Joseph B. Martin

Dynamic Studies of Growth Hormone and Prolactin Secretion in the Female Rat

Blood samples were removed via chronic intra-atrial cannulae every 15 min in female rats during the estrous cycle, the last week of pregnancy, parturition and suckling. Growth hormone (GH) secretion during the estrous cycle is characterized by episodic release, occurring approximately once hourly. The surges in GH increase during the last 3-4 days of gestation, and rise to high levels during delivery and with suckling. Prolactin (PRL) shows minimal fluctuations during the estrous cycle, except for a prominent pulsatile surge during proestrus. PRL rises 4-6 h prior to parturition and declines during delivery. These studies provide a basis for further studies on the dynamics of GH and PRL secretion in the female rat.

Corticosterone, Prolactin, and Growth Hormone Responses to Handling and New Environment in the Rat*

&NA; Temporal characteristics of hormonal responses to handling and novel environment were studied in the rat in order to determine whether the same factors which modify corticosterone responses, i.e., time of day and type of stimulus, also modify prolactin and GH responses. Resting corticosterone showed the expected difference between crest and trough of the diurnal cycle. In contrast, GH and prolactin showed no difference at these times. Prolactin elevation occurred in response to the same stimuli which produced adrenal activation. Prolactin responses, however, differed from adrenal responses in being more rapid at the trough of the adrenal cycle and slower at the crest. In contrast to prolactin and corticosterone, GH showed a drop (nonsignificant) following stimulation. It is concluded that prolactin and corticosterone both respond to identical stimuli but that the prolactin response shows different characteristics from the adrenal response suggesting that different regulatory mechanisms are involved.

Pulsatile growth hormone, prolactin, and thyrotropin secretion in rats with hypothalamic deafferentation

Fifteen minute sequential blood sampling of male rats via right atrial cannulae was used to examine the patterns of anterior pituitary hormone secretion following hypothalamic deafferentations. Growth hormone (rGH) profiles from rats with complete hypothalamic deafferentation (CC) showed persistence of episodic rGH secretion with greatly increased frequency and elevated trough values, but without apparent entrainment to the light-dark cycle. Anterior (AC) and posterior (PC) deafferentation had no effect on the normal 3 h periodicity of rGH secretory episodes, but light-dark entrainment was lost in AC rats. Prolactin (rPRL) secretion in CC rats remained at normal low baseline levels without secretory episodes, while in AC and PC rats, as in normal rats, bursts of rPRL secretion occurred, often temporally related to rGH bursts. Thyrotropin (rTSH) levels in CC rats were less variable, and lower than in normal rats, while rTSH secretory profiles appeared normal in AC and PC rats. These results suggest that the isolated medial basal hypothalamus (MBH) contains neural substrates for episodic rGH secretion, and to a lesser extent, for rTSH. It is hypothesized that excessive rGH secretion in CC rats results from surgery damaging the rhythmicity of the rGH releasing factor (GRF) michanism, so that both sustained secretion and more frequent bursts of GRF occur. An effective rPRL inhibitory mechanism remains intact within complete hypothalamic deafferentations, while episodic rPRL and rTSH secretion require intact lateral afferents to the MBH. Visual pathway connections to the MBH, which mediate light-dark cycle entrainment of episodic rGH secretion, appear to pass through the region of the anterior hypothalamic and suprachiasmatic nuclei.

Pulsatile Growth Hormone Secretion: Suppression by Hypothalamic Ventromedial Lesions and by Long-Acting Somatostatin

Sequential blood samples, obtained from freely behaving, nonstressed male rats, showed a pulsatile pattern of growth hormone secretion with a mean interval between peaks of 68 minutes. The bursts of secretion were blocked by lesions of the hypothalamic ventromedial nuclei and by administration of a longacting preparation of synthetic somatostatin.

Monosodium glutamate: acute and chronic effects on rhythmic growth hormone and prolactin secretion, and somatostatin in the undisturbed male rat.

The present in investigation was designed to determine the chronic effects of neonatal monosodium glutamate (MSG) administration (4 g/kg s.c.) and the acute effects of MSG (1 g/kg i.p.) on episodic growth hormone (GH) and prolactin (PRL) secretion and brain somatostatin (SRIF) in unanesthetized, chronically cannulated male rats. Adult rats showed the typical physical characteristics that result from neonatal MSG administration. Analysis of episodic GH secretion showed a significant reduction in : (1) the amplitude of GH secretory peaks. and (2) the mean 5.5-h plasma level of GH. Bursts of plasma PRL were inhibited by MSG, but the mean 5.5-h plasma levels were not affected. SRIF concentrations in the medial basal hypothalamus were reduced by 60% after neonatal MSG. Acute administration of MSG to adult rats caused an immediate, long-lasting suppression of rhythmic GH secretion and a rapid, transient release of PRL. These results suggest: (1) neonatally administered MSG causes a marked disturbance in episodic GH and PRL secretion in adult rats; (2) MSG induces a decrease in hypothalamic SRIF and possibly GH-releasing factor; and (3) the acute effects of MSG on GH and PRL may be due to the inhibition and/or excitation of a complex neuronal network involving monoaminergic and peptidergic systems.

PHYSIOLOGIC SECRETION OF GROWTH HORMONE AND PROLACTIN IN MALE AND FEMALE RATS

Growth hormone and prolactin are secreted episodically in man and experimental animals. To investigate physiologic mechanisms of GH and PRL secretion, a series of experiments were performed in individual, unanaesthetized male and female rats.

