Klinefelter's syndrome as a model of anomalous cerebral laterality: testing gene dosage in the X chromosome pseudoautosomal region using a DNA microarray.

Consistent handedness and language laterality are two of the most striking behavioral and cognitive asymmetries observed in humans. Alterations in the typical pattern of cerebral laterality, termed "anomalous dominance," is observed in left-handers and some patients with verbal learning disabilities. We undertook the study of a genetically distinct group of subjects, XXY males (Klinefelter's syndrome; KS), who demonstrate anomalous dominance in a variety of testing paradigms in order to begin to elucidate the molecular basis of anomalous dominance in this population.

Suppression of spermatogenesis in man induced by Nal-Glu gonadotropin releasing hormone antagonist and testosterone enanthate (TE) is maintained by TE alone.

GnRH antagonists plus testosterone (T) suppress LH and FSH levels and inhibit spermatogenesis to azoospermia or severe oligozoospermia. High-dose T treatment alone has been shown to be an effective male contraceptive (contraceptive efficacy rate of 1.4 per 100 person yr).

Triptolide: a potential male contraceptive.

The antifertility effect of triptolide and other related compounds, isolated from Tripterygium wilfordii, has been demonstrated in male rats. The exact sites and mechanism of action of triptolide remain unknown. Our objectives were to determine whether triptolide at selected dose levels that induce infertility has any detrimental effects on the testes and to determine the sites and the possible mechanisms of its action.

Comparative pharmacokinetics of three doses of percutaneous dihydrotestosterone gel in healthy elderly men--a clinical research center study.

Twenty-five men, 60-80 yr old, participated in a pharmacokinetic study to compare three doses (16, 32, and 64 mg/day, n = 8 or 9 in each group) of 5alpha-dihydrotestosterone (DHT) gel (0.7% hydroalcoholic gel with 2.3 g gel delivering 16 mg DHT) applied daily over one upper arm (16 mg); both arms and shoulders (32 mg); and bilateral arms, shoulders, and upper abdomen (64 mg), respectively.

Influence of pituitary disease on sexual development and functioning.

Pituitary disorders may have a major effect on sexual development and function. This review describes the regulation of normal reproductive hormonal function in the fetus, infant, adolescent and adult. The effects of pituitary insufficiency and pituitary adenomas on sexual development, reproductive function and sexuality in men and women are discussed.

Androgen-behavior correlations in hypogonadal men and eugonadal men. II. Cognitive abilities.

Sex-typed cognitive abilities were assessed in 33 hypogonadal men receiving testosterone replacement therapy, 10 eugonadal men receiving testosterone in a male contraceptive clinical trial, and 19 eugonadal men not administered testosterone. Prior to and following hormone administration, men completed four tests measuring visuospatial ability, three tests measuring verbal fluency, two tests measuring perceptual speed, and a measure of verbal memory. Group differences in testosterone levels were unrelated to performance on most cognitive measures, including visuospatial ability.

Spontaneous expression of inducible nitric oxide synthase in the hypothalamus and other brain regions of aging rats.

Our laboratory has demonstrated that aging in Brown-Norway rats is associated with decreased LH pulse amplitude and reduced GnRH and LH responsiveness to excitatory amino acids (EAA), presumably through the NMDA receptor (NMDAR). Nitric oxide (NO) is a neurotransmitter postulated to be involved in hypothalamic synaptic events required for normal GnRH regulation through the activation of neuronal nitric oxide synthase (nNOS). Paradoxically, excessive stimulation of nNOS by NMDAR or the expression of inducible nitric oxide synthase (iNOS) can lead to supraphysiological levels of NO acting as effector of apoptosis with resultant decreased regional neuronal function.

Ethnic differences in testicular structure and spermatogenic potential may predispose testes of Asian men to a heightened sensitivity to steroidal contraceptives.

Spermatogenesis in Asian men appears to be more susceptible to suppression by steroidal contraceptives administered in clinical trials than spermatogenesis in Caucasian men. The objective of this study was to determine whether ethnic differences exist in testicular structure and spermatogenic potential that might predispose Asians to a high sensitivity to steroidal contraceptives. Testes from 12 Chinese men were compared to those from 8 Hispanic men and 12 non-Hispanic Caucasian men of ages 29+/-3, 30+/-2, and 29+/-3 years, respectively.

