to produce a "moderate" effect on sex hormone levels in men with prostate cancer (notably providing indication that the drug has clinically-relevant antiandrogen effects in males at a dosage as low as 10 mg/day). the elevated levels of gonadotropins and gonadal steroids associated with nsaa monotherapy is a unique endocrine state which can be described as "hypergonadotropic hypergonadism". bicalutamide increases androgen and estrogen levels only in men, and does not do so in women. this is because androgen levels are comparatively far lower in women and in turn exert little to no basal suppression of the hpg axis. minimal or no changes of importance in levels of total testosterone, free testosterone, dihydrotestosterone, estradiol, androstenedione (a4), dehydroepiandrosterone (dhea), dehydroepiandrosterone sulfate (dhea-s), 3α-androstanediol glucuronide (3α-adg), progesterone, 17α-hydroxyprogesterone (17α-ohp), lh, fsh, prolactin, or shbg have been observed in women with hirsutism with or without polycystic ovary syndrome that were treated with 25 or 50 mg/day bicalutamide for 6 to 12 months. however, in one study in women with polycystic ovary syndrome, 25 mg/day bicalutamide significantly decreased levels of total and free testosterone and significantly increased levels of shbg. in addition to the minimal changes in hormone levels in women, although bicalutamide monotherapy increases gonadotropin and sex hormone levels in men, this will not occur if bicalutamide is combined with an antigonadotropin such as a gnrh analogue, estrogen, or progestogen, as these medications maintain negative feedback on the hpg axis. the reason that testosterone levels are elevated but almost always remain in the normal male range with bicalutamide monotherapy is thought to be due to the concomitantly increased levels of estradiol, as estradiol is potently antigonadotropic and limits secretion of lh. in fact, estradiol is a much stronger inhibitor of gonadotropin secretion than is testosterone, and even though circulating concentrations of estradiol are far lower than those of testosterone in men, it is said that estradiol is nonetheless likely the major feedback regulator of gonadotropin secretion in this sex. in accordance, clomifene, a selective estrogen receptor modulator with antiestrogenic activity, has been found to increase testosterone levels to as much as 250% of initial values in men with hypogonadism, and a study of clomifene treatment in normal men observed increases in fsh and lh levels of 70–360% and 200–700%, respectively, with increases in testosterone levels that were similar to the increases seen with the gonadotropins. in addition to systemic or circulating estradiol, local aromatization of testosterone into estradiol in the hypothalamus and pituitary gland may contribute to suppression of gonadotropin secretion. bicalutamide more than blocks the effects of the increased testosterone levels that it induces in men, which is evidenced by its dose-dependent antiandrogenic effects (e.g., psa decreases) and by the fact that monotherapy with the drug is about as effective as gnrh analogue therapy in the treatment of prostate cancer. however, in contrast, the effects of the elevated estrogen levels remain unopposed by bicalutamide, and this is importantly involved in the feminizing side effects (e.g., gynecomastia) of the drug in men. testosterone levels decline with age in men and younger men have higher testosterone levels on average than older men. men with prostate cancer treated with bicalutamide are relatively elderly. the increases in testosterone levels with nsaas like flutamide and bicalutamide may result in greater absolute levels of testosterone and estradiol in younger men than in older men. in one study that administered flutamide, free testosterone levels in young men increased from about 26 pg/ml at baseline to about 34 pg/ml with flutamide (+31%) and in elderly men from about 16 pg/ml at baseline to about 21 pg/ml (+31%) with flutamide. hence, free testosterone levels with flutamide were approximately 1.6-fold higher in young men than in elderly men in this study. in the case of estradiol, total estradiol levels in young men increased from about 26 pg/ml at baseline to about 45 pg/ml with flutamide (+73%) and in elderly men changed from about 31 pg/ml to about 30 pg/ml (–3%). other studies have similarly found relatively high absolute testosterone levels with nsaas in young males. for instance, one study administering flutamide to late-pubertal males found that total testosterone levels increased from 729 ng/dl at baseline to 991 