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Clinical Studies |
Departments of Medicine, Clinical Chemistry (A.S.), and Geriatrics (B.V.), University Hospital, Uppsala, Sweden
Address all correspondence and requests for reprints to: Pia Burman, M.D., Ph.D., Department of Medicine, University Hospital, S-751 85 Uppsala, Sweden.
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Abstract |
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The extent of GHD, assessed before therapy from basal GH secretion and GH release in response to provocative tests, did not differ between the two groups. The men, however, had higher serum insulin-like growth factor I concentrations than the women (mean ± SD, 126 ± 71 vs. 61 ± 32 µg/L; P = 0.0003), less body fat, and greater lean body mass. Upon treatment, insulin-like growth factor I concentrations increased more in men than in women (by 305 ± 136 and 198 ± 96 µg/L, respectively; P = 0.02). The men lost more body fat than the women (7.4 ± 4.1% vs. 3.3 ± 3.8%; P = 0.002), whereas the difference in gain in lean body mass failed to reach statistical significance. Serum levels of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, and plasminogen activator inhibitor-1 decreased in the male group (P = 0.003, P = 0.03, P = 0.0009, and P = 0.01, respectively), but not in the females. Serum markers of bone formation, namely osteocalcin, procollagen type I, bone-specific alkaline phosphatase, and a marker of bone resorption, telopeptide of collagen type I, increased more markedly in men than in women. Lipoprotein(a) increased to a similar extent in the male and female groups.
The data demonstrate that men and women with GHD display marked differences in their responsiveness to GH replacement therapy. These differences should be taken into consideration when optimizing the treatment of GHD patients.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In humans, the basal GH values and the pooled GH secretion over 24 h (15, 16, 17, 18) as well as the pituitary responsiveness to provocative stimuli (19, 20) have been shown to be higher in women than in men. In the rat, the male pulsatory GH secretory pattern is superior to that in the female in promoting growth (21). Despite this apparent sex dependency of GH secretion, to our knowledge there have been no studies on GH replacement in which gender has been considered in the evaluation of the outcome.
In the present study we examined the effects of a standardized GH replacement regimen on parameters related to body composition, cardiovascular morbidity, and bone metabolism with respect to gender.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The study comprised 36 patients with GH deficiency (GHD), 15 women (mean age, 47.5 ± 6.6 yr) and 21 men (mean age, 44.7 ± 7.4 yr). The mean duration of GHD was 10.4 yr (range, 1–33). In all but two patients, one with a craniopharyngioma and one with a hypothalamic disorder with onset during adolescence, pituitary insufficiency had developed in adult life as a result of surgery for and/or irradiation of a pituitary tumor (nonfunctioning adenoma, n = 18; craniopharyngioma, n = 4; prolactinoma, n = 4; ACTHoma, n = 3) or as a consequence of empty sella (n = 3), injury (n = 1), or pituitary apoplexy (n = 1).
All but two patients had complete pituitary insufficiency. Two women had only partial pituitary insufficiency, with lack of GH and gonadotropins. All patients were properly replaced with levothyroxine, adrenal and sex steroids, and in nine cases desmopressin for at least 6 months before enrollment. All men received gonadal hormone replacement (testosterone enanthate, 250 mg, im, in two men every 2 weeks, in 7 men every 3 weeks, and in 9 men every 4 weeks). Two men received oral testosterone undecanoate (160 and 200 mg daily, respectively) and one man was given human gonadotropin (5000 IU, im, once a week) and human menopausal gonadotropins (75 IU, im, three times a week). During the study period minor adjustments of the doses of levothyroxine and desmopressin were made in one patient each and of cortisone in two patients. Eight women (mean age, 43.2 ± 5.3 yr) were on replacement therapy with estrogens. Of these, two women took ethinyl estradiol (50 µg/day, orally) during weeks 1–3 combined with lynestrenol (1.0 mg in one case; in the other case, medroxyprogesterone acetate (5 mg each day) was given during week 4. Two women received estradiol (1 and 2 mg, respectively, orally) during weeks 1–3 with addition of 5 and 10 mg medroxyprogesterone acetate, respectively, during week 4. One woman was given estradiol (2 mg, orally) combined with norethisterone acetate (1.0 mg daily). Two were given transdermal estradiol; in one case, 25 µg/day with addition of medroxyprogesterone acetate (5 mg each day) during week 4 and in the other case 50 µg/day combined with transdermal norethisterone (250 µg/day in weeks 3–4). Finally, one woman received estriol 2 mg, orally, each day. Seven women (mean age, 52.3 ± 4.2 yr) were not given sex steroids. The body mass index of the men and women did not differ (26.6 ± 3.1 and 25.1 ± 3.2 kg/m2, respectively). None of the 36 patients had previously received GH.
