Showing papers on "Testosterone published in 1995"

Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor.

Abstract: Interleukin-6 is an essential mediator of the bone loss caused by loss of estrogens. Because loss of androgens also causes bone loss, we have examined whether the IL-6 gene is regulated by androgens, and whether IL-6 plays a role in the bone loss caused by androgen deficiency. Both testosterone and dihydrotestosterone inhibited IL-6 production by murine bone marrow-derived stromal cells. In addition, testosterone, dihydrotestosterone, and adrenal androgens inhibited the expression of a chloramphenicol acetyl transferase reporter plasmid driven by the human IL-6 promoter in HeLa cells cotransfected with an androgen receptor expression plasmid; however, these steroids were ineffective when the cells were cotransfected with an estrogen receptor expression plasmid. In accordance with the in vitro findings, orchidectomy in mice caused an increase in the replication of osteoclast progenitors in the bone marrow which could be prevented by androgen replacement or administration of an IL-6 neutralizing antibody. Moreover, bone histomorphometric analysis of trabecular bone revealed that, in contrast to IL-6 sufficient mice which exhibited increased osteoclast numbers and bone loss following orchidectomy, IL-6 deficient mice (generated by targeted gene disruption) did not. This evidence demonstrates that male sex steroids, acting through the androgen-specific receptor, inhibit the expression of the IL-6 gene; and that IL-6 mediates the upregulation of osteoclastogenesis and therefore the bone loss caused by androgen deficiency, as it does in estrogen deficiency.

Induction of spermatogenesis by androgens in gonadotropin-deficient (hpg) mice.

Abstract: Using a new experimental model for studying the hormonal induction of spermatogenesis, the hpg mouse, which has congenital functional gonadotropin deficiency due to a major deletion in the GnRH gene, we investigated the roles of testosterone (T) and dihydrotestosterone (DHT) in the initiation of spermatogenesis. Weanling homozygous hpg male mice were implanted subdermally with SILASTIC brand implants of varying lengths (0-2 cm) filled with T or DHT, using phenotypically normal (N/N or N/hpg) and untreated hpg/hpg mice as positive and negative controls. After 8 weeks, both T and DHT equally stimulated (approximately 14-fold) testis size and induced qualitatively complete spermatogenesis despite low intratesticular androgen levels and undetectable circulating FSH. Stereological quantitation of Sertoli and germ cells demonstrated a dose-dependent rise in the absolute numbers of all germ cell types induced by both T and DHT. At maximal androgen doses, germ cell numbers expressed per Sertoli cell and homogenization-resistant elongated spermatids expressed per mg testis were increased to more than 80% of non-hpg control values. An in vitro fertilization assay confirmed that both T and DHT induced quantitatively normal fertilizing capacity of the sperm in hpg males. We conclude that androgens, acting through the androgen receptor without need for aromatization, initiate qualitatively complete spermatogenesis in the mouse, including fertile sperm despite low intratesticular androgen levels and the absence of blood FSH levels. The hpg mouse model is a useful new paradigm to study the molecular basis of the hormonal induction of spermatogenesis.

Reproducibility of plasma hormone levels in postmenopausal women over a 2-3-year period.

Abstract: We evaluated the reproducibility of plasma hormone levels over time in 79 healthy postmenopausal women, ages 51-69 years at baseline, who were not using postmenopausal hormones. Three blood samples were collected between 1989 and 1992 from each of these women. We assessed plasma levels of estradiol, free estradiol, percentage of free estradiol, bioavailable estradiol, percentage of bioavailable estradiol, estrone, estrone sulfate, sex hormone-binding globulin (SHBG), androstenedione, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and prolactin at each of three sample collections. The means and SD for each of the plasma estrogens, SHBG, and prolactin were similar at each collection. For the androgens, plasma levels tended to decrease over time consistent with an aging effect; decreases with increasing age were statistically significant for androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. Intraclass correlation coefficients (ICCs) ranged from 0.92 (95% confidence interval = 0.89-0.95) for SHBG to 0.53 (95% confidence interval = 0.43-0.69) for prolactin. Most correlations were at least 0.70. The ICCs did not vary by age or time since menopause. Women who changed weight over the course of the study tended to have lower ICCs for a number of the hormones, although these differences were not statistically significant. These data indicate that, for most of these plasma hormones, a single measurement can reliably categorize average levels over at least a 3-year period in postmenopausal women.

