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At least 775 records · Page 43Linked to original sources
PubMed2002

Gleason score predicts androgen independent progression after androgen deprivation therapy.

OBJECTIVE: The Gleason system is the most widely utilized histologic grading system for prostate cancer and a powerful predictor of cancer behavior. In this study, we evaluated the prognostic value of the Gleason grading system in predicting progression to androgen independent prostate cancer (AIPC). METHODS: Records from 150 patients with advanced or metastatic prostate cancer treated with androgen deprivation therapy (ADT) were retrospectively reviewed. Androgen independent progression was defined as two consecutive elevations of serum prostate specific antigen (PSA) above the nadir value. Kaplan-Meier and the Cox proportional hazards methods were used to assess potential predictors of progression to AIPC. RESULTS: Patients with low and moderate Gleason scores experienced significantly longer remissions compared to those with Gleason score of 8-10 (p=0.0006, Log-Rank test). The cumulative hazard of progressing to AIPC increased by almost 70% for each unit increase in total Gleason score. CONCLUSION: In this patient cohort the Gleason score was the only independent predictor of progression to AIPC.

Aged↗
PubMed2002

Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset, neurodegenerative disorder affecting only males and is caused by expanded polyglutamine (polyQ) stretches in the N-terminal A/B domain of human androgen receptor (hAR). Although no overt phenotype was detected in adult fly eye photoreceptor neurons expressing mutant hAR (polyQ 52), ingestion of androgen or its known antagonists caused marked neurodegeneration with nuclear localization and structural alteration of the hAR mutant. Ligand-independent toxicity was detected with a truncated polyQ-expanded A/B domain alone, which was attenuated with cytosolic trapping by coexpression of the unliganded hAR E/F ligand binding domain. Thus, our findings suggest that the full binding of androgen to the polyQ-expanded hAR mutants leads to structural alteration with nuclear translocation that eventually results in the onset of SBMA in male patients.

Animals↗
PubMed1997

4-Methyl-3-oxo-4-aza-5alpha-androst-1-ene-17beta-N-aryl-carboxamides: an approach to combined androgen blockade [5alpha-reductase inhibition with androgen receptor binding in vitro].

4-Aza-5alpha-androstan-3-one 17beta-(N-substituted carboxamides) are potent human type 2 5alpha-reductase (5aR) inhibitors with generally poor binding to the human androgen receptor (hAR). When the 17-amide N-substituent included an aromatic residue, potent dual inhibitors of both type 1 and 2 5aR are produced, but hAR binding remained poor. Tertiary-substituted-17-amides have reduced inhibition of both 5aR isozymes. The addition of an N4-methyl substitutent to the A-ring profoundly increased hAR affinity and the addition of unsaturation to the A-ring (delta1) modestly augmented hAR binding. The unsubstituted carbanilides in the delta1-N4-methyl series show some selectivity for type 1 5aR over the type 2 isozyme, whereas addition of aryl substituents, particularly at the 2-position, increased type 2 5aR binding to provide dual inhibitors with excellent hAR binding, e.g. N-(2-chlorophenyl)-3-oxo-4-methyl-4-aza-5alpha-androst-1-ene-17bet a-carboxamide (9c). Compounds of this type exhibit low nanomolar IC50s for both human 5aR isozymes as well as the human androgen receptor. Kinetic analysis confirms that the prototype 9c displays reversible, competitive inhibition of both human isozymes of 5aR with K(i) values of less than 10 nM. Furthermore, this compound binds to the androgen receptor with an IC50 equal to 8 nM. Compounds in this series are projected to be powerful antagonists of testosterone and dihydrotestosterone action in vivo, with potential utility in the treatment of prostatic carcinoma (PC).

5-alpha Reductase Inhibitors↗
PubMed2002

Structural basis for the glucocorticoid response in a mutant human androgen receptor (AR(ccr)) derived from an androgen-independent prostate cancer.