Failure of naloxone to influence physiological growth hormone and prolactin secretion.

Morphine and the opioid peptides, fl-endorphin, [MetZ]enkephalin and [LeuZ]enkephalin are reported to stimulate growth hormone (GH) and prolactin (PRL) secretion in the rat2-5,7, 9,14. Hormone release has been demonstrated after both systemic [intravenous (IV), intraperitoneal (IP) or subcutaneous (SC)] and intracerebral ventricular (ICV) injections; the amounts given have, in general, been large (1-100 mg systemic or 1-100 #g ICV) and anesthetized rats have commonly been used. Shaar et al. is reported that enkephalin analogs administered SC in doses of 10 mg/kg also elicited GH and PRL release in the female rat. The site and mechanism of action of these effects has not been determined. A hypothalamic or other brain locus is suggested by the fact that the substances fail to elicit hormone release from pituitary glands in vitro 1. Martin et al. 1° showed that large hypothalamic lesions failed to completely block morphine-induced GH release and postulated that the effects were mediated at the level of the median eminence. Both enkephalin and fl-endorphin containing cell perikarya occur in the hypothalamus with axons that terminate in the median eminence ~,s. The role of endogenous opioids in the regulation of physiologic GH and PRL secretion is controversial. Previous reports in which single samples of blood were obtained by decapitation suggested a suppression of baseline G H and PRL levels after administration of naloxone, an opioid antagonist 2,7. Stress and suckling-induced PRL responses are also reported to be inhibited by prior administration of opioid antagonists 7. The objective of the present studies was to investigate the effects of naloxone on GH and PRL secretion in unanesthetized rats and in human subjects during sleep. Experiments in our laboratory have documented that physiologic GH secretion in unanesthetized, freely behaving rats is episodic with abrupt surges of secretion occurring at intervals of 3-4 h12, ~9. Basal PRL secretion in such rats is low (less than 10 ng/ml) with infrequent small secretory surges. Sleep-associated changes in GH and PRL secretion are well documented in man, a surge of GH occurring within 2 h of sleep

COMPARISON OF THE EFFECT OF APOMORPHINE AND l‐DOPA ON SERUM GROWTH HORMONE LEVELS IN NORMAL MEN

Apomorphine hydrochloride (0.75 mg s.c.) has been compared with l‐dopa (500 mg p.o.) in their effects on growth hormone secretion in a double blind cross‐over study involving nine healthy men. Apomorphine increased serum GH levels above 10 ng/ml in all nine subjects 30–60 min after injection. In contrast, only six of these subjects showed a similar elevation with l‐dopa and in only three had the level increased above 6 ng/ml by 60 min. One subject failed to respond to l‐dopa and in two others the peak was less than 6 ng/ml. GH levels were significantly higher at 30, 45 and 60 min following apomorphine than following l‐dopa. Apomorphine‐induced GH release was not related to changes in serum cortisol or blood sugar. Benztropine mesylate (1 mg i.m.) had no effect on apomorphine‐induced GH release. These results suggest: (a) apomorphine may have advantages over l‐dopa as a provocative agent to assess GH secretory capacity; (b) a dopaminergic mechanism subserves GH secretion; (c) cholinergic mechanisms do not antagonize dopaminergic‐related GH release.

Episodic GH Secretion: Evidence for a Hypothalamic Dopaminergic Mechanism

With the development of specific radioimmunoassays for human anterior pituitary (AP) hormones, it became apparent that concentrations of the various hormones in random blood samples often varied widely. It was subsequently recognized by frequent sampling, that blood levels of the AP hormones fluctuated abruptly. This phenomenon, originally described for growth hormone (GH) and adrenocorticotrophic hormone (ACTH) is also demonstrated by other AP hormones, and is presumed to be due to intermittent rather than continuous hormonal secretion. Abrupt changes in hormonal clearance rate, peripheral storage, or excretion which might contribute to such a phenomenon have not been sought extensively, but would appear to be unlikely factors.

Dissociation of effects of somatostatin antiserum on growth hormone and insulin secretion

Growth hormone (GH) secretion in the rat is governed by an endogenous ultradian rhythm with major episodes of GH secretion occurring at approximately 3,3-hr intervals throughout a 24-hr period. Plasma GH concentrations reach levels of 400–800 ng/ml during a secretory burst and fall to undetectable levels (< 1 ng/ml) during trough periods.1 We have recently reported that the rGH secretory episodes are markedly suppressed in response to prolonged food deprivation.2 However, the mechanism of this suppression is unknown. Furthermore, the mechanism mediating the well-known suppression response of plasma insulin to starvation3 remains to be firmly established. Somatostatin, a tetradecapeptide originally isolated from sheep hypothalami on the basis of its ability to inhibit GH release from rat anterior pituitary cells,4 has subsequently been shown to be a potent inhibitor of both GH5–8 and insulin9–12 release in a wide variety of species. If the starvation-induced suppression of plasma GH and insulin levels is due to circulating somatostatin, we hypothesized that its effects might be neutralized or blocked by the administration of a specific antiserum to somatostatin. The aim of the experiments described in this report was to assess the role of somatostatin in mediating the inhibitory effects on GH and insulin observed during starvation.