Testosterone Increases Human Platelet Thromboxane A2 Receptor Density and Aggregation Responses

Abstract: Background The incidence of thrombotic cardiovascular disease is greater in men than in premenopausal women. Testosterone has been implicated as a significant risk factor for cardiovascular disease and for acute myocardial infarctions and strokes in young male athletes who abuse anabolic steroids. Thromboxane A2 (TXA2) is a vasoconstrictor and platelet proaggregatory agent that has been implicated in the pathogenesis of cardiovascular disease. We therefore tested the hypothesis that testosterone regulates the expression of human platelet TXA2 receptors. Methods and Results In a double-blind, placebo-controlled, randomized, parallel-group study, we determined the effects of testosterone cypionate 200 mg IM given twice, 2 weeks apart, or saline placebo in 16 healthy men. Platelet TXA2 receptor density (Bmax) and dissociation constant (Kd) were measured by use of the TXA2 mimetic 125I-BOP. Platelet aggregation responses to I-BOP and to thrombin and plasma testosterone concentrations were measured before trea...

Ageing of the Hypothalamo-Pituitary- Testicular Axis in Men

Abstract: In distinction to the course of reproductive ageing in women, men do not experience a rapid decline of Leydig cell function or irreversible arrest of reproductive capacity in old age. Hence, strictu sensu, the andropause does not exist. Nevertheless, both spermatogenesis and fertility as well as Leydig cell function do decline with age, as shown by a decrease of +/- 35% of total and of 50% of free testosterone levels between the age of 20 and 80 years. The origin of this decline of Leydig cell function resides on the one hand in the testes, and is essentially characterized by a decreased number of Leydig (and Sertoli) cells and on the other hand in the hypothalamo-pituitary complex characterized by a decreased luteinzing hormone (LH) pulse amplitude, LH pulse frequency being maintained. As the responsiveness of the gonadotrophs to gonadotropin-releasing hormone (GnRH) remains unimpaired, one may assume that the amount of GnRH released at each pulse is also reduced, possibly as the consequence of a reduction of the cellular mass of GnRH neurones. Plasma levels of testosterone below the lower normal limit occur, however, only in a minority of elderly men from 7% in the age group 40-60, to 20% in the age group 60-80 and 35% in the age group over 80 years old. Factors influencing testosterone levels in elderly men are multiple: hereditary, environmental (obesity, stress), psychosocial (depression, smoking, drugs) or socioeconomical (diet, hygiene). Whether these elderly men should be substituted with androgens remains controversial.(ABSTRACT TRUNCATED AT 250 WORDS)

Dihydrotestosterone is the active androgen in the maintenance of nitric oxide-mediated penile erection in the rat

Abstract: Androgens are essential for the expression of normal libido in the male, but their role in the maintenance of the erectile response in humans is controversial. It has been shown previously in the rat that castration induces 1) loss of penile reflexes; and 2) considerable reduction in the erectile response to electric field stimulation (EFS) of the cavernosal nerve. Both of these effects can be reversed by testosterone replacement. The current study was performed to determine whether these testosterone effects are mediated via its conversion to dihydrotestosterone (DHT), and to what extent the synthesis of the mediator of penile erection, nitric oxide, is affected by castration and androgen replacement. Five-month-old rats were either castrated or left intact. The orchiectomized rats were implanted with SILASTIC brand silicon tubing (Dow Corning) containing testosterone or DHT with or without daily injections of the 5 alpha-reductase inhibitor finasteride. After 7 days, rats were submitted to EFS and the intracavernosal pressure was recorded. Castration reduced the EFS-induced erectile response by 50% in comparison with intact rats and testosterone restored this decrease to normal. When finasteride was given to these testosterone-treated castrate rats, erectile response was not restored. DHT was as effective as testosterone in restoring response to EFS in castrates and this effect was not decreased by finasteride. Nitric oxide synthase activity in the penile cytosol was measured by the arginine-citrulline conversion and was found to correlate with the EFS determinations. These results show that DHT is the active androgen in the prevention of erectile failure seen in castrated rats, and suggest that this effect may be mediated, at least partially, by changes in nitric oxide synthase levels in the penis.

Insulin regulates testosterone and sex hormone-binding globulin concentrations in adult normal weight and obese men.

