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Independent and Combined Effects of Testosterone and Growth Hormone on Extracellular Water in Hypopituitary Men

Pituitary Research Unit, Garvan Institute of Medical Research and Department of Endocrinology, St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia

Address all correspondence and requests for reprints to: Dr. Ken K. Y. Ho, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia. E-mail: k.ho{at}garvan.org.au.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Symptoms of fluid retention in GH-deficient patients during GH replacement are greater in men than in women, suggesting that testosterone may augment or estradiol may attenuate the antinatriuretic actions of GH. The mechanisms underlying the sodium-retaining effects of GH are poorly understood.

Aim: The aim of this study was to investigate the effects of GH and testosterone, alone and in combination, on extracellular water (ECW) and the hormonal mechanisms involved.

Design: Two separate, open-label, randomized, two-period, crossover studies were performed; the first compared the effects of GH alone with those of GH and testosterone, and the second compared the effects of testosterone alone with those of GH and testosterone.

Participants: Twelve hypopituitary men with GH deficiency and hypogonadism were studied.

Intervention: During the weeks of intervention, GH (0.5 mg/d) and testosterone enanthate (250 mg) were administered by im injection.

Outcome Measures: The outcome measures were ECW, IGF-I, plasma renin activity (PRA), aldosterone (Aldo), and atrial natriuretic peptide (ANP).

Results: GH treatment significantly increased (P < 0.05) both IGF-I and ECW, and these changes were enhanced by cotreatment with testosterone (P = 0.07 for both). PRA, Aldo, and ANP levels did not change. Testosterone treatment alone did not change the IGF-I concentration, whereas cotreatment with GH induced a marked increase. Testosterone alone increased (P < 0.05) ECW, and the effect was augmented (P < 0.01) by cotreatment with GH. Although PRA and ANP did not change, plasma Aldo decreased after single and combined treatments.

Conclusion: GH and testosterone exerted independent and additive effects on ECW. The mechanisms of fluid retention for both hormones are likely to be exerted on the renal tubules. This is the first direct evidence that testosterone increases ECW.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
GENDER-DEPENDENT CHANGES in body composition appear at the time of puberty (1), suggesting an important role of sex steroids. Total body water and fat-free mass are greater, whereas total body fat is lower, in men than in women. The proportion of fat-free mass accounted for by water and the proportion of body weight accounted for by extracellular water (ECW) are also greater in men (2). The water content of body cell mass and ECW is highly consistent between subjects and even between mammals, reflecting strong basic regulatory mechanisms controlled by hormones (3), including insulin, catecholamines, those of the renin-angiotensin-aldosterone system (RAAS), and natriuretic peptides.

The antinatriuretic effect of GH has been recognized for decades (4). The pathophysiological importance of this effect is evident from studies demonstrating reduced and increased ECW in adults with GH deficiency and acromegaly, respectively (4, 5, 6). Although the mechanistic processes underlying the antinatriuretic action of GH have not been fully elucidated, several have been proposed. The observations that GH increases serum and tissue levels of IGF-I, and that both GH and IGF-I receptors are expressed in renal tubules (7) have suggested that both hormones could play a role in the fluid retention (8). Evidence that the effect of GH is exerted indirectly is conflicting, with some (9, 10, 11, 12), but not all (13), studies demonstrating activation of RAAS; some (14, 15, 16), but not all (13, 17), researchers have reported that GH may act through suppression of plasma atrial natriuretic peptide (ANP). Although the exact mechanisms remain unclear, these studies indicate that the GH/IGF-I axis plays an important role in sodium-fluid homeostasis.

The involvement of testosterone in sodium homeostasis is less clear. Some evidence comes from early clinical observations of edema developing during treatment with supraphysiological doses of testosterone for anemia secondary to hematological disorders and uremia (18). High doses of testosterone have been reported to increase, decrease, or exert no effect on plasma volume (19, 20) and to reduce urinary sodium excretion (18, 21). Furthermore, testosterone stimulates GH secretion (22) through an estrogen-dependent pathway (23, 24), making it possible that high doses of testosterone in GH-replete subjects may induce sodium and water retention indirectly through the actions of GH and IGF-I.

