Showing papers on "Testosterone published in 1997"

Effect of testosterone and estradiol in a man with aromatase deficiency.

Abstract: Recent reports of disruptive mutations of the genes for the estrogen receptor or for cytochrome P-450 aromatase1–6 have shed new light on the role of estrogen. In females the lack of estrogen due to aromatase deficiency leads to pseudohermaphroditism and progressive virilization at puberty, whereas in males pubertal development is normal. In members of both sexes epiphyseal closure is delayed, resulting in a eunuchoid habitus, and osteopenia is present.6 These findings suggest a crucial role of estrogen in skeletal maturation.1–6 We describe the responses to androgen and estrogen in a man with a novel, homozygous inactivating mutation of . . .

The Endocrinology of Aging

Abstract: Most aging individuals die from atherosclerosis, cancer, or dementia; but in the oldest old, loss of muscle strength resulting in frailty is the limiting factor for an individual's chances of living an independent life until death. Three hormonal systems show decreasing circulating hormone concentrations during normal aging: (i) estrogen (in menopause) and testosterone (in andropause), (ii) dehydroepiandrosterone and its sulphate (in adrenopause), and (iii) the growth hormone/insulin-like growth factor I axis (in somatopause). Physical changes during aging have been considered physiologic, but there is evidence that some of these changes are related to this decline in hormonal activity. Hormone replacement strategies have been developed, but many of their aspects remain controversial, and increasing blood hormone levels in aging individuals to those found during mid-adult life has not been uniformly proven to be safe and of benefit.

Testosterone Replacement in Older Hypogonadal Men: A 12-Month Randomized Controlled Trial

Abstract: A decline in testicular function is recognized as a common occurrence in older men However data are sparse regarding the effects of hypogonadism on age-associated physical and cognitive declines This study was undertaken to examine the year-long effects of testosterone administration in this patient population Fifteen hypogonadal men (mean age 68 ± 6 yr) were randomly assigned to receive a placebo, and 17 hypogonadal men (mean age 65± 7 yr) were randomly assigned to receive testosterone Hypogonadism was defined as a bioavailable testosterone <60 ng/dL The men received injections of placebo or 200 mg testosterone cypionate biweekly for 12 months The main outcomes measured included grip strength, hemoglobin, prostate-specific antigen, leptin, and memory Testosterone improved bilateral grip strength (P < 005 by ANOVA) and increased hemoglobin (P < 0001 by ANOVA) The men assigned to testosterone had greater decreases in leptin than those assigned to the control group (mean ± sem: −20 ± 09 ng/dL vs

A role for oestrogens in the male reproductive system

Abstract: Oestrogen is considered to be the 'female' hormone, whereas testosterone is considered the 'male' hormone. However, both hormones are present in both sexes. Thus sexual distinctions are not qualitative differences, but rather result from quantitative divergence in hormone concentrations and differential expressions of steroid hormone receptors. In males, oestrogen is present in low concentrations in blood, but can be extraordinarily high in semen, and as high as 250 pg ml(-1) in rete testis fluids, which is higher than serum oestradiol in the female. It is well known that male reproductive tissues express oestrogen receptors, but the role of oestrogen in male reproduction has remained unclear. Here we provide evidence of a physiological role for oestrogen in male reproductive organs. We show that oestrogen regulates the reabsorption of luminal fluid in the head of the epididymis. Disruption of this essential function causes sperm to enter the epididymis diluted, rather than concentrated, resulting in infertility. This finding raises further concern over the potential direct effects of environmental oestrogens on male reproduction and reported declines in human sperm counts.

Marked Decline in Serum Concentrations of Adrenal C19 Sex Steroid Precursors and Conjugated Androgen Metabolites During Aging

