J. Endocrinol. Invest. 7: 157, 1984 REVIEW ARTICLE

Pineal gland, photoperiodic responses, and puberty 1 D.P. Cardinali, and M.I. Vacas

Centro de Estudios Farmacologicos y de Principios Naturales (CEFAPRIN), Serrano 665/669, 1414 Buenos Aires, Argentina

PINEAL GLAND AND PHOTOPERIODIC CHANGES OF REPRODUCTION

INTRODUCTION Reproductive function in mammals consists of an intricate interplay of hormonal events that are responsible for the development and maturation of gametes, puberty' the major events of the estrous cycle (i.e. ovulation and sexual receptivity), and the preparation of the uterus for the possible implantation of embryos. In the majority of wild species most of these processes are restricted to a specific time of the year; indeed during the course of evolution nature has selected against those animals whose offsprings are born when conditions for survival are not optimal. The major environmental variable controlling seasonal reproductive activity is the photoperiod; this is not surprising since on a given day photoperiod is constant from year to year, whereas other environmental parameters such as temperature or humidity are quite variable (1, 2). In long-day breeders like ferrets, voles or hamsters, short photoperiods induce gonadal regression, while long photoperiods hasten development or recrudescence; the opposite effect is observed in animals like sheep, goats or deer, that mature in fall or winter. In general puberty occurs at about the same time of the adult maturing season and therefore is also a photoperiodic reproductive phenomenon. In species with rapid development (e.g. rodents) animals born early in the year mature rapidly and reproduce within the same season, while in animals born at the end of breeding season, puberty is delayed until the beginning of the next season. Since the activity of the pineal gland is known to be dependent on the lighting environment, and it in turn affects many aspects of reproductive physiology, the possible influence of the pineal on puberal maturation has been a popular subject of scientific quest (3). The present article discusses some of the latter developments in this field.

Two main hypotheses exist to explain how living organisms respond to changes in daylength (1 ). I n one, it is proposed that the response depends on the absolute number of hours of light or dark in each 24-hour period (hourglass model). In the other, the response depends on the way the daily photoperiod influences circadian rhythms generated endogenously by the animal (circadian hypothesis). Support for the circadian model comes from experiments on a wide range of insects, birds and mammals. Organisms possessing an endogenous circadian rhythm in the sensitivity to light exhibit two half-cycles (12 h each), the so-called photophillic and scotophillic phases. In long-days (light period more than 12 h) light impinges into the photophillic phase, that is, the half of the daily cycle which is sensitive to light, and in long-day breeders this produces a photO-induced response. An equivalent mechanism, albeit opposite, can be envisaged for a short-day species. Light has the dual role of inducer (or suppressor) and entraining agent for endogenous circadian rhythms, or it only serves to entrain the endogenous rhythms, induction being the result of internal phase relationship of at least two separate rhythms (1, 2). In mammals transmission of photic information mediating control of reproductive activity begins with the eyes. Retinal photoreceptors most likely transmit the information to the suprachiasmatic nuclei of the hypothalamus via a monosynaptic pathway known as the retino-hypothalamic tract. The age at which direct retinohypothalamic projections to the suprachiasmatic nuclei mature in the rat is about 17 days (4). Studies in several species show that the suprachiasmatic nuclei are essential components of the photoperiodic mechanism participating in. the generation of circadian rhythms, including the rhythm in photosensitivity. Although specific neural tracts have not been identified beyond the suprachiasmatic nuclei, the photoperiodic information is probably transmitted to the pineal gland by way of descending pathways to the superior cervical ganglia. Since there are no known neural efferents from the pineal, a humoral Signal from this gland is presumed to transmit the information to the hypothalamic-pituitary axis. The involvement of the pineal gland in photoperiodic

1Studies ,n authors' laboratory were supported by grants from the Consejo Naeional de Investigae,ones Cientif,eas y Teenieas (CONICET) (no. 6638) and the "Fundacion Alberta J. Roemmers", Argentina. The authors are Established Investigators, CONICET, Argentina

Key-words: Puberty, pineal gland, melatonin, photoperiodicity, biological rhythms

Correspondence- Or. DP. Cardinali, CEFAPRIN, Serrano 665/669, 1414 Buenos Aires, Argentina

