X-linked adrenomyeloneuropathy associated with 14 novel ALD-gene mutations: no correlation between type of mutation and age of onset.

Adrenomyeloneuropathy (AMN) represents a milder form of X-linked adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder. The disease is characterised by an abnormal accumulation of saturated, very long chain, fatty acids, because of altered peroxisomal beta-oxidation that concomitantly leads to demyelination in the central and peripheral nervous systems. ALD shows a highly variable phenotypic expression and extensive mutation analysis in ALD patients has failed to establish a genotype-phenotype correlation, even in the presence of the same ALD-gene defect. Therefore, we have looked for a relationship between the molecular lesion and the age of onset in 19 patients with a well-classified clinical course of AMN. The nearly complete novel spectrum of ALD gene mutations identified has revealed no obvious correlation between the type of mutation and age of AMN onset in this small series. However, intrafamiliar concordance could be observed with respect to the occurrence of adrenocortical insufficiency. This supports the idea of one (or more) additional gene(s) contributing to the phenotypic expression of ALD.

Serum sex hormones are altered in patients with chronic temporal lobe epilepsy receiving anticonvulsant medication.

PURPOSE: To evaluate the changes in serum sex hormones of gonadal or adrenal origin, the gonadotropic hormones, and sex hormone-binding globulin (SHBG) in men and women with chronic temporal lobe epilepsy (TLE), who are undergoing monotherapy with carbamazepine or receiving carbamazepine in combination with other anticonvulsant drugs. METHODS: Gonadal hormones (estradiol, testosterone, free testosterone, and inhibin B), adrenal hormones [cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and 17alpha-hydroxyprogesterone], and gonadotropic hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) were measured in 22 women and 26 men with TLE. The study also measured prolactin; human growth hormone and its major mediator, insulin-like growth factor-I; thyroid hormones (free thyroxine and free triiodothyronine); thyroid-stimulating hormone (TSH); and SHBG. The results were compared with those obtained from 60 healthy women and 106 healthy men. RESULTS: In the female patients, TSH, DHEAS, follicular-phase LH, and luteal-phase estradiol were significantly lower than in the control groups, with prolactin and SHBG significantly higher. In the male patients, DHEAS, 17alpha-hydroxyprogesterone, free testosterone, inhibin B, and the testosterone/LH ratio were significantly lower than in the control group, with LH, FSH, and SHBG significantly higher. Increased FSH in 31% of the men indicates an impairment of spermatogenesis; lowered inhibin B in 12% indicates an impaired Sertoli's cell function; and the decreased testosterone/LH ratio in 50% indicates an impaired Leydig's cell function. CONCLUSIONS: The case patients had endocrine disorders, mainly concerning the gonadotropic and gonadal functions in both sexes; the adrenal function, with lowered DHEAS levels in both sexes; and lowered 17alpha-hydroxyprogesterone levels in the men. SHBG levels were increased in patients taking anticonvulsant medications.

Evaluation of five devices for self-monitoring of blood glucose in the normoglycaemic range.

Although hypoglycaemia is a serious risk of intensive insulin therapy, studies on the accuracy of devices for self-monitoring of blood glucose (SMBG) include only a few values below 100 mg/dl. This study evaluated five SMBG devices in the normal range of blood glucose. In three separate series, capillary blood was taken from 207, 214 and 49 healthy subjects and was analysed with the SMBG devices and a laboratory method. Mean (+/- standard deviation) blood glucose values were 86+/-13 mg/dl, 83+/-12 mg/dl and 90+/-16 in series 1-3. All measurements with SMBG devices differed significantly from the laboratory method. The relative deviation from the laboratory method was 5.5% (2.4-10.5%, median and interquartile range) for Accutrend, 7.1% (3.6-12.6%) for Precision QID, 7.5% (3.7-13.7%) for Accu-Chek III, 14.1% (6.2-22.2%) for Companion 2 and 15.2% (10.3-21.3%) for One Touch II (p < 0.05). In conclusion, this study shows important differences in the accuracy of five SMBG devices in the normoglycaemic range. Accutrend and--to a lesser degree--Accu-Chek III and Precision QID obtained better results and can be recommended for SMBG in patients treated with intensive insulin therapy.

Pretreatment follicle-stimulating hormone: a prognostic serum marker of spermatogenesis status in patients treated for germ cell cancer.