Abstract: The present data show a dramatic decline in the circulating levels of dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), androst-5-ene-3 beta,17 beta-diol (5-diol), 5-diol-sulfate, 5-diol-fatty acid esters, and androstenedione in both men and women between the ages of 20-80 yr. In the 50- to 60-yr-old group, serum DHEA decreased by 74% and 70% from its peak values in 20- to 30-yr-old men and women, respectively. the serum concentrations of the conjugated metabolites of dihydrotestosterone (DHT), namely androsterone (ADT)-G, androstane-3 alpha,17 beta-diol (3 alpha-diol-G), androstane-3 beta,17 beta-diol (3 beta-diol-G), and ADT-sulfate are the most reliable parameters of the total androgen pool in both men and women, whereas serum testosterone and DHT can be used as markers of testicular secretion in men and interstitial ovarian secretion in women. The serum concentration of these various conjugated androgen metabolites decreased by 40.8% to 72.8% between the 20- to 30-yr-old and 70- to 80-yr-old age groups in men and women, respectively, thus suggesting a parallel decrease in the total androgen pool with age. As estimated by measurement of the circulating levels of these conjugated metabolites of DHT, it is noteworthy that women produce approximately 66% of the total androgens found in men. In women, most of these androgens originate from the transformation of DHEA and DHEA-S into testosterone and DHT in peripheral intracrine tissues, whereas in men the testes and DHEA and DHEA-S provide approximately equal amounts of androgens at the age of 50-60 yr. An additional potentially highly significant observation is that the majority of the marked decline in circulating adrenal C19 steroids and their resulting androgen metabolites takes place between the age groups of 20- to 30-yr olds and 50- to 60-yr-olds, with smaller changes are observed after the age of 60 yr.

Testosterone Replacement Increases Fat-Free Mass and Muscle Size in Hypogonadal Men

Abstract: Testosterone-induced nitrogen retention in castrated male animals and sex-related differences in the size of the muscles in male and female animals have been cited as evidence that testosterone has anabolic effects. However, the effects of testosterone on body composition and muscle size have not been rigorously studied. The objective of this study was to determine the effects of replacement doses of testosterone on fat-free mass and muscle size in healthy hypogonadal men in the setting of controlled nutritional intake and exercise level. Seven hypogonadal men, 19-47 yr of age, after at least a 12-week washout from previous androgen therapy, were treated for 10 weeks with testosterone enanthate (100 mg/week) by im injections. Body weight, fat-free mass measured by underwater weighing and deuterated water dilution, and muscle size measured by magnetic resonance imaging were assessed before and after treatment. Energy and protein intake were standardized at 35 Cal/kg.day and 1.5 g/kg.day, respectively. Body weight increased significantly from 79.2 +/- 5.6 to 83.7 +/- 5.7 kg after 10 weeks of testosterone replacement therapy (weight gain, 4.5 +/- 0.6 kg; P = 0.0064). Fat-free mass, measured by underwater weighing, increased from 56.0 +/- 2.5 to 60.9 +/- 2.2 kg (change, +5.0 +/- 0.7 kg; P = 0.0004), but percent fat did not significantly change. Similar increases in fat-free mass were observed with the deuterated water method. The cross-sectional area of the triceps arm muscle increased from 2421 +/- 317 to 2721 +/- 239 mm2 (P = 0.045), and that of the quadriceps leg muscle increased from 7173 +/- 464 to 7720 +/- 454 mm2 (P = 0.0427), measured by magnetic resonance imaging. Muscle strength, assessed by one repetition maximum of weight-lifting exercises increased significantly after testosterone treatment. L-[1-13C]Leucine turnover, leucine oxidation, and nonoxidative disappearance of leucine did not significantly change after 10 weeks of treatment. There was no significant change in hemoglobin, hematocrit, creatinine, and transaminase levels. Replacement doses of testosterone increase fat-free mass and muscle size and strength in hypogonadal men. Whether androgen replacement in wasting states characterized by low testosterone levels will have similar anabolic effects remains to be studied.

Men Homozygous for an Inactivating Mutation of the Follicle-Stimulating Hormone (FSH) Receptor Gene Present Variable Suppression of Spermatogenesis and Fertility

Abstract: Gonadal function is controlled by the two pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). While LH mainly regulates gonadal steroidogenesis, FSH is considered essential for folliculogenesis in the female and spermatogenesis in the male. We recently discovered that an inactivating point mutation in the FSH receptor (R) gene causes a recessively inherited form of hypergonadotropic ovarian failure in homozygous females. This 566C-->T mutation, predicting an alanine to valine substitution, is located in exon 7 of the FSHR gene, in the region encoding the extracellular domain of the receptor molecule. Functional testing showed a clear-cut reduction in ligand binding and signal transduction by the mutated receptor. Hence, lack of FSH function is incompatible with ovarian follicular maturation and female fertility. In the male, FSH is generally considered essential for the pubertal initiation of spermatogenesis and maintenance of quantitatively normal sperm production in adults. We report here the first characterization of males homozygous for an inactivating FSHR mutation. They have variable degrees of spermatogenic failure, but, surprisingly, do not show azoospermia or absolute infertility. These results question the essential role of FSH for the initiation of spermatogenesis, and demonstrate that FSH is more important for female than for male fertility.

