First case of cyproterone acetate induced multiple meningiomas in identical female twins: A case report.

Meningiomas are the most common tumors of the central nervous system. Most meningiomas are benign and occur mainly in middle-aged women. Only a few cases of meningiomas in identical twins have been reported. Cyproterone acetate (Androcur® Bayer Healthcare SAS) (CPA) is an antiandrogenic progestin used to treat female hirsutism in some countries including France. We report a case of identical twin sisters who developed multiple, atypically located meningiomas in the setting of long-term CPA use. Eighteen-month follow-up showed spontaneous decrease of meningiomas after cessation of CPA. This case illustrates CPA's ability to induce development of atypically located meningiomas that differ even between identical twins, confirms benefit of surgical abstention, and raises questions regarding security of use of CPA.

Anti-androgenic therapy in young patients and its impact on intensity of hirsutism, acne, menstrual pain intensity and sexuality - a preliminary study.

OBJECTIVES: Using anti-androgenic contraception is one of the methods of birth control. It also has a significant, non-contraceptiveimpact on women's body. These drugs can be used in various endocrinological disorders, because of their abilityto reduce the level of male hormones.The aim of our study is to establish a correlation between taking different types of anti-androgenic drugs and intensity ofhirsutism, acne, menstrual pain intensity and sexuality. MATERIAL AND METHODS: 570 women in childbearing age that had been using oral contraception for at least three monthstook part in our research. We examined women and asked them about quality of life, health, direct causes and effects ofthat treatment, intensity of acne and menstrual pain before and after. Our research group has been divided according tothe type of gestagen contained in the contraceptive pill: dienogest, cyproterone, chlormadynone and drospirenone. Additionally,the control group consisted of women taking oral contraceptives without antiandrogenic component. RESULTS: The mean age of the studied group was 23 years ± 3.23. 225 of 570 women complained of hirsutism.The mean score for acne intensity before the use of contraception was 2.7 ± 1.34. The mean score for acne intensity after3 months of using contraception was 1.85 ± 1.02 (p < 0.001). 192 women reported excess hairiness in one or more areabefore treatment. Mean value based on Ferriman-Gallway scale before the treatment was 6.23 ± 6.21 and 5.39 ± 5.6 afterthe treatment (p < 0.001). CONCLUSIONS: All groups of drugs effectively reduced pain and acne severity. Cyproterone and drospirenone turned outas the most effective drugs in treating hirsutism. Surprisingly, according to our research, dienogest does not have anyimpact on body hairiness.

[Intra cranial meningiomas and long term use of cyproterone acetate with a conventional dose in women. A report of two cases of tumor decrease after treatment withdrawal]. / Méningiomes intracrâniens et utilisation prolongée d'acétate de cyprotérone à dose conventionnelle chez la femme: à propos de deux cas de régression tumorale après arrêt du traitement.

The action of synthetic progestogens, prescribed at a conventional dose in women, for a meningioma, is still poorly understood, and could be related to progesterone receptors. We report two cases illustrating multiple meningiomas with stabilization or tumor reduction after withdrawal of cyproterone acetate originally prescribed for a long term period. We also review the influence of synthetic progestogens on meningiomas, particularly the impact of treatment withdrawal.

The effects of sex-steroid administration on the pituitary-thyroid axis in transsexuals.

OBJECTIVE: Estrogen and androgen administration modulate the pituitary-thyroid axis through alterations in thyroid hormone-binding globulin (TBG) metabolism, but the effects of sex steroids on extrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion in humans are unknown. DESIGN AND METHODS: We studied 36 male-to-female and 14 female-to-male euthyroid transsexuals at baseline and after 4 months of hormonal treatment. Male-to-female transsexuals were treated with cyproterone acetate (CA) 100 mg/day alone (n = 10) or in combination with either oral ethinyl estradiol (or-EE) 100 microg/day (n = 14) or transdermal 17beta-estradiol (td-E) 100 microg twice a week (n = 12). Female-to-male transsexuals were treated with i.m. testosterone 250 mg twice a week. A t-test was used to test for differences within groups and ANOVA with post hoc analysis to test for differences between the groups. RESULTS: Or-EE increased TBG (100 +/- 12%, P < .001) and testosterone decreased TBG (-14 +/- 4%, P = 0.01), but free T4 did not change. Td-E and CA did not affect TBG concentrations. TSH was not different between groups at baseline or after treatment. CA decreased T3/T4 ratios (-9 +/- 3%, P = 0.04), suggesting that T4 to T3 conversion was lower. Testosterone increased T3/T4 ratios (30 +/- 9%, P = 0.02), which probably reflects higher T4 to T3 conversion. CONCLUSION: Oral but not transdermal estradiol increases TBG, whereas testosterone lowers TBG. Testosterone increases T3/T4 ratios. Estradiol does not affect T3/T4 ratios, irrespective of the route of administration.