PURPOSE: We evaluate the use of pretreatment follicle-stimulating hormone (FSH) in patients with germ cell tumors as a prognostic serum marker of spermatogenesis after standard treatment. Additionally, Leydig cell function was investigated by estimation of luteinizing hormone (LH) and testosterone (T), and calculation of the T/LH ratio. MATERIALS AND METHODS: Serum FSH, LH and T were determined radioimmunologically associated with semen analyses in 20 patients with seminoma (pathological stages IA to IIB) after unilateral orchiectomy before and up to 24 months after infradiaphragmatic radiotherapy. Additionally, hormone analyses were performed in 18 patients with nonseminomatous germ cell tumor (pathological stages IIA to C) before and up to 36 months after standard cisplatin based chemotherapy. RESULTS: Seminoma patients undergoing radiotherapy were divided into 2 groups consisting of 12 patients with normal pretreatment serum FSH and 8 with elevated FSH reflecting spermatogenesis deficits even before treatment. Six months after irradiation a significant increase in FSH (p <0.01) associated with a decrease in sperm density was observed in both groups and 24 months after radiotherapy patients with initially normal FSH had significantly lower serum FSH (p <0.01) associated with higher sperm density than those with initially elevated FSH (p <0.01), indicating less impairment of Sertoli cell function. Comparable results were observed in chemotherapy treated germ cell tumor patients with initially normal (11) and elevated serum FSH (7), respectively, and 36 months after chemotherapy patients with initially normal FSH had significantly lower FSH concentrations than those with initially elevated FSH (p <0.01). Compensated impairment of Leydig cell function reflected by a subnormal T/LH ratio was evident before chemotherapy in 16.7% of patients increasing up to 41.2% 36 months after therapy. In contrast, 24 months after radiotherapy only 25% of seminoma patients showed a subnormal ratio reflecting less damage to the Leydig cells caused by irradiation. CONCLUSIONS: Pretreatment FSH is a prognostic serum marker of spermatogenesis status of germ cell tumor patients receiving standard radiotherapy or chemotherapy. In contrast to seminoma patients after radiotherapy, impairment of Leydig cell function was evident in germ cell tumor patients after cisplatin based chemotherapy.

Gonadal function of patients treated with cisplatin based chemotherapy for germ cell cancer.

PURPOSE: The cure rate of patients with germ cell cancer of the testis has considerably improved since the introduction of cisplatin based chemotherapy. Because these patients are in their reproductive years and because some of them will be infertile after treatment, the effects of cytotoxic treatment on gonadal function are investigated by hormonal evaluations. MATERIALS AND METHODS: In a transversal trial, luteinizing hormone, follicle-stimulating hormone and testosterone were determined radioimmunologically in serum samples of 232 patients with germ cell tumors after unilateral orchiectomy (patient age 18 to 64 years) up to 153 months after chemotherapy. Additionally, 51 of these patients were investigated in a longitudinal trial before and up to 5 years after chemotherapy. All patients received at least 2 courses of different cisplatin based chemotherapy regimens: cisplatin/vinblastine/bleomycin, cisplatin/vinblastine/bleomycin/ifosfamide, cisplatin/etoposide/bleomycin, cisplatin/vinblastine/bleomycin/ifosfamide/etoposide. Additionally, 11 patients with germ cell tumors (age 22 to 38 years, stage I) were investigated within the first year after orchiectomy and retroperitoneal lymphadenectomy but without chemotherapy. RESULTS: In the transversal trial, 24 of 73 patients investigated during the first year after chemotherapy showed elevated luteinizing hormone concentrations, 5 had subnormal serum testosterone and 65 had elevated serum follicle-stimulating hormone, reflecting spermatogenesis deficits. In 28 patients studied longer than 8 years after chemotherapy (median followup 8.5 years, range 8.0 to 12.6), luteinizing hormone increased after chemotherapy and 60 months after treatment, and follicle-stimulating hormone was elevated in 1 patient, follicle-stimulating hormone was increased in 18 and testosterone was subnormal in 1. Patients without chemotherapy treatment showed gonadotropin and testosterone within normal range and 3 patients had elevated serum follicle-stimulating hormone. In the longitudinal study, mean serum luteinizing hormone plus or minus standard deviation (3.45 +/- 0.05 IU/l.), follicle-stimulating hormone (7.79 +/- 0.13 IU/l.) and testosterone (18.6 +/- 0.17 nmol./l.) were within the normal range before chemotherapy; serum follicle-stimulating hormone was still significantly elevated (16.9 +/- 0.71 IU/l., 19 cases, p < 0.001). Mean luteinizing hormone and testosterone levels were within the normal range, but 60 months after therapy the testosterone-to-luteinizing hormone ratio was still lower than before treatment (p < 0.05). CONCLUSIONS: In patients with germ cell tumors, a compensated insufficiency of the function of the Leydig cells was still observed up to 60 months after chemotherapy. Of these patients 68% showed elevated follicle-stimulating hormone levels, which reflected a functional insufficiency of the Sertoli cells with impaired spermatogenesis. This study shows that impairment of germinative functions is more severe and protracted than the impairment of the endocrine functions.

Testicular dysfunction in adrenomyeloneuropathy.