Evidence that sex steroids influence GH action came from the observation that fluid retention is more marked in men than in women during GH replacement therapy (25). The aim was to study the effects of GH and testosterone, alone and in combination, on ECW. To eliminate possible indirect actions of testosterone through the GH/IGF-I axis, subjects with combined hypogonadotropic hypogonadism and GH deficiency were studied.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Twelve hypopituitary men with GH deficiency and hypogonadotropic hypogonadism were recruited from the Endocrine Outpatient Clinic at St. Vincent’s Hospital (Sydney, Australia). The clinical characteristics of these patients are shown in Table 1. Two studies were undertaken, the first compared the effects of GH alone with those of GH and testosterone in 10 men, and the second compared the effects of testosterone alone with those of GH and testosterone in nine men. Seven of the 12 men participated in both studies. GH deficiency was confirmed by a peak GH response to insulin-induced hypoglycemia of less than 3 ng/ml (26), and hypogonadotropic hypogonadism was defined as a serum testosterone level measured in a morning sample less than 4 nmol/liter accompanied by a low serum LH level. The duration of hypopituitarism was at least 1 yr. All subjects were receiving stable hormone replacement for other deficiencies throughout and in between the study periods, and they were not receiving any other treatment that could affect their body fluid homeostasis. All subjects gave their written informed consent to participate in the study before entering the protocol. The study design was approved by the research ethics committee of St. Vincent’s Hospital.

Both studies were of open-label, randomized, crossover design, and together allowed comparison of the individual and combined effects of testosterone and GH while taking time-dependent effects into consideration. Before commencement of each study, subjects underwent a 6-wk run-in period when testosterone and GH were withdrawn. During this time and throughout the studies, they were instructed to follow their usual diet and habitual activities. In both studies, GH (Humatrope, Lilly Australia, Sydney, Australia) was administered at a dose of 1.5 IU/d (0.5 mg/d) daily, sc, by self-injection at 2000 h, and testosterone enanthate was administered at a dose of 250 mg, im, 2 wk before measurement.

The first study compared the effects of GH alone with those of combined GH and testosterone treatment in 10 subjects (Fig. 1). GH was administered daily for 6 wk. Testosterone was administered either at baseline (group A; n = 5) or wk 4 (group B; n = 5) of the study. Investigations were carried out at baseline, after 2 wk, and after 6 wk, so that the effects of testosterone were assessed 2 wk after administration. Thus, studies were carried out when subjects were not receiving GH or testosterone replacement, during replacement with GH alone, and during combined GH and testosterone replacement (Fig. 1).

View larger version (9K): [in this window] [in a new window]   FIG. 1. Study 1 compares the effects of GH alone with combined treatment with GH and testosterone (T). Ten patients were randomized to either group A or group B. T was administered as 250 mg testosterone enanthate, im, at wk 0 in group A and wk 4 in group B. GH was administered daily at bedtime by sc injections at a dose of 1.5 IU for 6 wk. Study 2 compares T alone with combined treatment with T and GH. Nine patients were randomized to either group A or B. The same doses of GH and T were administered as in study 1. Arrows indicate the times of measurements. , Period of GH treatment. T, Time of testosterone administration.

At each visit and after an overnight fast, all subjects underwent measurements of plasma IGF-I, testosterone, plasma renin activity (PRA), aldosterone (Aldo), ANP, and ECW using the bromide dilution technique. For the latter, a carefully weighed amount of sodium bromide (1.8–2.0 g) was diluted in 60 ml sterile water, of which 10 ml were injected. Serum samples were collected before and 4 h after the injection. All serum/plasma samples were frozen after collection and assayed in a single run at the end of both study periods. Body weight was measured barefoot wearing indoor clothing to the nearest 0.1 kg, and systolic and diastolic blood pressures were measured after 5 min of supine rest using a sphygmomanometer.

