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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 88-94
Copyright © 2003 by The Endocrine Society

Original Article

Effect of Growth Hormone (GH) and/or Testosterone Replacement on the Prostate in GH-Deficient Adult Patients

Annamaria Colao, Carolina Di Somma, Stefano Spiezia, Mariagiovanna Filippella, Rosario Pivonello and Gaetano Lombardi

Department of Clinical and Molecular Endocrinology and Oncology (A.C., C.D.S., M.F., R.P., G.L.), "Federico II" University of Naples; and Echo-Guided Surgery Unit, "Santa Maria del Popolo degli Incurabili" Hospital of Naples (S.S.), 80131 Naples, Italy

Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, University "Federico II" of Naples, Via Sergio Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The prostate is a target organ of the GH and IGF-I axis because prostate hypertrophy is found in acromegaly, reduced prostate size is found in GH deficiency (GHD) patients, and additionally, IGF-I is reported to be a positive predictor factor of prostate cancer.

To investigate whether GH replacement therapy in adult patients with GHD has adverse effects on the prostate, we studied the effect of 12-month GH or GH plus testosterone replacement on prostate pathophysiology in 24 adult patients with GHD (11 euandrogenemic and 13 hypoandrogenemic), compared with 24 age-matched healthy controls.

At study entry, GHD patients had lower prostate volume than controls (19.4 ± 1.7 vs. 24.9 ± 1.7 ml; P = 0.03). After 12 months of treatment, all hypoandrogenemic patients achieved normal testosterone levels, and prostate volume increased in the patients to the same level as controls (25.0 ± 1.9 ml). The percentage increase in prostate volume was greater in hypoandrogenemic patients receiving both GH and testosterone replacement (51 ± 11%) than in those receiving GH replacement alone (15 ± 3%; P < 0.0009). At baseline, prostate volume was similar in GHD patients below or above 60 yr of age (16.8 ± 1.3 vs. 23 ± 3.6 ml; P = 0.08), whereas after treatment it was higher in the latter patients (21.8 ± 1.2 vs. 29.5 ± 3.9 ml; P = 0.04). Prostate-specific antigen (PSA) and free PSA did not change, whereas PSA density was significantly reduced after treatment in hypoandrogenemic patients; there was also no change in calcifications, cysts, or nodules.

In conclusion, GH replacement restores prostate size to normal in both young and elderly patients, with no increase in prostate abnormalities. Because the simultaneous treatment with GH and testosterone induces an increase of prostate size by 50% of baseline on average, care is suggested in elderly patients with prostate hyperplasia to avoid any risk of prostate symptoms. In these cases, GH replacement might be performed sequentially to reduce the hypertrophic effect of combining GH and testosterone.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE EFFECT OF IGF-I and IGF-binding proteins (IGFBPs) on the prostate is receiving increasing attention (1). IGF-I has been shown to be directly correlated to prostate cancer risk, whereas IGFBP-3 was inversely correlated (2, 3). Although normal prostate epithelial cells, which are the cells originating prostate cancer, neither synthesize nor secrete significant amounts of IGF-I, they respond to its mitogenic stimulation (4). IGF-I is implicated in prostate overgrowth; specific binding sites for IGF-I are present in benign prostate hyperplasia (BPH) cells, and androgen deprivation by GnRH analog treatment increases their binding capacities and seems to modify the localization of IGF-I receptors in the prostate epithelium (5). The hypertrophic IGF-I effect on the prostate has also been demonstrated recently in acromegalic patients (6, 7); we found prostate hypertrophy in acromegalic patients compared with age-matched controls, even in younger ones not expected to have age-dependent prostate diseases. Moreover, suppression of circulating GH and IGF-I after treatment with octreotide, lanreotide, or surgery induced a significant reduction of prostate volume, mostly in young patients, suggesting a direct relationship between GH/IGF-I axis and prostate size (6, 8). In GH deficiency (GHD), we showed a decreased prostate volume, greater in hypoandrogenemic than in euandrogenemic patients, compared with controls (9). Structural prostate abnormalities, such as cysts, calcifications, and nodules, were also increased in patients with acromegaly (6, 7, 8) compared with controls, whereas in patients with GHD they were similar to controls (9).

Currently, adult GHD patients receive GH replacement to improve their physical performance, muscle mass, and bone density and to reduce the cardiovascular risk (10, 11, 12, 13). Most GHD patients also receive testosterone replacement for hypogonadism, because in adults GHD is generally associated with other pituitary hormone deficiencies (14). Whether GH replacement displays adverse effects on the prostate has never been investigated.

