| Effect of Combined Administrationof Recombinant Human Growth Hormone and Testosteroneon Erythropoiesis | ||
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CLINICAL VIGNETTE Effect of Combined Administrationof Recombinant Human Growth Hormone and Testosteroneon ErythropoiesisMaggie Ham, Pejman Cohan, M.D., Xiaohong Yan and Stanley G. Korenman, M.D. Case ReportIncreased rates of erythropoiesis leading to an elevated hematocrit and hemoglobin are associated with cerebrovascular accidents, atherosclerosis, increased blood pressure and sympathetic overac-tivity.1 Testosterone (T) increases erythropoiesis, and its defi-ciency results in a lowered hematocrit, often to the point of anemia in men who have had pituitary surgery.2 Testosterone replacement therapy increases hematocrit and hemoglobin in hypogonadal men within the first 3 months.3 Testosterone increases erythropoiesis by stimulating the renal production of erythropoietin (EPO), which induces proliferation and differentiation of erythroid precursor cells.4 Although EPO production is the primary means by which T increases erythropoiesis, T also binds to androgen receptors on erythroblasts.4,5 In hypogonadal men, testosterone replacement is accompanied by improve-ments in muscle mass, bone density, mood and anemia.3,6 Growth hormone (GH) also increases hematocrit, and impairment of erythropoiesis has been reported in adult growth hormone deficiency (AGHD). In AGHD patients without anemia, GH replacement reactivates erythropoiesis via insulin-like growth factor-1 (IGF-1).7 In anemic patients with GH deficiency, treatment with recombinant human growth hormone (rhGH) increased EPO within the first 2 weeks, followed by an increase in serum IGF-1 levels and a decrease in EPO.8 Thus, the effect of rhGH on erythropoiesis is mediated primarily by IGF-1 on IGF-1 receptors on erythroid precursor cells, or by increasing EPO production.9,10 Recombinant human growth hormone is now approved for use in AGHD, Turner syndrome, Prader-Willi syndrome and GH deficiency due to pituitary tumor.11 As a result of increasing numbers of patients taking a combination of rhGH and T, and the risks associated with increased hematocrit, we wished to determine whether the 2 hormones had an additive effect on erythropoiesis. Subjects and MethodsAfter approval from the Institutional Review Board, we conducted a retrospective chart review of the hypopituitary patients followed by 2 endocrinologists and a random selection of hypogonadal men encom-passing 52 men, with ages ranging from 21 to 78 years. Group 1 consisted of 14 hypopituitary patients with a median age of 48 years (range 21-78 years) who were treated with rhGH and T simultaneously. Group 2 included 17 hypopituitary patients who were treated with T alone (median age 45 years, range 18-74 years). Group 3 was composed of 20 hypogonadal men of non-pituitary origin, with a median age of 53 years (range 17-81 years) treated with T. Etiology of T and GH Deficiency The etiologies of hypopituitarism and hypogonadism are listed in Table 1.  1  Treatments Three different types of testosterone were adminis-tered, depending on the patient's tolerance and/or preference: the testosterone patch delivered 5 mg/day transdermally; the topical gel delivered 5 g/day trans-dermally; and the injection delivered an average of 92 mg/week via intramuscular injections. Recombinant human growth hormone was given subcutaneously at an average dose of 0.358 mg/day, with a goal of achieving a mid-normal gender- and age-appropriate IGF-1 level. Analysis Hematocrit and hemoglobin were used as markers of erythropoiesis. These parameters were assessed at baseline and various time points after initiating hormone replacement. A mixed model statistical analysis was utilized to evaluate the data. ResultsThere were no significant differences in average hematocrit (45.82 vs.43.86, p= 0.2684) or hemoglobin (15.50 vs. 14.65, p=0.3430) between Group 1 and Group 2, respectively (Figure 1, top). A similar analysis between Groups 1 and 3 showed hematocrit and hemoglobin averages of 45.43 and 15.37 for Group 1, and 44.83 and 15.15 for Group 3, with no significant differences between the two groups (p=0.2121 and 0.2574) (Figure 1, bottom). The rate of change of hematocrit and hemoglobin is shown in Figure 2. Group 1 demonstrated slopes of 0.056 and 0.01992, indicating significant increases in hematocrit and hemoglobin over time (p=0.0004 and 0.0006). Group 2 had slopes of -0.00673 and -0.00425 for hematocrit and hemoglobin, showing no change (p=0.4026 and 0.3114, respectively). Group 3 exhibited increases with a slope of 0.02285 for hema-tocrit, and 0.0066 for hemoglobin (p=0.0007 and 0.069). A comparison