Intern. J . Neuroscience, 1992, Vol. 63, p. 197-204 Reprints available directly from the publisher Photocopying permitted by license only

0 1992 Gordon and Breach Science Publishers S.A. Printed in the United States of America

THE PINEAL GLAND AND THE MENSTRUAL CYCLE REUVEN SANDYK Department of Psychiatry, Albert Einstein College of Medicine/Montefore Medical Center, Bronx, NY 10461, U.S.A.

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(Received June 30, 1991)

The menstrual cycle reflects the expression of a cyclical process involving the interaction between the hypothalamic-pituitq axis and the ovaries. This complex process requires an integrated neural and humoral control mechanism. It is now well established that a hypothalamic “transducer” located in the medial basal hypothalamus integrates neural and humoral information and translates it into an oscillatory signal which eventually results in the release of the gonadotropin releasing hormone (GnRH), triggering the secretion of gonadotropins from the pituitary gland. Recent animal studies indicate that melatonin influences the functions of the hypothalamic-pituitary-gonadal axis by modifying the firing frequency of the hypothalamic GnRH pulse generator. Consequently, the pineal gland, through the action of melatonin, may exert an important modulatory effect on the mechanisms controlling menstrual cyclicity. Furthermore, abnormal melatonin functions may be involved in the pathogenesis of several disorders of the menstrual cycle including some forms of hypothalamic amenorrhea such as exercise and malnutritioninduced amenorrhea. Consideration of pineal melatonin functions provides a new dimension into the understanding of the neuroendocrine mechanisms governing the cyclical phenomena of the female reproductive system. Keywords: Pineal gland; melatonin; menstrual cycle; GnRH.

The menstrual cycle reflects the expression of a cyclical process involving the interaction between the hypothalamic-pituitary axis and the ovaries. The human menstrual cycle can be divided into two phases. The follicular phase is the initial period during which several follicles are recruited from a pool of primary follicular structures to yield one Graaffian follicle destined for ovulation. The luteal phase is characterized by the generation of the corpus luteum which secretes both progesterone and estradiol. The circulating levels of gonadotropins, estrogens, androgens, and progestins during the normal menstrual cycle exhibit a cyclical pattern, which reflects complex interactions among the hypothalamus, pituitary, and the ovaries. This interaction requires integrated neural and humoral control mechanisms. It is now well established that a hypothalamic “transducer,” located within the medial basal hypothalamus, integrates neural and endocrine information and translates it into an oscillatory signal of a given frequency and amplitude. This signal eventually results in the release of a gonadotropin releasing hormone (GnRH), which then triggers the secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland (Yen, 1986 a ) . One of the key elements in the gonadotropic control of ovarian functions is the episodic and pulsatile nature of the release of LH and FSH by the pituitary gland (Yen, 1986 b ) . It is now well recognized that the pulsatile release of LH and FSH is temporally related to the secretion of bursts of GnRH by the hypothalamus into the hypophyseal-portal circulation (Yen, 1986 a ) . Pulsatile gonadotropin release is Correspondence to Professor Reuven Sandyk, P.O. Box 203, Bedford Hills, NY, 10507, U.S.A 197

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subject to profound modulation by ovarian steroids. In the absence of gonadal steroid feedback, as is the case in the postmenopause, elevated gonadotropin levels are maintained by an increased amplitude and frequency of pulsatile discharge of LH and FSH (Yen, 1986 a ) . The importance of the pulsatile release of GnRH for optimal ovarian function is illustrated by the observations of Pohl and Knobil (1982), who noted that in monkeys with lesions of the arcuate nucleus, a nonphysiological increase in the frequency or continuous delivery of GnRH stimulation induces inhibition of gonadotropin release followed by the arrest of ovarian functions. Research over the past decade has demonstrated that the pulsatile release of the hypothalamic GnRH is an important determinant not only of the release of LH and FSH, but also of particular importance in regulating the relative amounts of LH and FSH secreted (Knobil, 1980). For instance, when the pulses of GnRH are relatively infrequent (such as during puberty), more FSH than LH is released. As the frequency increases to about one pulse per hour, the secretion of LH increases relative to FSH (Knobil, 1980). The frequency of the GnRH pulse generator appears to be critical for the maintainence of the normal menstrual cycle, which is associated with a changing pattern of high-frequency and low-amplitude pulses during the follicular phase followed by low-frequency and high-amplitude pulses uniquely observed during the luteal phase of the cycle (Yen et al., 1974). A periodicity of 60 to 120 minutes is seen during the early follicular phase, the early luteal phase, and at the midcycle LH surge, while a progressive decrease in pulse frequency, with intervals of more than 4 hours, occurs during the mid- and late luteal phases (Yen, 1986 b). Control of GnRH Secretion

