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PubMed2004

Comparative effects of DHEA vs. testosterone, dihydrotestosterone, and estradiol on proliferation and gene expression in human LNCaP prostate cancer cells.

Serum levels of the adrenal androgen dehydroepiandrosterone (DHEA) peak in men and women in the third decade of life and decrease progressively with age. Increasing numbers of middle-aged and older individuals consume over-the-counter preparations of DHEA, hoping it will retard aging by increasing muscle and bone mass and strength, decreasing fat, and improving immunologic and neurobehavioral functions. Because DHEA can serve as a precursor to more potent androgens and estrogens, like testosterone (T), dihydrotestosterone (DHT), and 17beta-estradiol (E2), supplemental DHEA use may pose a cancer risk in patients with nascent or occult prostate cancer. The steroid-responsive human LNCaP prostate cancer cells, containing a functional but mutated androgen receptor (AR), were used to compare effects of DHEA with those of T, DHT, and E2 on cell proliferation and protein and/or gene expression of AR, prostate-specific antigen (PSA), IGF-I, IGF-I receptor (IGF-IR), IGF-II, IGF-binding proteins-2, -3, and -5, (IGFBPs-2, -3, and -5), and estrogen receptor-beta (ERbeta). Cell proliferation assays revealed significant stimulation by all four steroids. DHEA- and E2-induced responses were similar but delayed and reduced compared with that of T and DHT. All four hormones increased gene and/or protein expression of PSA, IGF-IR, IGF-I, and IGFBP-2 and decreased that of AR, ERbeta, IGF-II, and IGFBP-3. There were no significant effects of hormone treatment on IGFBP-5 mRNA. DHEA and E2 responses were similar, and distinct from those of DHT and T, in time- and dose-dependent studies. Further studies of the mechanisms of DHEA effects on prostate cancer epithelial cells of varying AR status, as well as on prostate stromal cells, will be required to discern the implications of DHEA supplementation on prostatic health.

Blotting, Western↗
PubMed1984

Androgen cytosol binding in exercise-induced sparing of muscle atrophy.

This study was undertaken to determine whether the exercise-induced sparing of glucocorticoid-induced muscle atrophy is related to increased androgen cytosol binding. Female rats were divided into a sedentary or an exercise group that was trained by treadmill running 100 min/day for 13-15 wk. During the last 12 days of training, each of these groups was further subdivided into groups that received daily subcutaneous injections of cortisone acetate (CA) (100 mg/kg body wt) or the vehicle 1% carboxymethyl cellulose. Exercise prevented 30-40% of the weight loss due to CA treatment in gastrocnemius and plantaris muscles. Scatchard analyses of specific binding of [3H]methyltrienolone (R1881), a synthetic androgen that binds to androgen receptors, were nonlinear in muscles from vehicle-treated sedentary and trained rats and were resolved by a two-component binding model. The lower affinity component, which was attributed to a glucocorticoid receptor, disappeared in muscles of glucocorticoid-treated animals as evidenced by linear Scatchard plots. Receptor concentrations of the androgenic component of [3H]methyltrienolone binding were similar in gastrocnemius and plantaris muscles in all treatment groups. In binding specificity studies of gastrocnemius muscles, the relatively high competition by various glucocorticoids and progesterone for [3H]methyltrienolone binding in the vehicle-treated groups was reduced by CA treatment. The lack of change in androgen cytosol receptor levels suggests that this is not a mechanism by which exercise protects against glucocorticoid-induced muscle atrophy.

Androgens↗
PubMed2000

Effects of an androgenic steroid on exercise-induced cardiac remodeling in rats.

