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The pituitary endocrine mechanisms involved in mammalian maturation: maternal and photoperiodic influences
Vol. 10, No. 1
3
REVIEW
The pituitary endocrine mechanisms involved in mammalian maturation: maternal and photoperiodic inuences Marta Wakowska1, Jolanta Polkowska Department of Endocrinology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabonna, Poland
Received: 3 February 2009; accepted: 4 November 2009
SUMMARY This review is designed to describe some pituitary mechanisms indispensable for growth and sexual maturation during the neuroendocrine adaptation of the female mammal to the extrauterine environment. We dene the phases of postnatal development on the basis of secretory patterns of hormones. The infantile period is characterized by accelerated growth, and elevated secretion of growth hormone (GH) and follicle-stimulating hormone (FSH) in contrast to the diminished secretion of luteinizing hormone (LH). The transition from infancy to prepuberty generates the attenuation of somatic growth in non-primate mammals and the beginning of sexual maturation. The mechanisms of this transition involve the effects of weaning, which is associated with a rupture of the young-mother bond and, if abrupt, results in the stress of maternal deprivation. Maternal deprivation involves the stress-like endocrine response of pituitary and inuences the mechanisms 1
Corresponding author: Department of Endocrinology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabonna, Poland; e-mail: [email protected]
Copyright © 2010 by the Society for Biology of Reproduction
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underlying the secretion of GH and FSH. An acute decrease in the secretion of GH and FSH at the initiation of prepuberty and an increase in the storage and pulsatile release of LH according to progressive prepubertal stages are pituitary endocrine features of post-infantile maturation. There are two factors important for timing of puberty, the maturity of gonadotroph population manifested by the adequate size of LH-containing cell subpopulation and the circumstances of an external environment optimal for reproductive functions in adults. Thus, the intrapituitary endocrine mechanisms of maturation have a psychosomatic nature during weaning and histomorphological nature during the postinfantile transition to puberty. In seasonal breeders, the endocrine timing of puberty has a circumannual seasonal nature. Reproductive Biology 2010 10 1: 3-18. Key words: stress, growth, seasonality, puberty, ACTH, GH, LH, FSH
INTRODUCTION Somatic maturation is affected by the interaction between environmental and genetic factors and depends on the coordinated functions of different hypothalamo-pituitary axes. The pituitary gland reaching maturity is a seminal event in ontogeny leading to neuroendocrine control of many complex functions of the organism. Adrenocorticotrophic, somatotrophic and gonadotrophic cells, as the sites of ACTH, GH, LH and FSH secretion, respectively, provide pituitary effector mechanisms of the stress response, systemic growth and functions of the reproductive system. Thus, pituitary cells are the setting for endocrine mechanisms that prepare an organism for extrauterine life and for the pivotal systemic activity – reproduction. Weaning and puberty involve neuroendocrine states which evoke major changes in the secretion of hormones, and thus are transitional for postnatal development. These endocrine changes lead to the full presentation of the adult phenotype, i.e. physiological and behavioral maturity [54, 57, 58]. Weaning involves a rupture in the mammalian mother-infant psychoemotional and nutritive bonds and, if abrupt, results in the stress of maternal deprivation, i.e. psychoemotional and, consequently, physiological distur-
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bances of homeostasis. These psychosomatic effects should be treated as natural mechanisms of the transition from the infantile to juvenile period of postnatal ontogeny [56]. However, it should be reminded, that early-life stressful stimulation can induce long-lasting effects on the hypothalamopituitary-gonadal (HPG) axis [23]. In contrast to maternal regulations which predominate during the infantile period, post-infantile maturation is under external inuences which regulate reproductive functions in adults [53]. In this regard, the onset of puberty in seasonal breeders is determined by the circumannual environment, i.e. photoperiod and/or seasonal availability of food [55, 57, 58].
THE EFFECT OF STRESS ON THE SECRETION OF HORMONES DURING THE TRANSITION FROM THE INFANTILE TO JUVENILE PERIOD OF ONTOGENY The activation of the hypothalamo-pituitary-adrenal (HPA) axis, is the main dening feature of neuroendocrine adaptation known as the stress response [30]. The mammalian HPA system is under maternal regulation, namely, the mother appears to actively inhibit HPA responses in her postnatally developing offspring [24, 29, 31]. The development of different aspects of the HPA system in young is regulated by different aspects of maternal behavior [31]. Feeding appears to regulate adrenal sensitivity whereas tactile stimuli inhibit the activation of centrally-controlled components of the axis [49]. The mother probably has rewarding properties for her young, associated with nutritive suckling, and maternal deprivation increases reward value of mother for pup [1]. In rodents and lambs, maternal deprivation results in the disregulation of the HPA axis at multiple levels. This effect is observed even at the time of weaning or beyond the time of weaning, when the young are capable of self-feeding and no longer require tactile stimulation to induce some systemic functions [30, 39, 47, 56]. In maternally deprived weanling lambs, the increase in the release of corticotrophin-releasing hormone from the nerve terminals in the median eminence to the pituitary portal circulation is followed by an increase in the accumulation of ACTH. The increase
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in the storage of ACTH is manifested by hypertrophy and hyperplasia of corticotrophs in response to the prolonged psychoemotional challenge to homeostasis [56]. Similar secretory changes and normal cortisol secretion in response to exogenous ACTH are observed in the hypothalamo-pituitary unit of adult ewes after prolonged electric foot-shocks [41, 45]. Also in rats, chronic stress elevates the ACTH content in the pituitary gland without changes in peripheral blood plasma ACTH and corticosteroid levels [64]. This increase is probably due to both the increase in biosynthesis and the decrease in the processing of ACTH [48]. Thus, in mammals during longer exposure to stressful stimuli, attenuated ACTH release may cause the hypocortisolemia. The resemblance of the HPA axis responsiveness during the development of lambs after the neonatal period to that of mature ewes [38, 41, 56] implies, that the maturation of intrapituitary stress responsivity is likely a result of developmental modications that occur before the weaning period. Altogether, the psychosomatic state evoked by maternal deprivation affects the HPA axis and causes the stress-like endocrine response of the pituitary gland in the infantile mammal. The stress of both physical and emotional origin affects the reproductive system of the female mammal by the suppression of the HPG axis secretory activity and reduction of gonadal functions [8, 21, 23, 44, 46, 56, 59]. However, the predominant impact of the psychosomatic stress of maternal deprivation is on the FSH secretory activity of pituitary gonadotrophs [56]. Maternal deprivation induces an increase in gonadotropin-releasing hormone (GnRH) storage in the nerve terminals of the median eminence and/or suspending of GnRH release in lambs [56]. Similar changes are observed in adult ewes submitted to prolonged [46] or long-term [42] stressful stimulation. The alterations observed in the hypothalamic processing of GnRH are followed by changes pertaining to secretion of gonadotropins in the pituitary cells [42, 56]. The evident contrast is observed between the acute decrease in the secretion of FSH and no changes in the LH in maternally deprived lambs. This diversity may be partially explained by the different pre-translational regulation of LH and FSH synthesis [56]. Similarly to the HPG axis, maternal deprivation affects the somatotrophic axis. This effect involves the enhancement of GH secretion via restraining
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of somatostatin output in lambs during the weaning period (J. Polkowska and M. Wakowska, unpublished). In conclusion, the stressful disruption of social interactions between the young and mother can affect the intrapituitary mechanisms underlying the secretion of gonadotrophic hormones and GH during the transition from the infantile to juvenile period of ontogeny. This stress response is important for the maintenance of homeostasis in the weanling mammal.
