An enhanced sebaceous gland activity with production of proinflammtory sebaceous lipids belongs to the major pathogenetic factors of acne. Hormonal antiandrogen treatment targets the androgen-metabolizing cells of the pilosebaceous unit, i. e. follicular kertinocytes and sebocytes, and leads to sebostasis, with a reduction of the sebum secretion rate of 12.5 to 65 %. Concerning their mechanism of action, hormonal antiandrogens are classified in androgen receptor blockers, inhibitors of circulating androgens by affecting the ovarial function (oral contraceptives), inhibitors of circulating androgens by affecting the pituitary (gonadotrophin-releasing hormone agonists and dopamin agonists in hyperprolactinemia), inhibitors of the adrenal function, and inhibitors of peripheral androgen metabolism (5-reductase inhibitors, inhibitors of other enzymes).
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Reverse transcriptase-polymerase chain reaction was used to confirm androgen receptor expression in the human TCC lines 253J and T24. A reporter construct containing an androgen response element was used to establish the integrity of androgen mediated signal transduction. Subsequently the dose dependent effect of dihydrotestosterone (DHT) on BCG induced IL-6 expression and NF-kappaB signaling was evaluated. Two pharmacological androgen receptor blockers were used to determine if receptor blockade inhibited the effect of DHT on activation of the androgen response element, NF-kappaB signaling and BCG induced IL-6 expression.
Testosterone treatment resulted in an increased proteinuria as well as profound glomerulosclerosis, tubulointerstitial fibrosis, and mononuclear cell infiltration that paralleled enhanced intragraft mRNA levels of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor-A and -B chain (PDGF-A and -B). In contrast, flutamide and finasteride reduced glomerulosclerosis as well as the inflammatory cell infiltration associated with decreased TGF-beta, PDGF-A, and -B chain mRNA expression. No gender-related donor differences were noted between the groups.
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We have recently demonstrated that gonadal steroid hormones decrease formalin-induced temporomandibular joint nociception in rats. Given that the attenuation of inflammation is a potential mechanism underlying this antinociceptive effect, we evaluated the effect of gonadal steroid hormones on formalin-induced temporomandibular joint inflammation. Plasma extravasation, a major sign of acute inflammation, and neutrophil migration, an important event related to tissue injury, were evaluated. Formalin induced significantly lower temporomandibular joint plasma extravasation and neutrophil migration in proestrus females than in males and in diestrus females. Since estradiol serum level is high in proestrus females and low in diestrus females and in males, these findings suggest that the high physiological level of estradiol decreases temporomandibular joint inflammation. Estradiol but not progesterone administration in ovariectomized females significantly decreased formalin-induced plasma extravasation and neutrophil migration, an effect that was blocked by the estrogen receptor antagonist ICI 182780. Plasma extravasation and neutrophil migration were not affected by orchiectomy, but testosterone or estradiol administration in orchidectomized males significantly decreased them. The androgen receptor antagonist flutamide blocked the anti-inflammatory effect of testosterone while ICI 182780 blocked that of estradiol in males. Previous intravenous administration of a nonspecific selectin inhibitor significantly decreased formalin-induced temporomandibular joint nociception and neutrophil migration in males, revealing a potent and positive correlation between temporomandibular joint nociception and inflammation. Taken together, these findings demonstrate a pronounced anti-inflammatory effect of estradiol and testosterone in the temporomandibular joint region and suggest that this effect may mediate, at least in part, the antinociceptive effect of these hormones.
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Of the 915 men 901 were evaluated at a median followup of 18.5 months. The incidence of hot flashes was 30.1% and 74.3% in the polyestradiol phosphate and complete androgen ablation groups, respectively (p <0.001). In the polyestradiol phosphate group the frequency of and distress due to hot flashes were significantly lower than in the androgen ablation group. There was complete relief from hot flashes in 50% of the men on polyestradiol phosphate during followup compared with none on androgen ablation. The incidence of hot flashes did not differ in men with and without tumor progression.