In primates and humans, GnRH neurons have been shown to reside in the arcuate nucleus of the hypothalamus (Yen, 1986 a ) . The control of GnRH release is subject to modulation by several factors including estradiol, dopamine, serotonin, prostaglandins (PG), and endogenous opiates (Yen, 1986 a ; Ferin, 1984). Inhibitory effects on GnRH release have been demonstrated for estradiol, dopamine, serotonin, and the endogenous opiates, while PGE2 exerts a predominantly stimulatory effect on GnRH release (Yen, 1986 a ) . The endogenous opioids are particularly important for the regulation of the menstrual cycle since the opiate receptor antagonist naloxone raises LH levels only when administered during the luteal phase of the cycle (Ferin, 1984). It has therefore been suggested that the opioid peptides affect primarily a change in the frequency of GnRH pulses (Ferin, 1984). The Pineal Gland and GnRH Secretion

It is now well established that photoperiodic information exerts an important influence on mammalian reproductive physiology (Vaughan et al., 1978; Goldman and Darrow, 1983; Kauppila et al., 1987; Ebling and Foster, 1989; Reiter, 1991). This information is dependent on the synthesis of the pineal hormone melatonin, the secretion of which is under the control of the photoperiod acting via the suprachiasmatic nucleus (SCN) of the hypothalamus (Reiter, 1991). Under normal circumstances, the pineal gland is activated at night by the SCN through the sympathetic nervous system to stimulate the release of melatonin. During the day, retinal messages, acting via the retinohypothalamic tract, quell the activity of the SCN and inhibit melatonin secretion. Since animals and humans in their natural habitat ex-

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perience diurnal and seasonal variations in day length, the melatonin signal appears to provide important information that adjusts organismal physiology on a diurnal and seasonal basis. It is now well accepted that the pineal gland, via photoperiodic information, exerts a profound influence on reproductive functions (Kaupilla et al., 1987; Reiter, 1991). Whereas initial studies suggested that melatonin exerted an antigonadotrophic effect exclusively, more recent investigations have shown that melatonin mediates the effects of the photoperiod on reproductive functions (Carter and Goldman, 1983; Reiter, 1991). Although this influence is often inhibitory, it can likewise be stimulatory or even inconsequential. In all likelihood, the response of the neuroendocrine system to melatonin may depend, among other factors, on the internal hormonal millieu (Reiter, 1991). Although most of the studies aimed at elucidating the role of the pineal gland in reproductive functions have been conducted in experimental animals, there is evidence that the pineal gland has similar functions in humans. For instance, precocious puberty is associated with pineal tumors (Gupta, 1986) and the level of melatonin secretion may be related to the timing of the onset of puberty (Silman et al., 1979; Waldhauser and Steger, 1986). Moreover, abnormal melatonin rhythms have been observed in females with hypothalamic amenorrhea (Berga et al., 1988; Brezenzinski et al., 1988) and anorexia nervosa (Brambilla et al., 1988; Tortosa et al., 1989) as well as in males with oligospermia or aspermia (Karasek et al., 1990). Anovulatory cycles and reduced conception rates occur more frequently in North European women during the dark months of the winter (Vaughan et al., 1978; Sandahl, 1978; Puolakka et al., 1985). In addition, since melatonin plasma levels are low during ovulation and high premenstrually (Wetterberg et al., 1976; Hariharasubramanian et al., 1985) and since administration of melatonin before the midcycle LH surge blocks ovulation in humans (Hariharasubramanian et al., 1985), melatonin may provide an important photoperiodic cue for the regulation of the normal menstrual cycle. Melatonin and the GnRH Pulse Generator

