1 Departments of Pediatrics and of Neurology and Neurosurgery, McGill University, and the Neuropeptide Physiology Laboratory, McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec H3H 1P3, Canada; and 2 Department of Internal Medicine, University of Virginia Health Sciences Center and the National Science Foundation Center for Biological Timing, Charlottesville, Virginia 22908
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The neonatal gonadal steroid milieu is known to be important in imprinting the striking sexual dimorphism of growth hormone (GH) secretion; however, the influence of the sex steroids on GH control in adult life and their mechanism/site of action are largely unknown. In the present study, we tested the hypothesis that testosterone (T) subserves the gender-specific regularity of the GH release process in adulthood. The approximate entropy statistic (ApEn) was used to quantify the degree of regularity of GH release patterns over time. Eighteen hours after a single subcutaneous injection of 1 mg T, both sham-operated and ovariectomized (OVX) female adult rats displayed plasma GH profiles that were strikingly similar to the regular male-like ultradian rhythm of GH secretion. The highest ApEn values, denoting greater disorderliness of GH secretion, were observed in the ovary-intact group, and T injection significantly (P < 0.001) reduced this irregularity whether or not the ovaries were present. Serial intravenous injections of GH-releasing hormone (GHRH) caused a similar increase in plasma GH levels in sham-operated females independently of time of administration. In contrast, female rats administered T exhibited a male-like intermittent pattern of GH responsiveness to GHRH, the latter known to be due to the cyclic release of endogenous somatostatin. These results demonstrate that acute exposure to T during adult life can rapidly and profoundly "masculinize" GH pulse-generating circuits in the female rat. Our findings suggest that the enhanced orderliness characteristic of the GH release process in males, compared with females, is regulated by T. We postulate that this T-induced regularity is mediated at the level of the hypothalamus by inducing regularity in somatostatin secretion, which in turn governs overall GH periodicity.
sexual dimorphism; growth hormone pulsatility; somatostatin; growth hormone-releasing hormone; approximate entropy
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
THE SEXUAL DIMORPHISM of growth hormone (GH) secretion and postpubertal growth has been investigated intensively in both the rodent (23) and human (16). For example, in the rat, there is a striking gender difference in the pattern of GH secretion and rate of somatic growth (10, 16, 23). Whereas males exhibit high-amplitude GH secretory bursts at very regular 3.3-h intervals separated by low or undetectable plasma GH nadir levels (45), females show more frequent, seemingly irregular lower-amplitude GH pulses and an elevated GH baseline concentration (7, 11, 41). These distinct sex differences in the temporal patterns of GH release are of biological significance, because they evoke remarkable male-female differences in body growth (22, 40), liver enzyme gene expression (29, 49), and GH intracellular signaling pathways (50). Thus an understanding of the physiological mechanisms that govern the differential orderliness of the GH release process is important for a better comprehension of GH-regulated growth and metabolism.
There is considerable evidence that the gender-related differences in GH secretion and growth rate are attributable, at least in part, to the influence of gonadal steroids during the neonatal period (24-27). In general, testosterone (T) appears to play an important "organizational" role in generating the high-amplitude GH pulses and rapid growth rate typical of the male rat, whereas estradiol (E2) in early development is responsible for the elevated basal GH level observed in the female. Although it is well documented that the neonatal gonadal steroid milieu is an important determinant of the adult pattern of GH secretion and body growth, the influence of the sex steroids on GH control in adult life and their mechanism/site of action are largely unknown.
We recently demonstrated that the effects of the gonadal steroids are not limited to the critical period of neonatal imprinting; indeed, short-term exposure of adult male rats to E2 had profound effects on both the GH secretory pattern and the rate of somatic growth (35). There are, however, conflicting reports regarding the impact of T in adulthood. Gonadectomy of adult male rats was shown to suppress GH pulse amplitude, in one study (35), whereas other studies failed to demonstrate a significant effect of either prepubertal (24, 25) or adult (3, 15) orchidectomy. Moreover, although T treatment of adult rats was reported to enhance the GH response to GH-releasing hormone (GHRH) in vivo (51), T has been reported to decrease (18), increase (12, 20), or have no effect (13, 51) on basal and/or GHRH-induced GH release from pituitaries in vitro.
