Bone mineral density and bone markers in hypogonadotropic and hypergonadotropic hypogonadal men after prolonged testosterone treatment.

After prolonged treatment (76.4+/-10 and 70.1+/-12.3 months, respectively) (mean+/-SE) with testosterone enanthate (250 mg i.m. every 3 weeks), bone mineral density (BMD) and bone metabolism were evaluated in 12 patients (aged 29.3+/-1.4 yr) affected by idiopathic hypogonadotropic hypogonadism (IHH), in 8 patients (29.6+/-2.6 yr) affected by Klinefelter's syndrome (KS), and in 10 healthy men (30.6+/-1.7 yr) matched according to age and BMI. Spinal BMD in IHH was significantly lower than in controls (0.804+/-0.04 vs 1.080+/-0.01 g/cm2; p<0.001), while there was no difference in neck BMD (0.850+/-0.01 vs 0.948+/-0.02 g/cm2). Neither spinal (0.978+/-0.05 g/cm2) nor neck (0.892+/-0.03 g/cm2) BMD in KS were significantly different from controls. Six IHH and one KS subjects were osteoporotic, while 6 IHH and 2 KS subjects were osteopenic. A significant inverse correlation was found between spinal BMD and age at the treatment onset in IHH (r=-0.726, p=0.007). In IHH there were significant increases in bone formation (alkaline phosphatase=318.3+/-33.9 vs 205.4+/-20.0 IU/l; osteocalcin=13.44+/-1.44 vs 8.57+/-0.94 ng/ml; p<0.05) and in bone resorption (urinary cross-linked N-telopeptides of type I collagen=149.1+/-32.3 vs 47.07+/-8.4 nmol bone collagen equivalents/mmol creatinine; p<0.05) compared to controls, while such differences were not present in KS. Our results outline the importance of BMD evaluation in all hypogonadal males. Nevertheless, bone loss is a minor characteristic of KS, while it is a distinctive feature of IHH. Therefore, early diagnosis and age-related replacement therapy coupled with a specific treatment for osteoporosis could be useful in preventing future severe bone loss and associated skeletal morbidity.

Estrogens and health in males.

Estrogen receptor concentrations are higher in the male reproductive tract than in other organs. Brain structure, neuronal organization and behavioral sex differences result from brain conversion of testosterone into estradiol within the brain. Estrogens modulate hormonal secretion at pituitary level and immune function at thymus level. Estrogens promote vasodilatatory and protective effects on the cardiovascular system by acting on the vascular smooth muscle and endothelium. Adult men with mutations in genes for estrogen receptor or aromatase are affected by osteopenia and tall stature, open epiphysis, which is corrected by estrogen treatment. Over the past few years there has seen a decline in sperm concentration, which has been attributed to exposure of fetal testes to estrogens. Many substances have estrogen-like properties and inhibit the action of estradiol or testosterone action. In conclusion, estrogens play a pivotal role in men also. In particular, taking in account their prevalent origin from testosterone aromatization at tissue and peripheral levels the presence and the distribution of the two receptors (ERalpha and ERbeta) are responsible for different responses in physiological and pathological conditions.

Hormonal and seminal evaluation of Leydig cell tumour patients before and after orchiectomy.

Seven patients (aged 25-38 years) were admitted because of mono- or bilateral gynaecomastia. Plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, testosterone, 17-beta-estradiol, delta4-androstenedione, dehydropiandrosterone sulphate (DHEA-S) and 17-OH-progesterone were determined and semen analysis was carried out. FSH and LH levels were also measured after acute LH-RH administration (100 microg intravenously), and testosterone and 17-beta-estradiol were also evaluated after acute human chorionic gonadotrophin (hCG) administration (5000 IU intramuscularly). Testicular echography demonstrated the presence of a solid hypoechoic tumour. Therefore all patients were submitted to hemicastration by orchidofuniculotomy and a benign Leydig cell tumour was diagnosed in the removed testes. Hormonal and semen evaluations were repeated 3, 6, 9 and 12 months after surgery. The data before and after surgery were compared with a control group of 10 age-matched males. Before surgery, patients showed low FSH basal plasma levels; high levels of 17-beta-estradiol and low testosterone levels similar to those after hCG administration. A dyspermia was observed. Unilateral orchidectomy eliminated the autonomous secretion of oestrogen(s) so an increase of LH, FSH and testosterone levels, together with an improvement of spermatogenesis, were obtained.

FSH treatment improves sperm function in patients after varicocelectomy.

