Androgens and cardiovascular disease

Globally, cardiovascular disease will continue causing most human deaths for the foreseeable future. The consistent gender gap in life span of approximately 5.6 yr in all advanced economies must derive from gender differences in age-specific cardiovascular death rates, which rise steeply in parallel for both genders but 5-10 yr earlier in men. The lack of inflection point at modal age of menopause, contrasting with unequivocally estrogen-dependent biological markers like breast cancer or bone density, makes estrogen protection of premenopausal women an unlikely explanation. Limited human data suggest that testosterone exposure does not shorten life span in either gender, and oral estrogen treatment increases risk of cardiovascular death in men as it does in women. Alternatively, androgen exposure in early life (perinatal androgen imprinting) may predispose males to earlier onset of atherosclerosis. Following the recent reevaluation of the estrogen-protection orthodoxy, empirical research has flourished into the role of androgens in the progression of cardiovascular disease, highlighting the need to better understand androgen receptor (AR) coregulators, nongenomic androgen effects, tissue-specific metabolic activation of androgens, and androgen sensitivity. Novel therapeutic targets may arise from understanding how androgens enhance early plaque formation and cause vasodilatation via nongenomic androgen effects on vascular smooth muscle, and how tissue-specific variations in androgen effects are modulated by AR coregulators as well as metabolic activation of testosterone to amplify (via 5alpha-reductase to form dihydrotestosterone acting on AR) or diversify (via aromatization to estradiol acting upon estrogen receptor alpha/beta) the biological effects of testosterone on the vasculature. Observational studies show that blood testosterone concentrations are consistently lower among men with cardiovascular disease, suggesting a possible preventive role for testosterone therapy, which requires critical evaluation by further prospective studies. Short-term interventional studies show that testosterone produces a modest but consistent improvement in cardiac ischemia over placebo, comparable to the effects of existing antianginal drugs. By contrast, testosterone therapy has no beneficial effects in peripheral arterial disease but has not been evaluated in cerebrovascular disease. Erectile dysfunction is most frequently caused by pelvic arterial insufficiency due to atherosclerosis, and its sentinel relationship to generalized atherosclerosis is insufficiently appreciated. The commonality of risk factor patterns and mechanisms (including endothelial dysfunction) suggests that the efficacy of antiatherogenic therapy is an important challenge with the potential to enhance men's motivation for prevention and treatment of cardiovascular diseases.     

Postmenopausal hormone therapy and atherosclerotic disease

Several lines of evidence suggest that estrogen is an important determinant of cardiovascular risk in women. Epidemiologic data document low rates of coronary heart disease (CHD) in premenopausal women, a narrowing of the gender gap in CHD mortality after menopause, and elevated risk of CHD among young women with bilateral oophorectomy not treated with estrogen. Nearly all of the more than 30 observational studies of exogenous estrogen replacement therapy have indicated a reduced risk of CHD among women receiving estrogen therapy. In a meta-analysis comparing estrogen users and nonusers, the estimated reduction of CHD among users was 44%. In angiographic studies, women taking estrogen were less likely to have coronary artery stenosis. Estrogen is known to affect a wide range of physiologic processes that may have an impact on CHD risk. Use of oral estrogen has favorable effects on serum lipid profiles; it increases high-density lipoprotein cholesterol levels by 10% to 15% and decreases low-density lipoprotein cholesterol levels by a similar magnitude. Other proposed mechanisms include inhibition of endothelial hyperplasia, reduced arterial impedance, enhanced production of prostacyclin, increased insulin sensitivity, and inhibition of oxidation of low-density lipoprotein. Nevertheless, the role of hormone replacement therapy in preventing clinical atherosclerotic events in women remains inconclusive because of the absence of randomized trial data. The benefit-to-risk ratio must be reliably assessed, because estrogen has complex actions, including postulated benefits (CHD, osteoporosis, and menopausal symptoms) and postulated risks (endometrial cancer, breast cancer, and gallstones). Furthermore, the addition of a progestin, which is commonly given to protect the endometrium, may attenuate the lipid benefits of estrogen; the benefit-to-risk ratio of such a combined regimen is even less certain. The Women's Health Initiative, a recently launched large-scale randomized trial of estrogen, estrogen-progestin, and placebo, as well as other ongoing randomized trials, will provide invaluable information to aid postmenopausal women in making the complex decision about whether to take hormone replacement therapy.     