The primary control of GH secretion from the pituitary gland is exerted through two hypothalamic hormones, somatostatin (SRIF) and GHRH, whose sexually dimorphic signaling patterns at the level of the pituitary appear to generate the sex-specific patterns of GH secretion (8, 34, 39, 44). Various gender-related differences in GH control by SRIF and GHRH have been described. A growing body of evidence suggests that the effects of the sex steroids are mediated at the level of the hypothalamus via alterations in the expression of both SRIF (6, 52) and GHRH (53) genes. Despite the foregoing evidence favoring a hypothalamic, rather than pituitary, site of action for T, this inference is still somewhat controversial (31).
In the present study, we tested the hypothesis that neuroendocrine actions of T can subserve the gender-specific regularity of the GH release process in adulthood. To accomplish this, we examined the effects of acute (single-dose) exposure to T on both spontaneous and GHRH-stimulated GH secretion in free-moving, intact, and ovariectomized adult female rats. Parameters of GH pulsatility were assessed by Cluster analysis, and the approximate entropy statistic was used to quantify the degree of serial orderliness or regularity of the GH release process over time.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals and experimental procedure. Adult female Sprague-Dawley rats (210-225 g) were obtained from Charles River Canada (St. Constant, QC, Canada). The animals were either bilaterally ovariectomized (OVX) or sham-operated under ether anesthesia and were then housed in groups of three or four for 2 wk on a 12:12-h light-dark cycle (lights on between 0600 and 1800) in a temperature (22 ± 1°C)- and humidity-controlled room. Purina rat chow (Ralston-Purina, St. Louis, MO) and tap water were constantly available, and body weight was monitored daily. Subsequently, chronic intracardiac venous cannulas were implanted under pentobarbital sodium (25-30 mg/kg ip) anesthesia by use of a previously described method (45). After surgery, the rats were placed directly in isolation test chambers with food and water available ad libitum until their body weights returned to preoperative levels (within 5-7 days).
In the first experiment, we examined spontaneous GH secretory patterns in both sham-operated and OVX females. On the test day, food was removed 1.5-2 h before sampling, and blood samples (0.35 ml) were drawn every 15 min for 6-h periods between 1000 and 1600. All blood samples were immediately centrifuged, and the plasma was separated and stored atHormone assays. Plasma GH concentrations were determined in duplicate by double-antibody RIA with materials supplied by the National Institute of Diabetes and Digestive and Kidney Diseases Hormone Distribution Program (Bethesda, MD). The mean sample plasma GH values are reported in terms of the rat GH reference preparation rGH-RP-2. The standard curve was linear between 0.62 and 160 ng/ml. The least detectable concentration of plasma GH under the conditions used was 1.2 ng/ml; all samples with values above 160 ng/ml were reassayed at dilutions ranging from 1:2 to 1:10. The intra- and interassay coefficients of variation were 6.3 and 7.5%, respectively, for duplicate samples of pooled plasma exhibiting a mean GH concentration of 14.8 ng/ml and were 8.6 and 12.1%, respectively, for duplicate samples of pooled plasma having a mean GH concentration of 102.7 ng/ml.
Plasma E2 and T concentrations were measured with commercial kits for E2 and T (Radio System Laboratories, Carson, CA). All samples of a given hormone were measured in a single assay.Statistical analysis.
The plasma GH profiles of individual rats in all groups were analyzed
using the Cluster analysis program as a model-free technique for
hormone pulse detection (48). Briefly, a pooled-variance t-statistic of 2 was selected to maintain a maximal
false-positive rate of 1% by using test cluster sizes of 2 consecutive data points each in the prepeak nadir, peak, and postpeak
nadir. ANOVA for repeated measures and the Tukey honestly significant
difference (HSD) post hoc test or Student's two-tailed t-tests
for unpaired and paired data, as appropriate, were used for statistical
comparisons between and within experimental groups. The results are
expressed as means ± SE. P < 0.05 was considered significant.
Approximate entropy. A sensitive metric of relative disorderliness of hormone concentration profiles, termed approximate entropy (ApEn), was utilized to quantify objectively the serial regularity or orderliness of GH release patterns over 6 h (38). This statistic is a finite positive nonzero real number developed for any single entire hormone pulse profile as an ensemble estimate of the "point-by-point" subpattern reproducibility within the data. As such, ApEn provides a scale-invariant and model-independent quantitation of relative disorderliness, wherein higher ApEn values denote greater relative disorderliness or reduced regularity of the release process (38). Technically, ApEn designates the negative logarithm of the probability that a given pattern of successive hormone measurements is repeated upon next incremental comparison within a tolerance r for a data window length m. The parameter r is typically set at 20% of the individual within-series standard deviation to normalize ApEn for unequal mean serum hormone concentrations. For series of lengths <200, m is typically given as unity. This choice of m and r yields high statistical replicability (37). Thus ApEn is a family of statistics conditional on m and r. ApEn is relatively insensitive to occasional outliers within the data and to experimental variability (noise) smaller in magnitude than r. Monte Carlo simulations (300 runs/series) were used to estimate the SD of ApEn for each series based on the within-sample variance of the GH assay (above).