This open longitudinal study was designed to investigate the effect of GH replacement and GH plus androgen replacement on the prostate in adult patients who acquired GHD in adulthood.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Twenty-four men, aged 22–72 yr (median age, 53.5 yr), with pituitary tumors and 24 healthy men aged 26–74 yr (median age, 48.5 yr) were enrolled in this study; the subjects were free of previous or present prostate diseases and not under replacement treatment with {alpha}-adrenergic antagonists or antiandrogen drugs. None of them had previously experienced any episode suggesting prostate and/or urethral disorders, such as prostatitis, orchitis, inflammation of seminal vesicles, and spontaneous or precipitated acute urinary retention. The study was performed after approval of the local Ethical Committee. All patients and controls gave their informed consent to participate in the study. All subjects were tested with the combined arginine (ARG) plus GHRH test (ARG + GHRH). According to recent studies (15, 16, 17), a GH response to ARG + GHRH below 9 µg/liter was considered diagnostic of GHD. Among the 24 patients, 21 were diagnosed to have a very severe GHD (GH peak, <3 µg/liter), whereas three others had a severe GHD (GH peak, 3.1–9 µg/liter). Table 1Go shows anthropometrical and endocrine data of the GHD patients at study entry. All patients had previously undergone surgery for GH-secreting adenoma (patient 6), prolactin (PRL)-secreting adenoma (patients 12 and 21), nonfunctioning pituitary adenoma (patients 2–4, 7–11, 14–18, and 22–24), or craniopharyngioma (patients 1, 5, 13, 19, and 20), and 8 of them had also been irradiated (patients 1, 5, 7, 8, 13, 14, 19, and 20). Thirteen patients had untreated hypogonadism associated with GHD, whereas the other 11 patients had normal testosterone and dihydrotestosterone (DHT) levels either spontaneously or, in six patients, due to testosterone replacement before the study (patients 2, 4, 6–8, and 11; Table 1Go). Ten patients also received L-T4 (50–100 µg/d orally) replacement, and five received cortisone acetate (25–37.5 mg/d). The six patients with hypogonadism were treated with testosterone enanthate (250 mg/month im) for 0.5–10 yr (Table 1Go). Adequacy of hormone replacement therapy was periodically assessed by serum-free thyroid hormones, testosterone, serum and urinary Na+ and K+ assay, and blood pressure measurement. In patients receiving testosterone replacement, hormone levels were assessed within 1 wk before the next injection. None of the patients had ever received GH treatment. To avoid overestimation, the duration of the disease was calculated from the time of diagnosis, and the retrospective evaluation of symptoms presumably related to the pituitary disease was not considered. In this group, the average disease duration was 8.2 ± 1.3 yr (median, 8 yr).


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  		Table 1. Patients’ profiles at study entry and hormone response to GH or GH plus testosterone replacement

 
Seven patients and six controls were mild smokers; no patient in either group was a heavy alcohol drinker, and all followed a normal diet.