Abstract: There are no studies in vivo on the effects of insulin on androgens and sex hormone-binding globulin (SHBG) in men. We, therefore, investigated the effects of insulin suppression on testosterone and SHBG in two groups of eight nondiabetic adult obese men and six healthy normal weight men who underwent diazoxide treatment (100 mg, three times daily) for 7 days. Blood samples for hormone determination were obtained before the subjects had been selected for the study, immediately before diazoxide administration, and on the last day of treatment. A 24-h oral glucose tolerance test was also performed for glucose, insulin, and C-peptide determinations before and on the last day of treatment. Only one subject experienced significant side-effects, and no significant changes in mean body weight were found during the treatment. Diazoxide administration worsened glucose tolerance in several subjects and reduced fasting and glucose-stimulated insulin levels by approximately 50% in both control and obese subjects. No significant difference was present between historical and pretreatment hormone values in either group. Moreover, there were no differences in pretreatment gonadotropin and SHBG concentrations between the two groups, whereas testosterone (free and total) levels were lower in the obese than in the control subjects. After diazoxide administration, testosterone (free and total) decreased slightly, but significantly, whereas LH and SHBG significantly increased in both groups. Diazoxide treatment increased estradiol levels in controls, but not in obese men. In conclusion, these results indicate that in vivo, insulin is capable of stimulating testosterone production and, simultaneously, of inhibiting SHBG concentrations in both normal weight and obese men.

Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada.

Abstract: Differences in endogenous androgen levels have been hypothesized to explain ethnic differences in prostate cancer risk. To examine this hypothesis, we gathered data on serum concentrations of androgens and sex hormone-binding globulin (SHBG) in healthy older men from four ethnic groups at different levels of prostate cancer risk. As part of a population-based case-control study of prostate cancer we conducted in California, Hawaii, and Vancouver, Canada, 1127 African-American, white, Chinese-American, and Japanese-American control men, mostly ages 60 years or older (mean age, 69.9 years) provided information on various lifestyle factors and donated an early morning fasting blood sample between March 1990 and March 1992. We used these data to examine the distributions of serum androgens [testosterone (total, free, and bioavailable), dihydrotestosterone (DHT)], the ratio of DHT to total testosterone (DHT:testosterone ratio), and SHBG in these four ethnic groups. We also assessed correlations between concentrations of these measures with age, body size, physical activity, and other personal characteristics, and we evaluated ethnic differences in concentrations of androgens and SHBG after adjusting for these characteristics. In each of the four ethnic groups, concentrations of free and bioavailable testosterone declined with age, whereas SHBG concentrations increased with age. Age-adjusted concentrations of all androgen measures and SHBG decreased with increasing levels of Quetelet's index. After adjustment for age and Quetelet's index, androgens and SHBG showed no clear and consistent relationships to physical activity, alcohol consumption, or tobacco use. DHT:testosterone ratio was higher in men reporting a history of benign prostate disease than in men without such a history, and higher in vasectomized men than in nonvasectomized men. SHBG concentrations were higher in men reporting one or more first-degree relatives with prostate cancer than in men without such a family history. After adjustment for age and Quetelet's index, the levels of total and bioavailable testosterone were highest in Asian-Americans, intermediate in African-Americans, and lowest in whites. However, the DHT:testosterone ratio was highest in African-Americans, intermediate in whites, and lowest in Asian-Americans, corresponding to the respective incidence rates in these groups and providing indirect evidence for ethnic differences in 5alpha-reductase enzyme activity.

Effects of Androgens on Coronary Artery Atherosclerosis and Atherosclerosis-Related Impairment of Vascular Responsiveness

