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Original Studies |
Oregon Health Sciences University, Portland, Oregon 97201
Address all correspondence and requests for reprints to: David M. Cook, M.D., Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, L-607, Portland, Oregon 97201-3098. E-mail: cookd{at}ohsu.edu
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Abstract |
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Introduction |
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Early studies using GH to treat GH-deficient (GHD) adults have suggested that GH doses for adults are much lower than those needed for children. Doses originally selected for adults based upon that which is appropriate for children have resulted in a high rate of adverse side-effects in both adult men and women (10, 11, 12). Specifically, the GH replacement dose originally recommended for adults was 25 µg/kg·day, which resulted in severe side-effects of edema and arthralgias, necessitating a dose reduction in the majority of patients. More recent reports (12, 13) have suggested that adults are more prone to side-effects from GH therapy than children, and that symptom tolerance is often a limiting factor in adult GH replacement therapy. Starting doses used in this current study were based on the suggestion by Amato et al. (14) that sc injected GH is about 60% bioavailable, and replacement doses should be about twice the theoretical secretion rates. The objectives of the current study were to observe serum IGF-I responses to exogenous GH in GH-deficient patients. We theorized that it would require more exogenous GH in patients whose livers were exposed to higher estrogen concentrations (patients taking oral estrogen) than in women not on oral estrogen. Additionally, we wanted to ascertain what determined the final or maintenance dose of GH therapy, such as IGF-I concentrations or other factors. We selected GH-deficient adult patients and prospectively raised their GH replacement dose to symptom tolerance or to a mid- to high normal serum IGF-I concentration. Women receiving oral estrogen, women not receiving oral estrogen (i.e. endogenous or transdermal hormone exposure), and men were studied to determine what constituted a final GH replacement dose in these three groups.
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Subjects and Methods |
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lists the study patient characteristics
and GH stimulation tests. Pituitary or central nervous system tumor was
the most common etiology causing GHD. Stimulation tests used were
arginine (30 g, iv, over 30 min), arginine combined with
L-DOPA (500 mg, orally), or insulin-induced
hypoglycemia. Plasma glucose required to constitute a valid insulin
test was 40 mg/100 dL or less and signs of hypoglycemia
(i.e. tachycardia and diaphoresis). All patients were taking
stable replacement doses of other hormones, i.e. thyroid,
cortisol, and testosterone when deficient in males. The mean ages in
the three study groups were not significantly different. Specifically,
the average age for men was 45.5 ± 3.2 yr, that for women not
taking oral estrogen was 46.5 ± 2.2 yr, and that for women taking
oral estrogen was 44.8 ± 3.5 yr.
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Our earlier experience with adult GH therapy suggested that symptoms of GH excess appeared if the starting dose was too high, even if this dose was eventually subtherapeutic. These "start-up" symptoms we learned could be avoided with low initial doses. For this reason and also because we suspected women taking oral estrogen would need more GH, we used the following dose regimens. Women taking oral estrogen began with 4 µg/kg·day and advanced by 2 µg/kg·day every 6–8 weeks. All others began at 2 µg/kg·day and advanced by 1 µg/kg·day every 6–8 weeks. The final dose of GH was determined by symptom tolerance or an IGF-I level in the mid- to high normal range based upon age and sex. If a dose was not tolerated, we reduced it to the previously tolerated dose level. Muscle or joint pain caused by GH therapy was easily recognized by patients. Carpal tunnel syndrome was diagnosed clinically by the physician in charge (D.M.C.) based upon typical symptoms and positive tinnel signs. GH used in this study was obtained from Eli Lilly & Co. (Humatrope; Indianapolis, IN).
Study groups
Patients were divided into three groups, which included 1) men,
2) women not taking oral estrogen treatment (e.g. women
receiving transdermal estrogen or premenopausal women with endogenous
estrogen production), and 3) women taking oral estrogen therapy. There
were 12 men, 13 women not taking oral estrogen, and 12 women taking
oral estrogen in each of the three groups (Table 1
). Women requiring
transdermal estrogen wore patches designed to deliver either 0.05 or
0.1 mg/day. Women determined to have normal endogenous estrogen levels
had regular cycling menstrual periods.
Statistical analysis
Statistical differences among groups were determined using ANOVA
with Tukey-Kramer highest significant difference test (
= 0.05).
