I. Introduction WHILE the effects of hyper- and hypothyroidism1 in female gonadal functions are well established (1, 2), controversy exists regarding the impact of thyroid diseases on male reproduction. This is due to various reasons: 1) the apparent clinical irrelevance of signs and symptoms related to male gonadal function, compared with the systemic effects of hyper- and hypothyroidism; 2) the paucity of well controlled clinical studies, due to the fact that thyroid diseases are more common in females than in males; and 3) the demonstration in the 1950s that the adult male gonad of experimental animals is metabolically unresponsive to thyroid hormone (3). Since then, the concept that the testis is unaffected by iodothyronines became widely accepted. For this reason, the potential of thyroid hormone in the modulation of male reproductive functions was not determined for several years. Indeed, in experimental studies on the effect of thyroid hormone in various tissues, the testis has been used as a negat...

Thyroid hormone and male gonadal function

first of these compounds isolated, and it had the interesting property of causing blanching of frog skin. A more important reason, however, arose from the belief that the terminal enzyme in the synthesis of melatonin, hydroxyindole-O-methyltransferase (HIOMT), was uniquely localized to pineal tissue. Consequently, melatonin and related methoxyindoles were, at least potentially, unique pineal products. Finally, interest in pineal products was generated because the pineal appeared to be involved in controlling important physiological functions, such as reproduction. Of the several related methoxyindoles, only 5-methoxytryptamine and 5-methoxytryptophol exhibit actions that, like those of melatonin, mimic certain influences of photoperiod on mammalian reproduction. Melatonin, however, appears to be at least 10 times more potent than any of the other naturally occurring methoxyindoles with respect to these actions (Reiter et al., 1975; Rollag, 1982; Goldman et al., 1984). This review focuses on melatonin’s role in two systems-the circadian system and the photoperiodic system. These two systems are discussed together because of the interrelationship between the circadian and photoperiodic systems: Many vertebrates utilize a circadian mechanism to measure daylength. A brief description of the structural evolution of the pineal and related organs is given as background for a more detailed discussion of melatonin’s role within the circadian and photoperiodic systems.

Vertebrate circadian and photoperiodic systems: role of the pineal gland and melatonin.

Seasonal reproductive transitions in ewes are generated endogenously and are synchronized by annual changes in photoperiod. Previous evidence indicates that thyroidectomy prevents the transition to anestrus in ewes maintained in a fixed day length, suggesting that the thyroid is needed for endogenously generated reproductive arrest. Here we tested the hypothesis that the thyroid is required for endogenous seasonal suppression of the neuroendocrine mechanism that regulates pulsatile LH secretion. Ewes were thyroidectomized (n = 6) in summer, 6 weeks before the onset of the breeding season, or they remained thyroid intact (n = 6). They were housed in a simulated natural photoperiod until the winter solstice; thereafter, they remained on that photoperiod (10 h of light, 14 h of darkness). To monitor pulsatile LH secretion, the ewes were ovariectomized and implanted with estradiol, and LH was measured in both frequent (every 6 min for 4 h) and infrequent (twice weekly) blood samples. In this model, high LH indicates low response to estradiol negative feedback and reproductive induction; low LH signifies high response to estradiol negative feedback and reproductive arrest. LH levels (samples twice weekly) rose some 50-fold in both groups concurrently at the start of the breeding season in September. Frequent sampling in midbreeding season (autumn) revealed that both thyroidectomized and thyroid-intact ewes exhibited frequent LH pulses, with no group difference, in either the presence or absence of the estradiol implant. A marked group difference, however, emerged at the end of the breeding season. LH fell to basal values in thyroid-intact ewes (onset of low values Feb 3 +/- 8 days), whereas levels remained elevated in thyroidectomized ewes through the end of the study (April 26). At this time, thyroidectomized ewes had more frequent LH pulses than thyroid-intact ewes both in the presence and absence of estradiol. The circadian pattern of melatonin secretion and the seasonal change in PRL were found to be unaffected by thyroidectomy. These observations support the hypothesis that the thyroid is necessary for endogenous suppression of neuroendocrine mechanisms that generate LH pulses, a suppression crucial for the transition to anestrus.

Role of the thyroid gland in seasonal reproduction: thyroidectomy blocks seasonal suppression of reproductive neuroendocrine activity in ewes.