Abstract: The factors responsible for the marked gender differences in risk of coronary heart disease and atherosclerosis severity remain largely undetermined. While some clinical and experimental evidence supports a protective effect of endogenous estrogen on the initiation and progression of atherosclerosis and incidence of coronary heart disease, much of the epidemiological data do not support this conclusion. The possibility that endogenous androgens may have adverse effects on atherosclerosis progression and coronary risk has received little attention. We investigated the effects of experimentally induced hyperandrogenism in female cynomolgus monkeys with diet-induced atherosclerosis. Animals were assigned randomly to one of four treatment groups: (1) untreated controls, (2) ovariectomized (sex hormone-deficient) controls, (3) treated with androstenedione and estrone (mild hyperandrogenism), or (4) treated with testosterone (male plasma androgen pattern). At necropsy, coronary atherosclerosis was approximately twice as extensive ( P <.05) in testosterone-treated animals relative to untreated controls, while treatment with androstenedione and estrone had no effect on atherosclerosis extent. Coronary plaque size was positively correlated with lumen size in intact and ovariectomized controls; however, there was no evidence of a similar relation between animals in either androgen treatment group. The atherogenic effects of testosterone were independent of variations in plasma lipoprotein and nonlipoprotein risk variables. Although chronic hyperandrogenism had adverse effects on atherosclerosis progression, it reversed ( P <.03) atherosclerosis-related impairment of endothelium-dependent vasodilator responses. We conclude that an experimentally induced male plasma androgen pattern results in exacerbation of diet-induced atherosclerosis and has potentially adverse effects on atherosclerosis-related arterial remodeling in female monkeys. The results indicate that testosterone may have a direct role in the increased rate of atherosclerosis progression and increased risk of coronary heart disease seen in men, relative to women, in most Western societies.

Implications of estrogen-dependent brain organization for gender differences in hypothalamo-pituitary-adrenal regulation.

Abstract: Estrogens, derived from the aromatization of testosterone in the brain, account for sex-specific organization of neural circuits controlling gonadotropin release and sexual behavior. This study examines the possible organizing role of perinatal gonadal steroids in the manifestation of known, albeit unexplained, male-female differences in basal and stress-related adrenocortical secretion. We document here the existence of gender-specific differences in the gene expression of hypothalamic corticotropin-releasing hormone (CRH), and hippocampal and hypothalamic glucocorticoid receptors (GR), diurnal corticosterone secretion, as well as in the responsiveness of CRH and GR mRNA levels to exogenous estradiol. In addition, we report that neonatal estrogenization of female rats profoundly affects several regulatory substrates of the hypothalamo-pituitary-adrenal (HPA) axis, namely, the gene expression of CRH, arginine-vasopressin (AVP) and GR in the brain, and the responsiveness of these parameters to estrogen. The neonatal treatment appeared to "defeminize" a number of neuroendocrine mechanisms related to HPA function; these changes were reminiscent of those observed in earlier studies on sexual differentiation of reproductive behavior and hormonal secretion. The results indicate a pivotal role for estrogens during early development for the determination of gender-specific differences in HPA function in the mature animal and demonstrate for the first time that the brain-organizing actions of gonadal steroids may extend to nonreproductive neuroendocrine axes.

Reduced testosterone and adrenal C19 steroid levels in obese men

Abstract: It has been reported that a high proportion of abdominal fat is associated with increased plasma androgen concentrations in women. Although less evidence is available, abdominal obesity appears to be associated with low plasma testosterone (T) levels in men. We have therefore examined in 80 men (aged 36.3 -+ 3.2 years, mean __ SD) the correlations between body fatness, adipose tissue (AT) distribution measured by computed tomography (CT), and circulating levels of the following steroids measured by radioimmunoassay after extraction from serum and chromatography: dehydroepiandrosterone (DHEA), androstenedione (A4-DIONE), androst-5-ene-3~,171~-diol (AS-DIOL), T, estrone, and estradiol. Sex hormone-binding globulin (SHBG) levels were also determined. T, adrenal C19 steroids, and SHBG levels were negatively correlated with total body fatness indices and abdominal fat deposition measured by CT (-.23 _ 7 Although less evidence is available in men, it has been suggested that obesity is associated with low levels of testosterone (T), free T and sex hormone-binding globulin (SHBG). s-12 However, the relation of steroid hormones to fat distribution in men is equivocal. Indeed, in one study, plasma T concentrations were negatively correlated with waist and hip circumferences, but not with the waist to hip ratio (WHR), suggesting no relation of androgens to body fat distribution. 8 On the other hand, Seidell et al 9 reported negative correlations between serum T levels and several indices reflecting abdominal fat accumulation that included the WHR and abdominal subcutaneous and visceral AT areas measured by computed tomography (CT). However, Khaw and Barrett-Connor ~3 reported that there were no negative correlations between androstenedione (A4-DIONE), T, SHBG, and WHR after adjustment for age and body mass index (BMI), suggesting no independent association between androgens and fat distribution in men. To examine further the potential associations between steroid hormones and abdominal fat deposition measured by CT, we studied a group of 80 men with a wide range of body fatness. Visceral AT areas were measured by CT, and in addition to T and estrogen levels, adrenal Ci9 steroid concentrations, namely dehydroepiandrosterone (DHEA), A4-DIONE, and androst-5-ene-3 [3,1713-diol (AS-DIOL), were determined.

