The impact of gonadal steroid hormone action on growth hormone secretion during childhood and adolescence.

0163-769X/92/1302-0281$03.00/0 Endocrine Reviews Copyright © 1992 by The Endocrine Society

Vol. 13, No. 2 Printed in U.S.A.

The Impact of Gonadal Steroid Hormone Action on Growth Hormone Secretion During Childhood and Adolescence* JAMES R. KERRIGAN AND ALAN D. ROGOL Departments of Pediatrics (J.R.K., A.D.R.), Pharmacology (A.D.R.), and National Science Foundation Science and Technology Center for Biological Timing (J.R.K., A.D.R.), University of Virginia Health Sciences Center, Charlottesuille, Virginia 22908

I. Introduction II. Human GH (hGH) Physiology A. Synthesis, secretion, and circulating forms of GH B. Regulation of GH secretion C. Additional controlling mechanisms for GH secretion and sites of action D. GH and IGF-I actions E. Mathematical modeling techniques: assessment of hormone secretion, elimination, and circulating concentration profiles III. Ontogenesis of Physiological GH Secretion: Influences of Gender and the Sex Steroid Hormone Environment A. Fetal and neonatal periods: lessons from investigations in the human and other species B. Childhood: a potential role of the gonadal steroid hormones in the physiological control of GH secretion C. Puberty: pulse amplitude-modulation of increased circulating GH concentrations 1. Independent actions of GH and sex steroid hormones 2. Dynamic interactions of GH and endogenous androgen 3. Impact of endogenous estrogen on GH secretion IV. Impact of Exogenous Sex Steroid Hormones on GH Secretion A. Alterations of GH release following exogenous androgen administration B. The impact of exogenous estrogen on GH secretion V. Discussion

I. Introduction

P

HYSIOLOGIC regulation of GH secretion has been an active subject of investigation recently. In particular, the interaction with, and independent functions of, the sex steroid hormones and GH have been the subjects

of a large number of studies, both in the basic sciences and in the clinical arena. Based on the results of multiple clinical studies, it has been observed that GH secretion is amplified in the presence of gonadal steroid hormones. During the course of male and female puberty, either normal, precocious, or pharmacologically induced, spontaneously circulating GH levels increase via an amplitude-modulated phenomenon. Using recently available mathematical modeling techniques, it has been possible to demonstrate that the mechanism of this increase is via sex steroid hormone-induced amplification of endogenous GH production rate, without demonstrable alterations of the frequency of secretory episodes or of hormone half-life. We intend to review what is understood about this relationship between the sex steroid hormones and GH in man with particular emphasis on clinical studies in the pediatric and adolescent age groups. A comprehensive review of the basic aspects of gonadal steroid hormone impact on GH physiology is provided by Wehrenberg and Giustina (1) in an accompanying paper. To provide a framework upon which to build this focused topic, we will first review the normal physiology of GH. Following this discussion, we will present the available data describing the ontogeny of GH secretion as it relates to concomitant changes in endogenous sex steroid hormone levels. Finally, the impact of exogenously administered gonadal steroid hormones on GH secretion will be discussed. II. Human GH (hGH) Physiology

Address requests for reprints to: James R. Kerrigan, M.D., MR-4 Building/Room 3037, Department of Pediatrics, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. "This work was supported in part by Clinical Investigator Award HD-00926 from the NICHHD (to J.R.K.), National Science Foundation Science and Technology Center for Biological Timing (J.R.K., A.D.R.), and a grant (RR-00847) from the USPHS (General Clinical Research Centers).

A. Synthesis, secretion, and circulating forms of GH GH is synthesized in somatotropes of the adenohypophysis as a pre-growth hormone molecule consisting of 217 amino acids. Subsequent cleavage yields the 191 amino acid (21.5 kilodaltons) mature peptide hormone. 281

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A smaller variant (20 kilodaltons) is synthesized following alternative splicing of the messenger RNA (mRNA) and differs from the predominant form by having an internal deletion of 15 amino acids (2, 3). The locus for hGH has been mapped to chromosome 17 q22-q24 and is composed of five genes: the hGH-1 (or N) gene for pituitary GH; the hGH-2 (or V) gene, a variant of hGH in the placenta; the hCS-5 gene, apparently a pseudo gene; and the hCS-1 and hCS-2 genes, which are also expressed in the placenta (4, 5). Expression of the GH gene in the somatotrope is controlled, at least in part, by GHF-1, a transcription factor that permits expression of the gene in response to GH-releasing hormone (GHRH), thyroid hormone, or glucocorticoids (6). Recent information suggests that GHF-1 also has a critical role in the growth and differentiation of somatotropes and the maintenance of the mature cell phenotype (7). GH molecules circulate in both bound and free forms. The bound hormones are complexed to small and large serum binding proteins (8); the smaller protein (higher affinity) is identical to the extracellular domain of the GH receptor (9). Indeed, patients with GH receptor deficiency, such as Laron-type dwarfism, lack this circulating GH binding protein (10). It is probable that an interaction occurs between GH bound to the smaller binding protein and the extracellular domain of the cellular GH receptor. A second binding site on the receptor-bound GH molecule permits dimerization of the receptor and subsequent signal transduction (11). Circulating levels of GH-binding protein are low in premature infants and neonates. Increases of binding protein activity occur throughout childhood and adolescence; maximal levels are reached by young adulthood (12-14). The absolute values, however, vary over a wide range. GH (15,16) and testosterone (16) appear to regulate the GHbinding protein. The heterogeneous nature of circulating GH forms results in a complexity of structure-activity relationships (3, 17). B. Regulation of GH secretion

The GH (or somatotrope) axis is composed of the central nervous system, hypothalamus, anterior pituitary, and peripheral tissues. As such, it is impacted upon, and responds to, multiple, often complex and competing factors. Among these are the hypothalamic neuropeptides, GHRH, and somatotropin release-inhibiting hormone (SRIH). GHRH is synthesized in the hypothalamic arcuate and ventromedial nuclei. Additional sites of GHRH synthesis include the placenta, small intestine, and pancreas, as well as some islet cell adenomas and carcinoid tumors. SRIH is produced in the periventricular and amygdaloid nuclei of the medial basal hypothalamus. It is also found in other organs such as those

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of the gastrointestinal system and urinary tract. The precise role of extrahypothalamic GHRH and SRIH in the control of GH release is not well defined. Axons from the GHRH- and SRIH-containing neurons terminate in the median eminence, at sites that are juxtaposed to the fenestrated capillaries of the primary plexus of the hypophyseal portal system. It is into this vascular network that these and other hypophysiotropic hormones are released and travel to the anterior pituitary gland. The pulsatile pattern of GH secretion is orchestrated by episodic increases and decreases in the release of GHRH and SRIH, respectively. The rhythmic surges of GHRH and SRIH each have a periodicity of 3-4 h (in the rat), and are virtually 180 ° out of phase (18, 19). The amount of GHRH released determines the amplitude of the GH secretory episodes, while the pattern of SRIH action determines the frequency and duration (20). Additional evidence suggests that SRIH may act cooperatively with GHRH to maximize somatotrope responsiveness (21, 22). Such combined actions of GHRH and SRIH may then result in a physiologically optimal pattern of GH release. The oscillatory control of these rhythmic patterns of GHRH and SRIH release may be intrinsic to the hypothalamus or may be under direct control by other neural mechanisms (23). C. Additional controlling mechanisms for GH secretion and sites of action In addition to those controls of GH secretion already discussed, the release of the hormone is regulated by "long, short, and ultra-short" loop feedback mechanisms. Basic amino acids {e.g. arginine, ornithine) increase circulating GH concentrations and maximal GH responses to GHRH in man (24). Insulin-like growth factor I (IGFI) mediates a long-loop feedback inhibition of GH secretion via effects at both hypothalamic and pituitary sites. Available data provide evidence for an inhibitory action of IGF-I on hypothalamic GHRH release (23), and a stimulatory effect of IGF-I on the secretion of SRIH from the medial basal hypothalamus (25). Circulating IGF-I also suppresses GH secretion from somatotropes in vitro (26, 27). Recently available information suggests that IGF-I, produced locally in the pituitary, may negatively regulate GH release via paracrine or autocrine mechanisms (28). GH is capable of diminishing its own secretion (shortloop feedback) by stimulating the release of hypothalamic SRIH and by inhibiting GHRH secretion (23). Another mechanism whereby GH may inhibit its release is through GH-stimulated increases in glucose or free fatty acid levels, the latter probably directly at a pituitary site (29). There are likely direct GHRH-SRIH interactions (ultra short-loop feedback) that directly impact


