Neuroendocrine control of pulsatile growth hormone release in the human: relationship with gender

Growth Hormone & IGF Research 1998, 8, 4 9 - 5 9

Review

Neuroendocrine control of pulsatile growth hormone release in the human: relationship with gender J. D. Veldhuis Division of Endocrinology, Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA

Experimental studies in rodents, sheep and other mammals have demonstrated that growth hormone (GH) secretion by somatotrophs is under at least dual hypothalamic control - by GH-releasing hormone (GHRH) and somatostatin. 1,2 In addition, several other potent neuromodulators probably influence the GH axis, such as sex steroids, cholinergic and adrenergic neurotransmitters, neuropeptide Y, galanin, 7-aminobutyric acid (GABA), endogenous opioids and the putative ligand for the GH-releasing peptide (GHRP) receptor. 3 Indeed, multiple regulatory signals from cholinergic, serotoninergic, GABAergic pathways, etc., as well as from several peptidergic effector systems, impinge directly or indirectly upon hypothalamic GHRH- and somatostatin-synthesizing neurones. 4,5 The pituitary secretion of a coherent burst of GH is the result of a brief GHRH-somatostatin imbalance in favour of GHRH, such as occurs following hypothalamic discharge of a pulse of GHREI into the portal circulation, with or without concurrent somatostatin withdrawalfi, z The pnlsatile mode of GH secretion may be mediated by interactions between GHRH and somatostatin neurones, as GHRH appears to stimulate somatostatin secretion and, conversely, somatostatin may inhibit GHRH release, s,9 Moreover, GH and insulin-like growth factor I (IGF-I) probably have a feedback effect, either alone or in combination, to inhibit GH secretion in the human. The present review will highlight some of the clinical studies that have delineated the effects of sex steroids on Correspondence to: J. D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.

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the secretory activity of the GH axis and, presumptively, on the specific activities of key hypothalamic regulatory signals, namely GHRH and somatostatin.

ORDERLINESS OF PULSATILE GH RELEASE

In both rats and humans, the pattern of GH release over 24 hours is more disorderly in females than in males (Fig. 1). This is one hallmark of the sex difference in the GH axis, 1° as recently quantified using an approximate entropy statistic. 11,12 Surgical and chemical gonadectomy of prepubertal male and female rats has revealed a hierarchy of disorderliness of GH secretion, with the greatest quantifiable irregularity in the GH release process occurring in intact females, followed by that in females ovariectomized chemically (using a gonadotrophinreleasing hormone [GnRH] agonist), surgically ovariectomized females, surgically orchidectomized males, chemically orchidectomized males and, finally, intact males. 11 In humans deprived of sex steroids, treatment with oestradiol, or with an aromatizable (but not nonaromatizable) androgen, increases the disorderliness of overnight and 24-hour pulsatile GH release (Fig. 2). 13 Thus, gender in general, and oestrogen in particular, govern the regularity of GH release over time. The pattern of release of GH is believed to reflect integration or network control of GHRH/somatostatin input and GH/IGF-I negative feedback within the GH axis.~l-~3 Pulsatile neurohormone release is a dominant physiological feature of the GHRH-somatostatin-GH axis in humans and experimental animals. Male rats secrete prominent GH pulses every 3-3.5 hours, © 1998 Churchill Livingstone

J. D. Veldhuis

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middle-aged men and (b) three similarly aged women. Volunteers underwent blood sampling every 10 minutes for 24 hours, followed by IFA of serum GH concentrations. Adapted from Van den Berg et al. 15 (c) Disorderliness of the 24-hour GH release process is gender dependent. According to a novel measure of the orderliness of the hormone release process (approximate entropy [ApEn]), men and women show marked sex differences in the regularity (or orderliness) of their GH release profiles. The ApEn statistic (either version 1 or 2) shows higher values, indicating significantly greater disorderliness of GH release, in women than men. Adapted from Pincus et al. 12

b e t w e e n which serum GH concentrations are undetectable. In contrast, consistently detectable lowamplitude irregular GH pulses define the pattern of GH release in female r o d e n t s Y ,14 Recent application of a highly sensitive i m m u n o fluorometric assay (IFA) indicates that premenopausal w o m e n secrete consistently more GH per pulse, have a similar GH secretory burst frequency, and a similar GH half-life compared with men. Thus, the amount of GH secreted per pulse (or the pulse amplitude) is the primary gender difference. 15 The 24-hour secretory profile of GH in m e n and w o m e n can be distinguished b y a greater disorderliness of the GH release process and b y more GH secreted per burst in women. This gender difference would be expected to recede at the menopause, when oestrogen concentrations fall. Recent clinical investigations of the variations in activity of the GH-IGF-I axis in w o m e n throughout the normal menstrual cycle have demonstrated a two- to threefold increase in m e a n serum GH concentrations in the late follicular phase, concurrently with increases in plasma concentrations of IGF-I and oestradiol. 16J7 Accordingly, marked physiological regulation of the GH-IGF-I axis occurs on a day-to-day basis in healthy