157

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Cardinall~

and M.1. Vacas winter in many ruminants including cattle, goat, sheep and deer (8-1 0). Indeed pinealectomy or pineal denervation has been shown to alter annual serum prolactin profiles in rams, goats and deer (8), Pinealectomy also abolishes the influence of photoperiod on plasma prolactin levels in castrate lambs, Additionally, pinealectomy alters the seasonal tunning of peak prolactin responses after TRH injection in deer (8-10),

gonadal responses was first studied in the golden hamster; in this species pinealectomy prevents the effect of short days or blinding which normally induce gonadal regression (3), Although these effects of pinealectomy have led to the general opinion that the pineal gland is essentially antigonadotropic, other observations in Djungarian hamsters (5) and ferrets (6) as well as in birds (7) tend to support the conclusion that the pineal is neither progonadotropic nor antigonadotropic but rather it is an essential organ for the photic entrainment of the annual reproductive cycle, Not only pinealectomy but also interference with its sympathetic innervation suppresses photoperiodic effects. Surgical interruption of the nervi conarii, which innervate the pineal, or extirpation of the superior cervical ganglia, or chemical sympathectomy, has been shown to inhibit the effects of short photoperiods in rats, hamsters and voles (3, 5), Decentralization of the ganglia or interruption of the multisynaptic pathway described above, has the same effect.

PINEAL ROLE IN PUBERTY, EXPERIMENTAL STUDIES Puberal maturation involves a delicate interplay of hormones from the hypothalamus, pituitary and gonads that result in a resetting of feedback threshold and other adjustments of the hypothalamic-pituitary-gonadal axis that characterize the adult, reproduclively functional mammal (11 ), On this basis puberty can be defined as the time when the hypothalamic-hypophysial unit is competent to respond to an effeclive increment in Circulating estrogens with a preovulatory surge of LH and FSH, At this time of transition the reproductive physiology of mammals appears to be particularly sensitive to the influence of the pineal gland (3). Such sensitivity was explored in rodents, I n rats neonatal pinealectomy advances the time of vaginal opening (12), while darkness from the 21 st day of the life delays it and impedes development of testes, seminal vesicles and coagulating glands (3). Pinealectomy prevents the effects of constant dark; it has been also reported to advance pregnant mare's serum (PMS)-induced ovulation in rats (13), Of course all these observations do not answer the question whether the site of action of the presumptive pineal hormones is central or peripheral. Two studies describing the effects of prepuberal pinealectomy in male and female rats are depicted in Figure 1, Pinealectomy of males at the 30th day of life resulted in a transient increase of circulating testosterone about 20 days later, as well as in persistent increases of testicular weight, both indirect evidences of excess LH and FSH activity (14).

The normal patterns in hamsters suffering from pinealmediated gonadal atrophy have been described in considerable detail (3), Although FSH and LH levels are sometimes depressed in hamsters maintained under short-day conditions, there are instances when apparently normal plasma gonadotropin levels are measured in the presence of severe reduced gonadal weights, This observation portends an important role for another hormone in the maintenance of testicular size and function in hamster, Prolactin appears to be such a hormone since LHRH injection, which increases several-fold FSH and LH release, fails to overcome seasonal gonadal involution unless associated with experimental hyperprolactinemia, Such stimulatory role of prolactin is attributed to an effect on gonadal LH receptors (3), The possible involvement of the pineal in circannual endocrine rhythms in ungutates seems likely, since circulating prolactin concentrations follow a seasonal pattern in temperate zone latitudes, with highest levels occurring in summer monlils and lowest in the

Fig. 1 - Effect of pinealectomy (Px) on the development of steroid feedback on LH release In female rats (left panel) and on plasma testosterone levels and testicular weight In male rats (right panel) (data from references.' 74. 75).

Days of age

158

Pineal, photoperiods and puberty

Table 1 - Some compounds identified within the pineal gland.

Estrogen or progesterone injected into estrogenprimed mature animals or women induces LH and FSH release (8 , 11). The failure of ovarian steroids to activate LH release in female rats younger than 20-22 days of age indicates that at this age the different central structures involved in the mechanism reach maturation ; thus the central component of the steroid-positive feedback in the female rat is capable of responding to increased plasma estrogen levels about 2 weeks before the first ovulation (11 ). Female rats pinealectomized at 10 days of age (at the time when the pineal gland starts to synthesiie melatonin in the typical rhythmic fashion) showed positive feedback effects of sex steroids on LH release about 2 days in advance to shampinealectomized or intact rats (Fig . 1) (15) . Moreover, the negative feedback effect of sex steroids observed in control animals up to the 20th day of life, is not apparent in the pinealectomized ones at the 16th day of age. Together the results of Figure 1 support the conclusion that pinealectomy advances the maturation of the central mechanisms controlling gonadotropin release in rats.