GH AND GONADAL STEROID HORMONES

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upon GH release (30). GHRH may have a stimulatory effect on SRIH synthesis and secretion (31-33). Conversely, available data suggest that SRIH inhibits the release of GHRH (34, 35). The gonadal steroid hormones also play a critical role in the regulation of GH secretion. As discussed in other sections of this review, gender-specific patterns of pulsatile GH release characterize several animal species, including the human (36, 37). The sex steroid hormones exert their effects at multiple sites of the somatotrope axis. Gender-related differences exist in the rat for the expression of hypothalamic SRIH and GHRH gene expression (38). Male animals have increased gene transcript levels of both of these neurohormones when compared to those of female rats. Androgens increase hypothalamic GHRH mRNA levels (39). In a similar fashion, androgens increase hypothalamic SRIH content (40) and gene transcript levels (41, 42). Conversely, estrogens have a negative influence on SRIH content (40) and lack the ability to increase GHRH (39) and SRIH (42) mRNA levels. In addition, hepatic steroid metabolism appears to be regulated by the pattern of GH release in adult male and female rats. This pattern of circulating GH concentrations is itself dependent on the levels of gonadal steroid hormones (36). Gender-specific differences have also been demonstrated in the secretory capacity of somatotropes in vitro (43-45). Androgens appear to be facilitatory compared to estrogens in their ability to alter GH secretion from somatotropes (46-48). Estrogen action has been associated with increased numbers of somatotropes in culture systems (49, 50), increased cellular GH mRNA levels (51), and GH content (52). The integration of these effects of the gonadal steroid hormones, coupled with other controls of the GH axis, likely play a critical role in the manifestation of gender-specific circulating GH profiles. D. GH and IGF-I actions The GH molecule has multiple end-organ effects. Its primary biological actions are the stimulation of epiphyseal cartilage growth and specific metabolic actions on carbohydrate, lipid, and mineral metabolism. The actions of GH on cartilage growth are the result of both a direct effect by the hormone and an indirect effect mediated by locally produced IGF-I. GH directly stimulates differentiation of the stem cell chondrocytes, cells located in the proximal zone of the epiphyseal growth plate. These cells may then undergo a controlled degree of clonal expansion. More highly differentiated cells in the distal proliferative zones of the growth plate undergo clonal expansion in response to IGF-I action (53, 54). The ultimate biological effect of clonal expansion is skeletal growth. In addition to this locally produced IGF-I, GH also

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stimulates IGF-I production by the liver (which is likely the source of circulating IGF-I), fibroblasts, and other organ systems. Circulating IGF-I associates with high affinity binding proteins (IGFBPs). To date, six IGFBPs have been identified and fully characterized (55). While a primary role of the binding proteins may be the transport of IGF-I (and IGF-II) in extracellular fluids, complex responses occur whereby the IGFBPs may either inhibit or facilitate the biological actions of IGF-I. Thus, the IGFBPs are additional variables in the complex orchestration of physiological growth and GH secretion (56). The metabolic consequences of GH and IGF-I action are 1) stimulation of lipolysis; 2) increased circulating free fatty acids; 3) antagonism of insulin action; 4) increased urinary excretion of calcium; and 5) increased circulating serum phosphorus concentrations. For further details concerning these metabolic actions, the reader is referred to several reviews (57-59). E. Mathematical modeling techniques: assessment of hormone secretion, elimination, and circulating concentration profiles Critical to the advancement of the understanding of GH physiology is the availability of sophisticated, computer-assisted mathematical techniques with which to characterize the experimental data. In this section, we will outline such methods to provide a basic understanding of the more commonly used methods. We will restrict the discussion to those categories of analytic methods that are employed in the subsequently described investigations. In general, two broad categories of such methods have recently become available. The first of these techniques evaluates circulating hormone data series and provides specific characteristics of the pulsatile patterns of circulating hormone levels (60). Among such peak-detection algorithms are the CLUSTER (61), DETECT (62), PULSAR (63), and other similar computer-based programs. Several ideal characteristics of such programs include objectivity, validity, ease of use, independence of specific type of signal or noise in the actual data, versatility, concordance with visual inspection of the data series, and the ability to properly identify repetitive phenomena. The pulse detection program used in all but one of the subsequently detailed experiments is the CLUSTER algorithm. This involves an iterative search for all significant increases and decreases within a given data series. It is constrained by hormone- and sampling frequencyspecific statistical parameters. Application of this technique to experimental data sets provides the user with estimates of circulating hormone pulse characteristics such as frequency, amplitude, width, interpulse interval,


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nadir concentration, and mean hormone concentration. The ability to accurately detect circulating hormone pulses is related to the frequency of blood sampling (64). Decreasing the frequency of the sampling interval may result in serious underestimation of circulating hormone pulse frequency. The second category of methods is generally known as deconvolution analysis or convolution modeling (65, 66). The application of this technique to data series provides estimates of hormone secretion and clearance rate that represent the specific neuroendocrine secretory events and the resultant hormone clearance. In its most basic form, multiple parameter deconvolution analysis uses an a priori estimate of the hormone clearance to process calculations. In the case of GH (and other pituitary hormones), secretion occurs in a repetitive, burst-like fashion. Convolution modeling characterizes these bursts of pituitary hormone secretion by their frequency of occurrence, the mass of hormone released, the rate of hormone secretion, and the duration of the secretory process. Estimates of hormone production can be mathematically derived from the resultant data. Subject-specific estimates of hormone half-life (clearance) are derived from deconvolution analysis. Estimates for endogenous GH production rate and circulating hormone halflife are in agreement with independent estimates reported previously (67).