young women. In contrast, studies of the reproducibility (test-retest consistency) of 24-hour GH release profiles in m e n and boys indicate a remarkable stability in the mass of GH secreted per burst (and per 24 hours), and the quantifiable orderliness of the 24-hour pattern of GH release. 18,19 Such observations are consistent with the hypothesis that oestradiol, and/or other menstrual-cycledependent sex steroids, regulate(s) the GH axis.

GHRH

Sex differences and the effect of oestradiol on the GH-IGF-I axis presumably reflect differences in GHRH and somatostatin release and action, as well as differences in the activities of other neuroendocrine modulators of the hypothalamic-pituitary unit.¢ 1°,2°-22 Gelato et al. demonstrated a greater sensitivity of w o m e n than m e n to the stimulation of GH release b y GHRH, but no systematic differences over the menstrual cycleY Using a maximally effective dose of GHRH, Evans et al. also reported no differences in GHRH efficacy over the menstrual cycle. 24 Later studies b y Ho et al. demonstrated that oestradiol is the dominant positive correlate of the m e a n serum GH concentration and the

51

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Time (minutes) Fig. 2 (a) Oestradiol is able to increase the measurable irregularity or disorderliness of GH release. Prepubertal girls with Turner syndrome were treated with oral ethinyloestradiol (100 ng/kg daily) for 5 weeks. Approximate entropy (ApEn) was used to measure the disorderliness of GH secretion in overnight serum GH profiles. Increased ApEn values denote greater disorderliness, which rose significantly in response to 5 weeks of oestrogen treatment. Adapted from Veldhuis et al. 13 (b) Testosterone injections amplify the disorderliness of the 24-hour GH release process, as quantified by ApEn, in five boys with constkutionally delayed puberty. Volunteers were studied by frequent blood sampling at baseline, after treatment with testosterone or dihydrotestosterone (DHT), and again following treatment (baseline 2). The two accompanying sets of plots depict (c) the 24-hour pulsatile GH concentrations and (d) calculated GH secretion rates, with the individual ApEn values for one of the study subjects. ApEn (1,20%) denotes statistical irregularity measured across successive data points (m = 1) at a threshold of 0.2 SD (r= 20%). Adapted from Veldhuis et al. 13

GH pulse amplitude in a large cohort of men and women whose ages spanned the pre- and postmenopausal range. 25 In another investigation, Lang et al. found that the ability of GHRH to stimulate GH secretion was proportionate to the serum oestradiol concentration, when evaluated in a population of 1 16 men and women aged between 18 and 95 years. 26 The inference that the effect of GHRH is sensitized by oestrogen was supported by Franchimont et al. 27 and Benito et al.28 The latter investigators observed that women were more responsive to GHRH than men, although this view had previously been contradicted by Smals et al.29 From studies in women whose gonadotrophic axis has been down-regulated by leuprolide (a GnRH superagonist) and in girls with precocious puberty, clinical hypogonadism

has been shown to diminish basal and/or GHRHstimulated GH secretion. 3°-33 In concurrence with these findings, De Leo et al. reported that ovariectomy decreases the effects of GHRH, which are restored by oestrogen treatment. 34 A substantial body of evidence, but not all studies, therefore supports the hypothesis that oestrogen enhances the secretory responsiveness of the pituitary gland directly or indirectly to GHRH, possibly by reducing somatostatin secretion and/or by increasing the sensitivity to GHRH, rather than by heightening its efficacy (maximal GH-releasing action). (For review, see Veldhuis. 35) To our knowledge, however, detailed GHRH dose-response curves have not been evaluated in oestrogen-replete versus oestrogen-replaced women to appraise the specific effects of oestrogen, particularly in

52

J. D. Veldhuis

the somatostatin-withdrawn environment, on somatotroph sensitivity to GHRH. In addition, the GHsuppressive effects of pure GHRH antagonists have not yet been compared in women and men, or in oestrogendeprived versus oestrogen-replenished women, in order to evaluate the hypothesis that there are sex-dependent differences in GHRH actions on, and/or GHRH dependency of, the GH axis. SOMATOSTATIN