Testosterone induced Ca2+ influx in bone marrow-derived macrophages via surface binding sites.

The biological activity of testosterone is thought to occur predominantly through binding to the androgen receptor (AR), a member of the nuclear receptor superfamily that functions as a ligand-activated transcription factor. Here, we found that testosterone could induce a rapid rise in the intracellular free Ca2+ concentration ([Ca2+]i) of Fura-2 loaded bone marrow-derived macrophages (BMMs), which was found to be predominantly due to the influx of extracellular Ca2+ through Ni2+-blockable Ca2+ channels in the plasma membrane. However, these effects of testosterone could not be associated with the classical intracellular AR in BMMs, since AR was not detectable using different experimental techniques. Instead, it was found that testosterone could bind to the surface of BMMs by the use of an impermeable testosterone-BSA-FITC, and Ca2+ influx could also be induced by testosterone conjugated to BSA. Our data indicated a novel mode of direct action of testosterone on BMMs, which was not mediated through the classical AR response, but through the binding sites of testosterone on cell surfaces.

Male contraception: expanding reproductive choice.

The development of steroid-based oral contraceptives had revolutionized the availability of contraceptive choice for women. In order to expand the contraceptive options for couples by developing an acceptable, safe and effective male contraceptive, scientists have been experimenting with various steroidal/non-steroidal regimens to suppress testicular sperm production. The non-availability of a long-acting androgen was a limiting factor in the development of a male contraceptive regimen since all currently tested anti-spermatogenic agents also concurrently decrease circulating testosterone levels. A combination regimen of long-acting progestogen and androgen would have advantage over an androgen-alone modality since the dose of androgen required would be much smaller in the combination regimen, thereby decreasing the adverse effects of high steroid load. The progestogen in the combination regimen would act as the primary anti-spermatogenic agent. Currently, a number of combination regimens using progestogen or GnRH analogues combined with androgen are undergoing trials. The side effects of long-term use of androgens and progestogens have also undergone evaluation in primate models and the results of these studies need to be kept in view, while considering steroidal regimens for contraceptive use in men. Efforts are also being made to popularize non-scalpel vasectomy and to develop condoms of greater acceptability. The development of contraceptive vaccines for men, using sperm surface epitopes not expressed in female reproductive tract as source, still requires considerable research efforts.

El papel de los gestágenos en los anticonceptivos hormonales orales / The role of gestagens in oral hormonal contraceptives

El papel de los gestágenos en los anticonceptivos hormonales orales está en relación directa con los efectos secundarios y el impacto sobre el metabolismo. En la última década se han desarrollado cinco nuevos gestágenos con alta potencia progestogénica y sin actividad androgénica. Es necesario desarrollar y utilizar gestágenos más selectivos para que la píldora sea usada con seguridad y confianza, para aumentar el cumplimiento y así disminuir el número de embarazos no deseados

The role of gestagens in oral hormonal contraceptives was directly related to secondary effects and metabolic impact. In the last decade five new gestagens have been developed, each presenting high progestogenic potency and absent androgenic activity. It is necesary to develop more selective gestagens to reduce secondary effects in order to get a safe and confident use of contraceptive pill, to increase compliance and to decrease the number of unwanted pregnancies

Changes in treatment volume of hormonally treated and untreated cancerous prostate and its impact on rectal dose.