Small molecules

Peptides and proteins

Melatonin

Arginine vasopressin

Serotonin

Arginine vasotocin

Histamine

Oxytocin

Methoxytryptophol

Angiotensin I and 11

Epinephrine

TRH , VIP, LHRH

Norepinephrine

Anti-LHRH

Inositol

Anti-TRH

Taurine

Gonadotropin-inhibiting substance

Carbolines Gamma aminobutyric acid (GABA)

Lipotropins

Cyclic nucleotides

a-MSH, ACTH

Prostaglandins

Somatostatin

PINEAL SECRETIONS. CONTROL AND EFFECTS Of all pineal factors that have been isolated melatonin has received the greatest investigative effort, and it is widely considered to be partially or wholly responsible for the endocrine effects of the 'pineal gland (16). We are generally sympathetic with such a view; however we feel that it is probably unwise to assume that melatonin is the only pineal substance with physiological consequences. A list of endocrinologically relevant compounds identified within the mammalian pineal is shown in Table 1 (17) .

Hormone Sognol$

Melatonin The pineal gland synthesizes and secretes melatonin. In amphibians melatonin regulates skin col or; in birds it regulates circadian rhythrr,s; in mammals it may mediate the effects of photoperiod on reproductive cycles and maturation (16) . As discussed below, its role in man rema ins uncertain. The key intermediate in melatonin synthesis in serotonin, whose concentration is particularly high in the pineal. This compound is formed from tryptophan by the successive actions of tryptophan hydroxylase and I-aromatic amino acid decarboxylase (Fig. 2). In the pineal gland serotonin can be N -acetylated by serotonin-N-acetyltransferase, or oxidized by 2-3-dioxygenase or by monoamine oxidase. N-Acetylserotonin is O-methylated to form melatonin (18). A remarkable feature of the pineal gland is the circadian rhythm in the activity of several enzymes in the melatonin biosynthetic pathway. Maximal pineal melatonin production occurs during the dark phase of daily photoperiod in all animal species tested, regardless of whether the animal is nocturnally or diurnally

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Fig.2 - Schematic representation of the mechanisms involved in neura l and hormonal control of melatonin synthesis. TP, tryptophan ; HTP, 5 -hydroxytryptophan; 5HT, serotonin; NAS , N-acety/serotonin; HTOH, 5-hydroxytryptophol; HIAA, 5-hydroxyindoleacetic acid; MTOH, 5-methoxytryptophol; MIAA, 5 -methoxyindoleacetic acid (modified from reference: 16).

159

O.P. Cardinali. and M.I. Vaca s

otropins. Receptors for a number of hormones (estrogens, androgens, progestagens, prolactin) occur in the pineal gland and superior cervical ganglia. In addition several hormones affect the sympathetic afferent pathway to the pineal (Fig. 2) (25). Numerous studies in various neuroendocrin e situations have revealed significant endoc rin e effects of melatonin (16). Mel atonin treatment of rats delays vag inal opening , depresses the proportion of vaginal smears showing estrous phase, and inhibits, when injected during proestrus, LH release and ovulation. In male rats melatonin treatment decre ases testis weight, spermatogenesis, and plasma testosteron e leve ls. These changes are accompanied by a depress ion of FSH and LH release and by a decrease or in crease of prolactin release, depending on the way of administration . The hypothalamic content of LHRH also in creases, a finding that suggests a hypothalami c rath er than a pituitary site of action for melatonin. In accordance with this, melatonin perfusion s of portal vessels in adult rats did not re sult in hormon e modificati ons, and normal LH release was found after the injection of LHRH to melatonin-treated rats. The effect of single evening injections of melatonin on the steroid-induced LH release in femal e rats is shown in Figure 3. Treat ment of prepuberal (15) or mature rats (26) depressed significantly LH release elicited by estradioL Th e lack of direct effects of melatonin on th e adeno hypophysial functi.on in rats is an age-related process. In neonatal but not in adult pituitaries melatonin (1 O·BM) inhibited the stimulation of LH and FSH release brought about by LHRH in vitro (30) Melatonin injection in prepuberal rats partially disrupts steroid -induced gonadotropin release (Fig. 3) and inhibits reprodu cti ve