Behavioral effects of estrogen receptor gene disruption in male mice (sexual behavioryaggressionyopen-field behavioryandrogen receptorsyaromatization)

Abstract: Gonadal steroid hormones regulate sexually dimorphic development of brain functions and behaviors. Their nuclear receptors offer the opportunity to relate mo- lecular events in neurons to simple instinctive mammalian behaviors. We have determined the role of estrogen receptor (ER)activationbyendogenousestrogeninthedevelopmentof male-typical behaviors by the use of transgenic estrogen- receptor-deficient (ERKO) mice. Surprisingly, in spite of the fact that they are infertile, ERKO mice showed normal motivation to mount females but they achieved less intromis- sionsandvirtuallynoejaculations.Aggressivebehaviorswere dramatically reduced and male-typical offensive attacks were rarely displayed by ERKO males. Moreover, ER gene disrup- tiondemasculinizedopen-fieldbehaviors.Inthebrain,despite the evident loss of functional ER protein, the androgen- dependent system appears to be normally present in ERKO mice. Together, these findings indicate that ER gene expres- sion during development plays a major role in the organiza- tion of male-typical aggressive and emotional behaviors in addition to simple sexual behaviors. Itiswellestablishedthatgonadalsteroidhormones,byactingon the central nervous system, regulate various neuroendocrine eventsrelatedtoreproductionandreproductivebehaviorsinboth sexes. In males, testosterone is a major hormone that facilitates both sexual and aggressive behaviors. The mechanisms underly- ing the behavioral effects of testosterone, however, are compli- cated by the fact that endogenous testosterone can act not only throughtheandrogenreceptor(AR)ascantestosteronemetab- olite (5a-reduced dihydrotestosterone), but also can act through

Dehydroepiandrosterone Activates Mutant Androgen Receptors Expressed in the Androgen-Dependent Human Prostate Cancer Xenograft CWR22 and LNCaP Cells

Abstract: An androgen receptor (AR) gene mutation identified in the androgen-dependent human prostate cancer xenograft, CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT for histidine to TAT for tyrosine and abolished a restriction site for the endonuclease SfaNI. SfaNI digestion of AR exon H DNA from normal but not from prostate cancer tissue indicated H874Y is a somatic mutation that occurred before the initial tumor transplant. CWR22, an epithelial cell tumor, expresses a 9.6-kb AR mRNA similar in size to the AR mRNA in human benign prostatic hyperplasia. AR protein is present in cell nuclei by immunostaining as in other androgen-responsive tissues. Transcriptional activity of recombinant H874Y transiently expressed in CV1 cells in the presence of testosterone or dihydrotestosterone was similar to that of wild type AR. With dihydrotestosterone at a near physiological concentration (0.01 nM), H874Y and wild type AR induced 2-fold greater luciferase activity than did the LNCaP mutant AR T877A. The adrenal androgen, dehydroepiandrosterone (10 and 100 nM) with H874Y stimulated a 3- to 8-fold greater response than with wild type AR and at 100 nM the response was similar with the LNCaP mutant. H874Y, like the LNCaP cell mutant, was more responsive to estradiol and progesterone than was wild type AR. The antiandrogen hydroxyflutamide (10 nM) had greater agonist activity (4- to 7-fold) with both mutant ARs than with wild type AR. AR mutations that alter ligand specificity may influence tumor progression subsequent to androgen withdrawal by making the AR more responsive to adrenal androgens or antiandrogens.

Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia

Abstract: Blood samples were collected from 52 incident cases of histologically confirmed prostate cancer, an equal number of cases of benign prostatic hyperplasia (BPH) and an equal number of apparently healthy control subjects. The three groups were matched for age and town of residence in the greater Athens area. Steroid hormones, sex hormone-binding globulin, and insulin-like growth factor 1 (IGF-1) were measured in duplicate by radioimmunoassay in a specialized US centre. Statistical analyses were performed using multiple logistical regression. The results for IGF-1 in relation to prostate cancer and BPH were adjusted for demographic and anthropometric factors, as well as for the other measured hormones. There was no relation between IGF-1 and BPH, but increased values of this hormone were associated with increased risk of prostate cancer; an increment of 60 ng ml(-1) corresponded to an odds ratio of 1.91 with a 95% confidence interval of 1.00-3.73. There was also some evidence for an interaction between high levels of testosterone and IGF-1 in relation to prostate cancer. This finding suggests that, in addition to testosterone, IGF-1 may increase the risk of prostate cancer in humans.

Contribution of androgens to the gender difference in leptin production in obese children and adolescents.