III. Ontogenesis of Physiological GH Secretion: Influences of Gender and the Sex Steroid Hormone Environment A. Fetal and neonatal periods: lessons from investigations in the human and other species The investigation of GH physiology in the human fetus has been constrained by practical as well as ethical issues (68). Because of these limitations, investigators have utilized various animal models to study GH secretion and metabolism during fetal development. We shall first discuss the results of work in the rat and ovine models, and then present data from studies involving human fetuses, newborns, and neonates. GH physiology in the rat, while differing from human physiology in certain aspects, shares several key similarities with GH metabolism in man. For example, although elevated levels of circulating GH levels are observed in states of stress and illness in man, diminished GH release occurs in the stressed or ill rat. In humans with diabetes mellitus, spontaneous GH release is increased compared to that of the healthy state (69). On the contrary, the diabetic rat exhibits marked decreases of circulating GH concentrations (70). However, the major hypothalamic controlling mechanisms that influence GH secretion from the somatotrope operate in an analogous fashion in

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both species (71, 72). Because of these factors, as well as practical concerns, the rat serves as an excellent model in which observations about GH secretion may further the knowledge of hGH physiology. Jansson and colleagues (36) have discussed the role of gonadal steroid hormones in the development of sexually dimorphic patterns of circulating GH release in the rat. GH levels are demonstrably greater in the fetus and newborn than at later times in life. The hypothalamus appears to play an important role in this phenomenon, since GH levels are substantially lowered by encephalectomy of the fetal rat (73). Differences in GH secretion have been observed between male and female animals by 30 days of postnatal life (74). Subsequently, a distinct dimorphism develops throughout pubertal maturation and is fully manifest in adult animals (75). In adult male animals GH is secreted in an episodic burst-like fashion. This episodic release occurs every 3-4 h with low levels of GH in the intervening trough periods. In the adult female rat GH is secreted in a less regular fashion characterized by higher basal levels with dysynchronous pulses. Fetal and neonatal alterations of the sex steroid hormone milieu appear to impart a sex-specific patterning of GH release in later adult life. Exposure of male rats to a normal sex steroid hormone milieu prenatally, followed by gonadectomy on the first day of life, is associated with elevated GH levels during puberty, but diminished hormone concentrations in the adult. In fact, the circulating GH levels of these animals were similar to those of intact adult female rats (76). Administration of androgen to neonatally castrated female rats resulted in elevated pulses of circulating GH in the young adult animals (36). Thus, it appears that the sex steroid hormones play a critical role during fetal and early neonatal development in the determination of specific genderrelated patterns of spontaneous GH profiles. A significant amount of research into fetal GH physiology has been performed in the ovine fetal model. A distinct developmental pattern shared by other mammalian species exists. GH release is pulsatile in the ovine fetus. Circulating hormone levels are elevated during midgestation and subsequently decline throughout lategestation (77). A dramatic fall in circulating GH levels occurs after parturition due, at least in part, to decreased hormone secretion, increased free fatty acid levels, and a maturation-associated increase in SRIH inhibition of GHRH-stimulated GH release (78, 79). During the neonatal period, SRIH continues to dampen GHRH-stimulated GH release. After parturition, however, GH pulsations appear to coincide with diminished SRIH secretion and concomitant increased GHRH release (79). Most of the information in human fetal physiology has been obtained from abortuses or stillborn infants. (For an excellent overview of this topic, the reader is referred


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to Ref. 80.) Fetal pituitary GH mRNA levels rise progressively throughout weeks 16-27 of gestation (81), the only period of gestation investigated. Pituitary concentrations of GH rise to a maximum by 25-30 weeks and remain virtually unchanged throughout the remainder of gestational development. The adenohypophysis of the fetus is capable of releasing GH in vitro as early as 5 weeks of gestational age (82). GH is present in the plasma as early as 68 days of gestation. Circulating levels of GH rise during gestation, reaching peak values at about 24 weeks. Subsequently GH concentrations decline through the remainder of fetal development (83). Levels of GH in umbilical cord blood of premature infants are demonstrably greater than those of full-term babies (84-86). Likewise, measurements of urinary GH levels have revealed higher GH excretion in preterm infants as compared to GH excretion levels in full-term infants (87). After parturition, circulating GH levels fall progressively. By 8 weeks of life, GH levels of premature and full-term infants are indistinguishable (84). These values, however, are distinctly greater than those observed in adult humans. While no apparent differences in the gender-related patterns of GH secretion during fetal development have been reported, distinct developmental patterns of hypothalamic-pituitary-(placental)-gonadal activity have been observed. In both sexes, the release of gonadotropins into the fetal circulation occurs by 11-12 weeks gestational age (68, 88). Maximal levels of circulating testosterone are observed at 11-16 weeks of gestation (89, 90) in the male fetus. Recently, Beck-Peccoz and colleagues (91) demonstrated that biologically active free testosterone levels are markedly higher at midgestation in the male fetus compared to that in the female fetus. In late gestation, free testosterone concentrations are indistinguishably elevated in both sexes. What role these intriguing gender-specific patterns of in utero sex steroid hormone secretion may impart on the regulation of GH physiology in the human remains an interesting area of investigation. During the first month of life, randomly obtained GH levels from a cross-sectional group were higher in male than in female neonates. After parturition, a distinct pattern of sex steroid hormone secretion has been observed (92, 93). In the male neonate, circulating testosterone levels rise sharply at about 2 weeks of life and reach maximal values at 1-2 months. The testosterone concentrations then decline to reach prepubertal levels by 6 months of age. In the female neonate, testosterone concentrations decline from maximal levels at term to approximate childhood values by the second week of life. Estradiol concentrations are increased in both sexes at term, but then display a variable pattern throughout childhood in both males and females; such levels often

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are at or below the level of detectability of commonly employed assays. While highly speculative, the elevated androgen levels observed for the male neonate may be causally related to the higher GH levels in the male infant during the first month of life as described by Cornblath and colleagues (84). Additional substantiating data are needed to support such a concept. Studies assessing the pulsatile nature of GH release in newborn infants have been limited. In one such investigation, mean circulating GH levels for premature (31.0 ± 0.4 weeks gestation) infants were observed to be higher than those of full-term babies (94). Both groups exhibited a pulsatile pattern of GH release. The GH pulse amplitude contributed to the greater GH levels in the premature infants. While a greater pulse frequency was observed for the premature babies, the blood sampling period of every 30 min may have been suboptimal to allow accurate detection of this property in both study groups. As such, caution should be exercised in the interpretation of the data. Despite these greater GH levels, the premature infants had diminished IGF-I concentrations compared to those of full-term infants. A negative correlation between IGF-I levels and circulating GH concentrations was observed. An inverse relationship between IGF-I levels and GH secretion has also been observed in older infants and children with severe malnutrition (95). The lipolytic effect (by GH) and the diminished lipogenic action (by IGF-I) may be important in the physiological regulation of metabolic fuel supply (fatty acids) in the premature infant. Certainly, additional investigation should yield interesting results that will aid in the understanding in this important area of fetal/neonatal metabolism. Esparza and colleagues (96) examined the role of postnatal age on GH pulse properties in full-term infants. The infants were divided into EARLY (22 ± 5 h; mean ± SEM) and LATE (73 ± 4 h) groups, based on their postnatal age. Similar to their earlier investigation (94), pulsatile patterns of GH release were observed. Mean GH levels declined significantly from EARLY to LATE ages. A decline in pulse amplitude and detectable pulse frequency contributed to this postnatal decline of GH concentrations. No conclusions can be made, however, about the impact of gender and gonadal steroids from the available data of these preliminary studies. While the preceding discussion has focused on GH physiology in the fetus (and neonate), the hormone plays a limited role in fetal growth; for example, the birth length of the anencephalic fetus, the fetus with absence of the pituitary, and children with idiopathic hypopituitarism is normal (97-99). Additional factors such as metabolic substrate supply, thyroid hormone action, IGF production, and placental lactogen concentration are


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apparently more critically involved in the normal growth processes during fetal development (78, 100, 101). B. Childhood: a potential role of the gonadal steroid hormones in the physiological control of GH secretion