Clinical review: The rationale for banning human chorionic gonadotropin and estrogen blockers in sport

CONTEXT: The objective of the study was to review the rationale underlying the banning of human chorionic gonadotropin (hCG) and estrogen blockers (antiestrogens, specific estrogen receptor modulators, aromatase inhibitors) in sports for male and female athletes in the light of gender differences in regulation of reproductive physiology. EVIDENCE ACQUISITION: We reviewed well-controlled clinical studies of exogenous testosterone effects on human muscle size and strength in men and all available evidence relevant to the effects of hCG and estrogen blockers on blood testosterone in men and women. EVIDENCE SYNTHESIS: Well-designed placebo-controlled clinical studies in men with suppressed pituitary-testicular axis establish a strong case that, across a wide range from sub- to supraphysiological doses, muscle growth and strength is proportional to exogenous testosterone dose and resulting blood testosterone concentrations. In men, there is unequivocal evidence that hCG and estrogen blockers cause consistent and sustained rise in blood testosterone concentrations. In women, although there has been no direct testing of ergogenic or myotrophic properties of exogenous testosterone in healthy women, either hCG or estrogen blockers do not produce any consistent or biologically significant increase blood testosterone concentrations. CONCLUSIONS: In men undergoing potential stimulation of endogenous blood testosterone concentrations, blood testosterone concentration is a reasonable surrogate measure for muscle growth and increased strength in men. Because hCG and estrogen blockers produce marked increase in blood testosterone concentration in men, this provides strong evidence to support the banning of hCG and estrogen blockers in men. In women, however, the negligible effect on blood testosterone suggests that drug-induced performance enhancement by hCG or estrogen blockers is highly unlikely. Furthermore, routine urinary hCG testing in young women risks invasion of privacy by detecting unrecognized pregnancy. These considerations suggest that prohibition of hCG and estrogen blockers should be restricted to men in which they are well justified.     

Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line

Much clinical evidence indicates that androgens have beneficial effects in the treatment of breast cancer in women. Physiological concentrations of androgens strongly inhibit both basal and estrogen-induced cell proliferation in the human breast cancer cell line ZR-75-1 through their interaction with the androgen receptor. The present study shows that androgens strongly suppress estrogen receptor (ER) and progesterone receptor contents in this model, as measured by radioligand binding and anti-ER monoclonal antibodies. Similar inhibitory effects are observed on the levels of ER messenger RNA (mRNA) measured by ribonuclease protection assay. The androgenic effect is observed at subnanomolar concentrations of the nonaromatizable androgen 5 alpha-dihydrotestosterone, regardless of the presence of estrogens, and is competitively reversed by the antiandrogen hydroxyflutamide. Such data on ER expression provide an explanation for at least part of the antiestrogenic effects of androgens on breast cancer cell growth and moreover suggest that the specific inhibitory effects of androgen therapy could be additive to the standard treatment limited to blockade of estrogens by antiestrogens.     

Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women

BACKGROUND: The role of androgens in breast cancer etiology has been unclear. Epidemiologic studies suggest that endogenous testosterone levels are positively associated with breast cancer risk in postmenopausal women. Given the increasing trend in the use of hormone therapies containing androgens, we evaluated the relation between the use of estrogen and testosterone therapies and breast cancer. METHODS: We conducted a prospective cohort study in the Nurses' Health Study from 1978 to 2002 to assess the risk of breast cancer associated with different types of postmenopausal hormone (PMH) formulations containing testosterone. During 24 years of follow-up (1 359 323 person-years), 4610 incident cases of invasive breast cancer were identified among postmenopausal women. Information on menopausal status, PMH use, and breast cancer diagnosis was updated every 2 years through questionnaires. RESULTS: Among women with a natural menopause, the risk of breast cancer was nearly 2.5-fold greater among current users of estrogen plus testosterone therapies (multivariate relative risk, 2.48; 95% confidence interval, 1.53-4.04) than among never users of PMHs. This analysis showed that risk of breast cancer associated with current use of estrogen and testosterone therapy was significantly greater compared with estrogen-only therapy (P for heterogeneity, .007) and marginally greater than estrogen and progesterone therapy (P for heterogeneity, .11). Women receiving PMHs with testosterone had a 17.2% (95% confidence interval, 6.7%-28.7%) increased risk of breast cancer per year of use. CONCLUSION: Consistent with the elevation in risk for endogenous testosterone levels, women using estrogen and testosterone therapies have a significantly increased risk of invasive breast cancer.     