Abstract: Recent studies demonstrated significantly higher serum leptin concentrations in females as compared with males, even after correction for differences in body fat mass. The aim of our study was to measure serum leptin concentrations in a large group of obese children and adolescents to determine the possible role of sex steroid hormones on both leptin serum concentrations and production in human adipocytes. Obese girls were found to have significantly higher leptin concentrations than boys at the same degree of adiposity (25.2+/-14.1 vs. 17.2+/-12.6 ng/ml, P < 0.001). In a multiple regression analysis with age and body mass index (percent body fat) as fixed variables, it turned out that testosterone had a potent negative effect on serum leptin in boys, but not in girls. In vitro experiments using newly developed human adipocytes in primary culture showed that both testosterone and its biologically active metabolite dihydrotestosterone are able to reduce leptin secretion into the culture medium by up to 62%. Using a semiquantitative reverse transcriptase-PCR method, testosterone was found to suppress leptin mRNA to a similar extent. These results suggest that, apart from differences in body fat mass, the higher androgen concentrations in obese boys are responsible for the lower leptin serum concentrations compared with obese girls.

Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome

Abstract: OBJECTIVE Polycystic ovary syndrome (PCOS) is a common endocrinopathy of unknown aetiology. The aims of this study were to identify whether ovarian thecal cell steroidogenesis is abnormally regulated in PCOS by measuring steroid responses to a single dose of hCG before, and during, suppression of endogenous LH levels by a GnRH analogue (GnRHa). DESIGN Serum levels of LH, FSH, 17αhydroxyprogesterone (17OHP), androstenedione, testosterone and dehydroepiandrosterone sulphate were measured before, and 48 hours after, a single intramuscular injection of 10 000 IU hCG. The test was repeated 4 weeks after suppression of endogenous LH levels by GnRHa. PATIENTS The ovarian responses to hCG were compared in three groups of women. Eleven women had normal ovaries and regular cycles, eight had polycystic ovaries but no clinical features of the syndrome (PCO group) and eight had polycystic ovaries, anovulation and either severe hirsutism or alopecia (PCOS group). RESULTS Before GnRHa treatment, LH levels were significantly higher in the PCOS group but hCG stimulated a similar rise in 17OHP in all three groups. Following analogue, LH levels were suppressed in all three groups but the 17OHP responses to hCG were significantly higher in both the PCO and PCOS groups compared with normal controls. CONCLUSIONS These findings provide further evidence in favour of an intrinsic abnormality of thecal cell steroidogenesis in the polycystic ovary.

Neuroendocrine regulation of gonadotrophin II release and gonadal growth in the goldfish, Carassius auratus.

Abstract: The goldfish, a member of the carp family, is a widely used model for reproductive neuroendocrine studies of economically important fish. The two gonadotrophin (GTH) molecules released from the fish anterior pituitary, GTH-I and GTH-II, are structurally similar to tetrapod FSH and LH, respectively. Gonadotrophin II is the best studied, and in goldfish stimulates gonadal growth and steroidogenesis, ovulation and sperm release. Growth hormone also has gonadotrophic actions in fish which enhance gonadal steroidogenesis. The principal stimulatory and inhibitory systems regulating GTH-II release are the gonadotrophin-releasing hormone (GnRH) and dopamine neurones in the preoptic-hypothalamic region. In goldfish there are two native GnRH forms, salmon GnRH and chicken GnRH-I; both stimulate GTH-II release but use different signal transduction pathways. In contrast to mammals, teleost fish do not have a median eminence and the GTH-II cells are thus directly innervated by neurones producing GnRH, dopamine and other stimulatory neurohormones. For most of these factors, the ability to stimulate GTH-II release varies seasonally. The amino acid neurotransmitter, gamma-aminobutyric acid, has the most prominent stimulatory actions which enhance GnRH release and inhibit dopamine turnover in the hypothalamo-pituitary complex. Neuropeptide Y stimulates GTH-II release by a combined direct action on the gonadotroph and also by enhancing GnRH release. Positive and negative sex steroid feedback mechanisms act concurrently to regulate GTH-II release in adults of both sexes. The principal site of positive feedback is the GTH-II cell where testosterone and oestradiol potentiate GnRH-stimulated GTH-II release. Negative feedback by sex steroids involves activation of inhibitory dopamine neurones, thus maintaining tight control over circulating GTH-II concentrations.