Multiple factors are critically involved in the processes of growth and development during childhood (102). Among these are nutrition, genetic constitution, presence or absence of serious systemic disorders, endocrine function, and psychosocial well-being. Normal GH and thyroid hormone action are essential endocrine components for the regulation of physiological growth in children. This is clearly evident in the poor growth rates of children with deficiencies of either of these two endocrine systems. The role of gender and the sex steroid hormones in the process of childhood growth is apparently of lesser importance. Normal growth patterns of males and females significantly overlap during this period. Likewise, the growth of children with hypogonadism (with normal karyotype) does not differ markedly from that of normal children before puberty (103). Other investigators have independently observed normal prepubertal growth patterns in hypogonadotropic subjects (104). Several investigators have carefully examined GH physiology during the childhood period of normally growing, normal stature subjects. In one study, a significant positive correlation was demonstrated between physical stature and circulating levels of GH (105). This same group of investigators, applying a mathematical model to study GH kinetics, has subsequently reported a positive relationship between the amount of GH secreted and the linear height of children (106). We are unaware of confirmatory data from other investigators. The mode whereby physiological changes in circulating GH concentrations promote normal childhood growth is likely through amplitude modulation of GH pulses (107). Gender is not an important determinant of GH release in the prepubertal child. In studies of normally growing children, no relationship has been shown to exist between either a child's gender and peripheral GH concentrations (105,108) or the amounts of GH secreted (105). Similar findings have been obtained in a study of prepubertal

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children with short stature (109). Costin and colleagues (110), however, observed that prepubertal females tended to have higher mean circulating GH concentrations than did males, although these results did not reach statistical significance. Wide variations in the average daily GH levels were observed, perhaps due to infrequent sampling. The hypogonadal subject provides a clinical model for the evaluation of the role of gonadal steroid hormones in GH secretion. The physiology of GH has been previously investigated in prepubertal females with Turner's syndrome. These children possess a chromosomal abnormality (45, X) with associated findings of ovarian dysgenesis, short stature, structural cardiac defects, and anatomical renal anomalies (111). No specific alterations of circulating GH concentrations have been demonstrated in subjects less than 9 yr of age (112), suggesting that the gonadal steroid hormones, at least in the prepubertal female, are not critically involved in normal GH physiology. Veldhuis and co-workers (113) have utilized deconvolution analysis (114, 115) to study the dynamics of GH secretory events and metabolic clearance in a cohort of subjects with Turner's syndrome. When compared to normal prepubertal females, the children with Turner's syndrome had a prolonged GH half-life, diminished number of detectable GH secretory bursts, and prolongation of the GH secretory bursts. No differences were observed for the mean serum GH levels, the mass of GH released per burst, the maximal rate of GH secretion, or the 12-h secretion rates (when corrected for body mass). While the overall production rates for GH were unaltered, different mechanisms were operative. The gonadal steroid hormones have a positive effect on GH metabolic clearance, as demonstrated by steady state infusions of the recombinant hormone in prepubertal and adult subjects (116). Likewise, very small amounts of exogenous estrogen have a stimulatory effect on the number of secretory episodes (117). Even the low levels of estrogen in the prepubertal female may facilitate GH secretion. Association of GH with the circulating binding protein prolongs the hormone half-life (118). However, the role of GH-binding protein in the decreased metabolic clearance of GH in prepubertal girls with Turner's syndrome is unknown. No obvious rationale for the

TABLE 1. Clinical characteristics of the study subjects Group

Chronologic age (yr)

Skeletal age (yr)

Testicular size (cm)

Height percentile

PRE EARLY LATE POST ADULT

9.0 ± 0.3" 11.5 ± 0.26 14.4 ± 0.2c 16.4 ± 0.4d 23.0 ± 0.6e

8.2 ± 0.4" 11.9 ± 0.36 15.0 ± 0.4c Fused

1.9 ± 0.1" 3.1 ± 0.2" 4.7 ± 0.1* 4.6 ± O.I6 ND

53 ± 8 " 55 ±6° 58 ±5° 61 ±6" 47 ±7"

ND

Values are represented as mean ± SEM; ND, not determined. Values within a column with different superscripts differ significantly from each other (P < 0.001). [Adapted from P. M. Martha Jr. et al\ J Clin Endocrinol Metab 69:563,1989 (133).


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observed increase of secretory burst duration is available. Acute administration of estrogen to prepubertal girls with Turner's syndrome had no demonstrable impact on this aspect of GH release (117). Further investigation in this area may provide insight to the mechanisms whereby the low, but real, prepubertal levels of gonadal steroid hormones impact on normal GH physiology.

20-

A D

10

Illl.

C. Puberty: pulse amplitude-modulation of increased circulating GH concentrations 1. Independent actions of GH and sex steroid hormones. Puberty is a dynamic process involving dramatic changes in physical and sexual maturation, as well as marked fluctuations in the hormonal environment. A characteristic feature of adolescent development is the pubertal growth spurt. In females, maximal growth velocity occurs at an average age of 11-12 yr. The peak height velocity typically occurs at 13-14 yr in males (119). Numerous investigators have studied various factors associated with the rapid increase in linear height during adolescence. Among these, GH and the sex steroid hormones are of paramount importance. The important role of GH in the pubertal growth spurt has been demonstrated by the suboptimal growth patterns of GH-deficient children. In a study of GH-deficient male and female pubertal subjects, Tanner and colleagues (120) demonstrated the requirement of GH for adolescent growth. Some of their study subjects had concomitant gonadotropin deficiency and were treated with gonadal steroids to correct the hypogonadal state. After the addition of sex steroid hormone therapy, an additional acceleration of the height velocity was observed. Thus, independent and additive contributions of GH and gonadal steroid hormones to the adolescent growth spurt were evident. In an independent study of the role of sex steroid hormones in pubertal growth, children with combined GH deficiency and hypogonadotropism were treated with androgen alone or in combination with GH. Based on linear growth velocities following therapeutic intervention, Aynsley-Green and colleagues (121) concluded that gonadal steroid hormones alone are insufficient to promote normal adolescent growth. Augmentation of height velocity was observed only when androgens were administered in combination with GH. Sex steroid hormone action, however, is a necessary component of the normal pubertal growth spurt (122). Studies on children with sexual precocity and GH deficiency have provided additional evidence for an important role of the gonadal steroid hormones in promoting adolescent growth independent of GH action (123, 124). Another important action of gonadal steroid hormones during puberty is a limiting effect on ultimate linear height.

287

PRE

EARLY

LATE

POST

ADULT

PRE

EARLY

LATE

POST

ADULT

18

12

=5 Q.

X

.^ c

CL

o —

lili i PRE

EARLY

LATE

POST

ADULT

FlG. 1. Augmentation of circulating GH concentration during normal male puberty. Shown in this figure are the mean (± SEM) 24-h GH concentrations (panel A), GH pulse areas (panel B), and the number of GH pulses (panel C) for the different groups of study subjects. GH concentrations were determined using an immunoradiometric assay for serum samples obtained every 20 min for 24 h. The CLUSTER algorithm was applied to the serial GH concentration data to obtain the specific pulse characteristics. For each graph, bars not identified by the same letter(s) represent statistically different (P < 0.05) values. The mean 24-h circulating GH levels are increased in boys with advanced (LATE) pubertal development. Contributing to this increase are greater average GH pulse areas and pulse amplitudes (data not shown). The frequency of detectable GH pulses remains unchanged. [ Reproduced with permission from P. M. Martha, Jr. et. al.\ J Clin Endocrinol Metab 69:563,1989 (133). ®The Endocrine Society.]

