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Semiquantification of Hypothalamic GH-Releasing Hormone Output in Women: Evidence for Sexual Dimorphism in the Mechanism of the Somatopause

Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan Medical Center (J.J.O., M.R.-A., A.L.B.), and Department of Veterans Affairs Medical Center (R.D.-F., A.L.B.), Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Ariel L. Barkan, M.D., Division of Endocrinology and Metabolism, 3920 Taubman Center, Room 0354, University of Michigan Medical Center, Ann Arbor, Michigan 48109. E-mail: abarkan{at}umich.edu

Abstract

The neuroendocrine mechanisms underlying the decline of GH with aging (somatopause) are uncertain. We recently found that the age-dependent diminution of the hypothalamic GH-releasing hormone (GHRH) output contributes to the somatopause in men. As the regulatory mechanisms of GH secretion are sexually dimorphic, we assessed the suppressibility of spontaneous and GHRH-stimulated GH secretion by graded doses of a specific competitive GHRH receptor antagonist in nine young (20–27 yr old) and eight elderly (65–77 yr old) healthy nonobese women to semiquantify hypothalamic GHRH output. Nocturnal mean GH was lower in elderly women (2.2 ± 0.4 vs. 0.9 ± 0.2 µg/liter; P = 0.01). Graded boluses of GHRH-44 resulted in similar GH responses in both populations (P = 0.28). Graded infusions of GHRH antagonist inhibited in a dose-dependent manner the GH responses to GHRH in both groups (P = 0.0001–0.04). The dose-inhibition curve for the lowest GHRH bolus dose was shifted to the left compared with the highest one (P = 0.04). However, the dose-inhibition curves for spontaneous GH secretion were not different in young and elderly women (P = 0.50). Thus, the female somatopause is not associated with a measurable decrease in hypothalamic GHRH output. When the dose-inhibition curves for young men and young women were compared, the latter was shifted to the left (P = 0.009), suggesting that the somatotropic system in women operates with less GHRH. We conclude that the contribution of endogenous GHRH to the maintenance of GH secretion and the neuroendocrine mechanisms of somatopause in humans are sexually dimorphic.

THE REGULATION OF GH secretion depends mainly on two hypothalamic peptides: GH-releasing hormone (GHRH), which stimulates the synthesis and release of GH, and somatostatin, which inhibits GH release (1). The role of ghrelin (2) in the generation of GH pulsatility has not yet been defined.

Normal aging in humans is accompanied by a diminution in GH secretion (3, 4) and lower serum IGF-I concentrations (5). A decrease in hypothalamic GHRH or ghrelin, pituitary senescence, or an increase in somatostatinergic tone have been proposed as possible mechanisms (6, 7) as a result either of the aging process per se or of its epiphenomena, i.e. higher percentage of body fat, lower serum gonadal steroid milieu, and decreased physical fitness (7, 8, 9).

The existing information about the potential mechanisms of somatopause is derived from direct experiments in animals or from indirect approaches in humans. Species specificity does not allow the results found in animal models to be directly applied to human subjects (10). Experimental approaches for measurement of GHRH or somatostatin in humans in the pituitary-portal or peripheral blood are either impractical or do not reflect the actual hypothalamic output, respectively (11, 12). We have recently developed a model for semiquantification of hypothalamic GHRH output in vivo (13). This model is based upon estimation of the suppressibility of spontaneous and GHRH-stimulated GH secretion by graded doses of a specific competitive GHRH receptor antagonist. In agreement with the conventional pharmacodynamic principles, the higher the GHRH milieu, the lower the percent inhibition of GH by a given dose of GHRH antagonist. Similar models have been previously validated for the endogenous opioid (14, 15) and GnRH (16) systems. Using this model, the GH dose-inhibition curve in elderly men was shifted to the left, suggesting that, at least in males, there is an age-dependent diminution of hypothalamic GHRH output contributing to the somatopause (13).

The regulatory mechanisms of GH secretion are sexually dimorphic (17, 18, 19). Thus, we used the same experimental approach (13) to establish whether the normal aging process in women is also accompanied by relative GHRH deficiency.