The most widely accepted mechanism whereby melatonin is thought to influence the functions of the hypothalamic-pituitary-gonadal axis is through its ability to modify the firing rate of the hypothalamic GnRH pulse generator (Bittman et al., 1985; Yellon and Foster, 1986; Robinson et al., 1986; Robinson, 1987). Melatonin may influence the activity of the GnRH pulse generator directly through its binding sites in either the SCN or the pars tuberalis (Cardinali et al., 1979; Glass and Lynch, 1981; Vanecek et al., 1987) and/or indirectly through its interaction with the hypothalamic serotonergic (Olcese, 1985) and endogenous opioid systems (Kumar et al., 1984). Melatonin has been shown to interact with the endogenous opioids (Satake, 1979; Lissoni et al., 1986), which, in turn, may act as a transducer of pinealmediated inhibition of gonadotropin release (Kumar et al., 1984). Evidence for the action of melatonin on the GnRH pulse generator is provided by the observations in which nightly 8-hour infusions of melatonin into pinealectomized ewes produced the low-frequency , high-amplitude pulses of gonadotropin release Characteristic of the anestrous season (Robinson et al., 1986). Conversely, 16-hour infusions of melatonin resulted in the high-frequency, low-amplitude pulses typical of the breeding season. Since the pineal gland, through its nocturnal secretion of melatonin, mediates the photoperiodic control of seasonal reproduction in both long and short-day breeders (Robinson et al., 1986) and since melatonin does not alter the pituitary response to GnRH in adult rats (Martin and Sattler, 1979), it appears

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that melatonin acts to exert these effects by modifying the activity of the hypothalamic GnRH pulse generator (Robinson, 1987).

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Melatonin and the Menstrual Cycle

There is evidence that the pineal gland is involved in the regulation of the human menstrual cycle (Wetterberg et al., 1976; Hariharasubramanian et al., 1985; Webley and Leidenberger, 1986; Brun et al., 1987; Brzezinski et al., 1987 a ; b ) . Although a recent study failed to demonstrate a relationship between circadian melatonin secretion and the phases of the menstrual cycle (Berga and Yen, 1990), three groups of investigators have reported that nocturnal plasma melatonin levels were lowest in the midmenstrual period and highest during the premenstrual period (late luteal phase) (Wetterberg et al., 1976; Hariharasubramanian et al., 1985; Webley and Leidenberger, 1986). In another investigation, urinary melatonin levels were found to be higher in the luteal phase (Brun et al., 1987). Since the lowest nocturnal concentrations of melatonin were found to correlate temporally with the midcycle LH surge (Wetterberg et al., 1976; Brzezinski et al., 1987 b ) , it has been proposed that the low melatonin concentration found in the midcycle may be necessary for ovulation (Hariharasubramanian et al., 1986; Brzezinski et al., 1988) as it is in other mammalian species (Reiter, 1971; Ying and Greep, 1973; Walker et al., 1982). Likewise, it is possible that the progressive rise in plasma melatonin in the late luteal phase (Webley and Leidenberger, 1986) may be involved in the onset of menstruation. In normal menstruating women, increased GnRH pulse frequency is noted at midcycle (Yen, 1986 a ) a period associated with the lowest melatonin plasma levels (Wetterberg et al., 1976; Hariharasubramanian et al., 1986). Conversely, decreased GnRH pulse frequency occurs during the late luteal phase (Yen, 1986 a ) when melatonin plasma levels have been shown to reach their highest levels in the menstrual cycle (Wetterberg et al., 1976; Hariharasubramanian et al., 1986; Webley and Leidenberger, 1986; Brun et al., 1987). Collectively, these findings suggest that pineal melatonin may modify the pituitary release of LH and FSH during the various phases of the menstrual cycle by modifying the firing rate of the GnRH pulse generator. In support of this hypothesis are the observations that administration of melatonin in humans prior to the midcycle LH surge blocks ovulation (Hariharasubramanian et al., 1986) which is associated with activation of the GnRH pulse generator (Yen, 1986 a ) . Moreover, melatonin-mediated slowing of the GnRH pulse frequency in the late luteal phase may partly explain the findings of an increased FSH:LH ratio found at the end of the luteal phase (Yen, 1986 a ) . Since the midcycle LH surge is known to be critical for ovulation and the rise in FSH secretion at the end of the luteal phase is responsible for the recruitment of the pool of ovarian follicles which will mature during the ensuing follicular phase (Yen, 1986 a ) , it appears that melatonin may be actively involved in the control of menstrual cyclicity in humans. The hypothesis that the action of melatonin results in an inhibition of the GnRH pulse generator raises the possibility that abnormalities in pineal melatonin functions may be implicated in various disorders of the menstrual cycle (Parry et al., 1990; Sandyk, in press) including some forms of hypothalamic amenorrhea. Disturbances in melatonin secretion could lead to inappropriate GnRH pulse frequencies associated with failure to achieve proper gonadotropin ratios necessary for normal ovarian morphological transformations during the menstrual cycle. This hypothesis finds support in the findings of altered waveform of nocturnal melatonin secretion in women with premenstrual depression (Parry et al., 1990), in the beneficial effects of bright evening light therapy in patients with premenstrual depression (Parry et al., 1989), in