The crystal structure of a mutant androgen receptor (AR) ligand-binding domain (LBD) in complex with the agonist 9alpha-fluorocortisol has been determined at 1.95 A resolution. This mutant AR contains two mutations (L701H and T877A) and was previously reported as a high-affinity cortisol/cortisone responsive AR (AR(ccr)) isolated from the androgen-independent human prostate cancer cell lines MDA PCa 2a and 2b (Zhao et al. Nature Med. 2000, 6, 703-6). The three-dimensional structure of the AR(ccr) LBD complexed with 9alpha-fluorocortisol shows the typical conformation of an agonist-bound nuclear receptor in which helix 12 is precisely positioned as a "lid" for the ligand-binding pocket. Binding of 9alpha-fluorocortisol to the AR(ccr) involves favorable hydrogen bond patterns on the C17 and C21 substituents of the ligand due to the mutations at 701 and 877 in the AR(ccr). Our studies provide the first structural explanation for the glucocorticoid activation of AR(ccr), which is important for the development of new therapeutic treatments for androgen-independent prostate cancer.

Algorithms↗
PubMed1996

Expression of the androgen receptor and an androgen-responsive protein, apolipoprotein D, in human breast cancer.

Little is known regarding the activity and function of the androgen receptor (AR) in human breast cancer. In the present study AR was evaluated in untreated primary breast cancers using antisera to the amino- and carboxy-termini of the receptor and quantitated using colour video image analysis. A strong correlation between tissue concentration and percentage AR-positive cells was observed for each antiserum. However, comparison of percentage positive cells using the amino- and carboxy-terminal AR antisera in individual breast cancer specimens revealed a subset of tumours with discordantly increased staining for the carboxy terminus. These findings suggest the presence of amino-terminal-truncated AR in a proportion of breast cancer cells or presence of AR mutations or associated protein alterations that affect binding of the amino-terminal AR antiserum. Immunohistochemical expression of the androgen-regulated glycoprotein, apolipoprotein D (apo-D), was also evaluated in the breast cancer specimens. Focal positivity of apo-D staining, which did not always co-localise with AR-positive cells, was observed within breast tumours. Furthermore, no correlation was evident between percentage positive cells stained for AR and apo-D in breast cancer specimens. These findings indicate that, although apo-D expression is androgen regulated in human breast cancer cell lines in vitro, its expression in primary breast cancers may be regulated by other factors. The expression of AR in primary breast cancers also suggests that the receptor may be involved in tumour responsiveness or in abnormal responses to endocrine therapies.

Adult↗
PubMed2004

Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line.

Androgen receptor (AR) overexpression is one of the characteristics of prostate cancer (PC) that progresses to hormone independence. An androgen-independent (AI) derivative, with much higher AR-mRNA and protein levels than the parental LNCaP cell line, whose proliferation was androgen dependent (AD), was used to explore the mechanism of AR overexpression. We found that a suppressor element (ARS), previously identified in mouse AR and located in the 5'-untranslated region of human AR gene, malfunctions in AI cells. Transfection of constructs that included ARS element into AD cells reduced the transactivating activities of both AR promoter and a heterologous SV40 promoter. The deletion of ARS resulted in an eightfold increase in AR-promoter activity in AD cells, but had no effect in AI cells. Moreover, the nuclear extracts of AD cells contained proteins that produced a specific, ARS-binding complex, while this complex appeared to have been lost from AI cells. Most importantly, treatment of AI cells with a demethylating agent or histone deacetylase inhibitors restored the lost ARS-binding complex. The restoration of the complex coincided with a reduced expression of AR-mRNA and protein and a reduced rate of AR-gene transcription, determined by nuclear run-on experiment. Thus, epigenetic transcriptional silencing of the suppressor protein(s) may be responsible for AR overexpression in AI cells, and its reversal in hormone-independent PC may normalize AR levels and restore their hormone dependence.

5' Untranslated Regions↗
PubMed2004

Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells.

Androgen receptor (AR) signaling pathways mediate critical events in normal and neoplastic prostate growth. Shortening of the polymorphic N-terminal polyglutamine (poly(Q)) tract of the AR gene leads to transcriptional hyperactivity and has been correlated with an increased risk of prostate cancer. The underlying mechanisms for these effects are poorly understood. We show here that androgen-dependent cellular proliferation and transcription in prostate cancer cells is inversely correlated to the length of the AR poly(Q) region. We further show that AR proteins containing a shortened poly(Q) region functionally respond to lower concentrations of androgens than wild type AR. Whereas DNA binding activity is relatively unaffected by AR poly(Q) variation, we found that ligand binding affinity and the ligand-induced NH(2)- to COOH-terminal intramolecular interaction is enhanced when the poly(Q) region is shortened. Importantly, we show that AR proteins containing a shortened poly(Q) region associate in vivo with higher levels of specific p160 coactivators and components of the SWI/SNF chromatin remodeling complex as compared with the wild type AR. Collectively, our findings suggest that the AR transcriptional hyperactivity associated with shortened poly(Q) length stems from altered ligand-induced conformational changes that enhance coactivator recruitment.