Endocrine abnormalities of obesity

Abstract: Studies have shown that patients with central obesity have increased cortisol secretion, probably because they have increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. A high waist-to-hip ratio (WHR) is associated with low production of sex steroids, such as testosterone in men, and a low rate of secretion of growth hormone. High levels of cortisol and insulin combined with low levels of growth hormone and sex steroid can cause lipid accumulation. These hormonal changes probably produce more deposition of visceral than subcutaneous fat. Patients who are deficient in either testosterone or growth hormone show a reduction in visceral adiposity when their hormone levels are normalized. Stress has been shown to activate the HPA axis and may cause the hormonal changes associated with obesity. Individuals with elevated WHR have indications of high levels of stress and anxiety. Monkeys that were stressed by social disruption were found to have increased cortisol levels and low sex steroid levels. Many of these animals had insulin resistance and visceral adiposity. Stimulants, such as alcohol and smoking, also increase the activity of the HPA axis.

A prospective study of plasma hormone levels, nonhormonal factors, and development of benign prostatic hyperplasia.

Abstract: We assessed the relation of plasma hormone levels and nonhormonal factors with subsequent occurrence of surgical treatment for benign prostatic hyperplasia (BPH) among participants in the Physicians' Health Study. Frozen plasma samples, collected at the study onset, were available for 320 men who developed surgically treated BPH up to 9 years later and for 320 age-matched controls. Plasma testosterone (T), dihydrotestosterone (DHT), androstenedione, estradiol (E2), and estrone (E1) were measured for each case-control pair. In unadjusted analyses, none of the hormones or hormone ratios were associated with BPH; for example, for T and E2 the odds ratios (OR) comparing the highest quintile (Q5) with the lowest (Q1) were 0.74 (95% CI = 0.42, 1.30) and 1.07 (95% CI = 0.51, 2.22), respectively. However, in multivariate analyses controlling diastolic blood pressure, exercise, alcohol, E1, and DHT:T ratio, we observed a strong trend for increasing risk across quintiles for E2 (Q5 vs. Q1 OR = 3.56, P trend = 0.009), and a weak inverse trend for E1 (Q5 vs Q1 OR = 0.51, P trend = 0.07). The excess risk associated with E2 was confined to men with relatively low androgen levels. Three nonhormonal factors previously suspected as risk factors were independently associated with surgical BPH in these data. The OR for a 1-mm Hg difference in diastolic blood pressure was 1.04 (95% CI = 1.01, 1.07). Alcohol use and infrequent exercise were inversely associated with risk of BPH surgery; however, risk estimates were not consistent across categories of exercise and alcohol frequency. Our results indicate that normal variation in circulating androgen levels does not influence development of BPH, but that variation in estrogen levels might be important.

Longitudinal evaluation of serum androgen levels in men with and without prostate cancer.

Abstract: Androgens are thought to play a role in the pathogenesis of prostate cancer. We evaluated androgen levels in 3 age-matched groups of men who were part of the Baltimore Longitudinal Study of Aging: 1) 16 men with no prostatic disease by urologic history and exam (control group); 2) 20 men with a histologic diagnosis of benign prostatic hyperplasia (BPH) who had undergone simple prostatectomy; and 3) 20 men with a histologic diagnosis of prostate cancer (16 with local/regional cancer, and 4 with metastatic cancer). Luteinizing hormone (LH), total testosterone (T), and free T were measured on stored AM sera by radioimmunoassay (RIA). Free T was also calculated from the measured concentrations of total T and sex hormone binding globulin (SHBG). The median number of repeated sex steroid measurements ranged from 6-9 over a period from 7-25 years prior to the diagnosis of prostate disease. There were no significant differences in age-adjusted LH, total T, SHBG, or calculated free T levels among the groups at 0-5, 5-10, and 10-15 years before diagnosis. These data suggest that there are no measurable differences in serum testosterone levels among men who are destined to develop prostate cancer and those without the disease.

