Showing papers on "Testosterone published in 1996"
TL;DR: High levels of circulating testosterone and low levels of SHBG-both within normal endogenous ranges-are associated with increased risks of prostate cancer, and circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk.
Abstract: Background: Sex steroids, particularly androgens, have been implicated in the pathogenesis of prostate cancer. Data from previous studies comparing circulating hormone levels in men with and without prostate cancer are difficult to interpret, since the studies were limited in size, hormone levels were analyzed in blood drawn after the diagnosis of cancer, nonrepresentative control subjects were used, and hormone and hormone-binding protein levels were not simultaneously adjusted. Purpose: We conducted a prospective, nested casecontrol study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) levels in healthy men were related to the subsequent development of prostate cancer. Methods: Among participants in the Physicians' Health Study who provided plasma samples in 1982, we identified 222 men who developed prostate cancer by March 1992. Three hundred ninety control subjects, matched to the case patients on the bases of age, smoking status, and length of follow-up, were also identified. Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3a-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 °C) plasma samples. Correlations between individual hormone levels and between hormone levels and SHBG in the plasma of control subjects were assessed by use of Spearman correlation coefficients (r). Odds ratios (ORs) and 95% confidence intervals (CIs) specifying the prostate cancer risk associated with quartile levels of individual hormones, before and after adjustment for other hormones and SHBG, were calculated by use of conditional logistic regression modeling. Reported P values are two-sided. Results: No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all /> 2.5 ng/mL) were excluded from the analyses. Conclusions: High levels of circulating testosterone and low levels of SHBG—both within normal endogenous ranges—are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor. Circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk. [J Natl Cancer Inst 1996;88:1118-26] A longstanding and diverse body of evidence suggests that sex steroids, particularly androgens, play a role in the etiology of prostate cancer. Androgens are essential for normal growth and maintenance of the prostate, stimulate the proliferation of human prostate cancer cells in vitro, and, when given in large amounts, can produce prostate cancer in rodents {12)- In addition, eunuchs rarely develop prostate cancer, and androgen ablation frequently causes prostate tumors to regress (3). In contrast, a reduced risk of prostate cancer has been associated with certain hyperestrogenic states (4), and estrogen therapy has a palliative effect in advanced cases (J). These observations on extreme variations in sex-steroid exposure add credibility to the hypothesis that prostate cancer risk is also related to the smaller contrasts in levels of androgens and estrogens that are found within the normal endogenous range (7). However, studies com
798 citations
TL;DR: In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism.
Abstract: Background Insulin resistance and increased ovarian cytochrome P450c17α activity are both features of the polycystic ovary syndrome. P450c17α, which is involved in androgen biosynthesis, has both 17α-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17α-hydroxyprogesterone in response to stimulation by gonadotropin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17α activity. Methods We measured serum steroid concentrations during fasting and the response of serum 17α-hydroxyprogesterone to leuprolide, a gonadotropin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome. Results In the 11 women given metformin, the mean (±SE) area under the serum insulin curve after oral glucose administration decreased from 9303±1603 to 4982±911 ...
742 citations
TL;DR: The androgen receptor is a member of the family of nuclear receptors that is able to regulate a specific expression of target genes and is expressed at high levels in male reproductive tissues.
Abstract: The androgen receptor is a member of the family of nuclear receptors. In its activated form as an androgen receptor ligand complex (the ligand can either be testosterone or 5a-dihydrotestosterone), the androgen receptor is able to regulate a specific expression of target genes. The androgen receptor is expressed at high levels in male reproductive tissues. Mutations in the androgen receptor gene are the molecular cause of the androgen insensitivity syndrome, which is characterized by an aberrant male or an apparently female phenotype. Expansion of a CAG-repeat, encoding a polymorphic glutamine stretch is the cause of a rare motor neuron disease (Kennedy's disease). Hormonal therapy is the treatment of choice for metastatic prostate cancer. Hormone refractory prostate tumors in general still express androgen receptor. In a proportion of the late stage prostate tumors, somatic mutations in the androgen receptor gene have been described. Mutations can result in diminished ligand specificity of the androgen receptor. Furthermore, it has been hypothesized that ligand independent mechanisms can also be involved in androgen receptor activation.
