Showing papers on "Testosterone published in 2005"

Hormonal Responses and Adaptations to Resistance Exercise and Training

Abstract: Resistance exercise has been shown to elicit a significant acute hormonal response. It appears that this acute response is more critical to tissue growth and remodelling than chronic changes in resting hormonal concentrations, as many studies have not shown a significant change during resistance training despite increases in muscle strength and hypertrophy. Anabolic hormones such as testosterone and the superfamily of growth hormones (GH) have been shown to be elevated during 15-30 minutes of post-resistance exercise providing an adequate stimulus is present. Protocols high in volume, moderate to high in intensity, using short rest intervals and stressing a large muscle mass, tend to produce the greatest acute hormonal elevations (e.g. testosterone, GH and the catabolic hormone cortisol) compared with low-volume, high-intensity protocols using long rest intervals. Other anabolic hormones such as insulin and insulin-like growth factor-1 (IGF-1) are critical to skeletal muscle growth. Insulin is regulated by blood glucose and amino acid levels. However, circulating IGF-1 elevations have been reported following resistance exercise presumably in response to GH-stimulated hepatic secretion. Recent evidence indicates that muscle isoforms of IGF-1 may play a substantial role in tissue remodelling via up-regulation by mechanical signalling (i.e. increased gene expression resulting from stretch and tension to the muscle cytoskeleton leading to greater protein synthesis rates). Acute elevations in catecholamines are critical to optimal force production and energy liberation during resistance exercise. More recent research has shown the importance of acute hormonal elevations and mechanical stimuli for subsequent up- and down-regulation of cytoplasmic steroid receptors needed to mediate the hormonal effects. Other factors such as nutrition, overtraining, detraining and circadian patterns of hormone secretion are critical to examining the hormonal responses and adaptations to resistance training.

The decline of androgen levels in elderly men and its clinical and therapeutic implications.

Abstract: Aging in men is accompanied by a progressive, but individually variable decline of serum testosterone production, more than 20% of healthy men over 60 yr of age presenting with serum levels below the range for young men. Albeit the clinical picture of aging in men is reminiscent of that of hypogonadism in young men and decreased testosterone production appears to play a role in part of these clinical changes in at least some elderly men, the clinical relevancy of the age-related decline in sex steroid levels in men has not been unequivocally established. In fact, minimal androgen requirements for elderly men remain poorly defined and are likely to vary between individuals. Consequently, borderline androgen deficiency cannot be reliably diagnosed in the elderly, and strict differentiation between “substitutive” and “pharmacological” androgen administration is not possible. To date, only a few hundred elderly men have received androgen therapy in the setting of a randomized, controlled study, and many of th...

Androgen Levels in Adult Females: Changes with Age, Menopause, and Oophorectomy

Abstract: Context: Changes in androgen levels across the adult female life spanandtheeffectsofnaturalmenopauseandoophorectomyhavenot been clearly established. Objective: The objective of this study was to document the effects of age on androgen levels in healthy women and to explore the effects of natural and surgical menopause. Design, Setting, and Participants: A cross-sectional study was conducted of 1423 non-healthcare-seeking women, aged 18–75 yr, randomly recruited from the community over 15 months. Main Outcome Measures: Serum levels by age of total testosterone (T), calculated free T, dehydroepiandrosterone sulfate, and androstenedione in a reference group of women free of confounding factors. Women in the reference group had no usage of exogenous steroid therapy; no history of tubal ligation, hysterectomy, or bilateral oophorectomy; and no hyperprolactinemia or polycystic ovarian syndrome. The effects of natural and surgical menopause on sex steroid levels were also examined. Results:Inthereferencepopulation(n595),totalT,calculatedfree T, dehydroepiandrosterone sulfate, and androstenedione declined steeply with age (P 0.001), with the decline of each being greater in the earlier than the later decades. Examination of serum androgen levels by year in women aged 45–54 yr showed no independent effect of menopausal status on androgen levels. In women aged 55 yr or older, those who reported bilateral oophorectomy and were not on exogenous steroids had significantly lower total T and free T levels than women 55 yr or older in the reference group. Conclusions: We report that serum androgen levels decline steeply intheearlyreproductiveyearsanddonotvarybecauseaconsequence of natural menopause and that the postmenopausal ovary appears to be an ongoing site of testosterone production. These significant variationsinandrogenswithagemustbetakenintoaccountwhennormal ranges are reported and in studies of the role of androgens in women. (J Clin Endocrinol Metab 90: 3847–3853, 2005)

Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males.

Abstract: Context: Mutation of the G protein-coupled receptor 54 is associated with a failure of reproductive function. The endogenous neuropeptide agonist for G protein-coupled receptor 54, kisspeptin, potently stimulates the hypothalamic-pituitary-gonadal axis in rodents and primates. Objective: The present study was designed to determine the effects of elevating circulating kisspeptin levels on LH, FSH, and testosterone in male volunteers. Design: This was a double-blind, placebo-controlled, crossover study. Setting: This was a hospital-based study. Participants: Male volunteers (n = 6) were recruited. Interventions: Each volunteer received a 90-min iv infusion of kisspeptin-54 (4 pmol/kg·min) and a control infusion of saline (0.9%) in random order. Main Outcome Measure: Plasma LH, FSH, and testosterone concentrations were measured. Results: Kisspeptin-54 infusion significantly increased plasma LH, FSH, and testosterone concentrations compared with saline infusion (mean 90-min LH: kisspeptin, 10.8 ± 1.5 vs. sali...

Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T.

Abstract: Testosterone (T) therapy in older men with low serum T levels increases lean body mass and decreases fat mass. These changes might improve physical performance and strength; however, it has not been established whether T therapy improves functional outcome in older men. Moreover, concerns exist about the impact of T therapy on the prostate in older men. The administration of finasteride (F), which partially blocks the conversion of T to the more potent androgen, dihydrotestosterone, attenuates the impact of T replacement on prostate size and prostate-specific antigen. We hypothesized that T replacement in older, hypogonadal men would improve physical function and that the addition of F to this regimen would continue to provide the T-induced improvements in physical performance, strength, and body composition. Seventy men with low serum T (<350 ng/dl), age 65 yr and older, were randomly assigned to receive one of three regimens for 36 months: 1) T enanthate, 200 mg im every 2 wk, with placebo pills daily (...

Testosterone and Dihydrotestosterone Tissue Levels in Recurrent Prostate Cancer

Abstract: Purpose: Prostate cancer eventually recurs during androgen deprivation therapy despite castrate levels of serum androgens. Expression of androgen receptor and androgen receptor–regulated proteins suggests androgen receptor activation in recurrent prostate cancer. Many groups have pursued mechanisms of ligand-independent androgen receptor activation but we found high levels of testicular androgens in recurrent prostate cancer tissue using RIA. Experimental Designs: Prostate specimens from 36 men were procured preserving blood flow to prevent ischemia and cyropreserved immediately. Recurrent prostate cancer specimens from 18 men whose cancer recurred locally during androgen deprivation therapy and androgen-stimulated benign prostate specimens from 18 men receiving no hormonal treatments were studied. Tissue levels of testosterone and dihydrotestosterone were measured in each specimen using liquid chromatography/electrospray tandem mass spectrometry. Testosterone and dihydrotestosterone levels were compared with clinical variables and treatment received. Results: Testosterone levels were similar in recurrent prostate cancer (3.75 pmol/g tissue) and androgen-stimulated benign prostate (2.75 pmol/g tissue, Wilcoxon two-sided, P = 0.30). Dihydrotestosterone levels decreased 91% in recurrent prostate cancer (1.25 pmol/g tissue) compared with androgen-stimulated benign prostate (13.7 pmol/g tissue; Wilcoxon two-sided, P P > 0.2). Conclusions: Recurrent prostate cancer may develop the capacity to biosynthesize testicular androgens from adrenal androgens or cholesterol. This surprising finding suggests intracrine production of dihydrotestosterone and should be exploited for novel treatment of recurrent prostate cancer.

Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition

Abstract: Considerable experimental and epidemiological evidence suggests that elevated endogenous sex steroids - notably androgens and oestrogens - promote breast tumour development. In spite of this evidence, postmenopausal androgen replacement therapy with dehydroepiandrosterone (DHEA) or testosterone has been advocated for the prevention of osteoporosis and improved sexual wellbeing. We have conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. Levels of DHEA sulphate (DHEAS), (Delta 4-androstenedione), testosterone, oestrone, oestradiol and sex-hormone binding globulin (SHBG) were measured in prediagnostic serum samples of 677 postmenopausal women who subsequently developed breast cancer and 1309 matched control subjects. Levels of free testosterone and free oestradiol were calculated from absolute concentrations of testosterone, oestradiol and SHBG. Logistic regression models were used to estimate relative risks of breast cancer by quintiles of hormone concentrations. For all sex steroids the androgens as well as the oestrogens - elevated serum levels were positively associated with breast cancer risk, while SHBG levels were inversely related to risk. For the androgens, relative risk estimates (95% confidence intervals) between the top and bottom quintiles of the exposure distribution were: DHEAS 1.69 (1.23-2.33), androstenedione 1.94 (1.40-2.69), testosterone 1.85 (1.33-2.57) and free testosterone 2.50 (1.76-3.55). For the oestrogens, relative risk estimates were: oestrone 2.07 (1.42-3.02), oestradiol 2.28 (1.61-3.23) and free oestradiol (odds ratios 2.13 (1,52-2.98)). Adjustments for body mass index or other potential confounding factors did not substantially alter any of these relative risk estimates. Our results have shown that, among postmenopausal women, not only elevated serum oestrogens but also serum androgens are associated with increased breast cancer risk. Since DHEAS and androstenedione are largely of adrenal origin in postmenopausal women, our results indicated that elevated adrenal androgen synthesis is a risk factor for breast cancer. The results from this study caution against the use of DHEA(S), or other androgens, for postmenopausal androgen replacement therapy.

FSH and testosterone signaling in Sertoli cells

Abstract: Testosterone and follicle-stimulating hormone (FSH) are required to obtain full reproductive potential. In the testis, somatic Sertoli cells transduce signals from testosterone and FSH into the production of factors that are required by germ cells as they mature into spermatozoa. Recent advances in identifying new signaling pathways that are regulated by FSH and testosterone have allowed for refinement in the understanding of the independent, overlapping and synergistic actions of these hormones. In this review, we discuss the signaling pathways that are regulated by FSH and testosterone as well as the resulting metabolic and gene expression changes that occur as related to Sertoli cell proliferation, differentiation and the support of spermatogenesis.