THE INTRAPITUITARY PROCESSING OF LH AND FSH DURING THE TRANSITION FROM INFANCY TO PUBERTY The pre-translational regulation of LH and FSH synthesis during maturation is similar in rats [65] and sheep [54]. Namely, LHE and FSHE mRNA contents rise slowly during the infantile period and then fall during the juvenile period until peri-puberty (g. 1). It should be noted, that the regulation of gonadotropin subunits’ gene expression and translation may be inuenced by alterations in the stability and half-life of mRNA (for review see: [4]). Thus, transcriptional synthesis of gonadotrophic E subunits is highest during the transition from infancy to prepuberty, i.e. the initiation of the juvenile period of sexual maturation [54]. In contrast to the synthesis, storage patterns of LH and FSH are different in rats and sheep during the transition from infancy to the peripubertal stage around the time of neuroendocrine initiation of puberty (g. 1; [28, 54]). First, the number of gonadotrophs per pituitary tissue as well as the amounts of LH and FSH in pituitary cells increase during infancy, which is reected by the low plasma LH levels [2, 15]. Then, in rats the number of LH-containing cells remains high until puberty [28], whereas in sheep increases from weaning until peripuberty [54] when the plasma LH pulse frequency and mean concentration are heightened [16, 54]. It is generally accepted that an increase in the frequency of episodic LH secretion is a key event leading to the onset of ovarian cycles [27]. In contrast to LH, the number of FSH-containing gonadotrophs decreases from the beginning of the weaning period in rats [28] and from the post-
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Figure 1. The schematic comparison of LH, FSH and GH secretory patterns dening the phases of postnatal development in female sheep until puberty. (): increase, (): decrease, (=): similar level in comparison with the previous indicated stage, ?: unknown. Unpublished compilation of data reported in Refs. 7, 15, 16, 22, 27, 36, 43, 54, 57 and 58.
weaning stage in sheep [54] until puberty. Thus, the storage of FSH is extremely high during the weaning period and extremely low during the juvenile period in both species (g. 1; [28, 54]). In the case of FSH release, the relatively low plasma FSH level during the neonatal period and the beginning of infancy are followed by an increase during weaning and the post-weaning stage and a decrease during prepuberty and peri-pubertal initiation of puberty in both species [16, 25]. It should be mentioned, that in the rhesus monkey during the juvenile-adult transition, the pituitary gonadotroph population increases and a large number of monohormonal FSH gonadotrophs are likely to become bihormonal [34]. These ndings on rats, sheep and primates attest that gonadotrophs can switch their hormonal identity in response to maturational circumstances. In this regard, the neuroendocrine transition from infancy to prepuberty changes GnRH neurobiology in the preoptic area-hypothalamus to the pattern which results in the maturational increase from the low infantile
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terminal storage of GnRH in the median eminence to the high peripubertal one and thus allows the initiation of ovine puberty [55]. Altogether, the similar pre-translational regulation of LH and FSH synthesis but clearly different storage and release patterns are characteristic for prepubertal mammals. Mechanisms responsible for divergent LH and FSH secretion during somatic maturation may be explained by the differential posttranscriptional regulation [54, 57]. This is in agreement with the notion, that the secretion of both LH and FSH throughout sexual development are differentially regulated by changes in the proportion of gonadotroph subtypes within the total pituitary gonadotroph population [34]. A feature of the GnRH/ LH secretory pathway is the ability of LH protein to be stored [4, 32]. The secretory pattern of LH does not reect its transcriptional rate, but is related to posttranslational intrapituitary mechanisms due to the storage and transportation of secretory granules within the gonadotrophs [4, 51]. This intracellular mechanism probably switches non-releasing gonadotrophs into a potentially releasable state [5]. The above-discussed discrepancies imply the existence of the histomorphological feature of intrapituitary regulation of posttranscriptional processing and release of LH during the transition from the infantile to peripubertal activity of gonadotroph population. In contrast to LH, the release of FSH is primarily constitutive [11, 12]. FSH is trafcked to the site of exocytosis shortly after synthesis, and released. Thus, a strong relationship exists between the level of pituitary FSHE mRNA and plasma FSH, which is representative for constitutively secreted hormones [4]. These ndings imply the maturational importance of the relationship between the transcriptional synthesis and storage of FSH in contrast to the relationship between the storage and release of LH [54]. In conclusion, the differential regulation of both gonadotropins in the postnatally developing mammal is on the level of posttranscriptional processing and release rather than on the level of gene expression. The suggested requirement for sexual maturation is the change in the histomorphological feature of gonadotroph population, dependent on the increase in the number of LH-containing cells.