620 citations
TL;DR: The influence of age, smoking, body mass index (BMI), serum albumin, insulin, GH, and insulin-like growth factor I (IGF-I) levels, respectively, on androgen levels and SHBG-binding capacity in a nonobese healthy population as well as in an obese population before and after weight loss is investigated.
Abstract: Several aspects of the regulation of androgen secretion and plasma levels in males remain controversial. Among these, we cite the problem of whether the age-related decrease in testosterone (T) levels is an intrinsic aging phenomenon or is a sequel of previous illness, the mechanisms underlying the increase in sex hormone-binding globulin (SHBG)-binding capacity in aging men and the supranormal capacity observed immediately after a weight-reducing diet, and the role of insulin in the age-associated decrease in dehydroepiandrosterone (sulfate) [DHEA (DHEAS)] levels. To gain further insight into these issues, we investigated the influence of age, smoking, body mass index (BMI), serum albumin, insulin, GH, and insulin-like growth factor I (IGF-I) levels, respectively, on androgen levels and SHBG-binding capacity in a nonobese healthy population (n = 250) as well as in an obese population (n = 50) before and after weight loss. The influence of GH supplementation on SHBG, DHEAS, DHEA, and insulin levels was st...
443 citations
TL;DR: It is concluded that testosterone replacement in hypogonadal men enhanced skeletal muscle mass by stimulating the muscle protein synthesis rate.
Abstract: Testosterone replacement in hypogonadism has long been known to promote nitrogen retention and increase body density, but the mechanisms of nitrogen retention and body composition changes are poorly defined. We measured body composition and muscle protein synthesis in five hypogonadal men before and 6 months after initiating testosterone replacement. Body composition was examined using dual energy X-ray absorptiometry. Muscle mass was estimated both by excretion of creatinine on a meat-free diet and from appendicular mass measured using dual energy X-ray absorptiometry. Muscle protein synthesis was assessed by measuring the increment of [13C]leucine in mixed muscle protein and myosin heavy chain during a continuous infusion of L-[l-13C]leucine. In all subjects there was an increase in fat-free mass (average, 15%; range, 10-22%; P = 0.02) and a decrease in fat mass (-11%; range, -0.4% to -22.0%; P = 0.03). Muscle mass also increased in everybody (mean, 20%; range, 11-32%; P = 0.04) such that 65% of the increase in fat-free mass could be attributed to accretion of muscle. The accumulation of muscle was associated with a 56% (P = 0.015) increase in the fractional synthesis rate of mixed skeletal muscle proteins and a trend toward a similar increase in the fractional synthesis rate of myosin heavy chain (46%; P = 0.098). We conclude that testosterone replacement in hypogonadal men enhanced skeletal muscle mass by stimulating the muscle protein synthesis rate.
430 citations
TL;DR: This prospective study provides further evidence in support of the already established association between elevated estrogen levels and breast cancer and provides new evidence that high serum testosterone levels precede breast cancer occurrence.
Abstract: Background : High levels of androgens and estrogens have been reported to be associated with breast cancer. However, the multiplicity of factors that influence hormone levels and methodologic issues complicate the study of the relationship between steroid sex hormones and breast cancer. Purpose : Using an improved study design, we assessed prospectively the relationship between the principal steroid sex hormones in serum and the subsequent occurrence of invasive breast cancer in postmenopausal women. Methods : Four thousand fifty-three healthy postmenopausal women, aged 40-69 years, were enrolled from June 1987 through June 1992 in a prospective investigation of hormones and diet in the etiology of breast tumors (ORDET study) as part of a larger volunteer cohort of 10 788 premenopausal and postmenopausal women from Varese Province, northern Italy. At recruitment, blood samples were taken between 8 :00 AM and 9 :30 AM (after overnight fasting), and sera were preserved in -80 °C freezers. Women who had received hormone treatment in the 3 months prior to enrollment, who had a bilateral ovariectomy, or who had a history of cancer or liver disease were not recruited. Twenty-five women in the final eligible cohort of 4040 postmenopausal women developed histologically confirmed, invasive breast cancer during the first 3.5 years of follow-up for the cohort (13 537 woman-years). For each case subject, four control subjects were randomly chosen after matching for factors possibly affecting hormone preservation in serum. One case subject and eight control subjects were excluded because premenopausal hormonal patterns were found ; thus, after also excluding the four control subjects matched to the ineligible case subject, we included 24 case and 88 control subjects. In the spring of 1994, stored sera of case and control subjects were assayed in a blinded manner for dehydroepiandrosterone sulfate and estradiol (E 2 ) by in-house radioimmunoassay and for total and free testosterone and sex hormone-binding globulin by commercially available nonextraction iodination kits. Mean differences in risk factors were tested by analysis of variance for paired data. Relative risks (RRs) were estimated by conditional logistic regression analysis. All P values resulted from two-sided tests. Results : Age-adjusted mean values of total testosterone, free testosterone, and E 2 were significantly higher in case subjects than in control subjects : total testosterone, 0.34 ng/mL versus 0.25 ng/mL (P<.001) ; free testosterone, 1.07 pg/mL versus 0.77 pg/mL (P =.006) ; and E 2 , 25 pg/mL versus 22 pg/mL (P = .027). Age-adjusted RRs for breast cancer in increasing tertiles were as follows: for total testosterone, 1.0, 4.8, and 7.0 (P for trend =.026) ; for free testosterone, 1.0, 1.8, and 5.7 (P for trend =.005) ; and for total E 2 , 1.0, 7.1, and 5.5 (P for trend =.128). Conclusions and Implications : This prospective study provides further evidence in support of the already established association between elevated estrogen levels and breast cancer. Even more importantly, it provides new evidence that high serum testosterone levels precede breast cancer occurrence
336 citations
TL;DR: The data indicate that the regulation of apoptosis by T is one mechanism involved in the sexual differentiation of the SDN-POA.
309 citations
TL;DR: The data indicate that the sex difference in myointimal proliferation after vascular injury is estrogen dependent, and the responsiveness of this gene to balloon injury of the artery is more rapid and more robust in the male than in the female rat.
Abstract: Background Vascular disease progresses more slowly in females with functional ovaries than in males. The mechanisms of this vasoprotective effect of female sex are incompletely understood. This study tested (1) whether there is a sex difference in the development of myointimal proliferation after balloon injury of the rat carotid artery in vivo, (2) whether this response is estrogen or androgen dependent, and (3) whether there is a sexual dimorphism in expression of the c- myc proto-oncogene in intact and/or damaged rat carotid arteries.
Methods and Results Ten-week-old male and female Sprague-Dawley rats were either gonadectomized or studied intact. Gonadectomized rats of both sexes were implanted with estradiol, testosterone, or nothing (control) 3 days before vascular injury. Two weeks later, the rats were killed by overdose of pentobarbital, and the injured right and uninjured control left carotid arteries were fixed and subjected to morphometric analysis for evaluation of the degree of myointimal thickening. Separate groups of intact male and female rats were killed at 1 and 2 hours after vascular injury, and total RNA from injured and uninjured vessels was subjected to Northern blot analysis for assessment of steady state c- myc mRNA levels. Neointimal area and the ratio of neointimal to medial area were significantly less in intact female rats than in intact male rats ( P <.05). Gonadectomy of female rats was associated with a greater increase in neointima formation after balloon injury than that observed in intact females ( P <.05), but testosterone replacement did not further enhance this response. Estradiol treatment significantly inhibited myointimal proliferation after vascular injury in gonadectomized rats of both sexes ( P <.05). Neither gonadectomy nor gonadectomy plus testosterone replacement altered the myointimal proliferative response to balloon injury in male rats. Steady state c- myc mRNA levels were detectable in undamaged carotid arteries in intact rats of both sexes and were significantly greater in males than in females; c- myc mRNA levels were increased in both sexes after carotid injury, but the response was significantly larger in magnitude and more rapid in males than in females.
Conclusions These data indicate that the sex difference in myointimal proliferation after vascular injury is estrogen dependent. C- myc gene expression is greater in the undamaged carotid artery of the male than in that of the female, and the responsiveness of this gene to balloon injury of the artery is more rapid and more robust in the male than in the female rat. These findings have direct implications for the prevention and treatment of vascular disease in humans.
260 citations
TL;DR: The findings indicate that testicular morphology and functions are affected by severe selenium deficiency and that the element is necessary for testosterone biosynthesis and the formation and normal development of spermatozoa.