Testosterone Substitution Normalizes Elevated Serum Leptin Levels in Hypogonadal Men

Abstract: The ob gene product leptin (OB) is a feedback signal from the adipocyte to the hypothalamus and is involved in regulation of food intake and energy expenditure in rodents. A major determinant of serum OB levels is fat mass. Several studies suggest that men have lower OB levels than women even after adjustment for percent body fat. We, therefore, investigated the influence of testosterone (T) substitution in hypogonadal men on serum OB levels. Hypogonadal men with T levels of 3.6 nmol/L or less and off substitution therapy for at least 3 months were assigned to two treatment groups: testosterone enanthate (TE; 250 mg, im, every 21 days; n = 10) or a single sc implantation of 1200 mg crystalline T (TPEL; n = 12). Blood samples for determination of T, 5α-dihydrotestosterone (DHT), sex hormone-binding globulin, and 17β-estradiol were obtained before therapy and then every 21 days until day 189 and at follow-up visits on days 246 and 300. Serum OB levels were assessed on days 0, 42, 84, 126, 168, and 300. OB l...

17α-Estradiol Exerts Neuroprotective Effects on SK-N-SH Cells

Abstract: Estradiol (E2) has been shown to exert organizational, neurotrophic, and neuroprotective effects in the CNS. The present study assessed the specificity of the neuroprotective effects of estradiol for the potent 17β-isomer. SK-N-SH cells from a human neuroblastoma cell line, which we have shown to be estrogen-responsive, were cultured at low or high plating density. Then cells were exposed to 17β-E2 (0.2 or 2 nm), 17α-E2 (0.2 or 2 nm), or cholesterol, testosterone, dihydrotestosterone, progesterone, or corticosterone (all at 2 nm). Cultures were insulted by serum deprivation, which caused a profound loss of cells. At 1 or 2 d of serum deprivation and steroid hormone replacement, the protection afforded cells by the steroid addition was assessed. Serum deprivation killed ∼90% of cells cultured at both low and high plating density. Both 17α- and 17β-E2 provided protection of SK-N-SH cells at either plating density. Further, a 10-fold molar excess of tamoxifen antagonized only approximately one-third of the neuroprotective effects of either isomer of estradiol, and a 100-fold excess of tamoxifen had no additional effect on the neuroprotection by 17β-E2. By contrast, none of the other steroids tested protected cells from the insult of serum deprivation. These results indicate that the neuroprotective effects of estrogens are not attributable to the general steroid structure, and the majority of the neuroprotection may not be mediated via a tamoxifen-antagonized receptor mechanism.

Serum inhibin B in healthy pubertal and adolescent boys: relation to age, stage of puberty, and follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol levels.

Abstract: Inhibin B levels were measured in serum from 400 healthy Danish prepubertal, pubertal, and adolescent males, aged 6-20 yr, in a cross-sectional study using a recently developed immunoassay that is specific for inhibin B, the physiologically important inhibin form in men. In addition, serum levels of FSH, LH, testosterone, and estradiol levels were measured. Serum levels of inhibin B, FSH, LH, testosterone, and estradiol all increased significantly between stages I and II of puberty. From stage II of puberty the inhibin B level was relatively constant, whereas the FSH level continued to increase between stages II and III. From stage III of puberty the FSH level was also relatively constant, although there was a nonsignificant trend of slightly decreased FSH levels at pubertal stage V compared to stage IV. The levels of serum LH, testosterone, and estradiol increased progressively throughout puberty. In prepubertal boys younger than 9 yr, there were no correlation between inhibin B and the other three hormones. In prepubertal boys older than 9 yr, a significant positive correlation was observed between inhibin B and FSH, LH, and testosterone. However, at this pubertal stage, each hormone correlated strongly with age, and when the effect of age was taken into account, only the partial correlation between inhibin B and LH/testosterone remained statistically significant. At stage II of puberty, the positive partial correlation between inhibin B and LH/testosterone was still present. At stage III of puberty, an negative partial correlation between inhibin B and FSH, LH, and estradiol was present, whereas no correlation between inhibin B and testosterone could be observed from stage III onward. The negative correlation between inhibin B and FSH persisted from stage III of puberty onward, whereas the correlation between inhibin B and LH and between inhibin B and estradiol was nonsignificant at stages IV and V of puberty. In conclusion, in boys, serum inhibin B levels increase early in puberty; by pubertal stage II the adult level of inhibin B has been reached. The correlation of inhibin B to FSH, LH, and testosterone changes during pubertal development. Early puberty is characterized by a positive correlation between inhibin B and LH/testosterone, but no correlation to FSH. Late puberty (from stage III) is characterized by a negative correlation between inhibin B and FSH (which is maintained in adult men), a diminishing negative correlation between inhibin B and LH, and no correlation between inhibin B and testosterone, suggesting that developmental and maturational processes in the hypothalamic-pituitary-gonadal axis take place, leading to the establishment of the closed loop feedback regulation system operating in adult men. The positive correlation between inhibin B and LH/ testosterone at the time when serum inhibin B levels rise early in puberty suggests that Leydig cell factors may play an important role in the maturation and stimulation of Sertoli cells in the beginning of pubertal development.