Sex Hormone–Binding Globulin and the Free Androgen Index Are Related to Cardiovascular Risk Factors in Multiethnic Premenopausal and Perimenopausal Women Enrolled in the Study of Women Across the Nation (SWAN)

Abstract: Background— Recent clinical trials have shifted attention away from estrogens and toward androgens and sex hormone–binding globulin (SHBG) as potential mediators of increasing cardiovascular (CV) risk in women at midlife. Methods and Results— The correlation between reproductive hormones and CV risk factors was evaluated in a multiethnic (white, black, Hispanic, Chinese, and Japanese) sample of 3297 premenopausal and perimenopausal women. Testosterone and estradiol (E2) were evaluated along with SHBG and the free androgen index (FAI), the amount of testosterone not bound by SHBG. Low SHBG and high FAI were strongly and consistently related to elevated CV risk factors (higher insulin, glucose, and hemostatic and inflammatory markers and adverse lipids) even after controlling for body mass index (P<0.001 for all). Low levels of E2 were associated with elevated CV risk factors to a lesser degree. These observations were consistent across the 5 ethnic groups. Compared with whites, blacks had higher levels of ...

Stress hormone and male reproductive function

Abstract: The Leydig cell is the primary source of testosterone in males. Levels of testosterone in circulation are determined by the steroidogenic capacities of individual Leydig cells and the total numbers of Leydig cells per testis. Stress-induced increases in serum glucocorticoid concentrations inhibit testosterone-biosynthetic enzyme activity, leading to decreased rates of testosterone secretion. It is unclear, however, whether the excessive glucocorticoid stimulation also affects total Leydig cell numbers through induction of apoptosis and thereby contributes to the stress-induced suppression of androgen levels. Exposure of Leydig cells to high concentrations of corticosterone (CORT, the endogenously secreted glucocorticoid in rodents) increases their frequency of apoptosis. Studies of immobilization stress indicate that stress-induced increases in CORT are directly responsible for Leydig cell apoptosis. Access to glucocorticoid receptors in Leydig cells is modulated by oxidative inactivation of glucocorticoid by 11 beta-hydroxysteroid dehydrogenase (11 betaHSD). Under basal levels of glucocorticoid, sufficient levels of glucocorticoid metabolism occur and there is likely to be minimal binding of the glucocorticoid receptor. We have established that Leydig cells express type 1 11 betaHSD, an oxidoreductase, and type 2, a unidirectional oxidase. Generation of redox potential through synthesis of the enzyme cofactor NADPH, a byproduct of glucocorticoid metabolism by 11 betaHSD-1, may potentiate testosterone biosynthesis, as NADPH is the cofactor used by steroidogenic enzymes such as type 3 17beta-hydroxysteroid dehydrogenase. In this scenario, inhibition of steroidogenesis will only occur under stressful conditions when high input amounts of CORT exceed the capacity of oxidative inaction by 11 betaHSD. Changes in autonomic catecholaminergic activity may contribute to suppressed Leydig cell function during stress, and may explain the rapid onset of inhibition. However, recent analysis of glucocorticoid action in Leydig cells indicates the presence of a fast, non-genomic pathway that will merit further investigation.

Hormonal inXuences on sexually diVerentiated behavior in nonhuman primates

Abstract: Sexually dimorphic behavior in nonhuman primates results from behavioral predispositions organized by prenatal androgens. The rhesus monkey has been the primary primate model for understanding the hormonal organization of sexually dimorphic behavior. Historically, female fetuses have received high prenatal androgen doses to investigate the masculinizing and defeminizing eVects of androgens. Such treatments masculinized juvenile and adult copulatory behavior and defeminized female-typical sexual initiation to adult estrogen treatment. Testosterone and the nonaromatizable androgen, 5-dihydrotestosterone, produced similar eVects suggesting that estrogenic metabolites of androgens are not critical for masculinization and defeminization in rhesus monkeys. Long duration androgen treatments masculinized both behavior and genitalia suggesting that socializing responses to the females’ malelike appearance may have produced the behavioral changes. Treatments limited to 35 days early or late in gestation diVerentially aVected behavioral and genital masculinization demonstrating direct organizing actions of prenatal androgens. Recent studies exposed fetal females to smaller doses of androgens and interfered with endogenous androgens using the anti-androgen Xutamide. Low dose androgen treatment only signiWcantly masculinized infant vocalizations and produced no behavioral defeminization. Females receiving late gestation Xutamide showed masculinized infant vocalizations and defeminized interest in infants. Both late androgen and Xutamide treatment hypermasculinized some male juvenile behaviors. Early Xutamide treatment blocked full male genital masculinization, but did not alter their juvenile or adult behavior. The role of neuroendocrine feedback mechanisms in the Xutamide eVects is discussed. Sexually diVerentiated behavior ultimately reXects both hormonally organized behavioral predispositions and the social experience that converts these predispositions into behavior.

Normal, bound and nonbound testosterone levels in normally ageing men: results from the Massachusetts Male Ageing Study.