Adrenomyeloneuropathy (AMN) is a disorder due to a disturbance in the peroxisomal beta-oxidation of saturated very long chain fatty acids. It is characterized by symptoms of the nervous as well as the endocrine systems, especially the adrenal cortex and the gonads. We investigated the testicular function in 49 male AMN patients aged 36.2 +/- 1.5 years (range, 18.5-59 years). Twenty-four of these patients were suffering from adrenocortical insufficiency. Twenty-five AMN patients showed neurological symptoms without 'Addison's disease'. To register the frequency and the degree of gonadal impairment, LH and FSH, testosterone, free testosterone and inhibin-B were determined. Gonadotropin concentrations were significantly higher in AMN patients than in healthy controls (LH, 8.0 +/- 1.2 vs 2.77 +/- 0.11 IU/l; FSH, 10.1 +/- 1.6 vs 4.0 +/- 0.17 IU/l; P < 0.001). Serum LH was elevated in 31 patients (63.3%); 28 patients (57.1%) showed elevated serum FSH indicating deficient spermatogenesis. Mean testosterone did not differ significantly between patients and healthy controls, but mean free testosterone was significantly lower in patients than in controls (16.3 +/- 1.0 vs 28.5 +/- 1.68 pg/ml, P < 0.002). Inhibin-B concentrations did not differ between AMN patients and healthy men. The testosterone/LH ratio reflecting an impairment of the Leydig cells was significantly lower in AMN patients than in controls (P < 0.01). An impairment of the Leydig cells and/or of the Sertoli cells was evident in 81.6% of AMN patients. Twenty-one of thirty-nine patients (53.8%) admitted erectile dysfunction. These data indicate that endocrine dysfunction in AMN is not only confined to adrenocortical functions, but testicular dysfunctions also frequently occur, thus permitting the term 'adreno-testiculo-myelo-neuropathy'.

Opiate antagonists in erectile dysfunction: a possible new treatment option? Results of a pilot study with naltrexone.

Opioids have an inhibitory effect on sexual functions in both animals and humans. Twenty patients with idiopathic, nonvascular, nonneurogenic erectile dysfunction were treated with the opiate receptor antagonist naltrexone in a randomized, placebo-controlled, double-blind study for 8 weeks. Libido and frequency of sexual intercourse were not significantly altered, but early-morning erections increased significantly under naltrexone therapy. This response was not related to levels of androgens or gonadotropins, neither was it dose dependent. There was no change in any of the measured parameters under placebo. Further clinical studies with the substance should be conducted to evaluate its possible role in the oral treatment of male impotence.

Immunoreactive inhibin concentrations in human gonads and adrenals during the first years of life.

We determined immunoreactive inhibin (irINH) concentration in the gonads and adrenals of healthy children (0-75 months) who had died suddenly. Testicular irINH peaked in the first 3 months of life with a significant drop in the 4th month (p < 0.05). In ovarian tissue, irINH was significantly lower than in the testes (p < 0.001) with highest levels during the first 4 months of life parallel to the highest estradiol concentrations. A significant correlation between gonadal testosterone/estradiol and irINH was observed. In adrenal tissue, irINH levels were significantly lower than in the gonads without sex-specific differences.

Attempted protection of spermatogenesis from irradiation in patients with seminoma by D-Tryptophan-6 luteinizing hormone releasing hormone.

Possible protective effects of D-Tryptophan-6 luteinizing hormone releasing hormone (D-Trp-6-LH-RH) against irradiation-induced testicular damage were investigated for the first time in patients with seminoma. After unilateral orchiectomy 12 men were allocated to receive the long-acting gonadotropin releasing hormone (GnRH) agonist D-Trp-6-LH-RH prior to and for the duration of radiotherapy. Eight patients with the same disease served as a control group. In contrast to several trials to protect spermatogenesis from chemotherapy by GnRH agonists, we first suppressed the pituitary-testicular axis before starting the treatment. As a new schedule this adjuvant GnRH agonist treatment was combined with cyproterone acetate for the first 20 days to diminish the amount and the duration of the initial stimulation of gonadotropins and testosterone. Irradiation started after suppression of the pituitary-gonadal axis. In all patients luteinizing hormone and testosterone were completely suppressed throughout the treatment compared to the controls, whereas the initial suppression of follicle-stimulating hormone was not completely maintained until radiotherapy was completed. At the follow-up at 18 months after completion of therapy, all patients reached their initial concentration of gonadotropins, testosterone, and motile spermatozoa independently of D-Trp-6-LH-RH treatment. With the dose and schedule investigated, the GnRH agonist showed no protective effects against testicular damage caused by radiotherapy.

Secretion pattern of immunoreactive inhibin in men.

