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Original Article |
Departments of Molecular and Clinical Endocrinology and Oncology (A.C., M.D.R., R.P., A.D.S., G.L.) and Neurosurgery (P.C.), "Federico II" University of Naples, 80131 Naples; and Department of Endocrinology (A.B., V.R., C.C.), University of Modena, 41100 Modena, Italy
Address all correspondence and requests for reprints to: Annamaria Colao, Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, via S. Pansini 5, 80131 Napoli, Italy. E-mail: . colao{at}unina.it
Abstract
Experimental data support a role for GH and IGF-I in the reproductive process in humans, but the effect of chronic GH excess on gonadal and reproductive function in men has been never investigated. To understand the effects of short-term GH and IGF-I suppression on the gonadal axis and seminal fluid characteristics in men with acromegaly, we evaluated 35 patients (age 27–59 yr) with active disease and 35 age-matched healthy controls. Gonadal hormones and seminal fluid analysis were evaluated before and 6 months after surgery or lanreotide (LAN) (60 mg/month).
At study entry, FSH, testosterone (T), and dihydrotestosterone (DHT) (P < 0.0001) levels, seminal volume, sperm count, total motility and forward progression, normal morphology, and vitality were significantly lower in patients with acromegaly than in controls. After 6 months, 22 patients achieved disease control after surgery (n = 11) or LAN (n = 11), whereas 13 had uncontrolled disease. Serum T and DHT levels and sperm number significantly increased in all groups. FSH and LH levels and total motility increased only in patients achieving disease control. Posttreatment IGF-I levels significantly correlated with total motility (r = -0.45; P = 0.006).
In conclusion, short-term GH and IGF-I suppression after surgery or LAN significantly increased T and DHT levels and improved sperm number and motility in acromegalic men.
THE IMPAIRMENT OF gonadal function is a common clinical finding of acromegaly in both sexes (1, 2). Although it has been attributed to FSH/LH deficiency and/or hyperprolactinemia (2), it has not been evaluated in detail and its pathogenesis remains unclear. In women, pregnancy has been reported to be rare (1, 3). Clinical and laboratory observations indeed suggest a role for GH in regulating testicular function. In vitro studies indicate that GH administration increases Leydig and Sertoli cell response to FSH and LH (4, 5). However, GH might also act by stimulating the local production of IGF-I as shown by in vivo experimental studies demonstrating the relevant role of IGF-I in regulating steroidogenesis and spermatogenesis (6, 7). In addition, although LH is the prime regulator both of IGF-I peptide and receptor synthesis in Leydig cells, GH seems to play an indirect, and probably minor, role in regulating testicular IGF-I production by raising gonadotropins action. GH administration to oligospermic men was shown to enhance the efficacy of exogenous gonadotropins in inducing sperm production (8). Similarly, in a small series of adult patients with isolated GH deficiency, we recently found increased seminal plasma volume after GH replacement (9).
The effects of chronic GH and IGF-I excess on gonadal function have been poorly investigated, and data on semen analysis in acromegalic men are lacking. We have recently reported that hypogonadism is rather frequent in acromegalic men (10), even in young patients (11), and is associated with a high prevalence of prostate disorders (10, 11).
The aim of this open prospective controlled study was to investigate the effect of short-term GH and IGF-I suppression on gonadal function and seminal fluid characteristics in a series of adult de novo acromegalic men.
Patients and Methods
Patients
Thirty-five newly diagnosed acromegalic men, aged 29–59 yr, and 35 healthy men age-matched with the patients, who agreed to serve as control, all free of previous or present prostate diseases and not under replacement treatment with androgen, 
-adrenergic antagonists, or antiandrogen drugs, were enrolled in this study. None of them had previously experienced any episodes, suggesting prostate, gonadal and/or urethral disorders, such as prostatitis, orchitis, inflammation of seminal vesicles, or spontaneous or precipitated acute urinary retention. The diagnosis of acromegaly was based on elevated GH levels not suppressible less than 1 µg/liter by oral glucose test (71.0 ± 5.9 µg/liter), high IGF-I levels for age (1073 ± 89.6 µg/liter), signs and symptoms of disease, radiological evidence of pituitary adenoma (12). Five patients had a microadenoma, whereas 30 had a macroadenoma. After baseline evaluation, 13 patients underwent surgery by trans-sphenoidal approach, whereas 22 were treated with lanreotide (LAN), a slow release somatostatin analog (Ipstyl, Ipsen, Italy). Among the 22 patients treated with LAN, 7 had been previously operated on unsuccessfully, whereas the remaining 15 were newly diagnosed and received LAN as presurgical treatment (13). As currently accepted (12, 14), disease control after surgery or LAN was considered when GH levels were 2.5 µg/liter or less as fasting values or 1 µg/liter or less after glucose load (75 g orally) together with age-normalized IGF-I levels. Because hyperprolactinemia profoundly affects gonadal hormones and seminal parameters per se (15, 16, 17, 18), patients with concomitant hyperprolactinemia (prolactin >15 µg/liter), either before or after treatment, were excluded.