Abstract: Summary Objective There is little consensus on what androgen levels are ‘normal’ for healthy, ageing men. Using data from the Massachusetts Male Ageing Study (MMAS), we estimated age-specific, normal androgen levels for men aged 40 ‐79 years while accounting for health status and behavioural factors known to influence hormone levels. Design Prospective, observational study. Patients Community-based random sample of men aged 40 ‐79 years: n = 1677 men studied at T1 (1987‐1989), n = 1031 at T2 (1995 ‐ 1997) and n = 631 at T3 (2002‐2004), for a total of 3339 observations. The average number of years between the T1 and T2 interviews was 8·8 (range 7·1‐10·4 years) and 6·4 (range 5·6 ‐7·9 years) between T2 and T3. Measurements Serum total testosterone (T) and sex hormonebinding globulin (SHBG) were measured on nonfasting blood samples collected within 4 h of subject’s awakening. Free and bio-available T were calculated from T and SHBG using the Sodergard equation. Tr ained interviewers administered an in-home questionnaire of health, medication and lifestyle. Participants were considered apparently healthy if all of the following were met: (i) absence of self-reported chronic disease (diabetes, heart disease, high blood pressure, cancer, ulcer); (ii) not on prescription medication believed to affect hormone levels; (iii) body mass index (BMI) not exceeding 29 kg /m 2 ; (iv) alcohol consumption less than or equal to six drinks/ day; and (v) nonsmoking. Results Chronic disease and high BMI significantly decreased whereas smoking tended to increase total, free and bio-available T concentrations. Apparently healthy men had significantly higher median hormone concentrations at most time points than did not apparently healthy men. Due to the opposite effects of smoking and the other components of the definition, apparently healthy men were compared to nonsmoking, apparently unhealthy men. The former group had significantly higher androgen levels (Wilcoxon ranksum P -values ranged from 0·01 to 0·0001) for all hormones at all interviews. Ninety-five percent of apparently healthy men in their 40s, 50s, 60s and 70s would be expected to have total T in the range (2·5‐97·5th percentile): 8·7‐31·7, 7·5‐30·4, 6·8‐29·8 and 5·4‐28·4 n  (251‐914, 216 ‐ 876, 196 ‐ 859, 156 ‐ 818 ng /dl), respectively. Conclusions Age, health and lifestyle factors impact androgen levels and should be accounted for in calculations of normal reference ranges. We propose the following age-specific thresholds, below which a man is considered to have an abnormally low total T: 8·7, 7·5, 6·8 and 5·4 n  (251, 216, 196 and 156 ng /dl) for men in their 40s, 50s, 60s and 70s, respectively. These cutoffs correspond to the 2·5th percentile in our data; thus, approximately 2·5% of men aged 40 ‐79 years would have abnormally low T levels based on hormone levels alone.

Sex Steroid Hormones and the Androgen Receptor Gene CAG Repeat and Subsequent Risk of Prostate Cancer in the Prostate-Specific Antigen Era

Abstract: Objective: Sex steroid hormones are thought to contribute to the growth, differentiation, and progression of prostate cancer. We investigated plasma levels of sex steroid hormones and length of the androgen receptor gene CAG repeat in relation to incident prostate cancer diagnosed in the prostate-specific antigen (PSA) era. Methods: Using a nested case-control design, we included 460 prostate cancer cases diagnosed after providing a blood specimen in 1993 but before February 1998 among men in the Health Professionals Follow-up Study. Controls were 460 age-matched men without prostate cancer who had a screening PSA test after the date of providing a blood specimen. We measured plasma concentrations of total testosterone, free testosterone, dihydrotestosterone, androstanediol glucuronide, estradiol, and sex hormone binding globulin (SHBG) and determined the length of the androgen receptor gene CAG repeat. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer. Results: Mean concentrations of the sex steroids adjusted for SHBG, and mean CAG repeat length did not differ significantly between the prostate cancer cases and controls. No significant associations with total prostate cancer were detected for plasma total testosterone concentration (comparing highest versus lowest quartiles: OR, 0.78; 95% CI, 0.48-1.28; P trend = 0.73) or the other sex hormones after adjusting for SHBG. However, plasma total testosterone concentration was positively associated with low-grade disease (Gleason sum < 7: OR, 1.91; 95% CI, 0.89-4.07; P trend = 0.02) and inversely associated with high-grade disease (Gleason sum ≥ 7: OR, 0.26; 95% CI, 0.10-0.66; P trend = 0.01). Similar patterns for grade were observed for free testosterone. Short CAG repeat length was not associated with total prostate cancer (≤ 19 versus ≥ 24: OR, 0.84; 95% CI, 0.57-1.23; P trend = 0.22) or grade of disease. No clear associations with regionally invasive or metastatic (≥ T3b, N1, or M1) were found for any of the hormones or the CAG repeat, although the number of these cases was small. Conclusions: The overall lack of association of prostate cancer diagnosed in the PSA era with sex steroid hormones and the androgen receptor gene CAG repeat length is consistent with the hypothesis that these factors do not substantially contribute to the development of early prostate cancer in the PSA era. The influence of plasma total and free testosterone concentrations on prostate cancer grade merits further evaluation.