Assays

Serum IGF-I was measured by RIA after acid-ethanol extraction as previously described (27), with intraassay coefficients of variation (CVs) of 9.4, 8.3, and 10.3% at 48, 254, and 1510 µg/liter, respectively. Testosterone was measured by a solid-phase chemiluminescent enzyme immunoassay (Immulite 2000, Diagnostic Products Corp., Los Angeles, CA) that had an intraassay CV of 9.6% at 6.7 nmol/liter. PRA was measured indirectly by RIA of angiotensin I (PerkinElmer Life Sciences, Los Angeles, CA). The level of endogenous angiotensin I was corrected by running an inhibited assay tube kept at 4 C while the 37 C generation of angiotensin I was occurring. Renin activity was maximized by preincubating the samples at pH 6.0. Plasma Aldo was measured by a solid phase immunoassay (Coat-A-Count TKAL2, Diagnostic Products Corp.) that has an interassay precision of 6.2%. Plasma samples for ANP measurement was stored at –70 C before assay using a solid-phase immunoradiometric assay (Shionogi & Co. Ltd., Osaka, Japan) with an intraassay CV of 6.3% at 18.9 ng/liter and a detection limit of 2.5 ng/liter.

Serum bromide was measured by HPLC. The serum samples were deproteinated by centrifugation through a filtration unit with cut-off size of 10 kDa (Amicon YM10, Millipore Corp., Bedford, MA). The protein-free ultrafiltrate was run through an anion exchange column (IC-Pak A, Waters Corp., Milford, MA) at a flow rate of 0.35 ml/min and a detection wavelength of 195 nm. The bromide concentration was determined using the area under the curve and comparing with known bromide standards. The intraassay CV for the bromide concentration determined by HPLC was 2.1%. ECW was calculated from the change in the serum bromide concentration 4 h after injection of a known amount of bromide using the formula reported by Miller et al. (2): ECW (liters) = 0.9 x 0.95 x Br dose (mmol)/ Br serum (mmol/liter), where Br serum is the change in serum bromide concentration, 0.9 is the correction factor for nonextracellular distribution of bromide, and 0.95 is the correction factor for Donnan equilibrium. The mean day to day intrasubject CV for ECW based on four subjects studied on two occasions was 5.7%.

Statistical analysis

Data are presented as the mean ± SEM. The overall within-group treatment effect in each trial was determined using Friedman’s ANOVA for repeated measurements. Post hoc analysis was performed using Wilcoxon’s matched pairs, signed rank-sum test corrected for the number of measurements. The analysis of between-study levels was performed using the Mann-Whitney U test. An analysis of interactions between treatment and sequence was performed in which the direct and residual effects of treatment were measured separately to detect carryover effects. No such interaction was found. Statistical significance was considered at P 0.05.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
None of the patients reported side effects, and no clinical symptoms or signs associated with excess fluid retention were observed during treatment with the doses and regimen used for GH, testosterone, or their combination. No sequence effect was observed in either of the studies. Baseline values were comparable in the two studies, with the exception of IGF-I, which was slightly higher in study 2 (11.9 ± 1.1 vs. 8.4 ± 0.9 nmol/liter in study 1; P < 0.05).

GH and combined testosterone treatment (Table 2)

The serum IGF-I concentration increased in response to GH treatment alone and increased further when testosterone was added (P = 0.07), but the difference was not statistically significant. Serum testosterone concentrations were subnormal at baseline and during the GH treatment phase, and increased into the normal range during testosterone replacement therapy.

