ESTIMATES OF GH secretion in normal adult males have

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1 X/99/$03.00/0 Vol. 84, No. 11 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright 1999 by The Endocrine Society Route of Estrogen Administration Helps to Determine Growth Hormone (GH) Replacement Dose in GH-Deficient Adults* DAVID M. COOK, WILLIAM H. LUDLAM, AND MARIE B. COOK Oregon Health Sciences University, Portland, Oregon ABSTRACT We prospectively studied two groups of GH-deficient patients during GH therapy based upon exposure of the liver to elevated (oral estrogen) or not elevated (endogenous or transdermal) sources of estrogen. We wondered whether higher concentrations of estrogen at the liver level (oral estrogen) might inhibit insulin-like growth factor I (IGF-I) secretion and alter exogenous GH requirements. In this study we compared GH replacement requirements in these two groups of women as well as with GH-treated adult hypopituitary males. The final GH dose was based upon maintenance IGF-I levels in the mid- to high normal range adjusted for age and sex or symptom tolerance. Each group [women taking oral estrogen (n 12), women ESTIMATES OF GH secretion in normal adult males have suggested rates of 1 g/kg day; by contrast, GH secretion in premenopausal females is approximately 3 times that in normal males (1). Other studies have similarly suggested that premenopausal women produce more GH than men (2 4). Furthermore, normal postmenopausal women secrete more GH when given oral estrogen replacement therapy (5, 6). Presumably, oral estrogen inhibits liver insulinlike growth hormone I (IGF-I) secretion/production by a first pass effect(s) and causes an increase in pituitary GH secretion via a decreased negative feedback of IGF-I (6). Increasing the number of transdermal estrogen patches in normal postmenopausal women can also elevate endogenous GH secretion similar to levels observed in women taking oral estrogen (6), suggesting that liver exposure to higher concentrations of estrogen from any route can influence liver IGF-I production and, by feedback mechanisms, increase pituitary GH secretion. Because estrogen appears to be a major factor in influencing IGF-I production, hypopituitary men might be predicted to have lower requirements for exogenous GH than hypopituitary women taking estrogen. Recent studies in men using IGF-I as a guide to titrate GH replacement doses (7 9) have verified these predictions. 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 Received May 10, Revision received July 13, Accepted July 22, 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 cookd@ohsu. edu. * This work was supported in part by USPHS Grant 5M01-RR not taking oral estrogen (n 13), and men (n 12)] was similar in age and final IGF-I concentration. Women taking oral estrogen required g/kg day or g/day GH, women not taking oral estrogen required g/kg day or g/day, and men required g/kg day or g/day to achieve similar IGF-I concentrations. GH requirements in men were not different from those in women not taking oral estrogen, but the GH requirements in both groups were significantly different from GH requirements in women taking oral estrogen. These observations may be useful in anticipating appropriate starting and final doses of GH in adult hypopituitary patients. (J Clin Endocrinol Metab 84: , 1999) have resulted in a high rate of adverse side-effects in both adult men and women (10 12). Specifically, the GH replacement dose originally recommended for adults was 25 g/ 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 GHdeficient 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. Subjects and Methods This study, which used an approved drug, was prospective and did not require institutional review and/or informed consent. Patients had to meet all of the three following criteria of GH deficiency (GHD) to be included in the study: 1) an organic cause of GHD, such as the presence of a pituitary tumor, pituitary surgery, irradiation, hy- 3956

2 GH THERAPY AND ESTROGEN 3957 pophysitis, etc.; 2) low IGF-I for gender and age using an acidextracted radioisotopic assay; and 3) failure to respond to a standard GH stimulation test (maximum response, 2.5 ng/ml, using a twosite chemiluminescent GH assay). Table 1 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 yr, that for women not taking oral estrogen was yr, and that for women taking oral estrogen was yr. GH dosing and titration 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 g/kg day and advanced by 2 g/kg day every 6 8 weeks. All others began at 2 g/kg day and advanced by 1 g/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). TABLE 1. Characteristics of the study patients Patient no. Age (yr) Cause of low GH Stimulation test Route of E 2 exposure Final GH ( g/kg day) Final GH ( g/day) Final IGF-I (ng/ml) Men 1 32 Optic glioma Arginine N/A Familial Arginine N/A Pituitary tumor Arginine N/A Pituitary tumor Arginine N/A Hypophysitis Arginine/L-DOPA N/A Pituitary tumor Arginine N/A CNS irradiation Insulin N/A Pituitary tumor Arginine N/A CNS trauma Insulin N/A Pituitary tumor Arginine N/A Pituitary tumor Arginine N/A Pituitary tumor Arginine N/A Women not on oral E Pituitary tumor Arginine Transdermal Hypophysitis Arginine/L-DOPA Transdermal Pituitary abscess Arginine Transdermal Pituitary tumor Arginine Transdermal Hypophysitis Arginine/L-DOPA Endogenous CNS trauma Arginine/L-DOPA Endogenous CNS trauma Arginine/L-DOPA Endogenous Pituitary tumor Arginine Endogenous Pituitary tumor Arginine Transdermal Hypophysitis Arginine Transdermal Pituitary tumor Arginine Transdermal Empty sella Arginine/L-DOPA Endogenous Hypophysitis Arginine/L-DOPA Transdermal Women on oral E Optic glioma Arginine Oral Pituitary tumor Arginine Oral Hypophysitis Arginine/L-DOPA Oral Hypophysitis Arginine/L-DOPA Oral Hypophysitis Arginine/L-DOPA Oral Hypophysitis Arginine/L-DOPA Oral CNS irradiation Insulin Oral Hypophysitis Clonidine/L-DOPA Oral Pituitary tumor Insulin Oral Sheehan s Insulin Oral CNS irradiation Arginine/L-DOPA Oral Hypophysitis Arginine/L-DOPA Oral

