Studies on Growth on Men and Women

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TweetTaken from Endojournals.org:
Original Studies

The Effect of Four Weeks of Supraphysiological Growth Hormone Administration on the Insulin-Like " href="https://www.ar-r.com"Growth Factor Axis in Women and Men1

R. Dall2, S. Longobardi2, C. Ehrnborg, N. Keay, T. Rosén, J. O. L. Jørgensen, R. C. Cuneo, M. A. Boroujerdi, A. Cittadini, R. Napoli, J. S. Christiansen, B. A. Bengtsson, L. Sacca, R. C. Baxter, E. E. Basset, P. H. Sönksen and on behalf of the gh-2000 study group


Department of Medicine M (Endocrinology and Diabetes), Aarhus University Hospital (R.D., J.O.L.J., J.S.C.), DK-8000 Aarhus, Denmark; Department of Clinical Medicine and Cardiovascular Sciences, University Federico II (S.L., A.C., L.S., R.N.), 80131 Naples, Italy; Research Center for Endocrinology and Metabolism, Sahlgrenska Hospital (C.E., T.R., B.A.B.), S-41345 Gothenburg, Sweden; Metabolic Research Unit, Department of Medicine, and Department of Social and Preventive Medicine, University of Queensland, Princess Alexandra Hospital (R.C.C.), 4102 Brisbane, Queensland, Australia; Department of Endocrinology, St. Thomas’s Hospital (N.K., M.A.B., P.H.S.), London, United Kingdom SE1 7EH; Institute of Mathematics and Statistics, University of Kent (E.E.B.), Canterbury, Kent, United Kingdom CT 7NF; and Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital (R.C.B.), St. Leonards 2065, New South Wales, Australia

Address all correspondence and requests for reprints to: Rolf Dall, M.D., Aarhus Kommunehospital, Department of Medicine M (Endocrinology and Diabetes), Aarhus University Hospital, DK-8000 Aarhus, Denmark. E-mail: rd@dadlnet.dk.
Measurements of serum insulin-like " href="https://www.ar-r.com"growth factor I (IGF-I) and related markers are routinely used in the diagnosis and treatment of GH deficiency and excess. The validity of these markers for assessment of exogenous GH exposure in healthy adults is, however, unknown. We therefore conducted a double blind, placebo-controlled GH treatment trial in 99 healthy subjects [49 women and 50 men; mean ± SE age, 25.6 ± 0.6 (women)/25.7 ± 0.6 yr (men)]. Blood was collected weekly during a 4-week treatment period (days 1–28), and the subjects were subsequently followed for additional 8 weeks (days 29–84). The treatment arms included: I) 0.1 IU/kg·day GH (n = 30; GH 0.1), II) 0.2 IU/kg·day GH (n = 29; GH 0.2), and III) placebo (n = 40). At baseline no gender-specific differences existed, except that the acid-labile subunit (ALS) levels were higher in females. Serum insulin-like " href="https://www.ar-r.com"growth factor I (IGF-I) levels in males receiving GH increased significantly through day 42 with no significant difference between the 2 doses. The absolute " href="https://www.ar-r.com"IGF-I response was significantly lower in females, and there was a clear dose-response relationship. ALS levels in males increased through day 30 (P < 0.001). In females ALS levels were only modestly increased on day 28 compared with those in the placebo group (P < 0.02). IGF-binding protein-3 (IGFBP-3) levels in males increased significantly in the GH 0.1 and the GH 0.2 groups on day 30 (P < 0.03), whereas no solid IGFBP-3 increase was detected in females. IGFBP-2 levels decreased insignificantly during GH exposure in both genders. A gender-specific upper normal range for each analyte was arbitrarily defined as 4 SD above the mean level at baseline. On the basis of " href="https://www.ar-r.com"IGF-I levels alone, GH exposure in the GH 0.2 group was detected in 86% of the males and in 50% of the females on day 21. On day 42 GH exposure was only weakly detectable in males and was not detectable in females. We conclude that 1) males are significantly more responsive than females to exogenous GH; 2) the increase in " href="https://www.ar-r.com"IGF-I is more robust compared with those in IGFBP-3 and ALS; 3) IGFBP-2 changes very little during GH treatment; and 4) among " href="https://www.ar-r.com"IGF-related substances, IGF-I is the most specific marker of supraphysiological GH exposure.
SINCE THE REPORT by Salmon and Daughaday (1) it has become well established that the anabolic actions of GH to a large extent are mediated through hepatic and peripheral synthesis of insulin-like " href="https://www.ar-r.com"growth factor I (IGF-I) (2). With the development of specific RIAs for " href="https://www.ar-r.com"IGF-I, it was subsequently revealed that serum " href="https://www.ar-r.com"IGF-I concentrations are low in GH-deficient children and are distinctly elevated in active acr*****ly (3). The dependence of " href="https://www.ar-r.com"IGF-I on GH status was substantiated by demonstrating that GH administration to GH-deficient children increases serum " href="https://www.ar-r.com"IGF-I concentrations in a dose-dependent manner (4), and that successful treatment of acr*****ly resulted in normalization of circulating " href="https://www.ar-r.com"IGF-I levels (5). Today, measurement of serum " href="https://www.ar-r.com"IGF-I is routinely used in the diagnosis and monitoring of both GH-deficient and acr*****lic patients.



