Signs of testicular insufficiency in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy: a retrospective study

X-linked adrenoleukodystrophy (X-ALD) is characterized by central nervous system demyelination, and impaired steroidogenesis in the adrenal cortex and testis. Most patients develop adrenocortical insufficiency. We studied retrospectively the frequency and severity of testicular dysfunction in 26 men with X-ALD. Twenty-one had adrenomyeloneuropathy and five patients were neurologically asymptomatic. In addition to obtaining a routine history and physical examination, we studied plasma levels of testosterone, sex hormone binding globulin, the free androgen index, and the plasma concentrations of dehydroepiandrosterone-sulphate, LH and FSH. In a subset of patients, the testosterone response to hCG and the LH and FSH responses to GnRH were also determined. Clinical signs of gonadal dysfunction were manifested by diminished libido (46%), largely overlapping with erectile dysfunction (58%), and failure of the testes to descend (15%). Physical examination revealed diminished body sexual hair (50%), gynaecomastia (35%), and small testes (12%). Laboratory studies showed low plasma total testosterone levels in 12%, and an insufficient increase after stimulation with hCG in 88% (15 of 17 patients tested). Plasma LH concentration was increased in 16%, and the plasma FSH level was elevated in 32%. The response of LH concentrations to GnRH stimulation was abnormally high in 47% (nine of 19 patients studied), and the response of FSH levels was too low in 16% (three of 19 patients tested). In conclusion, in a retrospective study of 26 men' with X-ALD, in 20 some signs of clinical hypogonadism were found. Plasma testosterone values were generally in the normal range, but upon testing of the hypothalamo-pituitary-testis axis some abnormalities became apparent.     

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.     

Testicular endocrine function in patients with prostatic cancer receiving medical castration by long-term administration of LH-RH agonists

Six patients with advanced prostatic cancer who had been treated by long-term administration of LH-RH agonistic preparations (Buserelin or Leupron) were tested for their pituitary-testicular endocrine functions. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), prolactin (PRL), estradiol (E2) and dihydrotestosterone (DHT) were measured consecutively. In all medically castrated patients, serum levels of LH, FSH, T, DHT and E2 were suppressed and particularly serum T levels were below the castration level of 1.0 ng/ml. On the other hand, serum PRL levels were unchanged after the long-term treatment with the agonists. Serum LH and FSH levels failed to respond to LH-RH stimulation after the treatment, whereas serum T responded to stimulation by human chorionic gonadotropin (hCG) to various degrees. It was remarkable that, in 4 out of 6 medically castrated patients treated up to more than 3 years, serum T response levels above 1.0 ng/ml were noted. It is suggested that testicular endocrine function to secrete T and DHT in patients under treatment with long-term LH-RH agonist administration are still preserved in response to hCG stimulation.     

Effects of chronic neuroleptic therapy on human PRL secretion and testicular function

Correlation between secretion of testicular steroids and plasma prolactin (PRL) levels, before and during bromocriptin treatment, was studied in 20 psychiatric patients under neuroleptic therapy for two years or longer. Eleven of them were under additional treatment with antiparkinson drugs (AP group). Plasma PRL, testosterone (T), 5 alpha dihydrotestostérone (DHT), 17 beta-estradiol (E2), 17 alpha OH-progestérone (17 alpha OHP), and dehydroepiandrosterone-sulfate (D-S) were measured by specific RIA both at basal level and in response to testicular stimulation by hCG. Mean basal PRL levels were normal in the patients under neuroleptic treatment along (Ne group), and slightly elevated in the AP group. In the Ne group, an unexpected, significant increase occurred in mean plasma PRL during the hCG stimulation, before bromocriptine treatment. Mean basal steroid levels were normal in both groups. The testicular responses to hCG, as reflected by the T, E2, 17 alpha OHP, and DHT mean plasma levels, were within the normal ranges in the AP group; in the Ne group, however, T and DHT displayed a subnormal mean increase, while E2 and 17 alpha OHP responses were within the normal range. These results suggest that some modifications of the enzymatic activity for testicular steroidogenesis could be induced in the patients under neuroleptic treatment alone. Moreover, a significant reverse correlation was found between PRL and T basal in both group; this correlation disappeared during the bromocriptine treatment.     