Abstract: For four generations rats were fed a low selenium diet (2-7 micrograms Se kg-1) or the same diet with 250 or 300 micrograms Se kg-1 added as selenite. In male rats of the first generation that had been fed the diets from the age of 20 days onwards, selenium depletion led to slightly delayed testis growth during pubertal development that was compensated for in the later stages of maturation. In adult rats fed the low selenium diet for nearly a year no changes in testicular mass and morphology were observed. The serum concentration of testosterone of 6-month-old, selenium-depleted animals was, however, slightly lower than that of adequately supplied controls, and the stimulation of testosterone secretion by administration of GnRH or LH resulted in a significantly less marked rise in the serum concentration of testosterone. From the second generation onwards the testis mass, expressed as a percentage of the body mass, decreased and in the fourth generation was less than 50% of that of the controls. The male gonads of fourth generation animals showed a severe bilateral atrophy, in which the seminiferous tubules were considerably reduced in diameter and almost entirely lined by Sertoli cells and a few stem cells. Differentiated spermatozoa could not be detected. The alterations were reversible and spermatogenesis was restored by feeding the selenium-adequate diet. The findings indicate that testicular morphology and functions are affected by severe selenium deficiency and that the element is necessary for testosterone biosynthesis and the formation and normal development of spermatozoa.
223 citations
TL;DR: It is suggested that the common mechanism for testosterone formation in postpubertal subjects with this disorder is the conversion of circulating androstenedione to testosterone by one or more of the unaffected 17 beta-hydroxysteroid dehydrogenase isoenzymes.
Abstract: Autosomal recessive mutations in the 17 beta-hydroxysteroid dehydrogenase 3 gene impair the formation of testosterone in the fetal testis and give rise to genetic males with female external genitalia. Such individuals are usually raised as females, but virilize at the time of expected puberty as the result of increases in serum testosterone. Here we describe mutations in 12 additional subjects/families with this disorder. The 14 mutations characterized to date include 10 missense mutations, 3 splice junction abnormalities, and 1 small deletion that results in a frame shift. Three of these mutations have occurred in more than 1 family. Complementary DNAs incorporating 9 of the 10 missense mutations have been constructed and expressed in reporter cells; 8 of the 9 missense mutations cause almost complete loss of enzymatic activity. In 2 subjects with loss of function, missense mutations testosterone levels in testicular venous blood were very low. Considered together, these findings strongly suggest that the common mechanism for testosterone formation in postpubertal subjects with this disorder is the conversion of circulating androstenedione to testosterone by one or more of the unaffected 17 beta-hydroxysteroid dehydrogenase isoenzymes.
209 citations
TL;DR: Social interactions may have an important modulatory effect on sex steroid concentrations in Cichlid fish Oreochromis mossambicus.
TL;DR: It is proposed that testosterone facilitates the onset of offensive aggression, at least partly, through an activation of AVP receptors within the VLH, a site involved in the control of aggression in several species of mammals.
TL;DR: The results indicate that aromatase is expressed mainly in tumor epithelial cells and that sufficient amounts of estrogen are synthesized by the tumor to produce a proliferative response.
Abstract: The expression of aromatase by breast cancer cells and the role of locally produced estrogen in the stimulation of tumor growth has been controversial. The present study was performed to determine the site of aromatization in human breast cancers, using both immunocytochemistry and in situ hybridization. The functional significance of locally produced estrogens on growth of the tumor was addressed by measuring aromatase activity and a marker of proliferation (PCNA score). In addition, histocultures of some tumors were carried out to investigate whether testosterone aromatization could stimulate tumor proliferation. Of the 19 tumors investigated, 10 (52.6%) showed significant immunoreactivity to antiaromatase antibody in the cytoplasm of tumor epithelial cells and in surrounding stromal cells. The presence of aromatase mRNA detected by ISH was also located in tumor epithelial cells and stromal cell, and the pattern of expression was the same as with immunocytochemistry. In the ten tumors that showed immunoreaction to aromatase, the average aromatase activity measured in cryosections was 286.5 +/- 18.6 (SE) fmol estrogen/mg protein.h, whereas in nine tumors with weak aromatase immunoreaction, the enzyme activity was 154.7 +/- 19.3 (SE) fmol estrogen/mg protein-h (P < 0.05). The mean PCNA score was 33.8 +/- 5.1 (SE)% in strongly stained tumors and 20.8 +/- 2.0 (SE)% in weakly stained tumors (P < 0.05). Aromatase activity level and PCNA score were significantly correlated. In histoculture of four tumors, estradiol increased the incorporation of [3H]-thymidine into DNA. In two of these tumors, aromatase activity was high and [3H]-thymidine incorporation into DNA was also stimulated by testosterone. In the other two tumors that had low aromatase activity, no such stimulation occurred with testosterone. The results indicate that aromatase is expressed mainly in tumor epithelial cells and that sufficient amounts of estrogen are synthesized by the tumor to produce a proliferative response. It is concluded that estrogen synthesis by cancer cells could play a important role in promoting growth in a significant proportion of breast tumors.