Study design

The study protocol included hormonal tests performed by using commercially available kits and, subsequently, prostate transrectal ultrasonography (TRUS). ARG was administered at the dose of 0.5 g/kg, up to a maximal dose of 30 g slowly infused from time 0 to 30 min, whereas GHRH was given at the dose of 1 µg/kg as iv bolus at 0 min (16, 17). Blood samples were taken every 15 min from -15 min to 90 min. Circulating IGF-I, PRL, testosterone, DHT, prostate-specific antigen (PSA), free PSA (f-PSA), and prostate acid phosphatase levels were assessed at least twice. In this study, the average value of the two assays was shown. The cut-off value of 4 µg/liter was considered as the upper limit for PSA concentrations. The calculation of PSA density, expressed as the ratio of PSA levels to prostate volume was considered as a risk factor for prostate cancer when higher than 0.15 (18). All assessments were age-adjusted. Serum GH levels were measured by immunoradiometric analysis using commercially available kits (HGH-CTK-IRMA, Sorin Biomedica, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/liter. The intra- and inter-assay coefficients of variation (CV) were 4.5 and 7.9%, respectively. Plasma IGF-I was measured by immunoradiometric analysis after ethanol extraction. The sensitivity of the assay was 0.8 µg/liter. The normal IGF-I range in our laboratory was 100–502, 100–303, and 78–258 µg/liter for patients aged 20–40, 41–60, and over 60 yr, respectively. The intra-assay CV were 3.4, 3.0, and 1.5% for low, medium, and high points on the standard curve, respectively. The inter-assay CV were 8.2, 1.5, and 3.7% for low, medium, and high points on the standard curve. Plasma IGFBP-3 was measured by RIA after ethanol extraction. The sensitivity of the assay was 0.5 µg/liter. The intra-assay CV were 3.9, 3.2, and 1.8% for low, medium, and high points on the standard curve, respectively. The inter-assay CV were 0.6, 0.5, and 1.9% for low, medium, and high points on the standard curve. The normal IGFBP-3 range in our laboratory for 20–40, 41–60, and over 60-yr-old subjects was 2.7–7.2, 2.0–4.3, and 2–4 mg/liter, respectively. The kits for IGF-I and IGFBP-3 assay were purchased from Diagnostic Systems Laboratories, Inc. (Webster, TX). Because testosterone levels (19) and not DHT levels (20) decline by approximately 0.8% per year of age (21) but the normal testosterone range in our laboratory does not present age-related variations, we analyzed testosterone levels in our GHD population with similar age-decade limits as for IGF-I and IGFBP-3 in our controls, giving the mean ± 2 SD of normality (Table 1Go): 20–40 yr, 5.6–8 µg/liter; 41–60 yr, 4.7–7.7 µg/liter; and over 60 yr, 3.2–6.4 µg/liter.

Treatment protocol

According to previous studies (22, 23), all patients received recombinant GH at the starting dose of 4–5 µg/kg·d. Subsequently, the dose was adjusted on the basis of serum IGF-I concentrations normal for age. At the end of the study, the median GH dose was 5 µg/kg·d, and the maximal dose was 5.5 µg/kg·d; 15 patients received GH thrice a week, whereas the remaining 9 patients were treated every day.

TRUS study

Before TRUS, all 48 subjects received a preliminary enema with 200 ml of sorbitol and a digital rectal exploration. TRUS was performed by means of an Esaote AU5 harmonic EPI and a 5.6–7.5 MHz biconvex (Esaote, Genoa, Italy) transrectal transducer with Power Echo Color Doppler module to display prostate angiographic micromaps (24). The transducer, covered with ultrasound transmission gel (Aquasonic, Parker Laboratories, Orange, NJ) and a disposable rubber sheath, was lubricated and gradually inserted about 3 cm into the rectum, then directed toward the anterior rectal wall. The prostate examination covered the anteroposterior diameter (APD), transversal diameter (TD), and cranio-caudal diameter (CCD); the transitional zone; the morphology of boundaries; the occurrence of calcifications and nodules; and the evaluation of seminal vesicles and inflammatory events not previously reported by the patients. The volume of the prostate and of the transitional zone was calculated by means of the standard ellipsoid formula (0.52 x APD x TD x CCD). Echo-guided prostate biopsies with power Doppler enhancement were performed if clinical or hormonal conditions required it. All scans were performed by the same investigator (S.S.), blind in respect to examination of subjects and replacement treatment. Prostate hyperplasia was considered for prostate volume greater than 30 ml, in line with the accepted criteria for BPH (25).

Statistical analysis

Data are reported as mean + SEM. Intergroup analysis was performed by means of a GraphPad (GraphPad Software, Inc., San Diego, CA) package using ANOVA. The significance was set at 5%. Post hoc analysis was performed by means of paired and unpaired t test applying Bonferroni’s correction. The effect of GH or GH plus testosterone replacement was assessed by the Student’s t test for paired data. The {chi}2 test was also applied where appropriate.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Individual data of GHD patients are shown in Table 1Go, whereas the comparison between GHD patients and controls is shown in Table 2Go. As expected, GH peak after ARG + GHRH (P < 0.0001), IGF-I (P < 0.0001), and IGFBP-3 (P < 0.0001) levels in the patients were significantly lower than in controls (Table 2Go). Testosterone levels were below the normal range in 13 patients, whereas they were normal in the remaining 11 (Table 1Go); DHT levels were below the normal range in 10 of the 13 patients with low testosterone levels and normal in the remaining patients (data not shown). When patients were divided according to gonadal status, no difference was found in disease duration between euandrogenemic (7 ± 2 yr) and hypoandrogenemic GHD patients (9 ± 2 yr; P = 0.2). At study entry, plasma IGF-I levels were below the age-adjusted normal range in 12 patients, i.e. 5 euandrogenemic and 7 hypoandrogenemic (Table 1Go). PSA levels were normal in all but two (patients 9 and 21).