Subjects and Methods

Human subjects

The protocol was approved by the institutional review board of the University of Michigan Medical School and the Department of Veterans Affairs Medical Research Service. Each woman signed a consent form before her participation in the study.

Nine young (20–27 yr old) and eight elderly (65–77 yr old) healthy women were recruited from the community. None was taking any medication known to modify GH secretion, including E. Young women were studied during the early follicular phase of their menstrual cycle, as demonstrated by the menstrual diaries for at least two cycles before the study as well as low E2 concentrations during each visit. Young women were physically active, but did not participate in competitive sports activities; elderly women were also physically active and engaged in recreational exercise (walking, swimming, aerobics, etc.). Body mass index was below 27 kg/m² in all participants. The demographic data are summarized in Table 1.

The protocol has been previously described (13). Briefly, each woman was admitted three to five times to the General Clinical Research Center of the University of Michigan. All had a baseline study with normal saline infusion and two to four admissions with varying doses of GHRH antagonist [(N-Ac-Tyr¹,D-Arg²)GHRH-(1–29)-NH₂, Bachem, King of Prussia, PA). Blood sampling was performed every 10 min from 2000 h on d 1 to 1100 h on d 2. Continuous iv infusions of either normal saline or GHRH antagonist (0.033, 0.1, 0.33, and 1.0 µg/kg·h) were administered from 2100 h on d 1 to 1100 h on d 2. Intravenous boluses of GHRH-44 (Peninsula Laboratories, Inc., Belmont, CA; 0.1, 0.33, and 1.0 µg/kg BW) were given at 0500, 0700, and 0900 h, respectively, on d 2.

Body composition

Total fat mass, lean body mass, and fat percentage were assessed in eight of the young and seven of the elderly women using a total body dual energy x-ray absorptiometry scan (IQ analysis software version 4.1, Lunar Corp., Madison, WI).

Assays

Plasma GH was measured in duplicate in a chemiluminometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). The assay sensitivity was 0.01 µg/liter, and the mean intraassay coefficient of variation (CV) was 9% between 0.01–0.1 µg/liter and 5% between 0.1–40 µg/liter. The interassay CV was 7% at 9 µg/liter. IGF-I and E2 were measured in a sample made by pooling plasma taken every 10 min from 2100–2200 h during the normal saline infusion. Total IGF-I was determined after acid-ethanol extraction by an immunoradiometric assay (Diagnostics Systems Laboratories, Inc., Webster, TX) with sensitivity of 0.03 µg/liter. Plasma E2 was measured using a commercial assay (Coat-A-Count, Diagnostic Products, Los Angeles, CA) with a sensitivity of 8 ng/liter. All samples with measured concentrations below the sensitivity of the assay were assigned the value of the assay sensitivity.

Calculations

The integrated GH concentration (IGHC; micrograms per min/liter) was calculated by the trapezoidal rule. Maximal GH (micrograms per liter) was defined as the highest GH concentration measured during the specific time interval. Spontaneous GH output was defined as the IGHC during the 2100–0500 h interval. The responses to GHRH stimulation were defined as maximal GH and IGHC over the 2-h period after the GHRH bolus injection.

GH output (spontaneous or GHRH induced) during each GHRH antagonist dose was calculated as a percentage of the corresponding GH measurement during baseline saline infusion (percent residual output) in each subject. Percent inhibition was calculated as 100% - percent residual output. To reduce the influence of the intrasubject variability in daily GH secretion, GH output was also calculated as a percentage of the mean GH concentration during baseline saline infusion for each specific population.

Statistical analysis

To detect potential shifts in the dose-inhibition curves for young vs. elderly, the percent inhibition of both spontaneous and GHRH-stimulated IGHC by varying doses of GHRH antagonist was analyzed by repeated measures ANOVA. Tukey-Kramer adjustments were used in post-hoc testing as appropriate (20). Paired or unpaired t tests were used to compare all other parameters. Logarithmic transformation of data were performed as appropriate. Statistical significance was assumed for P < 0.05.