TL;DR: Results suggest that testosterone may suppress immunoglobulin production of human PBMC directly by inhibiting B cell activity and indirectly by reducing IL‐6 production of monocytes, and indicated that this hormone may have protective and therapeutic effects on human autoimmune diseases.
Abstract: We studied the in vitro effect of testosterone on spontaneous immunoglobulin production by human peripheral blood mononuclear cells (PBMC). Testosterone inhibited IgG and IgM production by PBMC both from males and females. The inhibitory effect of testosterone was revealed at doses more than 1 nM, increased dose-dependently, and reached a plateau at 100 nM. At doses < 1000 nM, testosterone did not reduce cell viability. Testosterone treatment reduced IgG production by 59.0% and that of IgM by 61.3% compared with control. Immunoglobulin production by B cells was also suppressed by testosterone, though the magnitude of the suppressive effect on B cells was lower than that on whole PBMC; testosterone-induced decrease of IgG production compared with control was 26.9% and that of IgM was 24.9%. Exogenous IL-6 partially restored the impaired immunoglobulin production of testosterone-treated PBMC; IgG production in testosterone culture was increased by IL-6 from 35.6% to 66.5% of control and that of IgM was also increased from 38.9% to 71.2%, respectively. Testosterone treatment reduced IL-6 production of monocytes by 78.4% compared with control, but neither affected that of T cells or B cells. These results suggest that testosterone may suppress immunoglobulin production of human PBMC directly by inhibiting B cell activity and indirectly by reducing IL-6 production of monocytes. It is thus indicated that this hormone may have protective and therapeutic effects on human autoimmune diseases.
TL;DR: Castration before soft-tissue trauma and hemorrhagic shock maintains normal immune function in male mice, but sham-castrated male mice show significant immunodepression, concluding that male sex steroids are involved in the immunodEPression observed after trauma-hemorrhage.
Abstract: Objective: To determine whether male sex steroids contribute to the depression in cell-mediated immunity following trauma-hemorrhage and resuscitation. Design: Two weeks before the induction of soft-tissue trauma (2.5-cm midline laparotomy) and hemorrhagic shock (mean [±SEM] blood pressure, 35±5 mm Hg), male C3H/HeN mice were castrated or sham castrated. Following trauma-hemorrhage, the mice were resuscitated and killed 24 hours thereafter to obtain whole blood and the spleen. Results: Splenocyte proliferation and splenocyte interleukin-2 and interleukin-3 release were significantly depressed in sham-castrated animals after trauma-hemorrhage. In contrast, these variables in castrated mice after trauma-hemorrhage were similar to those in shamoperated animals. Corticosterone plasma levels were significantly elevated in both trauma-hemorrhage groups compared with those in sham-operated mice. Plasma testosterone levels were undetectable in castrated animals and detectable in sham-castrated mice. Conclusions: Castration before soft-tissue trauma and hemorrhagic shock maintains normal immune function in male mice, but sham-castrated male mice show significant immunodepression. The maintenance of immune function by androgen deficiency does not seem to be related to changes in the release of corticosterone. We conclude that male sex steroids are involved in the immunodepression observed after trauma-hemorrhage. Thus, the use of testosterone-blocking agents following trauma-hemorrhage should prevent the depression of immune functions and decrease the susceptibility to sepsis under those conditions. Arch Surg. 1996;131:1186-1192
TL;DR: The results suggest that free D-Asp is involved in the steroidogenesis, and it is demonstrated that this amino acid induces the synthesis of testosterone.