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the reports of abnormal nocturnal melatonin secretion in patients with functional hypothalamic amenorrhea (Berga et al., 1988; Brzenzinski et al., 1988) and in patients with reproductive dysfunction associated with anorexia nervosa (Tortosa et al., 1989). Moreover, it is possible that abnormal melatonin functions may be related to the pathogenesis of other endocrine disorders such as the polycystic ovary syndrome, which is characterized by the presence of amenorrhea and hirsutism associated with high LH levels and an increased LH:FSH ratio (Yen et al., 1970). Likewise, since melatonin plasma levels are increased during exercise in women (Carret al., 1981) and following long distance running in men (L’Hermite-Baleriaux et al., 1986), increased melatonin secretion may contribute to the development of exercise-induced abnormalities of reproductive functions such as luteal phase defects ,, amenorrhea, and delayed menarche in prepubertal girls (Yen, 1986 b). In fact, a study from Finland reported a seasonal variation in gonadotropin and ovarian function in women participating in exercise training program; the short photoperiod in autumn was found to be associated with low FSH levels and follicular and luteal defects, whereas the long photoperiod in the spring appears to be partly overcome by the suppressive effects on ovarian function due to physical training (Ronkainen et al., 1985). It is now well accepted that weight loss, whether occurring in the setting of diet restriction or exercise, may cause several endocrine abnormalities including delayed puberty, delayed menarche, and amenorrhea. Since malnutrition and acute weight loss are associated with a reduced pulsatile LH activity and a reversion to a peripubertal sleep-entrained episodic LH secretory pattern (Kapen et al., 1981), it has been suggested that hypothalamic GnRH dysfunction may be responsible for the amenorrhea associated with weight loss (Yen, 1986 a). There is evidence, however, that abnormal melatonin functions may be implicated also in the pathogenesis of amenorrhea induced by malnutrition and weight loss. For instance, it has been shown that among women of the primitive “Bushman” population of Botswana in Southern Africa, seasonal changes in nutrition, body weight, and physical activity are associated with the peak time of childbirth. This period follows exactly 9 months after achievement of maximal weight (Van der Walt et al., 1978). Specifically, seasonal suppression of ovulation and luteal phase defects occur in these women during the summer months (December through March) at a time they have the lowest body weight due to decreased availability of food. It is, therefore, possible that the pineal gland, by modifying the secretory program of the GnRH, is intimately associated with the pathogenesis of malnutrition-associated menstrual disorders (such as seen in patients with anorexia nervosa). Finally, since an increased FSH:LH ratio is a characteristic endocrine finding of the postpartum and postmenopausal periods (Yen, 1986 b ) , it is possible that the pineal gland is involved in maintaining the hypogonadotropic state of the postpartum period (Yen, 1986 b) as well as determining the timing of the menopause (cf. Lehrer, 1985). CONCLUSION The interaction of the hypothalamic-pituitary axis with ovarian functions has been the main focus in the research of the endocrine mechanisms underlying the regulation of the human menstrual cycle and in the search for its abnormalities. From the above discussion it appears that the pineal gland should be considered an integral part of the endocrine system involved in the regulation of the human menstrual cycle. Hence,

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further understanding of disorders of the menstrual cycle will be enhanced by the elucidation of the role of the pineal gland in the integration of the various humoral and neural elements influencing menstrual cyclicity. This may result in the development of new therapeutic approaches in the management of menstrual disturbances. For instance, if pineal-mediated chronobiological abnormalities are involved in disturbances of the menstrual cycle, then administration of melatonin or the manipulation of other major synchronizers of melatonin such as sleep or light may be beneficial for the treatment of these disorders. Furthermore, since prolonged photoperiod (cf. Vaughan et al., 1978) or administration of melatonin prior to the midcycle LH surge has been shown to inhibit ovulation in humans (Hariharasubramanian et al., 19861, oral contraceptive drugs may be acting to inhibit ovulation in part via the pineal gland. Indeed, increased melatonin plasma levels have been found in women receiving the contraceptive pill (Arendt, 1979; Webley and Leidenberger, 1986). Consequently, melatonin, given orally several days prior to the expected ovulation, may be therapeutically effective as a new contraceptive agent. Conversely, since increased nocturnal plasma melatonin levels have been found in patients with functional hypothalamic amenorrhea (Berga et al., 1988), administration of melatonin receptor antagonists (Zisapel and Laudon, 1987) or drugs which inhibit melatonin secretion such as propranolol or clonidine (Lewy et al., 1986), could be beneficial in the treatment of stress, weight loss, and exercise-induced amenorrhea.