Acquired hypogonadotropic hypogonadism presenting as decreased seminal volume

A 32-year-old man with decreased ejaculatory volume was found to have acquired hypogonadotropic hypogonadism. Initial evaluation demonstrated castrate levels of testosterone with low serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. Semen analysis revealed a volume of 0.35 cc and severe oligospermia. Administration of gonadotropin-releasing hormone (GnRH) did not effect an increase in LH or FSH, indicating a pituitary defect. Magnetic resonance imaging revealed a partially empty sella turcica. Treatment with human chorionic gonadotropin (hCG) alone resulted in normalization of testosterone levels, sperm concentration, and semen volume, as well as the successful conception and delivery of a healthy baby girl. The findings from this case demonstrate the importance of considering low serum testosterone levels in the evaluation of low semen volume, as well as the role of hCG alone as an infertility treatment for acquired hypogonadotropic hypogonadism.     

Endocrine, seminal and peripheral effects of depot medroxyprogesterone acetate and testosterone enanthate in men

Depot medroxyprogesterone acetate (D-MPA, 250 mg) and testosterone enanthate (TE, 200 mg) were administered twice with a 4-week interval to nine healthy men, and the levels in blood of steroids, gonadotrophins, lipoproteins, sex hormone binding globulin (SHBG) and prostaglandins (PGs) were measured, as well as steroid levels in semen and the sperm count and motility. The hormones analysed were: MPA, testosterone, androstenedione (A), dihydrotestosterone (DHT), oestradiol (E2), cortisol (C), luteinizing hormone (LH), follicle stimulating hormone (FSH) and the sulphoconjugated forms (-S) of testosterone, DHT, pregnenolone (5-P) and dehydroepiandrosterone (DHEA). Peak values of MPA (10.2 +/- 4.6 nmol/l) and testosterone (28.0 +/- 10.0) were found in the first blood samples 2 days after each injection. Thereafter the levels of MPA decreased gradually and reached the limit of detection 18-20 weeks after the second injection. Blood levels of testosterone fell sharply from the peak values and were grossly subnormal 2 weeks after each injection; levels did not return to pretreatment values during 24 weeks of follow-up. The pattern of change of DHT, A, E2 and sulphonated androgens was similar to that of testosterone. These data suggest that D-MPA and TE are absorbed at similar rates, and that the TE is metabolized rapidly. The subsequent reduction in the levels of A, testosterone-S and DHT-S was less marked and reached pretreatment values earlier than did the testosterone levels. No obvious changes were found in the levels of C, 5-P-S and DHEA-S or in the seminal plasma levels of the various steroids studied. The blood levels of LH and FSH fell precipitously 2 days after the first injection, then started to increase 4 weeks after the second injection to reach pretreatment values 12 weeks later. Of the lipoproteins studied only the levels of HDL-cholesterol and SHBG were found suppressed after treatment. Severe oligozoospermia and the complete absence of progressively motile sperm, in at least one semen sample, was observed in all subjects at 3-7 and at 5-16 weeks, respectively, after the last injection, suggesting that the men were infertile for at least 1 month after treatment. A spurious increase in the PG content of semen was also observed. In spite of the low blood testosterone levels, no subject reported changes in sexual behaviour or other signs of anabolic imbalance during or after the study. However, the increase in levels of E2 in some individuals should be kept in mind as a possible cause of side-effects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sleep deprivation and adaptive hormonal responses of healthy men

To study the effects of sleep deprivation on the pituitary-testis axis physiology, we measured the circulating levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), testosterone (T), androstanedione (A), dihydrotestosterone (DHT), estradiol (E2), and cortisol (C) in eight healthy men as follows: phase I (control), phase II (24-h restless period), phase III (48-h restless period), and phase IV (24-h recovery period). All samples were taken at 8:00 a.m. There was a significant decrease of T, A, DHT, and E2 in phase II but no decrease in FHS, LH, PRL, or C. In phase III there was no further decrease in any androgen, although E2 decreased along with the increase of PRL. In phase IV E2 and PRL tended to return to baseline values, and the androgens were very similar to the controls. FHS, LH, and C showed no change under the effects of phase III. These data extend the adaptive androgenic response and the association of the role of E2 and PRL to restricted or disturbed sleep in men.     