TL;DR: In vivo TBT inhibits sulfur conjugation of testosterone and its phase I metabolites and their excretion resulting in a build-up of pharmacologically active androgens in the tissues, consistent with the hypothesis that TBT-induced imposex in sensitive gastropods, such as stenoglossans, may arise from peturbations in sex steroid metabolism.
TL;DR: It is indicated that testosterone replacement therapy in hypogonadal and elderly men may have a beneficial effect on lipid metabolism through decreasing total cholesterol and atherogenic fraction of LDL-cholesterol without significant alterations in HDL-ch cholesterol levels or its subfractions HDL2-C and HDL3-C.
TL;DR: The reproductive and growth effects of lead are complex and sex-dependent, and appear to involve multiple sites on the hypothalamic-pituitary-gonadal axis, particularly at the level of gonadal steroid biosynthesis.
TL;DR: The absence of female sex hormones appears to decrease insulin-mediated whole-body glucose uptake via an impaired insulin-stimulated translocation of GLUT4 to the plasma membrane and by decreased protein expression of glycogen synthase.
Abstract: The absence of female sex hormones, as well as testosterone treatment of oophorectomized (OVX) female rats has been demonstrated to result in decreased whole-body insulin-mediated glucose uptake. The cellular mechanism behind this insulin resistance and the role of low levels of female sex hormones as a risk factor for development of peripheral insulin resistance are not yet fully clarified. We assessed the protein expression of GLUT4 and glycogen synthase, as well as insulin-induced translocation of GLUT4 to the plasma membrane, in soleus skeletal muscle from control rats, OVX rats, and OVX rats treated for 8 weeks with testosterone (OVX + T). Whole-body insulin-mediated glucose uptake assessed by the hyperinsulinemic-euglycemic clamp procedure was 25% lower in OVX rats ( P P P P P
TL;DR: Findings indicate that androgens, besides affecting proliferation and protein secretion, also markedly stimulate the production and accumulation of neutral lipids, revealing a novel interesting aspect of androgen regulation of LNCaP cells.
Abstract: Microscopic evaluation of LNCaP cells stained with the lipophilic dye Oil red O revealed that androgens induce a marked stimulation of lipid droplet accumulation. As determined by quantitative analysis of the Oil red O extracted from the stained cells, stimulatory effects of the synthetic androgen R1881 became apparent at concentrations as low as 10(-11) M. Maximal induction (15-fold) was reached at 10(-8) M. Increases were observed 2 days after hormone addition and were maximal 1 day later. Accumulation of lipid droplets was also induced by mibolerone (another synthetic androgen) and by the natural androgens testosterone and dihydrotestosterone. In agreement with the aberrant ligand specificity of the mutated androgen receptor in LNCaP cells, stimulation of lipid accumulation was also apparent after treatment with progesterone and estradiol. Cortisol and the synthetic glucocorticoid dexamethasone were ineffective. The androgen antagonist Casodex (bicalutamide) abolished the stimulatory effect of R1881, further supporting the involvement of the androgen receptor. In agreement with this conclusion, no changes in lipid accumulation were observed after androgen treatment of the androgen receptor-negative prostate tumor lines PC-3 and DU-145. To investigate the nature of the lipids affected by androgens, lipid extracts were analyzed by TLC, complemented with enzymatic lipid analyses. Androgens were shown to have major effects on the content of triglycerides and cholesterol esters (33- and 7-fold stimulation, respectively), the two main classes of lipids stained by Oil red O. Phospholipid and cholesterol contents were increased by a factor of 2. Incorporation studies with [2-14C]acetate revealed that androgens caused a major stimulation of 2-14C incorporation into triglycerides and cholesterol esters (11- and 13-fold, respectively), suggesting that androgens act at least in part at the level of lipid synthesis. Taken together, these findings indicate that androgens, besides affecting proliferation and protein secretion, also markedly stimulate the production and accumulation of neutral lipids, revealing a novel interesting aspect of androgen regulation of LNCaP cells.
TL;DR: The addition of a single depot dose of a progestin to a suboptimal testosterone dose (6 mg/day) markedly enhances the extent, but not the rate, of spermatogenic suppression, with negligible biochemical androgenic side-effects.