3 3958 COOK, LUDLAM, AND COOK JCE&M 1999 Vol 84 No 11 Results The number of dosing changes, weeks required for dose titration to a final dose, and factors that led to a final GH dose are listed in Table 2. 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 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 weeks (Table 2). The mean final IGF-I concentrations after attaining therapeutic GH replacement doses were not significantly different among the three groups (Fig. 1). The mean IGF-I concentration in men was ng/ml, that in women not taking oral estrogen was ng/ml, and that in women taking oral estrogen was ng/ml. As shown in Figs. 2 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 g/kg day or g/day, women not taking oral estrogen required g/ kg day or g/day, and women taking oral estrogen required g/kg day or g/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. As depicted in Fig. 4, 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 g/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 g/kg day. Discussion In this prospective study we found that GHD men required less GH replacement therapy than GH-deficient TABLE 2. Parameters of GH dosing Weeks of titration required to attain final GH dose Mean SEM 28 3 Range No. of dosing changes made Mean SEM Range 0 6 Symptom or IGF-I level that prompted change to final dose Elevated IGF-I 3 patients Low IGF-I 13 patients Muscle aching 14 patients Joint aching 5 patients Carpel tunnel 2 patients FIG. 1. Final IGF-I level (nanograms per ml) in each GH treatment group. Error bars represent the SEM. FIG. 2. Final total GH dose (micrograms per day) in each treatment group. Error bars represent the SEM. *, Statistical difference from the other two groups (by ANOVA). FIG. 3. Final GH dose by weight (micrograms per kg/day) in each treatment group. Error bars represent the SEM. *, Statistical difference from the other groups (by ANOVA). women taking oral estrogen. If estrogen was replaced transdermally in women, however, GH requirements were much less and similar to those in men. The end points of therapy included serum IGF-I and symptom tolerance. The effect of oral estrogen on liver synthesis or secretion of IGF-I was thought to be influenced by higher concentrations of estrogen as it passed through the liver after oral administration. It appeared to require a much lower GH dose for a comparable serum IGF-I concentration in men and in women using transdermal estrogen compared to that in women taking oral estrogen.

4 GH THERAPY AND ESTROGEN 3959 FIG. 4. Time course of GH dose (micrograms per kg/day) and IGF-I (nanograms per ml) in patient 18 (see Table 1), who was switched from oral to transdermal estrogen during her course of treatment. 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 g/kg day, and older adults require 2 4 g/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 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 g/kg day and advance the dose by 1 g/kg day every 4 6 weeks based upon symptoms and IGF-I levels. For women taking oral estrogen we begin at 4 g/kg day and advance by 2 g/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 g/day and advance by 50 g/day every 4 6 weeks. We do not exceed 300 g/day in any patient as an initial dose. Using doses above 300 g/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 g/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.

5 3960 COOK, LUDLAM, AND COOK JCE&M 1999 Vol 84 No 11 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. Acknowledgments We thank Mr. Robert Schuff, Information Systems Manager at the Clinical Research Center of Oregon Health Sciences University, for his assistance in the statistical analysis. We thank Judith Clay and Anne Cota for their help in preparing this manuscript. References 1. Van den Berg G, Veldhuis JD, Frolich M, Roelfsema F An amplitudespecific divergence in the pulsatile mode of growth hormone (GH) secretion underlies the gender difference in mean GH concentrations in men and premenopausal women. J Clin Endocrinol Metab. 81: Ho KY, Evans WS, Blizzard RM, et al Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab. 64: Chapman IM, Hartman ML Straume M, Johnson ML, Veldhuis JD, Thorner MO Enhanced sensitivity growth hormone (GH) chemiluminescence assay reveals lower postglucose nadir GH concentrations in men than women. 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