Results

Demographic and hormonal characteristics

All demographic characteristics (except for age) were similar between both populations (Table 1). Plasma E2 and IGF-I concentrations in aged women were significantly lower than those in their younger counterparts (P = 0.004–0.013; Table 2).

Elderly women had lower spontaneous maximal GH concentrations (8.5 ± 1.8 vs. 3.9 ± 0.8 µg/liter; P = 0.037), nocturnal spontaneous IGHC (1053 ± 182 vs. 430 ± 101 µg/min·liter; P = 0.01), and mean GH (2.2 ± 0.4 vs. 0.9 ± 0.2 µg/liter; P = 0.01) than young women (Table 2). Administration of three consecutive bolus injections of GHRH during the saline infusion day resulted in similar IGHC responses in both populations (P = 0.28), with no dose response of GH to increasing doses of exogenous GHRH boluses (P = 0.37; Fig. 1).

View larger version (34K): [in this window] [in a new window]   Figure 1. GH responses to three different boluses of GHRH-44 during baseline saline infusion studies (mean ± SE). IGHC responses are similar in both populations (P = 0.28), with no dose response of GH to increasing doses of GHRH (P = 0.37; n = 9 for young; n = 8 for elderly; n = 17 for combined group).

Inhibition of GH responses to standard amounts of exogenous GHRH. Increasing doses of GHRH antagonist resulted in a dose-dependent GH suppression at each GHRH bolus dose (P = 0.0001–0.04; Fig. 2). At each dose of exogenous GHRH, the IGHC responses to GHRH antagonist in young and elderly women were similar (P = 0.14–0.88). There were no significant interactions between age effect and dose effect (P = 0.33–0.77). Thus, data from both populations for each GHRH bolus dose were pooled (Fig. 3).

View larger version (22K): [in this window] [in a new window]   Figure 2. GH/GHRH antagonist dose-inhibition curves (mean ± SE) for graded GHRH-44 boluses. There is no difference between the curves for young and elderly women for each particular bolus dose (n = 4–9/group).

View larger version (18K): [in this window] [in a new window]   Figure 3. Shift in GH/GHRH antagonist dose-inhibition curves after administration of varying doses of GHRH-44. The dose-inhibition curve for 0.1 µg/kg GHRH was significantly shifted to the left compared with those for 0.33 µg/kg (P = 0.02) and 1.0 µg/kg GHRH (P = 0.04; n = 12–16/group).

Inhibition of spontaneous nocturnal GH output. To ascertain whether there is a sexual dimorphism in the nocturnal GHRH output between the sexes, we compared dose-inhibition curves obtained in young women in the present study with similar data obtained in young men (13). The dose-inhibition curve in young women was significantly (P = 0.009) shifted to the left compared with that in young men (Fig. 4), suggesting that the somatotropic system in women operates with less GHRH.

View larger version (19K): [in this window] [in a new window]   Figure 4. GH/GHRH antagonist dose-inhibition curves for nocturnal spontaneous GH output in young men and women. The dose-inhibition curve in young women is significantly shifted to the left compared with that in young men from our previous study (13 ) (n = 8–14/group).

View larger version (20K): [in this window] [in a new window]   Figure 5. GH/GHRH antagonist dose-inhibition curves for nocturnal spontaneous GH output in young and elderly women. There was an obvious GHRH antagonist effect for both populations (P = 0.0002), but the dose-inhibition curves for young and elderly women were not different (P = 0.50; n = 4–9/group).

We have shown that there is a marked dimorphism of GHRH output between young men and women, with the latter having noticeably lower GHRH output. Moreover, unlike in men, the somatopause in women is not associated with a measurable decrease in hypothalamic GHRH output (13). There was a dose-dependent GHRH antagonist suppression of GHRH-induced GH release, similar to our earlier data in men (13). This validates the model employed in this study, allowing us to distinguish a 3- to 10-fold difference in the magnitude of the endogenous GHRH output. The seeming leftward shift of the dose-inhibition curve for the spontaneous nocturnal GH output by GHRH antagonist in elderly women was not statistically significant. Power analysis suggested that at least 50 women in each group would be needed to demonstrate a statistically significant difference in GHRH output. Thus, even if GHRH output does in fact decline in elderly women, this would not be as important as and would be less easily detectable than that in elderly men. Our data provide additional evidence of sexual dimorphism in the regulatory mechanisms of GH secretion.