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Effects of OVX on somatic growth.
As shown in Fig. 1, OVX accelerated somatic
growth. There was a twofold increase in mean rate of body weight gain
in the OVX rats compared with that in sham-operated females
[5.5 ± 0.9 (SE) vs. 2.6 ± 0.5 g/day; P < 0.001]. A significant difference between groups was noted at
8 days post-OVX and thereafter.
|
Effects of OVX on spontaneous GH secretory profiles.
Sham-operated female rats exhibited the characteristic female pattern
of GH secretion, with frequent irregular GH pulses of variable
amplitude separated by an elevated baseline GH concentration (Fig.
2A). At 3-4 wk after OVX,
basal plasma GH levels were markedly reduced (Fig. 2B).
|
Effects of acute T treatment on GH secretory dynamics in
sham-operated and OVX females.
Eighteen hours after a single subcutaneous T injection, there was a
striking alteration in the irregular female GH secretory pattern in
both sham-operated and OVX rats compared with their respective
oil-treated controls (Fig. 3). Both
T-treated groups displayed a regular male-like ultradian rhythm of GH
secretion, with higher-amplitude GH pulses occurring at precise
intervals separated by prolonged periods of low or undetectable plasma
GH levels (Fig. 3, C and D). Cluster analysis (Fig.
4) showed that T treatment of OVX rats
resulted in a significant decrease in both the GH peak frequency
(P < 0.01) and GH nadir (P < 0.02) and a
significant augmentation of GH peak amplitude (P < 0.01) as
well as a prolongation of GH interpeak interval (P < 0.01) compared with OVX rats administered oil.
|
|
ApEn.
ApEn was calculated as an objective statistical measure of the serial
regularity or orderliness of the GH release process over time. Because
the GH time series are relatively short (25 samples), we calculated
ApEn for fixed m = 1 and r = 0.2 times the
within-series SD, and we also estimated (see MATERIALS AND METHODS) the standard deviation of each ApEn value for any given GH series. Individual ApEn values and their Monte Carlo-estimated SD
values for each animal in the four treatment groups are given in Fig.
5. Higher ApEn values denote greater
relative disorderliness of the release process.
|
Effects of OVX and T treatment on GH responsiveness to GHRH
injection.
Figure 6 illustrates the effects of OVX and
T treatment on GH responsiveness to GHRH in individual rats
representative of the four experimental conditions. In sham-operated
control females (Fig. 6A), the intravenous administration of 1 µg rGRF- (129)NH2 at 1100 and 1300 caused a similar
increase in plasma GH levels at both time points. In contrast, rats
subjected to OVX or T treatment exhibited an intermittent pattern of GH
responsiveness to GHRH independent of the time of administration (Fig.
6, B, C, and D); the sequences of the
large-to-small or small-to-large responses were not consistent within
these groups. In both OVX- and T-treated animals there was a marked
difference in the integrated (5- and 15-min postinjection) GH response
to GHRH observed at 1100 vs. 1300; the ratio of the large to small GH
response in each of these three groups was significantly higher than
that observed in sham-operated controls (Table
1).
|
|
Plasma E2 and T levels. The mean plasma E2 level in OVX rats (n = 6) was significantly decreased compared with that of a group of normal female rats (n = 5) killed at various times in the estrous cycle (33 ± 0.9 vs. 83 ± 25 pg/ml; P < 0.02). Plasma T levels observed at 24 h after T injection in five Sham+T-treated females (147 ± 31 ng/dl) were similar to those seen in a group (n = 6) of normal adult male rats (141 ± 26 ng/dl).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In the present study we have shown that withdrawal of ovarian hormones in adult life markedly reduces the elevated GH baseline characteristic of the female rat. This finding, along with our earlier demonstration of a rapid E2-induced elevation of GH nadir levels in adult males (35), provides further support for the notion of a major role for E2 in maintaining higher interpulse GH secretion in the adult female compared with the male rat. Although it was previously shown that neonatal OVX resulted in an increased GH pulse amplitude in adulthood (24), our study failed to demonstrate an effect of adult OVX on either GH peak amplitude or GH peak frequency. These results are supportive of the hypothesis that neonatally secreted testicular androgen is a prerequisite for imprinting the high GH pulse amplitude observed in postpubertal males (25), and that it is the presence of T during the neonatal period, rather than the absence of E2 in the adult, that is the important determinant of adult GH pulse height.