The contribution of hypogonadism to the development of osteoporosis in thalassaemia major: new therapeutic approaches

Abstract: Summary OBJECTIVE The osteoporosis seen in thaiassaemia major is of multifactorial origin. The aim of the study was to evaluate the contribution of hypogonadism to the development of this osteoporosis and to assess the efficacy of new sex hormone replacement therapy regimens. DESIGN AND PATIENTS Sixty-Seven patients were studied: 12 were hypogonadal, 32 had been on previous hormone replacement therapy (conjugated oestrogens plus medroxyprogesterone for females, depot testosterone esters for males): 10 had received continuous courses of treatment and 22 3-monthly on/off courses, and 22 were eugonadal without previous replacement therapy. Twenty-seven of the above patients were evaluated prospectively at 16 and 32 months during different therapeutic approaches (12 without treatment, 7 on continuous replacement and 8 on/off schemes followed by continuous therapy during the second observation period). The continuous schemes comprised either trans-dermal oestradiol (100 μg) plus medroxyprogesterone for females or hCG to produce serum testosterone concentrations within normal range, for males. MEASUREMENTS Bone mineral density (BMD) and bone mineral content (BMC) of lumbar spine and distal end of radius were measured by dual-energy X-ray absorptiometry. RESULTS Spinal BMD was found to be more than 30% lower than that of controls matched for sex and age with no difference between sexes. Radial BMD was less impaired and showed significantly (P<0·01) higher levels in males (decrease of 5·8±2·3, mean±SD) than In femalea (-14·5±3·4%, mean±SD). In the retrospective evaluation it was found that the hypogonadal group had the lowest (P<0·0001) BMD levels (0·62±0·01, mean ± SE) and the highest were observed on the continuous replacement group (0·83 ± 0·04), whereas the values of the other groups were similar. In a multiple regression analysis model it was found that only sex steroid levels were related to the BMD measurements (for oestradiol t=2·6, P= 0·01 and for testosterone t= 6·5, P= 0·0001), whereas parameters related to haemolytic anaemia and desferrioxamine treatment were not. In the prospective study the continuous replacement group increased BMD and BMC values more than the on/off treatment courses (P= 0·01). CONCLUSIONS Hypogonadism seems to play an important role in the development of osteopenia-osteoporosis in thalassaemia major; continuous hormone replacement therapy with transdermal oestrogen for females or hCG for responding males best improves the bone density parameters.

Nitric oxide mediated erectile activity is a testosterone dependent event: a rat erection model.

Abstract: Classically, androgens were thought to be linked to sexual activity in man through their action on increased libido. Recently, the sex hormone dependent nature of nitric oxide synthase (NOS), the enzyme system producing the neurotransmitter of erection (nitric oxide) has been reported. Our study evaluated how changes in testosterone levels alter erectile function. In forty-seven rats the erectile response to cavernous nerve electrostimulation was recorded 1, 5, 10, 20 and 30 d post-bilateral orchiectomy, and compared to controls. Penile tissue was subsequently stained for the presence of NOS, using an NADPH diaphorase technique. Forty eight rats were used in part two. After orchiectomy exogenous testosterone was administered and the erectile function as well as density of NOS positive nerve fibers was assessed. All castrated animals showed a rapid decrease in serum free testosterone levels within 24 h. In contrast, a gradual decrease in intracavernous pressure was recorded with cavernous nerve stimulation, proportional to the time post orchiectomy. NADPH diaphorase staining showed a decreased density of nonadrenergic noncholinergic (NANC) nerve fibers innervating the cavernosal tissue proportional to the time post orchiectomy. With reconstitution of the androgen mileu the erectile response returned to near normal values and recovery of NADPH-positive nerve fibers was observed. Based on presented data we conclude that testosterone or a metabolite plays a direct role in erection acting through an effect on nitric oxide synthase within the corpora cavernosa.

Testosterone and regional fat distribution.