The sexually dimorphic parameters of GH pulsatility and secretion are the manifestation of dissimilar regulatory mechanisms at the hypothalamic-pituitary level. This had been attributed to different GHRH and somatostatin inputs to the pituitary (21). Male rats have been shown to have higher GHRH and somatostatin mRNA contents in the hypothalami (22, 23). In different models, T or DHT increased GHRH mRNA, GHRH content, and GHRH release (21, 24, 25, 26), although in other experiments this effect was not observed (22, 27). E, on the other hand, decreased GHRH mRNA and GHRH content in the hypothalami of male rats (28). This suggests that maintenance of the overall output and the pulsatile parameters of GH secretion in male and female rats is accomplished by sexually dimorphic parameters of GHRH and somatostatin secretion (7). Our data provide the first direct evidence that GHRH output is attenuated in young women in the follicular phase of the cycle compared with that in young men. This is evidenced by the shift to the left of the dose-inhibition curve of spontaneous nocturnal GH secretion by GHRH antagonist in women. The quantitatively similar GH output between the sexes (18) would be compatible with concomitantly lower somatostatin secretion in women, also in accord with the animal data (7).

The role of progressive GHRH decline or somatostatin increment in the female aging process has been previously explored, but it is still controversial. GHRH content and mRNA levels are either lower (27) or the same (29) in the hypothalami of aged rats compared with those in their young controls. Likewise, some studies have suggested that there is a progressive increase in hypothalamic somatostatin content (29, 30) in female aged rats, although others have shown that the hypothalamic somatostatin mRNA levels are, conversely, decreased (31).

In humans, hypothalamic GHRH deficiency appears to be a more likely explanation for the age-related GH decline. Exogenous administration of GHRH restored normal GH and IGF-I concentrations in a group of elderly subjects (32, 33). Likewise, somatostatin withdrawal-related GH rebound, a mechanism thought by the researchers to depend on GHRH release, was lower in elderly subjects, although this finding was only significant for women (34). On the other hand, the lack of a GHRH antagonist effect on the somatostatin withdrawal-induced GH rise (35) complicates the interpretation of those data.

The role of increased somatostatinergic tone is less clear in humans. Previous studies have shown that the GHRH-stimulated GH response in elderly subjects is blunted with aging (36, 37), although we found similar GH responses in both populations (13, 18). Our present finding of lower GH secretion in the context of an apparently unchanged hypothalamic GHRH output in aged women could suggest that female somatopause is accompanied by an increase in somatostatin or a decrease in ghrelin.

GH secretion was diminished in elderly subjects, and this was further reflected in the lower IGF-I levels. As a result of the postmenopausal state, serum E2 levels were significantly lower in the elderly. Hypoestrogenism may account for lower GH concentrations in the menopause. Indeed, when postmenopausal women received oral E, hepatic IGF-I synthesis was suppressed, with a concomitant increase in GH secretion due to reduced feedback inhibition (38, 39, 40, 41, 42). Thus, it is conceivable that the attenuated parameters of GH secretion detected in elderly women might be explained at least partially by differences in the sex steroid hormonal milieu. However, in another study older women of reproductive age, who had lower IGHC and IGF-I levels than young control subjects, had higher E2 concentrations on the day of sampling than their younger counterparts (43).

We previously found that a subgroup of young and elderly men with identical body composition and gonadal steroid concentrations also had similar IGHC and spontaneous maximal GH despite the preserved decline in the GHRH output in the elderly (13). Thus, the relative deficiency of GHRH is necessary, but not sufficient to explain the somatopause, and other variables may play a role. In elderly women, however, severe GH deficiency occurred despite grossly unaltered body composition and apparently unchanged GHRH output. Thus, the mechanisms leading to somatopause are also sexually dimorphic, and the aging-associated decline in GH secretion in women as opposed to men occurs through a mechanism largely separate from GHRH.

