age. He found that heifers on a higher plane of nutrition reach puberty at an earlier age than similar heifers with lower average daily gain.26 However, heifers may have similar body weights but vary in frame size, indicating they have differing body composition. For any given frame size, heifers that are heavier reach puberty at an earlier age. Body weight at puberty has a heritability coefficient of 0.40.27 Overall, heifers reared on higher planes of nutrition are heavier but younger than nutritionally restricted animals at puberty.28 Puberty does not occur at similar body composition or metabolic status in all heifers29 but is positively correlated with body fat percentage and negatively correlated with carcass moisture percentage.29 The precise mechanisms involved in the relationship of body composition and puberty are not clearly defined. However, it is known that somatotropin and the insulin-like growth factor (IGF)-I system are involved.30 The process of developing heifers as replacements must begin during the cow-calf production phase. Age and weight at puberty are affected by several factors, including breed. Generally, breeds of a larger size at maturity are older and heavier when reaching puberty.31 A classic example of the effect of breed on puberty is illustrated in the study by Laster et al.32 They found that female progeny of a Charolais bull were 50 days older and 120 kg heavier at puberty than progeny of a Jersey bull when all dams were Angus cows. Although the Charolais × Angus heifers grew faster than the Jersey × Angus heifers, they did not reach puberty at as young an age as the Jersey × Angus heifers due to breed effect which, in this case, overrode the influence of rate of gain. Generally, European breeds reach puberty younger but at slightly heavier weights than Hereford or Angus heifers.32 In their study on the effects of heterosis on age at puberty, Wiltbank et al.33 found half to three-fourths of the heterosis effect on age at puberty was independent of heterosis effects on average daily gain. Thus there is a significant heterosis effect on age at puberty independent of heterosis effects on average daily gain.33 Sire within breed also has a significant effect on age of puberty of his female offspring. The heritability coefficient for age at puberty is 0.41.27 Body energy reserves and metabolic state are relevant modifiers of puberty onset and fertility. For instance, heifers in a peripubertal state may be induced to ovulate by abruptly increasing the plane of nutrition,34 whereas heifers of adequate body weight for puberty may be rendered anestrus by severe nutritional restriction.35 The study by Chelikani et al.36 involving Holstein dairy heifers illustrates this point. Heifers were fed to gain 1.1, 0.8, or 0.5 kg/day from 100 kg liveweight. Age at puberty for the three groups was 9, 11, and 16 months respectively. How nutrition and metabolism are linked to reproductive cyclicity is not clearly understood but it appears several neuropeptides operating in a reciprocal manner (orexigenic and anorexigenic) are involved. A primary candidate for modulating the effects of nutrition on reproduction is kisspeptin. Much of the work with this hormone has been in a rodent model but one may speculate that the same mechanisms are operational in cattle. Kisspeptin signaling in the hypothalamus has appeared as a pivotal positive regulator of the GnRH pulse generator.37 In the mid-1990s, the adipose hormone leptin was proven as an essential signal for transmitting metabolic information to the centers governing puberty and reproduction and kisspeptins, a family of neuropeptides encoded by the Kiss1 gene, have emerged as conduits for the metabolic regulation of reproduction and putative effectors of leptin actions on GnRH neurons.38 Leptin is produced by adipocytes and regulated by long-term and recent nutritional status.39 Circulating leptin concentrations increase as puberty approaches but do not change appreciably in response to dietary change when percentage of total carcass body fat is above a minimum, indicating that a certain minimum body condition is required for puberty.40 Ghrelin and other metabolic effector hormones known to modulate the hypothalamic–pituitary–gonadal axis, such as neuropeptide Y, melanocortins, and melanocyte-concentrating hormone, are additional putative regulators of the hypothalamic kisspeptin system.38 Two of the major factors that influence reproductive efficiency in cattle are age at puberty and postpartum anestrous interval. We now have the technology to evaluate genetic markers for age at puberty in cattle. For example, quantitative trait loci have been identified that predict male reproductive traits including age at puberty in cattle.41 Similarly, random amplified polymorphic DNA markers have been used for identifying Nelore bulls with early (precocious) or late (nonprecocious) puberty.42 In heifers, an association weight matrix (AWM) has been constructed based on 22 related traits with single nucleotide polymorphisms.43 The AWM results recapitulated the known biology of puberty, captured experimentally validated binding sites, and identified candidate genes and gene–gene interactions for further investigation. Advances in genomic technologies will likely provide a powerful tool for selecting heifers at birth that will have a greater probability of being reproductively successful if managed correctly. Early studies reported a favorable genetic correlation between yearling scrotal circumference (SC) in bulls and age at puberty in half-sib heifers in populations of purebred animals.44,45 A favorable relationship between SC in Brahman bulls and age at puberty in Brahman heifers reared under subtropical conditions has also been reported.46 However, more recent work suggests that the correlation between genetic response in female reproductive traits (including age at puberty) and sire yearling SC may be expected to be less effective than previously reported in the literature.47 In an Australian study, no significant relationship was found between age at puberty in heifers and the age and SC at puberty in related bulls.48 Results of another experiment designed to investigate this correlation using Limousin bulls bred to crossbred cows indicated that selection of resulting replacement heifers based on sire SC phenotype did not significantly influence heifer age at puberty.49
Initiation of Puberty in Heifers
Introduction
Endocrine events
Development of the female reproductive tract
Factors that influence age of puberty
Weight and body composition
Breed
Plane of nutrition
Genetic markers for age at puberty
Correlation between sire scrotal circumference and age at puberty of daughters
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