The rate of body weight gain was enhanced twofold in OVX females compared with sham-operated controls, which is consistent with an inhibitory role attributed to E2 on body growth (9). It has been proposed that the sex difference in the GH secretory pattern of the rat may account, at least in part, for the striking sex difference in somatic growth of this species (22, 40). Our findings are congruent with this view and further suggest that it is the period of low or no plasma GH between the GH secretory episodes, and hence the pattern of GH release, rather than the magnitude of the individual GH pulses per se, that is key to the male's characteristically rapid rate of somatic growth. A similar conclusion has been reached in the case of GH-regulated hepatic proteins; e.g., Waxman et al. (49) showed that it is neither the total GH exposure nor the GH pulse amplitude, but rather the interval between pulses, that governs the sexually dimorphic expression of hepatic cytochrome P-450.
The results of our experiments examining the impact of T on the GH release process clearly indicate that acute exposure to T in adulthood rapidly and profoundly alters the irregular female pattern of GH secretion. We demonstrate here for the first time that T (at physiological levels similar to those observed in normal males) can induce a rapid "masculinization" of inferred GH pulse-generating circuits of the female in adulthood. Eighteen hours after a single subcutaneous injection of T, both sham-operated and OVX female rats displayed plasma GH profiles that were strikingly similar to the male-like ultradian rhythm of GH secretion (45), characterized by regular GH secretory bursts occurring at 3- to 4-h intervals separated by prolonged periods of typically undetectable plasma GH levels (see Fig. 3). In particular, OVX female rats administered T exhibited a significant increase in both GH peak amplitude and interpeak interval, concomitant with a decrease in GH peak frequency and GH nadir, compared with corresponding parameters in oil-treated OVX controls. These findings are concordant with a previous observation that adult female rats given subcutaneous T implants exhibit a sex reversal of their GH secretory pattern after 1 wk of treatment (32).
We used ApEn to quantify the degree of serial regularity or orderliness of the GH plasma profiles in the four treatment groups. Previous studies have shown that ApEn distinguishes male and female GH time series (14, 36) and discriminates between tumoral and physiological hormone release profiles in the case of GH, adrenocorticotropic hormone, prolactin, and aldosterone (17, 43, 47). Higher ApEn values denote greater disorderliness or reduced regularity of release. The highest ApEn values were observed in the ovary-intact group. T injection significantly reduced this irregularity, whether or not the ovaries were present. The OVX GH time series were less orderly than those of OVX+T but relatively more regular than that of Sham+Oil. Thus OVX reduces the irregularity of GH release seen in the intact female, and this irregularity is even further reduced by T injection, whether or not the ovaries are present. These findings strongly suggest that T has a major role in determining gender differences in the regularity of GH secretion and provide support for the notion that the enhanced orderliness of the GH release process in males, compared with females, is regulated by T.
The mechanism(s) by which T masculinizes the orderliness of GH secretion was evaluated by sequential GHRH injections. Assessment of GH responsiveness to GHRH stimulation revealed that neither OVX nor T treatment significantly altered the magnitude of the GH response to GHRH, in agreement with earlier findings of Wehrenberg et al. (51). These data differ from those of Shulman et al. (42), who found greater GH responses to GHRH in OVX rats; however, this difference likely reflects the use of pentobarbital-anesthetized animals in the latter study, as distinguished from the conscious rats used here. Of further importance, whereas sham-operated females exhibited similar GH release after serial GHRH injections, consistent with that previously reported for the female rat (8, 34), OVX and T-treated groups showed an intermittent pattern of responsiveness to GHRH that is characteristic of the male rat (34, 44). This male-like partial refractoriness to successive GHRH stimuli observed in OVX animals fits well with our previous report demonstrating that E2 during adult life can feminize the male pattern of GHRH-stimulated GH secretion (35).