The role of aromatization in testosterone supplementation Effects on cognition in older men

Abstract: Objective: To determine the contribution of conversion of testosterone (T) to estradiol on cognitive processing in a population of healthy older men who received T supplementation. Methods: Sixty healthy, community-dwelling volunteers aged 50 to 90 years completed a randomized, double-blind, placebo-controlled study. Participants were randomized to receive weekly IM injections of 100 mg T enanthate plus daily oral placebo pill (T group, n = 20), 100 mg testosterone enanthate plus 1 mg daily of anastrozole, an aromatase inhibitor (oral pill), to block the conversion of T to estradiol (AT group, n = 19), or saline injection and placebo pill (placebo group, n = 21) for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, week 3 and week 6 of treatment, and after 6 weeks of washout. Results: Circulating total T was increased from baseline an average of 238% in the T and AT treatment groups. Estradiol increased an average of 81% in the T group and decreased 50% in the AT group during treatment. Significant improvements in spatial memory were evident in the AT and T treatment groups. However, only the group with elevated estradiol levels (T group) demonstrated significant verbal memory improvement. Conclusion: In healthy older men, improvement in verbal memory induced by testosterone administration depends on aromatization of testosterone to estradiol, whereas improvement in spatial memory occurs in the absence of increases in estradiol.

Abnormal Leydig Cell aggregation in the fetal testis of rats exposed to di (n-butyl) phthalate and its possible role in testicular dysgenesis.

Abstract: Fetal exposure of male rats to di (n-butyl) phthalate (DBP) induces testicular changes remarkably similar to testicular dysgenesis syndrome in humans; these include induction of focal areas of dysgenetic tubules in otherwise normal testes. In searching for the fetal origins of the latter, we used image analysis to show that exposure to 500 mg/kg DBP [embryonic day (E)13.5-20.5)] caused abnormal aggregation of Leydig cells centrally in the fetal testis. This aggregation was not due to increase in Leydig cell number, and Leydig cell size was significantly reduced in DBP-exposed animals, as were testosterone levels and immunoexpression of P450 side-chain cleavage enzyme. The Leydig cell aggregates did not exhibit evidence of focal proliferation at E17.5-19.5. Using confocal microscopy and Leydig (3beta-hydroxysteroid dehydrogenase) and Sertoli (anti-Mullerian hormone) cell-specific markers, we show that fetal Leydig cell aggregates in DBP-exposed animals trap isolated Sertoli cells within them at E21.5. These areas of intermingled cells are still apparent on postnatal d 4, after cessation of DBP treatment, when they may form misshapen seminiferous cords that trap (intratubular) Leydig cells within them. These centrally located dysgenetic tubules contain germ cells in early puberty, but by adulthood they are Sertoli cell only, implying that presence of intratubular Leydig cells interferes with spermatogenesis. It is concluded that DBP-induced fetal Leydig cell aggregation may be a key event in formation of focal dysgenetic areas in the testis, and identification of the mechanisms underlying these events may give new insights into the fetal origins of testicular dysgenesis syndrome disorders in the human.

Fetal Programming: Prenatal Testosterone Treatment Causes Intrauterine Growth Retardation, Reduces Ovarian Reserve and Increases Ovarian Follicular Recruitment

Abstract: Exposure to testosterone (T) during d 30-90 of fetal life results in low-birth-weight offspring, hypergonadotropism, multifollicular ovaries, and early cessation of cyclicity. The multifollicular phenotype may result from failure of follicles to regress and consequent follicular persistence or, alternatively, increased follicular recruitment. We tested the hypothesis that prenatal exposure to excess T causes intrauterine growth retardation and increases ovarian follicular recruitment. Time-mated pregnant ewes were treated with 100 mg T propionate in cottonseed oil or vehicle twice weekly from d 30-90 of gestation. Ewes were euthanized near term, from d 139-141 of gestation (term is 147 d). After determining fetal measures and organ weights, ovaries were removed from fetuses of control and T-treated dams, and follicular distribution in each ovary was determined by morphometric quantification. Total number and percentage distribution of the various classes of follicles (primordial, primary, preantral, and antral follicles) were compared between treatment groups. Prenatally T-treated female fetuses were smaller in size, had an increased head circumference to fetal weight ratio (P < 0.01), increased adrenal to fetal weight ratio (P < 0.05), decreased number of follicles (P < 0.05), a decrease in percentage of primordial follicles (P < 0.001), and a corresponding increase in the remaining classes of follicles (P < 0.05). Ovarian findings support decreased ovarian reserve and enhanced follicular recruitment, potential contributors of early reproductive failure. The extent to which metabolic changes associated with intrauterine growth retardation contribute toward altered trajectory of ovarian folliculogenesis remains to be determined.

The Metabolic Syndrome and Disturbances in Hormone Levels in Long-Term Survivors of Disseminated Testicular Cancer

Abstract: Purpose The metabolic syndrome may be an important risk factor for cardiovascular disease in long-term survivors of testicular cancer (TC). We investigated the associations between hormone levels and the metabolic syndrome in these men. Patients and Methods We included TC patients cured by orchidectomy and cisplatin-based chemotherapy, stage I TC patients after orchidectomy only, and healthy men of comparable age. Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III. Thyroid-stimulating hormone, follicle-stimulating hormone (FSH), inhibin B, luteinizing hormone (LH), total testosterone, sex-hormone–binding globulin, free testosterone, estradiol, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 were determined in blood. Cortisol metabolite excretion was measured in urine. Results Eighty-six chemotherapy patients (median follow-up, 7 years) were compared with 44 stage I patients and 47 controls. LH and FS...