Risks versus benefits in the clinical application of aromatase inhibitors

Third-generation aromatase inhibitors are able to reduce circulating plasma estrogen concentrations in postmenopausal women to below detectable limits and significantly inhibit aromatase, the enzyme responsible for estrogen synthesis, in normal breast tissue and breast tumors. Their role in the treatment of advanced breast cancer is well established and their use in adjuvant therapy is currently being explored. On the basis of these trials, evaluation of these inhibitors in the prevention of breast cancer may be appropriate. Aromatase inhibitors have non-specific toxic side effects including (but not limited to): asthenia, headache, nausea, peripheral edema, fatigue, vomiting and dyspepsia. In addition, certain endocrinological side effects in postmenopausal women are notable, namely hot flushes and vaginal dryness. In advanced breast cancer, these side effects result in treatment withdrawal in few (<4%) women. Of concern, however, are the potential long-term endocrinological side effects in women receiving treatment as first-line adjuvant therapy or in sequence or combination with tamoxifen or other selective estrogen receptor modulators (SERMs). Current studies of adjuvant treatments for breast cancer in healthy women are carefully evaluating, in addition to general toxicities, the effects on bone, lipid metabolism, cardiovascular risk, quality of life and menopausal symptoms. Careful evaluation of all-cause morbidity and mortality is necessary to plan trials and justify long-term use of aromatase inhibitors in the treatment or prevention of breast cancer in healthy women.     

Hormone replacement therapy and fractures in older adults

Estrogen deficiency in women is associated with accelerated bone loss, and estrogen replacement therapy has been proven to be effective in preventing osteoporosis and fractures in postmenopausal women. The introduction of selective estrogen receptor modulators that have an estrogen-like effect on the skeleton but have a different pattern of effects on other tissues may have an important role in the management of osteoporosis in women in the near future. In men, androgen deficiency has been shown to be associated with osteoporosis. Although androgen replacement in hypogonadal men may decrease bone resorption and increase bone mass, long-term placebo-controlled trials are needed to better define the benefits and risks of such therapy before it can be recommended. Sex hormone deficiency is linked to the development of osteoporosis in both women and men. In women, hormonal replacement by estrogen or the newly developed selective estrogen receptor modulators may prevent the development of osteoporosis and its related fractures. In men, there is early evidence that testosterone replacement therapy may enhance bone mass in hypogonadal men.     

Clinical review: Controversies regarding transdermal androgen therapy in postmenopausal women

CONTEXT: Recently, the field of androgen therapy in postmenopausal women has received much attention and press. Although the ovary ceases to produce follicles and estrogen at menopause, it continues to produce androgens. Hence, many oophorectomized women complain of sexual dysfunction (despite adequate estrogenization). Previous studies of nontransdermal testosterone replacement have shown an improvement in libido and sexual frequency, although at the cost of supraphysiological testosterone levels. Transdermal testosterone patch (Intrinsa) was developed to deliver a physiological amount of testosterone. In 2004, the Food and Drug Administration voted not to approve Intrinsa until long-term safety data are available. EVIDENCE ACQUISITION: Recent trials of Intrinsa in postmenopausal women were included. A MEDLINE search was conducted for articles published over the last 40 yr based on the key words androgen therapy/replacement and postmenopausal women. Relevant placebo-controlled trials of nontransdermal androgen therapy in postmenopausal women were also reviewed. EVIDENCE SYNTHESIS: Early results from industry-funded trials show that transdermal testosterone therapy results in only moderate (although statistically significant) improvement in libido in surgically menopausal women (on estrogen). However, the published data are of short duration (24 wk). Hence, long-term safety in these women remains unclear. CONCLUSION: We recommend a short-term trial (not to exceed 24 wk) of transdermal testosterone therapy (once approved) in surgically menopausal (estrogenized) women with distressful sexual dysfunction. Until the patch gets approval, a short trial of oral methyltestosterone in deserving estrogenized women may be justified.     

Androgen replacement in women: a commentary.