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SOME ENDOCRINE ASPECTS OF THE GROWTH-PROMOTED MATURATION The somatotrophic cells, as the site of GH secretion, are the morphological setting for the pituitary effector mechanism of the neuroendocrine aspects of systemic growth. In female sheep, serum GH concentration declines to a low level at approximately 12-14 weeks of age, i.e. at the end of infancy and no obvious pubertal increase occurs [50, 58]. In contrast, in humans [37], monkeys [60] and rats [40] serum GH is elevated during puberty. In the sheep, the functional development of the GH axis is complete just before the beginning of the juvenile period during the postweaning stage (g. 1) independently of photoperiodic inuences [58]. However, the developmental processing within the hypothalamo-hypophyseal unit prolongs after the postweaning stage and concerns the importance of somatostatin as the hypophysiotrophic factor controlling somatic maturation. This increasing role of somatostatin from the postweaning stage until late prepuberty is the reason for the natural fall in the circulating level of GH with postnatal age in the female sheep [58]. The suppressive effect of somatostatin on the GH response to GH-releasing hormone increases acutely at birth [7], and generally GH secretion in the neonate is more sensitive to the inhibitory inuence of somatostatin in comparison with the fetus [22, 52]. The pattern of early postnatal GH secretion in sheep is important for the shift between infancy and prepuberty. This shift depends upon the intensive somatic growth [58]. In contrast, in female primates an increased GH level is involved in the pubertal growth spurt, i.e. correlates strongly with height velocity characteristic for the major period of accelerated linear growth observed during pubertal maturation [35]. In rats, plasma GH level is elevated during puberty, which suggests a physiological role of GH in the control of the pubertal process in this species [40]. However, in contrast to primates, in female rats the adult-like high GH level during puberty does not correlate with the acute growth. In female rats and lambs, the increase in the slope of the curve of body weight gain is observed until the juvenile period [40, 58]. In female sheep puberty is not a weight- or growth-promoted event. Likewise the post-infantile decrease in GH secretion is not a requirement for
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puberty and does not provide a direct cue for the normal timing of neuroendocrine sexual maturation [50, 58]. This fall in serum GH level corresponds with the natural postweaning stage and the beginning of the phase of lower daily live-weight gains [58]. This reects a decline from the high prenatal and neonatal levels to the low level similar to those observed in adult sheep [50]. The postweaning stage is transitional for the maturation of the GH/ IGF-I relationship [50] and corresponds with the ending of intensive growth and beginning of fat deposition [6, 33, 58]. In conclusion, the pattern of GH secretion during weaning is important for the infantile/prepubertal shift. This shift depends upon the maturation of the neuroendocrine somatotrophic system and, consequently, is related to the intensive systemic growth. The development of the morphological and physiological basis for GH secretion is nished just after weaning, independently of photoperiodic inuences. Then the GH secretion is under the maturing hypophysiotrophic inuences of somatostatin.
THE NATURE OF ENDOCRINE MECHANISMS TIMING THE PUBERTAL TRANSITION TO ADULTHOOD IN SEASONAL BREEDERS In the female sheep, the intrapituitary mechanism that prepares the gonadotroph population for puberty is represented by an increase in the storage of LH accompanied by a comparable decrease in the storage of FSH (gs. 1 and 2; [57]). The heterogeneity in the patterns of LH and FSH posttranscriptional processing is resultant of different regulations on the level of synthesis and storage rather than on the level of release. First, during peripuberty the increase in the transcription and stability of LHE mRNA is observed. Then, in the initiation of puberty the mechanisms dominate which depend upon the increase in both the translational processing and storage of LH, accompanied by the decrease in both the synthesis and storage of FSH (gs. 1 and 2; [57]). Since the overt sign of puberty in the female lamb is rst behavioral estrus, puberty would be more adequately dened by the ability to ovulate and to allow insemination by the ram [9]. Foster et al. [20] have previously
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Figure 2. Pituitary gonadotrophs containing in situ hybridised mRNA transcripts encoding LH-subunit or FSH-subunit and immunoreactive LH or FSH in the representative infantile and pubertal female sheep. Calibration bars: 50 m. Note the small population of gonadotrophs containing LH mRNA, FSH mRNA and FSH and great population of LH-containing gonadotrophs in pubertal lamb in comparison with infantile lamb. Unpublished photographs from authors’ database.
associated puberty with three consecutive ovulatory surges producing the luteal-phase progesterone increases. The rst ovulatory surge during the life produces a short luteal phase, the second one produces a luteal phase sufcient to provide adequate progesterone priming, so that the third ovulatory surge is accompanied by behavioral estrus (for review see: [17]). Ovulation in pubertal lambs is related to similar regulation on the level of LH and FSH transcriptional synthesis and release rather than on the level of their storage. In comparison with pubertal sheep, the patterns of posttranscriptional regulation for LH and FSH during the estrous cycle of adult ewes are quite different (for review see [57]). Altogether, the heterogeneity in the posttranscriptional regulation of LH and FSH in the initiation of puberty contrasts with the similarity in this regulation during the ovine pubertal cycle. Once the peripubertal endocrine mechanisms are initiated, a sequence of neuroendocrine events is set in motion that leads to puberty independently of any inuences of the external environment. However, in females of numerous wild-living species, which may be represented by such domesticated ruminants as sheep, seasonal changes in day length (photoperiod) are the primary environmental cue responsible for the annual activity of the repro-
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ductive system. In female sheep, the neuroendocrine mechanisms which integrate growth and sexual maturation may be seasonal in nature [58]. The peripubertal GnRH neurobiology in the preoptic area-hypothalamus, related to the later neuroendocrine-hypophysiotrophic pubertal function of GnRH, is primarily seasonal in nature [55]. Moreover, daylight exposure requirements for puberty in female lambs differ from those for the onset of the breeding season in adult ewes [10]. In such short day breeders as female sheep from cold and temperate climates, the seasonal decrease in photoperiod is necessary for the normal timing of puberty [18] irrespective of time of birth and probably reects the limited photoperiodic history of the lamb [17]. However, puberty does not occur at the appropriate age if the decrease in day length is experienced very early in postnatal life, as seen in the rst 10 weeks [14, 62]. These observations prompt the hypothesis that the seasonal breeder is able to transduce changes in day length into the appropriate endocrine cues for sexual maturation during its later postnatal life. This is possible when gonadotrophs attain full peripubertal efciency manifested by sufcient LH storage [57]. Namely, female lambs are highly sensitive to changes in photoperiod with respect to the suspension of maturational gonadotrophic functions at peripuberty on the level of LH storage and release, but not on the level of LH synthesis [57]. The postnatal development of the gonadotroph population in the female sheep lasts approximately seven months [54]. Thus, the lamb must be born near the vernal equinox (i.e. in the season) to attain the ‘pubertal age’, resulting from gonadotroph population maturity, during the breeding season of the rst year of life [57]. In females born after the summer solstice, the full peripubertal efciency of gonadotroph cells is attained after the winter solstice, i.e. during the increasing photoperiod [57]. Consequently, endocrine maturation is masked, and reproductive cycles do not occur at the expected time of puberty although the gonadotrophic axis has achieved the appropriate endocrine prole for the initiation of ovulation. Finally, lambs become anestrous young adults which paradoxically are still peripubertal [18, 57]. In this regard, the summer- or autumn-born female lambs of the aseasonal [57] and highly seasonal [13] breeds, reach the pubertal age during the anestrous season and thus their endocrine puberty is delayed until the following breeding season. Sexual maturation is then expressed by the
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transition from post-maturational anestrous, and this reects the initiation of puberty rather than the onset of the breeding season in adults [57]. Thus, the prepubertal short-day breeder must experience some long days of summer to fulll an important photoperiodic requirement for the normal timing of sexual maturation [19, 62, 63]. Exposure to as little as one week of long days at late prepuberty is sufcient for resetting puberty to the normal age [18, 62]. However, prenatal and early postnatal photoperiod treatments alter neither the reproductive neuroendocrine development nor the timing of puberty, as is the case for such treatments later in life [3, 26, 57]. The failure of early long day exposure to induce puberty several weeks later is due to a postpineal gland deciency [20] related to a developing the HPG axis, which itself is unable to respond to photoperiodic changes [14, 57, 61]. In conclusion, the maturational transition from infantile spring to pubertal autumn phenotypes occurs when the number of LH-containing gonadotrophs and day length exceed simultaneously a minimum threshold termed the endocrine maturity of the gonadotroph population and critical photoperiod during the optimal season for reproductive functions. In shortday breeders, the pubertal pattern remains basically seasonal in nature on the level of the neuroendocrine integration of growth and sexual maturation. This provides evidence of an inherent endogenous rhythm controlling mammalian maturation.