Habitual exercise results in a rightward shift in left ventricular end diastolic (LVED) pressure-volume or internal dimension (P-D) relationships [left ventricular (LV) remodeling]. However, exercise-mediated LV hypertrophy (LVH) produces an increased LV relative wall thickness [ratio (h/r) of wall thickness (h) to internal radius (r)] and hence a decrement in diastolic wall stress despite LV remodeling. In this study, the effect of chronic administration of an androgenic steroid on exercise-induced LV remodeling and h/r was examined in rats. Habitual exercise on voluntary running wheels resulted in LVH and a rightward shift in the LVED P-D relationships. However, LVH was sufficient to increase LVED h/r. Androgenic steroid administration to exercised rats, without influencing the development of exercise-induced LVH, produced a further rightward shift in the LVED P-D relationship associated with an increased diameter intercept. As a consequence, LVED h/r was reduced to control values. The steroid-mediated effects were not associated with alterations in either the quantity or quality of LV collagen. In conclusion, high-dose androgenic steroid administration alters exercise-induced LV remodeling and subsequently reduces the beneficial effect of physiological LVH on LV h/r.

Anabolic Agents↗
PubMed2000

Psychiatric and medical effects of anabolic-androgenic steroid use in women.

BACKGROUND: Although numerous studies have documented the psychiatric and physiological effects of anabolic-androgenic steroids (AAS) in males, virtually no studies have investigated the effects of illicit AAS use in women. METHODS: We performed psychiatric and medical evaluations of 75 dedicated women athletes, recruited by advertisement primarily from gymnasiums in the Boston, Mass., area. RESULTS: Twenty-five (33%) of the women reported current or past AAS use. Users were more muscular than nonusers and reported use of many other 'ergogenic' (performance-enhancing) drugs in addition to AAS. Some described a frank syndrome of ergogenic polysubstance dependence, often with significant morbidity. Fourteen (56%) of the users reported hypomanic symptoms during AAS use and 10 (40%) reported depressive symptoms during AAS withdrawal, but none met full DSM-IV criteria for a hypomanic or major depressive episode. Nineteen (76%) users reported at least one adverse medical effect associated with AAS use. Perhaps the most interesting findings were several unusual psychiatric syndromes reported by both the AAS users and nonusers. These included rigid dietary practices (which we have termed 'eating disorder, bodybuilder type'), nontraditional gender roles and chronic dissatisfaction and preoccupation with their physiques (a syndrome which we have termed 'muscle dysmorphia'). CONCLUSIONS: Dedicated women athletes exhibit not only AAS abuse, but use of many other ergogenic drugs, sometimes associated with significant morbidity. In addition, these athletes frequently display several psychiatric syndromes which have not previously been well described.

Adolescent↗
PubMed2000

Response to treatment in patients with partial androgen insensitivity due to mutations in the DNA-binding domain of the androgen receptor.

The androgen insensitivity syndrome is a disorder caused by deficient function of the androgen receptor, characterized by varying degrees of undermasculinization in karyotypic males. We have identified four mutations in the androgen receptor gene, in the region encoding the DNA-binding domain of the protein. Two mutations, R607X and R615G, were found in patients with complete insensitivity to androgens, whereas the other two, S578T and A596T, were found in patients with partial insensitivity. The functional consequences of the three missense mutations were assayed in vitro after transient expression of the receptors in COS cells. All mutants showed normal androgen binding but abnormal abilities to stimulate transcription of an androgen-responsive reporter gene. R615G abolished transactivation whereas S578T and A596T were partially malfunctional. The function of A596T, but not of S578T, was normalized at high androgen concentrations in vitro, reflecting the in vivo situation. Thus, patients with specific mutations in the DNA-binding domain of the androgen receptor may benefit from androgen treatment.

Amino Acid Sequence↗
PubMed1990

Androgen binding sites in human temporal cortex.

We have characterized putative androgen receptor binding sites in five separate biopsy samples of human temporal cortex from epilepsy patients using an in vitro exchange assay with soluble fractions and [3H]5 alpha-dihydrotestosterone as radioligand. The results revealed highly specific, saturable binding with an apparent affinity constant (Kd) of approximately 2 nM with a moderate capacity (Bmax) of approximately 50 fmol/mg protein. In competition studies, we found that only testosterone and 5 alpha-dihydrotestosterone competed effectively (i.e. at low nanomolar concentrations) for [3H]5 alpha-dihydrotestosterone binding sites. These data indicate the presence of androgen receptors in human cortex that are pharmacologically very similar to that previously described in rodent and infrahuman primate CNS, and suggest the existence of a possible mechanism whereby circulating androgens might influence neuronal events in human cortex.