ng/dl with flutamide (+34%). changes in hormone levels with bicalutamide monotherapy testosterone levels with 10, 30, and 50 mg/day bicalutamide monotherapy in men with prostate cancer. testosterone levels with 10 to 200 mg/day bicalutamide monotherapy in men with prostate cancer. estradiol levels with 10, 30, and 50 mg/day bicalutamide monotherapy in men with prostate cancer. estradiol levels with 10 to 200 mg/day bicalutamide monotherapy in men with prostate cancer. differences from castration it has been proposed that the increase in estrogen levels caused by nsaas like bicalutamide compensates for androgen blockade in the brain, which may explain differences in the side effect profiles of these drugs relative to gnrh analogues/castration, combined androgen blockade, and cpa (which, in contrast, decrease both androgen and estrogen levels). in the case of sexual interest and function, this notion is supported by a variety of findings including animal studies showing that estrogen deficiency results in diminished sexual behavior, treatment with tamoxifen resulting in significantly lowered libido in 30% of men receiving it for male breast cancer, and estrogen administration restoring libido and the frequency of sexual intercourse in men with congenital estrogen deficiency, among others. several metabolites of testosterone and dht, including estradiol, 3α-androstanediol, and 3β-androstanediol, are estrogens (mainly potent erβ agonists in the cases of the latter two), and 3α-androstanediol is additionally a potent gabaa receptor-potentiating neurosteroid. due to the fact that bicalutamide does not lower testosterone levels, the levels of these metabolites would not be expected to be lowered either, unlike with therapies such as gnrh analogues. (indeed, testosterone, dht, and estradiol levels are actually raised by bicalutamide treatment, and for this reason, levels of 3α- and 3β-androstanediol might be elevated to some degree similarly.) these metabolites of testosterone have been found to have ar-independent positive effects on sexual motivation, and may be involved in the preservation of sexual interest and function by bicalutamide and other nsaas. however, a study found that a combination of bicalutamide and dutasteride, a 5α-reductase inhibitor and inhibitor of neurosteroid biosynthesis, produced fewer sexual side effects than gnrh analogue therapy, specifically suggesting the role of estradiol in the preservation sexual interest and function with bicalutamide monotherapy rather than of dht metabolites. as an alternative possibility to testosterone metabolites preserving sexual desire and function with bicalutamide, it has been suggested that bicalutamide may not be able to block the actions of androgens in the brain to a degree sufficient to cause substantial sexual impairment. it has been reported that bicalutamide, surprisingly, has no antianabolic effect on testosterone propionate-induced increases in levator ani muscle weight at doses that inhibit and even completely prevent testosterone propionate-induced growth of the prostate gland and seminal vesicles in rats. as such, it has been said that, based on preclinical research, bicalutamide does not have marked antianabolic effects. however, higher doses of bicalutamide are able to considerably inhibit the growth of the levator ani muscle in rats. in any case, analogously to animal findings, high-dose bicalutamide monotherapy appears to preserve lean muscle mass and muscle strength in men with prostate cancer relative to gnrh agonists. it is notable that in contrast to castration, bicalutamide preserves and increases estrogen levels, and estrogens are thought to have positive effects on skeletal muscle, including on muscle mass. paradoxical stimulation of late-stage prostate cancer though a pure, or silent antagonist of the ar under normal circumstances, bicalutamide, as well as other earlier antiandrogens like flutamide and nilutamide, have been found to possess weak partial agonist properties in the setting of ar overexpression and agonist activity in the case of certain mutations in the ligand-binding domain (lbd) of the ar. as both of these circumstances can eventually occur in prostate cancer, resistance to bicalutamide usually develops and the drug has the potential to paradoxically stimulate tumor growth when this happens. this is the mechanism of the phenomenon of antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of tumor growth. the newer drug enzalutamide has been shown not to have agonistic properties in the context of overexpression of the ar, though certain mutations in