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39. Napolitano F, Annicchiarico G, Caroprese M, De Rosa G, Taibi L, Sevi A 2003 Lambs prevented from suckling their mothers display behavioral, immune and endocrine disturbances. Physiology & Behavior 78 81-89. 40. Ojeda SR, Jameson HE 1977 Developmental patterns of plasma and pituitary growth hormone (GH) in the female rat. Endocrinology 100 881-889. 41. Polkowska J, Przekop F 1988 Immunocytochemical changes in hypothalamic and pituitary hormones after acute and prolonged stressful stimuli in the anestrous ewe. Acta Endocrinologica (Copenhagen) 118 269-276. 42. Polkowska J, Przekop F 1992 Neuroendocrine responses to footshock stress in anestrous ewes. Stress-neuroendocrine and molecular approaches, pp. 467-472. Eds Kvetnanski R, McCarty R, Axelrod J. Gordon and Breach Science Publishers, Philadelphia. 43. Polkowska J, Wakowska M, Riddestråle Y, Wójcik-Gadysz A, Madej A, Tillet Y 2008 Prepubertal changes in the synthesis, storage and release of growth hormone and luteinising hormone and in the immunoreactivity of oestrogen receptor-D in lambs pituitary cells. Journal of Chemical Neuroanatomy 35 257-267. 44. Przekop F, Woliska-Witort E, Mateusiak K, Sadowski B, Domaski E 1984 The effect of prolonged stress on the oestrous cycles and prolactin secretion in sheep. Animal Reproduction Science 7 333-342. 45. Przekop F, Stupnicka E, Wolinska-Witort E, Mateusiak K, Sadowski B, Domaski E 1985 Changes in circadian rhythm and suppression of plasma cortisol level after prolonged stress in the sheep. Acta Endocrinologica 110 540-545. 46. Przekop F, Polkowska J, Mateusiak K 1988 The effect of prolonged stress on the hypothalamic luteinizing hormone-releasing hormone (LHRH) in the anoestrous ewe. Experimental and Clinical Endocrinology 91 334-340. 47. Schmidt M, Okimoto DK, Dent GW, Gordon MK, Levine S 2002 Maternal regulation of the hypothalamic-pituitary-adrenal axis in the 20-day-old rat: consequences of laboratory weaning. Journal of Neuroendocrinology 14 450-457. 48. Shiomi H, Watson SJ, Kelsey JE, Akil H 1986 Pretranslational and posttranslational mechanisms for regulating beta-endorphin-adrenocorticotropin of the anterior pituitary lobe. Endocrinology 119 1793-1799. 49. Suchecki D, Rosenfeld P, Levine S 1993 Maternal regulation of the hypothalamicpituitary-adrenal axis in the infant rat: the roles of feeding and stroking. Brain Research. Developmental Brain Research 75 185-192. 50. Suttie JM, Kostyo JL, Ebling FJP, Wood RI, Bucholtz DC, Skottner A, Adel TE, Towns RJ, Foster DL 1991 Metabolic interfaces between growth and reproduction. IV. Chronic pulsatile administration of growth hormone and the timing of puberty in the female sheep. Endocrinology 129 2024–2032. 51. Thomas SG, Clarke IJ 1997 The positive feedback action of estrogen mobilizes LHcontaining, but not FSH-containing secretory granules in ovine gonadotropes. Endocrinology 138 1374-1350. 52. Torronteras R, Gracia-Navarro F, Elsaesser F 1997 Control of growth hormone secretion from porcine fetal and neonatal pituitary tissue in vitro by growth hormone-releasing hormone, somatostatin, and insulin-like growth factor. Neuroendocrinology 65 117128.