We (34, 44) and others (8) have hypothesized that the sexual dimorphism of GH secretion in the rat is primarily due to a gender difference in the mode of hypothalamic SRIF signaling to pituitary somatotropes, with females exhibiting tonic, rather than episodic, SRIF secretion compared with males. Furthermore, we have demonstrated that the variable responsiveness to GHRH in the male rat is due to antagonism of GH secretion by the cyclic release of endogenous SRIF (44). Thus the present results in females suggest that the removal of ovarian hormones and/or the administration of T alters the postulated continuous pattern of hypothalamic SRIF secretion, converting it to a cyclical mode of release. This phasic release of SRIF likely plays a key role in determining the pulsatility and periodicity of GH secretion (46). The absence of full male-like synchronization of the GH responses to GHRH (44) indicates that, despite the dramatic influence of T on the pattern of spontaneous GH secretion in adulthood, it is not sufficient to initiate the light-dark entrainment of GH pulses that characterizes the GH secretory profile of the adult male rat (45). On the other hand, we cannot discount the possibility that T during the neonatal period plays a role in entraining the GH secretory episodes, because adult circadian hormone rhythms have been attributable to the organizational effects of early gonadal hormone exposure (30).
Although reports of a direct effect of T on pituitary somatotropes are limited and conflicting (12, 13, 18, 20, 51), there is compelling evidence for one or more hypothalamic site(s) of T's actions on GH secretion. Clear sex differences exist in the mRNA (1, 6, 31) and peptide (28) content of SRIF and GHRH neurons, as well as in the expression of SRIF receptor subtypes (54), in the hypothalamus. In particular, gonadal steroids appear to be intimately involved in the regulation of hypothalamic SRIF. Female and male rats subjected to OVX or gonadectomy exhibit a decrease in SRIF mRNA levels in the periventricular region of the hypothalamus (6, 52). T, administered either neonatally (5) or in adulthood (6, 52), stimulates expression of the SRIF gene in the periventricular nucleus. This response may represent a direct effect of T on SRIF transcript accumulation, because androgen receptors are expressed by SRIF neurons in a sexually dimorphic manner (19, 21). Furthermore, the effects of T are not dependent on its aromatization to E2, because dihydrotestosterone, a nonaromatizable androgen, but not E2, was capable of inducing an increase in SRIF mRNA (2, 55). Consistent with this concept, androgen-resistant (testicular feminized) rats, which lack functional androgen receptors, display GH secretory profiles resembling those of intact females (33). Finally, the present interpretation of GH neuroregulation recognizes that the effects of E2 on the GH secretion profile (35) are opposite to those reported here for T. Although in some studies expression of the GHRH gene appears to be stimulated by T through activation of androgen receptors (1, 53), other reports have noted that neither orchidectomy of male rats nor T administration to OVX rats influences hypothalamic GHRH mRNA levels (4, 31). Taken together, these findings suggest that T masculinizes the orderliness of GH secretion by stimulating hypothalamic SRIF synthesis and/or release, putatively by way of an androgen receptor-dependent pathway.
In conclusion, the present experiments demonstrate that acute single-dose exposure to T during adult life can rapidly (within 24 h) and profoundly masculinize GH pulse-generating behavior in the female rat. Our findings further suggest that the enhanced orderliness characteristic of the GH release process in males, compared with females, is regulated by T. We postulate that this T-induced regularity is mediated at the level of the hypothalamus by inducing regularity in SRIF secretion, which in turn governs overall GH periodicity. Further investigations are warranted to substantiate the latter proposal more directly.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Martine Lapointe for expert technical assistance, Julie Temko for skillful preparation of the manuscript, and Drs. Steve Pincus and Martin Straume for technical implementation of ApEn calculations. We are grateful to the National Institute of Diabetes and Digestive and Kidney Diseases Hormone Distribution Program for the continuing supply of rat GH RIA materials.
![]() |
FOOTNOTES |
---|
This work was supported by Grant MT-6837 (to GS Tannenbaum) from the Medical Research Council of Canada and National Institutes of Health Grant AG-14799 (to JD Veldhuis). GS Tannenbaum is a Chercheur de Carrière of the Fonds de la Recherche en Santé du Québec. JC Painson was the recipient of a Studentship Award from the Fonds pour la Formation de Chercheurs et l'Aide à la Recherche.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. S. Tannenbaum, Neuropeptide Physiology Laboratory, McGill University-Montreal Children's Hospital Research Institute, 2300 Tupper St., Montreal, QC, Canada H3H 1P3 (E-mail: mcta{at}musica.mcgill.ca).
Received 17 September 1999; accepted in final form 8 December 1999.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Argente, J,
Chowen JA,
Zeitler P,
Clifton DK,
and
Steiner RA.
Sexual dimorphism of growth hormone-releasing hormone and somatostatin gene expression in the hypothalamus of the rat during development.
Endocrinology
128:
2369-2375,
1991[Abstract].
2.
