PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. It will be important to correlate known effects with local production of PRL to differentiate classic endocrine from autocrine/paracrine effects. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones. On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. (ABSTRACT TRUNCATED)

Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice

1.1. General overview
The strategic location of the skin as the barrier between the environment and internal milieu determines its critical function in the preservation of body homeostasis, and ultimately organism survival (Slominski, 2005, Slominski and Wortsman, 2000, Slominski et al., 2000c, Zmijewski and Slominski, 2011). It also exposes skin to numerous pathological agents, processes, and events. Thus, the capability to locally recognize, discriminate and integrate various signals within a highly heterogeneous environment, and to immediately launch appropriate responses, is a vital property of skin (Slominski and Wortsman, 2000). These skin functions are integrated into the skin immune, pigmentary, epidermal and adnexal systems, and are in continuous communication with the systemic immune, neural and endocrine systems (Arck et al., 2006, Slominski, 2009c, Slominski et al., 2004c, Slominski and Wortsman, 2000, Slominski et al., 2007a, Stenn and Paus, 2001).

These fundamental functions results from the location of the skin, which is the largest body’s organ, at the interphase between external and internal environment, requiring development of efficient sensory and effector capabilities to differentially react to changes in external environment. They are represented by inducible production of biologically active compounds (hormones, neurohormones and neurotransmitters) that act both locally and at the systemic levels (Fig. 1).



Figure 1

Skin senses changes in the environment through cutaneous neuroendocrine system, which computes and translates the received information into chemical, physical and biological messengers that regulate global (A and B) and local (B) homeostasis. These signals ...



The skin being continuously exposed to many external biological or environmental factors (acute transfers of solar, thermal or chemical energy), had to evolve optimal mechanism(s) to protect, restore or maintain local and global homeostasis in relation to hostile environment (Slominski et al., 1993b, Slominski and Pawelek, 1998, Slominski and Wortsman, 2000, Slominski et al., 2000c). We have proposed that precise coordination and execution of these responses are mediated by a cutaneous neuroendocrine system, which also is able to reset the body homeostatic adaptation mechanisms (Slominski and Wortsman, 2000). Superimposed on this is the impact of psychological stress on skin physiology and pathology, placed in the context of the bidirectional brain-skin communication (Arck et al., 2006, Slominski, 2005a, Slominski et al., 2008b). To summarize, in reaction to changing external and also internal environment, the skin can generate signals to produce rapid (neural) or slow (humoral or immune) responses at the local and systemic levels (Fig. 1).

Coordination between these local and systemic responses is mediated by the skin neuroendocrine system (Slominski and Wortsman, 2000a), which employs local equivalents of the hypothalamo-pituitary-adrenal axis (HPA) (Slominski et al., 2007a), hypothalamo-pituitary-thyroid (HPT) axis (Pisarchik and Slominski, 2002, van Beek et al., 2008), catecholaminergic (Schallreuter et al., 1997), serotoninergic, melatoninergic (Slominski et al., 2008a, Slominski et al., 2005c), cholinergic (Grando, 2006, Grando et al., 2006), steroidogenic (Slominski et al., 2008b) and secosteroidogenic (Bikle, 2010, Holick, 2003, Slominski et al., 2010) systems (Fig. 2). Given their common embryonic origins, it is not surprising that skin shares numerous mediators with the CNS and endocrine system. Recent research has revealed that skin also harbors a complex opioidogenic (Grando et al., 1995, Slominski et al., 2011c) and canabinnoidogenic (Biro et al., 2009) systems, which role in the maintenance of cutaneous homeostasis is currently being intensively explored.



Figure 2

Skin neuroendocrine system follows the algorithms of classical neuroendocrine or endocrine systems. It also forms a natural platform of signal exchange between internal organs and environment. For this purpose skin cells not only are subjected to neurohormonal ...



In this monograph we will discuss the role of various components of the skin neuroendocrine system in sensing the environment with subsequent regulation of local and global homeostasis with a main focus on the algorithms of classical neuroendocrine axes.