A limited number of studies suggests that oestradiol may modify the activity of somatostatin. Merimee and Fineberg demonstrated that the stimulatory effect of L-arginine on GH release (presumed to be mediated by acute somatostatin withdrawal) was greatest in the preovulatory phase of the menstrual cycle. 36 In addition, anovulatory women (with decreased serum oestradiol concentrations) may exhibit decreased GH release following L-arginine stimulation. 37 In a recent study, we observed that infusion of L-arginine was significantly more effective in stimulating GH secretion in young women in the early follicular phase of the menstrual cycle than it was in young men. 38 Although intravenous infusion of somatostatin suppresses GH pulse frequency and amplitude in men, 39 to our knowledge the responses of the GH axis to such infusions have not been compared in men and women. As an alternative neuroendocrine probe, pyridostigmine has been utilized in an effort to restrict somatostatin release. GH secretion was greater in women than in men after pyridostigmine and GHRH treatment, and was also higher in women in the late follicular phase of the normal menstrual cycle compared with the early follicular phase. 35 The magnitude of the effect of pyridostigmine was proportional to the serum oestradiol concentration. Arvta et al., however, showed equal pyridostigmine stimulation of GH secretion in men and women. 4° Unfortunately, pure somatostatin antagonists, which would be helpful in evaluating the relative roles of somatostatin in men and women, are not yet available for use in humans. Data from the above studies suggest that somatostatin inhibitory tone operates in both men and women, but may be more substantial or more uniform in women. MAXIMAL SOMATOTROPH RELEASING CAPACITY

The absolute releasing capacity of somatotrophs in the anterior pituitary gland is difficult to evaluate definitively. However, a combination of a GHRP and L-arginine, or GHRH and L-arginine, produces massive secretion of GH in humans and experimental animals. 41

We have used the combined triple stimulus of GHRP-2, 5-arginine and exercise to compare maximal GH release in six young men and six young women. GH release rates were maximal and equal in these men and women following this triple stimulus. 38 In contrast, L-arginine, given alone, was more potent in women, and GHRP-2 was more potent in men in inducing GH release. The gender distinction was minimal for the exercise stimulus alone. These data, while not conclusive, suggest that the maximal GH-releasing capacity of the human somatotroph population may be equal in the two sexes, at least in young healthy adults. Whether the maximal GH secretory capacity increases in the late follicular phase of the normal menstrual cycle has not been studied by paired comparisons in the same women receiving combined (double or triple) GH secretagogues. MENSTRUAL CYCLE

During the normal menstrual cycle, plasma IGF-I, mean serum GH concentrations and the daily GH secretion rate rise significantly. 1¢17,42Using deconvolution analysis and an IFA on blood samples taken every 20 minutes for 24 hours, serum GH concentration profiles were recently obtained in ten women. Increased pulsatile GH secretion rates were revealed in the late follicular phase compared with the early follicular phase in the same women. 17 Unexpectedly, the preovulatory increase in pulsatile GH secretion was due predominantly to an acceleration of the frequency of detectable GH secretory bursts, rather than to a rise in GH pulse mass. On the other hand, detailed comparisons of GH concentration profiles obtained by 10-minute blood samples over 24 hours from middle-aged women and similarly aged men revealed that women secrete a greater mass of GH per burst than men, with no difference in GH half-life or pulse frequency. I5 The two studies described above showed concurrent increases in plasma concentrations of IGF-I and serum GH (in both the preovulatory versus the early follicular phase and in women compared with men), with expected parallel changes in serum oestradiol concentrations. The different mechanisms for increased pulsatile secretion of GH in middle-aged women compared with middle-aged men, and in the preovulatory phase compared with the early follicular phase, may reflect sampling differences or suggest that menstrual-cycle differences in the GH-IGF-I axis are mediated by factors (e.g. visceral fat; see below) other than oestradiol per se. Thus, further mechanistic studies are required to understand the regulatory dynamics of the GH axis throughout the normal menstrual cycle, to elucidate the effect of oestrogen on the human GH-IGF-I axis and to clarify the specific basis of the gender differences in the premenopausal age group.