早期先兆流产妇女血浆β-内啡肽的研究

为了解有自然流产史早期先兆流产妇女外周血浆β 内啡肽（β ＥＰ）、促性腺激素释放激素（ＧｎＲＨ）、人绒毛膜促性腺激素（ｈＣＧ）和孕酮（Ｐ４）的变化。随机选择孕７～８周的有反复自然流产史的先兆流产妇女２０例，于治疗前及后（孕１０～１２周）测血浆β ＥＰ、ＧｎＲＨ、ｈＣＧ和Ｐ４水平（ＲＩＡ法）。随机选择正常早孕妇女２０名，分别于孕７～８和１０～１２周进行上述４项测定，收集孕１０～１２周不全流产妇女外周血同样进行以上测定，后两组作为对照。结果：（１）正常早孕妇女孕１０～１２周血浆β ＥＰ、ＧｎＲＨ、ｈＣＧ和Ｐ４水平比孕７～８周时值明显上升（Ｐ＜０．０１）。（２）孕７～８周时，先兆流产妇女血浆β ＥＰ值明显高于正常相应孕周水平（Ｐ＜０．０１），ＧｎＲＨ、ｈＣＧ和Ｐ４则明显低于正常早孕组（Ｐ＜０．０１）。经过给予心理支持、中药综合治疗后，先兆流产症状消失，１６例足月分娩，其孕１０～１２周时的４项水平与相应孕周间无显著差异（Ｐ＞０．０５）。（３）不全流产组除血β ＥＰ值明显高于正常早孕组水平（Ｐ＜０．０１）外，其他则明显低于正常妊娠早孕组水平（Ｐ＜０．０１）。认为β ＥＰ在自然流产的发生中可能起着重要作用。     

Endocrine profiles and gonadotropin response to Gn-RH of men with testicular cancer

PURPOSE: To investigate the function of the hypothalamic-pituitary-testicular axis in testicular germ cell tumors, we evaluated gonadotropin responses to gonadotropin-releasing hormone (Gn-RH), semen quality, and serum levels of sex steroid hormones in patients with testicular cancer. PATIENTS AND METHODS: Basal serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and human chorionic gonadotropin-beta (hCG-beta) were measured before and after high orchiectomy in 20 patients with germ cell tumors of the testicle (9 with seminoma and 11 with nonseminomatous tumor). Semen quality and basal serum levels of testosterone, free testosterone, and estradiol were measured before orchiectomy. The Gn-RH test was performed before orchiectomy in all patients and after orchiectomy in patients without detectable gonadotropin levels in pre-operative serum samples. Gonadotropin levels were measured at 0, 30, 60, 90, and 120 minutes after intravenous injection of 100 micrograms of luteinizing hormone-releasing hormone (LH-RH). RESULTS: Serum gonadotropin concentrations were not detectable in 6 of 8 (75%) men with hCG positive tumors or in 4 of 12 (33.3%) men with hCG negative tumors before orchiectomy. Before surgery, 10 men without detectable gonadotropin levels showed complete suppression of the LH and FSH responses to LH-RH and 10 men with detectable gonadotropin levels showed significant increases in the LH and FSH responses (p < 0.01) at 30 minutes. After surgery, the Gn-RH test was performed in 9 men without detectable gonadotropin levels prior to surgery. Seven of these 9 men exhibited significant increases in the LH and FSH responses (p < 0.01) at 30 minutes while no response to LH-RH before or after surgery was seen in 2 men with detectable serum hCG-beta. We observed a significantly lower sperm density (median 7.5 x 10(6)/ml, range 0.4 to 17.8) in men with hCG positive tumors than in men with hCG negative tumors (median 33 x 10(6)/ml, range 0 to 103) (p < 0.002). Although testosterone levels did not differ significantly in men with hCG positive tumors and men with hCG negative tumors, free testosterone levels were significantly higher in men with hCG positive tumors (median 28.4 ng/ml, range 8.5 to 39.8) compared with men with hCG negative tumors (median 18.7 ng/ml, range 4.9 to 24.1) (p < 0.002). Estradiol levels were significantly increased in men with hCG positive tumors (median 44 pg/ml, range 26 to 110) compared with men with hCG negative tumors (median 33.5 pg/ml, range 10 to 87) (p = 0.002). CONCLUSION: The present findings indicate that serum hCG producing testicular cancers are associated with a complete suppression of the gonadotropin response to Gn-RH at the pituitary level, resulting in an inhibition of LH and FSH secretion, and also that serum hCG secreted by testicular cancers may suppresses spermatogenesis and may stimulate androgen and estradiol production by the testes. Since suppressed serum gonadotoropin levels are found in men with hCG non-producing testicular cancers, other factors derived from the tumor may cause downregulation of the gonadotropin response to Gn-RH.     