Residual secretion of GH was assessed by repetitive serum sampling
every 20 min between 2200–0400 h by the use of a vacuum pump and by
two stimulation tests: insulin-induced hypoglycemia (blood glucose,
2.2 mmol/L) and iv injection of 1 µg/kg BW GHRH (Groliberin,
Pharmacia, Stockholm, Sweden). GHD was defined as a peak response of
serum GH of 3 µg/L or less during insulin-induced hypoglycemia.
Study protocol
The trial was double blind and placebo-controlled with a cross-over design. Each treatment period lasted for 9 months and was separated by a 3-month wash-out interval. No specific recommendations were given to the patients regarding exercise during the study. The patients visited the clinic for physical examination and laboratory assessment at baseline and after 3 and 9 months of therapy. Serum samples were collected after an overnight fast. Measurements of body composition were performed before and after the treatment periods. rhGH (Norditropin, Novo Nordisk Pharma, Copenhagen, Denmark) or placebo was administered sc at bedtime by the patient. The initial dose was 0.5 U/m2 body surface area, and this was increased to 1 U/m2 after 2 weeks and to 2 U/m2 after another 4 weeks. In patients experiencing side-effects (mainly peripheral edema, stiffness of extremities, or arthralgia), the dose escalation was stopped, and if side-effects remained, the dose was reduced by 25%, and in the cases with side-effects still remaining, the dose was further reduced by 25–50%. The final mean daily dose administered during the study was 2.4 U (1.25 U/m2; range, 0.5–4 U) and did not differ between men and women (1.3 ± 0.7 and 1.2 ± 0.7 U/m2, respectively). Written informed consent was obtained from all patients. The study was approved by the ethical committee of the Uppsala University Hospital (Uppsala, Sweden).
Methods
Body composition was measured by dual energy x-ray absorptiometry with the DPX-L equipment from Lunar Radiation Corp. (Madison, WI). Bone mineral and soft tissue mass were calculated by analysis of the differential attenuation of two different photon energies with a radiation dose of 0.02 mrem (22).
Plasma GH was assayed by a RIA using polyclonal antibodies (23). The lowest level of detection was 0.3 µg/L. Insulin-like growth factor I (IGF-I) in serum was measured by an immunoradiometric assay after formic acid-ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA). The reference ranges for the relevant ages were 150–450 µg/L (20–40 yr) and 100–340 µg/L (41–60 yr).
Total cholesterol (reference range, 2.7–7.1 mmol/L), high density lipoprotein (HDL) cholesterol (reference ranges: men, 0.7–1.6; women, 0.8–1.9 mmol/L) and triglycerides (reference range, 0.23–1.70 mmol/L) were measured in serum by routine methods at the Department of Clinical Chemistry, University Hospital. Low density lipoprotein (LDL) cholesterol concentrations were calculated according to the formula suggested by Friedewald et al. (24). The concentrations of apolipoprotein (Apo) A-1 and B were determined by immunoturbidimetry in the Monarch apparatus, using monospecific polyclonal antibodies against Apo A-1 and B (Orion Diagnostica, Espoo, Finland). Reference ranges for Apo A-1 and Apo B are 0.97–1.42 and 0.70–1.49 g/L, respectively, for men and 1.07–1.59 and 0.66–1.53 g/L, respectively, for women. Lipoprotein(a) [Lp(a)] was measured by the Pharmacia Apo(a) RIA (Pharmacia Diagnostics AB, Uppsala, Sweden). The Apo(a) concentration is expressed in units per L. One unit of Apo(a) is approximately equal to 0.7 mg Lp(a) according to the manufacturer (reference range, <250 mg/L). The intra- and interassay variations for the apolipoprotein determinations were less than 3% and 6%, respectively.