Gender and GH release

GH F E E D B A C K

Studies in the rat indicate that the feedback exerted by GH on the hypothalamic-pituitary unit (so-called GH autonegative feedback) is distinguishable mechanistically in males and females. 43-46 Repeated GH infusions significantly inhibit subsequent stimulation of GH secretion by GHRH in the male rat, but not in the female. Indeed, a single GH pulse, whether due to exogenous GH or stimulated by endogenous GHRH, inhibits subsequent responsiveness to GHRH in the male rat, but not in the female. Thus, there is a sex difference in the efficacy of GH autonegative feedback, at least in the rat. 35 To our knowledge, similar studies have not been carried out in humans, either to elucidate any gender differences or to evaluate the impact of oestrogen or the stage of the menstrual cycle on GH autonegative feedback. R O U T E OF O E S T R O G E N D E L I V E R Y

Oral administration of oestrogen tends to decrease plasma IGF-I levels and increase GH secretion. 47-51 In contrast, in some studies, transdermal oestrogen delivery did not stimulate the GH axis. 52,53 A more recent investigation, however, using higher doses of transdermal oestrogen, found that both oral and percutaneous oestradiol stimulate pulsatile GH secretion and reduce circulating IGF-I concentrations. 5~ Thus, current evidence suggests that appropriate amounts of oral and transdermal oestrogen can diminish IGF-1 negative feedback by reducing plasma IGF-I concentrations, and perhaps thereby augment pulsatile GH secretion. However, intravenous infusion of IGF-I has not been given to test this hypothesis directly. Thus, additional actions of oestrogen are not excluded; for example, oestrogen may increase the central drive of the GH axis via GHRH, GHRPs, etc. (with or without concomitantly decreased somatostatin tone). In addition, the preovulatory phase of the normal menstrual cycle and the maximal pubertal growth phase are both marked by hypersomatotrophism (increased mean serum GH concentrations and daily GH secretion rates) and concomitantly higher plasma IGF-I concentrations. 17,54 This pattern is seen not only in these two physiological states in women, and after testosterone injection in men, 55-57but also in acromegaly or in states in which the GH axis is driven pharmacologically (e.g. after pulsatile or continuous GHRH infusions). (For review, see Giustina and Veldhuis. 3) Thus, whereas a component of the mechanism of action of orally replaced oestrogen is via presumptive partial withdrawal of the negative-feedback effect of IGF-I, the physiologically hyperoestrogenaemic states of the late follicular phase in young women and during maximal growth in pubertal girls apparently

53

stimulate the hypothalamic-pituitary-IGF-I axis centrally, resulting in concerted increases in both GH and IGF-I. O T H E R R E G U L A T O R S OF GH RELEASE

Although multiple modulators of the GH-IGF-I axis have been recognized (e.g. exercise, neuropeptides), the impact of gender or sex steroids on these regulators has been less well defined. An early study by Frantz and Rabkin showed that the potent non-steroidal oestrogen, diethylstilboestrol, increases the GH response to exercise in men, which was otherwise reduced compared with that in women. 42 In addition, the neuropeptide galanin stimulates greater GH release in women than men. 5~ Our studies indicate that GHRP-2 (1 ~tg/kg i.v. bolus) stimulates greater GH secretion in young men than in early follicular-phase women, whereas L-arginine stimulates more GH secretion in women than in men. 38 In some studies, the ability of insulin-induced hypoglycaemia to stimulate GH secretion was similar in men and women, whereas in other studies it was greater in women, or greater in men. (For review, see Veldhuis). 35 More recent analyses, using an ultrasensitive chemiluminescence assay for GH, showed that the suppression of GH release by glucose was greater in men (< 0.07 gg/1) than in women (< 0.7 gg/1), s9 The polypeptide glucagon stimulated GH secretion equally in men and women, whereas clonidine and the GABA modulator baclofen stimulated greater GH release in men than in women. 35 Leptin, which is another presumptive peptidic modulator of the GH axis, is released from adipocytes in a pulsatile manner, with higher levels secreted by women than m e n Y Thus, a variety of other neuromodulators of the GH axis show gender differences, which appear to be specific to the neuromodulator in question. P R I N C I P A L P H Y S I O L O G I C A L M O D U L A T O R S OF T H E GH AXIS: G E N D E R D I F F E R E N C E S

Gender strongly influences the relative impact of age, percentage body fat, and physical fitness on the GH axis (Fig. 3). 61-6~ In particular, premenopausal women are relatively protected (by approximately 50%) against the age-related fall in GH. 6~ Young women are also less sensitive than men to the inferred GH-suppressing effects of increased total percentage body fat. In addition, oxygen consumption, as a measure of physical fitness, is a weaker positive determinant of GH secretion in women than in menfi 1,67,68 Nonetheless, long-term physical training in women above the individual lactate threshold significantly increases resting 24-hour GH release, as demonstrated in a prospective study of women distance runners. 67 Whether such gender distinctions arise solely from differences in oestrogen levels is not known.