Similar to men (13), there was no effect of aging in women on pituitary responsiveness to graded boluses of GHRH, making pituitary senescence an unlikely explanation for the somatopause. However, in contrast to young and elderly men, GH responses were already maximal to the lowest dose of exogenous GHRH in both young and elderly women. This confirms the earlier data reported by Gelato et al. (44), who found that the half-maximal GHRH dose (ED₅₀) for women was approximately half that for men. Perhaps, even lower doses of GHRH antagonist and GHRH might be employed in future studies in women to better characterize the dose-response relations.

In conclusion, we have performed semiquantification of hypothalamic GHRH output in young and elderly women. We have shown that the nocturnal GHRH output in women is likely to be lower than that in men and that the aging-associated GH decline in women is not accompanied by appreciable changes in endogenous GHRH output. This is distinctly different from the parallel decline in both GH and GHRH outputs observed in elderly men. Thus, the neuroendocrine mechanisms of GH regulation in young people and of somatopause in the elderly appear to be sexually dimorphic.

Acknowledgments

We are indebted to Nicole Carlson, Kathy Welch, and Morton Brown, Ph.D., for statistical consultation, to all the participants of this study for their cooperation, and to the nurses and the supportive staff of the University of Michigan General Clinical Research Center for their invaluable clinical assistance. We thank the Nuclear Medicine Service at the Ann Arbor Department of Veterans Affairs Medical Center for their clinical and technical support.

Footnotes

This work was supported by NIH Grants RO-1-DK-38449 (to A.L.B.), MO-1-RR-00042 (General Clinical Research Center), and P30-AG-08808 (Claude D. Pepper Older Americans Independence Center), and the Department of Veterans Affair Medical Research Service (to A.L.B.).

Abbreviations: GHRH, GH-releasing hormone; IGHC, integrated GH concentration.

Received February 26, 2001.

Accepted July 31, 2001.