Late chronic side effects of the rectum constitute one of the principal limiting factors for curative radiation therapy in patients with prostate cancer. The purpose of the study was to determine the impact of immediate androgen deprivation (IAD) prior to conformal radiotherapy on rectal volume exposed to high doses, as compared with a deferred treatment strategy (DAD). Twenty-five patients (13 in the IAD group and 12 in the DAD group) with bulky tumours of the prostate, T3pN1-2M0 from the prospective EORTC trial 30846 were analysed. Three-dimensional conformal radiation treatment plans (3DCRT) using a 4-field box technique were generated based on the digitized computed tomographic or magnetic resonance findings acquired during the first 9 months after inclusion in the EORTC trial. Dose-volume histograms (DVHs) were calculated for the prostate and rectum. In the DAD group, there was no obvious alteration in the mean size of the prostate or other evaluated structures. In the IAD patients, a statistically significant reduction of approximately 40% of the gross tumour volume (GTV) was reached after a 6 months' course of hormonal treatment (p < 0.001). High-dose rectal volume was correlated with the volume changes of the GTV (p < 0.001). Mean rectal volume receiving 95% or more of the target dose was significantly reduced by 20%. Our study confirms the effect of downsizing of locally advanced prostate tumours following AD treatment and demonstrates the interdependence of the high-dose rectal volume with the volume changes of the GTV. However, the mean beneficial sparing of rectal volume was outweighed in some patients by considerable inter-patient variations.

Cyproterone, norethindrone, medroxyprogesterone and levonorgestrel are less potent local human growth hormone and insulin-like growth factor I secretion stimulators than progesterone in human breast cancer explants expressing the estrogen receptor.

The aim of the present study was to compare the ability of natural progesterone and synthetic progestins to stimulate local growth hormone (GH) and insulin-like growth factor I (IGF-I) secretion by breast cancer explants. Explants obtained during surgery were divided according to their estrogen/progesterone receptor phenotype - ER(+)PR(-); ER(+)PR(+); ER(-)PR(+) - as determined by immunocytochemistry. Natural progesterone (10(-5) mol/l) and synthetic progestins (cyproterone acetate (5 x 10(-7) mol/l), norethindrone (10(-5) mol/l), medroxyprogesterone acetate (10(-7) mol/l), and levonorgestrel (10(-7) mol/l) were tested in vitro for their ability to induce secretion of proliferation-promoting agents such as human GH (hGH) and IGF-I. All hormone-dependent breast cancer cell types responded to progesterone stimulation with increased local hGH secretion, while in the non-malignant tissue this effect was observed only in PR(+) cells. Moreover, progesterone in only PR(+) cells in vitro stimulated local IGF-I secretion by both malignant and non-malignant tissue. Medroxyprogesterone and levonorgestrel increased GH secretion by both malignant and non-malignant ER(-)PR(+) breast cancer explants, while cyproterone stimulated it only in non-malignant tissue. None of the synthetic progestins tested in this experiment exerted an effect on GH secretion by both malignant and non-malignant tissue of ER(+) breast cancer explants. The present data additionally showed that, apart from cyproterone, which increased IGF-I secretion in the same manner as progesterone by both malignant and non-malignant ER(-)PR(+) breast explants, other progestins tested had either no effect on IGF-I local secretion or decreased it. Medroxyprogesterone and levonorgestrel induced a decrease in IGF-I secretion noted in ER(+) explants of non-malignant tissue and in malignant ER(-)PR(+) breast tissue. All progestins tested decreased IGF-I secretion by malignant ER(+)PR(+) explants. Taken together, the tested synthetic progestins widely used as oral contraceptives and in hormone replacement therapy were less potent than progesterone in inducing secretion of proliferation-promoting agents such as hGH and IGF-I in ER-containing breast tissue. Despite the lack of confirmation of the link between the use of progestins and breast cancer risk, patients should be informed that the use of certain estrogen/progestin preparations is of no influence on breast cancer risk while others may increase it.

Treatment of paraphilia with luteinizing hormone-releasing hormone agonists.

Up to now there have been no published results of therapy of paraphilia (for example, pedophilia or sadism) and sexual aggressive impulsiveness with luteinizing hormone-releasing hormone (LHRH) agonists in the German-speaking countries. After a short introduction about physiologic features and the present state of investigations in treatment of paraphilia with LHRH agonists we describe 11 patients who were treated with the LHRH agonist Leuprolide Acetate over a period of 12 months. The patients showed no tendency toward sexually aggressive behavior and reported an evident reduction of penile erection, ejaculation, masturbation, sexually deviant impulsiveness, and fantasies. One patient died from suicide. In combination with other treatments, LHRH Agonists seem to be a very promising alternative to cyproterone acetate and its possible carcinogene effects.

Effect of antihormones in amygdala-kindled seizures in rats.