of the rates of increase between Group 1 and 2 showed that Group 1 hematocrit and hemo-globin increased considerably faster than Group 2 (hematocrit: p=0.0002, hemoglobin: p=0.0001). A similar comparison between Group 1 and 3 showed that Group 1 hematocrit and hemoglobin also increased significantly faster (hematocrit: p=0.0021, hemoglobin: p=0.0037). Of the 14 patients in Group 1, 8 (57%) had hormone dosages adjusted based on serum IGF-1 and hemat-ocrit levels. Of these patients, 4 (28.6%) required lower doses of T due to an elevated hematocrit. Group 2 had 1 patient (5.9%) and Group 3 had 5 patients (25%) who had T doses lowered as well. Body mass index (BMI) and T treatment type (patch, gel or injection) were not related to hematocrit or hemoglobin. DiscussionOur data indicate that hypopituitary men simultane-ously receiving rhGH and T had a significantly faster rate of hemoglobin increase compared to hypopitu-itary patients or hypogonadal patients treated with only T. This suggests that combination therapy with rhGH and T in hypopituitary men has an additive effect on the rate of erythropoiesis. This effect is likely mediated by the effect of T on erythropoietin and androgen receptors on erythroblasts combined with the effect of IGF-1 on EPO and IGF-1 receptors on erythroblasts.4,5,8-10 In these hypopituitary  patients, T was also unable to stimulate GH produc-tion directly because they were all shown to be profoundly GH deficient. Testosterone itself increases serum GH levels, exerting its effects via an unknown mechanism, distinct from GH releasing hormone secretion.16,17 Hematocrits and hemoglobins did not differ signifi-cantly between the 3 groups. We suspect that this was due to the constant adjustment of hormone dosages. Whereas the doses of rhGH were slowly titrated up until the normalization of serum levels of IGH-1 levels, the dose of T was partly adjusted based on hematocrit levels. Consequently, all patients' IGF-1 and hematocrit levels were carefully monitored for any fluctuations. This may also explain why there was no correlation between the method of T adminis-tration and hematocrit level. If testosterone injections caused a substantial increase in hematocrit, it was immediately reduced or changed to a less potent method of delivery, such as a patch or gel. Our findings are similar to those of Jepson and McGarry.12 In their study, pituitary dwarfs with testosterone deficiency were treated with 2.5 mg of rhGH 3 times a week and 200 mg of intramuscular testosterone enanthate biweekly. In some subjects, the dose of rhGH was increased to 5 mg daily in order to maximize growth. On this regimen, mean hemo-globin and reticulocyte counts increased, with a three-fold increase in erythropoietin-stimulating factor excretion. The initial treatment with rhGH alone resulted in the rise in erythropoietin-stimulating factor excretion, which was maintained with T, even when rhGH was stopped. As a result, they found that GH and T had an additive effect on erythropoiesis. Blackman et al13 conducted a study to determine if small supplemental doses of GH and T given to other-wise healthy elderly people would improve body composition, strength and endurance. In this study, participants were given a starting rhGH dose of 30μg/kg, which was reduced to 20μg/kg subcuta-neously, 3 times/week. The dose of testosterone was 100 mg biweekly. They found that there were no significant increases in hematocrit in any treatment groups. The lack of increase in erythropoiesis is likely due to the lower dose T. Compared to our study, these subjects on average were given 54.3% lower doses of T and 119% higher doses of GH. Hematocrits greater than 45.2% are associated with significantly higher cholesterol, triglycerides, insulin and glucose levels.1 It has also been shown that men with a hematocrit of greater than 58% had a fourfold increased risk of type 2 diabetes mellitus.14 Another study associated hematocrit with atherosclerosis.15 Extrapolating from these studies, based on the average hematocrits, all 3 groups we investigated were at risk for these complications. The major shortcoming of our study is the retrospec-tive study design and small sample size. A prospec-tive study in which T-and GH-deficient adults are given standardized replacement doses of T and GH is needed. Until such is study is completed, we recom-mend that patients treated with rhGH and T be moni-tored closely when beginning combined therapy, as hematocrit and hemoglobin levels can rise to poten-tially dangerous levels, especially in patients with normal or upper limit hematocrit levels. REFERENCES
Submitted on October 2, 2006 |
© copyright 2009 Stephen Ng & UCLA Department of Medicine