Abstract: Hormonally induced azoospermia induced by weekly im injections of testosterone enanthate provides effective and reversible male contraception, but more practical regimens are needed. Given our previous findings that six 200-mg pellets implanted subdermally produced more stable, physiological T levels and reduced the delivered T dose by more than 50% while maintaining equally effective suppression of sperm output with fewer metabolic side-effects than weekly 200-mg testosterone enanthate injections, we sought in this study to determine 1) whether further dose-sparing could be achieved by lower testosterone doses while maintaining efficacy and 2) the efficacy of adding a depot progestin to a suboptimally suppressive depot testosterone dose as a model depot progestin/androgen combination male contraceptive. Healthy volunteers were randomized into groups (n = 10) who received either of two lower T doses (two or four 200-mg T pellets) or four 200-mg T pellets plus a single im injection of 300 mg depot medroxyprogesterone acetate (DMPA). Two T pellets (400 mg, 3 mg/day) had a negligible effect on sperm output. Four T pellets (800 mg, 6 mg/day) suppressed sperm output between the second to fourth postimplant months; output returned to normal by the seventh postimplant month, although only 4 of 10 men became azoospermic or severely oligozoospermic (< 3 mol/L/mL). The addition of a depot progestin markedly increased the extent, but not the rate, of sperm output suppression, with 9 of 10 becoming azoospermic and 10 of 10 becoming severely oligozoospermic. There were no serious adverse effects during the study. Plasma total and free testosterone levels remained within the eugonadal range at all times with each treatment. Plasma epitestosterone was suppressed by all 3 regimens, consistent with a dose-dependent inhibition of endogenous Leydig cell steroidogenesis. Plasma LH and FSH measured by a two-site immunoassay were suppressed in a dose-dependent fashion by T and further suppressed by the addition of DMPA. Sex hormone-binding globulin levels were decreased by DMPA, but not by either T dose. Prostate-specific antigen and lipids (total, low or high density lipoprotein cholesterol, and triglycerides) were not significantly changed in any group. Thus, a depot testosterone preparation with zero order release must be delivered at between 6-9 mg/day to provide optimal (but not uniform) efficacy at inducing azoospermia. The addition of a single depot dose of a progestin to a suboptimal testosterone dose (6 mg/day) markedly enhances the extent, but not the rate, of spermatogenic suppression, with negligible biochemical androgenic side-effects. These findings provide a basis for the use of a progestin/androgen combination depot for hormonal male contraception.
TL;DR: Current low-dose OCs were found to have similar impact on the endogenous androgen metabolism with significant decreases of serum testosterone, DHT, A, and DHEA-S, which may be equally beneficial in women with androgen related syndromes such as acne and hirsutism.
TL;DR: The findings suggest that glucoprivic suppression of LH pulses is potentiated by gonadal steroids in both sexes, and the hypothalamo-hypophyseal axis of the female rat seems to be more sensitive to the decreased glucose availability induced by 2DG than that of the male.
Abstract: Glucose availability controls reproductive activity through modulation of LH secretion. The aim of the present study was to determine whether the glucoprivic suppression is potentiated by gonadal steroids and if glucoprivic suppression of pulsatile LH release is sexually differentiated. Pulsatile LH secretion was examined in rats after peripheral (jugular) administration of the competitive inhibitor of glycolysis, 2-deoxyglucose (2DG). Fourteen days after gonadectomy, blood samples were collected every 6 min for 3 h. One hour after the onset of sampling, 2DG was administered peripherally (200, 400, or 800 mg/kg BW, iv), and food intake was determined after 2DG injection in gonadectomized males and females in the presence or absence of sex steroids (testosterone or estradiol). To test the ability of the pituitary to produce LH under glucoprivic conditions, LHRH was injected every 30 min for 2.5 h in ovariectomized (OVX) rats 30 min after treatment with 400 mg/kg 2DG. At all peripheral doses of 2DG in females and at the middle and high doses of 2DG in males, mean plasma LH and LH pulse frequency decreased (P < 0.05) in the presence of steroids. However, in the absence of sex steroids, the lowest dose in females and the middle dose in males were not effective. Pituitary function appeared normal, because increases in mean plasma LH in response to the exogenous LHRH occurred in OVX rats treated with the middle dose of 2DG. Food intake significantly (P < 0.05) increased after 2DG injection in all groups except estrogen-treated OVX females at the low and high doses of 2DG. These findings suggest that glucoprivic suppression of LH pulses is potentiated by gonadal steroids in both sexes. Moreover, the hypothalamo-hypophyseal axis of the female rat seems to be more sensitive to the decreased glucose availability induced by 2DG than that of the male.