Hormonal and cellular regulation of Sertoli cell anti-Müllerian hormone production in the postnatal mouse.

Abstract: Anti-Mullerian hormone (AMH) is secreted by immature testicular Sertoli cells. Clinical studies have demonstrated a negative correlation between serum AMH and testosterone in puberty but not in the neonatal period. We investigated AMH regulation using mouse models mimicking physiopathological situations observed in humans. In normal mice, intratesticular, not serum, testosterone repressed AMH synthesis, explaining why AMH is downregulated in early puberty when serum testosterone is still low. In neonatal mice, AMH was not inhibited by intratesticular testosterone, due to the lack of expression of the androgen receptor in Sertoli cells. We had shown previously that androgen-insensitive patients exhibit elevated AMH in coincidence with gonadotropin activation. In immature normal and in androgen-insensitive Tfm mice, follicle stimulating hormone (FSH) administration resulted in elevation of AMH levels, indicating that AMH secretion is stimulated by FSH in the absence of the negative effect of androgens. The role of meiosis on AMH expression was investigated in Tfm and in pubertal XXSxrb mice, in which germ cells degenerate before meiosis. We show that meiotic entry acts in synergy with androgens to inhibit AMH. We conclude that AMH represents a useful marker of androgen and FSH action within the testis, as well as of the onset of meiosis.

Androgens stimulate fatty acid synthase in the human prostate cancer cell line LNCaP.

Abstract: In addition to modulation of cell proliferation and stimulation of prostate-specific antigen secretion, one of the most striking effects of androgens on the human prostate cancer cell line LNCaP is the accumulation of neutral lipids. These lipids are synthesized de novo, suggesting that LNCaP cells express all enzymes required for endogenous lipogenesis and that the expression and/or activity of some of these enzymes is affected by androgens. One of the key enzymes involved in lipogenesis is fatty acid synthase (FAS), a potential prognostic enzyme and therapeutic target that is found to be frequently overexpressed in a variety of cancers including prostate cancer. Here, using Northern blot analysis, the gene encoding FAS is shown to be abundantly expressed in LNCaP cells and in two other prostate cancer cell lines tested (PC-3 and DU-145). In LNCaP cells, androgen treatment (10(-8) M R1881) causes a 3-4-fold increase in FAS mRNA levels. Concomitantly with the increase in FAS gene expression, androgens induce a 10-12-fold stimulation of FAS activity. Effects are dose- and time-dependent and follow courses similar to those of the androgen induction of lipid accumulation. In support of the involvement of the androgen receptor, steroid specificity of regulation of FAS activity is in agreement with the aberrant ligand specificity of the mutated androgen receptor in LNCaP cells. Stimulation of FAS activity is inhibited by the antiandrogen Casodex (bicalutamide) and is absent in the androgen receptor-negative cell lines PC-3 and DU-145. Taken together, these data demonstrate that androgens, mediated by the androgen receptor, stimulate the expression and activity of FAS and suggest that stimulation of FAS activity represents at least part of the mechanism by which androgens induce the accumulation of neutral lipids in LNCaP cells.

Transgenic Mice Overexpressing the Prolactin Gene Develop Dramatic Enlargement of the Prostate Gland

Abstract: An altered endocrine status of elderly men has been hypothesized to be important for development of prostate hyperplasia. The present study addresses the question whether increased PRL expression is of importance for development of prostate hyperplasia in mice. Three lines of PRL transgenic mice were generated having serum levels of PRL of approximately 15 ng/ml, 100 ng/ml, and 250 ng/ml, respectively. These mice developed dramatic enlargement of the prostate gland, approximately 20 times the normal prostate weight and they had a 4- to 5-fold increased DNA content. Histologically, the prostate glands in the transgenic mice were distended from secretion, and the amount of interstitial tissue was increased. The levels oftestosterone and IGF-I were increased in the PRL transgenic animals. In mice overexpressing the bovine GH gene, displaying elevated IGF-I levels, the prostate gland was slightly larger compared with normal mice, indicating that the effect of PRL was not primarily mediated through elevated plasma IGF-I levels. The present study suggests that PRL is an important factor in the development of prostate hyperplasia acting directly on the prostate gland or via increased plasma levels of testosterone.