Study protocol
FSH, LH, testosterone (T), dihydrotestosterone (DHT), and 17ß- estradiol (E2) assay and seminal fluid evaluation were performed in all patients and controls. At diagnosis, serum GH was calculated as the mean of a 6-h blood sampling (0800–1400 h with 30-min sampling), whereas all the other hormone evaluations were performed in a single sample, at 0800 h, as previously reported (3). In patients reevaluated after surgery, cure was established on the basis of a 6-h GH profile (0800–1400 with 30-min sampling) and 2-h profile after 75 g oral glucose tolerance test (with blood samples taken every 30 min), whereas in those reevaluated during LAN treatment the final GH level was calculated as the average value from at least three blood samples collected, at 15-min intervals, just before the next im injection of the drug (19). In all patients, IGF-I levels were assayed in duplicate in a single sample.
Treatment protocol
LAN treatment was initially administered im at a dose of 30 mg every 14 d for 3 months. Thereafter, the frequency of LAN injection was increased to 10-d intervals on the basis of GH levels 5 µg/liter or greater (19, 20). At the end of the study, the frequency of LAN injections was 14 d in 10 patients and 10 d in 12 patients.
Assays
Circulating IGF-I, FSH, LH, testosterone, DHT, and E2 levels were assessed at least twice. In our laboratory, T and DHT levels in adult subjects were normal when between 3.5–9 µg/liter and 40–160 pmol/liter, respectively. The limits of the sensitivity of the assays were 0.5 mU/liter for FSH and LH, 10 ng/liter for E2, 0.5 µg/liter for T, 10 pmol/liter for DHT. The intraassay and interassay coefficients of variation were less than 5% and 10%, respectively, for FSH, LH, E2, T, and DHT. Serum GH levels were measured by IRMA using commercially available kits (HGH-CTK-IRMA Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/liter. The intra- and interassay coefficients of variation (CV) were 4.5 and 7.9%, respectively. Plasma IGF-I was measured by IRMA after ethanol extraction using DSL kits (Diagnostic Systems Laboratories, Inc., Webster, TX). The sensitivity of the assay was 0.8 µg/liter. The intraassay CV were 3.4, 3.0, and 1.5% for the low, medium and high points on the standard curve, respectively. The interassay CV was 8.2, 1.5, and 3.7% for the low, medium, and high points on the standard curve. Fasting GH levels were considered above the normal range when more than 2.5 µg/liter. In our laboratories, the normal IGF-I range was 110–502 µg/liter in 20–30, 100–450 µg/liter in 31–40, 100–300 µg/liter in 41–50, 90–270 µg/liter in 51–60, and 78–258 µg/liter in 60-yr-old or older subjects.
Seminal fluid analysis
Seminal fluid evaluation was performed after at least 3 d of abstinence, in line with the guidelines described in the World Health Organization Laboratory Manual (21). The evaluation of number and motility of the sperms was carried out in a Makler Counting Chamber (x40); the morphology was analyzed after dilution (1:1) with saline phosphate buffer and Giemsa. The normal ranges of sperm patterns following the WHO manuals are: volume more than 2 ml, pH 7.2–8.0; sperm concentration, more than 20 x 106 spermatozoa/ml; total sperm count, more than 40 x106 spermatozoa/ejaculate; total motility 50% or more or 25% or more forward progression within 60 min of ejaculation; morphology, 30% or more with normal forms; vitality, 75% or more live.
Statistical analysis
Data are shown as mean ± SE. Comparison between patients and controls was performed by the Mann-Whitney test. All the individual values of hormone levels and seminal sperm count before and after treatment in each group (patients cured by surgery, patients controlled by LAN, and patients not controlled) were compared by the Wilcoxon matched pairs test. Correlation between GH and IGF-I levels, both before and after treatment, and T, DHT, seminal volume, count and motility (rapid progression, slow progression, nonprogressive and absence of motility), before and after 6 months of treatment was evaluated by calculating the Pearson’s coefficient. Significance was set at 5%.
Results
Basal evaluation
FSH, T, and DHT were significantly lower, whereas E2 levels were significantly higher in patients than in controls (Table 1
). Serum T and DHT were below the normal range in 25 (42.8%) and 23 (65.7%) patients, respectively. Compared with controls, seminal volume, sperm number, total motility, forward progression, normal morphology and vitality were all reduced, whereas pH was increased in acromegalic patients (Table 1). Seminal volume, sperm count/ml, total sperm count, total motility, forward progression, normal morphology and vitality were below the normal range in 10 (28.6%), 9 (25.7%), 8 (22.8%), 35 (100%), 27 (77.1%), 8 (22.8%), and 25 (71.4%) patients, respectively. Basal GH and IGF-I levels were inversely correlated with DHT levels (Fig. 1) and directly correlated with E2 levels (r = 0.43; P = 0.009 and r = 0.41; P = 0.013), but with none of seminal fluid parameters, except for an inverse correlation between basal GH levels and seminal volume (r = -0.34; P = 0.04).