View larger version (13K): [in this window] [in a new window]   FIG. 2. Mean (±SE) ECW (kilograms) during study 1, comparing GH alone with combined treatment with GH and T (A), and during study 2, comparing T treatment alone with combined T and GH treatment (B). *, P < 0.05; and **, P < 0.01, compared with baseline values.

Testosterone and combined GH treatment (Table 3)

Testosterone treatment alone did not change the mean serum IGF-I concentration, whereas adding GH to the treatment induced an increase into the normal range. Serum testosterone concentrations were low at baseline and increased into the normal range after the two treatment phases of testosterone alone and combined GH and testosterone.

Between-study comparisons

The average gain in body weight during testosterone treatment alone in study 2 exceeded the change in body weight during GH treatment alone in study 1 (1.5 ± 0.4 vs. 0.5 ± 0.3 kg; P < 0.05). There were no significant differences in the gain in ECW induced by GH and testosterone, nor were there differences between the gain in ECW induced by combined GH and testosterone treatment between the two studies. No significant correlations were found between changes in or levels of IGF-I and ECW during the different treatment periods.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
These two randomized, controlled trials have examined the individual and combined effects of GH and testosterone on ECW. The principal novel findings were that testosterone alone significantly increased ECW and amplified the GH-induced increase in ECW. By limiting the study to male subjects with combined severe GH deficiency and hypogonadotropic hypogonadism, the potentially confounding influence of stimulation of pituitary GH release by testosterone was avoided.

The GH-induced increase in ECW has been consistently reported and probably explains the dose-dependent symptoms related to fluid retention that commonly accompany GH replacement in adults (28, 29). Only one study has quantified changes in ECW using doses considered appropriate for replacement therapy in adults (16). After 1 wk of treatment, PRA, but not Aldo, levels increased, whereas after 12 months of treatment, the levels of both were not different from baseline. In the present study, 2–6 wk of GH treatment increased ECW without significantly affecting PRA or the concentration of Aldo. These findings contrast with those of previous shorter trials, which found stimulation of the RAAS in normal subjects after treatment with supraphysiological dose of GH, approximating two to three times that used in the present study (11, 12). The collective observations suggest that during physiological GH replacement, the sustained increase in ECW is unlikely to be mediated through the RAAS (16). This does not, however, rule out a role of RAAS in the early sodium-retaining effect of GH that peaks 1–3 d after commencing GH treatment (30).

This is the first controlled study demonstrating that testosterone increases ECW. Previous data concerning the effects of testosterone on plasma volume (19, 20) and urinary sodium excretion (18, 21) are limited and conflicting. The underlying mechanism is unknown, but several possibilities exist. Testosterone could act directly on the kidney, because androgen receptors are expressed in renal tubules (31). There is evidence that androgens stimulate the expression of the angiotensinogen gene in the kidney (32, 33). Therefore, androgens could activate the local renal RAAS to stimulate sodium and water retention through an autocrine or paracrine mechanism (34). The epithelial sodium channel plays an important role in the sodium balance, as demonstrated by genetic abnormalities in its activity, such as in Liddle’s syndrome (35). It has recently been reported that androgens increase mRNA expression of the -subunit of the epithelial sodium channel in a human renal cell line (36), providing a potential mechanism of sodium and water retention by testosterone.

Adults with GH deficiency have reduced ECW whether adjusted for lean body mass or expressed as ECW/total body water ratio (13, 37). After 4 wk of GH treatment of adult GH deficiency patients, the level of ECW and the ECW/total body water ratio was normalized without any significant change in intracellular water (37). With continuing therapy, no additional increase was noted in ECW, whereas there was an increase in intracellular water, suggesting a preferential increase in body cell mass (37). These data, based on bromide, deuterium, and sodium dilution techniques, indicate that most of the initial changes in lean body mass in response to GH are related to changes in ECW.