Aging results in attenuated gonadotropin releasing hormone-luteinizing hormone axis responsiveness to glutamate receptor agonist N-methyl-D-aspartate.

Reproductive aging in the Brown Norway rat occurs because of testicular as well as hypothalamic-pituitary dysfunction. Excitatory amino acids (EAA) participate in the regulation of pulsatile secretion of hypothalamic GnRH and pituitary LH. In the present study, we studied the EAA-GnRH-LH axis for possible age-related alterations in prepubertal (35 days), young (3-4 months), middle-aged (12-13 months) and old (21-23 months) rats.

Graded testosterone infusions distinguish gonadotropin negative-feedback responsiveness in Asian and white men--a Clinical Research Center study.

Recently, multicenter clinical trials to determine male contraceptive efficacy disclosed that testosterone-induced suppression of spermatogenesis to azoospermia occurred in about 90% of Asian but only 60-70% of white men. To test whether there are ethnic differences in the sensitivity of gonadotropin secretion to suppression by testosterone, we administered constant infusions of testosterone at 0, 7, 14, and 28 mg/1.7 m2 x 24 h i.

Androgen replacement therapy.

Androgen therapy has been primarily used for replacement therapy in symptomatic hypogonadal men. Other indications under clinical investigation include androgen replacement therapy for older men with age-associated decline in serum testosterone levels, muscle-wasting disease, male contraception and as adjunctive therapy to oestrogen (and progesterone) hormone replacement for postmenopausal women. Recent scientific and pharmaceutical interests led to development of new long-acting injectables, transdermal delivery systems and sublingual preparations.

Spontaneous germ cell apoptosis in humans: evidence for ethnic differences in the susceptibility of germ cells to programmed cell death.

Spontaneous death of certain classes of germ cells has been shown to be a constant feature of normal spermatogenesis in a variety of mammalian species, including the human. Recent studies on various animal models have demonstrated that apoptosis is the underlying mechanism of germ cell death during normal spermatogenesis. Withdrawal of gonadotropins and/or testosterone further accelerates the germ cell apoptosis.

Significance of apoptosis in the temporal and stage-specific loss of germ cells in the adult rat after gonadotropin deprivation.

The major objectives of the present study were to document the temporal and stage-specific acceleration of germ cell apoptosis in adult rats after selective suppression of pituitary gonadotropins by GnRH antagonist (GnRH-A) treatment, and to examine the possibility that apoptosis is the sole mechanism of germ cell death in response to hormonal deprivation. Groups of adult male rats were given a daily injection of a vehicle for 14 days or GnRH-A (1.25 mg/kg BW) for 2, 5, 7, and 14 days.

Separation of germ cell apoptosis from toxin-induced cell death by necrosis using in situ end-labeling histochemistry after glutaraldehyde fixation.

In situ end-labeling of fragmented DNA is routinely being used to detect apoptotic cells in various tissues including the testis. In this study, we examined the influence of various fixatives (neutral buffered formalin, paraformaldehyde, and glutaraldehyde) on the testicular structural integrity and immunoreactivity of fragmented DNA in apoptotic germ cells of the adult rat. Accelerated apoptosis of germ cells was induced in the adult rate by gonadotropin deprivation.

Effect of increased scrotal temperature on sperm production in normal men.

Objective: To determine whether application of polyester-lined athletic supports to bring the testes closer to the abdomen increases scrotal temperature and decreases sperm production.

Design: Prospective clinical study.

Setting: University academic medical center.

In the male brown-Norway (BN) male rat, reproductive aging is associated with decreased LH-pulse amplitude and area.

The Brown-Norway (BN) rat has been proposed as a rodent model for the study of human male reproductive aging. As in man, reduction in serum or plasma testosterone (T) and both testicular (primary) and hypothalamic-pituitary (secondary) reproductive dysfunction have been associated with aging in male BN rats. However, the presence of secondary testicular failure in this rodent, as indicated by low serum luteinizing hormone (LH) levels, needs further corroboration.