Steroid 5α-Reductase Isozymes I and II in Recurrent Prostate Cancer

Abstract: Purpose: Prostate cancer recurs during androgen deprivation therapy despite reduced circulating androgens. We showed that recurrent prostate cancer tissue has testosterone levels similar to androgen-stimulated benign prostate, whereas dihydrotestosterone levels were reduced 82% to 1.45 nmol/L, sufficient for androgen receptor activation. The altered testosterone/dihydrotestosterone ratio in recurrent prostate cancer suggests loss of 5α-reducing capability. The aim of this study was to characterize steroid 5α-reductase isozymes I (S5αRI) and II (S5αRII) in prostate tissues. Experimental Design: A tissue microarray was constructed from 22 recurrent prostate cancer specimens and matched pairs of androgen-stimulated benign prostate and androgen-stimulated prostate cancer from 23 radical prostatectomy specimens. Immunoblots were constructed from eight recurrent prostate cancers, eight androgen-stimulated benign prostate, and eight androgen-stimulated prostate cancer specimens. Isozyme expression was examined in microarray sections and immunoblots using S5αRI and S5αRII polyclonal antibodies. Isozyme activities were measured in 12 recurrent prostate cancer, 12 androgen-stimulated benign prostate, and 12 androgen-stimulated prostate cancer specimens. Results: Nuclear immunostaining exhibited higher S5αRI expression than S5αRII in recurrent prostate cancer, androgen-stimulated benign prostate, and androgen-stimulated prostate cancers ( P P > 0.05). Immunoblots confirmed immunohistochemistry; S5αRI was expressed in recurrent prostate cancer specimens and S5αRII was not detected. The activity of S5αRI (114.4 pmol/mg epithelial protein/minute) was 3.7-fold higher than S5αRII (30.7 pmol/mg epithelial protein/minute) in recurrent prostate cancer specimens. Conclusions: Expression levels and isozyme activity shifts from S5αRII toward S5αRI in recurrent prostate cancer. Dual inhibition of S5αRI and S5αRII should reduce dihydrotestosterone biosynthesis and may prevent or delay growth of recurrent prostate cancer.

Insulin-Like Factor 3 Serum Levels in 135 Normal Men and 85 Men with Testicular Disorders: Relationship to the Luteinizing Hormone-Testosterone Axis

Abstract: Insulin-like factor 3 (INSL3) serum levels were measured in 135 andrologically well-characterized normal men and 85 patients with testicular disorders to investigate how the hormone, which is a major secretory product of human Leydig cells, is related to testosterone (T), LH, and semen quality. INSL3 was measured by using a newly developed fluorescence immunoassay. Median (2.5-97.5 percentiles) INSL3 serum levels were as follows: normal men (n = 135), 0.99 (0.55-1.73) ng/ml; infertile men (n = 23), 1.11 (0.60-2.07) ng/ml; anorchid men (n = 21), nondetectable (ND); patients with 47, XXY, Klinefelter syndrome (n = 21), 0.12 (ND-0.78) ng/ml; men with hypogonadotropic hypogonadism and T substitution (n = 11), ND; and men with hypogonadotropic hypogonadism and human chorionic gonadotropin (hCG) treatment (n = 5), 0.36 (0.13-0.73) ng/ml. Before testicular biopsy, two infertile men had blood samples drawn directly from vena spermatica. Here, the serum INSL3 levels were 15-fold higher than in serum from peripheral blood samples (13.84 and 14.00 ng/ml, respectively). In two unilaterally orchiectomized former testis cancer patients, who underwent hCG stimulation test, INSL3 serum levels were unchanged 72 and 96 h after hCG stimulation. In conclusion, we provide a normal range for INSL3 serum levels in adult men and show that the majority, if not all, circulating INSL3 derives from the testes. Furthermore, our data strongly indicate that INSL3 secretion is dependent on the differentiating effect of LH on Leydig cells but independent of the steroidogenic LH-mediated action. Thus, even though T and INSL3 are both dependent on LH, these two Leydig cell hormones are regulated differently.