REFERENCES Arendt, J. (1 979). Radioimmunoassayable melatonin: circulating patterns in man and sheep. Progress in Brain Research, 5 2 , 249-257. Berga, S . L. & Yen, S. S. C. (1990). Circadian pattern of plasma melatonin concentrations during four phases of the human menstrual cycle. Neuroendocrinology, 51, 606-612. Berga, S. L. Mortola. J. F. & Yen, S. S. C. (1988). Amplification of nocturnal melatonin secretion in women with hypothalamic amenorrhca. Journal of Clinical Endocrinology and Metubulism, 6 6 , 242-244. Bittman, E. L., Kaynard, A. K. & Olster, D. H. (1985). Pineal melatonin mediates photoperiodic control of pulsatile lutehizing hormone secretion in the ewe. Neuroendocrinology, 40,409-41 8. Brambilla, F., Fraschini, F., Esposti, G., Bossolo, P. A., Marelli, G. & Ferrari, E. (1988). Melatonin circadian rhythm in anorexia nervosa and obesity. Psychiatry Research, 2 3 , 267-276. Brezezinski, A . , Seibel, M. M., Lynch, H. H., Deng, M. H. & Wurtman, R. J. (1987 a). Melatonin in human preovulatory follicular fluid. Journal of Clinical Endocrinology and Metabolism, 6 4 , 865-867. Brezezinski, A., Lynch, J. H., Seibel, M. M. & Wurtman, R. J. (1987 b). Possible contribution of melatonin to the timing of the luteinizing hormone surge. New England Journal ofhfedicine, 316, 1550-1555. Brezezinski, A , , Lynch, H. J. & Seibel, M. M., Deng, M. H., Nader, T. M. & Wurtman, R. J. (1988). The circadian rhythm of plasma melatonin during the normal menstrual cycle and in amenorrheic women. Journal of Clinical Endocrinology and Metabolism, 6 6 , 89 1-895. Brun, J . , Claustrat, B. & David, M. (1987). Urinary melatonin, LH, oestradiol, progesterone excretion during the menstrual cycle or in women taking oral contraceptives. Acta Endocrinologica (Copenh), 116, 145-149. Cardinali, D. P., Vacas, M. I. & Boyer, E. E. (1979). Specific binding of melatonin in the bovine brain. Endocrinology, 105, 437-441. Cam, D. B . , Reppert, S. M . , Bullen, B., Skrinar, G., Beitins, I., Arnold, M., Rosenblatt, M., Martin, J. B. & McArter, J. W. (1981). Plasma melatonin increases during exercise in women. Journal of’Clinical Endocrinology and Metabolism, 5 3 , 224-225. Carter, D. S. & Goldman, B. D. (1983). Progonadal role of the pineal in Djungarian hamster: mediation by melatonin. Endocrinology, 113, 1268-1273. Ebling, F. J . P. &Foster, D. L. (1989). Pineal melatonin rhythms and the timing of puberty in mammals. Experientia, 4 5 , 946-954.

Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 11/04/14 For personal use only.