Reversal of the sex difference in serum leptin levels upon cross-sex hormone administration in transsexuals

Abstract: Women have higher circulating leptin levels than men. This sex difference is not simply explained by differences in the amount of body fat and is possibly influenced by their different sex steroid milieus. This prompted us to study prospectively the effects of cross-sex steroid hormones on serum leptin levels in 17 male to female transsexuals and 15 female to male transsexuals. Male to female transsexuals were treated with 100 micrograms ethinyl estradiol and 100 mg cyproterone acetate (antiandrogen) daily, and female to male transsexuals received testosterone esters (250 mg/2 weeks, im). Before and after 4 and 12 months of cross-sex hormone treatment, serum leptin levels and measures of body fatness were assessed. Before treatment, female subjects had higher serum leptin levels than male subjects independently of the amount of body fat (P < 0.01). Cross-sex hormone administration induced a reversal of the sex difference in serum leptin levels. Estrogen treatment in combination with antiandrogens in male subjects increased median serum leptin levels from 1.9 ng/mL before treatment to 4.8 ng/mL after 4 months and 5.5 ng/mL after 12 months of treatment (P < 0.0001). Testosterone administration in female subjects decreased median serum leptin levels from 5.6 to 2.6 ng/mL after 4 months and to 2.5 ng/mL after 12 months (P < 0.0001). Analysis of covariance revealed that the changes in serum leptin levels were independent of changes in body fatness in both groups (P < 0.01). In conclusion, these results indicate that sex steroid hormones, in particular testosterone, play an important role in the regulation of serum leptin levels. The prevailing sex steroid milieu, not genetic sex, is a significant determinant of the sex difference in serum leptin levels.

Androgen Supplementation in Eugonadal Men with Osteoporosis: Effects of Six Months' Treatment on Markers of Bone Formation and Resorption

Abstract: There is no established treatment for osteoporosis in men, a common and disabling condition the incidence of which is increasing rapidly. We conducted an open study to investigate the efficacy and mode of action of testosterone therapy in eugonadal men with osteoporotic vertebral crush fracture. Twenty-one men, aged 34–73 (mean 58), were treated with intramuscular testosterone esters (Sustanon 250®) every 2 weeks for 6 months. Bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry was performed at baseline and 6 months. We also measured biochemical markers of bone turnover, testosterone, estradiol, sex hormone binding globulin (SHBG), and gonadotrophins at baseline and after 3 and 6 months of treatment. Treatment was well tolerated, and side effects were uncommon. Lumbar spine BMD increased by 5% from 0.799 to 0.839 g/cm2 (p < 0.001). All bone markers decreased, indicating that treatment suppressed bone turnover. Although serum osteocalcin levels fell only slightly, there were large reductions in urinary deoxypyridinoline and N-telopeptide (p < 0.05), which were correlated with the increase in spinal BMD. Interpretation of the findings with other markers, such as bone-specific alkaline phosphatase and pyridinoline, was confounded by the wide scatter of values. Serum testosterone increased by 55%, while SHBG decreased by 20%, leading to a rise in free androgen of 90%. Serum estradiol also increased by 45%. The change in spine BMD was significantly correlated with a change in serum estradiol but not with a change in serum testosterone. We therefore conclude that testosterone is a promising treatment for men with idiopathic osteoporosis, acting to suppress bone resorption by a mechanism that may involve estrogen.

Adult-onset idiopathic hypogonadotropic hypogonadism--a treatable form of male infertility.

Abstract: Background Men with isolated gonadotropin-releasing hormone (GnRH) deficiency typically present with an absence of pubertal development. We describe an adult-onset form of idiopathic hypogonadotropic hypogonadism that develops after puberty. Methods We studied 10 men (age, 27 to 57 years) with normal sexual maturation, idiopathic infertility, sexual dysfunction, low serum testosterone concentrations, and apulsatile secretion of luteinizing hormone on frequent blood sampling. All the men had otherwise normal anterior pituitary hormone secretion and sellar anatomy. We compared the results of semen analyses and measurements of testicular volume, serum testosterone, inhibin B, and gonadotropins in these men with the results in 24 men with classic GnRH deficiency before and during GnRH-replacement therapy and in 29 normal men of similar age. Results Serum gonadotropin concentrations in the men with adult-onset GnRH deficiency were similar before and during pulsatile GnRH administration to those in the men with...