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  		Table 2. Endocrine and ultrasonographic findings (expressed as mean ± SEM) in 24 adult GHD patients and 24 controls

 
At study entry, GHD patients had lower prostate volume but higher volume of the transitional zone than controls (Table 2Go). Prostate hyperplasia was found in nine controls (37.5%) and three patients (12.5%; P = 0.09), of whom one was euandrogenemic and two were hypoandrogenemic. Age and IGF-I levels were significantly correlated with prostate volume in controls but not in GHD patients (Fig. 1Go). Prostate volume was similar in GHD patients below or above 60 yr (16.8 ± 1.3 vs. 23 ± 3.6 ml; P = 0.08). Calcifications were detected in 12 GHD patients (50%; 5 hypo- and 7 euandrogenemic), and 7 controls (29.2%; P = 0.2); cysts were found in 6 patients (25%; 3 hypo- and 3 euandrogenemic) and 4 controls (16.7%; P = 0.7). Prostate nodules were detected in two patients (one hypo- and one euandrogenemic) and two controls; at echo-guided needle aspiration, cytological examination found nodular fibroadenomatous hyperplasia. Sextant biopsies of the prostate were performed in two other patients due to elevation of PSA levels and/or PSA density, and in none of them was prostate cancer found.



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  		Figure 1. Correlation analysis between prostate volume and age (A) and IGF-I (B) in GHD patients and controls.

 
After 12 months of treatment, IGF-I levels were normalized in all patients, and after testosterone replacement, androgen levels were normalized in all patients (Table 1Go). All hypoandrogenemic patients achieved normal testosterone and DHT levels, although they were still slightly lower than in euandrogenemic patients (Table 3Go). Prostate volume increased in both groups (Table 3Go) and was similar to controls (Table 2Go). Individual data of prostate volume are shown in Fig. 2Go. The percentage increase in prostate volume was greater in hypoandrogenemic patients receiving both GH and testosterone replacement (51 ± 11%) than in those receiving GH replacement alone (15 ± 3%; P < 0.0009). Similar to the five euandrogenemic patients, the six patients who were euandrogenemic because of testosterone replacement that was initiated before entering the study also had a less remarkable increase of prostate volume (12 ± 4%; P < 0.001) compared with those receiving GH and testosterone replacement simultaneously. A significant increase was observed in patients aged both below and above 60 yr, but in neither group was prostate volume higher than in controls (Fig. 3Go). Prostate volume was higher in GHD patients who were 60 or older than in those younger than 60 yr (29.5 ± 3.9 vs. 21.8 ± 1.2 ml; P = 0.04). Conversely, the transitional zone volume was increased only in patients receiving GH plus testosterone replacement (Table 3Go). PSA and f-PSA did not change, whereas PSA density was significantly reduced after treatment in hypoandrogenemic patients (Table 3Go).


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  		Table 3. Endocrine and ultrasonographic findings (expressed as mean ± SEM) in adult GHD patients before and after replacement according with gonadal status

 


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  		Figure 2. Individual data of prostate volume in euandrogenemic (A) and hypoandrogenemic (B) GHD patients at study entry and after GH replacement alone (A) or GH plus testosterone replacement (B). The interrupted line indicates the limit of prostate hyperplasia. Patients are numbered according to Table 1Go.

 


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  		Figure 3. Prostate volume in controls, hypoandrogenemic, and euandrogenemic GHD patients subdivided in line with age.

 
After 12 months of GH or GH plus testosterone replacement, calcifications were still detected in 12 GHD patients; cysts were found in 7 patients (29.2%), because one hypoandrogenemic patient developed a cyst; prostate nodules were still detected in 2 patients without any change compared with baseline; and repeated echo-guided needle aspiration cytological examination was negative.