In the circulation most " href="https://www.ar-r.com"IGF-I circulates as a 150-kDa ternary complex consisting of " href="https://www.ar-r.com"IGF-I plus a specific binding protein (IGFBP-3) and a nonbinding component, termed acid labile subunit (ALS) (6, 7). Both IGFBP-3 and ALS are partly regulated by GH, as reflected by low and elevated levels in GH deficiency and active acr*****ly, respectively (7).

In contrast to patients with GH disorders, less is known about the regulation of serum " href="https://www.ar-r.com"IGF-I in healthy adults. Serum " href="https://www.ar-r.com"IGF-I levels decline gradually with age, which is weakly correlated with the concomitant decline in GH secretion (8), but it has recently been shown that endogenous GH status is a surprisingly weak predictor of serum " href="https://www.ar-r.com"IGF-I (9). Possible residual determinants of " href="https://www.ar-r.com"IGF-I in normal adults include gender and sex steroids, body composition, and physical fitness. Even less is known about the impact of exogenous GH exposure on " href="https://www.ar-r.com"IGF-I and related variables in healthy adults. Such information would seem to be of general interest when considering the use of GH for nonlicensed indications such as catabolic states, sarcopenia, and ************ of age-associated changes in body composition. Moreover, there is increasing evidence to suspect widespread illicit use of GH as a performance-enhancing agent among athletes (10).

The aim of the present study was to assess the effects of GH administration in supraphysiological doses on serum concentrations of " href="https://www.ar-r.com"IGF-I and pertinent related variables and subsequently to evaluate the usefulness of such variables to predict exposure to exogenous GH. To this end a large cohort of healthy, fit, young adults of both sexes were studied before, during, and after GH administration with two doses in a randomized, placebo-controlled, parallel trial.
Subjects



Ninety-nine subjects (50 men and 49 women) were recruited among healthy volunteers in 4 different countries: Denmark (n = 31), Italy (n = 27), Sweden (n = 30), and the United Kingdom (n = 11). The inclusion criteria were age between 18–40 yr, unremarkable medical history, no intake of medications, and regular participation in at least 2 exercise sessions/week for at least 1 yr. None of the subjects was an elite athlete, and participation in organized sport competitions was not allowed during the study period. All women documented a negative pregnancy test before study entry and were confirmed to be using safe contraception; 9 women used oral contraceptives (1 in the placebo group, 3 in the 0.1 IU/kg·day GH group, and 5 in the 0.2 IU/kg·day group), and the remaining females used barrier methods. Treatment with GH/placebo started randomly with respect to the menstrual cycle. In each country the protocol was approved by the ethical committee system and the national health authorities. Design