Abstract: The effects of testosterone treatment of abdominally obese men have been assessed by evaluating the following parameters: The metabolic activity of different adipose tissue regions in vivo (using lipid label as a tracer) and in vitro (measuring lipoprotein lipase (LPL) activity), the total and visceral adipose tissue mass, insulin sensitivity, fasting blood glucose, blood lipids, and blood pressure as well as prostate volume. Middle-aged men with abdominal obesity were treated with transdermal administration of testosterone (T), dihydrotestosterone (DHT) or placebo (P) during 9 months. The study was double-blind. Treatment with T was followed by an inhibited uptake of lipid label in adipose tissue triglycerides, a decreased LPL-activity and an increased turn-over rate of lipid label in the abdominal adipose tissue region in comparisons with the DHT and P groups. These effects on adipose tissue metabolism were not detected in the femoral adipose tissue region in any of the groups. T treatment was also followed by a specific decrease of visceral fat mass (measured by CT-scan), by increased insulin sensitivity (measured with the euglycemic glucose clamp), by a decrease in fasting blood glucose, plasma cholesterol and triglycerides as well as a decrease in diastolic blood pressure. In the DHT group an increased visceral mass was detected. No other changes in these variables were found in the DHT and P groups. There were no detectable changes in prostate volume (measured by ultra-sound), prostate specific antigen concentration, genito-urinary history or urinary flow measurements in any of the groups. It is suggested that T substitution to a selected group of men results in general metabolic and circulatory improvements. The prostate area needs further careful attention.

Differential Regulation of the Two Forms of Gonadotropin-Releasing Hormone (mGnRH and cGnRH-II) by Sex Steroids in the European Female Silver Eel (Anguilla anguilla)

Abstract: The effect of steroids on the two gonadotropin-releasing hormone (GnRH) forms present in the eel (mammalian GnRH, mGnRH and chicken GnRH-II, cGnRH-II), as well as on gonadotropin (GTH), was studied using specific radioimmunoassays. Female silver eels received chronic treatments with various steroids (estradiol, testosterone, androstenedione, 5α-androstane-3β,17β-diol). Estradiol or the combination of estradiol and androgens induced increases in brain and pituitary mGnRH levels and pituitary GTH level, whereas androgens given alone had no significant effect. In contrast, androgens or their combination with estradiol reduced brain cGnRH-II levels (this form remaining undetectable in the pituitary), estradiol given alone having no significant effect. This work demonstrates that the two forms of GnRH undergo a differential regulation by steroids, with a positive estrogen-dependent feedback on mGnRH (as well as on GTH) and a negative androgen-dependent feedback on cGnRH-II. These data are in agreement with previous results obtained in experimentally matured female eels (induced by a gonadotropic treatment which stimulates the production of both estrogens and androgens) showing increases in mGnRH and GTH levels, as well as a decrease in cGnRH-II [1]. The positive feedback of steroids on the mGnRH-GTH axis adds credence to the hypothesis according to which mGnRH would be the main form involved in the control of the gonadotropic function. This positive feedback would play an important role, amplifying pubertal stimulation of the gonadotropic axis, in this fish species.

Growth of LNCaP human prostate cancer cells is stimulated by estradiol via its own receptor

Abstract: We report that growth of LNCaP human prostate cancer cells is significantly stimulated (up to 120% above control) by physiological estradiol (E2) concentrations. This growth increase appears to be comparable to that induced by either testosterone or dihydrotestosterone, as also reported by others. This paper presents novel illustrative evidence for estrogen-binding proteins and messenger RNA transcripts in LNCaP cells. In fact, 1) the reverse transcriptase-polymerase chain reaction system documented normal messenger RNA for estrogen receptors (ER); 2) the radioligand binding assay allowed the detection of high affinity, reduced capacity binding sites in both soluble and nuclear cell fractions; and 3) the immunocytochemical analysis showed a consistently intensive staining for both ER and progesterone receptors. Compared to other human estrogen-responsive mammary cancer cells, MCF7 and ZR75-1, ER expression in LNCaP cells was not significantly lower, as shown by levels of the ER transcripts, number of site...

Menstrual disturbance and hypersecretion of progesterone in women with congenital adrenal hyperplasia due to 21‐hydroxylase deficiency