active. This rhythm is mirrored by similar rises of melatonin concentration in plasma, cerebro-spinal fluid (CSF) or urine (16). The sympathetic nervous system is responsible for the control of the circadian variations in pineal melatonin secretion. Shining a light into the rat's eyes diminishes the frequency of action potentials in the cervical sympathetic trunk. Similarly electrical stimulation of the suprachiasmatic nuclei greatly decreases neural activity in the superior cervical ganglia (4). The reduced activity in the sympathetic trunk causes a decreased release of norepinephrine in the pineal and as consequence the organ remains in an inactive state. Conversely during the dark phase of daily photoperiod the pineal gland is activated due to augmented neurotransmitter release (19). ,8-adrenergic stimulation of pinealocytes leads to the activation of the adenylate cyclase-cAMP system, and cAMP formed activates protein kinase, 't/ith concomitant phosphorylation of a specific nuclear protein and synthesis of messenger RNA (18). An alternative pathway for adenylate cyclase stimulation is provided by norepinephrine-induced prostaglandin E2(PGE 2) formation via a-adrenoreceptors (20). Ultimately the activity of enzymes in the melatonin synthetic pathway and melatonin secretion increases (Fig . 2). Superimposed to the neural control of melatonin synthesis mediating the effects of environmental lighting, a feedback control by hormones takes place at the pineallevel (21 ). In humans a menstrual cycle rhythm in Circulating or urinary melatonin has been described (22-24). Results in humans and experimental animals are compatible with the view that melatonin production , and probably the synthesis of antigonadal peptides, decrease at the time of the preovulatory peak of gonad-

(\', day 24) 1200

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Kd (10-ilM)

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Binding sites (%)

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Fig. 3 - Effect of melatonin on LH release in prepuberal and adult spayed rats (left panel), and PGE ). cA MP and cG MP synthesis m me dial basal hypothalamus (MBH) of adult rats. tnsert: dissociation con s/ant and maximal number of bmding sites for putative melatonm re ceptors m brain. (data from references 15. 26-29). Veh = vehicle. E 2P = estradiol-progesterone-mjected rats.

Pineal, photoperiods and puberty

WINTER CNS target cell

SUMMER CNS target cell

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Downregulation of receptors

Recovery phase

O6OOh

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1800h

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Recovery . . Gonadal phase . . quiescence

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I

High plasma melatonin levels

Fig. 4 - Current hypothesis on melatonin-mediated seasonal changes in hamster's reproductive activity. Exposure to high melatonin levels during the dark phase of daily photoperiod causes desensitization of the neuroendocrine system to melatonin by down regulation of receptor sites whereas during daytime the number of receptors increases because melatonin levels are low and restoration of sensitivity occurs at the end of the light phase (3, 33). Melatonin production must coincide with the sensitivity of the animal to melatonin; this synchrony is achieved only during winter (3). organ growth (16). Perhaps the impending age-related adenohypophysial insensitivity to melatonin is one of the signals to induce puberty onset in rats. Several mechanisms have been advanced to explain the action of melatonin on central nervous system (CNS) (16). Among them the inhibition of PGE 2 and cAMP synthesis, and stimulation of cGMP synthesis are observed at physiological concentrations that saturate the receptor sites (Fig. 3). Melatonin inhibits basal and norepinephrine-stimulated PGE 2 release by MBH in vitro (27) and by brain tissue in vivo (31 ); therefore, the possibility should be considered that the effect of melatonin on cyclic nucleotide synthesis and pituitary hormone release is mediated by PG synthesis inhibition. I ndeed there are striking similitudes between the neuroendocrine effects of melatonin and indomethacin (20). The importance of target organ sensitivity in determining the effects of melatonin must be stressed. While appropriately timed (late evening) injections of small, physiological amounts of melatonin can induce gonadal atrophy in male hamsters maintained on long days, similar injections can inhibit the testicular regression induced by short days (2,3,5, 32). Melatonin beeswax pellets or capsules that deliver a constant amount of melatonin prevent the short day-induced gonadal regression as well as that following evening melatonin injections; they can also stimulate growth in hamsters with regressed testes that are maintained on short days