The majority of seasonally breeding mammals show a seasonal pattern of prolactin secretion with peak concentrations in spring or summer and a nadir in autumn or winter. Photoperiod influences prolactin secretion via its effects on the secretion of the pineal hormone melatonin. Preliminary evidence suggests that the effects of melatonin on both prolactin and gonadotrophin secretion are via a common target area, possibly within the anterior hypothalamus, and that differences in response to photoperiod may be due to differences in the processing and/or interpretation of the melatonin signal. In contrast to seasonal gonadotrophin secretion, the seasonal changes in prolactin are not due to changes in the sensitivity of a feedback loop and so must be due to direct effects on the hypothalamic pathways that control prolactin secretion. Little else can be said with confidence about the neuroendocrine mechanisms that lead to the seasonal changes in prolactin secretion. Dopamine and noradrenaline turnover in the arcuate nucleus and median eminence decrease under short daylength. If catecholamine turnover in these structures is positively correlated with catecholamine concentrations in the long or short hypophysial portal vessels, it is unlikely that the decrease in prolactin concentration in winter is due to the effects of increased concentrations of dopamine or noradrenaline in the portal vessels. There is, however, evidence for increased pituitary sensitivity to dopamine under short daylength, so increased dopamine concentrations may not be required for suppression of prolactin secretion at this time. In addition to the diminished secretion of prolactin under short daylength, rate of prolactin synthesis and pituitary content of prolactin also decline although the mechanisms that regulate these changes are poorly understood. Although all seasonal breeders show a seasonal change in prolactin secretion, there are continuously breeding species in which prolactin secretion is also under photoperiodic control. It is likely therefore that a seasonal pattern of prolactin secretion is only evidence of neuroendocrine sensitivity to changing photoperiod. Depending upon the species, this sensitivity to the seasonal changes in daylength may or may not be accompanied by seasonal changes in a biological endpoint such as seasonal reproduction or indeed other adaptations. Whether the seasonal change in prolactin secretion is an endocrine mediator of such adaptations remains in contention. Certainly in some species this signal does have a role in reproduction. For example, in species with an obligate seasonal embryonic diapause, the seasonal increase in prolactin can act as a luteotrophin (mink and western spotted skunk) or luteostatin (Bennett's and tammar wallabies.(ABSTRACT TRUNCATED AT 400 WORDS)

Seasonal prolactin secretion and its role in seasonal reproduction: a review.

The Pineal Control of Aging

Experiments in minks, as in a number of other seasonal breeders, clearly demonstrate that the pineal gland is essential for the photoperiodic control of reproduction. While maintenance of pineal-intact minks under natural photoperiods results in a set of seasonally appropriate changes in testicular activity, pinealectomized minks undergo none of these changes but rather remain sexually inactive as under long-day conditions. Thus, the consequences of pinealectomy differ from one photoperiodic species to another, but the unifying feature is the organism's need for the pineal gland to respond appropriately to changes in day length.



Although the precise mechanism by which the pineal regulates hypothalamic-pituitary gonadal function remains unknown, the results of the present study indicate that, in the mink, luteinizing hormone-releasing hormone axonal transport is affected by pinealectomy.



Furthermore, our results suggest that the pineal does not act exclusively upon the neuroendocrine-gonadal system but also acts on other functions that are influenced by photoperiod. Pinealectomized minks left in natural conditions cannot adjust their prolactin secretion in response to either long or short photoperiods. Operated animals continued to have plasma prolactin variations but at irregular intervals and with no apparent relation to the time of the year. The data strengthen the hypothesis that melatonin may act at some point on the hypothalamic neuroendocrine systems, which regulate the two functions differently, and that melatonin is not an anti- or progonadal substance but rather a seasonal transducer.

Long-term effects of pinealectomy on testicular function, luteinizing hormone-releasing hormone hypothalamic system, and plasma prolactin levels in the mink, a short-day breeder.

It has been demonstrated that an endogenous mechanism is involved in photoperiodic time measurement in the mink, a short-day-breeding mannal. A study of testicular activity (testicular volume, plasma testosterone concentration) and plasma prolactin level was carried out in sexually resting minks (the experiment began in November). Groups of minks were kept in the natural photoperiod or subjected to different resonance light-dark (LD) cycles (LD 4:8, LD 4:20, LD 4:32, LD 4:44); an additional group of animals was reared in an ahemeral photoperiod (LD 4:16). A rapid increase of testicular activity was observed in control animals or those kept in LD 4:20 (T 24) and LD 4:44 (T 48). In the other groups of animals, those kept in LD 4:8 (T 12), LD 4:32 (T 36), and LD 4:16 (T 20), testicular function remained at rest. Prolactin secretion was, in contrast, stimulated in the groups kept in LD 4:8 (T 12). LD 4:32 (T 36), and LD 4:16 (T 20), and remained low in the groups kept in LD 4:20 (T 24) and LD 4:44 (T 48). The...

Circadian participation in the photoregulation of testis activity and prolactin secretion in the mink, a short-day breeder.

Influence de la thyroïdectomie sur les variations au cours du printemps et de l'été, de l'activité testiculaire et de la prolactinémie chez le vison

The possible role of thyroid hormones in the setting of sexual quiescence was investigated in the mink, since levels of thyroid hormones were earlier shown to rise while testicular activity decreased. When performed at the beginning of the sexual period, thyroidectomy transiently stimulated testosterone production, and significantly prolonged the duration of maximal testicular development. These results indicate that mink conforms to a pattern of inhibitory thyroid-testis interactions similar to that previously described in several species of birds and mammals. Thyroidectomy was unable, however, to prevent ultimately the installation of sexual quiescence which also appears independent of the photoperiod. On the other hand, thyroidectomy did not modify, from February to October, the general pattern of prolactin secretion, even though the vernal stimulation of prolactin secretion, induced by increasing daylength, was significantly enhanced in the absence of thyroid hormones.

J. M. Jacquet

Papers

Long-term effects of pinealectomy on testicular function, luteinizing hormone-releasing hormone hypothalamic system, and plasma prolactin levels in the mink, a short-day breeder.

Circadian participation in the photoregulation of testis activity and prolactin secretion in the mink, a short-day breeder.

Influence de la thyroïdectomie sur les variations au cours du printemps et de l'été, de l'activité testiculaire et de la prolactinémie chez le vison

Effect of thyroidectomy on variations during the spring and summer of the testicular activity and blood prolactin in the mink