Cervical sympathectomy affects gonadotropin-releasing hormone,luteinizing hormone and testosterone in male rats

To examine the effects of bilateral cervical sympathectomy on the secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and testosterone (TS), 24 male rats were divided into four groups: control (C), light (L), sympathectomy (S), and light-sympathectomy (LS) groups. The C and S groups were kept under a 12-h light-dark cycle and the L and LS groups were kept under continuous light for 2 weeks. After 2 weeks, blood was collected and the rats were perfused with a fixative. GnRH neurons in the hypothalamus were stained immunohistochemically, and serum LH and TS levels were measured by radioimmunoassay. Although the difference in the number of GnRH neurons between the C and S groups was not significant, the L group was significantly lower than the C or LS groups. The serum LH and TS levels in the L group were higher than in the other groups. The present results suggest that continuous light increases GnRH secretion in the hypothalamus, followed by increased secretions of LH in the pituitary and TS in the testes, and bilateral cervical sympathectomy under continuous light inhibits these hormonal changes. However, a normal circadian rhythm does not affect gonadotropin secretion. Therefore, long-term and repeated stellate ganglion block may inhibit the increases of GnRH, LH, and TS secretions induced by continuous light.     

Effects of short- and long-term administration of tamoxifen on hCG-induced testicular steroidogenesis in man: no evidence for an oestradiol-induced steroidogenic lesion

hCG-induced testicular desensitization is characterized by inhibition at the level of the C-17,20-lyase enzyme. This defect has been attributed to an early rise in oestradiol (E2) following hCG administration. To test this hypothesis the E2-receptor antagonist, tamoxifen, was employed. From in vitro studies the evidence suggests that tamoxifen depletes the E2-receptor within 24 h. In this in vivo study, short-term (36 h) administration of tamoxifen (to 6 eugonadal men) did not affect basal plasma levels of LH, FSH, 17 alpha-hydroxyprogesterone (17-OHP), testosterone (T) and E2, whereas long-term (3 months) tamoxifen with treatment of 6 normogonadotrophic oligozoospermic men increased LH and T levels, indicating a biological effect of tamoxifen. The response of 17-OHP, T, E2 and the 17-OHP/T ratio to hCG was similar in short-term and long-term tamoxifen-treated men as well as in 6 untreated eugonadal male controls. These results do not suggest a role for endogenous E2 in the hCG-induced testicular steroidogenic block.     

Inhibition of spermatogenesis in men using various combinations of oral progestagens and percutaneous or oral androgens

Eight men (experiment 1) requesting male contraception received a daily oral dose of 20 mg medroxyprogesterone acetate (MPA) combined with 125 mg percutaneous dihydrotestosterone (DHT). Three months later the mean sperm count was only diminished slightly; the replacement of DHT for four men by percutaneous testosterone at the same concentration led to a dramatic fall in sperm count. For 6-18 months all men were treated with MPA plus percutaneous testosterone (250 mg daily). The latter dose restored physiological levels of plasma testosterone. Follicle-stimulating hormone levels were inhibited more severely than in the DHT-treated group, whereas LH levels were variable. Azoospermia was achieved and maintained in six cases; two men were oligozoospermic and in one case a moderate secondary rise in the sperm count was observed. Twelve volunteers (experiment 2) received a daily oral dose of either 5 or 10 mg norethisterone acetate plus percutaneous testosterone (250 mg daily). All of them achieved azoospermia within 2 months, but two subjects later exhibited a partial restoration in sperm count. Follicle-stimulating hormone and LH levels were inhibited more severely than in the first experiment. The sperm count and gonadotrophin levels returned to initial values within 6 months after cessation of the treatment in both experiments. No side-effects were noted concerning blood parameters, libido or body weight. However, several female partners had elevated levels of plasma testosterone. In experiment 3 (13 volunteers), percutaneous testosterone was replaced by oral testosterone undecanoate (160 mg daily). Only seven men were azoospermic and most of them had lowered levels of plasma testosterone. Thus, the combination of percutaneous testosterone and oral progestagens appears to be the most convenient for male hormonal contraception.     