after capsule implantation (2, 3, 5). Massive daily doses of melatonin, even at evening hours were without effect on the hamster reproductive system. Thus a wide variety of circumstances (photoperiod length, dosage, time and way of administration during daily photoperiod) govern the presence or absence of melatonin effects. The common factor for all of them can be thR extert and length of exposure of target cells to melatonin, that may cause down-regulation of receptor sites (Fig. 4). Collectively these results suggest that the biological activity of melatonin depends not only on the circulating levels of the hormone but also, and to a larger extent, on the state of sensitivity of the target tissue. This is a major drawback for clinical studies on circulating or urinary melatonin levels, since low levels of the hormone can be accompanied by high receptor number and high brain sensitivity to melatonin (like in under-nutrition), while under certain circumstances high circulating levels of melatonin lack bi,ological activity because of the refractory state induced by downregulation of receptors (3, 16).

Other pineal compounds The presence of unidentified antigonadotropic substances in the pineal gland has been confirmed by numerous purification studies on crude extracts. It has been suggested that a certain number of these may be polypeptidic, based mainly in that they are inactivated by proteolytic enzymes. The purification of these bio161

O.P. Ca rdinaIi, and M.t. Vacas from 11-to 14-year-old girls, corresponding to an approximately 30% seasonal increase in daily hours of sunshine, has been reported (39). The correlation between average daily hours of sunshifle and seasonal incidence of menarche was highly significant in data on about 5,000 girls in 8aghdag (40). In another series maximal growth spurt in partially sighted or blind children was evenly distributed throughout the year, whereas sighted children exhibited maximal growth spurt during months of increasing photoperiod length (41 ). The invesHgation of the role of the pineal gland in the onset of puberty has been a continuing effort since the recognition that pineal tumors (pinealomas) may be associated with precocious puberty in humans. I ndeed the term pinealoma has been losely applied to all tumors arising from the pineal gland and posterior third ventricle. They are rare, constituting less than 2% of intracranial tumors. Tumors arising from pineal parenchymal cells (true pinealomas) are less common than germ cell neoplasmas (germinomas, teratomas, endodermal sinus tumors, or primary intracranial choriocarcinoma). I n the majority of larger series reported germinomas are the most frequent tumors of the pineal region (greater than 50%). Primary tumors derived from the pineal cells have usually constituted no more than 20% of these series (42). Most cases of sexual precocity occur in non-parenchymal tumors, whereas hypogenitalism occurs among the patients with parenchyma I tumors. The incidence of precocious puberty among patients with pineal tumors is about 30%. Most of the affected patients are males; indeed precocious puberty in boys is more likely to be of intracranial origin than in girls, and over 10% of precocious boys may have pineal tumors (43). Precocious puberty resulting from a pineal neoplasm can be explained by various mechanisms, including local compression, removal of a maturation brake provided by the pineal hormones, or secretion of gonadotropin or gonadotropin-releasing hormones by the tumor. Experimenta
results like those depicted in Figure 1 offer support to the true precocious puberty nature of sexual precocity associated with non-parenchymal pineal tumors. However the capacity of certain pineal germinomas to produce human chorionic gonadotropin (hCG) has recently been demonstrated, and the regression of physical signs of puberty when plasma concentration of hCG becomes undetectable suggests that in these patients sexual precocity is independent of activation of the hypothalamic-pituitary axis and develops at a time when the system is immature (44). The relative incidence of pseudoprecocious and true precocious puberty after pineal tumors is presently unknown. Perhaps because of the milder nature of the clinical symptoms, pinealoma-associated hypogonadism is much less common than precocious puberty; in some cases melatonin was shown to be a suitable tumor marker for these neoplasms (45).