Argente, J,
Chowen-Breed JA,
Steiner RA,
and
Clifton DK.
Somatostatin messenger RNA in hypothalamic neurons is increased by testosterone through activation of androgen receptors and not by aromatization to estradiol.
Neuroendocrinology
52:
342-349,
1990[ISI][Medline].
3.
Carlsson, L,
Eriksson E,
Seeman H,
and
Jansson J-O.
Oestradiol increases baseline growth hormone levels in the male rat: possible direct action on the pituitary.
Acta Physiol Scand
129:
393-399,
1987[ISI][Medline].
4.
Chomczynski, P,
Downs TR,
and
Frohman LA.
Feedback regulation of growth hormone (GH)-releasing hormone gene expression by GH in rat hypothalamus.
Mol Endocrinol
2:
236-241,
1988[Abstract].
5.
Chowen, JA,
Argente J,
Torre-Saleman I,
Gonzalez-Parra S,
and
Garcia-Segura LM.
Effects of the neonatal sex steroid environment on growth hormone-releasing hormone and somatostatin gene expression.
J Pediatr Endocrinol
6:
211-218,
1993[Medline].
6.
Chowen-Breed, JA,
Steiner RA,
and
Clifton DK.
Sexual dimorphism and testosterone-dependent regulation of somatostatin gene expression in the periventricular nucleus of the rat brain.
Endocrinology
125:
357-362,
1989[Abstract].
7.
Clark, RG,
Carlsson LMS,
and
Robinson ICAF
Growth hormone secretory profiles in conscious female rats.
J Endocrinol
114:
399-407,
1987[Abstract].
8.
Clark, RG,
and
Robinson ICAF
Growth hormone responses to multiple injections of a fragment of human growth hormone-releasing factor in conscious male and female rats.
J Endocrinol
106:
281-289,
1985[Abstract].
9.
Dubuc, PU.
Prepuberal estrogen treatment and somatic growth in rats.
Endocrinology
98:
623-629,
1976[Abstract].
10.
Edén, S.
Age- and sex-related differences in episodic growth hormone secretion in the rat.
Endocrinology
105:
555-560,
1979[ISI][Medline].
11.
Edén, S,
Albertsson-Wikland K,
and
Isaksson O.
Plasma levels of growth hormone in female rats of different ages.
Acta Endocrinol
88:
676-690,
1978[ISI][Medline].
12.
Evans, WS,
Krieg RJ,
Limber ER,
Kaiser DL,
and
Thorner MO.
Effects of in vivo gonadal hormone environment on in vitro hGRF-40-stimulated GH release.
Am J Physiol Endocrinol Metab
249:
E276-E280,
1985
13.
Fukata, J,
and
Martin JB.
Influence of sex steroid hormones on rat growth hormone-releasing factor and somatostatin in dispersed pituitary cells.
Endocrinology
119:
2256-2261,
1986[Abstract].
14.
Gevers, EF,
Pincus SM,
Robinson ICAF,
and
Veldhuis JD.
Differential orderliness of the GH release process in castrate male and female rats.
Am J Physiol Regulatory Integrative Comp Physiol
274:
R437-R444,
1998
15.
Gevers, EF,
Wit J-M,
and
Robinson ICAF
Effects of long term GnRH-analogue treatment on growth, growth hormone (GH) secretion, GH-receptors and GH-binding protein in the rat.
Pediatr Res
43:
111-120,
1998[Abstract].
16.
Giustina, A,
and
Veldhuis JD.
Pathophysiology of the neuroregulation of GH secretion in experimental animals and the human.
Endocr Rev
19:
717-797,
1998
17.
Hartman, ML,
Pincus SM,
Johnson ML,
Matthews DH,
Faunt LM,
Vance ML,
Thorner MO,
and
Veldhuis JD.
Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release.
J Clin Invest
94:
1277-1288,
1994[ISI][Medline].
18.
Haug, E,
and
Gautvik KM.
Effects of sex steroids on growth hormone production in cultured rat pituitary cells.
Acta Endocrinol (Copenh)
87:
40-54,
1978[Medline].
19.
Herbison, AE.
Sexually dimorphic expression of androgen receptor immunoreactivity by somatostatin neurons in rat hypothalamic periventricular nucleus and bed nucleus of the stria terminalis.
J Neuroendocrinol
7:
543-553,
1995[ISI][Medline].
20.
Hertz, P,
Silbermann M,
Even L,
and
Hochberg Z.
Effects of sex steroids on the response of cultured rat pituitary cells to growth hormone-releasing hormone and somatostatin.