Plasma activity of plasminogen activator inhibitor (PAI-1; reference range, <15 kU/L) was measured with Spectrolyse/pL kits (Biopool, Umea, Sweden) using poly-D-lysine as a stimulator. The intra- and interassay variations were 8% and 9%, respectively, for values less than 15 kU/L, and 2.7 and 5.5%, respectively, for values more than 15 kU/L. The plasma concentration of fibrinogen (reference range, 2.0–3.6 g/L) was measured by rate immunonephelometry using an Array instrument (Beckman Instruments, Stockholm, Sweden). Coagulation factor VII (reference range, 70–140%) was measured by one-stage clotting assay using a factor VII-deficient substrate plasma (Helene Laboratories, Beaumont, TX). ß-Thromboglobulin (reference range, <50 µg/L) was measured in the plasma of 11 men and 10 women by RIA (ß-Tg RIA kit, Amersham, Aylesbury, UK; intra- and interassay variations, <7.5% and <10%, respectively).
Osteocalcin in serum (reference range, 5–16 µg/L) was determined by RIA (CIS Biointernational, Oris Industries, Gif-Sur-Yvette, France; intra- and interassay variations, <7%). Serum concentrations of carboxyl-terminal cross-linked telopeptide of type I collagen (reference range, 1.3–4.9 µg/L) and carboxyl-terminal propeptide of type I procollagen (reference range, 56–228 µg/L) were measured by commercially available RIAs (Orion Diagnostica, Espoo, Finland; intra- and interassay variations, <7%). Bone-specific alkaline phosphatase activity in serum (reference range, 0.3–1.8 µkat/L) was calculated from measurements of the enzyme activity in untreated serum and after extraction with wheat germ lectin (Boehringer Mannheim, Mannheim, Germany).
Statistics
Descriptive values are given as the mean ± SD. The effects of treatment were compared within groups by use of the Wilcoxon signed rank test and between groups by the Mann-Whitney U test. For evaluating relationships between two variables, Pearson’s product-moment correlation coefficient was calculated. P < 0.05 was considered significant. All effects reported to be of statistical significance were also significantly different in comparison with placebo, but for simplicity, these P values are not given.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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GH secretion at baseline and after stimulation tests did not
differ between male and female patients (Table 1
), and
there was no difference between women with and without estrogen
replacement (data not shown). The IGF-I levels, however, were lower in
women than in men. The women who received sex steroids had the same
IGF-I levels as those who did not [mean ± SD,
62 ± 39 µg/L (n = 8) vs. 60 ± 23 µg/L
(n = 7)].
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In response to an equal dose of rhGH the increase in the serum
IGF-I concentration was greater in the men than in the women
(P = 0.02). The serum concentrations before and after 9
months of replacement therapy were 126 ± 71 and 431 ± 158
µg/L in the men (P = 0.0001) and 61 ± 32 and
259 ± 113 µg/L in the women (P = 0.0007; Fig. 1). The posttreatment concentrations of IGF-I were the
same in women who did and did not receive estrogens (260 ± 138
and 257 ± 86 µg/L). A linear relation between the administered
dose of rhGH and the increase in IGF-I in serum was observed in the men
(r = 0.60; P = 0.004), but not in the women.
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The percent total body fat decreased upon treatment with rhGH by
7.4 ± 4.1% in the men (P = 0.0001) and by
3.3 ± 3.8% in the women (P = 0.002). This
difference was significant (Fig. 2). The decrease in
total body fat was negatively related to the increase in serum IGF-I in
men, but not in women (Fig. 3). Women treated and not
treated with sex steroids lost 2.9 ± 3.3% and 3.9 ± 4.5%
of their body fat, respectively, a nonsignificant difference. Regional
assessment showed a larger decrease in the abdominal fat mass and in
the fat mass of the upper extremities in the men than in the women
(P = 0.003 and P = 0.003,
respectively), whereas the reduction in fat mass of the lower
extremities did not differ between the sexes (P =
0.09).
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); this
difference was not significant. The gain in lean body mass in the women
who received sex steroids was 2.1 ± 2.4 kg compared with 2.5
± 1.3 kg in the women who did not. In the men, total body weights
before and after therapy were 85.2 ± 11.6 and 83.4 ± 11.3
kg; in the women, the corresponding values were 68.9 ± 11.2 and
69.6 ± 10.0 kg (P = NS).
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Total serum cholesterol decreased by 0.5 ± 0.7 mmol/L
(P = 0.008), LDL cholesterol by 0.5 ± 0.6 mmol/L
(P = 0.03), and Apo B by 0.13 ± 0.19 g/L
(P = 0.0009) in the men, whereas no reductions in these
variables were observed in the women (Table 2
). Before therapy, the
women had higher HDL cholesterol and Apo A-1 concentrations
(P = 0.001 and P = 0.0002,
respectively) than the men. No significant changes were noted in either
sex upon treatment with rhGH. The LDL/HDL ratio was higher in the men
before therapy (P = 0.001), and after therapy the ratio
was lowered in the men but not in the women. Lp(a) increased to a
similar extent in men and women during therapy, whereas triglycerides
remained unchanged (Table 2). Neither the baseline concentrations of
lipids and lipoproteins nor the effects of rhGH on these variables
differed between women with and without estrogen replacement
therapy.