Tamoxifen (TXF; an antiestrogen), cyproterone acetate (CYP; an antiandrogen) and mifepristone (MIF; an antigestagen) did not affect kindling parameters (afterdischarge threshold, seizure severity, seizure duration and afterdischarge duration) in fully-kindled rats. TXF (50 mg/kg) and CYP (50 mg/kg), when combined with carbamazepine, or phenobarbital, both antiepileptics administered at their highest subprotective doses of 15 mg/kg, resulted in significant reduction of the seizure and afterdischarge durations, both in male and female rats. Additionally, the combination of carbamazepine and cyproterone markedly increased the afterdischarge threshold in fully-kindled rats of both genders. The interaction between antihormones and carbamazepine, or phenobarbital, was not reversed by the respective gonadal hormones (estradiol, progesterone, and testosterone), kainic acid, or strychnine. However, the TXF-, and CYP-induced effect on the action of carbamazepine was abolished by bicuculline, N-methyl-D-aspartic acid and aminophylline. The effect of TXF on the protective activity of phenobarbital was reversed by bicuculline and N-methyl-D-aspartic acid. Finally, the CYP-mediated effect on phenobarbital action was abolished by bicuculline and aminophylline. Neither TXF nor CYP altered free plasma levels and brain levels of carbamazepine or phenobarbital, so a pharmacokinetic interaction between antihormones and antiepileptic drugs is not probable. In view of the present data, it may be suggested that the protective activity of the antiestrogen and antiandrogen are mostly associated with the enhancement of GABA-ergic and purinergic transmission in the central nervous system. Also the augmentation of glutamatergic transmission, realized through NMDA receptors, may be involved in the mechanism of antiseizure action of TXF and CYP.

Dynamics of intracellular movement and nucleocytoplasmic recycling of the ligand-activated androgen receptor in living cells.

An expression construct containing the cDNA encoding a modified aequorea green fluorescent protein (GFP) ligated to the 5'-end of the rat androgen receptor (AR) cDNA (GFP-AR) was used to study the intracellular dynamics of the receptor movement in living cells. In three different cell lines, ie. PC3, HeLa, and COS1, unliganded GFP-AR was seen mostly in the cytoplasm and rapidly (within 15-60 min) moved to the nuclear compartment after androgen treatment. Upon androgen withdrawal, the labeled AR migrated back to the cytoplasmic compartment and maintained its ability to reenter the nucleus on subsequent exposure to androgen. Under the condition of inhibited protein synthesis by cycloheximide (50 microg/ml), at least four rounds of receptor recycling after androgen treatment and withdrawal were recorded. Two nonandrogenic hormones, 17beta-estradiol and progesterone at higher concentrations (10(-7)/10(-6) M), were able to both transactivate the AR-responsive promoter and translocate the GFP-AR into the nucleus. Similarly, antiandrogenic ligands, cyproterone acetate and casodex, were also capable of translocating the cytoplasmic AR into the nucleus albeit at a slower rate than the androgen 5alpha-dihydrotestosterone (DHT). All AR ligands with transactivation potential, including the mixed agonist/antagonist cyproterone acetate, caused translocation of the GFP-AR into a subnuclear compartment indicated by its punctate intranuclear distribution. However, translocation caused by casodex, a pure antagonist, resulted in a homogeneous nuclear distribution. Subsequent exposure of the casodex-treated cell to DHT rapidly (15-30 min) altered the homogeneous to punctate distribution of the already translocated nuclear AR. When transported into the nucleus either by casodex or by DHT, GFP-AR was resistant to 2 M NaCl extraction, indicating that the homogeneously distributed AR is also associated with the nuclear matrix. Taken together, these results demonstrate that AR requires ligand activation for its nuclear translocation where occupancy by only agonists and partial agonists can direct it to a potentially functional subnuclear location and that one receptor molecule can undertake multiple rounds of hormonal signaling; this indicates that ligand dissociation/inactivation rather than receptor degradation may play a critical role in terminating hormone action.

Differential effects of 17beta-estradiol and testosterone on the contractile responses of porcine coronary arteries.