Androgen deprivation is associated with enhanced endothelium-dependent dilatation in adult men.

Abstract: Male gender is an independent risk factor for coronary artery disease, and androgen administration has been associated with increased atherosclerosis in experimental animals. Since endothelial dysfunction is an important event in the atherogenic process, we hypothesized that androgen deprivation in adult men might be associated with enhanced arterial endothelial function. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilatation) and after nitroglycerin (an endothelium-independent dilator). We studied 30 adult males aged 40 to 70 years: 10 had had bilateral orchidectomy and/or maximal androgen blockade for > or = 6 months for treatment of prostate cancer, and all were in complete remission (group 1). Ten healthy controls (group 2) and 10 controls who had remission from nonprostate cancers (group 3) were matched for age and smoking history. Testosterone levels were lower in men in group 1 versus groups 2 or 3 (0.8 +/- 0.1 versus 19.2 +/- 8.4 or 16.1 +/- 4.9 nmol/L, P .25). The withdrawal of male sex hormones may be associated with enhanced endothelial function in adult men. This is consistent with a deleterious effect of physiologic levels of male sex steroids on the arterial wall.

Physiological relationships between inhibin B, follicle stimulating hormone secretion and spermatogenesis in normal men and response to gonadotrophin suppression by exogenous testosterone

Abstract: Inhibin has been postulated to be secreted by Sertoli cells in response to follicle stimulating hormone (FSH) and in turn to exert an inhibitory effect on FSH production. The authors have investigated this relationship using an assay specific for dimeric inhibin B. A total of 56 normal men received 200 mg testosterone enanthate (TE) im weekly for 65 +or- 1 weeks in a trial of hormonal male contraception. Before treatment a significant negative correlation between inhibin B and FSH concentration (r = 0.49 P < 0.001) was observed. During TE treatment luteinizing hormone (LH) and FSH were rapidly suppressed. This was followed by a parallel decline in inhibin B and sperm concentration. During the early recovery phase inhibin B concentrations remained suppressed in men who showed a delay in resumption of spermatogenesis despite higher FSH concentrations. Inhibin B returned to pretreatment concentrations after 24 weeks recovery when the inverse relationship with FSH was restored. The authors results showed the expected inverse physiological relationship between inhibin B and FSH in normal men with a decline during TE treatment and a subsequent resumption of the inverse relationship during recovery. These data clearly support the hypothesis that inhibin B plays a physiological role in the feedback control of FSH secretion and reflects FSH-stimulated Sertoli cell function. (authors)

Endocrine aspects of anabolic steroids

Abstract: Understanding of the mechanism of androgen action has been enhanced by advances in knowledge on the molecular basis of activation of the androgen receptor and the importance of tissue conversion of circulating testosterone to dihydrotestosterone and estradiol. New evidence supports the view that supraphysiological doses of anabolic steroids do have a definite, positive effect on muscle size and muscle strength. However, the nature of the anabolic action of androgens on muscle is currently unclear and may involve mechanisms independent of the androgen receptor. The dose-response relationships of anabolic actions vs the potentially serious risk to health of androgenic-anabolic steroids (AAS) use are still unresolved. Most of the adverse effects of AAS are reversible but some are permanent, particularly in women and children. The reported incidence of acute life-threatening events associated with AAS abuse is low, but the actual risk may be underrecognized or underreported; the exact incidence is unknown. The long-term consequences and disease risks of AAS to the sports competitor remain to be properly evaluated.

Fetal death in mice lacking 5α-reductase type 1 caused by estrogen excess

Abstract: Female mice deficient in steroid 5α-reductase type 1 have a decreased litter size. The average litter in homozygous deficient females is 2.7 pups vs. 8.0 pups in wild type controls. Oogenesis, fertilization, implantation, and placental morphology appear normal in the mutant animals. Fetal loss occurs between gestation days 10.75 and 11.0 commensurate with a midpregnancy surge in placental androgen production and an induction of 5α-reductase type 1 expression in the decidua of wild type mice. Plasma levels of androstenedione and testosterone are 2- to 3-fold higher on gestation day 9, and estradiol levels are chronically elevated by 2- to 3-fold throughout early and midgestation in the knockout mice. Administration of an estrogen receptor antagonist or inhibitors of aromatase reverse the high rate of fetal death in the mutant mice, and estradiol treatment of wild type pregnant mice causes fetal wastage. The results suggest that in the deficient mice, a failure to 5α-reduce androgens leads to their conversi...