Effects on blood-clotting factors
The serum activity of PAI-1 decreased by 4.9 ± 8.8 U/mL
(P = 0.01) in the men and by 1.2 ± 6.4 U/mL in
the women (P = NS; Table 2). The serum concentrations
of fibrinogen, factor VII, and ß-thromboglobulin were not affected by
GH therapy in either men or women, and there were no differences
between women with and without estrogen supplementation.
Effects on serum markers of bone turnover
Before therapy, the serum markers of bone remodeling were similar
in men and women. After treatment, the serum concentration of
osteocalcin was increased by 14.5 ± 4.9 µg/L (P
= 0.0001) in the men and by 9.3 ± 3.5 µg/L (P =
0.001) in the women (Fig. 4). The carboxyl-terminal
propeptide of type I procollagen level in serum increased by 96.2
± 47 µg/L (P = 0.0001) in the men and by 59 ±
29 µg/L (P = 0.0007) in the women. The serum activity
of bone-specific alkaline phosphatase increased by 1.2 ± 0.6
µkat/L (P = 0.0001) in the men and by 0.8 ± 0.6
µkat/L (P = 0.0015) in the women. The serum level of
carboxyl-terminal cross-linked telopeptide of type I collagen, a marker
of bone resorption, increased by 10.7 ± 4.8 µg/L
(P = 0.0001) in the men and by 6.5 ± 4.0 µg/L
(P = 0.0007) in the women. The differences in response
to treatment between the sexes were significant (Fig. 4). Neither the
basal levels of the studied bone markers nor the effects of therapy on
these markers differed between women treated and those not treated with
sex steroids (data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A sex-dependent variation in GH release in humans has been found by
several investigators. As early as in 1965, Frantz and Rabkin (15)
reported that the serum GH concentration rose after ambulation in women
but not in men, and that administration of high doses of estrogen
changed the male pattern of GH release to the female one. The basal GH
concentration (17), the 24-hour integrated GH secretion (16, 18, 27),
and the pituitary response to GHRH (19, 20) and arginine (28) are
higher in premenopausal women than in men of a comparable age.
Recently, the use of a highly sensitive assay revealed that the
post-glucose nadir of GH was lower in men than in women (17). As men
and women have similar concentrations of circulating IGF-I (29), it
thus appears that the target response to a given dose of GH differs and
could be influenced by sex hormones. This issue has not previously been
addressed in the treatment of patients with GHD, nor has the sex
difference in GH secretion been taken into consideration when men and
women have been investigated for possible GHD. In the present study the
severity of GHD, as assessed from the residual spontaneous GH secretion
and the GH response to stimulation tests, was similar in the male and
female groups of patients. Equal doses of rhGH, adjusted to body
surface area, had more pronounced effects on several of the outcome
measures in men than in women. There were no changes in body
composition or biochemical parameters during the placebo period. It
seems likely that sex steroids influenced the observed gender
differences. High doses of estrogen have been shown to ameliorate the
signs and symptoms of acromegaly (30), suggesting an antagonism between
estrogen and GH in peripheral tissues. A reduction of circulating IGF-I
after oral estrogen replacement has been observed in healthy
postmenopausal women (31, 32). Further, a reduced effect of rhGH on
metabolic indexes as well as on the body composition was found in a
group of healthy elderly women receiving estrogen compared with that in
women not given estrogen (33). In the present study, sex steroid
replacement did not alter the outcome of GH treatment in the women.
This finding might be explained by the small number of patients, the
different estrogen/progestagen regimens, and the difference in mean age
(
9 yr) between the two female groups.
Several observations indicate that androgen- and GH-dependent pathways interact. In sexually immature boys who are given gonadal steroids, the development of secondary sex characteristics is improved by the addition of GH (34). A positive relation between serum concentrations of testosterone and IGF-I has been reported in healthy men (35), and treatment of obese men with testosterone has been found to reduce visceral fat mass (36). Androgens have been shown to stimulate catecholamine-induced lipolysis in rats (37), and a similar effect has been observed after treatment with GH in GHD patients (38). Further, both androgens (39) and GH (40) inhibit the activity of lipoprotein lipase in adipose tissue. The increased response to GH in men may then reflect a synergy between GH and androgens at the peripheral level.