1. We investigated the effects of short-term exposure to physiological levels of 17beta-estradiol and testosterone on vasocontractile responses in porcine coronary artery rings. 2. Concentration-response curves to endothelin-1, 5-hydroxytryptamine, the thromboxane analogue U46619 and KCl were constructed in endothelium-intact and endothelium-disrupted artery rings. 3. Thirty minutes exposure to 17beta-estradiol (1 and 30 nM) significantly attenuated vasoconstriction to endothelin-1, 5-hydroxytryptamine and U46619. Conversely, the same concentrations of testosterone significantly potentiated responses elicited by these contractile agents. These inhibitory effects of 17beta-estradiol and enhancing actions of testosterone on contractions were endothelium-independent. KCl-mediated contractions were unaffected by the presence of either sex hormones. 4. The oestrogen receptor antagonists, tamoxifen (10 microM) and ICI 182,780 (10 microM), were unable to reverse the inhibitory influence 1 nM 17beta-estradiol had on the agonist-mediated contractile responses. Similarly, the androgen receptor antagonists, flutamide (10 microM) and cyproterone acetate (10 microM), failed to affect the potentiating activities of 1 nM testosterone. The alteration in vasoconstrictive responses observed following acute exposure to either 1 nM 17beta-estradiol and 1 nM testosterone were apparent even in the presence of the protein synthesis inhibitor cycloheximide (10 microM) and the transcription inhibitor actinomycin D (10 microM). 6. In conclusion, we report a unique type of sex hormone action on the coronary vasculature. These events occur at low nanomolar concentrations of 17beta-estradiol and testosterone, are insensitive to conventional sex hormone receptor antagonists, are not blocked by de novo protein synthesis inhibitors and have rapid time-courses that are uncharacteristic of classical genomic activities.

Acute impairment of relaxation by low levels of testosterone in porcine coronary arteries.

OBJECTIVES: While there are many suggested reasons for the marked gender bias in cardiovascular events, much of the available data indicate that circulating estrogens are cardioprotective. The possibility that endogenous androgens may be detrimental to the cardiovascular system has received relatively less attention. We investigated the short-term modulatory effects of various concentrations of testosterone on vascular function in isolated porcine coronary artery rings. RESULTS: The higher concentrations (> 1 microM) of testosterone relaxed U46619-contracted coronary artery rings in an endothelium-independent manner. This direct effect was insensitive to the testosterone receptor antagonists, flutamide and cyproterone acetate. Short-term exposure (20 min) to low levels of testosterone (1-100 nM), which were ineffective on their own on vascular function, significantly diminished relaxation to bradykinin and calcium ionophore A23187 but not those produced by levcromakalim and sodium nitroprusside. The inhibitory effect observed with 1 nM testosterone was only partially reversed by flutamide and cyproterone acetate and unaltered in the presence of actinomycin D and cycloheximide. CONCLUSIONS: These results demonstrate that acute treatment with testosterone, at concentrations that have no effect on their own, reduces vasorelaxation. Furthermore, they suggest that this modulatory action may be in part independent of the classical testosterone receptor since it was not completely sensitive to the anti-androgens and was not inhibited by the transcriptional and translational inhibitors. These findings support the postulation that testosterone may have unfavorable influences on vascular function.

Prostate cancer treated by anti-androgens: is sexual function preserved? EORTC Genitourinary Group. European Organization for Research and Treatment of Cancer.

This paper reports on results of the EORTC protocol 30892, an open, prospective, randomized study of 310 patients with previously untreated metastatic prostate cancer with favourable prognostic factors who were treated by either flutamide (FLU) or cyproterone acetate (CPA) monotherapy. The final analysis with regard to the main end points, time to progression and survival are still pending. Final results related to the evaluation of sexual functioning prior to and under treatment are reported here. Of 310 randomized patients 294 were eligible for evaluation within this side study. The median age was 71 years (range 48-85). Potential risk factors related to age, general health and prostate cancer were evaluated. For evaluation of sexual functions a five-item questionnaire was used which was administered by the investigator. The protocol allowed time dependent observations at 3-monthly follow-up visits. Sexual functioning was dependent on age but not on prostate cancer-related parameters. Sexual functions at entry were similar within the two treatment groups, spontaneous (nightly) erections and sexual activity were seen in 43-51% and 29-35% of cases. Under treatment, sexual functions under FLU and CPA declined slowly with median times of 12.9 and 5.8 months versus 13.7 and 8.9 months respectively for spontaneous erections and sexual activity. Eventually, with an average observation time in excess of 2 years, loss of spontaneous erections and of sexual activity occurred in 80% versus 92% and in 78% versus 88% of men under FLU versus CPA treatment respectively. None of these differences reached statistical significance. Maintenance of potency under treatment with FLU as reported in the literature is not confirmed in this study. However, loss of sexual functions under monotherapy with both antiandrogens is slow and 10-20% of men retain sexual activity after 2-6 years of treatment. This observation can be exploited in new treatment schemes and is likely to lead to improved quality of life. The advantage of FLU in time and total preservation of sexual functions is statistically not significant and must be balanced against the side effects of FLU and other pure antiandrogens, which may exceed those of CPA especially with respect to gynaecomastia. Hepatic toxicity may limit the long-term use of both drugs.