Hibi and colleagues (125) studied the impact of pubertal timing on adult height in GH-deficient males and females who were appropriately treated with exogenous GH. Those subjects who had concomitant gonadotropin deficiency and underwent artificial puberty at a late age attained a greater mean final height than subjects with spontaneous pubertal development. The results of this investigation are in agreement with those of other studies (126-128). The available data strongly suggest that both GH and the sex steroid hormones can augment growth during the normal process of puberty. The gonadal steroid hormones also have a limiting effect on ultimate height gain, likely via their action on skeletal maturation and epi-


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physeal growth plate closure. Although the impact of GH and the gonadal steroid hormones on ultimate height may be, at least in part, oppositional, substantial evidence suggests a positive, dynamic physiological interrelationship during the period of rapid linear growth. 2. Dynamic interactions of GH and endogenous androgen. Exogenous androgens have a stimulatory effect on GH secretion after provocative testing and spontaneously circulating GH concentrations. However, the physiological relevance of this phenomenon is unclear. Several investigators have demonstrated increased circulating GH levels during the normal process of pubertal development as assessed by circulating serum levels (108,129134) or by urinary GH levels (135). Other investigators, however, have not been able to document alterations of spontaneous GH concentrations during male adolescent maturation (136-139). Differences in experimental design such as the application of objective pulse detection algorithms to assess specific GH pulse characteristics and various frequencies of repetitive blood sampling over a 24-h period may account for some of the apparent discrepancies of the reported studies. Males with precocious puberty have been observed to have greater levels of circulating IGF-I than normal children of similar chronological ages (140). Concentrations of testosterone were significantly correlated with the IGF-I levels. After gonadal suppression with a LH-releasing hormone agonist, IGF-I levels and mean spontaneous nocturnal GH concentrations decreased. These results provide additional support for the positive impact of androgens on GH release. Kamp and colleagues (141) have suggested that alterations of GH physiology occurring in children with precocious puberty may be critically and inversely related to body mass index. As such, the choice of proper controls in the assessment of GH secretion becomes critical. To evaluate the role of endogenous male sex steroid hormones on the GH axis, 24-h circulating GH levels were obtained for a cross-sectional cohort of pubertal males and evaluated by an objective pulse analysis algorithm, the CLUSTER program (61), and by deconvolution (114, 115) analysis (133, 142). Study subjects were young, healthy males of normal stature representing all stages of sexual development; clinical characteristics are provided in Table 1. As a group, 24-h mean GH concentrations and average GH pulse amplitude (and GH pulse area) were greatest for the LATE pubertal group than for all other groups; no differences were observed for GH pulse frequency (see Fig. 1). Similarly, plasma IGF-I concentrations were greatest for the LATE pubertal groups when compared to those of all other groups. Statistically significant correlations were observed between the serum testosterone concentrations from the

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PRE, EARLY, and LATE pubertal groups and their plasma IGF-I concentrations (r = 0.68, P < 0.001), 24-h mean GH level (r = 0.47, P < 0.001), the mean and sum of GH pulse areas (r = 0.68, P < 0.001; and r = 0.54, P < 0.001, respectively), and the mean and sum of GH incremental pulse amplitudes (r = 0.58,; P < 0.001; and r = 0.47, P < 0.001, respectively.) The application of deconvolution analysis to such data has provided mechanistic insight into the secretion and elimination kinetics of GH as altered by physiological changes of endogenous sex steroid hormones in the pubertal male. The LATE pubertal group was distinguished from all other groups by the greater mass of GH secreted in a 24-h period. Contributing to the observed increased production rate was an augmentation of maximal rate of GH release per secretory episode resulting in a greater mass of GH released per secretory burst. No significant changes were observed for the duration or frequency of the GH secretory episodes or for serum GH half-life. Representative profiles from individual subjects in each of the EARLY, LATE, and ADULT groups are illustrated in Fig. 2. The results obtained by analysis of the data by deconvolution mechanics are shown in Table 2. These results show that endogenous GH levels rise during middle to late puberty, the developmental stages associated with marked elevations of circulating gonadal steroid hormone levels. Similar results have been obtained independently (106). The principal mode whereby these physiological alterations of GH occur is through changes in GH pulse amplitude. Whereas metabolic clearance of GH and secretory episode frequency are apparently unaltered during the course of male pubertal development, dramatic changes occur in pituitary somatotrope secretory activity. In a similar manner, GHbinding protein and body mass index vary throughout male puberty. Both are inversely related to GH secretion (15, 142). 3. Impact of endogenous estrogen on GH secretion. Numerous investigators have independently detected a positive relationship between serum estrogen levels and circulating GH concentrations (143,144) and IGF-I levels (140, 144-150). Other investigators, however, have been unable to find such a relationship between estrogen and GH levels (151, 152) and IGF-I levels (153), or have observed a negative relationship between estrogen concentrations and IGF-I levels (143), presumably due to a biphasic effect of estrogen on hepatic IGF-I production. Low doses of estrogen stimulate hepatic IGF-I production, but high doses are inhibitory. In a similar fashion, physiological alterations of endogenous estrogen levels and/or the accelerated growth that occur during the course of female pubertal development have been shown to relate positively to sponta-


May, 1992

GH AND GONADAL STEROID HORMONES Late

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Time (min) FIG. 2. Increased endogenous GH production throughout normal male adolescent development. Twenty four-hour profiles of serum GH concentration {upper panels) and deconvolution-resolved GH secretory bursts {lower panels) for a subject with early pubertal {two left panels), late pubertal development {two middle panels), and a young adult {two right panels) are illustrated. Please note the different range of values for the separate ordinate axes. Contributing to an increased GH production rate in the LATE pubertal group were a heightened rate of pituitary hormone release and an augmented mass of GH released per secretory episode. [Reproduced with permission from P. M. Martha Jr. et. al.: J Clin Endocrinol Metab, 74:336, 1992 (142). ® The Endocrine Society.]

puberty. After suppression of ovarian function, circulating concentrations of GH and IGF-I are decreased (140, 155). These results point to a critical dependency of GH secretory dynamics on the gonadal steroid hormone environment during the course of normal and advanced female sexual development. Rose and co-workers (134) have reported their findings obtained from examining spontaneous GH profiles in pubertal subjects. These investigators studied 132 children (64 female and 68 male). The average overnight GH concentration and the GH pulse amplitude were greater for pubertal age females than for prepubertal subjects. The investigators observed an augmented GH pulse am-

neous GH concentrations (106, 108, 134, 154), urinary GH excretion (135), and to plasma IGF-I concentrations (134, 146). Other investigators have reported no significant change in circulating GH levels of pubertal females when compared to those of prepubertal females (130, 151). Plotnick and colleagues studied only pubertal females with early sexual development (Tanner II-III) whereas only daytime GH levels were evaluated by Miller and co-workers. Thus, the apparent differences in the results of the studies cited may be at least partially explained by limitations of study design. Augmented spontaneous GH secretion (139) and IGF-I levels (140) have been observed in females with central precocious TABLE 2. Increased GH production during late puberty in normal males

Secretory burst frequency (/24 h) Production rate (^g/Lv-24 h) Half-life (min)

PRE

EARLY

LATE

POST

ADULT

11 ± 1 270 ± 25°'c 21 ± 1

10 ± 1 230 ± 390'* 21 ±1

11 ± 1 440 ± 63C 24 ± 1

8±1 160 ± 33a'6 26 ± 2

12 ± 2 170 ± 27" 26 ± 1

Values are represented as mean ± SEM. The volume unit (Lv) refers to plasma distribution volume for GH. o.t>.c Values within a row without identical superscripts are statistically different from each other {P < 0.05). [Adapted from J. M. Martha Jr. et al.: J Clin Endocrinol Metab 74:336, 1992 (142).]