J. D. Veldhuis

54

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Further clinical studies are therefore required to evaluate the ability of oestrogen replacement to modify the interactions between the GH axis and age, adiposity and physical fitness. Moreover, investigations are needed to clarify how oestrogen itself modifies body composition and physical fitness (i.e. the training effect of exercise). The distribution of total body fat is now known to influence the activity of the GH axis. 69 In a study of middle-aged men and women, a strongly negative relationship was found between visceral fat mass and the daily GH secretion rate, and this relationship was similar in men and w o m e n / ° Indeed, the negative correlation between 24-hour GH secretion (or serum concentration) and visceral fat mass accounted for the majority of the variation in activity of the GH axis, even after adjusting for oestrogen concentrations (Fig. 4). This, and other observations, suggest that at least some of the long-term actions of sex steroids, and some of the gender differences in the function of the GH axis, may be attributable to changes in visceral fat deposition. However, the acute effects of oestrogens and aromatizable androgens, which occur within hours or days, are not explained by changes

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Gender and GH release

in body composition, as sex steroids can clearly activate the GH axis before altering visceral fat accumulation. In addition, the exact metabolic signal conveyed to the hypothalamic-pituitary-GH axis from visceral and other fat depots, in the presence or absence of sex steroids, has not been established. A recent study in elderly women showed a strongly negative correlation between s e r u m leptin concentrations and 24-hour GH secretion rates. 71 The mechanism behind the inverse relationship between body fat mass and GH secretion is not fully understood, but the recent discovery of leptin has led to several plausible hypotheses. 72 GH secretion is inversely correlated with serum leptin concentrations,7~,73 although direct hypothalamic actions of leptin on somatostatin and/or GHRH release have not yet been established. On the other hand, leptin receptors are present in hypothalamic neurones, and administration of leptin inhibits the expression of neuropeptide Y in the hypothalamus. 74 In addition, leptin advances puberty in mice by stimulating the hypothalamic secretion of GnRH, and overcomes the suppressive effects of fasting on the reproductive axis in the same manner. 75 Leptin also acts on the thyroid axis by stimulating neurones in the paraventricular nucleus that secrete thyrotrophinreleasing hormone. 76 These observations suggest that leptin may act on relevant hypothalamic neurones to modify somatostatin and/or GHRH release, and thereby mediate, at least in part, the apparent negative-feedback effects of increased body fat on the GH axis. ETHNICITY

An unexplained ethnic difference in GH secretion has been observed in men: black men secrete significantly more GH over 24 hours than their white counterparts, and have significantly greater bone mineral density. 77 Unexpectedly, black women and white women, despite a higher bone mineral density in the former, have similar daily GH secretion rates. 7s The basis for this gender difference is not known. A C T I O N S OF A N D R O G E N S

The serum concentrations of testosterone in boys at various stages of puberty correlate strongly with the pubertal increase in total GH secreted over 24 hours, with pulsatile GH secretion, and, particularly, with the GH secretory pulse mass. 79 Furthermore, administration of even small amounts of aromatizable androgens, such as testosterone, stimulates the GH axis consistently. ~3,3e,57,80 Non-aromatizable androgens, however, such as 5adihydrotestosterone, methyltestosterone and fluoxymesterone, which cannot be converted to oestrogens by the aromatase reaction, are less consistently active or are

55

inactive in stimulating the GH axis. In addition, antioestrogens, but not anti-androgens, lower basal and testosterone-stimulated GH secretion. 3°,55,8~,a2 A recent clinical study in boys with GnRH-deficient hypogonadotrophism revealed that aromatizable androgen augments overnight pulsatile GH secretion by increasing the amount of GH secreted in each pulse (Fig. 5)fi7 Testosterone treatment in these boys also evoked a significantly more irregular pattern of GH secretion. 57 An experimental model of GnRH-induced down-regulation of the luteinizing hormone axis (by leuprolide treatment) in healthy young men has allowed the close-dependent actions of androgen in stimulating plasma IGF-I concentrations and the daily GH secretion rate to be defined. The mechanism predominantly involves an increased GH secretory burst mass. 56 Stanozolol (a synthetic androgen) was inactive in these studies. Accordingly, the actions of aromatizable androgens probably occur via the oestrogen receptor, as they are antagonized by specific anti-oestrogens (see above), and are not mimicked effectively by non-aromatizable androgens. The anabolic actions of androgens on bone and muscle are amplified by concurrent stimulation of the somatotrophic axis. 10,56,57,79,80