Sensing the Environment: Regulation of Local and Global Homeostasis by the Skin's Neuroendocrine System

Androgens are required for sexual hair and sebaceous gland development. However, pilosebaceous unit (PSU) growth and differentiation require the interaction of androgen with numerous other biological factors. The pattern of PSU responsiveness to androgen is determined in the embryo. Hair follicle growth involves close reciprocal epithelial-stromal interactions that recapitulate ontogeny; these interactions are necessary for optimal hair growth in culture. Peroxisome proliferator-activated receptors (PPARs) and retinoids have recently been found to specifically affect sebaceous cell growth and differentiation. Many other hormones such as GH, insulin-like growth factors, insulin, glucocorticoids, estrogen, and thyroid hormone play important roles in PSU growth and development. The biological and endocrinological basis of PSU development and the hormonal treatment of the PSU disorders hirsutism, acne vulgaris, and pattern alopecia are reviewed. Improved understanding of the multiplicity of factors involved in normal PSU growth and differentiation will be necessary to provide optimal treatment approaches for these disorders.

Role of Hormones in Pilosebaceous Unit Development

Recent declines in numbers and juvenile recruitment in many elk (Cervus elaphus) herds in the western U.S. has sparked interest in factors that may cause these declines. Inadequate nutrition or delayed parturition, the latter of which may be caused by inadequate numbers of mature bulls (i.e., highly skewed sex ratios), may have separate or synergistic effects on population dynamics and productivity. We evaluated the implications of late parturition and summer-autumn nutrition on reproduction and survival of Rocky Mountain elk (C. e. nelsoni) using a captive herd of 57 cow elk.



We induced early (Sep) and late breeding (Oct) and 3 levels of summer-autumn nutrition on the cows. Food was offered ad libitum at 3 levels of digestible energy (DE): high = 2.9-3.0 kcal of DE/g of diets, medium = 2.6-3.0 kcal/g, and low = 2.3-3.0 kcal/g. Within these ranges, DE content was gradually reduced from late June through early November to mimic seasonal changes in the wild. During summer and autumn, we measured calf growth; body mass, nutritional condition, and breeding dynamics of cows; and growth and pregnancy of yearlings. We also measured carry-over (i.e., time-lag) responses including over-winter calf and cow survival and parturition date and birth mass, as functions of previous summer-autumn nutrition and previous parturition date. Between autumn 1995 and spring 1998, we conducted 2 years of parturition-date, summer-autumn nutrition experiments, 2 winters of calf survival experiments, and 1 winter of cow survival experiments.



Early birth provided calves with more time to grow before onset of winter. This “head-start” advantage was maintained through late autumn, but its magnitude was diluted in some instances due to faster growth of some late-born calves. Body mass, body fat, and timing and probability of conception by cows in autumn were little influenced by parturition date the previous spring.



Summer-autumn nutrition significantly affected calves and their mothers. Growth of calves in the low and medium nutrition groups ceased by mid-September and late October. By December, calves in the high nutrition group were 40% and 70% heavier than calves in the medium and low groups, respectively. Cows in the high nutrition group accumulated about 75% and 300% more fat than cows in the medium and low groups by mid-October. Eighty percent of cows in the low nutrition group failed to conceive, and those in the medium group bred 10–14 days later than cows in the high group. Summer-autumn nutrition of calves influenced their probability of becoming pregnant as yearlings. Probability of pregnancy approached 100% for those yearlings that had high summerautumn nutrition as calves and yearlings, despite near starvation their first winter of life.



Winter survival of calves was related to their size at the onset of winter. Smaller calves lost more body mass daily than did large calves, and thus they survived fewer days through winter. Summer-autumn nutrition largely determined calf body size at the start of winter and, consequently, determined the proportion of winter survived. Survival of cows over winter was as related to body fat at the onset of winter as it was to nutrition during winter.



Carry-over effects of summer-autumn nutrition and parturition date on birth characteristics the following spring were minor. We detected no significant carry-over effect of summer-autumn nutrition or autumn condition on birth mass, although reduced condition in autumn delayed subsequent parturition date. Extent of body fat depletion in cows during the winter-survival experiments in 1998 accounted for 45% of the variation in parturition date. Ninety percent depletion delayed parturition an average of 34 days.



Delayed parturition, of a magnitude expected due to highly skewed sex ratios (3 weeks under extreme conditions), probably has only a weak influence on vital rates of free-ranging elk. In contrast, fat accretion and probability of pregnancy of cows, and growth and overwinter survival of calves, were sensitive to small (10–20%) differences in DE content of food. Digestible energy levels of our 2 lower nutrition levels reflect DE ranges reported for large ungulate herds during summer and autumn in western North America. Thus, our data suggest that limiting effects of summer-autumn nutrition on populations may be greater than often assumed, perhaps greater than those during winter in some ecosystems, and consequently indicate a need for greater understanding of nutrition's influence on population dynamics and how this influence varies across space and time. To enhance future research, we present animal- and vegetation-based guidelines for evaluating nutritional influences on elk populations.