PINEAL GLAND AND THE MENSTRUAL CYCLE

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Ferin, M. (1984). Endogenous opioid peptides and the menstrual cycle. Trends in Neurosciences, 8 , 194-1 96. Glass, J. D. & Lynch, G. R. (1981). Melatonin: identification of sites of antigonadal action in mouse brain. Science, 214, 821-823. Goldman, B. D. & Darrow, J. M. (1983). The pineal gland and the mammalian photoperiodism. Neuroendocrinology, 37, 386-396. Gupta, D. (1986). Human development and the pineal gland. In D. Gupta & R. J. Reiter (Eds.), The pineal gland during development: from fetus to adult (pp. 117-133). London: Croom Helm. Hariharasubramanian, N., Nair, N. P. V. & Pilapil, C. (1985). Circadian rhythm of plasma melatonin and cortisol during the menstrual cycle. In G. M. Brown & S. D. Wainwright (Eds.), The pineal gland. endocrine aspects (pp. 3 1-36). Oxford: Pergamon Press. Kapen, S., Sternthal, E. & Braverman, L. (1981). Case report: A pubertal 24-hour luteinizing hormone (LH) secretory pattern following weight loss in the absence of anorexia nervosa. Psychosomatic Medicine, 4 3 , 177-181. Kaupilla, A., Kivela, A., Pakarinen, A. & Vakkuri, 0. (1987). Inverse seasonal relationship between melatonin and ovarian activity in humans in a region with a strong seasonal contrast in luminosity. Journal of Clinical Endocrinology and Metabolism, 6 5 , 823-828. Knobil, E. (1980). The neuroendocrine control of the menstrual cycle. Recent Progress in Hormone Research, 36, 53-88. Kumar, M. S. A., Besch, E. L., Millard, W. J., Sharp, D. C. & Leadem, C. A. (1984). Effect of short photoperiod on hypothalamic methionine-enkephalin and LHRH content in serum beta-endorphin-like immunoreactivity (beta-end LI) levels in golden hamsters. Journal of Pineal Research, I , 197-205. Lehrer, S. (1985). Puberty and menopause in the human: possible relation to gonadotropin-releasing hormone pulse frequency and the pineal gland. Pineal Research Reviews, 3, 237-257. Lewy, A. J . , Siever, L. J., Uhde, T. W. & Markey, S . P. (1986). Clonidine reduces plasma melatonin levels. Journal of Pharmacy and Pharmacology, 3 8 , 555-556. L’Hermitte-Baleriaux, M., Casteels, S., De Meirleir, K., Baeyens, L. & L’Hermitte, M. (1986). Running increases melatonin. Journal of Neural Transmission, 21 (suppl), 486. Lissoni, P., Esposti, D., Esposti, G., Mauri, R., Resentini, M., Morabito, F., Fumagali, P., Santagostino, A,, Delitala, C . & Fraschini, A. (1986). A clinical study on the relationship between the pineal gland and the opioid system. Journal of Neural Transmission, 6 5 , 63-73. Martin, J. E. & Sattler, C. (1979). Developmental loss of the acute inhibitory effect of melatonin on the in vitro pituitary luteinizing hormone and follicle stimulating hormone responses to luteinizing hormone releasing hormone. Endocrinology, 105, 1007-1012. Olcese, J. M. (1985). Enhancement of melatonin’s antigonadal action by daily injection of the serotonin uptake inhibitor fluoxetine in male hamsters. Journal of Neural Transmission, 6 4 , 151-161. Parry, B. L., Berga, S. L., Mostofi, N., Sependa, P. A., Kripke, D. F. & Gillin, J. C. (1989). Morning versus evening bright light treatment of late luteal phase dysphoric disorder. American Journal of Psychiatry, 146, 1215-12 17. Parry, B. L., Berga, S. L., Kripke, D. F., Klauber, M. R., Laughlin, G. A , , Yen, S. S. C. & Gillin, J. C. (1990). Altered waveform of plasma nocturnal melatonin secretion in premenstrual depression. Archives of General Psychiatry, 4 7 , 1139-1 146. Pohl, C. R. & Knobil, E. (1982). The role of the central nervous system in the control of ovarian function in higher primates. Annual Review of Physiology, 4 4 , 583-594. Puolakka, J., Jarvinen, P. A. & Kauppila, A. (1985). Changing pattern of childbirth in northern Finland over the past three decades. In R. Fortuine (Ed.), Circumpolar health 8 4 , (pp. 181-184). Seattle and London: University of Washington Press. Reiter, R. J. (1971). Inhibition of luteinizing hormone release and ovulation in PMS-treated rats by peripherally administered melatonin. Contraception, 4 , 385-392. Reiter, R. J. (1991). Pineal gland. Interface between the photoperiodic environment and the endocrine system. Trends in Endocrinology and Metabolism, 2 , 13-19. Robinson, J . E. (1987). Photoperiodic and steroidal regulation of the luteinizing hormone pulse generator in ewes. In W. F. Crowley & J. G . Hofler (Eds.), The episodic secretion of hormones (p. 159). Wiley: New York. Robinson, J. E., Kaynard, A. H. & Karsch, F. J. (1986). Does melatonin alter pituitary responsiveness to gonadotropin-releasing hormone in the ewe? Neuroendocrinology, 4 3 , 635-640. Ronkainen, H., Pakarinen, A,, Kirkinen, P. & Kaupilla, A. (1985). Physical exercise-induced changes and season-associated differences in the pituitary-ovarian function of runners and joggers. Journal of Clinical Endocrinology and Metabolism, 6 0 , 416-422. Sandahl, B. (1978). Seasonal birth pattern in Sweden in relation to birth order and maternal age. Acra Obsretrica Gynecologica Scandinavica, 5 7 , 393-400.

Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 11/04/14 For personal use only.

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Sandyk, R. (in press). Dysmenorrhea and the pineal gland. Znrernational Journal of Neuroscience. Satake, N. (1979). Effect of melatonin and methionine-enkephalin on surfacing response in goldfish. Physiulogy and Behavior, 23, 995-999. Silman, R . E . , Leone, R . M . , Hooper, R . J. L. & Preece, M. A. (1979). Melatonin, the pineal gland and human puberty. Nature, 282, 301-303. Tortosa, F., Puig-Domingo, M . , Peinado, M. A., Oriola, J., Webb, S. M. & de Leiva, A. (1989). Enhanced circadian rhythm of melatonin in anorexia nervosa. Acta Endocrinologica (Copenh), 120, 514-578. Van der Walt, L. A , , Wilmsen, A. E. N. & Jenkins, T. (1978). Unusual sex hormone patterns among desert-dwelling hunter-gatherers. Journal of Clinical Endocrinology and Metabolism, 46, 658-663. Vanecek, I., Pavlik, A. & Illnerova, H. (1987). Hypothalamic melatonin receptor sites revealed by autoradiography. Brain Research, 4 3 5 , 359-362. Vaughan, G . M . , Meyer, G. G. & Reiter, R. J. (1978). Evidence for a pineal-gonad relationship in human. Progress in Reproductive Biology (Basel: Karger), 4 , 191-223. Waldhauser, F. & Steger, H. (1986). Changes in melatonin secretion with age and pubcscencc. Journal of Neural Transmission, 21 (supp), 183-197. Walker, R. F., McCamant, S . & Timiras, P. S . (1982). Melatonin and the influence of the pineal gland on timing of the LH surge in rats. Neuruenducrinology. 3 5 , 37-42. Webley, G . E. & Leidenberger, F. (1986). The circadian pattern of melatonin and its positive relationship with progesterone in women. Journal of Clinical Endocrinology, 63, 323-328. Wetterberg, L., Arendt, J., Paunier, L., Sizonenko, P. C . , Von Donselaer, W. & Heyden, T. (1976). Human serum melatonin changes during the menstrual cycle. Journal of Clinical Endocrinology and Metabolism, 4 2 , 185-188. Yellon, S. M. & Foster, D. L. (1986). Melatonin rhythms time photoperiod-induced puberty in the female lamb. Endocrinology. 119, 44-49. Yen, S . S . C. (1986 a). The human menstrual cycle. In S. S. C. Yen & R. B. Jaffe (Eds.). Reproductive endocrinology, physiology, pathophysiology and clinical management (pp. 200-236). Philadelphia: W. B . Saunders. Yen, S. S . C . (1986 b). Chronic anovulation due to CNS-hypothalamic-pituitary dysfunction, In S. S. C. Yen & R. B. Jaffe (Eds.), Reproductive mdocrinology. physiology, pathophy.~iolu,qyand clinical management (pp. 500-545). Philadelphia: W. B . Saunders. Ycn. S. S. C., Vela, P. & Rankin, J. (1970). Inappropriate secretion of follicle stimulating hormone and luteinzing hormone in polycystic ovarian disease. Journal of Clinical Endocrinology and Meraholism, 3 0 , 435-442. Ying. S . Y . & Creep, R. 0. (1973). Inhibition of ovulation by melatonin in the cyclic rat. Endocrinologyy,92, 333-335. Zisapel, N. & Laudon, M. (1987). A novel melatonin antagonist affccts melatonin-mediated processes in vitro and in vivo. European Jouriial offharmacology, 136, 259-260.

The pineal gland and the menstrual cycle.

The menstrual cycle reflects the expression of a cyclical process involving the interaction between the hypothalamic-pituitary axis and the ovaries. T...
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