Adolescent↗
PubMed1976

Binding of methyltrienolone to various androgen-dependent and androgen-responsive tissues in four animal species.

Comparative sucrose gradient studies of the in vitro binding of dihydrotestosterone (DHT) and of a synthetic androgen, methyltrienolone (R 1881), have been done with the cytosols of various tissues of the rat, mouse, cock and man. With rat prostate cytosol, the amount of R 1881 and DHT binding in the 8-9S region of the gradient was found to be comparable. Specific 8-9S peaks of R 1881 were also found in rat levator ani/bulbocavernosus and skeletal muscles and in the mouse kidney. Only 4-5S peaks could be demonstrated in the cock's comb while DHT under the same conditions showed both 8-9S and 4-5S binding. Binding of R 1881 to the cytosol of the hyperplastic prostate was polydispersed, and showed evidence of the presence of aggregates. Evidence was also found that R 1881 could bind to the progesterone receptor in rat uterus. Our study supports the theory that in a given species the androgen receptors are similar if not identical in all the tissues. The synthetic androgen R 1881 appears to be a useful tool for androgen receptor studies in various animal species provided that the tissue under study contains no progesterone receptor.

Animals↗
PubMed1976

Comparative binding specificity of methyltrienolone in human and rat prostate.

The binding of methyltrienolone (R 1881) in crude human hyperplastic prostate cytosol was determined by a charcoal assay. Maximum binding was observed after 2-3 h of incubation at 0 degrees C. This binding decreased steadily thereafter and reached 41% of the 2-hour values after 96 h of incubation. In human hyperplastic prostate, the binding of 3H-R 1881 was competed by low concentrations of R 1881, R 5020 and progesterone and by high concentrations of dihydrotestosterone (DHT) and 17 alpha-methyl-DHT. In the rat prostate, on the other hand, this binding was competed by low concentrations of DHT and 17 alpha-methyl-DHT and only by high concentrations of progesterone and R 5020. The apparent association constant (Ka) of R 1881 was determined in three human prostates and found to be 0.2-0.4 X 10(9) liters/mol; the number of binding sites ranged from 101 to 158 fmol per mg of protein. These findings constitute further evidence for the existence of relatively large amounts of a progesterone-binding component in human hyperplastic prostate.

Animals↗
PubMed1988

Androgen and erythropoiesis: evidence for an androgen receptor in erythroblasts from human bone marrow cultures.

The techniques for culturing erythroid precursors made possible the study of the effect of steroids on these cells, and it has been well established that androgens and 5 beta-steroids have a direct effect on erythroid precursor cells from animal or human bone marrow. By contrast, their mechanisms of intracellular action remain poorly understood. We used tritiated methyltrienolone (R1881), a synthetic androgen that binds strongly to the androgen receptor, to characterize the binding activity in nuclear extracts of erythroblasts from human bone marrow cultures. The nuclear extracts contained binding sites that were saturable at low concentrations of 3H-R1881 (8-12 nM). Scatchard analysis revealed that the dissociation constant of the hormone-receptor complexes (Kd) was 10-20 nM, and the number of binding sites was 64-103 fmol/mg of protein. On linear sucrose density gradient analysis (5-20%), the hormone-receptor complexes sedimented in the region of 3.9 S. Finally, 5 beta-dihydrotestosterone had also a strong affinity for the binding sites. The nuclear component binding has all the physicochemical characteristics usually attributed to androgen receptors. These data strongly suggest that androgen action on erythropoiesis is mediated by a nuclear androgen receptor.

Bone Marrow Cells↗
PubMed1991

Therapeutic indications for delayed puberty and hypogonadism in adolescent boys.