References

1. Scanlon MF, Issa BG, Dieguez C 1996 Regulation of growth hormone secretion. Horm Res 46:149–154[Medline]
2. Kojima M, Hosoda H, Date Y, Nakazato, M, Matsuo H, Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660[CrossRef][Medline]
3. Lamberts SW, van den Beld AW, van der Lely AJ 1997 The endocrinology of aging. Science 278:419–424[Abstract/Free Full Text]
4. Ho KK, Hoffman DM 1993 Aging and growth hormone. Horm Res 40:80–86[Medline]
5. Corpas E, Harman SM, Blackman, MR 1993 Human growth hormone and human aging. Endocr Rev 14:20–39[Abstract/Free Full Text]
6. Muller EE, Cella SG, Parenti M, Deghenghi R, Locatelli V, De Gennaro Colonna V, Torsello A, Cocchi D 1995 Somatotropic dysregulation in old mammals. Horm Res 43:39–45[Medline]
7. Giustina A, Veldhuis JD 1998 Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 19:717–797[Abstract/Free Full Text]
8. Vahl N, Jorgensen JO, Jurik AG, Christiansen JS 1996 Abdominal adiposity and physical fitness are major determinants of the age associated decline in stimulated GH secretion in healthy adults. J Clin Endocrinol Metab 81:2209–2215[Abstract]
9. Veldhuis JD, Iranmanesh A 1996 Physiological regulation of the human growth hormone (GH)-insulin-like growth factor type I (IGF-I) axis: predominant impact of age, obesity, gonadal function, and sleep. Sleep 19:S221–S224
10. Dutour A, Briard N, Guillaume V, Magnan E, Cataldi M, Sauze N, Oliver C 1997 Another view of GH neuroregulation: lessons from the sheep. Eur J Endocrinol 136:553–565[Abstract/Free Full Text]
11. Rosskamp R, Becker M, Haverkamp F, Thomas B, Bruhl S, Klumpp J, Liappis N 1987 Plasma levels of growth hormone-releasing hormone and somatostatin in response to a mixed meal and during sleep in children. Acta Endocrinol (Copenh) 116:549–554[Abstract/Free Full Text]
12. Penny ES, Penman E, Price J, Rees LH, Sopwith AM, Wass JA, Lytras N, Besser GM 1984 Circulating growth hormone releasing factor concentrations in normal subjects and patients with acromegaly. Br Med J 289:453–455
13. Russell-Aulet M, Jaffe CA, Demott-Friberg R, Barkan AL 1999 In vivo semiquantification of hypothalamic growth hormone-releasing hormone (GHRH) output in humans: evidence for relative GHRH deficiency in aging. J Clin Endocrinol Metab 84:3490–3497[Abstract/Free Full Text]
14. Cicero TJ, Owens DP, Schmoeker PF, Meyer ER 1983 Morphine-induced supersensitivity to the effects of naloxone on luteinizing hormone secretion in the male rat. J Pharmacol Exp Ther 225:35–41[Abstract/Free Full Text]
15. Ferin M, Van Vugt D, Wardlaw S 1984 The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides. Recent Prog Horm Res 40:441–485
16. Hall JE, Taylor AE, Martin KA, Rivier J, Schoenfeld DA, Crowley Jr WF 1994 Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women. Proc Natl Acad Sci USA 91:6894–6898[Abstract/Free Full Text]
17. Jansson JO, Eden S, Isaksson O 1985 Sexual dimorphism in the control of growth hormone secretion. Endocr Rev 6:128–150[Abstract/Free Full Text]
18. Jaffe CA, Ocampo-Lim B, Guo W, Krueger K, Sugahara I, De Mott-Friberg R, Bermann M, Barkan AL 1998 Regulatory mechanisms of growth hormone secretion are sexually dimorphic. J Clin Invest 102:153–164[Medline]
19. Hindmarsh PC, Dennison E, Pincus SM, Cooper C, Fall CH, Matthews DR, Pringle PH, Brook CG 1999 A sexually dimorphic pattern of growth hormone secretion in the elderly. J Clin Endocrinol Metab 84:2679–2685[Abstract/Free Full Text]
20. Fisher LD, van Belle G 1993 Biostatistics: a methodology for the health sciences. New York: Wiley & Sons; 596–629
21. Painson JC, Tannenbaum GS 1991 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[Abstract/Free Full Text]
22. Maiter D, Koenig JI, Kaplan LM 1991 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[Abstract/Free Full Text]
23. Hasegawa O, Sugihara H, Minami S, Wakabayashi I 1992 Masculinization of growth hormone (GH) secretory pattern by dihydrotestosterone is associated with augmentation of hypothalamic somatostatin and GH-releasing hormone mRNA levels in ovariectomized adult rats. Peptides 13:475–481[CrossRef][Medline]
24. Chowen JA, Argente J, Gonzalez-Parra S, Garcia-Segura LM 1993 Differential effects of the neonatal and adult sex steroid environments on the organization and activation of hypothalamic growth hormone-releasing hormone and somatostatin neurons. Endocrinology 133:2792–2802[Abstract/Free Full Text]