One-hundred and eighty-three patients affected with idiopathic left varicocele, aged between 18 and 45 years, surgically treated have been studied. They were divided in 3 subsets according to sperm count: group A: <10 x 10(6)/ml, group B: 10-20 x 10(6)/ml, group C: >20 x 10(6)/ml. Six months after surgery 115 patients were treated for 3 months with pure human FSH: 75 IU i.m. every other day, while 68 patients treated with placebo served as control group. After therapy, group A showed a significant clear-cut improvement of sperm parameters: count, forward progression, swollen tails and cervical mucus penetration test (CMPT). In group B a significant improvement of sperm motility, viability, DNA integrity and CMPT was observed, while in group C only a significant improvement of CMPT was observed. In conclusion, it can be suggested that FSH treatment in patients after varicocelectomy could improve spermatogenesis, particularly in those who previously have more compromised sperm quality. On the contrary, no significant difference of sperm patterns was recorded in the control group before and after placebo.

The effect of chronic treatment with GH on gonadal function in men with isolated GH deficiency.

Eleven adult males, previously submitted to neurosurgery because of a pituitary lesion (three with craniopharyngioma, three with clinically non-functioning adenoma and five with macroprolactinoma) were treated with recombinant GH for 12 months after the diagnosis of GH deficiency was made. Circulating FSH, LH, prolactin, testosterone, 17 beta-estradiol (E2), dehyroepiandrosterone (DHEA-S), androstenedione. 17-OH-progesterone (17OHP), IFG-I, and steroid hormone-binding protein (SHBG) levels were assayed before and after CG test at study entry and 6 and 12 months after GH treatment. A significant increase in plasma IGF-I levels was obtained after 6 and 12 months of GH treatment. In addition, CG-stimulated, but not baseline, testosterone levels showed a significant increase after 6 and 12 months of GH treatment when compared with study entry (9.6 +/- 0.5 and 9.9 +/- 0.5 vs 7.9 +/- 0.5 ng/ml; P < 0.05). Baseline, but not CG-stimulated, serum 17OHP levels were significantly increased only after 12 months of GH treatment (1.7 +/- 0.1 vs 1.4 +/- 0.1 ng/ml; P < 0.05). No significant difference was found as far as both basal and CG-stimulated E2, androstenedione, DHEA-S and SHBG were concerned. With regards to the semen analysis, only seminal plasma volume was significantly increased after 12 months of GH treatment (2.9 +/- 0.3 vs 1.7 +/- 0.3 ml; P < 0.05). No significant change in sperm count, motility and abnormal forms was observed. These data show that GH treatment displays a clear-cut effect upon Leydig cell function and increases the production of seminal plasma volume in fertile adult males with isolated GH deficiency.

Cabergoline treatment rapidly improves gonadal function in hyperprolactinemic males: a comparison with bromocriptine.

This study evaluated the effects of chronic treatment with cabergoline (CAB), a new, potent and long-lasting ergoline-derived dopamine agonist, on seminal fluid parameters and sexual and gonadal function in hyperprolactinemic males in comparison with the effect of bromocriptine (BRC) treatment. Seventeen males with macroprolactinoma were treated with CAB at a dose of 0.5-1.5 mg/week (n = 7), or BRC at a dose of 5-15 mg/day (n = 10) for 6 months. Baseline prolactin (PRL) was 925.7 +/- 522.6 microg/l in the CAB-treated group and 1059.4 +/- 297.6 microg/l in the BRC-treated group. All the patients suffered from libido impairment, ten from reduced sexual potency, and six had infertility. In five patients provocative bilateral galactorrhea was found. Seminal fluid analysis, functional seminal tests and penis rigidity and tumescence, measured by nocturnal penile tumescence (NPT) using Rigiscan equipment, were assessed before and after 1, 3 and 6 months of CAB or BRC treatment. Hormone profiles were assessed before and after 15, 30, 60, 90 and 180 days of both treatments. Before treatment, all patients had a low sperm count with oligoasthenospermia, reduced motility and rapid progression with an abnormal morphology and decreased viability, and a low number of erections. After 1 month, serum PRL levels were significantly reduced in both groups of patients (20.6 +/- 6.6 microg/l during CAB and 256.3 +/- 115.1 microg/l during BRC treatment) and were normalized after 6 months in all patients (CAB: 7.9 +/- 2.2 microg/l; BRC: 16.7 +/- 1.8 microg/l). After 6 months, a significant increase of number, total motility, rapid progression and normal morphology was recorded in patients treated with both CAB and BRC. An increase in the number of erections during the first 3 months of both treatments was noted by NPT. However, the improvements in seminal fluid parameters and sexual function were more evident and rapid in patients treated with CAB. The number of erections was normalized after 6 months of treatment in all patients submitted to CAB treatment, and in all patients but one treated by BRC. In addition, a significant increase of serum testosterone (from 3.7 +/- 0.3 to 5.3 +/- 0.2 microg/l) and dihydrotestosterone (from 0.4 +/- 0.1 to 1.1 +/- 0.1 nmol/l) was recorded. At the beginning of treatment, mild side-effects were recorded in two patients after CAB and mild-to-moderate side-effects in five patients after BRC administration. The treatment with CAB normalized PRL levels, improving gonadal and sexual function and fertility in males with prolactinoma, earlier than did BRC treatment, providing good tolerability and excellent patient compliance to medical treatment.