The influence of age on Leydig cell function in patients with varicocele

In a large group of patients with varicocele (n = 108, mean age: 30.9 years) Leydig cell function was investigated by determining the plasma levels of gonadotrophins under basal conditions and after GnRH stimulation, and by measuring the plasma levels of 17-OH-progesterone (17-OH-P), testosterone (T), dihydrotestosterone (DHT) and oestradiol (E2). There was a significant positive correlation between age and the peak plasma LH values after GnRH stimulation (n = 48, r = 41, P less than 0.01). Conversely, an inverse correlation was observed between age and the basal plasma levels of 17-OH-P (n = 56, r = 0.47, P less than 0.01) and T (n = 108, r = 0.27, P less than 0.01). In normals controls of the same age range (n = 46, mean age: 30 years) such correlations were absent. In patients with varicocele, the 17-OH-P/T ratio was increased significantly in peripheral plasma under basal conditions (P less than 0.01) and after hCG stimulation (P less than 0.05), and a similar increase was found in spermatic venous blood. This suggests that in varicocele patients there is some enzymatic impairment involving the last steps of T biosynthesis. In order to verify the influence of ologozoospermia on plasma steroid levels we divided the patients into 2 groups according to sperm count (more than or less than 10 X 10(6)/ml). Three analyses of variance were then carried out between these 2 groups of patients: 1) analysis of peripheral plasma T levels; 2) analysis of peripheral plasma levels of 17-OH-P and 3) spermatic vein levels of these 2 steroids. However, none of these analyses revealed any significant difference between the 2 groups of patients. When we re-grouped the patients according to age (15-30 and 30-45 years) the same analyses of variance revealed significant differences. These results therefore suggest that the duration of idiopathic varicocele per se influences Leydig cell activity.     

Role of the hypothalamic opioidergic system in the control of gonadotropin secretion in elderly men1

Summary: The role of opioidergic system in controlling gonadotropin secretion in elderly men still remains uncertain. In the present study, we attempted to examine the opioidergic inhibitory tone imposed on GnRH release mechanism in elderly men by monitoring the plasma gonadotropin response to the opiate receptor antagonist naloxone hydrochloride. Six normal young men and 10 elderly men with no endocrinological diseases volunteered for the present study. In young men, plasma LH showed a biphasic increase in response to naloxone and plasma LH level during naloxone treatment was significantly higher than the mean of pre-naloxone control levels. In contrast, plasma LH in elderly men was not affected by naloxone. The ratio of the peak plasma LH response during naloxone treatment to the mean pre treatment LH level (plasma peak/basal LH ratio) declined with the advance of age (r = -0.74, P < 0.005) and also correlated significantly with plasma free testosterone level (r = 0.45, P < 0.05). These data suggest (1) that the hypothalamic opioidergic tone is reduced in elderly men and (2) that the primary testicular insufficiency with the advance of age may play a major role in the decline of the hypothalamic opioidergic tone in elderly men.     

Testicular responsiveness to human chorionic gonadotrophin in growth hormone deficient pre-pubertal boys: lack of effect of replacement therapy

The effect of hGH therapy on testicular response to hCG was studied in 7 pre-pubertal boys with known growth hormone deficiency. Each boy received 2000 IU hCG intramuscularly for 3 consecutive days either before starting hGH therapy or 4 months after temporarily discontinuing hGH therapy. A second 3 day series of hCG injections was administered after each boy had received 4 months of hGH treatment. Before each hCG challenge, serum concentrations of testosterone, LH and FSH were obtained and an iv GnRH test was performed. Growth hormone treatment either maintained or established linear growth velocities equal to or greater than expected for the patient's skeletal age. Testicular response off hGH therapy, either maximum serum concentration of testosterone or maximum rise above baseline, was not significantly different than testicular response while on hGH therapy. Testicular responses did not correlate significantly with either basal concentration of gonadotrophins or gonadotrophin responses to GnRH. Despite its effectiveness in stimulating growth, hGH did not effect testicular responsiveness to hCG in pre-pubertal boys with hGH deficiency.     