25. Fernandez G, Sanchez-Franco F, de los Frailes MT, Tolon RM, Lorenzo M, Lopez J, Caçicedo L 1992 Regulation of somatostatin and growth hormone-releasing factor by gonadal steroids in fetal rat hypothalamic cells in culture. Regul Pept 42:135–144[CrossRef][Medline]
26. Zeitler P, Argente J, Chowen-Breed JA, Clifton DK, Steiner RA 1990 Growth hormone-releasing hormone messenger ribonucleic acid in the hypothalamus of the adult male rat is increased by testosterone. Endocrinology 127:1362–1368[Abstract/Free Full Text]
27. De Gennaro Colonna V, Cocchi D, Lima L, Maggi A, Muller EE 1991 Testosterone and GHRH gene expression in adult and old rats. Peptides 12:309–312[CrossRef][Medline]
28. Senaris RM, Lago F, Lewis MD, Dominguez F, Scanlon MF, Dieguez C 1992 Differential effects of in vivo estrogen administration on hypothalamic growth hormone releasing hormone and somatostatin gene expression. Neurosci Lett 141:123–126[CrossRef][Medline]
29. Ge F, Tsagarakis S, Rees LH, Besser GM, Grossman A 1989 Relationship between growth hormone-releasing hormone and somatostatin in the rat: effects of age and sex on content and in-vitro release from hypothalamic explants. J Endocrinol 123:53–58[Abstract/Free Full Text]
30. Forman LJ, Sonntag WE, Hylka VW, Meites J 1985 Pituitary growth hormone and hypothalamic somatostatin in young female rats versus old constant estrous female rats. Experientia 41:653–654[CrossRef][Medline]
31. Martinoli MG, Ouellet J, Rheaume E, Pelletier G 1991 Growth hormone and somatostatin gene expression in adult and aging rats as measured by quantitative in situ hybridization. Neuroendocrinology 54:607–615[Medline]
32. Corpas E, Harman SM, Pineyro MA, Roberson R, Blackman MR 1992 Growth hormone (GH)-releasing hormone-(1–29) twice daily reverses the decreased GH and insulin-like growth factor-I levels in old men. J Clin Endocrinol Metab 75:530–535[Abstract]
33. Corpas E, Harman SM, Pineyro MA, Roberson R, Blackman MR 1993 Continuous subcutaneous infusions of growth hormone (GH) releasing hormone 1–44 for 14 days increase GH and insulin-like growth factor-I levels in old men. J Clin Endocrinol Metab 76:134–138[Abstract]
34. degli Uberti EC, Ambrosio MR, Cella SG, Margutti R, Transforini G, Riramonti AE, Petrone E, Muller EE 1997 Defective hypothalamic growth hormone (GH)-releasing hormone activity may contribute to declining GH secretion with age in man. J Clin Endocrinol Metab 82:2885–2888[Abstract/Free Full Text]
35. Jaffe CA, DeMott-Friberg R, Barkan AL 1996 Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli. J Clin Invest 97:934–940[Medline]
36. Muggeo M, Fedele D, Tiengo A, Molinari M, Crepaldi G 1975 Human growth hormone and cortisol response to insulin stimulation in aging. J Gerontol 30:546–551[Abstract/Free Full Text]
37. Ghigo E, Arvat E, Gianotti L, Lanranco F, Broglio F, Aimaretti G, Macca M, Camanni F 1996 Human aging and the GH-IGF-I axis. J Pediatr Endocrinol Metab 9(Suppl 3):271–278
38. Dawson-Hughes B, Stern D, Goldman J, Reichlin S 1986 Regulation of growth hormone and somatomedin-C secretion in postmenopausal women: effect of physiological estrogen replacement. J Clin Endocrinol Metab 63:424–432[Abstract/Free Full Text]
39. Duursma SA, Bijlsma JW, Van Paassen HC, van Buul-Offers SC, Skottner-Lundin A 1984 Changes in serum somatomedin and growth hormone concentrations after 3 weeks oestrogen substitution in post-menopausal women; a pilot study. Acta Endocrinol (Copenh) 106:527–531[Abstract/Free Full Text]
40. Weissberger AJ, Ho KK, Lazarus L 1991 Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 72:374–381[Abstract/Free Full Text]
41. Kelly JJ, Rajkovic IA, O’Sullivan AJ, Sernia C, Ho KK 1993 Effects of different oral oestrogen formulations on insulin-like growth factor-I, growth hormone and growth hormone binding protein in post-menopausal women. Clin Endocrinol (Oxf) 39:561–567[Medline]
42. Friend KE, Hartman ML, Pezzoli SS, Clasey JL, Thorner MO 1996 Both oral and transdermal estrogen increase growth hormone release in postmenopausal women–a clinical research center study. J Clin Endocrinol Metab 81:2250–2256[Abstract]
43. Wilshire GB, Loughlin JS, Brown JR, Adel TE, Santoro N 1995 Diminished function of the somatotropic axis in older reproductive-aged women. J Clin Endocrinol Metab 80:608–613[Abstract]
44. Gelato MC, Pescovitz OH, Cassorla F, Loriaux DL, Merriam GR 1984 Dose-response relationships for the effects of growth hormone-releasing factor-(1–44)-NH₂ in young adult men and women. J Clin Endocrinol Metab 59:197–201[Abstract/Free Full Text]

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