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53. Veldhuis JD, Roemmich JN, Richmond EJ, Bowers CY 2006 Somatotropic and gonadotropic axes linkages in infancy, childhood, and the puberty-adult transition. Endocrine Reviews 27 101-140. 54. Wakowska M, Polkowska J 2006 The postnatal ontogeny of gonadotroph cells in the female sheep. Developmental patterns of synthesis, storage and release of gonadotrophic hormones. Journal of Chemical Neuroanatomy 31 130-138. 55. Wakowska M, Polkowska J 2009 Gonadotrophin-releasing hormone and GnRHassociated peptide neurobiology from the rearing period until puberty in the female sheep. Journal of Chemical Neuroanatomy 38 9-19. 56. Wakowska M, Starzec A, Counis R, Polkowska J 2006 Effects of maternal deprivation on the adrenocorticotrophic and gonadotrophic axes in the hypothalamo-pituitary unit of preweanling female sheep: the histomorphometric approach. Journal of Chemical Neuroanatomy 31 51-58. 57. Wakowska M, Misztal T, Romanowicz K, Wójcik-Gadysz A, Polkowska J 2008 The intrapituitary endocrine events during maturation and timing of puberty in the female sheep. Animal Reproduction Science 105 258-271. 58. Wakowska M, Romanowicz K, Polkowska J 2008 The neuroendocrine events during the ovine growth-promoted maturation: the developmental importance of hypophysiotrophic action of somatostatin in ewes. Animal Reproduction Science 109 146-160. 59. Warren MP, Fried JL 2001 Hypothalamic amenorrhea. The effects of environmental stresses on the reproductive system: a central effect of the central nervous system. Endocrinology and Metabolism Clinics of North America 30 611-629. 60. Wilson ME, Gordon TP, Rudman CG, Tanner JM 1989 Effects of growth hormone on the tempo of sexual maturation in female rhesus monkeys. Journal of Clinical Endocrinology and Metabolism 68 29-38. 61. Wood RI, Claypool LE, Ebling FJ, Foster DL 1989 Entrainment of the melatonin rhythms in early postnatal lambs and their mothers. Journal of Biological Rhythms 4 457-465. 62. Yellon SM, Foster DL 1985 Alternate photoperiods time puberty in the female lamb. Endocrinology 116 2090-2097. 63. Yellon SM, Foster DL 1986 Melatonin rhythms time photoperiod-induced puberty in the female lamb. Endocrinology 119 44-49. 64. Young EA, Akil H 1985 Corticotropin releasing factor stimulation of adrenocorticotropin and E-endorphin release: effects of acute and chronic stress. Endocrinology 117 23-30. 65. Zapatero-Caballero H, Sanchez-Franco F, Fernandez-Mendez C, Garcia-San Frutos M, Botella-Cubells LM, Fernandez-Vazquez G 2004 Gonadotropin-releasing hormone receptor gene expression during pubertal development of female rats. Biology of Reproduction 70 348-355.
3
REVIEW
The pituitary endocrine mechanisms involved in mammalian maturation: maternal and photoperiodic inuences Marta Wakowska1, Jolanta Polkowska Department of Endocrinology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabonna, Poland
Received: 3 February 2009; accepted: 4 November 2009
SUMMARY This review is designed to describe some pituitary mechanisms indispensable for growth and sexual maturation during the neuroendocrine adaptation of the female mammal to the extrauterine environment. We dene the phases of postnatal development on the basis of secretory patterns of hormones. The infantile period is characterized by accelerated growth, and elevated secretion of growth hormone (GH) and follicle-stimulating hormone (FSH) in contrast to the diminished secretion of luteinizing hormone (LH). The transition from infancy to prepuberty generates the attenuation of somatic growth in non-primate mammals and the beginning of sexual maturation. The mechanisms of this transition involve the effects of weaning, which is associated with a rupture of the young-mother bond and, if abrupt, results in the stress of maternal deprivation. Maternal deprivation involves the stress-like endocrine response of pituitary and inuences the mechanisms 1
Corresponding author: Department of Endocrinology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabonna, Poland; e-mail: [email protected]
Copyright © 2010 by the Society for Biology of Reproduction
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underlying the secretion of GH and FSH. An acute decrease in the secretion of GH and FSH at the initiation of prepuberty and an increase in the storage and pulsatile release of LH according to progressive prepubertal stages are pituitary endocrine features of post-infantile maturation. There are two factors important for timing of puberty, the maturity of gonadotroph population manifested by the adequate size of LH-containing cell subpopulation and the circumstances of an external environment optimal for reproductive functions in adults. Thus, the intrapituitary endocrine mechanisms of maturation have a psychosomatic nature during weaning and histomorphological nature during the postinfantile transition to puberty. In seasonal breeders, the endocrine timing of puberty has a circumannual seasonal nature. Reproductive Biology 2010 10 1: 3-18. Key words: stress, growth, seasonality, puberty, ACTH, GH, LH, FSH
INTRODUCTION Somatic maturation is affected by the interaction between environmental and genetic factors and depends on the coordinated functions of different hypothalamo-pituitary axes. The pituitary gland reaching maturity is a seminal event in ontogeny leading to neuroendocrine control of many complex functions of the organism. Adrenocorticotrophic, somatotrophic and gonadotrophic cells, as the sites of ACTH, GH, LH and FSH secretion, respectively, provide pituitary effector mechanisms of the stress response, systemic growth and functions of the reproductive system. Thus, pituitary cells are the setting for endocrine mechanisms that prepare an organism for extrauterine life and for the pivotal systemic activity – reproduction. Weaning and puberty involve neuroendocrine states which evoke major changes in the secretion of hormones, and thus are transitional for postnatal development. These endocrine changes lead to the full presentation of the adult phenotype, i.e. physiological and behavioral maturity [54, 57, 58]. Weaning involves a rupture in the mammalian mother-infant psychoemotional and nutritive bonds and, if abrupt, results in the stress of maternal deprivation, i.e. psychoemotional and, consequently, physiological distur-
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bances of homeostasis. These psychosomatic effects should be treated as natural mechanisms of the transition from the infantile to juvenile period of postnatal ontogeny [56]. However, it should be reminded, that early-life stressful stimulation can induce long-lasting effects on the hypothalamopituitary-gonadal (HPG) axis [23]. In contrast to maternal regulations which predominate during the infantile period, post-infantile maturation is under external inuences which regulate reproductive functions in adults [53]. In this regard, the onset of puberty in seasonal breeders is determined by the circumannual environment, i.e. photoperiod and/or seasonal availability of food [55, 57, 58].