Effects of 3-methyl-4-nitrophenol in diesel exhaust particles on the regulation of testicular function in immature male rats

We investigated the effects of 3-methyl-4-nitrophenol (4-nitro-m-cresol, PNMC) isolated from diesel exhaust particles (DEP) on the reproductive functions of male rats. Twenty-eight-day-old rats were injected subcutaneously with PNMC (1, 10, or 100 mg/kg) daily for 5 days. The weights of the epididymis, seminal vesicle, and Cowper gland were significantly decreased in rats treated with 10 mg/kg PNMC. The plasma concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were significantly increased by PNMC at 100 mg/kg. However, the plasma concentrations of testosterone and immunoreactive (ir)-inhibin were significantly decreased by PNMC at 100 mg/kg. The testosterone content of the testicles was significantly decreased in the group treated with 100 mg/kg PNMC compared with the control group. Furthermore, testicular concentration of ir-inhibin was significantly decreased by PNMC at 1 mg/kg or 100 mg/kg. To investigate the direct effects of PNMC on the secretion of LH and FSH from the anterior pituitary gland, and on the secretion of testosterone from the testes, we exposed cultured anterior pituitary and interstitial Leydig cells to PNMC (10(-6), 10(-5), 10(-4) M) with or without gonadotropin-releasing hormone (GnRH; 10 nM) (for the LH and FSH tests) and human chorionic gonadotropin (hCG; 0.1 IU/mL) (for the testosterone test) for 24 hours. PNMC did not change either the basal or GnRH-stimulated levels of FSH and LH secretion. However, PNMC significantly inhibited both basal and hCG-stimulated testosterone production. These findings suggest that PNMC has a direct effect on the testes of immature male rats, causing a reduction in testosterone secretion.     

The gonadotropin-releasing hormone (GnRH) agonist-induced initial rise of bioactive LH and testosterone can be blunted in a dose-dependent manner by GnRH antagonist in the non-human primate

Summary Gonadotropin-releasing hormone (GnRH) agonists induce a clinically undesirable, transitory but very pronounced initial rise of gonadotropin and gonadal steroid secretion. We investigated, in a non-human primate model, whether the initial stimulatory effects of GnRH agonists can be avoided by a short period of pretreatment and simultaneous treatment with a GnRH antagonist. Three groups of five adult male cynomolgus monkeys (Macaca fascicularis) received a single s.c. biodegradable implant loaded with the GnRH agonist, buserelin ([D-Ser(TBu)⁶-desGly-NH₂]-GnRH), releasing approximately 50 g buserelin daily. From 1 week before to 1 week after inception of administration of GnRH agonist, group 1 received the GnRH antagonist vehicle, and groups 2 and 3 were given s.c. injections of the GnRH antagonist Nal-Glu ([Ac-D-Nal(2)¹,D-4-Cl-Phe², D-Pal³, D-Arg⁵,D-Glu⁶(AA),D-Ala¹⁰]-GnRH) at a dose of 450 or 2250 g/kg daily. In the absence of GnRH antagonist, the GnRH agonist induced a marked elevation of serum luteinizing hormone (LH) and testosterone lasting for 2 and 5 days, respectively. In group 2, Nal-Glu reduced basal hormone secretion and delayed the peak of GnRH-agonist-induced hormone secretion by 1 day. In group 3, the GnRH-agonist-induced rise of LH and testosterone was prevented in three animals and did not exceed baseline hormone levels in the other two animals. Areas under the LH and testosterone curves were significantly reduced in group 3 compared to group 1. After withdrawal of the GnRH antagonist, a second transient rise of hormone secretion was observed. Except for testosterone in group 2, this rise did not exceed the baseline range of hormone concentrations. The study demonstrates that high doses of GnRH antagonist can prevent the GnRH agonist-induced initial rise of LH and testosterone secretion, while after withdrawal of the GnRH antagonist a second rise of hormone secretion occurs, which is less pronounced than with GnRH agoniit alone.Supported by the Deutsche Forschungsgemeinschaft, grant DFG Ni 130/11-A1Recipient of an Alexander von Humboldt Research Fellowship     

A case of Kallmann's syndrome

A 13-year-old boy visited our hospital with the chief complaint of right undescended testis and retardation of secondary sexual characteristics. Central hyposmia and sensorineural hearing loss were found. The plasma levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were low and the reaction to LH-releasing hormone (RH) test was poor. After repeated LH-RH tests, a good response in plasma levels of LH and FSH was observed. The diagnosis of Kallmann's syndrome was made from the above findings. The testicular biopsy specimen from him showed immature testis without any developed Leydig or Sertoli cells. To induce secondary sexual characteristics, 2000 I.U. of human chorionic gonadotropin (hCG) was administered to him twice a week for 3 months. The administration of hCG resulted in elevation of plasma testosterone level, swelling of testes, increase of pubic hair and spurt of height.     