Oligozoospermia induced by exogenous testosterone is associated with normal functioning residual spermatozoa.

Objective: To determine the functional capacity of residual spermatozoa in semen samples from normal men with T enanthate-induced oligozoospermia.

Design: Prospective clinical study.

Setting: Academic research center.

Androgen-behavior correlations in hypogonadal men and eugonadal men. I. Mood and response to auditory sexual stimuli.

Mood and response to auditory sexual stimuli were assessed in 33 hypogonadal men receiving testosterone (T) replacement therapy, 10 eugonadal men receiving T in a male contraceptive clinical trial, and 19 eugonadal men not administered T. Prior to and after 6 weeks of hormone administration, men completed a mood questionnaire, rated sexual arousal to and sexual enjoyment of auditory sexual stimuli, and performed a dichotic listening task measuring selective attention for sexual stimuli. Mood questionnaire results suggest that T has positive effects on mood in hypogonadal men when hormone levels are well below the normal male range of values, but does not have any effects on mood when hormone levels are within or above the normal range.

Early effects of vasectomy on testicular structure and on germ cell and macrophage apoptosis in the hamster.

This study provides quantitative information on the early (up to 3 months) effects of vasectomy on apoptosis in the hamster testis. Groups of five adult male golden hamsters were either bilaterally vasectomized or sham-operated and sacrificed at intervals of 3, 6, and 12 weeks after surgery. In all three postvasectomy groups, testis weight and testicular and plasma testosterone (T) levels were not different from controls.

The interaction between beta-endorphin and gonadal steroids in regulation of luteinizing hormone (LH) secretion and sex steroid regulation of LH and proopiomelanocortin peptide secretion by individual pituitary cells.

Reported studies using the conventional pituitary cell culture technique suggest that beta-endorphin (B-EP) produced locally in the pituitary or reaching it from the hypothalamus acts in conjunction with estradiol (E2) to initiate and in conjunction with progesterone (P4) to terminate the midcycle surge of LH. In addition, the reverse hemolytic plaque assay (RHPA) was used to investigate the effects of E2 and P4 on the secretory activity of individual pituitary cells. The results of these experiments indicate that 1) E2 enhances the secretion of LH, ACTH, and B-EP by individual pituitary cells; 2) E2 increases the number of secreting cells for each of the three hormones; 3) the rise in B-EP and ACTH secretion antecede that of LH; 4) P4 augments ACTH and B-EP secretion by individual pituitary cells; and 5) P4 has dual effects, acutely (1 h) potentiating LH secretion from already active cells and subsequently (8 h) recruiting cells that formerly had little or no secretory activities.

Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men--a clinical research center study.

To study the effects of androgen replacement therapy on muscle mass and strength and bone turnover markers in hypogonadal men, we administered sublingual testosterone (T) cyclodextrin (SLT; 5 mg, three times daily) to 67 hypogonadal men (baseline serum T, < 8.4 nmol/L) recruited from 4 centers in the U.S.

Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study.

The effect of testosterone (T) replacement on changes in mood was studied for 60 days in 51 hypogonadal men. All patients were withdrawn from their prior T replacement for at least 6 weeks before enrollment. Of these patients, 18 received T enanthate 200 mg im every 20 days, 16 received sublingual T cyclodextrin (SLT) at a dose of 2.

Androgens are not major down-regulators of androgen receptor levels during growth of the immature rat penis .

This study was undertaken to investigate the prevalent hypothesis that androgens are responsible for the organ-specific down-regulation of penile androgen receptors (ARs) and decline of penile growth in the rat during sexual maturation. Sexually immature male rats (21 days old) were castrated and treated for 3 days ("short-term"), with high doses of: (a) testosterone and the alpha-reductase inhibitor finasteride (T/F); (b) dihydrotestosterone (DHT); or (c) finasteride alone (F). Intact and castrate controls received vehicle only.

Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate--a clinical research center study.

We studied and compared the pharmacokinetics and bioefficacy of two doses of sublingual testosterone cyclodextrin (SLT; 2.5 and 5.0 mg, administered three times per day) with testosterone enanthate (TE; 200 mg) given once every 20 days by im injections over a 60-day study period in 63 hypogonadal men.