Sex Steroids Modulate Human Aortic Smooth Muscle Cell Matrix Protein Deposition and Matrix Metalloproteinase Expression

Abstract: Large artery stiffening increases cardiovascular risk and promotes isolated systolic hypertension which is more prevalent in elderly women than men. Variation in sex steroid levels between males and females and throughout life may modulate arterial stiffness. We hypothesized that sex steroids directly influence expression of important structural proteins which determine arterial biomechanical properties. Human aortic smooth muscle cells were incubated with physiological concentrations of 17-estradiol, progesterone, 17-estradiol and progesterone, or testosterone for 4 weeks. Collagen, elastin, and fibrillin-1 deposition was examined (histochemistry/immunohistochemistry). Gene and protein expression of 2 important matrix metalloproteinases (MMPs), MMPs 2 and 3, regulating matrix turnover was assessed. All sex steroids reduced collagen deposition relative to control (100%). However, the reduction was greater with female sex steroids than testosterone (control, 100%; 17-estradiol plus progesterone, 202%; testosterone 7412%, P0.001). Female sex steroids increased elastin deposition compared with control (control, 100%; 17-estradiol, 54060%; progesterone, 29040%; 17-estradiol plus progesterone, 40080%, all P0.01). The elastin/collagen ratio was 11-fold higher in the presence of 17-estradiol and progesterone compared with testosterone. Fibrillin-1 deposition was doubled in the presence of female sex steroids (17-estradiol plus progesterone) compared with testosterone (P0.01). MMP-2 gene and protein expression was unaffected by any sex steroid. Testosterone increased both gene and protein expression of MMP-3 relative to both control and female sex steroids (P0.01). This may contribute to degradation of elastic matrix proteins. In conclusion, female sex steroids promote an elastic matrix profile, which likely contributes to variation in large artery stiffness observed between sexes and with changes in hormonal status across the lifespan. (Hypertension. 2005;46:10.1161/01.HYP.0000187016.06549.96-.)

Sex Steroids, Cardiovascular Disease, and Hypertension: Unanswered Questions and Some Speculations

Abstract: The roles that both male and female sex steroids play in mediating or protecting against cardiovascular disease (CVD) and hypertension are controversial. For example, whereas animal studies have strongly implicated androgens as being mediators of CVD and hypertension, human epidemiological studies have shown that with chronic disease, including hypertension, serum testosterone levels are actually reduced.1 Thus, whether androgens are truly causative of CVD is not clear. However, premenopausal women are typically protected from CVD and hypertension compared with men, and this has been hypothesized to be because of the protective effects of estrogens. The negative findings of Heart and Estrogen/progestin Replacement Study (HERS) I and II2,3 and Women’s Health Initiative (WHI)4,5 studies on hormone replacement therapy (HRT) in postmenopausal women have shaken our previous ideas that HRT was protective against CVD. In this short review, the latest findings regarding the roles of sex steroids in hypertension and CVD are discussed, questions yet to be answered are suggested, and some speculations are made. In both males and females, the hypothalamus secretes gonadotropin-releasing hormone, which stimulates the anterior pituitary to release both luteinizing hormone and follicular-stimulating hormone. Luteinizing hormone binds to receptors on thecal cells in ovaries of females and Leydig cells in testes of males to cause testosterone to be synthesized. Follicular-stimulating hormone, however, binds to receptors on granulosa cells in females or Sertoli cells in males and stimulates the synthesis of aromatase, which converts testosterone to estradiol. There are 2 main types of estrogen receptors, ERα and ERβ, but several variants of both have also been identified. ERβ is present in a greater number of tissues than is ERα, but both isoforms are present in kidneys and the vasculature. ERβ has been found to be the predominant isoform in human vascular smooth muscle cells. The androgen receptor …

Neuroendocrine Consequences of Prenatal Androgen Exposure in the Female Rat: Absence of Luteinizing Hormone Surges, Suppression of Progesterone Receptor Gene Expression, and Acceleration of the Gonadotropin-Releasing Hormone Pulse Generator

Abstract: Preovulatory GnRH and LH surges depend on activation of estrogen (E2)-inducible progesterone receptors (PGRs) in the preoptic area (POA). Surges do not occur in males, or in perinatally androgenized females. We sought to determine whether prenatal androgen exposure suppresses basal or E2-induced Pgr mRNA expression or E2-induced LH surges (or both) in adulthood, and whether any such effects may be mediated by androgen receptor activation. We also assessed whether prenatal androgens alter subsequent GnRH pulsatility. Pregnant rats received testosterone or vehicle daily on Embryonic Days 16-19. POA-hypothalamic tissues were obtained in adulthood for PgrA and PgrB (PgrA+B) mRNA analysis. Females that had prenatal exposure to testosterone (pT) displayed reduced PgrA+B mRNA levels (P < 0.01) compared with those that had prenatal exposure to vehicle (pV). Additional pregnant animals were treated with vehicle or testosterone, or with 5alpha-dihydrotestosterone (DHT). In adult ovariectomized offspring, estradiol benzoate produced a 2-fold increase (P < 0.05) in PgrA+B expression in the POA of pV females, but not in pT females or those that had prenatal exposure to DHT (pDHT). Prenatal testosterone and DHT exposure also prevented estradiol benzoate-induced LH surges observed in pV rats. Blood sampling of ovariectomized rats revealed increased LH pulse frequency in pDHT versus pV females (P < 0.05). Our findings support the hypothesis that prenatal androgen receptor activation can contribute to the permanent defeminization of the GnRH neurosecretory system, rendering it incapable of initiating GnRH surges, while accelerating basal GnRH pulse generator activity in adulthood. We propose that the effects of prenatal androgen receptor activation on GnRH neurosecretion are mediated in part via permanent impairment of E2-induced PgrA+B gene expression in the POA.

The relationship between testosterone and molecular markers of inflammation in older men.