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Effects of summer‐autumn nutrition and parturition date on reproduction and survival of elk

fie physiological limitation of individual energy budgets has been suggested as one determinant of animal reproductive performance and survival, independent of extrinsic environmental factors. 7Iis postulate helps to explicate the evolutionary optimization of life histories, foraging behaviours, and geographical distributions of species. Models of optimal resource allocution and of optimal foraging have been proposed within this framework. New empirical data help to identify the physiological mechanisms constraining energy budgets and allow quantification of otherwise vague arguments. Nevertheless, many questions remain unanswered or clouded.

https://www.cell.com/trends/ecology-evolution/pdf/0169-5347(92)90009-Z.pdf

Physiological limits to sustainable energy budgets in birds and mammals: Ecological implications

Non-domesticated seasonally breeding ungulates exhibit marked seasonal changes in metabolic rate, voluntary food intake (VFI), pelage growth and moult and hormone secretion. It is not known whether these seasonal rhythms are regulated by the same central processes which control the onset and termination of the breeding season. Here we compare two closely related deer species which have significantly different mating and calving seasons. Seasonal changes in VFI, liveweight, coat growth, plasma prolactin and tri-iodothyronine (T3), and the timing of the breeding season were examined over a 15-month period in six adult post-pubertal red and Pere David's deer from January to April the following year. The timing of the seasonal changes in prolactin, T3, VFI and coat growth were all significantly advanced by 56, 23, 60 and 54 days respectively in the Pere David's deer. The times of onset and termination of the breeding season of Pere David's deer were also significantly advanced by 90 days, but in both species, the breeding season was of similar duration (160 +/- 5 (S.E.M.) days). Changes in liveweight of adult red deer could be explained by changes in VFI rather than efficiency of utilization. This was not the case in Pere David's deer and may indicate seasonal changes in the efficiency of energy utilization. In order to establish whether these species differences develop with age, we undertook a second study in which seasonal changes in VFI, growth, plasma prolactin concentrations and the timing of the onset of the breeding season were recorded for ten red deer and six Pere David's deer from 6 to 18 months of age. Both species exhibited a similar decline in VFI in the first autumn of life. Subsequently, the Pere David's deer exhibited an advance in the timing of the seasonal peak in VFI and prolactin (21 and 66 days respectively); puberty occurred 3 months earlier than in red deer. The earlier breeding season of the Pere David's deer was associated with a significant advance in a range of seasonal endocrine and physiological parameters. These species differences may develop with age. Our data indicate that seasonal patterns of metabolism and growth may be closely linked to those mechanisms which also regulate the onset and termination of the breeding season.

A comparison of the seasonal hormone changes and patterns of growth, voluntary food intake and reproduction in juvenile and adult red deer (Cervus elaphus) and Père David's deer (Elaphurus davidianus) hinds.

Antler and testicular cycles were studied in a group of free ranging axis deer stags kept out of doors in southern England Within the herd, there was little evidence of a clear seasonal synchrony in the antler cycle Detailed information obtained from 4 stags indicated that there was a fixed relationship between stage of the antler cycle and testis diameter; minimum testis diameter occurred 1-2 months after antler casting whereas maximum testis diameter occurred when stags were in hard antler Changes in body weight, circumference of the neck and plasma testosterone concentrations largely paralleled those of testis diameter Motile spermatozoa were collected at all stages of the testis cycle Six animals in the early stages of antler growth were selected from the herd in May and 3 of these were implanted with 1 g melatonin in a Silastic rubber envelope Each animal was captured on 3 subsequent occasions at monthly intervals Melatonin was without effect on the rate of increase in size of the testis, circumference of the neck or growth and cleaning of the antlers although 1 of the treated animals failed to cast his antlers at the expected time 8 months after cleaning We conclude from this study that there is little or no seasonal photoperiodic entrainment of the antler and testicular cycles of males in this population of axis deer

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Cycles of antler and testicular growth in an aseasonal tropical deer (Axis axis)