THE EFFECT OF STRESS ON THE SECRETION OF HORMONES DURING THE TRANSITION FROM THE INFANTILE TO JUVENILE PERIOD OF ONTOGENY The activation of the hypothalamo-pituitary-adrenal (HPA) axis, is the main dening feature of neuroendocrine adaptation known as the stress response [30]. The mammalian HPA system is under maternal regulation, namely, the mother appears to actively inhibit HPA responses in her postnatally developing offspring [24, 29, 31]. The development of different aspects of the HPA system in young is regulated by different aspects of maternal behavior [31]. Feeding appears to regulate adrenal sensitivity whereas tactile stimuli inhibit the activation of centrally-controlled components of the axis [49]. The mother probably has rewarding properties for her young, associated with nutritive suckling, and maternal deprivation increases reward value of mother for pup [1]. In rodents and lambs, maternal deprivation results in the disregulation of the HPA axis at multiple levels. This effect is observed even at the time of weaning or beyond the time of weaning, when the young are capable of self-feeding and no longer require tactile stimulation to induce some systemic functions [30, 39, 47, 56]. In maternally deprived weanling lambs, the increase in the release of corticotrophin-releasing hormone from the nerve terminals in the median eminence to the pituitary portal circulation is followed by an increase in the accumulation of ACTH. The increase
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in the storage of ACTH is manifested by hypertrophy and hyperplasia of corticotrophs in response to the prolonged psychoemotional challenge to homeostasis [56]. Similar secretory changes and normal cortisol secretion in response to exogenous ACTH are observed in the hypothalamo-pituitary unit of adult ewes after prolonged electric foot-shocks [41, 45]. Also in rats, chronic stress elevates the ACTH content in the pituitary gland without changes in peripheral blood plasma ACTH and corticosteroid levels [64]. This increase is probably due to both the increase in biosynthesis and the decrease in the processing of ACTH [48]. Thus, in mammals during longer exposure to stressful stimuli, attenuated ACTH release may cause the hypocortisolemia. The resemblance of the HPA axis responsiveness during the development of lambs after the neonatal period to that of mature ewes [38, 41, 56] implies, that the maturation of intrapituitary stress responsivity is likely a result of developmental modications that occur before the weaning period. Altogether, the psychosomatic state evoked by maternal deprivation affects the HPA axis and causes the stress-like endocrine response of the pituitary gland in the infantile mammal. The stress of both physical and emotional origin affects the reproductive system of the female mammal by the suppression of the HPG axis secretory activity and reduction of gonadal functions [8, 21, 23, 44, 46, 56, 59]. However, the predominant impact of the psychosomatic stress of maternal deprivation is on the FSH secretory activity of pituitary gonadotrophs [56]. Maternal deprivation induces an increase in gonadotropin-releasing hormone (GnRH) storage in the nerve terminals of the median eminence and/or suspending of GnRH release in lambs [56]. Similar changes are observed in adult ewes submitted to prolonged [46] or long-term [42] stressful stimulation. The alterations observed in the hypothalamic processing of GnRH are followed by changes pertaining to secretion of gonadotropins in the pituitary cells [42, 56]. The evident contrast is observed between the acute decrease in the secretion of FSH and no changes in the LH in maternally deprived lambs. This diversity may be partially explained by the different pre-translational regulation of LH and FSH synthesis [56]. Similarly to the HPG axis, maternal deprivation affects the somatotrophic axis. This effect involves the enhancement of GH secretion via restraining
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of somatostatin output in lambs during the weaning period (J. Polkowska and M. Wakowska, unpublished). In conclusion, the stressful disruption of social interactions between the young and mother can affect the intrapituitary mechanisms underlying the secretion of gonadotrophic hormones and GH during the transition from the infantile to juvenile period of ontogeny. This stress response is important for the maintenance of homeostasis in the weanling mammal.
THE INTRAPITUITARY PROCESSING OF LH AND FSH DURING THE TRANSITION FROM INFANCY TO PUBERTY The pre-translational regulation of LH and FSH synthesis during maturation is similar in rats [65] and sheep [54]. Namely, LHE and FSHE mRNA contents rise slowly during the infantile period and then fall during the juvenile period until peri-puberty (g. 1). It should be noted, that the regulation of gonadotropin subunits’ gene expression and translation may be inuenced by alterations in the stability and half-life of mRNA (for review see: [4]). Thus, transcriptional synthesis of gonadotrophic E subunits is highest during the transition from infancy to prepuberty, i.e. the initiation of the juvenile period of sexual maturation [54]. In contrast to the synthesis, storage patterns of LH and FSH are different in rats and sheep during the transition from infancy to the peripubertal stage around the time of neuroendocrine initiation of puberty (g. 1; [28, 54]). First, the number of gonadotrophs per pituitary tissue as well as the amounts of LH and FSH in pituitary cells increase during infancy, which is reected by the low plasma LH levels [2, 15]. Then, in rats the number of LH-containing cells remains high until puberty [28], whereas in sheep increases from weaning until peripuberty [54] when the plasma LH pulse frequency and mean concentration are heightened [16, 54]. It is generally accepted that an increase in the frequency of episodic LH secretion is a key event leading to the onset of ovarian cycles [27]. In contrast to LH, the number of FSH-containing gonadotrophs decreases from the beginning of the weaning period in rats [28] and from the post-
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Figure 1. The schematic comparison of LH, FSH and GH secretory patterns dening the phases of postnatal development in female sheep until puberty. (): increase, (): decrease, (=): similar level in comparison with the previous indicated stage, ?: unknown. Unpublished compilation of data reported in Refs. 7, 15, 16, 22, 27, 36, 43, 54, 57 and 58.
weaning stage in sheep [54] until puberty. Thus, the storage of FSH is extremely high during the weaning period and extremely low during the juvenile period in both species (g. 1; [28, 54]). In the case of FSH release, the relatively low plasma FSH level during the neonatal period and the beginning of infancy are followed by an increase during weaning and the post-weaning stage and a decrease during prepuberty and peri-pubertal initiation of puberty in both species [16, 25]. It should be mentioned, that in the rhesus monkey during the juvenile-adult transition, the pituitary gonadotroph population increases and a large number of monohormonal FSH gonadotrophs are likely to become bihormonal [34]. These ndings on rats, sheep and primates attest that gonadotrophs can switch their hormonal identity in response to maturational circumstances. In this regard, the neuroendocrine transition from infancy to prepuberty changes GnRH neurobiology in the preoptic area-hypothalamus to the pattern which results in the maturational increase from the low infantile
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terminal storage of GnRH in the median eminence to the high peripubertal one and thus allows the initiation of ovine puberty [55]. Altogether, the similar pre-translational regulation of LH and FSH synthesis but clearly different storage and release patterns are characteristic for prepubertal mammals. Mechanisms responsible for divergent LH and FSH secretion during somatic maturation may be explained by the differential posttranscriptional regulation [54, 57]. This is in agreement with the notion, that the secretion of both LH and FSH throughout sexual development are differentially regulated by changes in the proportion of gonadotroph subtypes within the total pituitary gonadotroph population [34]. A feature of the GnRH/ LH secretory pathway is the ability of LH protein to be stored [4, 32]. The secretory pattern of LH does not reect its transcriptional rate, but is related to posttranslational intrapituitary mechanisms due to the storage and transportation of secretory granules within the gonadotrophs [4, 51]. This intracellular mechanism probably switches non-releasing gonadotrophs into a potentially releasable state [5]. The above-discussed discrepancies imply the existence of the histomorphological feature of intrapituitary regulation of posttranscriptional processing and release of LH during the transition from the infantile to peripubertal activity of gonadotroph population. In contrast to LH, the release of FSH is primarily constitutive [11, 12]. FSH is trafcked to the site of exocytosis shortly after synthesis, and released. Thus, a strong relationship exists between the level of pituitary FSHE mRNA and plasma FSH, which is representative for constitutively secreted hormones [4]. These ndings imply the maturational importance of the relationship between the transcriptional synthesis and storage of FSH in contrast to the relationship between the storage and release of LH [54]. In conclusion, the differential regulation of both gonadotropins in the postnatally developing mammal is on the level of posttranscriptional processing and release rather than on the level of gene expression. The suggested requirement for sexual maturation is the change in the histomorphological feature of gonadotroph population, dependent on the increase in the number of LH-containing cells.