There is increasing evidence to suggest that many postmenopausal women experience symptoms alleviated by androgen therapy and that such symptoms may be secondary to androgen deficiency. Affected women complain of fatigue, low libido, and diminished well-being, symptoms easily and frequently attributed to psychosocial and environmental factors. When such symptoms occur in the setting of low circulating bioavailable testosterone, testosterone replacement results in significant improvement in symptomatology and, hence, quality of life for the majority of women. Whether the apparent therapeutic effects of testosterone replacement are mediated by testosterone and its metabolite 5alpha- dihydrotestosterone or are a consequence of aromatization to estrogen is not known. Despite the paucity of data regarding its effects, inclusion of testosterone in postmenopausal hormone replacement regimens is not uncommon and is likely to become more widespread with the availability of preparations developed specifically for women. Other novel and even more controversial potential indications for androgen therapy in women are currently being evaluated. These include use in women with premature ovarian failure, premenopausal androgen deficiency symptoms, postmenopausal and glucocorticosteroid-related bone loss, alleviation of wasting syndrome secondary to human immunodeficiency virus infection, and management of premenstrual syndrome. The aim of this commentary is to very briefly review the rationale for the use of testosterone in women, create awareness of some of the therapeutic options available in various countries, and stimulate discussion of this important aspect of women's health.     

Lasofoxifene, a next generation estrogen receptor modulator: preclinical studies

Estrogen replacement therapy, in spite of efficacy in the prevention of osteoporotic fractures, has significant side effects and risks that limit its widespread usage in postmenopausal women. Thus significant medical need exists to find modalities that prevent osteoporosis, but without the side effects of estrogen. Selective estrogen receptor modulators (SERMs) have the potential to provide the skeletal benefits of estrogen without the increased risk of uterine and breast cancer. Tamoxifen, a first generation SERM is approved for the prevention and treatment of breast cancer, and raloxifene, a second generation SERM has been approved for the prevention and treatment of osteoporosis. Lasofoxifene, a new potent, nonsteroidal SERM, binds with high affinity to human estrogen receptors and acts as a tissue selective estrogen antagonist or agonist. In preclinical models of postmenopausal osteoporosis, lasofoxifene inhibited bone turnover and prevented bone loss throughout the skeleton. In studies designed to investigate the combination of lasofoxifene with estrogen, lasofoxifene blocked the hypertrophic effects of estrogen in the uterus, but did not block the bone protective effects. In immature and aged female rats, lasofoxifene did not affect the uterine weight and uterine histology. In preclinical studies designed to evaluate the effects of lasofoxifene on the uterus, a slight increase in wet uterine weight was observed in immature and aged female rats, but this difference was not observed in dry uterine weight suggesting that the increased uterine weight was due to increased water content in the tissue. In preclinical studies designed to evaluate the effects of lasofoxifene in breast cancer, lasofoxifene inhibited breast tumor formation in mice injected with human MCF-7 breast cancer cells and in rats bearing mammary carcinomas. Thus, in preclinical models, lasofoxifene, a next generation SERM, prevents estrogen deficiency-induced bone loss, inhibits breast tumor formation, and reduces serum cholesterol, without causing uterine hypertrophy. These data suggest that lasofoxifene is a new potential therapy for the prevention of osteoporosis in postmenopausal women.     

Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer

Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.     

Estrogen replacement therapy, atherosclerosis, and vascular function

There is strong evidence from both human and nonhuman primate studies supporting the conclusion that estrogen deficiency increases the progression of atherosclerosis. More controversial is the conclusion that postmenopausal estrogen replacement inhibits the progression of atherosclerosis. Estrogen treatment of older women (>65 years) with pre-existing coronary artery atherosclerosis had no beneficial effects. In contrast, estrogen treatment of younger postmenopausal women or monkeys in the early stages of atherosclerosis progression has marked beneficial effects. Whether progestogens attenuate the cardiovascular benefits of estrogen replacement therapy has been controversial for more than a decade. Current evidence from studies of both monkeys and women suggest little or no attenuation of estrogen benefits for coronary artery atherosclerosis. Lack of compliance with estrogen replacement therapy, usually because of fear of breast cancer, remains a major problem. Future regimens may overcome that fear by the co-administration of a breast cancer preventive agent (i.e., selective estrogen receptor modulators, phytoestrogens) with low dose estrogen.     

Postmenopausal hormone therapy and breast cancer: a clinician's message for patients

The Women's Health Initiative agrees with some but not all case-control and cohort studies that current use of postmenopausal estrogen-progestin therapy is associated with a small increase in the risk of breast cancer. It is not known whether this is because of new tumor growth or an effect of hormonal therapy on preexisting tumors. Many studies indicate that women who develop breast cancer while using postmenopausal hormone therapy have a reduced risk of dying from breast cancer; this is consistent with an effect on preexisting tumors so that tumors appear at a less virulent and aggressive stage.     