Blotting, Western↗
PubMed2007

Insulin-like growth factor 1/insulin signaling activates androgen signaling through direct interactions of Foxo1 with androgen receptor.

The androgen-androgen receptor (AR) system plays vital roles in a wide array of biological processes, including prostate cancer development and progression. Several growth factors, such as insulin-like growth factor 1 (IGF1), can induce AR activation, whereas insulin resistance and hyperinsulinemia are correlated with an elevated incidence of prostate cancer. Here we report that Foxo1, a downstream molecule that becomes phosphorylated and inactivated by phosphatidylinositol 3-kinase/Akt kinase in response to IGF1 or insulin, suppresses ligand-mediated AR transactivation. Foxo1 reduces androgen-induced AR target gene expressions and suppresses the in vitro growth of prostate cancer cells. These inhibitory effects of Foxo1 are attenuated by IGF1 but are enhanced when it is rendered Akt-nonphosphorylatable. Foxo1 interacts directly with the C terminus of AR in a ligand-dependent manner and disrupts ligand-induced AR subnuclear compartmentalization. Foxo1 is recruited by liganded AR to the chromatin of AR target gene promoters, where it interferes with AR-DNA interactions. IGF1 or insulin abolish the Foxo1 occupancy of these promoters. Of interest, a positive feedback circuit working locally in an autocrine/intracrine manner may exist, because liganded AR up-regulates IGF1 receptor expression in prostate cancer cells, presumably resulting in higher IGF1 signaling tension and further enhancing the functions of the receptor itself. Thus, Foxo1 is a novel corepressor for AR, and IGF1/insulin signaling may confer stimulatory effects on AR by attenuating Foxo1 inhibition. These results highlight the potential involvement of metabolic syndrome and hyperinsulinemia in prostate diseases and further suggest that intervention of IGF1/insulin-phosphatidylinositol 3-kinase-Akt signaling may be of clinical value for prostate diseases.

Animals↗
PubMed1992

Stimulation of growth by both androgen and estrogen of the EMP-K1 transplantable tumor with androgen and estrogen receptors from human extramammary Paget's disease in nude mice.

BACKGROUND: Experimental approaches using transplantable human tumors in nude mice have greatly improved studies on their pathogenesis and treatment. PURPOSE: We studied the establishment of a transplantable tumor, EMP-K1, derived from extramammary Paget's disease and the morphology and unique hormone dependence of this tumor. METHODS: Tissue fragments from a metastatic skin tumor of an 80-year-old man with primary genital extramammary Paget's disease were implanted into male nude BALB/c mice. Tissue fragments of the established tumor were implanted into 50 castrated male 8-week-old nude mice, which were given injections of 100 micrograms testosterone propionate (TP), 100 micrograms 5 alpha-dihydrotestosterone (DHT), 10 micrograms diethylstilbestrol (DES), or 1, 10, or 100 micrograms 17 beta-estradiol (E2). All injections were administered intramuscularly once daily, starting from the day of transplantation. The established tumors were examined immunohistochemically and biochemically. RESULTS: A transplantable tumor (EMP-K1) was established in the nude mouse. EMP-K1 tumor cells expressed antigens such as carcinoembryonic antigen and epithelial membrane antigen, cytokeratin, and c-erbB-2 protein and contained androgen, estrogen, and progesterone receptors. The growth of the EMP-K1 tumor was stimulated by TP, DHT, DES, and E2. CONCLUSIONS: These results suggest that both androgen and estrogen may stimulate the growth of the same tumor by both androgen receptor and estrogen receptor pathways. IMPLICATIONS: The EMP-K1 tumor is a useful tool for studies on the biology of extramammary Paget's disease, and further studies using these tumors will provide useful information concerning proper hormone therapy.

Aged↗
PubMed2005

Androgen regulation of stage-dependent cyclin D2 expression in Sertoli cells suggests a role in modulating androgen action on spermatogenesis.