In summary, the preponderance of current evidence indicates that androgen stimulates the GH axis via an oestrogenic pathway, at least in children and young adults, and does so by amplifying the amount of GH secreted in each pulse. Androgen, like oestrogen in girls and women and normal puberty in boys, also elicits more disorderly GH release. SUMMARY

Gender has multiple significant influences on the human GH axis in the premenopansal age group (Table 1), and attenuates by approximately 50% the negative impact of age on daily GH secretion rates, the inverse association between total adiposity and GH production, and the positive effect of increased physical fitness on GH secretion. The sex differences in GH axis activity are highly specific mechanistically, and namely entail the mass of GH secreted per burst (greater in women than men), and the orderliness of the 24-hour GH release process (less orderly pattern in women). Moreover, physiological regulation of the GH-IGF-I axis is evident within the follicular phase of the normal h u m a n menstrual cycle, wherein mean serum GH and plasma IGF-I concentrations rise concurrently with increased oestradiol secretion in the preovulatory phase. Oestrogen, directly or indirectly (e.g. via long-term changes in visceral and subcutaneous fat distribution), serves as the proximate mediator of m a n y gender

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.

,

200

A

....

400

p

6OO

Time (minutes)

Fig. 5 Impact of low-dose parenteral testosterone replacement in gonadotrophin-deficient prepubertal boys. Testosterone was administered intramuscularly at 25, 50 and 100 mg (increasing at 2-weekly intervals), and blood was sampled overnight every 20 minutes prior to a dose increase in order to monitor pulsatile GH release. As shown in (a) testosterone treatment increased the amplitude of GH pulses in blood and (b) the mass of GH secreted per burst, thereby augmenting mean serum GH concentrations even at the lowest dose of androgen tested. In addition, when approximate entropy (ApEn) was used to quantify the orderliness of GH release, testosterone doses of >_50 mg were found to significantly increase ApEn, thus denoting greater irregularity of hormone release. Adapted from Giustina et al. 57

differences, and probably mediates most of the acute sexsteroid effects of both testosterone and oestradiol on the h u m a n GH-IGF-I axis. Table 1 Summary of comparisons between GH secretion in men and women Relative magnitude GH secretion/pulse

Female > male

Orderliness of GH secretion

Female < male

Sensitivity to GHRH

Female > male

Somatostatin inhibitory tone

Female > male

L-Arginine-stimulated GH secretion

Female > male

Pyridostigmine

Female > male

GHRP-2-stimulated GH secretion

Female < male

Galanin-stimulated GH secretion

Female > male

Hypoglycaemia-induced GH secretion

Female - male

Hyperglycaemia-induced GH suppression

Female < male

Clonidine-stimulated GH release

Female < male

Baclofen (GABA modulator)-stimulated GH release

Female < male

Maximal GH-releasing capacity

Female = male

In conclusion, oestrogen regulates the physiological output of the GH-IGF-I axis both quantitatively (daily GH secretion rate) and qualitatively (organization or orderliness of GH release). The actions of oestrogen are probably achieved via alterations in GHRH and somatostatin activities and their reciprocal interactions. Current evidence concerning the role of oestrogen favours an increase in somatotroph responsiveness to GHRH, with or without decreased effects of somatostatin. Whether putative GHRPs, galanin, etc., participate in the potent amplifying actions of oestrogen on the GH axis is not known. Thus, gender and sex steroids are potent pathophysiological regulators of the orderliness and pulsatile mass of GH secreted in humans.

ACKNOWLEDGEMENTS

I thank Patsy Craig for her skillful preparation of the manuscript and Paula R Azimi for data analysis, management and graphics. This work was supported in part by NIH Grant MO1 RR00847 (to the General Clinical Research Center of the University of Virginia Health

Gender and GH release

S c i e n c e s Center), t h e B a x t e r H e a l t h c a r e C o r p o r a t i o n ( R o u n d Lake, IL), t h e U n i v e r s i t y o f V i r g i n i a P r a t t Foundation and Academic Enhancement Program, the N a t i o n a l S c i e n c e F o u n d a t i o n C e n t e r for Biological T i m i n g (Grant D I R 8 9 - 2 0 1 6 2 ) , a n d t h e N I H N I C H D P-30 C e n t e r for R e p r o d u c t i o n R e s e a r c h (HD-28934).

16.

17.

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