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plitude before the appearance of sexual development in the female subjects. No differences were noted for GH pulse frequency among the study groups (see Fig. 3). In a similar fashion, plasma IGF-I levels for Tanner Stage 3 female subjects were greater than those of prepubertal girls. An inverse relationship between average nighttime GH concentration and body mass index was observed. Similar to the studies described for peripubertal male subjects, the results of this study point to the dynamic relationship between physiological alterations of serum gonadal steroid hormone levels and GH release during (female) puberty. The GH axis is probably very sensitive to the stimulatory effect of estrogens as suggested by the rise of GH levels before any signs of sexual development. These findings are consistent with those reported by Mauras and colleagues (117, 156). Again, as with other studies described in this review, the physiological alteration of GH is manifested as a change in pulse amplitude 25 PULSE AMPLITUDE 20

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FIG. 3. Pulse amplitude-modulated increase of circulating GH concentrations in pubertal females (and males). The mean (± SEM) nighttime GH pulse amplitude (upper panel) and the mean (± SEM) number of GH pulses (bottom panel) are shown for boys and girls of differing bone ages. GH concentrations were determined in blood samples obtained every 20 min for 24 h using a RIA. +, Value differs from that of boys with same range of bone ages (P < 0.05). *, Value is greater than that of boys at bone age greater that 8 -11 yr (P < 0.05). **, Value is greater than those of girls at bone age 8 yr or greater (P < 0.01). y, Value is greater than those of the first and second groups of boys (P < 0.05). Average circulating GH concentrations increased during the course of pubertal development (data not shown). This increase was due to, at least in part, increased GH pulse amplitude. [Reproduced with permission from S. R. Rose et. al.: J Clin Endocrinol Metab 73:428,1991 (134). ®The Endocrine Society.]

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rather than as a change in hormone pulse frequency. Possible explanations for the observed findings include 1) increased secretion of hypothalamic GHRH; 2) decreased hypothalamic SRIH release; 3) increased and/or decreased responsivity of GH release by the somatotrope to GHRH and/or SRIH, respectively; and 4) altered distribution, elimination, or protein-binding of GH.

IV. Impact of Exogenous Sex Steroid Hormones on GH Secretion A. Alterations of GH release after exogenous androgen administration Multiple investigators have examined the impact of a changing gonadal steroid hormone environment on the GH axis. Administration of exogenous androgen normalizes the GH response to pharmacological testing in males with constitutional delayed development (157, 158) and anorchia (159). Likewise, administration of estrogen results in augmentation of the GH response to pharmacological stimuli (143, 160-162). To evaluate the role of exogenous male sex steroid hormone in the physiological alteration of GH secretion, testosterone and/or GH was administered to six GHdeficient, prepubertal males (163). In addition, testosterone was administered to four GH-sufficient males with delayed adolescent development. Plasma IGF-I levels were measured before and after the interventions. Although the administration of both GH alone, and the combination of GH and testosterone, increased IGF-I levels in the GH-deficient subjects, the use of testosterone alone failed to alter IGF-I concentrations in these boys. However, testosterone treatment of the GH-sufficient subjects resulted in a marked rise of plasma IGF-I levels. Measurement of the 24-h integrated concentration of GH in a single GH-sufficient subject before and after testosterone administration revealed a more than 2-fold rise in circulating GH levels. These results suggest that normal hypothalamic-somatotrope function is required for increased production of IGF-I in response to androgen administration. The authors speculated that pubertal levels of testosterone may be responsible for the rise of circulating GH and IGF-I levels with an associated increased height velocity during the adolescent growth spurt. The impact of exogenous androgen on the secretory dynamics and metabolic clearance of GH was recently studied (164). Twelve pre-/early pubertal male subjects with constitutional delayed development were administered testosterone or oxandrolone for 90 days. Deconvolution analysis was utilized to assess GH secretory and elimination kinetics (114,115). After the administration of either androgen, the investigators observed increased mean 24-h GH concentrations, augmented endogenous



May, 1992

GH production rate resulting from increased mass of hormone secreted per burst, and a higher maximal rate of GH secretion within each secretory episode (see Fig. 4). Androgen administration had no effect on the number and duration of GH secretory bursts or the subjectspecific half-life. These results demonstrate that testosterone is capable of augmenting circulating levels of GH by a pulse-amplitude modulated mode. This in turn may be the direct result of increased GH production without altered hormone clearance. The mechanism(s) whereby androgens stimulate GH secretion is not yet known. Although the results of the investigation by Ulloa-Aquirre and colleagues (164) suggest a mechanism independent of aromatase and estrogen receptor-mediated pathways, additional study will be required to clarify this issue. Independent investigations have confirmed the stimulatory effect of androgens on the somatotropic axis. In one such study, previously untreated adults with idiopathic hypogonadotropic hypogonadism were administered human CG (hCG)/hMG, testosterone, or GnRH. After such interventions, the investigators observed an increased 24-h mean GH level, GH pulse amplitude, and IGF-I concentrations; no differences were detectable for GH pulse frequency or pulse width (152). Children with constitutional delay of growth and adolescence have diTESTOSTERONE

500

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FIG. 4. Shown in this illustration are the 24-h profiles of circulating GH concentrations {upper two panels) and the deconvolution-resolved secretory bursts {lower two panels) in a single subject before {left two panels) and after {right two panels) administration of testosterone. GH concentrations were determined in blood samples obtained every 20 min for 24 h. Please note the different range of values for the ordinate axes. An increased mass of GH released per secretory burst and a higher maximal rate of hormone release were observed after treatment with the androgen. The number of GH secretory bursts and the hormone half-life were invariant. Consequently, testosterone treatment resulted in an increased 24-h GH production rate and greater mean circulating GH concentrations. [Reproduced with permission from Ulloa-Aguirre et. ai: 1990 J Clin Endocrinol Metab 71:846, 1990 (164). °The Endocrine Society.]

291

minished levels of circulating GH (131, 165-167). The role of delayed sex steroid hormone exposure on the dynamics of the somatotrope axis and physical may be critical. Treatment of children with constitutionally delayed development with testosterone (168) or GnRH (169) results in augmentation of circulating GH levels. Likewise, increased spontaneous GH concentrations are observed after administration of testosterone to pre-/ early pubertal males with idiopathic short stature (170). However, acute treatment with androgen does not alter endogenous circulating GH concentrations (171). During the course of iv testosterone infusion (18-24 h) to a cohort of peripubertal males, the investigators observed unaltered circulating GH profiles. The exogenous androgen was administered at the physiological adult male production rate, and resultant testosterone levels were within the normal adult male range. Serum estradiol concentrations remained undetectable in a relatively insensitive assay. Therefore, a "relative chronicity" of androgen action may be a prerequisite for its impact on the physiological regulation of GH secretion. B. The impact of exogenous estrogen on GH secretion Estrogen stimulates GH secretion in humans. Frantz and Rabkin (172) observed that, after estrogen (diethylstilbestrol) administration to adult males, activity-induced GH release was elevated to a level indistinguishable from that of normal adult females. Other investigators have observed that estrogen administration to adult males results in acute elevations of endogenous GH release (143) and an augmentation of the GH response to arginine (160, 173). Wiedemann and colleagues (143) observed decreased IGF-I levels after estrogen treatment; this phenomenon was attributed to a biphasic response to exogenous estrogen; small doses augment GH release (and IGF-I production) while large doses inhibit IGF-I production. Studies of the effects of estrogen administration on GH release in children have provided similar results. Rosenfield and Furlanetto (149) administered estrogen to teenage girls with Turner's syndrome and observed increased IGF-I levels. In a similar fashion, CarusoNicoletti and colleagues (148) observed augmented IGFI levels and ulnar growth after treatment of pre/early pubertal males with low dose estradiol (infusion of 4-90 jxg estradiol/day for 4 days). Studies of the GH response to pharmacological testing in short children after estrogen administration have also shown increased GH levels (161, 170, 174). The impact of estrogen on the physiological secretion of GH has been evaluated. The pulsatile administration of GnRH to females with constitutional delay of development or hypogonadotropic hypogonadism resulted in


292

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FIG. 5. Stimulatory effects of exogenous estrogen on GH secretory dynamics. Profiles of 24-h circulating GH concentrations (panels on left side) and deconvolution-resolved GH secretory bursts (panels on right side) from a prepubertal subject with Turner's syndrome before treatment (basal), 1 week (acute), and 5 weeks (chronic) after the administration of ethinyl estradiol (100 ng/kg/day) are illustrated. GH concentrations were determined in serum samples obtained every 20 min for 12 h (overnight) using an immunoradiometric assay. The reader should note the differences in the absolute ranges of values for the ordinate axes. After 5 weeks of treatment with the estrogen, GH production rates increased by more than 2-fold in all subjects. The half-life of endogenous GH was unaltered. [Reproduced with permisssion from N. Mauras et al.\ Pediatr Res 28:626,1990 (117).]