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Serum GH and IGF-I levels was significantly decreased in all patients 6 months after surgery or LAN treatment. Patients were divided into three groups according with treatment and outcome (Table 2). Eleven patients fulfilled the criteria of cure after surgery, 11 were controlled after LAN treatment, and 13 patients were unsuccessfully controlled. At the same time point, T and DHT levels were significantly increased in all groups, FSH and LH levels were significantly increased in both groups achieving disease control, and E2 levels were significantly reduced only when all controlled patients were considered together (from 20.2 ± 0.9 to 18.4 ± 1.1 ng/liter, P = 0.03). Serum T and DHT levels were normalized in 12 (48%) and 10 (43.5%) patients, respectively. Seminal volume increased only in patients cured after surgery, whereas pH did not significantly change in all groups. Total sperm number was significantly increased in all patients’ groups, whereas total motility was significantly increased in both groups achieving disease control (Table 2). Individual values of total motility before and after treatment in the three groups is shown in Fig. 2. All patients normalized their seminal volume and recovered normal sperm morphology, seven patients (87.5%) normalized their sperm number, eight (28.6%) normalized the rapid progression, five recovered a normal motility (14.3%), and four (16%) recovered a normal sperm vitality. Posttreatment IGF-I levels significantly correlated with total motility (Fig. 3).
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The results of this study demonstrated that most patients with acromegaly have hypogonadism, associated with a reduced sperm number and a remarkably reduced sperm motility. Short-term GH and IGF-I suppression in acromegaly significantly increased T and DHT levels, increased sperm count, and improved sperm motility.
Although, several lines of evidence suggest that GH may play a role in the regulation of reproductive process, data on the reproductive function in acromegalic men are lacking. Impairment of gonadal function is a common clinical finding of acromegaly both in women (1, 2), and in men (Refs. 10 and 11 , and present study). The testicular function is dependent upon pituitary gonadotropins and T, but these hormones exert only indirect actions on germ cells, and their effects are thought to be mediated by locally produced factors with a paracrine role in the testis (22, 23, 24). In fact, GH receptors have been demonstrated in the testis, opening the possibility of GH-regulated testicular effects by locally produced IGF-I (24, 25). In this study, hypogonadism, based on DHT levels, was frequent occurring in as high as 65.7% of adult acromegalic patients with age ranging 29–59 yr. In particular, compared with controls, the patients had a severe impairment of sperm motility. Short-term suppression of GH and IGF-I levels for 6 months, induced a significant increase of T and DHT levels, recovering hypogonadism in most patients. This was accompanied by normalization of seminal volume, improvement of sperm motility and increase of sperm number.
The beneficial effect of GH/IGF-I suppression on androgen secretion could be due to the restoration of a normal GnRH action on LH and FSH secretion, or directly on testicular function. Only in a previous experimental study (26), the effects of very high GH doses were investigated in male dogs as part of the toxicological GH documentation. In these animals, repeated administration of very high doses of GH induced severe testicular alterations with a paradoxical reduction of the weight of testis and prostate associated with germ cells degeneration and epithelial testis atrophy (26). GH administration also caused a notable reduction of LH and T levels. Testicular changes were considered to be more likely due to a GH interference at high dose with the physiological hormone regulation in the testis than to a direct toxic effect of GH (26). At partial variance with these experimental findings in the dog, patients with acromegaly have prostate enlargement with a high prevalence of prostate abnormalities (10, 11). The long-term suppression of GH/IGF-I after octreotide, LAN, or surgery induced a decrease in prostate size together with an increase in androgen levels, mostly in young acromegalic patients (11, 27). Therefore, the results of the current study indicate that alteration of androgen secretion in acromegaly can be early recovered by suppressing GH and IGF-I levels as well as most seminal abnormalities with the exception of total motility and forward progression that likely require a longer term of hormone control to be completely recovered. It should be also emphasized that the alteration of the seminal fluid in acromegalic patients refers to an impaired motility more than reduced sperm count: a potential implication of prostate secretion in determining this finding cannot be presently ruled out. It should also be emphasized that in patients with larger adenomas, a secondary and irreversible hypogonadism might follow: if T levels are not normalized after 6 months of disease control, T and/or gonadotropin replacement, depending on patients’ age and fertility desire, should be considered.
In conclusion, short-term GH and IGF-I suppression after surgery or LAN significantly increased T and DHT levels, so recovering hypogonadism in most patients with an early improvement of sperm number and motility in acromegaly.
Acknowledgments
Footnotes
Abbreviations: CV, Coefficient(s) of variation; DHT, dihydrotestosterone; E2, 17ß-estradiol; LAN, lanreotide; T, testosterone.
Received March 22, 2002.
Accepted May 28, 2002.
References
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