Endocrinology
125:
581-585,
1989[Abstract].
21.
Huang, X,
and
Harlan RE.
Androgen receptor immunoreactivity in somatostatin neurons of the periventricular nucleus but not in the bed nucleus of the stria terminalis in male rats.
Brain Res
652:
291-296,
1994[ISI][Medline].
22.
Jansson, J-O,
Albertsson-Wikland K,
Edén S,
Thorngren K-G,
and
Isaksson O.
Circumstantial evidence for a role of the secretory pattern of growth hormone in control of body growth.
Acta Endocrinol
99:
24-30,
1982[ISI][Medline].
23.
Jansson, J-O,
Edén S,
and
Isaksson O.
Sexual dimorphism in the control of growth hormone secretion.
Endocr Rev
6:
128-150,
1985[Abstract].
24.
Jansson, J-O,
Ekberg S,
Isaksson OGP,
and
Edén S.
Influence of gonadal steroids on age- and sex-related secretory patterns of growth hormone in the rat.
Endocrinology
114:
1287-1294,
1984[Abstract].
25.
Jansson, J-O,
Ekberg S,
Isaksson O,
Mode A,
and
Gustafsson J-A.
Imprinting of growth hormone secretion, body growth, and hepatic steroid metabolism by neonatal testosterone.
Endocrinology
117:
1881-1889,
1985[Abstract].
26.
Jansson, J-O,
and
Frohman LA.
Differential effects of neonatal and adult androgen exposure on the growth hormone secretory pattern in male rats.
Endocrinology
120:
1551-1557,
1987[Abstract].
27.
Jansson, J-O,
and
Frohman LA.
Inhibitory effect of the ovaries on neonatal androgen imprinting of growth hormone secretion in female rats.
Endocrinology
121:
1417-1423,
1987[Abstract].
28.
Jansson, J-O,
Ishikawa K,
Katakami H,
and
Frohman LA.
Pre- and postnatal developmental changes in hypothalamic content of rat growth hormone-releasing factor.
Endocrinology
120:
525-530,
1987[Abstract].
29.
Legraverend, C,
Mode A,
Westin S,
Strom A,
Eguchi H,
Zaphiropoulos PG,
and
Gustafsson J-A.
Transcriptional regulation of rat P-450 2C gene subfamily members by the sexually dimorphic pattern of growth hormone secretion.
Mol Endocrinol
6:
259-266,
1992[Abstract].
30.
MacLusky, NJ,
and
Naftolin F.
Sexual differentiation of the central nervous system.
Science
211:
1294-1302,
1981[ISI][Medline].
31.
Maiter, D,
Koenig JI,
and
Kaplan LM.
Sexually dimorphic expression of the growth hormone-releasing hormone gene is not mediated by circulating gonadal hormones in the adult rat.
Endocrinology
128:
1709-1716,
1991[Abstract].
32.
Millard, WJ,
Fox TO,
Badger TM,
and
Martin JB.
Gonadal steroid modulation of growth hormone secretory patterns in the rat.
In: Acromegaly: A Century of Scientific and Clinical Progress, edited by Robbins RJ,
and Melmed S. New York: Plenum, 1987, p. 139-150.
33.
Millard, WJ,
Politch JA,
Martin JB,
and
Fox TO.
Growth hormone-secretory patterns in androgen-resistant (testicular feminized) rats.
Endocrinology
119:
2655-2660,
1986[Abstract].
34.
Painson, J-C,
and
Tannenbaum GS.
Sexual dimorphism of somatostatin and growth hormone-releasing factor signaling in the control of pulsatile growth hormone secretion in the rat.
Endocrinology
128:
2858-2866,
1991[Abstract].
35.
Painson, J-C,
Thorner MO,
Krieg RJ,
and
Tannenbaum GS.
Short-term adult exposure to estradiol feminizes the male pattern of spontaneous and growth hormone-releasing factor-stimulated growth hormone secretion in the rat.
Endocrinology
130:
511-519,
1992[Abstract].
36.
Pincus, SM,
Gevers EF,
Robinson ICAF,
Van den Berg G,
Roelfsema F,
Hartman ML,
and
Veldhuis JD.
Females secrete growth hormone with more process irregularity than males in both humans and rats.
Am J Physiol Endocrinol Metab
270:
E107-E115,
1996
37.
Pincus, SM,
Hartman ML,
Roelfsema F,
Thorner MO,
and
Veldhuis JD.
Hormone pulsatility discrimination via coarse and short time sampling.