The adverse effects of hormonal therapy

Estrogen therapy must be cycled with progestin therapy in women with intact uteri in order to prevent uterine cancer. However, these women cannot be expected to benefit (with regard to cardiovascular disease) from any estrogen-induced changes in the lipoprotein profile, as progestins will either negate or overwhelm any estrogen effects. However, such women will definitely benefit from estrogen's effects with regard to menopausal symptoms and bone loss. These clearly beneficial effects of estrogen-progestin therapy are not outweighed by any known risks. However, in women without uteri (approximately 30 per cent of women), unopposed estrogen therapy in the menopause may protect against cardiovascular disease, as well as have beneficial effects on bone metabolism and menopausal symptoms. In this special case, the beneficial effects of unopposed estrogen therapy clearly outweigh any known risk.     

17 beta-hydroxysteroid dehydrogenases--their role in pathophysiology

17 beta-Hydroxysteroid dehydrogenases (17HSDs) regulate the biological activity of sex steroid hormones in a variety of tissues by catalyzing the interconversions between highly active steroid hormones, e.g. estradiol and testosterone, and corresponding less active hormones, estrone and androstenedione. Epidemiological and endocrine evidence indicates that estrogens play a role in the etiology of breast cancer, while androgens are involved in mechanisms controlling the growth of normal and malignant prostatic cells. Using LNCaP prostate cancer cell lines, we have developed a cell model to study the progression of prostate cancer. In the model LNCaP cells are transformed in culture condition into more aggressive cells. Our data suggest that substantial changes in androgen and estrogen metabolism occur in the cells, leading to increased production of active estrogens during the process. In breast cancer, the reductive 17HSD type 1 activity is predominant in malignant cells, while the oxidative 17HSD type 2 mainly seems to be present in non-malignant breast epithelial cells. Deprivation of an estrogen response by using specific 17HSD type 1 inhibitors is a tempting approach in treating estrogen-dependent breast cancer. Our recent studies demonstrate that in addition to sex hormone target tissues, estrogens may be important in the development of cancer in some other tissues previously not considered to be estrogen target tissues, such as the gastrointestinal tract.     

Androgen insufficiency in women

Androgens are directly secreted by the ovaries and adrenals in women, and androgen precursors from these glands are converted in a variety of peripheral tissues into androgens. The major androgen in women is testosterone, and its action in target tissues can be mediated through the androgen receptor or through the estrogen receptor after aromatization to estradiol. Low sexual desire that causes personal distress (or hypoactive sexual desire disorder [HSDD]) is the most common form of female sexual dysfunction, and androgen insufficiency is one cause of this problem. In addition to a low libido, the clinical construct of the female androgen insufficiency syndrome includes the presence of persistent, unexplained fatigue and a decreased sense of well-being. Although there is conflicting information about the relationship between serum testosterone concentrations and sexual desire, multiple randomized, double-blind, placebo-controlled treatment trials have demonstrated that testosterone improves libido significantly more than placebo. Doses that provide physiologic to slightly supraphysiologic serum free or bioavailable testosterone concentrations are safe and associated with only mild androgenic side effects of acne and hirsutism. Oral, but not parenteral or transdermal, testosterone may decrease high-density lipoprotein cholesterol. At present, no testosterone preparation has been approved by the FDA for the treatment of low sexual desire (HSDD), so all such therapy is considered to be off-label use at this time.     

Cardiovascular health in transgender people

This review examines the relationship between exogenous sex steroids and cardiovascular events and surrogate markers in trans (transgender) people. Data from trans populations is compared to data from postmenopausal women and hypogonadal men when appropriate. In an age-adjusted comparison with cisgender people, trans people appear to have an increased risk for myocardial infarction and death due to cardiovascular disease. It is uncertain whether hormone therapy in trans people affects their risk of stroke. In studies that followed trans people on hormone therapy, the rates of myocardial infarction and stroke were consistently higher in trans women than trans men. There is strong evidence that estrogen therapy for trans women increases their risk for venous thromboembolism over 5 fold. Extrapolating from studies of hormone therapy in postmenopausal women, transdermal estrogen likely carries a lower risk for venous thromboembolism than oral estrogen. Regarding red blood cells, testosterone therapy increases hemoglobin in trans men, and lowering testosterone in trans women has the opposite effect. Regarding blood pressure, the effects of hormone therapy on systolic blood pressure in trans women are inconsistent, with most studies showing an increase. In trans men, testosterone therapy consistently increases systolic blood pressure and may increase diastolic blood pressure. For lipids, hormone therapy may increase triglycerides in both trans women and men. In trans men, testosterone therapy also may increase LDL-cholesterol and decrease HDL-cholesterol.     