The study was performed in a randomized, double blind, placebo-controlled, parallel design involving three arms: I) 0.1 IU/kg·day GH (GH 0.1; maximum dose, 9.5 IU/day; n = 30; 15 women and 15 men), II) 0.2 IU/kg·day GH (GH 0.2; maximum dose, 19 IU/day; n = 29; 15 women and 14 men), and III) placebo (PLA; n = 40; 19 women and 21 men). GH (Genotropin, Pharmacia & Upjohn, Inc., Stockholm, Sweden; or Norditropin, Novo Nordisk, Copenhagen, Denmark) and placebo were administered as daily sc self-injections in the evening. To minimize side effects, only 50% of the target dose was given during the first week. In case of side effects the dosage was reduced by 50%, and treatment was discontinued if the complaints persisted for more than 1 week. Compliance was monitored by collection of " href="https://www.ar-r.com/shop/default.php?cPath=27"vials and reports about missing injections. At baseline the subjects attended the hospital for 1 day for blood sampling, interview, and physical examination. Blood samples were subsequently collected at the end of each week during the treatment phase (days 7, 14, 21, and 28) and on days 30, 33, 42, and 84 in the wash-out period.

Assays

All serum samples were stored at -80 C, and all samples from one subject were analyzed in the same run. Serum " href="https://www.ar-r.com"IGF-I was measured by RIA using a monoclonal antibody after acid-ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA).
Statistical analyses



Unpaired two-tailed t test was used to test for gender differences at baseline. The variance in the PLA group was tested by ANOVA for repeated measures approached by general linear modeling (GLM repeated measures). The CVs for the variables in the PLA group were calculated as the mean ± SEM of the SD/mean for each subject. Temporal changes in serum levels of each variable were tested by GLM repeated measures with each time point as a with-in subject factor, and randomization and gender as between-factors. If GLM repeated measures revealed significant changes, post-hoc analysis was made by gender-stratified one-way ANOVA, and multiple comparisons were made using the Bonferroni correction. The area under the curve (AUC) during the treatment period (days 1–28) of each variable was estimated according to the trapezoidal rule. Differences in AUC among the three groups were analyzed by one-way ANOVA. Where appropriate, post-hoc analysis was performed by multiple comparisons with the Bonferroni correction. Pearson correlation analyses (r) as well as multiple linear regression analyses were used to relate variables. P < 0.05 was considered significant. Results are expressed as the mean ± SE.

Side effects

During the study, 8 subjects (3 women and 5 men) of the 30 enrolled in the GH 0.1 group experienced side effects; among these, 1 subject reduced the dose (1 men). In the GH 0.2 group, 20 subjects (7 women and 12 men) experienced side effects; among these, 5 reduced the dose (2 women and 3 men). In the PLA group, 12 subjects (7 women and 5 men) had side effects, of whom 1 subject reduced the dose and 1 subject stopped the treatment on day 14 due to headache and tachycardia. The most frequently reported side effects were attributable to transient fluid retention. In addition, increased sweating and arthralgia were reported.
At baseline, IGF-I correlated positively with IGFBP-3 (r = 0.5; P < 0.0005) and ALS (r = 0.6; P < 0.0005), whereas IGFBP-2 and ALS levels correlated negatively (r = -0.3; P < 0.002).