logically active substances has presented a formidable challenge since the extraction methods have failed so far to yield large quantities sufficient for structural elucidation. Moreover mixtures of stimulatory and inhibitory substances in closely related fractions, and the easy loss of activity when· standard purification methods are applied have added additional obstacles in this respect (34). One of the unidentified polypeptidic fractions present in the urine of children and attributed to the pineal gland is the gonadotropin-inhibiting substance (GIS) (35). When injected together with LH into 20-day-old mice, the stimulation of uterine growth was inhibited. Absence of urinary GIS in two patients with sexual precocity because of pineal tumors prompted Soffer et al. to propose that it was a pineal secretory product (35). Ota et al. (36) have verified these observations by examining GIS in rat urine; the authors say that it is a specific inhibitor of LH, disappears after pinealectomy in rats and is not melatonin. Recently the presence of a urinary antigonadotropin in children with Prader-Willi syndrome (who exhibited small genitalia, hypogonadism and delayed puberty) was described (37). The pineal gland of several lower vertebrates as well as mammalian species contains arginine vasotocin or an arginine vasotocin-like substance (38). This nonapeptide, which is present in the neurohypophysis of lower vertebrates has been proposed as the pineal antigonadotropin. The net effect of synthetic arginine vasotocin administration is an inhibition of various reproductive paradigms in rodents. Interestingly enough, arginine vasopressin, another nonapeptide present in the mammalian pineal (Table 1) shares many of the effects of arginine vasotocin. The release of pineal arginine vasotocin (or arginine vasotocin-like peptide) can be elicited by several stimuli, including neuropeptides like LHRH, somatostatin or MIF, neurotransmitters like norepinephrine or acetylcholine, or indoles like melatonin (38). It should be noted, however, that controversy continues on the occurrence of arginine vasotocin in the mammalian pineal gland; arginine vasotocin, arginine vasopressin, oxytocin, a 14-amino acid peptide with the biological activity of arginine vasotocin, or as yet unidentified peptides have been considered by several authors in this respect. Summarizing it can be said that several presumptive peptides and/ or proteins are present in pineal extracts, but relatively little is known of their nature or metabolism. Equally scarce is the information on the specific effects of these compounds on ttie endocrine system. However they deserve close attention because of their potential importance as hormonal envoys of the pineal gland.

PINEAL AND HUMAN PUBERTY Several observations suggest that the human puberty may be a seasonally-occurring phenomenon. A tenfold rise in gonadotropin activity of urinary extracts 162

Pineal, photoperiods and puberty

REFERENCES

Insofar the only way to assess the possible role of the pineal gland in normal human puberty is the measurement of circulating or urinary melatonin and/ or melatonin metabolite levels. Allegedly this is a narrow and rather restricted approach to the problem because i) it does not take in consideration non-melatonin pineal secretion; ii) as discussed above, in several circumstances normal melatonin levels are accompanied by a modified or even a suppressed melatonin sensitivity of the brain. Several reports have described changes in circulating melatonin as a function of puberal maturation in human. In a longitudinal study a statistically significant drop in daytime melatonin levels measured by a gas chromatographic-mass spectrometric (GCMS) technique was found at the onset of puberty in boys from Tanner stage I to Tanner stage II (46). Daytime melatonin values assessed by radioimmunoassay have been reported to be unchanged (47, 49) or depressed (23, 50) as a function of puberal maturation. There is also controversy as to whether the daily rhythm in circulating melatonin changes as a function of puberty in humans. Ehrenkranz et al. reported that the 24-hour profiles of plasma melatonin levels in normal or precocious puberty were undistinguishable (47); likewise obese or Prader Willi syndrome children had essentially normal diurnal fluctuation in circulating melatonin (51). In contrast Gupta et al. reported that in 87 normal children the delta increment in melatonin concentration from the light phase to dark phase' significantly declined from Tanner stage I to Tanner stage II (49). Other authors reported nocturnal rise in circulating melatonin coincident with the sleep-related LH release in puberal boys (52). Whether or not urinary melatonin excretion changes at puberty remains also unsettled. An age-dependent decrease in urinary melatonin determined by radioimmunoassay was found in boys from birth to adult age; such decrease was more accentuated at the time of the genital crisis of the newborn and later at the time of puberty (53). In contrast Penny (24) observed an increase in urinary melatonin both in boys and girls with initial signs of puberty (Tanner stage 11) and coinciding with an increase in gonadotropin excretion; the overall adult levels were about half those observed in children. In partial agreement with the latter observations a significant increase in 6-hydroxymelatonin excretion measured by a GCMS technique was observed at the time of the onset of breast development in girls (Tanner stage 11) (54). Obviously much work is needed before a definite answer can be given to the question whether melatonin is involved in human puberty. It is possible that the duration and timing phase of melatonin release as well as the phase angle between melatonin rhythms and other reprod~ctive hormones could be important as is known from studies of seasonally breeding animals. 163

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18.

Klein D.C., Auerbach DA, Namboodiri M.A.A., Wheler

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Cardinali DP., Vacas M.I., Boyer E.E. Specific binding of melatonin in bovine brain. Endocrinology 105: 437, 1979.

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