Plasma Aldo levels fell significantly during testosterone treatment, whereas a modest fall, which failed to reach significance, occurred during GH treatment. During combined treatments, a significant fall in Aldo was also observed. The uniform trend toward a fall in Aldo levels observed with single and combined treatments suggests an adaptive response to ECW expansion. The observation that the fall in Aldo was greater in the presence of testosterone suggests that additional androgen-mediated mechanisms are probably involved. Androgen receptors have been identified in human adrenocortical cells and appear to exert an inhibitory influence. In vitro studies have demonstrated that testosterone reduced the proliferation of human adrenal adenoma and adrenocortical cancer cell lines (38). It is possible that testosterone directly suppresses Aldo biosynthesis or secretion, but this remains to be demonstrated.

The effects of testosterone on the volume and distribution of ECW could theoretically occur secondary to aromatization to estrogen in peripheral tissues. Estrogen may cause fluid retention through reduction of the plasma antidiuretic hormone (arginine vasopressin)-plasma osmolality set point (39, 40) or stimulating the synthesis of hepatic angiotensinogen (41), enhancing the overall activity of RAAS and leading to sodium retention. However, this postulate is not supported by the observation that urinary sodium excretion is increased during oral contraceptive use (42) or that the plasma renin concentration is reduced in women receiving estrogen treatment (43). Moreover, estrogen reduces the plasma renin concentration, the activity of angiotensin-converting enzyme, and the Aldo response to angiotensin II (44, 45). These actions of estrogen putatively generated from aromatization of androgens could explain the slight reduction in plasma Aldo levels in response to testosterone in our study.

In hypophysectomized, castrated, male rats, testosterone administration does not increase serum levels of IGF-I or IGF-I gene expression in the liver (46). However, androgen-dependent body hair growth is increased during GH replacement in men receiving stable testosterone treatment (47), suggesting that tissue sensitivity to testosterone in humans is enhanced by GH action. This is supported by the present findings that testosterone enhanced the effect of GH on IGF-I production. Because IGF-I itself stimulates sodium retention (48), it is possible that the greater increase in ECW during combined treatment compared with GH alone may have been IGF-I mediated. However, this cannot explain the increase in ECW in response to testosterone alone, because there was no change in the serum IGF-I concentration. This observation provides additional support for the idea that testosterone may exert direct effects on the renal tubules to induce a sodium-sparing effect.

Few data exist concerning the influence of testosterone on ANP and brain natriuretic peptide. These peptides are characterized by natriuretic, diuretic, and vasodilatory activities (49) and are stimulated by conditions of intravascular volume expansion. Short-term testosterone administration to elderly men increased the plasma concentration of ANP (50), possibly as a compensatory mechanism to testosterone-induced fluid load or a direct effect of testosterone. In the present study, ANP was not affected by either testosterone or GH, indicating that it is unlikely to be a major mediator of fluid retention induced by these two hormones.

In conclusion, we provided the first evidence that testosterone increased ECW volume, adding to the fluid-retaining effects of GH during combined administration. Other endocrine systems known to regulate ECW were unaffected by testosterone, suggesting a direct effect of testosterone on renal tubular function. The positive interaction between testosterone and GH in sodium and fluid homeostasis highlights the greater susceptibility to the development of edema and calls for caution in the initiation of GH replacement therapy in men.

	Acknowledgments

 
We are most grateful to Maria Males, Amanda Idan, and Olivia Wong for clinical assistance, and to Nathan Doyle for technical support. We kindly thank Dr. Paul Williams for general assay support.

	Footnotes

 
This work was supported by Eli Lilly Australia and the National Health and Medical Research Council of Australia.

First Published Online April 12, 2005

Abbreviations: Aldo, Aldosterone; ANP, atrial natriuretic peptide; CV, coefficient of variation; ECW, extracellular water; PRA, plasma renin activity; RAAS, renin-angiotensin-aldosterone system.

Received March 11, 2005.