Regulation of spermatogenesis involves stage-dependent androgen action on Sertoli cells, but the pathways involved are unclear. We assessed if cyclin D2 could play a role. In rats, Sertoli cell nuclear, stage-dependent immunoexpression of cyclin D2 switched on after Day 10 and persisted through Day 35, but disappeared by adulthood. However, ethane dimethane sulfonate (EDS)-induced testosterone withdrawal in adult rats for 6 days induced stage-dependent cyclin D2 immunoexpression in Sertoli cells, with highest expression at stages IX-XII and nondetectable at stages VI-VIII (opposite that for androgen receptor [AR] immunoexpression). In EDS-treated rats, a single injection of testosterone but not of estrogen reversed this change in 4 h, and testosterone administration from the time of EDS treatment prevented expression of cyclin D2 in Sertoli cells. The EDS-induced changes in cyclin D2 immunoexpression were matched by changes in expression of Ccnd2 (cyclin D2) mRNA in isolated stage-dissected tubules. Treatment of adult rats with flutamide induced stage-dependent cyclin D2 immunoexpression in Sertoli cells within 18 h, and confocal microscopy revealed that immunoexpression of AR and cyclin D2 were mutually exclusive within individual seminiferous tubules in these animals. Sertoli cell-selective ablation of the AR in mice using Cre/loxP technology also resulted in stage-dependent Sertoli cell cyclin D2 immunoexpression. Downstream from cyclin D2 action is retinoblastoma 1 (RB1), a tumor suppressor protein, immunoexpression of which paralleled stage-dependent AR expression in Sertoli cells; RB1 stage specificity disappeared after EDS treatment. These results point to a non-cell cycle role for cyclin D2 and RB1 in mature Sertoli cells in the stage-dependent mechanisms regulated by AR expression and androgen action.

Animals↗
PubMed2002

Synthetic inhibitors of CDKs induce different responses in androgen sensitive and androgen insensitive prostatic cancer cell lines.

AIMS: Because of the high prevalence of prostatic cancer and the limitations of its treatment, enormous effort has been put into the development of new therapeutic modalities. One potential tool is the use of cyclin dependent kinase (CDK) inhibitors, which are based on the trisubstituted derivatives of purine. The aim of this study was to analyse alterations of the regulatory pathways in both androgen sensitive and androgen insensitive prostatic cancer cell lines (LNCaP and DU-145, respectively) after blockage of the cell cycle by the synthetic CDK inhibitors, olomoucine and bohemine. METHODS: The effects of olomoucine and bohemine were studied on the following parameters: (1) cell proliferation, by measurement of DNA content; (2) viability, by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) and/or XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide) test; and (3) the expression of p53, pRB, Bcl-2, Bax, p16, p21, p27, cyclins A, B, D1, E, p34(cdc2), and the androgen receptor (AR), by western blot analysis. RESULTS: Both olomoucine and bohemine were potent inhibitors of growth and viability; however, bohemine was two to three times more effective than olomoucine. The sensitivity of LNCaP cells to both agents was significantly higher. After treatment, both cell lines revealed quite different spectra of protein expression. CONCLUSIONS: These results indicate the existence of specific cell cycle regulating pathways in both cell lines, which may be associated with both p53 and AR status. CDK inhibitors exhibited valuable secondary effects on the expression of numerous regulators and thus may modulate the responsiveness of tumour cells to treatment, including treatment with hormone antagonists.

Cell Division↗
PubMed2006

Male germ cell-associated kinase, a male-specific kinase regulated by androgen, is a coactivator of androgen receptor in prostate cancer cells.

Androgen receptor (AR) is a ligand-induced transcriptional factor, which plays an important role in the normal development of prostate as well as in the progression of prostate cancer. Numerous coactivators, which associate with AR and function to remodel chromatin and recruit RNA polymerase II to enhance the transcriptional potential of AR, have been identified. Among these coactivators, few are protein kinases. In this study, we describe the characterization of a novel protein kinase, male germ cell-associated kinase (MAK), which serves as a coactivator of AR. We present evidence, which indicates that (a) MAK physically associates with AR (MAK and AR are found to be coprecipitated from cell extracts, colocalized in nucleus, and corecruited to prostate-specific antigen promoter in LNCaP as well as in transfected cells); (b) MAK is able to enhance AR transactivation potential in an androgen- and kinase-dependent manner in several prostate cancer cells and synergize with ACTR/steroid receptor coactivator-3 coactivator; (c) small hairpin RNA (shRNA) knocks down MAK expression resulting in the reduction of AR transactivation ability; (d) MAK-shRNA or kinase-dead mutant, when introduced into LNCaP cells, reduces the growth of the cells; and (e) microarray analysis of LNCaP cells carrying kinase-dead MAK mutant showed a significant impediment of AR signaling, indicating that endogenous MAK plays a general role in AR function in prostate cancer cells and likely to be a general coactivator of AR in prostate tissues. The highly restricted expression of this kinase makes it a potentially useful target for intervention of androgen independence.