Gender-stratified multiple linear regression models with " href="https://www.ar-r.com"IGF-I, IGFBP-2, IGFBP-3, and ALS as dependent variables and age and BMI as independent variables were performed at baseline. IGF-I correlated negatively with age in men [age: ß = -0.5; P < 0.0005; body mass index (BMI): ß = 0.07; P < 0.6; overall: P < 0.001; r2 = 0.23], but not in women (P < 0.22). For both genders IGFBP-2 levels correlated positively with age and negatively with BMI (women: age: ß = 0.4; P < 0.005; BMI: ß = -0.04; P < 0.03; overall: P < 0.008; r2 = 0.16; males: age: ß = 0.3; P < 0.04; BMI: ß = -0.4; P < 0.005; overall: P < 0.01; r2 = 0.16). ALS levels in females did not correlate significantly with age and BMI (P < 0.4), but in males there was a negative correlation with age (age: ß = -0.4; P < 0.02; BMI: ß = 0.1; P < 0.4; overall: P < 0.049; r2 = 0.08).

All variables in the PLA group remained stable during the entire study period, as ANOVA revealed no significant time effect in the PLA group during the study period (Table and 3–6). IGFBP-2 levels showed the highest intraindividual CV during the study period (20–25%), whereas the CVs for " href="https://www.ar-r.com"IGF-I, IGFBP-3, and ALS were between 10–16% (Table 4). The biological CVs, estimated as the intraindividual CVs minus the intraassay CVs, were 6–9% for " href="https://www.ar-r.com"IGF-I, IGFBP-3, and ALS and approximately 20% for IGFBP-2 (Table 4).
The aim of the present study was to assess the impact of GH administration in supraphysiological doses on the circulating levels of " href="https://www.ar-r.com"IGF-I and related variables in healthy adults of both sexes. Collection of such data is relevant in view of the ongoing interest in the use of exogenous GH for unlicensed indications in general and GH abuse by athletes in particular (12).



The main findings include 1) IGF-I is the most sensitive marker of GH exposure; 2) the GH-induced increase in IGFBP-3 and ALS is markedly lower compared with that in " href="https://www.ar-r.com"IGF-I; 3) IGFBP-2 responds very little to GH; and 4) a marked gender difference exists, with men being more responsive to exogenous GH administration.

The large sample size and the randomized design, including two different doses, strengthens the validity of the observations, but the study population, on the other hand, covered a narrow age range of young, healthy, and physically fit individuals. Extrapolations to older people or patients should therefore be made with caution.

At baseline no gender differences were recorded, apart from higher ALS levels among women. Comparable levels of " href="https://www.ar-r.com"IGF-I, IGFBP-3, and IGFBP-2 between healthy adult males and females has previously been reported (6, 13), but gender differences in " href="https://www.ar-r.com"IGF-I levels have been observed in particular age groups (14). Females may exhibit slightly higher " href="https://www.ar-r.com"IGF-I levels than males at puberty and in early adulthood, whereas the opposite has been reported in middle-aged adults (9, 15). In adult hypopituitary patients with documented GH deficiency " href="https://www.ar-r.com"IGF-I levels are consistently higher in men than in women (9, 16). Our observation of higher ALS levels in women has been reported recently (17), but is in contrast with a previous report in which no gender differences were observed in any age group (7).