[Evaluation of seminal and hormonal parameters in idiopathic varicocele before and after surgical intervention]. / Valutazione dei parametri seminologici ed ormonologici nel varicocele idiopatico prima e dopo intervento chirurgico.

268 patients (age 16-47 years) affected with idiopathic varicocele, submitted to surgery, have been studied. Semen analysis, pampiniphorm plexus doppler examination and testosterone, estradiol, D4 androstenedione, DHEA-S, HPRL, 17-OH-P, FSH and LH (basal and after LH-RH) evaluation, before and 6 months after surgery, were performed. The patients were divided in 3 groups (A, B and C) according to sperm count. Pre-surgery seminal parameters in A group were significantly reduced in comparison with control group. Six months after surgery, a significant increase of total and forward progression, Swelling test, Acridine Orange and in vitro penetration (CMPT) was observed. Sperm count showed an increase, although being still significantly reduced in comparison with normal controls. In B group, before surgery, sperm count, viability, Acridine Orange and CMPT were significantly reduced in comparison with controls. Six months after surgery, viability, Acridine Orange and CMPT resulted significantly improved. In C group, before surgery, CMPT resulted significantly reduced in comparison with controls. After surgery, semen framework improved without significant differences in comparison with normal controls. No significant differences were observed for hormonal patterns before and after surgery.

[Simultaneous and bilateral catheterization of inferior petrosal sinuses in the diagnosis of Cushing's syndrome: basal multiple sampling and after ACTH-releasing hormone test]. / Cateterismo simultaneo e bilaterale dei seni petrosi inferiori per la diagnosi della Sindrome di Cushing: prelievo multiplo basale e dopo test all'ACTH-releasing hormone.

In 22 patients with ACTH-dependent Cushing's syndrome we have performed multiple ACTH evaluations, baseline and after ACTH-releasing hormone (CRH), during simultaneous bilateral inferior petrosal sinus sampling. The basal inferior petrosal sinus/periphery ratio for ACTH was > 2 in 11/22 patients, CRH challenge caused the appearance of an inferior petrosal sinus/periphery ratio > 3 in 6 other patients. An ACTH-secreting adenoma was surgically proven in 17 patients with ACTH inferior petrosal sinus/periphery ratio > 2 basally or > 3 after CRH and in 1 patient with an inferior petrosal sinus/periphery ratio < 2 basally or 3 after CRH. In 4 patients the very high peripheral ACTH levels, the inferior petrosal sinus/periphery ratio and the lack of ACTH increase after CRH indicated the presence of an ectopic ACTH syndrome. An ACTH intersinus gradient > 1.4 was found in 11 patients. Among these patients the adenoma was correctly localised in 6 and wrongly in 5 patients. In conclusion, the diagnostic accuracy of the inferior petrosal sinus sampling was of 95.4% (21/22 cases) considering basal and CRH-stimulated ACTH levels. The multiple basal ACTH evaluation does not seem to be necessary associated with CRH-test, but may be helpful in some cases.

Short stature and azoospermia in a patient with Y chromosome long arm deletion.

We report on a 42-year old male with short stature, azoospermia and a wide deletion of long arm of Y chromosome. On physical examination, the patient showed height of 149 cm (< 1 degree centile) and reduced volume (3 ml) and consistency of the testes. On hormonal evaluation, he showed increased serum gonadotropins and normal serum testosterone levels though its HCG stimulated levels were limited. Serum thyroid hormones were normal. Serum GH levels in baseline evaluation as well as after GHRH and GHRH + pyridostigmine administration were normal. Serum IGF I levels were lower than normal in baseline evaluation whereas its response to the GH administration was in the normal range. The bilateral testicular biopsy showed tubular atrophy, hyalinosis, interstitial sclerosis and a histological picture of a Sertoli cell only syndrome. Moreover the patient showed arthropathy, otopathy, small chin, small mouth and truncal obesity. On genetic evaluation, the patient showed a 46,X,delY (pter--q11.1:) karyotype and loss of several DNA loci on Yq. In fact he preserved short arm SRY, centromeric DYZ3 and more proximal euchromatic region Yq loci, including DYS270, DYS271, DYS272, DYS11, DYS273, DYS274, DYS148, DYS275, and missed more distal DNA loci from DYS246 to DYZ2. These results disclosed a wide Y long arm deletion, including all hypothized Yq azoospermia loci (except for AZFa and probably for one of the RBM genes, which lie proximally to the deletion) and possibly the Y-specific growth control region (GCY), mapped between DYS11 and DYS246 loci. This deletion is responsible for the complete azoospermia of the patient and probably also for his short stature, even if other factors could be implicated in the statural impairment. It further possibly allowed to relate the GCY gene(s) to the control of GH or IGF-I receptor or post-receptor pathway, being the alteration of this gene(s) consistent with the hormonal pattern of the patient.