Chronological changes in serum concentrations of inhibin, a gonadal glycoprotein hormone, were studied in healthy male volunteers (age 24-27 years). Secretion profiles of immunoreactive inhibin (ir-inhibin) were compared with those of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone. Blood samples were collected every 15 min for 24 h. Serum inhibin concentrations were measured by a two-site immunoenzymatic assay with antibodies raised against distinct epitopes of the recombinant 1-32 amino acids of the alpha-subunit of human inhibin. The normal range for men was 0.79-3.1 U/l x 10(-3), the sensitivity of the assay was 0.1 U/l x 10(-3) (cv: within-assay, 6.8%; between-assay, 8.2%). Luteinizing hormone and FSH were measured by immunoradiometric assay and testosterone by radioimmunoassay. Secretion profiles of inhibin and testosterone were tested for diurnal variations by cosinor rhythmometry. Highest ir-inhibin concentrations were observed in the morning at 08.00 h, with peak values of 2.45-3.20 U/l x 10(-3). During the evening and the night, ir-inhibin levels were relatively low; lowest concentrations were observed between 01.00 h and 02.00 h at night: 1.20-1.86 U/l x 10(-3). Highest testosterone levels were observed in the morning (20.5-36.6 pmol/l), lowest concentrations were detected at night (7.35-12.6 pmol/l). Cosinor rhythmometry supported the suggestion that there is a clear circadian secretion of ir-inhibin and testosterone, respectively. The secretion pattern of ir-inhibin was analyzed by the Cluster pulse analysis computed algorithm, which identified four to seven inhibin pulses per day, depending on the person under observation.2+ volunteers follow a clear diurnal rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of idiopathic erectile dysfunction in men with the opiate antagonist naltrexone--a double-blind study.

Opiate antagonists can indirectly stimulate the secretion of luteinizing hormone (LH) and testosterone, as well as sexual functions in animals and humans. We therefore treated 20 otherwise healthy men with idiopathic erectile dysfunction aged 46.3 +/- 2.7 years (mean +/- SE, range 23.9-63.3) in a double-blind study with an opiate antagonist, naltrexone, or placebo. The erectile dysfunction of these men had persisted for 3.6 +/- 0.5 years despite libido maintenance; standard procedures had excluded any organic causes. Trial duration was 12 weeks overall. After a 4-week forerun, the patients received at first 25 mg naltrexone/day orally or placebo for 4 weeks followed by 4 weeks of a 50-mg dose of naltrexone/day or placebo. Each day the patients filled out a questionnaire detailing libido, degree of erection, frequency of sexual intercourse, and spontaneous morning erections. Serum concentrations of gonadotropins and testosterone were determined radioimmunologically in the initial stage and at the end of each phase. Both patient collectives had similar initial factors. The group treated with naltrexone showed a significant rise in spontaneous early morning erections during the treatment: from 2.8 +/- 0.3 to 4.2 +/- 0.3 a week (P < 0.001). The placebo group showed no significant change in spontaneous erections (2.4 +/- 0.3 and 2.6 +/- 0.3, respectively). The subjective parameters, however, such as libido, degree of erection, and frequency of sexual intercourse showed no significant difference within each group. There was no difference in LH, follicle-stimulating hormone, or testosterone concentrations in both groups. Thus, treatment with naltrexone significantly raises the rate of spontaneous early morning erections when compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoreactive plasma inhibin levels in men after polyvalent chemotherapy of germinal cell cancer.

In vitro studies have shown that the Sertoli cell is the primary source of inhibin in the male. We measured immunoreactive inhibin with a new two-site immunoenzymatic assay in the plasma of 92 men: 40 normal men, 7 patients with germinal cell cancer after unilateral orchidectomy and 45 patients with the same disease following unilateral orchidectomy and subsequent chemotherapy based on cisplatin. Normal men had inhibin levels of 1.77 +/- 0.09 U/l x 10(-3) (mean +/- SEM). Seven patients after unilateral orchidectomy had inhibin concentrations within the lower normal range (1.23 +/- 0.22 U/l x 10(-3)). Forty-five patients were investigated in a cross-sectional study up to 102 months after completion of chemotherapy. Inhibin levels were within the normal range in 25 patients (1.76 +/- 0.14 U/l x 10(-3)); 18 patients had significantly lower inhibin levels (0.48 +/- 0.05 U/l x 10(-3), p less than 0.005) when compared to patients after unilateral orchidectomy. Two patients had elevated inhibin levels (4.4 and 5.6 U/l x 10(-3)). The proportion of patients with normal and subnormal inhibin was not dependent on the time that elapsed after completion of chemotherapy or on the chemotherapy combination. There was no correlation between immunoreactive plasma inhibin and LH, FSH, testosterone or sperm count. The decrease in inhibin concentrations after chemotherapy may indicate long-term damage to Sertoli cells in some of the patients.