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Results |
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. Most final doses (21 of the
total 37 patients) were determined by symptom tolerance rather than by
IGF-I concentration, with muscle or joint aches as the most common
symptoms that prevented raising the dose. In the process of titrating
to a therapeutic GH dose, patients typically had dose adjustments every
6–8 weeks. The mean number of dosing changes made was 2.6 ± 0.2
dose changes, with a range of 0–6 changes, and the total number of
weeks of titration required to attain the final GH dose was 28 ±
3 weeks, with a range of 6–104 weeks (Table 2).
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). The mean IGF-I
concentration in men was 179 ± 12 ng/mL, that in women not taking
oral estrogen was 209 ± 14 ng/mL, and that in women taking oral
estrogen was 190 ± 16 ng/mL.
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and 3, expressing the daily dose in
micrograms per kg BW or micrograms per day did not change the results.
Men and women not taking oral estrogen require less GH than women
taking oral estrogen. Specifically, men required 4.1 ± 0.6
µg/kg·day or 376 ± 49 µg/day, women not taking oral
estrogen required 5.0 ± 0.7 µg/kg·day or 424 ± 57
µg/day, and women taking oral estrogen required 10.6 ± 0.7
µg/kg·day or 867 ± 45 µg/day. Dose requirements in men and
women not taking oral estrogen were not different from each other, but
both differed from those in women taking oral estrogen. Table 1
summarizes the final dosing by micrograms per kg/day and micrograms per
day as well as the IGF-I concentrations in the study population. Note
the variability in dose requirements, with a trend to very low doses
required in men.
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, one patient (no.
18, Table 1) was switched from oral to transdermal estrogen therapy
during the study. Although previously receiving a therapeutic GH dose
(8 µg/kg·day), within weeks of the changed route of estrogen
administration, the patient became symptomatic with muscle and joint
aching and had an elevated IGF-I. After several subsequent dose
reductions, symptoms of GH excess were relieved. IGF-I was normalized
at a dose of 4 µg/kg·day.
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Discussion |
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We cannot explain the similar requirements of men and those of women exposed to transdermal or endogenous estrogen. Theoretically, these women should require more than the men, but less than women receiving oral estrogen. Our data suggest a trend in this direction, but it was not statistically significant. Further data and experience may help to define dosing requirements in various groups, including those receiving transdermal delivery of estrogen and postmenopausal women not taking estrogen.
Our hypothesis for the increased GH requirements in women taking oral estrogen is as follows. Estrogen appears to inhibit liver IGF-I synthesis or secretion (5, 6). In normal patients (i.e. not GHD) taking oral estrogen therapy, the first pass of estrogen through the liver causes a fall in IGF-I concentration. This, in turn, causes a decrease in negative feedback of IGF-I at the pituitary level, which triggers an increase in pituitary GH secretion. In hypopituitary adults, however, who are deficient in GH secretion, the homeostatic mechanism that regulates GH level is missing, and GH plasma levels are completely dependant on the amount of exogenous GH administered. As a result, if a patient is receiving both oral estrogen and GH as replacement therapy, higher quantities of exogenous GH are required to raise serum IGF-I concentrations to the normal range. Alternative explanations for increased requirements to raise IGF-I concentrations for women on oral estrogen include an increase in IGF-I clearance or induction of GH resistance.
A number of factors regulating GH dosing appear to be emerging; these include age (15), gender, presence or absence of obesity (16), and symptom tolerance (14). Clearly, children need significantly more GH than elderly patients. Children appear to require 30–50 µg/kg·day, and older adults require 2–4 µg/kg·day (9). Many unanswered questions remain, however. What, for example, will be the requirements of young adults, i.e. those in their late teens and 20s? Will their GH replacement requirements be somewhere between those of older adults and children, or will they be more like the adults reported in this study? Further experience is needed in this age group before guidelines can be provided. The patients in the present study were all adults, with the mean age in each of the three groups in the mid-40s. In this age group, dose requirements appear to be influenced by sex differences as well as form of estrogen replacement therapy. The route of estrogen exposure, oral vs. transdermal or endogenous, appears to make a difference, with those patients receiving oral estrogen therapy requiring more GH than those receiving transdermal or endogenous estrogen delivery to normalize IGF-I.