Am J Physiol Endocrinol Metab
277:
E948-E957,
1999
38.
Pincus, SM,
and
Keefe DL.
Quantification of hormone pulsatility via an approximate entropy algorithm.
Am J Physiol Endocrinol Metab
262:
E741-E754,
1992
39.
Plotsky, PM,
and
Vale W.
Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat.
Science
230:
461-463,
1985[ISI][Medline].
40.
Robinson, ICAF,
and
Clark RG.
The secretory pattern of GH and its significance for growth in the rat.
In: Growth Hormone: Basic and Clinical Aspects, edited by Isaksson O,
Binder C,
Hall K,
and Hokfelt B. Amsterdam: Excerpta Medica, 1987, p. 109-127.
41.
Saunders, A,
Terry LC,
Audet J,
Brazeau P,
and
Martin JB.
Dynamic studies of growth hormone and prolactin secretion in the female rat.
Neuroendocrinology
21:
193-203,
1976[ISI][Medline].
42.
Shulman, DI,
Sweetland M,
Duckett G,
and
Root AW.
Effect of estrogen on the growth hormone (GH) secretory response to GH-releasing factor in the castrate adult female rat in vivo.
Endocrinology
120:
1047-1051,
1987[Abstract].
43.
Siragy, HM,
Vieweg WVR,
Pincus SM,
and
Veldhuis JD.
Increased disorderliness and amplified basal and pulsatile aldosterone secretion in patients with primary aldosteronism.
J Clin Endocrinol Metab
80:
28-33,
1995[Abstract].
44.
Tannenbaum, GS,
and
Ling N.
The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion.
Endocrinology
115:
1952-1957,
1984[Abstract].
45.
Tannenbaum, GS,
and
Martin JB.
Evidence for an endogenous ultradian rhythm governing growth hormone secretion in the rat.
Endocrinology
98:
562-570,
1976[Abstract].
46.
Turner, JP,
and
Tannenbaum GS.
In vivo evidence of a positive role for somatostatin to optimize pulsatile growth hormone secretion.
Am J Physiol Endocrinol Metab
269:
E683-E690,
1995
47.
Van den Berg, G,
Pincus SM,
Veldhuis JD,
Frolich M,
and
Roelfsema F.
Greater disorderliness of adrenocorticotropin and cortisol release accompanies pituitary-dependent Cushing's disease.
Eur J Endocrinol
136:
394-400,
1997[ISI][Medline].
48.
Veldhuis, JD,
and
Johnson ML.
Cluster analysis: a simple, versatile, and robust algorithm for endocrine pulse detection.
Am J Physiol Endocrinol Metab
250:
E486-E493,
1986
49.
Waxman, DJ,
Pampori NA,
Ram PA,
Agrawal AK,
and
Shapiro BH.
Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450.
Proc Natl Acad Sci USA
88:
6868-6872,
1991[Abstract].
50.
Waxman, DJ,
Ram PA,
Park SH,
and
Choi HK.
Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver-expressed, Stat 5-related DNA binding protein. Proposed role as an intracellular regulator of male-specific liver gene transcription.
J Biol Chem
270:
13262-13270,
1995
51.
Wehrenberg, WB,
Baird A,
Ying S-Y,
and
Ling N.
The effects of testosterone and estrogen on the pituitary growth hormone response to growth hormone-releasing factor.
Biol Reprod
32:
369-375,
1985[Abstract].
52.
Werner, H,
Koch Y,
Baldino F, Jr,
and
Gozes I.
Steroid regulation of somatostatin mRNA in the rat hypothalamus.
J Biol Chem
263:
7666-7671,
1988
53.
Zeitler, P,
Argente J,
Chowen-Breed JA,
Clifton DK,
and
Steiner RA.
Growth hormone-releasing hormone messenger ribonucleic acid in the hypothalamus of the adult male rat is increased by testosterone.
Endocrinology
127:
1362-1368,
1990[Abstract].
54.
Zhang, W-H,
Beaudet A,
and
Tannenbaum GS.
Sexually dimorphic expression of sst1 and sst2 somatostatin receptor subtypes in the arcuate nucleus and anterior pituitary of adult rats.
J Neuroendocrinol
11:
129-136,
1999[ISI][Medline].
55.
Zorrilla, R,
Simard J,
Rheaume E,
Labrie F,
and
Pelletier G.
Multihormonal control of pre-pro-somatostatin mRNA levels in the periventricular nucleus of the male and female rat hypothalamus.
Neuroendocrinology
52:
527-536,
1990[ISI][Medline].