There was no correlation between an undetectable PSA and a PSA > 0.1 ng/mL and the presence of tumor at the margin when 3 months of AD was given prior to RP. It is possible that longer periods of AD prior to RP will reduce PSA to an undetectable level in a higher percent of patients. However, these data suggest that an undetectable level will not result in less positive margins.
At our institution, a Phase II trial using androgen suppression followed by surgery was completed for men with Stage T3 disease and negative laparoscopic nodal dissection. We recently reported the unfavorable biochemical outcome of that experience. Because that analysis did not include a control group of irradiated patients, the current project was undertaken to compare that Phase II experience with clinical Stage T3 patients treated at our institution with definitive irradiation during an overlapping period of time.
Functional ovarian hyperandrogenism, a variant of polycystic ovary syndrome, is often associated with hyperinsulinism and dyslipidemia. The mechanisms interlinking this triad are poorly understood; both hyperandrogenism and hyperinsulinism have been proposed as factors involved in the pathogenesis of the dyslipidemia. Precocious pubarche (PP) in girls is a risk factor for subsequent anovulation, ovarian and adrenal hyperandrogenism, hyperinsulinism and dyslipidemia. Flutamide, a nonsteroidal antiandrogen, is known to be effective in reducing hirsutism in patients with ovarian hyperandrogenism. However, the effects of flutamide on the endocrine-metabolic correlates of hyperandrogenism are uncertain. We assessed the effects of low dose flutamide treatment (250 mg daily for 18 months) on hormonal and metabolic variables in 18 nonobese adolescent girls (age, 16.8 +/- 0.3 yr) with functional ovarian hyperandrogenism (diagnosis by GnRH agonist test) after PP. Flutamide treatment was accompanied by a marked decrease in the hirsutism score, free androgen index, and testosterone, androstenedione, and dehydroepiandrosterone levels and by an increase in sex hormone-binding globulin concentrations. However, there were no substantial changes in the pattern of menstrual cycles, gonadotropin, estradiol, or dehydroepiandrosterone sulfate concentrations, and there was no detectable effect on the 17-hydroxyprogesterone response to GnRH agonist. Serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels decreased markedly during flutamide therapy, whereas high-density lipoprotein cholesterol, fasting glycemia/insulinemia, and the insulin response to a glucose load remained unchanged. Flutamide was well tolerated. In conclusion, low dose flutamide treatment was found to be an effective and safe approach to reduce hirsutism and circulating androgen, low-density lipoprotein cholesterol, and triglyceride levels in girls with functional ovarian hyperandrogenism after PP. However, flutamide failed to increase high-density lipoprotein cholesterol levels or decrease hyperinsulinemia, i.e. to affect two major risk factors for subsequent cardiovascular disease.
To determine the onset and extent of combined androgen blockade (CAB)-induced anemia in prostate cancer patients without bone involvement.
The effects of a prolonged subcutaneous administration of SCH 13521 dissolved in 0.3% hydroxypropyl cellulose (2-8 weeks in daily doses of 0.2 or 1.0 mg amounting to an estimated equivalent of experimental and curative doses used by others in laboratory animals and men) were studied in males of the mouse inbred strain C57BL/6. Following the treatment, the activity of spermatogenesis (expressed as the mean number of seminiferous tubules containing mature sperm and epididymal sperm count) was inhibited while the testis weight was not reduced, obviously due to an absolute increase of the interstitial tissue which was a marked histological feature of the testes, particularly following the higher doses of SCH 13521. Lower doses and shorter-lasting administration of the compound seem to inhibit the activity more effectively because after a prolonged administration reparatory processes tend to be triggered via a stimulatory effect on the synthesis of testosterone in Leydig cells. The solvent alone, hydroxypropyl cellulose, had some inhibitory effect on spermatogenesis. The lymphoid system remained both morphologically and functionally unaffected by SCH 13521 unlike the steroidal antiandrogen cyproterone actetate.