Efectos del valerato de estradiol ciproterona sobre el síndrome climaterio y parámetros bioquímicos en mujeres chilenas / Effects of estradiol valerate and ciproterone acetate on climateric syndrome and biochemical parameters in Chilean women

La menopausia se asocia a un demostrado aumento del riesgo de enfermedad cardiovascular y de osteoporosis, lo que justifica el uso de terapia hormonal de reemplazo. Como ésta se plantea por tiempo prolongado, debe ser efectiva en prevenir las complicaciones y en suprimir el síndrome climatérico. Se estudió la eficacia de la asociación de valerato de estradiol (VE) y acetato de ciproterona (CPA) en la reducción de los síntomas asociados a menopausia. Se analizaron, prospectivamente, 342 mujeres durante 6 meses, consignando la intensidad de sus síntomas y los cambios en peso, presión arterial y parámetros bioquímicos. Las oleadas de calor, así como otros síntomas y signos, disminuyeron en intensidad. No hubo diferencia significativa en la evolución del peso ni de la presión arterial, aunque sí en algunos parámetros del perfil lipídico y hepático. Se concluye que la asociación VE y CPA reduce la intensidad de los síntomas climatéricos en el grupo estudiado

Testosterone signaling through internalizable surface receptors in androgen receptor-free macrophages.

Testosterone acts on cells through intracellular transcription-regulating androgen receptors (ARs). Here, we show that mouse IC-21 macrophages lack the classical AR yet exhibit specific nongenomic responses to testosterone. These manifest themselves as testosterone-induced rapid increase in intracellular free [Ca(2+)], which is due to release of Ca(2+) from intracellular Ca(2+) stores. This Ca(2+) mobilization is also inducible by plasma membrane-impermeable testosterone-BSA. It is not affected by the AR blockers cyproterone and flutamide, whereas it is completely inhibited by the phospholipase C inhibitor U-73122 and pertussis toxin. Binding sites for testosterone are detectable on the surface of intact IC-21 cells, which become selectively internalized independent on caveolae and clathrin-coated vesicles upon agonist stimulation. Internalization is dependent on temperature, ATP, cytoskeletal elements, phospholipase C, and G-proteins. Collectively, our data provide evidence for the existence of G-protein-coupled, agonist-sequestrable receptors for testosterone in plasma membranes, which initiate a transcription-independent signaling pathway of testosterone.

Synergistic activation of yeast-expressed rat androgen receptor by modulators of protein kinase-A.

We have employed a yeast (Saccharomyces cerevisiae) based rat androgen receptor expression system to examine the cross-talk between different signalling pathways. We report here the synergistic modulation of androgen regulated transcriptional activation of beta-galactosidase reporter activity by the activators of protein kinase-A, like forskolin and 8-bromo-cyclic AMP. A similar ligand-dependent enhancement of reporter activity compared to a DHT treated control has been noticed with okadaic acid, which is a potent inhibitor of protein phosphatase. The activation could be blocked by protein kinase-A/C inhibitor, H7. Forskolin treatment neither altered levels of receptor mRNA nor [3H]R1881 binding to the receptor. Although it promotes binding of receptor to an androgen response element, forskolin was unable to activate subsequent interaction with the transcription machinery in the absence of androgen. Additionally, the synergistic actions of these activators were independent of the degree of androgen response element occupancy. Anti-androgens, cyproterone acetate and flutamide, which failed to exhibit antagonistic behaviour with yeast expressed receptor, were able to antagonize only the forskolin mediated augmentation of reporter activity. Finally, analyses of mutants established the role of DNA and steroid binding domains of receptor for this synergism.