Reproductive Hormones and Longitudinal Change in Bone Mineral Density and Incident Fracture Risk in Older Men: The Concord Health and Aging in Men Project

The objectives of this study were to examine relationships between baseline levels of reproductive hormones in older men and (1) change in bone mineral density (BMD) over 5 years and (2) incident fractures over an average of 6 years' follow‐up. A total of 1705 men aged 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005–2007), 2 years follow‐up (2007–2009), and 5 years follow‐up (2010–2013). At baseline, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography–tandem mass spectrometry (LC‐MS/MS), and sex hormone–binding globulin (SHBG), luteinizing hormone (LH), and follicle‐stimulating hormone (FSH) by immunoassay. Hip BMD was measured by dual X‐ray absorptiometry (DXA) at all three time‐points. Fracture data were collected at 4‐monthly phone calls and verified radiographically. Statistical modeling was by general estimating equations and Cox model regression. Univariate analyses revealed inverse associations for serum SHBG, FSH, and LH and positive association for E1 but not DHT or E2 with BMD loss at the hip across the three time points. Serum levels of SHBG (β = –0.071), FSH (β = –0.085), LH (β = –0.070), and E1 (β = 0.107) remained significantly associated with BMD loss in multivariate‐adjusted models; however, we were unable to identify any thresholds for accelerated BMD loss according to reproductive steroids. Incident fractures (all, n = 171; hip, n = 44; and nonvertebral, n = 139) were all significantly associated with serum SHBG, FSH, and LH levels in univariate models but none remained significantly associated in multivariate‐adjusted model. Serum T, DHT, E2, and E1 levels were not associated with incident fractures in univariate or multivariate‐adjusted analyses. In older men, lower serum SHBG, FSH, and LH and higher E1 levels protected against loss of BMD without increasing fracture rate. This means these reproductive variables may be considered as novel biomarkers of bone health during male aging. © 2015 American Society for Bone and Mineral Research.     

The antigonadotropic action of testosterone but not 7alpha-methyl-19-nortestosterone is attenuated through the 5alpha-reductase pathway in the castrated male rat pituitary gland

The enzyme 5alpha-reductase plays a significant role in the prostate to amplify the action of testosterone (T) by converting it to a more potent androgen, dihydrotestosterone (DHT). The role of 5alpha-reductase in the testosterone feedback inhibition of gonadotropin secretion from the pituitary has not been elucidated. Therefore, we investigated the role of 5alpha-reductase on T action in in vitro and in vivo models. Castration has been reported to increase the 5alpha-reductase activity in pituitary glands. Hence, the effect of castration duration on the conversion of T to DHT by pituitary homogenates and the responsiveness of pituitary monolayer cell cultures to gonadotropin-releasing hormone (GnRH) challenge exposure were investigated. Incubation of [3H]-T with pituitary homogenates showed that the conversion of T to 5alpha-reduced metabolites was two- to threefold greater in pituitaries from rats who had been castrated for 14 days compared with those castrated for 1 day. In addition, the GnRH-stimulated release of LH from monolayer cell cultures of pituitaries from rats castrated for 1 day was twofold greater, whereas that from rats castrated for 2 weeks was six- to sevenfold greater compared with basal luteinizing hormone (LH) release. Hence we used rats castrated for 2 weeks to elucidate the role of 5alpha-reductase in T feedback inhibition. The inhibitory effects of the androgens T, 19-nortestosterone (19-NT), and 7alpha-methyl-19-nortestosterone (MENT) at 3 different concentrations (10(-9), 10(-7), and 10(-5) mol/L) on GnRH-stimulated LH release from monolayer cell cultures of pituitaries from rats castrated for 2 weeks were examined. All 3 androgens showed dose-dependent inhibition of LH release. MENT showed the greatest inhibition, followed by 19-NT and T. In the presence of finasteride (a 5alpha-reductase inhibitor), the inhibition of LH released by T and 19-NT were significantly greater. The inhibitory effect of MENT, which does not undergo 5alpha-reduction, was not altered by finasteride. In an in vivo study, rats castrated for 2 weeks received T with or without finasteride. There was a significantly greater suppression of serum LH in rats receiving T plus finasteride compared with those receiving T alone. These results suggested that 5alpha-reductase in the pituitary is not obligatory for the inhibitory action of T on gonadotropin secretion in the castrated rat. The action of MENT, a nonreducible androgen, on the pituitary is not affected by 5alpha-reductase.