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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.
Seventeen men with various stages of prostate cancer, all of whom were candidates for androgen deprivation therapy, were treated with finasteride plus flutamide and were followed for a mean of 13.6 months using measurements of serum prostate specific antigen (PSA), and an assessment of regression and side-effects.
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Alopecia is a common yet underreported adverse event of endocrine-based cancer therapies. Their long-term use heightens the importance of this condition on patients' quality of life. These findings are critical for pretherapy counseling, the identification of risk factors, and the development of interventions that could enhance adherence and mitigate this psychosocially difficult event.
We prepared models of castrated male rabbits. Pathological sections of aorta were performed hematoxylin-eosin (HE) staining and Masson's trichrome staining. Total plasma testosterone was measured using ADVIA Centaur Immunoassay System (Bayer, Germany). Serum TNF alpha and IL 6 were assayed using radio-immunoassay kit and serum sICAM-1 and MMP 2 were measured using ELISA kit. Our results showed that castration significantly lowered plasma testosterone levels, whereas testosterone replacement at a dose of 6 mg/kg/two-week restored circulating testosterone to physiological levels, without being altered by treatment with flutamide (a testosterone receptor inhibitor). Testosterone undecanoate replacement reduced the plaque area and the aortic intimal thickness, whereas the fibrous cap thickness and collagen contents increased in castrated rabbits. However, the presence of flutamide increased the plaque area and the aortic intimal thickness, whereas the fibrous cap thickness and collagen contents decreased in castrated rabbits again. Moreover, the levels of serum TNF alpha, IL 6, sICAM and MMP 2 increased in cholesterol-rich diet rabbits as compared with standard diet rabbits. Castration caused increases in the levels of serum TNF alpha, IL6, sICAM and MMP 2 in castrated rabbits as compared with sham-operated rabbits. Treatment of testosterone undecanoate reduced the levels of serum TNF alpha, IL 6, sICAM and MMP 2 in castrated rabbits, while the presence of flutamide increased the levels of serum TNF alpha, IL 6, sICAM and MMP 2 again.
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Before treatment and at the end of the sixth month, women were evaluated for hirsutism score and a CRF test was performed to evaluate ACTH, cortisol and adrenal androgen responses.
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Both the groups of patients under Flu therapy showed a marked decrease in hirsutism scores after 12 months compared with basal values. The maximum drug effect was observed after 2 years, and it was maintained during the following years of treatment. Androgens were strongly suppressed during treatment. During the first year of treatment, 6.0% of patients abandoned the study due to hepatic disorders related to the drug. During the following years with the lowest treatment regimen, none of the patients abandoned the study due to hepatic discomfort.
The effects of these hormones on BCRP protein and mRNA expression in BeWo cells were determined by immunoblotting and quantitative real-time RT-PCR, respectively. The effects of these hormones on membrane localization of BCRP in BeWo cells were examined by immunofluorescent confocal microscopy.
To evaluate the impact of flutamide on survival of patients with unresectable pancreatic cancer.
JNJ-10229570 dose dependently inhibited the production of sebaceous lipids in cultured primary human sebocytes. Topical treatment with JNJ-10229570 of human skins transplanted onto SCID mice resulted in a marked decrease in sebum-specific lipid production, sebaceous gland's size and the expression of the sebaceous differentiation marker epithelial-membrane antigen (EMA). Treatment with flutamide, a known inhibitor of sebum production, gave similar results, validating the human skin/SCID mouse experimental system for sebaceous secretion studies.
Previous studies indicate that after severe hemorrhage, immune functions are markedly depressed in males, whereas females do not show any depression. Although androgen depletion by castration of mice before soft-tissue trauma and hemorrhagic shock prevents the depression of cell-mediated immunity, it remains unknown whether testosterone per se is responsible for producing immune depression.