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TIME (min) the induction of pubertal development; overnight GH secretion (both the sum of GH peak concentrations and the GH peak areas) reached a maximum coincident with the maximal height velocity (169). Rose and colleagues (170) observed an increased number of spontaneous daytime GH pulses and the 24-h mean GH concentrations after ethinyl estradiol treatment of pre/early pubertal males and females with idiopathic short stature. The hypogonadal female has served as an excellent clinical model in which to study the impact of estrogen on GH physiology. Several groups of investigators have demonstrated the growth-promoting effects of estrogen in children with Turner's syndrome (147,175-179). The impact of low dose ethinyl estradiol on endogenous GH secretory dynamics and metabolic clearance was recently evaluated in a cohort of prepubertal girls with Turner's syndrome (117, 156). Nine young girls with Turner's syndrome were evaluated on three separate occasions. Subjects were studied before (I), after 1 week (II), and after 5 weeks (III) of ethinyl estradiol (100 ng/kg/day, orally) administration. Venous blood samples were obtained every 20 min from 2000 h to 0800 h for GH determinations. The CLUSTER algorithm (61) and deconvolution analysis (114, 115) were applied to the data to determine pulsatile hormone characteristics and secretion/clearance parameters, respectively. The pulsatile GH profiles and the GH secretory rates for a typical study subject are shown in Fig. 5. Results obtained by the application of the CLUSTER algorithm are shown

in Table 3; data for deconvolution analysis are presented in Table 4. These results demonstrate a remarkable stimulatory effect of small amounts of estrogen on circulating GH concentrations in prepubertal subjects with Turner's syndrome. This increase is manifested by augmentation of GH pulse amplitude, rather than alteration of pulse frequency. The endogenous GH production rate more than doubled in response to these extremely small doses of estrogen. An increase in secretory burst frequency (deconvolution analysis) and a trend toward increased maximal rate of GH release and mass of GH released per secretory burst were contributory to the rise. The halflife of endogenous GH was unaltered. The investigators concluded that the somatotropic axis is exquisitely sensitive to small amounts of biologically active estrogen. These changes could be attributable to enhancement of somatotrope responsiveness to GHRH action, increased GHRH release, and/or diminished somatostatin action. The observed increase of pulse frequency may be explained by enhanced GHRH action manifested as measurable rises of GH release. These findings support the contention that even low circulating concentrations of the female sex steroid hormone provide potent stimulation to the somatotrope.

V. Discussion The physiology of the hypothalamic- somatotrope IGF-I axis represents a dynamic system which manifests


May, 1992


TABLE 3. Increased spontaneous circulating GH concentrations after exogenous estrogen administration to prepubertal subjects with Turner's syndrome

[GH] (Mg/L) Pulse area (jig/L • min) Pulse amplitude (^g/L) Pulse frequency (/12 h)

Study I

Study II

Study III

6.7 ± 0.9 607 ± 43 14.1 ± 1.7 4.9 ± 0.5

10.9 ± 1.8 958 ± 135 22.3 ± 3.4 5.3 ± 0.4

12.8 ± 1.5° 1190 ± 229° 29.6 ± 5.2° 5.8 ± 0.5

Values are presented as mean ± SEM (n = 9 for each study group). The studies were conducted at baseline (study I), one week (study II), and 5 weeks (study III) after ethinyl estradiol (100 ng/kg/day, orally) administration. 0 P < 0.05 {us study I). [Adapted from J. M. Mauras Jr. et ai: Pediatr Res 28:626,1990 (117).]

developmental changes as well as control by multiple neural, hormonal, and metabolic influences. Although this review has presented in-depth details of the developmental alterations of GH secretion in man, it has focused primarily on the interaction of the sex steroid hormones and GH physiology. Many of the available data suggest that the role of the gonadal steroid hormones in the normal physiology of hGH release does not become of major importance until the time of pubertal development. Differences in circulating levels of sex steroid hormones, but not GH, have been detected during human fetal development. Genderspecific changes in GH physiology have been observed in the neonatal period and may be related to differences in circulating levels of gonadal steroid hormones. Furthermore, using a recently available mathematical technique to investigate the kinetics of GH physiology, Veldhuis and colleagues (113) have provided evidence for a potential impact of even the very low levels of estrogen in the prepubertal female on GH secretion. Thus, sex steroid hormones may impart a physiologically relevant modulatory effect on the human hypothalamic-pituitaryIGF-I axis as early as in utero development. Although these intriguing results are suggestive of such a relationship, further carefully designed studies employing sophisticated techniques will undoubtedly provide additional exciting insight. Based on the information presented in this review article, it is evident that pubertal levels of the sex steroid hormones (of either endogenous or exogenous sources) have dramatic effects on GH physiology. The alterations of circulating GH concentrations are manifested by augmentation of GH pulse amplitude. The biological relevance of these findings may relate to the strong association between GH pulse amplitude and linear height velocity as demonstrated by Hindmarsh and colleagues (107). In support of such an association, some children with short stature have diminished GH pulse amplitudes (167). A significant correlation has been demonstrated

293

between GH pulse amplitude and the incremental growth velocity after GH treatment by some investigators (180, 181), but not others (182). Therefore, the amplitude of spontaneously circulating GH pulses may be an important biological signal for growth of the organism. The sex steroid hormones also contribute to the rapid increase of linear height during puberty. The recent application of deconvolution analysis has provided useful insight into the mechanisms subserving gonadal steroid hormone modulation of GH pulse amplitude. The impact of the sex steroid hormones, of endogenous or exogenous origin, on GH physiology is an amplification of somatotrope secretory activity. The frequency of such secretory events and circulating GH halflife are unaltered; the net effect of gonadal steroid hormone action is an augmentation of endogenous GH production rate. The level at which the sex steroid hormones act in the human remains unknown. Likewise, the mechanism(s) by which the gonadal steroid hormones influence GH secretion is uncertain. Given that the majority of studies have demonstrated increased GH pulse amplitude in response to gonadal steroid hormone action and the recently available data showing increased GH production rates without altered elimination kinetics, it is likely that the episodic secretion of increased amounts of GHRH or increased somatotrope responsivity to GHRH action are primarily involved. Likewise, episodic increases and decreases of SRIH secretion (inversely coordinated with GHRH release), and possible cooperative actions of combined GHRH and SRIH may be altered by sex steroid hormone action. These effects may manifest as augmented GH release. Although clinical investigations have contributed significantly to an understanding of the interactional relationship of GH release and the sex steroid hormones, basic science investigations will continue to be highly

TABLE 4. Increased GH production in prepubertal subjects with Turner's syndrome after estrogen administration

Secretory burst frequency (/12 h) Secretory burst half-duration (min) Maximal rate of release (/*g/ Lv-min) Mass per burst (Mg/Lv) Production rate (/ug/Lv-12 h) Half-life (min)

Study I

Study II

Study III

5.3 ± 0.6

6.9 ± 0.3

7.9 ± 0.5"

27 ± 2.3

27 ± 2.5

29 ± 2.0

1.4 ± 0.1

1.5 ± 0.2

1.8 ± 0.3

39 ± 4 194 ± 22 19 ± 2

43 ± 6 290 ± 43 18 ± 1

51 ± 6 412 ± 66° 18 ± 1

Values are represented as mean ± SEM (n = 9 for each study group). The volume unit (Lv) refers to plasma distribution volume for GH. " P < 0.05 (vs. study I). [Adapted from N. Mauras Jr. et at. Pediatr Res 28:626, 1990 (117).]