Abstract: Aging is accompanied by a pro-inflammatory state expressed by the increasing levels of inflammatory cytokines, including interleukin-6 (IL- 6), tumor necrosis factor alpha (TNF-alpha) and interleukin- 1beta (IL-1beta). At the same time, aging is associated with a decrease in serum testosterone (T) levels. There is evidence from many experimental studies that IL-6, TNF-alpha and IL-1beta inhibit T secretion by their influence on the central (hypothalamic-pituitary) and peripheral (testicular) components of the gonadal axis. On the other hand, observational and interventional studies suggest that T supplementation reduces inflammatory markers in both young and old hypogonadal men. Preliminary data from 473 older male participants of the InCHIANTI population showed a significant inverse relationship between T and soluble IL-6 receptor (sIL-6r) levels (a soluble portion of the IL-6 receptor that may enhance the biological activity of IL-6) but not with other markers of inflammation. This study, together with previous observations, suggests that a close relationship exists between the development of a pro-inflammatory state and the decline in T levels, two trends that are often observed in aging men. In the context of this paradigm, we discuss androgen deprivation therapy, a treatment used in men with metastatic prostate cancer as an ideal model to improve our understanding of the relationship between T and inflammatory markers. We advocate the notion that changes in inflammatory markers and T in aging men are causally linked. However, longitudinal and interventional studies are needed to confirm that T can be used therapeutically, based on its anti-inflammatory properties.

Sex hormones modulate brain damage in multiple sclerosis: MRI evidence

Abstract: Background: Sex related differences in the course and severity of multiple sclerosis (MS) could be mediated by the sex hormones. Objective: To investigate the relation between serum sex hormone concentrations and characteristics of tissue damage on conventional magnetic resonance imaging (MRI) in men and women suffering from relapsing-remitting MS. Results: Serum testosterone was significantly lower in women with MS than in controls. The lowest levels were found in women with a greater number of gadolinium enhancing lesions. A positive correlation was observed between testosterone concentrations and both tissue damage on MRI and clinical disability. In men, there was a positive correlation between oestradiol concentrations and brain damage. Conclusions: The hormone related modulation of pathological changes supports the hypothesis that sex hormones play a role in the inflammation, damage, and repair mechanisms typical of MS.

Membrane androgen receptor activation induces apoptotic regression of human prostate cancer cells in vitro and in vivo.

Abstract: Nongenomic androgen actions imply mechanisms different from the classical intracellular androgen receptor (iAR) activation. We have recently reported the identification of a membrane androgen receptor (mAR) on LNCaP human prostate cancer cells, mediating testosterone signal transduction within minutes. In the present study we provide evidence that activation of mAR by nonpermeable, BSA-coupled testosterone results in 1) inhibition of LNCaP cell growth (with a 50% inhibitory concentration of 5.08 nM, similar to the affinity of testosterone for membrane sites); 2) induction in LNCaP cells of both apoptosis and the proapoptotic Fas protein; and 3) a significant decrease in migration, adhesion, and invasion of iAR-negative DU145 human prostate cancer cells. These actions persisted in the presence of antiandrogen flutamide or after decreasing the content of iAR in LNCaP cells by iAR antisense oligonucleotides. Testosterone-BSA was also effective in inducing apoptosis of DU145 human prostate cancer cells, negative for iAR, but expressing mAR sites. In LNCaP cell-inoculated nude mice, treatment with testosterone-BSA (4.8 mg/kg body weight) for 1 month resulted in a 60% reduction of tumor size compared with that in control animals receiving only BSA, an effect that was not affected by the antiandrogen flutamide. Our findings suggest that activators of mAR may represent a new class of antitumoral agents of prostate cancer.

Effects of chronic hyperghrelinemia on puberty onset and pregnancy outcome in the rat.

Abstract: Ghrelin, the endogenous ligand of the GH secretagogue receptor, has been recently involved in a wide array of biological functions, including signaling of energy insufficiency and energy homeostasis. On the basis of the proven reproductive effects of other regulators of energy balance, such as the adipocyte-derived hormone leptin, we hypothesized that systemic ghrelin may participate in the control of key aspects of reproductive function. To test this hypothesis, the effects of daily treatment with ghrelin were assessed in rats, pair-fed with control animals, in two relevant reproductive states, puberty and gestation, which are highly dependent on proper energy stores. Daily sc injection of ghrelin (0.5 nmol/12 h; between postnatal d 33 and 43) significantly decreased serum LH and testosterone levels and partially prevented balano-preputial separation (as an external index of puberty onset) in pubertal male rats. On the contrary, chronic administration of ghrelin to prepubertal females, between postnatal d 23 and 33, failed to induce major changes in serum levels of gonadotropins and estradiol, nor did it modify the timing of puberty, as estimated by the ages at vaginal opening and first estrus. Moreover, females treated with ghrelin at puberty subsequently displayed normal estrous cyclicity and were fertile. Conversely, ghrelin administration (0.5 nmol/12 h) during the first half of pregnancy (d 1-11) resulted in a significant decrease in pregnancy outcome, as estimated by the number of pups born per litter, without changes in the number of successful pregnancies at term or gestational length. Overall, our data indicate that persistently elevated ghrelin levels, as a putative signal for energy insufficiency, may operate as a negative modifier of key reproductive states, such as pregnancy and (male) puberty onset.