TL;DR: The direct effects of estradiol on mesangial cell collagen generation may help explain the slower development of glomerulosclerosis in women and therefore the "protective" effect of female gender on the progression of renal disease.
TL;DR: It is shown that male csfmop/csfmop mice have a sevenfold lower concentration of circulating testosterone (T) and a significantly lower intratesticular T concentration than wild-type mice, and the proposed function of these macrophages in the regulation of Leydig cell steroidogenesis suggest that CSF-1-regulated testicular macrophage play an important role in male reproduction.
Abstract: Previous studies have shown that the mononuclear phagocyte growth factor, colony-stimulating factor-1 (CSF-1), has an important role in female reproduction. Mating experiments with osteopetrotic (csfmop/csfmop) mice, which possess an inactivating mutation in the CSF-1 gene, suggested that there are male, as well as female, reproductive defects. In the present study, we have shown that male csfmop/csfmop mice have a sevenfold lower concentration of circulating testosterone (T) and a significantly lower intratesticular T concentration than wild-type mice. These lowered T concentrations were associated with a reduction in mating capability and a reduction in the number of viable sperm. Reconstitution of male csfmop/csfmop mice with either circulating T in the adult or circulating CSF-1 throughout the postnatal period completely restored viable sperm numbers and significantly restored sexual behavior. These observations, coupled with the close association of Leydig cells with testicular macrophages and the proposed function of these macrophages in the regulation of Leydig cell steroidogenesis, suggest that CSF-1-regulated testicular macrophages play an important role in male reproduction.
TL;DR: It is concluded that testosterone supplementation significantly increased bone mineral density in this heterogeneous group of men with idiopathic primary osteoporosis, without an overall adverse effect on cardiovascular risk factors.
TL;DR: Examination of the entire population of individual cells expressing aromatase mRNA in castrated males suggests that aromat enzyme mRNA may be regulated by steroid hormones differentially in specific populations of neurons within regions where activity is known to decrease following castration.
Abstract: Many of the effects of gonadal steroid hormones in the male brain are due to the actions of the testosterone metabolite estradiol, which is synthesized by the actions of the P450 enzyme aromatase. Aromatase activity is present in regions of the preoptic area, hypothalamus, and limbic system. Levels of aromatase activity in the brain are highly dependent on gonadal steroid hormones in many brain regions, but not all. We examined the distribution of aromatase mRNA in adult male and female rat brains as well as the regulation of the levels of aromatase mRNA in the brains of males by gonadal steroid hormones using in situ hybridization. This method was performed using a 35S-labelled cRNA probe, transcribed in vitro from the rat ovarian aromatase cDNA. In the adult male, many heavily labelled cells were found in the encapsulated bed nucleus of the stria terminalis (BNST), the medial preoptic nucleus (MPN), the ventromedial nucleus (VMN), the medial amygdala (mAMY), and the cortical amygdala (CoAMY). The regional distribution of aromatase mRNA was similar in females, but females tended to have a lower number of aromatase mRNA expressing cells in each region compared to males. Aromatase mRNA levels in the BNST, MPN, VMN, and mAMY tended to be lower in castrated males than in intact males, whereas aromatase mRNA levels were unaltered by castration in the CoAMY. The degree of reduction in mean levels of aromatase mRNA following castration does not simply account for the large changes measured in activity following castration. Examination of the entire population of individual cells expressing aromatase mRNA in castrated males suggests that aromatase mRNA may be regulated by steroid hormones differentially in specific populations of neurons within regions where activity is known to decrease following castration.
TL;DR: Sixteen subjects (from 10 Brazilian families) with male pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency have been evaluated in 1 clinic, with results indicating limited growth of the prostate and penis and increase in body and facial hair and enhancement of libido and sexual performance.
TL;DR: Information on the effects of androgens on haemostatis is limited and may be particularly incomplete due to the fact that interaction with other sex steroids appears to be an important confounder.