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instrumental to the understanding of the mechanisms involved. Up to the present, mutually coordinated efforts in both basic science and clinical research have resulted in exciting advancements in the understanding of the complex physiology of GH. These findings have been translated to direct clinical applications. Use of exogenous sex steroids alone, or in combination with GH therapy, is commonly employed in the management of children with disordered growth (183-185). Further advances will undoubtedly enhance the understanding of the physiological relationship between the sex steroid hormones and GH release. Such knowledge will then permit treatment of some children with disordered growth with optimal gonadal steroid hormone regimens.

Acknowledgements We are grateful for the assistance of Susan Lorek Fitzgerald and Lois Perry in the preparation of this manuscript. The superb assistance of the nursing staff and laboratory personnel, as well as the computer facilities of the General Clinical Research Center at the University of Virginia, made many of the studies described in this report possible.

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Vinay MC 1990 Evaluation of the growth hormone-binding proteins in human plasma using HPLC-gel filtration. J Clin Endocrinol Metab 71:1202 15. Martha Jr PM, Rogol AD, Blizzard RM, Shaw MA, Baumann G 1991 Growth hormone-binding protein activity is inversely related to 24 hour growth hormone release in normal boys. J Clin Endocrinol Metab 73:175 16. Postel-Vinay MC, Tar A, Hocquette JF, Clot JP, Fontoura M, Brauner R, Rappaport R 1991 Human plasma growth hormone (GH)-binding proteins are regulated by GH and testosterone. J Clin Endocrinol Metab 73:197 17. Baumann G 1988 Heterogeneity of growth hormone. In: Bercu BB (ed) Basic and Clinical Aspects of Growth Hormone. Plenum Press, New York, pp 13-31 18. Tannenbaum GS, Ling N 1984 The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion. Endocrinology 115:1952 19. Plotsky PM Vale W 1985 Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophyseal portal circulation of the rat. Science 230:461 20. Kracier J, Sheppard MS, Luke J, Lussier B, Moor BC, Cowan JS 1988 Effect of withdrawal of somatostatin and growth hormone (GH)-releasing factor on GH release in vitro. Endocrinology 122:1810 21. Weiss J, Cronin MJ, Thorner MO 1987 Periodic interactions of GH-releasing factor and somatostatin can augment GH release in vitro. Am J Physiol (Endocrinol Metab 116) 253:E508 22. Stachura ME, Tyler JM, Farmer PK 1988 Combined effects of human growth hormone (GH)-releasing factor-44 (GRF) and somatostatin (SRIF) on post-SRIF rebound release of GH and prolactin: a model for GRF-SRIF modulation of secretion. Endocrinology 123:1476 23. Muller EE 1987 Neural control of somatotropic function. Physiol Rev 67:962 24. Alba-Roth J, Muller OA, Schopohl J, von Werder K 1988 Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. J Clin Endocrinol Metab 67:1186 25. Berelowitz M, Szabo M, Frohman LA, Firestone S, Chu L, Hintz RL 1981 Somatomedin mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary. Science 212:1279 26. Ceda GP, Davis RG, Rosenfield RG, Hoffman AR 1987 The growth hormone (GH)-releasing hormone (GHRH)-GH-somatomedin axis: evidence for rapid inhibition of GHRH-elicited GH release by insulin-like growth factors I and II. Endocrinology 120:1658 27. Morita S, Yamashita S, Melmed S 1987 Insulin-like growth factor I action on rat anterior pituitary cells: effects of intracellular messengers on growth hormone secretion and messenger ribonucleic acid levels. Endocrinology 121:2000 28. Fagan JA, Pixley S, Slanina S, Ong J, Melmed S 1987 Insulinlike growth factor I gene expression in GH3 rat pituitary cells: messenger ribonucleic acid content, immunocytochemistry, and secretion. Endocrinology 120:2937 29. Casanueva FF, Villanueva L, Dieguez C, Diaz Y, Cabranes JA, Szoke B, Scanlon MF, Schally AV, Ferandez-Cruz A 1987 Free fatty acids block growth hormone (GH) releasing hormone-stimulated GH secretion in man directly at the pituitary. J Clin Endocrinol Metab 65:634 30. Frohman LA, Jansson J-0 1986 Growth hormone-releasing hormone. Endocr Rev 7:223 31. Aguila MC, McCann SM 1987 Evidence that growth hormonereleasing factor stimulates somatostatin release in vitro via /3endorphin. Endocrinology 120:341 32. Aguila MC, McCann SM 1988 Calmodulin dependence of somatostatin release stimulated by growth hormone-releasing factor. Endocrinology 123:305 33. Zeytin FN, Rusk SF, Dellis R 1988 Growth hormone-releasing factor and fibroblast growth factor regulate somatostatin gene expression. Endocrinology 122:1133 34. Katakami H, Downs TR, Frohman LA 1988 Inhibitory effect of


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38.

39.

40. 41. 42.

43. 44. 45. 46. 47. 48.

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Basic counterpoint: mechanisms and pathways of gonadal steroid modulation of growth hormone secretion.

Oxidative stress impact on growth hormone secretion in the eye.

Steroid hormone action: recent advances.

Caloric Restriction Effect on Proinflammatory Cytokines, Growth Hormone, and Steroid Hormone Concentrations during Exercise in Judokas.

Differential effects of arginine on growth hormone releasing hormone and insulin induced growth hormone secretion.

Effect of pyridoxine on pituitary release of growth hormone and prolactin in childhood and adolescence.

Cholinergic modulation of growth hormone-releasing hormone effects on growth hormone secretion in dementia.

Control of growth hormone secretion during the postpartum period.

Relationships between puberty and growth at adolescence in growth-hormone-deficient males: effect of growth hormone and of associated gonadal suppression therapy.

Controversies in the diagnosis and management of growth hormone deficiency in childhood and adolescence.

Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action.

[Regulation of growth hormone-releasing hormone gene expression and secretion].

Impaired secretion of growth hormone-releasing hormone, growth hormone and IGF-I in elderly men.

Growth hormone release inhibiting hormone: actions on thyrotrophin and prolactin secretion after thyrotrophinreleasing hormone.

Effects of hypothalamic dopamine on growth hormone-releasing hormone-induced growth hormone secretion and thyrotropin-releasing hormone-induced prolactin secretion in goats.

Diabetes mellitus in gonadal dysgenesis: studies of insulin and growth hormone secretion.

Thyroid - hormone effects on steroid - hormone metabolism.

Steroid hormone effects on sonatomedin. I. Somatomedin action in vitro.

Pyridostigmine blocks the inhibitory effect of glucocorticoids on growth hormone-releasing hormone stimulated growth hormone secretion in normal man.

Effects of cytidine 5'-diphosphocholine administration on basal and growth hormone-releasing hormone-induced growth hormone secretion in elderly subjects.

Tests for growth hormone secretion.

Tests for growth hormone secretion.

Tests for growth hormone secretion.

Tests for growth hormone secretion.