GH is involved in the regulation of lipoprotein metabolism, and GHD is associated with elevated serum levels of total cholesterol, LDL cholesterol, and Apo B, the major structural protein in LDL cholesterol (7, 41). Moreover, increased plasma PAI-1 activity, a risk factor for premature atherosclerosis (42), has been demonstrated in patients with GHD (43). In the present study, significant reductions in serum total cholesterol (by a mean of 8%), LDL cholesterol (10%), Apo B (11%), and PAI-1 (46%), and an increase in the LDL to HDL ratio (17%) were observed as an effect of treatment in the men, but not in the women. The data of combined cohort studies have indicated that a reduction in serum cholesterol concentration of about 10% would lower the risk of ischemic heart disease by about 40–50% in the relevant age groups (44). The serum concentrations of Lp(a) were increased by the therapy in both sexes. The possible importance of changes in serum Lp(a) concentrations per se is as yet unknown. High concentrations of Lp(a) have been suggested to adversely influence cardiovascular risk (45), although the results of some prospective studies do not support this association (45, 46).
As shown above, the effects on total and abdominal fat mass were more impressive in the men, illustrating that with respect to several cardiovascular risk factors, the men gained more from the replacement therapy than the women. However, as serum IGF-I were increased to concentrations above the upper reference level in a some of the men, future studies using lower doses of rhGH will clarify the overall outcome of rhGH with regard to cardiovascular risk.
Intact GH secretion is important for the maintenance of bone mass in adults, and institution of GH replacement in patients is accompanied by increases in serum and urinary indexes of bone metabolism (1). The serum markers of bone formation and bone resorption increased in parallel, and to a larger extent in the men, after the administration of GH in this study, indicating a higher rate of bone turnover in the men. It remains to be established whether the net effects of long term treatment on bone mass will be more advantageous to men than to women.
Recently, the optimal replacement dose of rhGH for restoring tissue hydration in young GH-deficient men was found to be about 1 U/m2 (47), i.e. similar to the dose employed in the present study of mainly middle-aged individuals. We suggest that in future studies the present findings of sex differences in the responsiveness to GH should be taken into account and the replacement doses adjusted not only for age, but also for gender, to achieve an optimal replacement regimen for both men and women with GHD.
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Acknowledgments |
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Footnotes |
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Received August 13, 1996.
Revised September 26, 1996.
Accepted October 8, 1996.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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rin P, Odén P, Björntorp P. 1995 Assimilation and mobilization of triglycerides in subcutaneous
abdominal and femoral adipose tissue in vivo in men: effects
of androgens. J Clin Endocrinol Metab. 80:239–243.[Abstract]
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A Munafo, T X Q Nguyen, O Papasouliotis, H Lecuelle, A Priestley, and M O Thorner Polyethylene glycol-conjugated growth hormone-releasing hormone is long acting and stimulates GH in healthy young and elderly subjects Eur. J. Endocrinol., August 1, 2005; 153(2): 249 - 256. [Abstract] [Full Text] [PDF]
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J. Gibney, T. Wolthers, G. Johannsson, A. M. Umpleby, and K. K. Y. Ho Growth hormone and testosterone interact positively to enhance protein and energy metabolism in hypopituitary men Am J Physiol Endocrinol Metab, August 1, 2005; 289(2): E266 - E271. [Abstract] [Full Text] [PDF]
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J. J. Christiansen, S. Fisker, C. H. Gravholt, P. Bennett, B. Svenstrup, M. Andersen, U. Feldt-Rasmussen, J. S. Christiansen, and J. O. L. Jorgensen Discontinuation of estrogen replacement therapy in GH-treated hypopituitary women alters androgen status and IGF-I Eur. J. Endocrinol., May 1, 2005; 152(5): 719 - 726. [Abstract] [Full Text] [PDF]
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J. D. Veldhuis, J. Frystyk, A. Iranmanesh, and H. Orskov Testosterone and Estradiol Regulate Free Insulin-Like Growth Factor I (IGF-I), IGF Binding Protein 1 (IGFBP-1), and Dimeric IGF-I/IGFBP-1 Concentrations J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2941 - 2947. [Abstract] [Full Text] [PDF]
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