Although serum GH levels were not obtained in this study, they would be expected to be proportional to the exogenous GH dose. Theoretically, this could have negative implications, because GH itself has biological effects that are independent from IGF-I. Are these patients who require more GH, for example, at greater risk for neoplasm? Additionally, there is a cost factor. If patients are placed on oral estrogen and require more GH than those taking transdermal estrogen, should we not replace estrogen transdermally to reduce cost? As the difference in total hormone given in these two groups is about half, the cost-savings benefit is substantial.
Titrating the GH dose after measuring IGF-I concentrations alone may not be the only important parameter to follow. Indeed, Lucidi, et al. (8) and others (17, 18, 19) suggested that in GHD adults, the increase in lean body mass induced by GH treatment does not correlate with IGF-I concentrations. Titration of GH dose may also be accomplished using bioimpedance. The use of this latter technique, however, has frequently resulted in elevated serum IGF-I concentrations when bioimpedance analysis parameters were normalized (20).
Dosing by weight remains controversial. Based upon our experience with GH replacement therapy and the impact of oral, transdermal, or endogenous estrogen, we follow a dosing regimen that incorporates these categories. For men and women receiving transdermal estrogen we begin GH at 2 µg/kg·day and advance the dose by 1 µg/kg·day every 4–6 weeks based upon symptoms and IGF-I levels. For women taking oral estrogen we begin at 4 µg/kg·day and advance by 2 µg/kg·day every 4–6 weeks. Because elderly patients can only tolerate small amounts of GH (21), we begin patients over 60 yr of age on 100 µg/day and advance by 50 µg/day every 4–6 weeks. We do not exceed 300 µg/day in any patient as an initial dose. Using doses above 300 µg/day usually results in symptoms of excess GH, such as muscle or joint pain, headache, or blurred vision. This follows the Fort Stevens consensus group suggestions (19), which suggested starting doses to be in the range of 150–300 µg/day.
Drake et al. used IGF-I concentrations alone for dose titration (22). They did not observe any difference in final dose in women taking oral estrogen, but did not study women receiving transdermal estrogen. These researchers did suggest that men required less GH than women to raise IGF-I to levels between the median and the upper limit of normal.
In this study we reported that symptoms of GH treatment may influence what GH dose a patient may tolerate. We also noticed a difference between what we refer to as start-up symptoms and those of chronic GH therapy. Many adult patients will have myalgias, arthralgias, headaches, and blurred vision at the initiation of therapy, even though the dose is low and subtherapeutic. The primary purpose of our very low starting doses is to avoid these start-up symptoms. Mårdh reviewed 12 placebo-controlled European trials of GH therapy in GH-deficient adults and observed similar findings (23). They found that although 30–35% of patients had edema and arthralgias or myalgias during the first 3 months of therapy, this dropped to 5–10% thereafter. Apparently, acute fluid and sodium retention in muscles and joints results in acute symptoms. Holmes and Shalet have recently conducted an analysis to determine which patients were the most likely to develop side-effects of GH therapy (24). They found that obese patients were more sensitive, and adult-onset compared to childhood-onset patients were more vulnerable to side-effects (22). Our final doses were not determined by start-up symptoms, but by chronic symptoms of GH excess, which are usually myalgias and/or arthralgias. Indeed, most of our patients’ final doses were determined by symptom tolerance and not an elevated IGF-I concentration.
Finally, it should be noted that the study was unblinded, and doses of GH could have been preselected to be higher in patients taking oral estrogen. This would not be consistent, however, with comparable serum IGF-I concentrations in the different groups and symptom tolerance. We believe that the observation of dramatically different requirements in these patients is valid and not preselected.
Summary
We found GH replacement therapy in adults to be not only dependent upon age and gender, but also on the route of estrogen replacement therapy. Women taking oral estrogen need about twice the amount to normalize IGF-I than women using transdermal estrogen. We believe that the difference is related to an effect of oral estrogen on hepatic IGF-I, the major source of circulating serum IGF-I. A potential cost savings of GH could be realized if women needing GH replacement therapy and exogenous estrogen chose transdermal rather than oral treatment.
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Acknowledgments |
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Footnotes |
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Received May 10, 1999.
Revised July 13, 1999.
Accepted July 22, 1999.
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References |
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