Accepted April 5, 2005.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Lu PW, Briody JN, Morley K, Howman-Giles R, Cowell CT 1995 Body-composition assessment by dual-energy x-ray absorptiometry in subjects aged 4–26 y. Am J Clin Nutr 61:746–753[Abstract/Free Full Text]
2. Miller ME, Cosgriff JM, Forbes GB 1989 Bromide space determination using anion-exchange chromatography for measurement of bromide. Am J Clin Nutr 50:168–171[Abstract/Free Full Text]
3. Wang Z, Deurenberg P, Wang W, Pietrobelli A, Baumgartner RN, Heymsfield SB 1999 Hydration of fat-free body mass: new physiological modeling approach. Am J Physiol 276:E995–E1003
4. Ikkos D, Luft R, Sjögren B 1954 Body water and sodium in patients with acromegaly. J Clin Invest 33:989–994
5. Rosén T, Bosaeus I, Tölli J, Lindstedt G, Bengtsson B-Å 1993 Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency. Clin Endocrinol (Oxf) 38:63–71[Medline]
6. O’Sullivan AJ, Kelly JJ, Hoffman DM, Freund J, Ho KKY 1994 Body composition and energy expenditure in acromegaly. J Clin Endocrinol Metab 78:381–386[Abstract]
7. Chin E, Zhou J, Bondy CA 1992 Renal growth hormone receptor gene expression: relationship to renal insulin-like growth factor system. Endocrinology 131:3061–3066[Abstract]
8. Blazer-Yost BL, Cox M 1988 Insulin-like growth factor 1 stimulates renal epithelial Na⁺ transport. Am J Physiol 255:C413–C417
9. Honeyman TW, Goodman HM, Fray JCS 1983 The effects of growth hormone on blood pressure and renin secretion in hypophysectomized rats. Endocrinology 112:1613–1617[Abstract]
10. Wyse B, Waters M, Sernia C 1993 Stimulation of the renin-angiotensin system by growth hormone in Lewis dwarf rats. Am J Physiol 265:E332–E339
11. Ho KY, Weissberger AJ 1990 The antinatriuretic action of biosynthetic human growth hormone in man involves activation of the renin-angiotensin system. Metabolism 39:133–137[CrossRef][Medline]
12. Møller J, Møller N, Frandsen E, Wolthers T, Jørgensen JOL, Christiansen JS 1997 Blockade of the renin-angiotensin-aldosterone system prevents growth hormone-induced fluid retention in humans. Am J Physiol 272:E803–E808
13. Hoffman DM, Crampton L, Sernia C, Nguyen TV, Ho KK 1996 Short term growth hormone (GH) treatment of GH-deficient adults increases body sodium and extracellular water, but not blood pressure. J Clin Endocrinol Metab 81:1123–1128[Abstract]
14. Møller J, Jørgensen JOL, Møller N, Hansen KW, Pedersen EB, Christiansen JS 1991 Expansion of extracellular volume and suppression of atrial natriuretic peptide after growth hormone administration in normal man. J Clin Endocrinol Metab 72:768–772[Abstract]
15. Møller J, Jørgensen JOL, Marqversen J, Frandsen E, Christiansen JS 2000 Insulin-like growth factor I administration induces fluid and sodium retention in healthy adults: possible involvement of renin and atrial natriuretic factor. Clin Endocrinol (Oxf) 52:181–186[CrossRef][Medline]
16. Johannsson G, Sverrisdottir YB, Ellegard L, Lundberg PA, Herlitz H 2002 GH increases extracellular volume by stimulating sodium reabsorption in the distal nephron and preventing pressure natriuresis. J Clin Endocrinol Metab 87:1743–1749[Abstract/Free Full Text]
17. Møller J, Frandsen E, Fisker S, Jørgensen JOL, Christiansen JS 1996 Decreased plasma and extracellular volume in growth-hormone deficient adults and the acute and prolonged effects of GH administration–a controlled experimental-study. Clin Endocrinol (Oxf) 44:533–539[CrossRef][Medline]