Menopausal hormone therapy

Although estrogen has been clinically available for more than 6 decades, women have been confused by different opinions regarding the risks and benefits of menopausal hormone therapy (HT), estrogen therapy (ET), and estrogen-progestin therapy (EPT). The main indication for HT use in postmenopausal women remains the relief of vasomotor symptoms and vulvovaginal atrophy, and is effective in the prevention of osteoporosis. In other areas of research, notably in cardiovascular and central nervous system effects, the recent literature has produced conflicting results. Treatment for up to 5 years does not add significantly to lifetime risk of breast cancer, but significantly decreases bone loss and risk of osteoporotic fractures. Some women may be susceptible to early thrombotic risk, but when appropriate HT is given after individual clinical evaluation, the benefits will far outweigh any potential risks and the treatment should be recommended. Clinical research continues into genetic factors influencing the response to ET/HT, different estrogen formulations, different modes of delivery and lower-dose options. Patients and clinicians should make treatment decisions on the basis of an individuals needs and risks, and should enhance a woman's ability to undergo the menopausal transition with minimal disruption to her quality of life. In women experiencing distressing climacteric symptoms during the peri and postmenopause there is conclusive evidence from abundant randomized controlled trials that systemic hormone therapy (HT) of any type affords symptom relief, with no alternative treatment producing similar effect. Future research is needed to identify new indications for HRT and to diminish or abolish its potential risks.     

Androgen modulation of prostate cancer cell androgen receptor content is cell line specific

Using methods for cell lysis and fractionation which yield essentially quantitative recovery of rat prostate cancer cell cytosolic and nuclear androgen receptors, we examined androgen modulation of androgen receptor content of clonally derived prostate cancer cell lines. We showed that testosterone elicited a concentration-dependent 2.3-fold increase in T5 cell androgen receptor content which was maximum after 48 h and was maintained through at least 72 h of culture. Testosterone caused only a 1.4-fold elevation in D2 cell androgen receptor content which was maximum between 6 and 12 h of culture and was maintained through at least 72 h culture. In contrast, testosterone did not cause a change in C3 cell androgen receptor content. Cycloheximide inhibition showed that both the testosterone-mediated increase in and maintenance of basal prostate cancer cell androgen receptor content required protein synthesis. Because testosterone and the nonmetabolizable androgen R1881 were essentially equipotent as effectors of the increase in T5 cell androgen receptor content, findings using testosterone appear to represent maximum effects. RU 23908 antagonized both R1881 and testosterone promoted elevations of prostate cancer cell androgen receptor content. Effectiveness of RU 23908 was comparable to the relative binding affinity of R1881, testosterone and RU 23908 for androgen receptors. This implies that at least part of the androgen-promoted increase in prostate cancer cell androgen receptor content is mediated through the action of androgen receptors and suggests that androgen receptors may act as both cis and trans regulatory elements. The mechanisms which determine basal or androgen-modulated prostate cancer cell androgen receptor content remain to be elucidated.     

What is the Rationale for Androgen Therapy for Women?

To date, no formal definition of female androgen insufficiency (FAI) based on strong epidemiological data exists. However the proposed key symptoms of FAI, being reduced libido, diminished well-being, and lowered mood, have been reported to respond well to testosterone replacement, generally without significant adverse effects. Androgens are quantitatively the predominant sex steroid in women, circulating in the micro- and nanomolar concentration range, compared with picomolar levels of estrogens. Androgens have important physiological roles in women, acting both as precursors for estrogen biosynthesis and directly via the androgen receptor. The most significant biologically active androgen is testosterone, which circulates bound tightly to sex hormone binding globulin and loosely to albumin. Circulating androgen levels decline in the years preceding menopause. This may be attributed to the gradual reduction in adrenal androgen production with age and to the loss of cyclical ovarian androgen production in the late reproductive years. Those who experience surgical menopause, have adrenal insufficiency or pituitary insufficiency, or those who experience premature ovarian failure, also have reduced androgen production. Androgen replacement therapy in the form of either dehydroepiandrosterone or testosterone is becoming increasingly widespread for the treatment of FAI. Evidence exists for the benefits of such therapy in relieving both the physical and psychological symptoms thought to be due to FAI in clinically affected women. However, clear guidelines regarding the diagnosis of androgen insufficiency, optimal therapeutic doses, and long-term safety remain lacking.