Seventeen red deer hinds were housed in individual pens and from 28 February until 11 November were injected each week with vehicle (group A; n = 6) or 5 (group B; n = 6) or 12.5 mg (group C; n = 5) of a long-acting formulation of bromocriptine. Liveweight and voluntary food intake (VFI) were recorded for each hind, and blood was collected for determination of progesterone, prolactin, tri-iodothyronine (T3) and cortisol concentrations by radioimmunoassay. Treatment with the high dose of bromocriptine was associated with a significant (P less than 0.05) reduction in VFI, with the effect being greatest between March and July. There was no treatment effect on liveweight, but there was a significant (P less than 0.01) interaction between time and treatment due to the faster rate of weight gain in control animals at the beginning of the experiment. Changes in liveweight could be explained by changes in VFI rather than by changes in the efficiency of utilization of intake. Termination of the breeding season was significantly (P less than 0.01) delayed by 54 days in group C hinds. Growth of the summer coat and subsequent winter coats was delayed by 1 and 3 months respectively in group C hinds, and in groups B and C the duration that animals were in summer coat was increased by about 1 month. The seasonal increase in prolactin concentrations was seen in all groups, but levels were significantly (P less than 0.05) lower in group C hinds. Concentrations of T3 and cortisol were not affected by bromocriptine.

Effects of chronic long-acting bromocriptine treatment on liveweight, voluntary food intake, coat growth and breeding season in non-pregnant red deer hinds.

Three groups of red deer hinds of 9–10 years of age were grazed upon an indigenous hill pasture (A), an improved species grass sward (predominantly perennial ryegrass) maintained at < 1500 kg D.M./ha (B), and one maintained at 2000 kg D.M./ha (C) from immediately after calving on 29 May until weaning on 22 September. Numbers of hinds in each treatment were 8, 6 and 9 respectively. Milk yields of hinds were estimated on swards A and C by the calf-suckling technique and hind and calf live-weight changes and hind grazing behaviour were recorded on all three swards during lactation.Hinds on award C yielded on average 60% more milk over the lactation period than hinds on sward A, day 40 yields being 2·2 and 1·5 kg/day respectively. Calf growth rates (treatment A, 257 ± 9·5, B, 324 ± 12·1 and C, 369 ± 14·5 g/day) were higher on the improved species sward than on the hill sward and higher on the improved sward with the greater herbage mass. On treatments A and C calf growth rates were significantly (P < 0·05, r = 0·69) correlated with milk yield throughout lactation. At weaning, calves on sward C were 7·5 and 4·5 kg heavier than those on swards A and B respectively. Biting rates were lower (33 v. 56 bites/min) and grazing times higher (11.7 v. 6.0 h) on sward A than swards B and C. The poorer performance of hinds and their calves on sward A was considered to be due to a lower quality of diet ingested, and to behavioural limitations on intake occurring when hinds graze indigenous swards of relatively high species diversity. These results are discussed in relation to the grazing behaviour of cattle and sheep on similar swards.The significance of the results to red deer farming in the U.K. is briefly discussed.

The lactation performance of red deer on hill and improved species pastures

Reproductive cycles were studied in a group of tame Pere David's deer hinds. The non-pregnant hind is seasonally polyoestrous and, in animals studied over 2 years, the breeding season began in early August (2 August +/- 3.3 days; s.e.m., N = 9) and ended in mid-December (18 December +/- 5.7 days; N = 8) and early January (6 January +/- 3.2 days; N = 11) in consecutive years. During the anoestrous period, plasma progesterone concentrations were low (0.2 +/- 0.01 ng/ml) or non-detectable. There was a small, transient increase in progesterone values before the onset of the first cycle of the breeding season. In daily samples taken during an oestrous cycle in which hinds were mated by a marked vasectomized stag, progesterone concentrations remained low (less than 0.5 ng/ml) for a period of about 6 days around the time of oestrus, showed a significant increase above oestrous levels by Day 4 (Day 0 = day of oestrus) and then continued to increase for 18 +/- 2.8 days to reach mean maximum luteal levels of 3.5 +/- 0.6 ng/ml. The plasma progesterone profiles from a number of animals indicated that marking of the hinds by the vasectomized stag did not occur at each ovulation during the breeding season and therefore an estimate of the cycle length could not be determined by this method. In the following year, detection of oestrus in 5 hinds was based on behavioural observations made in the absence of the stag. A total of 19 oestrous cycles with a mean length of 19.5 +/- 0.6 days was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

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A. S. I. Loudon

Papers

A comparison of the seasonal hormone changes and patterns of growth, voluntary food intake and reproduction in juvenile and adult red deer (Cervus elaphus) and Père David's deer (Elaphurus davidianus) hinds.

Cycles of antler and testicular growth in an aseasonal tropical deer (Axis axis)

Effects of chronic long-acting bromocriptine treatment on liveweight, voluntary food intake, coat growth and breeding season in non-pregnant red deer hinds.

The lactation performance of red deer on hill and improved species pastures

Oestrous cycles and the breeding season of the Père David's deer hind (Elaphurus davidianus).