Abstract: Summary OBJECTIVE While menstrual disturbance is often quoted as a feature of congenital adrenal hyperplasia (CAH), little is known about the mechanism of this symptom. We set out to determine the relationship between menstrual pattern and biochemical characteristics of women with CAH due to 21-hydroxylase deficiency. PATIENTS AND DESIGN All 21 female patients with classic CAH attending the adult endocrinology clinics at The Middlesex Hospital were reviewed. Their ages at menarche and menstrual pattern were recorded and blood samples were taken in the follicular phase of the menstrual cycle when on their usual maintenance therapy. MEASUREMENTS Measurements Of serum LH, FSH, progesterone, 17α-hydroxyprogesterone, testosterone, androstenedione and plasma renin activity were recorded. Urinary steroid profiles were obtained by gas chromatography and mass spectrometry. Molecular genetic analysis of the 21-hydroxylase gene was performed on leucocyte DNA. RESULTS In the 18 patients who had spontaneous menarche the degree of menstrual disturbance and progesterone excess was related to the effectiveness of adrenal suppressive therapy. Three out of 21 patients, however, failed to experience menarche on standard medical therapy. These patients with primary amenorrhoea were characterized by reduced endometrial thickening, by non-suppressible serum progesterone concentrations despite suppression of 17α-hydroxyprogesterone levels and by the presence of progesterone metabolites in urinary steroid profiles. Molecular genetic analysis did not differentiate between patients with raised progesterone concentrations and those without. CONCLUSION A subgroup of women with congenital adrenal hyperplasia have the triad of non-suppressible serum progesterone of adrenal origin, primary amenorrhoea and Infertility due to failure of endometrial thickening. The characteristic urinary steroid profile best distinguishes this subgroup of women from others with Congenital adrenal hyperplasia and menstrual disturbance due to inadequate adrenal suppression.

Association of dietary and life-style factors with sex hormones in postmenopausal women.

Abstract: We examined the relations between endogenous sex hormones and alcohol intake, dietary constituents, and life-style factors in a population-based sample of 253 postmenopausal women not using replacement hormones. Estrone, dihydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG), and free and total testosterone were measured in serum. Age and years since menopause were negatively associated with dihydroepiandrosterone sulfate and positively associated with sex hormone-binding globulin levels. Higher relative weight was strongly and negatively associated with sex hormone-binding globulin. Other factors were only very weakly associated with sex hormones. Since, except for weight, few potentially modifiable factors appear to influence these hormone profiles, it may be that behaviors earlier in life mediate hormone levels and subsequent disease risk.

The effects of recombinant follicle-stimulating hormone on the restoration of spermatogenesis in the gonadotropin-releasing hormone-immunized adult rat.

Abstract: The role of FSH in spermatogenesis is unclear as testosterone alone has been reported to be sufficient in the gonadotropin-deficient rat. This study examined the effects of recombinant FSH on the restoration of spermatogenesis after gonadotropin withdrawal by GnRH immunization. Adult Sprague-Dawley rats received GnRH immunogen (100 micrograms, sc, every 4 weeks) to induce gonadotropin deficiency, with severe spermatogenic regression occurring by 12 weeks. Recombinant human FSH was then given (10 or 50 IU/kg, sc, daily) for 7, 14, and 21 days, with data from both dosages combined in the analyses. Testes were perfusion fixed, and germ cell numbers were quantified by the optical disector technique. After 7 days of FSH, testis weight significantly increased by 43% (P 61% of control), type B spermatogonia/preleptotene spermatocytes (46%-->65%), leptotene/zygotene spermatocytes (39%-->55%), pachytene spermatocytes in stages I-VIII (11%-->30% control) and IX-XIV (4.3%-->22% control), and round spermatids in stages I-VIII (1.4%-->4.4% control). Prolonged FSH treatment did not further increase type A spermatogonial or pachytene spermatocyte number, whereas round spermatids increased to a peak of 12.8% of the control value. At no stage did FSH increase elongated spermatid numbers above 1% of the control level. The incorporation of bromode-oxyuridine into spermatogonial and early spermatocyte nuclei did not change after GnRH immunization or FSH treatment. Sertoli cell number was not altered by any treatment; however, Sertoli cell nuclear volume was significantly decreased from the control value by GnRH immunization (142 +/- 9 vs. 455 +/- 22 microns 3; P < 0.01) and increased after 7 and 14 days of FSH treatment to 212 +/- 10 and 259 +/- 24 microns 3, respectively. FSH treatment restored serum inhibin levels to normal, but did not increase serum or testicular androgen levels. We conclude that recombinant FSH partially restores spermatogenesis in the gonadotropin-deficient rat by increasing the number of spermatogonia and promoting subsequent maturational steps up to the round spermatid stage. Spermatid elongation was not restored by FSH, indicating the need for an additional factor(s), most likely testosterone.