The pattern among males was characterized by high and almost identical increments in " href="https://www.ar-r.com"IGF-I after the two GH doses. In women, the " href="https://www.ar-r.com"IGF-I response was lower, but a distinct dose responsiveness was observed. Thus, the lower GH dose group apparently reached the top of the dose-response curve in males, but not in females. It is evident that the present study involved the high end of the dose-response curve, but there is evidence from the literature that a gender difference in GH sensitivity also exists with lower GH doses. The relative GH resistance in women has been described by Ghigo et al. (18), who reported that the minimum exogenous GH dose needed to elicit an " href="https://www.ar-r.com"IGF-I response in normal subjects is higher in women than in men. Both spontaneous and stimulated GH levels are elevated in women compared with men (16, 19, 20), which has been causally linked to differences in estradiol levels. It is, however, unresolved whether the stimulatory effect of estradiol on GH release involves a central stimulation or a negative feedback linkage to peripheral reduction of " href="https://www.ar-r.com"IGF-I production. In favor of the latter hypothesis, several studies have shown that administration of exogenous estradiol lowers serum " href="https://www.ar-r.com"IGF-I levels concomitantly with amplification of endogenous GH release (21). It has, on the other hand, recently been reported that both GH release and serum " href="https://www.ar-r.com"IGF-I levels increase during the periovulatory phase in normal young women, which coincides with elevated endogenous estradiol levels (22). Alternatively, it could be hypothesized that androgens play a permissive role for GH-stimulated " href="https://www.ar-r.com"IGF-I production. This could explain the suppression of " href="https://www.ar-r.com"IGF-I production in postmenopausal women during exogenous estradiol administration, which is likely to inhibit endogenous androgen secretion, and it may also account for the low " href="https://www.ar-r.com"IGF-I levels in hypopituitary females. This theory is supported by Erfurth et al. (23), who found a significant correlation between free testosterone and " href="https://www.ar-r.com"IGF-I levels. Recently, Span et al. (24) reported that " href="https://www.ar-r.com/shop/product_info.php?cPath=23&products_id=42"estrogen replacement in GH-deficient women significantly increased GH requirements, and androgen substitution in GH-deficient men increased GH sensitivity. Regardless of the physiological mechanisms the present study demonstrates that women, relative to men, are resistant to GH in terms of " href="https://www.ar-r.com"IGF-I generation. A similar gender difference has recently been shown regarding the acute lipolytic response to a physiological GH bolus (25). These observations in healthy adults are in accordance with the idea that the GH dose requirements in hypopituitary adults are higher in female patients, as judged by serum " href="https://www.ar-r.com"IGF-I levels as well as changes in body composition (19). In both sexes GH discontinuation was followed by an abrupt decline in total " href="https://www.ar-r.com"IGF-I levels.

The elevations in IGFBP-3 and ALS were far less pronounced than those in " href="https://www.ar-r.com"IGF-I, and again, the response was lower in women than in men. Ghigo et al. (18) reported that IGFBP-3 levels were less increased than " href="https://www.ar-r.com"IGF-I levels after GH exposure.

It has previously been shown that the circulating total " href="https://www.ar-r.com"IGF-I/IGFBP-3 ratio is elevated in active acr*****ly (13) and after GH administration in both GH-deficient adults (26) and healthy controls (18). Accordingly, we also recorded a significantly increased " href="https://www.ar-r.com"IGF-I/IGFBP-3 ratio in the present study, which prevailed even 2 weeks after cessation of GH administration.

Serum IGFBP-2 concentrations did not consistently change during GH administration, which contrasts with at least one previous study in which GH administration suppressed circulating IGFBP-2 levels (27). Juul et al. reported decreased IGFBP-2 levels in acr*****lic patients (13), and Jørgensen et al. (5) observed suppressed IGFBP-2 levels in active acr*****ly, which became normalized after successful surgery, whereas Clemmons et al. (28) reported normal IGFBP-2 levels in active acr*****ly and moderately elevated levels in hypopituitary adults.

Our study clearly demonstrated that " href="https://www.ar-r.com"IGF-I is superior to IGFBP-2, IGFBP-3, and ALS regarding the ability to identify exposure to supraphysiological doses of exogenous GH in healthy subjects. Using the upper 4 SD level of " href="https://www.ar-r.com"IGF-I in the GH-untreated state as an arbitrary cut-off limit, 86% of men were identified while receiving the high GH dose, and the " href="https://www.ar-r.com"IGF-I level was not completely returned to baseline 14 days after termination of GH administration. As previously mentioned, this percentage was significantly lower in women. As a mean to detect GH abuse in athletes, a single measurement of " href="https://www.ar-r.com"IGF-I in serum is probably not sufficiently robust, at least not in females. Whether measurements of other GH-dependent growth markers, alone or in combination with " href="https://www.ar-r.com"IGF-I, will prove more efficacious must await further analysis.

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