At the end of treatment, IGF-I levels were still not correlated with posttreatment prostate volume (r = -0.07; P = 0.7), percentage prostate volume increase (r = -0.37; P = 0.07), transitional zone volume (r = -0.38; P = 0.06), PSA (r = 0.0005; P = 0.98), f-PSA (r = -0.08; P = 0.7), or PSA density (r = 0.01; P = 0.9).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of this study demonstrate that GH replacement increased the volume of the prostate and the transitional zone in adult patients with GHD. In patients with hypogonadism who received GH plus testosterone replacement, the increase of prostate volume was remarkably greater than that found in patients receiving only GH replacement; the increase was even greater than that found in those also receiving testosterone previous to GH. However, hypoandrogenemic GHD patients had lower prostate volume than euandrogenemic patients at study entry. Alterations in prostate structure were not increased by GH and/or testosterone replacement in this series. None of our patients developed prostate cancer.

Prostate cell growth has been shown to be stimulated by IGF-I and inhibited by IGFBP-3 (1, 26, 27, 28). In disease states characterized by alterations of the GH/IGF-I axis, we previously demonstrated a direct role on prostate growth; in acromegaly, prostate size was increased, whereas in adult patients with GHD it was decreased (6, 7, 8, 9). The abnormal prostate growth in acromegaly occurred although most patients had hypogonadism (29). In GHD, a decrease of prostate size is rather expected because FSH and LH deficiency is the most frequently associated hormone defect (14) and androgen deprivation notoriously causes impairment of prostate growth (30). However, a close relationship is hypothesized between androgen and IGF-I levels at the prostate because androgens were shown to modify the number of IGF-I receptors on prostate epithelium; in fact, an increase in the number of IGF-I receptor type I was demonstrated in cell cultures from patients with BPH after suppression by GnRH analogs (31).

Because evidence is accumulating that IGF-I is involved in prostate cell proliferation (32, 33) and it is current practice that adult patients with GHD undergo chronic GH replacement (10, 11, 12, 13), the possibility that prostate hyperplasia could develop during GH in these patients exists and has never been investigated. In a previous study, we showed that hypoandrogenemic GHD patients had lower prostate size than euandrogenemic GHD patients and controls (9), as also shown in other target organs like the heart (34) and confirmed in the current study. Abnormalities of prostate structure were similarly prevalent in patients and controls (Ref.9 and the current study). Because androgen replacement clearly affects prostate size, we examined the effect of GH replacement separately in patients with only GHD and in those with GH and testosterone deficiency treated with GH and testosterone simultaneously. It should be noted that 6 of the 11 patients who were euandrogenemic at study entry were already receiving testosterone replacement before the study. Prostate size increased in all patients after GH replacement, but when GH was given together with testosterone, the increase in prostate size was more evident. This effect was likely to be due to the simultaneous GH plus testosterone treatment and should subside during treatment continuation because, in the six patients who were already under testosterone replacement before GH replacement, the increase of prostate size was similar to euandrogenemic GHD patients. Long-term prospective data are required to exclude any further increasing effect of GH plus testosterone replacement on prostate size. It is interesting to note that GHD patients had increased transitional zone volume compared with controls; GH and androgen deprivation likely cause a rearrangement in prostate structure and dimensions, as also shown by the number of calcifications, cysts, and nodules in the prostate of GHD patients. However, PSA and f-PSA levels were normal in most cases; neither cytology on fine-needle aspirations nor sextant biopsies revealed prostate cancer in any case, and PSA density was even reduced after treatment. As expected, GHD patients age 60 yr and older had greater prostate volume at the end of GH replacement than those younger than 60 yr; in no case, however, did prostate dimensions overcome those found in age-matched controls.

In conclusion, a decrease in prostate size may be observed in adult patients with GH deficiency, but mostly in those with concomitant testosterone deficiency. GH replacement restores prostate size to normal in both young and elderly patients, with no increase in prostate abnormalities. No patient developed cancer, but the follow-up was too short to draw any conclusion. Because the simultaneous treatment with GH and testosterone induces an increase of prostate size by 50% of baseline on average, care should be taken in elderly patients with prostate hyperplasia to avoid any risk of prostate symptoms. In these cases, replacement should be performed sequentially to reduce the hypertrophic effect of combining GH and testosterone.


   Footnotes
 
Abbreviations: APD, Anteroposterior diameter; ARG, arginine; BPH, benign prostate hyperplasia; CCD, craniocaudal diameter; CV, coefficient(s) of variation; DHT, dihydrotestosterone; f-PSA, free PSA; GHD, GH deficiency; IGFBP, IGF binding protein; PRL, prolactin; PSA, prostate-specific antigen; TD, transversal diameter; TRUS, transrectal ultrasonography.

Received May 28, 2002.

Accepted September 12, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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