Testosterone and synthetic androgens have formerly been used indiscriminately, but are now applied more selectively. They are the only treatment of primary hypogonadism, but are also useful in gonadotropin deficiency and constitutional delay. 17-Alkylated androgens are no longer used. Oral testosterone undecanoate is not suitable for adolescents because of unreliable absorption. The prototype disorder where replacement is necessary is congenital anorchia. As a physiological replacement, an initial dose of 35 mg/m2 per month for 6 months, followed by 70 mg/m2 for 1 year, and 150 mg/m2 thereafter, is recommended. No general rules can be given for other types of primary hypogonadism. In testicular atrophy after cryptorchidism, defects of testosterone biosynthesis, galactosemia or other causes, it is advisable to carry out periodic testosterone determinations and to wait until the levels drop below normal. Progress has been made in the treatment of gonadotropin deficiency, and pulsatile gonadotropin-releasing hormone (GnRH) has been shown to be effective in the hypothalamic type. Nevertheless, androgens still have a temporary place in this condition. In constitutional delay of growth and adolescence, treatment is not necessary somatically, but there are often psychosocial reasons. Gonadotropins, GnRH or growth hormone (GH)-releasing hormone have been used. Also treatment with human GH is successful in accelerating height velocity. The most simple and economic treatment is still testosterone in a physiological dose for 3-6 months. Oxandrolone or other synthetic androgens have no advantages.

Adolescent↗
PubMed1980

Use of androgens in acquired aplastic anaemia. Relation of response to aetiology and severity.

124 adult patients with acquired aplastic anaemia (A.A.) were studied. 54 presented as severe A.A. (mean survival of the whole group, 2.7 months and in those who died, 2.5 months; mortality 88.8%) while 70 were mild (mean survival of the whole group, 27.2 months and in those who died , 22.7 months; mortality, 28.5%). Sixty-four did not live long enough to have adequate therapeutic trials or developed severe hepatic failure which made it impossible to continue treatment. The effectiveness of 78 therapeutic periods of treatment in the 60 evaluable cases was analyzed as to aetiology and severity. A response was obtained in 31 (40%), of which 24 were with oxymethalone; 17 showed improvement after 6 months of treatment. No conclusions could be drawn as to the effectiveness of methalone, cyclophosphamide and prednisone because of the limited number of treatments. In severe A.A. only one of 13 treatments was effective, whereas 30 of the 65 used in mild A.A. gave a response. Oxymethalone was used in 23 out of 41 (56%). The aetiology, sex and age appeared to have no influence on the response of the 60 patients analyzed. The only factor which appears useful for prognosis as to the effectiveness of treatment is the severity of the case.

Adolescent↗
PubMed1994

Androgen action in cultured dermal papilla cells from human hair follicles.

Androgens are major regulators of human hair growth with paradoxically different effects on hair follicles depending on their body site. They stimulate terminal growth in many regions including the face, have no effect on eyelashes, but may cause inhibition and balding on the scalp in genetically disposed individuals. How this occurs is unknown. However, androgens may act on the hair follicle via the cells of the dermal papilla; these would then influence the other cells of the hair follicle by altering the production of regulatory substances such as growth factors and/or extracellular matrix components. Therefore, primary lines of dermal papilla cells have been established from androgen-sensitive hair follicles, such as beard, and control, relatively androgen-independent, non-balding scalp cells and their mechanism of androgen action has been compared. Isolated beard dermal papillae were larger than those from scalp follicles. Although dermal papilla cells did not respond to in vitro androgens by alterations in growth, androgen-dependent dermal papilla cells contained higher levels of specific, low capacity, high affinity androgen receptors than non-balding scalp cells. The ability of the cells to metabolise testosterone to 5 alpha-dihydrotestosterone in culture also varied in parallel to that predicted from studies of hair growth in the 5 alpha-reductase deficiency syndrome. These results support the hypothesis that androgens act via the dermal papilla. They also show that dermal papilla cells retain differences in gene expression in culture which appear to correspond with their androgenic response in vivo. Further studies of such cells should help elucidate why bald men can grow beards!

Androgens↗
PubMed1988

Age-related changes in glucocorticoid and androgen receptors of cultured human pubic skin fibroblasts.