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SOME ENDOCRINE ASPECTS OF THE GROWTH-PROMOTED MATURATION The somatotrophic cells, as the site of GH secretion, are the morphological setting for the pituitary effector mechanism of the neuroendocrine aspects of systemic growth. In female sheep, serum GH concentration declines to a low level at approximately 12-14 weeks of age, i.e. at the end of infancy and no obvious pubertal increase occurs [50, 58]. In contrast, in humans [37], monkeys [60] and rats [40] serum GH is elevated during puberty. In the sheep, the functional development of the GH axis is complete just before the beginning of the juvenile period during the postweaning stage (g. 1) independently of photoperiodic inuences [58]. However, the developmental processing within the hypothalamo-hypophyseal unit prolongs after the postweaning stage and concerns the importance of somatostatin as the hypophysiotrophic factor controlling somatic maturation. This increasing role of somatostatin from the postweaning stage until late prepuberty is the reason for the natural fall in the circulating level of GH with postnatal age in the female sheep [58]. The suppressive effect of somatostatin on the GH response to GH-releasing hormone increases acutely at birth [7], and generally GH secretion in the neonate is more sensitive to the inhibitory inuence of somatostatin in comparison with the fetus [22, 52]. The pattern of early postnatal GH secretion in sheep is important for the shift between infancy and prepuberty. This shift depends upon the intensive somatic growth [58]. In contrast, in female primates an increased GH level is involved in the pubertal growth spurt, i.e. correlates strongly with height velocity characteristic for the major period of accelerated linear growth observed during pubertal maturation [35]. In rats, plasma GH level is elevated during puberty, which suggests a physiological role of GH in the control of the pubertal process in this species [40]. However, in contrast to primates, in female rats the adult-like high GH level during puberty does not correlate with the acute growth. In female rats and lambs, the increase in the slope of the curve of body weight gain is observed until the juvenile period [40, 58]. In female sheep puberty is not a weight- or growth-promoted event. Likewise the post-infantile decrease in GH secretion is not a requirement for
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puberty and does not provide a direct cue for the normal timing of neuroendocrine sexual maturation [50, 58]. This fall in serum GH level corresponds with the natural postweaning stage and the beginning of the phase of lower daily live-weight gains [58]. This reects a decline from the high prenatal and neonatal levels to the low level similar to those observed in adult sheep [50]. The postweaning stage is transitional for the maturation of the GH/ IGF-I relationship [50] and corresponds with the ending of intensive growth and beginning of fat deposition [6, 33, 58]. In conclusion, the pattern of GH secretion during weaning is important for the infantile/prepubertal shift. This shift depends upon the maturation of the neuroendocrine somatotrophic system and, consequently, is related to the intensive systemic growth. The development of the morphological and physiological basis for GH secretion is nished just after weaning, independently of photoperiodic inuences. Then the GH secretion is under the maturing hypophysiotrophic inuences of somatostatin.
THE NATURE OF ENDOCRINE MECHANISMS TIMING THE PUBERTAL TRANSITION TO ADULTHOOD IN SEASONAL BREEDERS In the female sheep, the intrapituitary mechanism that prepares the gonadotroph population for puberty is represented by an increase in the storage of LH accompanied by a comparable decrease in the storage of FSH (gs. 1 and 2; [57]). The heterogeneity in the patterns of LH and FSH posttranscriptional processing is resultant of different regulations on the level of synthesis and storage rather than on the level of release. First, during peripuberty the increase in the transcription and stability of LHE mRNA is observed. Then, in the initiation of puberty the mechanisms dominate which depend upon the increase in both the translational processing and storage of LH, accompanied by the decrease in both the synthesis and storage of FSH (gs. 1 and 2; [57]). Since the overt sign of puberty in the female lamb is rst behavioral estrus, puberty would be more adequately dened by the ability to ovulate and to allow insemination by the ram [9]. Foster et al. [20] have previously
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Pituitary and mammalian maturation
Figure 2. Pituitary gonadotrophs containing in situ hybridised mRNA transcripts encoding LH-subunit or FSH-subunit and immunoreactive LH or FSH in the representative infantile and pubertal female sheep. Calibration bars: 50 m. Note the small population of gonadotrophs containing LH mRNA, FSH mRNA and FSH and great population of LH-containing gonadotrophs in pubertal lamb in comparison with infantile lamb. Unpublished photographs from authors’ database.