the ar can still convert it from an antagonist to agonist. induction of breast development bicalutamide monotherapy and breast side effects in dose-ranging studies in men studyndosagegynecomastiabreast tendernessref tyrrell et al. (1998)a38610 mg/day9%11% 30 mg/day26%42% 50 mg/day36%48% 100 mg/day79%86% 150 mg/day78%89% 200 mg/day79%79% kennealey & furr (1991)b21010 mg/day29%38% 30 mg/day60%64% 50 mg/day52%60% zanardi et al. (2006)c660 mg/week (controls)0%0% 50 mg/week (~7 mg/day)44%32% 100 mg/week (~14 mg/day)50%64% footnotes: a = testosterone levels increased to ~460–610 ng/dl and estradiol levels to ~32–51 pg/ml. b = testosterone levels increased to ~505–715 ng/dl and estradiol levels to ~32–53 pg/ml. c = testosterone levels increased to ~540–600 ng/dl and estradiol levels to ~29–34 pg/ml. in transgender women, breast development is a desired effect of antiandrogen and/or estrogen treatment. bicalutamide induces breast development in individuals assigned male at birth by two mechanisms: 1) blocking androgen signaling in breast tissue; and 2) increasing estrogen levels. estrogen is responsible for the induction of breast development under normal circumstances, while androgens powerfully suppress estrogen-induced breast growth. it has been found that very low levels of estrogen can induce breast development in the presence of low or no androgen signaling. in accordance, not only does bicalutamide induce gynecomastia at a high rate when given as a monotherapy to men with prostate cancer (38–85%; 66% in one very large trial), similarly to high-dose estrogen therapy with diethylstilbestrol (41–77%), nsaas have been found to result in a higher incidence of gynecomastia in combination with a gnrh analogue (13–25%) relative to gnrh analogue therapy or castration alone (1–16%) (in spite of the presence of only castrate levels of estrogen in both cases). the rate of gynecomastia with cab is also higher than with cpa monotherapy (7%). a study of men treated with nsaa (flutamide or bicalutamide) monotherapy for prostate cancer found that nsaas induced full ductal development and moderate lobuloalveolar development of the breasts from a histological standpoint. the study also found that, in contrast, treatment of transgender women with estrogen and cpa (which is progestogenic in addition to antiandrogenic, unlike nsaas) resulted in full lobuloalevolar development, as well as pregnancy-like breast hyperplasia in two of the subjects. in addition, it was observed that the lobuloalveolar maturation reversed upon discontinuation of cpa after sex reassignment surgery in these individuals. it was concluded that progestogen in addition to antiandrogen/estrogen treatment is required for the induction of full female histological breast development (i.e., that includes complete lobuloalveolar maturation), and that continued progestogen treatment is necessary to maintain such maturation. it should be noted however that although these findings may have important implications in the contexts of lactation and breastfeeding, epithelial tissue accounts for approximately only 10% of breast volume (with the bulk of the breasts (80–90%) being represented by stromal or adipose tissue), and it is uncertain to what extent, if any, that development of lobuloalveolar structures (a form of epithelial tissue) contributes to breast size and/or shape. effects on spermatogenesis and fertility spermatogenesis and male fertility are dependent on fsh, lh, and high levels of testosterone within the testicles. lh does not seem to be involved in spermatogenesis outside of its role in inducing production of testosterone by the leydig cells in the seminiferous tubules (which make up approximately 80% of the bulk of the testes), whereas this is not the case for fsh, which is importantly involved. in accordance with the fact that the testes are the source of 95% of circulating testosterone in the body, local levels of testosterone inside of the testes are extremely high, ranging from 20- to 200-fold higher than circulating concentrations. moreover, high levels of testosterone within the testes are required for spermatogenesis, although only a small fraction (5–10%) of normal levels appears to actually be necessary for spermatogenesis. unlike with antigonadotropic antiandrogens like cpa and gnrh analogues, it has been reported that bicalutamide monotherapy (at 50 mg/day) has very little or no effect on the ultrastructure of the testes and on spermatogenesis in men even after long-term therapy (>4 years). this may be explained by the extremely high local levels of testosterone in the testes, in