Androgens↗
PubMed2005

Tetrahydrogestrinone is an androgenic steroid that stimulates androgen receptor-mediated, myogenic differentiation in C3H10T1/2 multipotent mesenchymal cells and promotes muscle accretion in orchidectomized male rats.

The discovery of tetrahydrogestrinone (THG) abuse by several elite athletes led the U.S. Congress to declare it a controlled substance, although conclusive evidence of its anabolic/androgenic activity is lacking. We determined whether THG affects myogenic differentiation and androgen receptor (AR)-mediated signaling, whether it binds to AR, and whether it has androgenic and anabolic effects in vivo. Accordingly, we measured the dissociation constant for THG with a fluorescence anisotropy assay using recombinant AR-ligand binding domain. The AR nuclear translocation and myogenic activity of androstenedione were evaluated in mesenchymal, multipotent C3H10T1/2 cells. We performed molecular modeling of the THG:AR interaction. The androgenic/anabolic activity was evaluated in orchidectomized rats. THG bound to AR with an affinity similar to that of dihydrotestosterone. In multipotent C3H10T1/2 cells, THG upregulated AR expression, induced AR nuclear translocation, dose dependently increased the area of myosin heavy chain type II-positive myotubes, and up-regulated myogenic determination and myosin heavy chain type II protein expression. The interaction between AR and the A ring of THG was similar to that between AR and the A ring of dihydrotestosterone, but the C17 and C18 substituents in THG had a unique stabilizing interaction with AR. THG administration prevented the castration-induced atrophy of levator ani, prostate gland, and seminal vesicles and loss of fat-free mass in orchidectomized rats. We conclude that THG is an anabolic steroid that binds to AR, activates AR-mediated signaling, promotes myogenesis in mesenchymal multipotent cells, and has anabolic and androgenic activity in vivo. This mechanism-based approach should be useful for rapid screening of anabolic/androgenic agents.

Animals↗
PubMed1983

Inhibition of development of both androgen-dependent and androgen-independent pigment cells in scrotal skin dermis of the rat by antiandrogen treatment during fetal growth.

Testosterone controls the melanogenic activity of epidermal melanocytes, but not that of brown dermal pigment cells, in scrotal skin of the adult rat. The effect of prenatal treatment with the antiandrogen flutamide on the development of scrotal skin pigmentation and the male reproductive system was examined. Treatment with flutamide on days 14-20 of gestation resulted in hypospadias, the absence or only rudimentary growth of prostate and seminal vesicles, and the presence of a vagina in male offspring. The scrotal coloration of these animals was lighter than controls, an effect due to the complete absence of dermal pigment cells. There was no effect of prenatal treatment with flutamide on melanin content, morphology, and relative number of epidermal melanocytes. Thus, the administration of antiandrogen during the fetal period of androgen-induced differentiation of secondary genital organs of the male rat prevents development of the androgen-independent dermal pigment cells. It would appear, therefore, that there is a transitory period during development when the dermal pigment cells or other elements in the scrotal dermal environment which regulate their function are under androgen control.

Androgen Antagonists↗
PubMed1989

Fusion proteins containing androgen receptor sequences and their use in the production of poly- and monoclonal anti-androgen receptor antibodies.

Complementary DNA segments that encode different domains of human and rat androgen receptors were fused to the Escherichia coli trpE gene using pATH expression vectors. Fusion proteins expressed by the bacteria were used to immunize rats and rabbits to obtain polyclonal antibodies to androgen receptors. Spleen cells of immunized rats were fused with myeloma cells to obtain stable hybridomas that produced monoclonal antibodies. Gradient centrifugation and immuno-precipitation assays indicated that the antibodies interacted with androgen receptors specifically.

Amino Acid Sequence↗
PubMed1992

Complete deletion of the androgen receptor gene: definition of the null phenotype of the androgen insensitivity syndrome and determination of carrier status.