associated puberty with three consecutive ovulatory surges producing the luteal-phase progesterone increases. The rst ovulatory surge during the life produces a short luteal phase, the second one produces a luteal phase sufcient to provide adequate progesterone priming, so that the third ovulatory surge is accompanied by behavioral estrus (for review see: [17]). Ovulation in pubertal lambs is related to similar regulation on the level of LH and FSH transcriptional synthesis and release rather than on the level of their storage. In comparison with pubertal sheep, the patterns of posttranscriptional regulation for LH and FSH during the estrous cycle of adult ewes are quite different (for review see [57]). Altogether, the heterogeneity in the posttranscriptional regulation of LH and FSH in the initiation of puberty contrasts with the similarity in this regulation during the ovine pubertal cycle. Once the peripubertal endocrine mechanisms are initiated, a sequence of neuroendocrine events is set in motion that leads to puberty independently of any inuences of the external environment. However, in females of numerous wild-living species, which may be represented by such domesticated ruminants as sheep, seasonal changes in day length (photoperiod) are the primary environmental cue responsible for the annual activity of the repro-
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ductive system. In female sheep, the neuroendocrine mechanisms which integrate growth and sexual maturation may be seasonal in nature [58]. The peripubertal GnRH neurobiology in the preoptic area-hypothalamus, related to the later neuroendocrine-hypophysiotrophic pubertal function of GnRH, is primarily seasonal in nature [55]. Moreover, daylight exposure requirements for puberty in female lambs differ from those for the onset of the breeding season in adult ewes [10]. In such short day breeders as female sheep from cold and temperate climates, the seasonal decrease in photoperiod is necessary for the normal timing of puberty [18] irrespective of time of birth and probably reects the limited photoperiodic history of the lamb [17]. However, puberty does not occur at the appropriate age if the decrease in day length is experienced very early in postnatal life, as seen in the rst 10 weeks [14, 62]. These observations prompt the hypothesis that the seasonal breeder is able to transduce changes in day length into the appropriate endocrine cues for sexual maturation during its later postnatal life. This is possible when gonadotrophs attain full peripubertal efciency manifested by sufcient LH storage [57]. Namely, female lambs are highly sensitive to changes in photoperiod with respect to the suspension of maturational gonadotrophic functions at peripuberty on the level of LH storage and release, but not on the level of LH synthesis [57]. The postnatal development of the gonadotroph population in the female sheep lasts approximately seven months [54]. Thus, the lamb must be born near the vernal equinox (i.e. in the season) to attain the ‘pubertal age’, resulting from gonadotroph population maturity, during the breeding season of the rst year of life [57]. In females born after the summer solstice, the full peripubertal efciency of gonadotroph cells is attained after the winter solstice, i.e. during the increasing photoperiod [57]. Consequently, endocrine maturation is masked, and reproductive cycles do not occur at the expected time of puberty although the gonadotrophic axis has achieved the appropriate endocrine prole for the initiation of ovulation. Finally, lambs become anestrous young adults which paradoxically are still peripubertal [18, 57]. In this regard, the summer- or autumn-born female lambs of the aseasonal [57] and highly seasonal [13] breeds, reach the pubertal age during the anestrous season and thus their endocrine puberty is delayed until the following breeding season. Sexual maturation is then expressed by the
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Pituitary and mammalian maturation
transition from post-maturational anestrous, and this reects the initiation of puberty rather than the onset of the breeding season in adults [57]. Thus, the prepubertal short-day breeder must experience some long days of summer to fulll an important photoperiodic requirement for the normal timing of sexual maturation [19, 62, 63]. Exposure to as little as one week of long days at late prepuberty is sufcient for resetting puberty to the normal age [18, 62]. However, prenatal and early postnatal photoperiod treatments alter neither the reproductive neuroendocrine development nor the timing of puberty, as is the case for such treatments later in life [3, 26, 57]. The failure of early long day exposure to induce puberty several weeks later is due to a postpineal gland deciency [20] related to a developing the HPG axis, which itself is unable to respond to photoperiodic changes [14, 57, 61]. In conclusion, the maturational transition from infantile spring to pubertal autumn phenotypes occurs when the number of LH-containing gonadotrophs and day length exceed simultaneously a minimum threshold termed the endocrine maturity of the gonadotroph population and critical photoperiod during the optimal season for reproductive functions. In shortday breeders, the pubertal pattern remains basically seasonal in nature on the level of the neuroendocrine integration of growth and sexual maturation. This provides evidence of an inherent endogenous rhythm controlling mammalian maturation.
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5. Currie RJW, McNeilly AS 1995 Mobilization of LH secretory granules in gonadotrophs in relation to gene expression, synthesis and secretion of LH during the preovulatory phase of the sheep oestrous cycle. Journal of Endocrinology 147 259-270. 6. Davis SL, Hossner KL, Ohlson DL 1984 Endocrine regulation of growth in ruminants. Manipulation of growth in farm animals, pp. 151-178. Eds Roche JF, O’Callaghan D. Martinus Nijhoff, The Hague. 7. DeZeghner F, Daaboul J, Grumbach MM, Kaplan SL 1989 Hormone ontogeny in the ovine fetus and neonate. XXII. The effect of somatostatin on the growth hormone (GH) response to GH-releasing factor. Endocrinology 124 1114-1117. 8. Domey JH, Gunn RG, Grifts JG 1973 The effect of premating stress on the onset of oestrus and ovulaion rate in scottish blackface ewes. Journal of Reproduction and Fertility 35 381-384. 9. Dýrmundsson ÓR 1983 The inuence of environmental factors on the attainment of puberty in ewe lambs. In: Sheep production, pp. 393-408. Eds Haresign W. Butterworths, London. 10. Ebling FJP, Foster DL 1988 Photoperiod requirements for puberty differ from those for the onset of the adult breeding season in the female sheep. Journal of Reproduction and Fertility 84 283-293. 11. Farnworth PG, Robertson DM, de Kretser DM, Burger HG 1988 Effects of 31 kilodalton bovine inhibin on follicle-stimulating hormone and luteinizing hormone in rat pituitary cells in vitro: actions under basal conditions. Endocrinology 122 207-213. 12. Farnworth PG, Thean E, Robertson DM 1995 Ovine anterior pituitary production of follistatin in vitro. Endocrinology 136 4397-4406. 13. Foster DL 1981 Mechanism for delay of rst ovulation in lambs born in the wrong season (Fall). Biology of Reproduction 25 85-92. 14. Foster DL 1983 Photoperiod and sexual maturation of the female lamb: early exposure to short days perturbs estradiol feedback inhibition of luteinizing hormone secretion and produces abnormal ovarian cycles. Endocrinology 112 11-17. 15. Foster DL, Jaffe RB, Niswender GD 1975 Sequential patterns of circulating LH and FSH in female sheep during the early postnatal period: effect of gonadectomy. Endocrinology 96 15-21. 16. Foster DL, Lemons JA, Jaffe RB, Niswender GD 1975 Sequential patterns of circulating luteinizing hormone and follicle-stimulating hormone in female sheep from early postnatal life through the rst estrous cycles. Endocrinology 97 985-994. 17. Foster DL, Karsch FJ, Olster DH, Ryan KD, Yellon SM 1986 Determinants of puberty in a seasonal breeder. Recent Progress in Hormone Research 42 331-384. 18. Foster DL, Yellon SM, Ebling FJ, Claypool LE 1988 Are ambient short-day cues necessary for puberty in a short-day breeder? Biology of Reproduction 38 821-829. 19. Foster DL, Ebling FJ, Claypool LE, Woodll CJ 1988 Cessation of long day melatonin rhythms time puberty in a short day breeder. Endocrinology 123 1636-1641. 20. Foster DL, Ebling FJ, Claypool LE, Wood RI, Adel TE, Schramm W 1989 Amplitude modulation of the nightly melatonin rise in the neonatal lamb and the subsequent timing of puberty. Biology of Reproduction 40 920-928. 21. Genazzani AD 2005 Neuroendocrine aspects of amenorrhea related to stress. Pediatric Endocrinology Reviews 2 661-668.
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