18. Mooradian AD, Morley JE, Korenman SG 1987 Biological actions of androgens. Endocr Rev 8:1–28[Abstract]
19. Lundh B, Gardner FH 1971 The effect of testosterone in pharmacological doses on plasma volume and on some serum proteins in patients with sickle cell aneamia and in sexually impotent men. Scand J Lab Invest 28:72–78
20. Whitworth JA, Scoggins BA, Andrews J, Williamson PM, Brown MA 1992 Haemodynamic and metabolic effects of short term administration of synthetic sex steroids in humans. Clin Exp Hypertens A 14:905–922[Medline]
21. Shahidi NT 1973 Androgens and erythropoiesis. N Engl J Med 289:72–80
22. Weissberger AJ, Ho KK 1993 Activation of the somatotropic axis by testosterone in adult males: evidence for the role of aromatization. J Clin Endocrinol Metab 76:1407–1412[Abstract]
23. Metzger DL, Kerrigan JR 1994 Estrogen receptor blockade with tamoxifen diminishes growth hormone secretion in boys: evidence for a stimulatory role of endogenous estrogens during male adolescence. J Clin Endocrinol Metab 79:513–518[Abstract]
24. Eakman GD, Dallas JS, Ponder SW, Keenan BS 1996 The effects of testosterone and dihydrotestosterone on hypothalamic regulation of growth hormone secretion. J Clin Endocrinol Metab 81:1217–1223[Abstract]
25. Johannsson G, Bjarnason R, Bramnert M, Carlsson LMS, Degerblad M, Manhem P, Rosén T, Thorén M, Bengtsson B-Å 1996 The individual responsiveness to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH binding protein, body mass index, age and gender. J Clin Endocrinol Metab 81:1575–1581[Abstract]
26. Hoffman DM, O’Sullivan AJ, Baxter RC, Ho KKY 1994 Diagnosis of growth hormone deficiency in adults. Lancet 343:1064–1068[CrossRef][Medline]
27. Baxter RC, Brown AS, Turtle JR 1982 982 Radioimmunoassay for somatomedin C: comparison with radioreceptor assay in patients with growth-hormone disorders, hypothyroidism, and renal failure. Clin Chem 28:488–495[Abstract/Free Full Text]
28. Johannsson G, Rosén T, Bengtsson B-Å 1997 Individualized dose titration of growth hormone (GH) during GH replacement in hypopituitary adults. Clin Endocrinol (Oxf) 47:571–581[CrossRef][Medline]
29. Drake WM, Coyte D, Camacho-Hübner C, Jivanji NM, Kaltsas G, Wood DF, Trainer PJ, Grossman AB, Besser GM, Monson JP 1998 Opimizing growth hormone replacement therapy by dose titration in hypopituitary adults. J Clin Endocrinol Metab 83:3913–3919[Abstract/Free Full Text]
30. Valk NK, vd Lely AJ, de Herder WW, Lindemans J, Lamberts SWJ 1994 The effects of human growth hormone (GH) administration in GH-deficient adults: a 20-day metabolic ward study. J Clin Endocrinol Metab 79:1070–1076[Abstract]
31. Wilson CM, McPhaul MJ 1996 A and B forms of the androgen receptor are expressed in variety of human tissues. Mol Cell Endocrinol 120:51–57[CrossRef][Medline]
32. Ellison KE, Ingelfinger JR, Pivor M, Dzau VJ 1989 Androgen regulation of rat renal angiotensinogen messenger RNA expression. J Clin Invest 83:1941–1945
33. Yang G, Merrill DC, Thompson MW, Robillard JE, Sigmund CD 1994 Functional expression of the human angiotensinogen gene in transgenic mice. J Biol Chem 269:32497–32502[Abstract/Free Full Text]
34. Ingelfinger JR, Zuo WM, Fon EA, Ellison KE, Dzau VJ 1990 In situ hybridization evidence for angiotensinogen messenger RNA in the rat proximal tubule. An hypothesis for the intrarenal renin angiotensin system. J Clin Invest 85:417–423
35. Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JRJ, Ulick S, Milora RV, Findling JW, Canessa CM, Rossier BC, Lifton RP 1994 Liddle’s syndrome: heritable human hypertension caused by mutations in the ß subunit of the epithelial sodium channel. Cell 79:407–414[CrossRef][Medline]
36. Quinkler M, IJB, Kaur K, Hughes SV, Hewison M, Stewart PM, Testosterone enhances renal expression of the -subunit of the epithelial sodium channel (-ENaC). Program of the 86th Annual Meeting of The Endocrine Society, New Orleans, LA, 2004, p 150 (Abstract OR54-3)
37. Janssen YJH, Deurenberg P, Roelfsema F 1997 Using dilution techniques and multifrequency bioelectrical impedance to assess both total body water and extracellular water at baseline and during recombinant human growth hormone (GH) treatment in GH-deficient adults. J Clin Endocrinol Metab 82:3349–3355[Abstract/Free Full Text]
38. Rossi R, Zatelli MC, Valentini A, Cavazzini P, Fallo F, del Senno L, degli Uberti EC 1998 Evidence for androgen receptor gene expression and growth inhibitory effect of dihydrotestosterone on human adrenocortical cells. J Endocrinol 159:373–380[Abstract]
39. Stachenfeld NS, DiPietro L, Palter SF, Nadel ER 1998 Estrogen influences osmotic secretion of AVP and body water balance in postmenopausal women. Am J Physiol 274:R187–R195
40. Aitken JM, Lindsay R, Hart DM 1974 The redistribution of body sodium in women on long-term oestrogen therapy. Clin Sci Mol Med 47:179–187[Medline]
41. Michelakis AM, Yoshida H, Dormois JC 1975 Plasma renin activity and plasma aldosterone during the normal menstrual cycle. Am J Obstet Gynecol 123:724–726[Medline]
42. Kang AK, Duncan JA, Cattran DC, Floras JS, Lai V, Scholey JW, Miller JA 2001 Effect of oral contraceptives on the renin angiotensin system and renal function. Am J Physiol 280:R807–R813
43. Schunkert H, Danser AH, Hense HW, Derkx FH, Kurzinger S, Riegger GA 1997 Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation 95:39–45[Abstract/Free Full Text]
44. Miller JA, Anacta LA, Cattran DC 1999 Impact of gender on the renal response to angiotensin II. Kidney Int 55:278–285[CrossRef][Medline]
45. Fischer M, Baessler A, Schunkert H 2002 Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc Res 53:672–677[Abstract/Free Full Text]
46. Phillip M, Palese T, Hernandez ER, Roberts Jr CT, LeRoit D, Kowarski AA 1992 Effect of testosterone on insulin-like growth factor-I (IGF-I) and IGF-I receptor gene expression in the hypophysectomized rat. Endocrinology 130:2865–2870[Abstract]
47. Blok GJ, de Boer H, Gooren IJG, van der Veen E 1997 Growth hormone substitution in adult growth hormone deficient men augments androgen effects on the skin. Clin Endocrinol (Oxf) 47:29–36[CrossRef][Medline]
48. Walker JL, Ginalska-Malinowska M, Romer TE, Pucilowska JB, Underwood LE 1991 Effects of the infusion of insulin-like growth factor I in a child with growth hormone insensitivity syndrome (Laron dwarfism). N Engl J Med 324:1483–1488[Medline]
49. Levin ER, Gardner DG, Samson WK 1998 Natriuretic peptides. N Engl J Med 339:321–328[Free Full Text]
50. Wu S, Weng X 1993 Regulation of atrial natriuretic peptide, thromboxane and prostaglandin production by androgen in elderly men with coronary heart disease. Chin Med Sci J 8:207–209[Medline]

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