The molecular basis of androgen insensitivity was investigated in a family with the complete form of the syndrome. Polymerase chain reaction amplification and Southern blot analysis of genomic DNA revealed a deletion of the entire androgen receptor (AR) gene in affected individuals. The carrier status of female members of this family was examined using a HindIII restriction fragment length polymorphism associated with the AR gene. Obligate carriers were hemizygous for one of the two alleles at this locus, while heterozygosity for the polymorphic alleles, implying the presence of two copies of the AR gene, indicated noncarrier status. This conclusion was supported by gene dosage studies using comparative densitometric analysis of Southern blots hybridized simultaneously with an AR cDNA probe and a control cDNA probe from an unrelated gene. Finally, the pattern of inheritance of another X-linked DNA polymorphism allowed us to conclude that the original mutation had occurred in the germ line of the maternal great-grandfather of the index patient. Although rare, complete deletion of the AR gene is of particular importance in terms of correlation between molecular defect and phenotype, as it represents the quintessential form of complete androgen insensitivity, the null phenotype.

Alleles↗
PubMed1998

Prostate-sparing effects in primates of the potent androgen 7alpha-methyl-19-nortestosterone: a potential alternative to testosterone for androgen replacement and male contraception.

7alpha-Methyl-19-nortestosterone (MENT) is a potent synthetic androgen that cannot be converted to dihydrotestosterone. In this study we determined the relative androgenic, antigonadotropic, and anabolic potencies of testosterone vs. MENT in the nonhuman primate M. fascicularis. In castrated monkeys, dose-response relationships were generated for the effects of testosterone and MENT on gonadotropin levels, prostate growth, body weight, and lipid metabolism. In a pilot study, four monkeys were castrated, and magnetic resonance imaging (MRI) was used to document a 50% loss of prostate volume within 8 weeks, verifying that MRI is a reliable means to measure prostate size in this species. Two additional groups of six monkeys each were then castrated and serially administered four graded dosages of testosterone or MENT via osmotic minipumps over 20 weeks. Complete suppression of LH was achieved with a minimum of 0.3 mg/day MENT, compared to 3.0 mg/day testosterone. MENT supported body weight 10 times more potently than did testosterone. Baseline prostate volumes were maintained with 0.1-0.2 mg/day MENT vs. 0.3 mg/day testosterone. Thus, in monkeys, MENT is 10 times more potent than testosterone with regard to the clinically desirable end points of gonadotropin suppression and anabolism, but only twice as potent at stimulating prostate growth. These results suggest that MENT may have a wider therapeutic index than testosterone for human androgen replacement and male contraception.

Anabolic Agents↗
PubMed1998

Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression.

Women with adrenal insufficiency suffer from chronic dehydroepiandrosterone (sulfate) [DHEA(S)] deficiency. To define a suitable dose for DHEA replacement, we studied the pharmacokinetics and biotransformation of orally administered DHEA in nine healthy female volunteers (mean age 23.3 +/- 4.1 yr, mean body mass index 22.5 +/- 1.8 kg/m2) with transient suppression of adrenal androgen secretion because of dexamethasone (dex) administration (4 x 0.5 mg/day for 4 days). Diurnal blood sampling was performed during the early follicular phase of four subsequent menstrual cycles (study period 1: baseline; study periods 2-4: dex + placebo, dex + 50 mg DHEA or dex + 100 mg DHEA in a randomized cross-over design). Dex induced not only a significant suppression of serum cortisol (to 8% of baseline) but also of DHEA (18%), DHEA(S) (16%), and androstenedione (26%), as well as of testosterone (28%), dihydrotestosterone (43%), and estrone (54%). Oral administration of 50 mg DHEA led to restoration of DHEA(S) baseline levels, whereas 100 mg induced supraphysiological concentrations [baseline vs. 50 mg DHEA vs. 100 mg DHEA: area under the concentration-time curve (AUC) 0-12 h DHEA: 280 +/- 85 vs. 241 +/- 73 vs. 383 +/- 106 nmol/L x h; AUC 0-12 h DHEA(S): 89.1 +/- 48.4 vs. 139.6 +/- 43.5 vs. 213.3 +/- 21.6 mumol/L x h). Serum concentrations of dihydrotestosterone and estrone were restored to baseline after 50 mg DHEA, whereas baseline testosterone and androstenedione levels were only achieved by administration of 100 mg DHEA. In conclusion, 50 mg DHEA seems to be a suitable replacement dose in females with adrenal insufficiency. Furthermore, the rapid and lasting conversion to potent androgens demonstrates a potential role of DHEA for androgen replacement in females in general.

Administration, Oral↗