In order to evaluate age-related changes in glucocorticoid receptor and androgen receptor of cultured human pubic skin fibroblasts in young and aged men, we determined both [3H]dexamethasone binding and [3H]methyltrienolone (R1881, potent androgenic steroid) binding, using dispersed whole cell assay. Scatchard analyses of specific [3H]dexamethasone binding to the fibroblasts of young and aged men showed a single class of high-affinity binding sites with a mean (+/- SD) binding site concentration (Bmax) of 12.69 +/- 2.36 X 10(4) and 12.87 +/- 12.21 X 10(4) sites/cell, respectively, and mean (+/- SD) dissociation constant (Kd) of 5.60 +/- 0.41 and 7.36 +/- 2.17 nM, respectively. Scatchard analyses of specific [3H]R1881 binding to the same cultured skin fibroblasts of young and aged men showed a single class of high-affinity binding sites with a mean Bmax of 5.77 +/- 1.02 X 10(3) and 2.82 +/- 0.97 X 10(3) sites/cell, respectively, and a mean Kd of 0.56 +/- 0.23 and 0.50 +/- 0.28 nM, respectively. These findings indicate that there were no significant age-related changes in binding site and affinity of glucocorticoid receptor in cultured human pubic skin fibroblasts, whereas binding sites of androgen receptor significantly decreased in those of aged men as compared to young men, without significant change in affinity.

Adult↗
PubMed1978

[Androgen therapy of incurable breast neoplasms. Controlled clinical study: nandrolone-testololactone-drostanolone].

In 91 patients with advanced breast cancer testololactone, drostanolone, and nandrolone were compared in a controlled clinical trial. Remissions were registered after 4 weeks and after another 12 week period; during this second interval the patients received an additional treatment with cyclophosphamide. There was no difference in the effectivity between the three drugs. Remission rate was in average after 4 weeks 24% and after 16 weeks 46%.

Androstanols↗
PubMed1982

Uptake and retention of sex steroids by the neonatal rat adrenal gland.

The uptake of radioactivity in the adrenal glands of 5-day-old male and female rats was examined 2 h following injection of radiolabeled testosterone, R1881, diethylstilbestrol, or estradiol. The adrenals of both sexes had higher levels of radioactivity than blood after testosterone or synthetic androgen (R 1881) injection. The adrenals of neither sex showed any significant accumulation of radioactivity, following 3H-estradiol injection. When, however, cytosol prepared from neonatal adrenal glands was incubated with 2 nM 3H-estradiol, and the incubate subjected to column chromatography on Sephadex G-100, radioactivity was eluted with the void volume; this peak was absent with the addition of 100-fold unlabeled estradiol to the incubation. The possible role of alpha-fetoprotein in preventing the in vivo uptake and retention of 17 beta-estradiol is discussed since 3H-diethylstilbestrol, an estrogen which has low affinity for this protein, was retained by the adrenals of male rats. It is concluded that estrogens or androgens can have a direct effect on the neonatal adrenal gland.

Adrenal Glands↗
PubMed1980

The endocrine background of human renal cell carcinoma. V. Binding of the highly potent androgen methyltrienolone (R 1881) by tumour cytosol.

The binding of methyltrienolone (R 1881, 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-trien-3-one), a highly active synthetic androgen, by cytosol preparations from human renal cell carcinoma was investigated. High-affinity, low-capacity binding components for R 1881 were detected in 3 out of 8 tumours analysed. The apparent dissociation constant of the R 1881-binder complexes was found to be in the range of 1.1-2.3 x 10(-9) mol/l. The number of binding sites in the positive tumours varied from 2.1 to 9.7 fmol/mg cytosol protein. Studies of binding specificity indicated a requirement for androgens. It is concluded that these binding components may be hormone receptors. If in consecutive studies this hypothesis holds true, progestins, most widely used in hormonal therapy of metastatic renal cancer, may possibly act on the tumour tissue by inhibiting the secretion of gonadotropins, thus lowering the blood levels of eventually growth-promoting.

Adenocarcinoma↗