Androgénothérapie: Quels sont les risques?

Androgens play an important biological role at all phases of a man’s life. The objective of treatment of androgen deficiency is to maintain physiological testosterone levels. Misuse and abuse of androgen as anabolic steroids are frequent in sportsmen and body-builders or for erectile dysfunction. The main concerns for the potential adverse effects of testosterone treatment are the prostate and the cardiovascular system (lipid metabolism). Liver function must also be monitored. There is no evidence, at the present time, that testosterone replacement therapy in hypogonadal men increases the risk of prostate cancer. Only sporadic cases have been reported. Because of the risk of stimulating an existing prostate cancer, each patient must be monitored every six months (PSA and DRE).     

Testostérone circulante et cancer de la prostate. Revue de données récentes

In vitro andin vivo studies show that androgens stimulate prostate cancer. However, evidence from epidemiological studies of an association between circulating levels of androgens and prostate cancer risk has been inconsistent, but most studies have likely been undersized given that the association may be relatively weak. We review prospective studies on the association of serum levels of free and total testosterone, the principal androgen in circulation with risk of prostate cancer. No significant association between total or free testosterone and risk of prostate cancer was found in studies that together included 1,525 cases of prostate cancer and 4,349 controls. No support was found for the hypothesis that high levels of circulating testosterone within a physiological range stimulate development and growth of prostate cancer. Intraprostatic androgen metabolism may still be of importance for prostate cancer development.     

Traitement androgénique substitutif et cancer prostatique

Epidemiological studies show that the risk of prostate cancer was not related to testosterone blood levels. Androgens do not seem to be able to cause prostatic cancer in men. However, administration of exogenous androgens can unmask a prostatic cancer that was, until then, hidden by hypogonadism. Screening of a latent prostatic cancer before the induction of an androgenic treatment must follow the usual recommendations based on digital rectal examination and PSA level determination. A special attention is to be paid when beginning an androgen replacement therapy with a control at six months; thereafter a follow up including digital rectal examination and PSA must be performed every year.     

Androgen deficiency in the aging male: benefits and risks of androgen supplementation

There is now convincing evidence that in a subset of aging men, increasing with age, plasma testosterone levels fall below a critical level resulting in hypogonadism. This state of testosterone deficiency has an impact on bone, muscle and brain function and is maybe a factor in the accumulation of visceral fat which again has a significant impact on the cardiovascular risk profile. From the above it follows that androgen replacement to selected men with proven androgen deficiency will have beneficial effects. There is, however a concern that androgen administration to aging men may be harmful in view of effects on prostate disease. Benign prostate hyperplasia (BPH) and prostate cancer are typically diseases of the aging male, steeply increasing with age. But epidemiological studies provide no clues that the levels of circulating androgen are correlated with or predict prostate disease. Similarly, androgen replacement studies in men do not suggest that these men suffer in a higher degree from prostate disease than control subjects. It seems a defensible practice to treat aging men with androgens if and when they are testosterone-deficient, but long-term studies including sufficient numbers of men are needed.     

Fundamental aspects of hypogonadism in the aging male

With aging in men, serum testosterone levels decline progressively and the prevalence of hypogonadism increases; these changes are associated with alterations in androgen-regulated physiological functions. In young hypogonadal men, similar alterations improve with testosterone replacement. In older men, short-term testosterone treatment trials suggest benefits (eg, on body composition and bone mineral density), without significant adverse effects. Therefore, androgen deficiency may contribute to physiological decline with aging, and testosterone therapy is reasonable for older men with clinical manifestations of androgen deficiency and low testosterone levels. However, the long-term benefits and potential risks (eg, for prostate disease) of testosterone treatment in older men are unknown.     

Androgen supplementation and prostate cancer risk: strategies for pretherapy assessment and monitoring

Since in men androgen levels decrease with age and result in symptoms of hypogonadism, the use of testosterone supplementation to treat symptoms resulting from hypogonadism is increasing. One potential complication of this treatment is the possibility of an increased risk of prostate cancer. Although most authorities agree that androgen is involved in the exacerbation of existing carcinoma of the prostate, the action of androgens on the carcinogenic process is not well understood. Attempts to demonstrate a correlation between hormone levels and prostate cancer have yielded inconsistent results. No clear evidence exists that androgen supplementation to restore physiologic levels produces any deleterious effects on the prostate. It is highly doubtful that when testosterone therapy is administered to middle-aged or older men, any potential prostate cancer promotion effect will be clinically manifested in the absence of already established cancer. It is, however, imperative that existing or developing prostate cancer be ruled out before initiation and during androgen replacement therapy. As with any therapeutic regimen, careful monitoring of the patient receiving treatment is recommended and constitutes good medical care.     

Réflexion multidisciplinaire sur la prise en charge du Déficit androgénique lié à l’âge

The diagnosis of the androgen deficiency of the aging male (ADAM) is suspected in the presence of relatively unspecific clinical symptoms. The biological evidence of androgen deficiency should be given by using an assay taking into account the level of the sex hormone binding protein (SHBG), such as the bioavailable testosterone assay or, at least, the free testosterone index or the calculated free testosterone which both require measuring total testosterone and SHBG levels. Although the threshold value for defining ADAM has not been fully investigated, the lower limit of normal values in healthy young men which is commonly used for including subjects in therapeutic trials, seems appropriate. According to the currently available data, testosterone replacement therapy in hypogonadal aging men seems to be beneficial to quality of life, sexuality, metabolic status, body composition and osteoporosis. The initiation of androgen replacement therapy requires a careful screening for prostate cancer. Prostate and hematocrit must be monitored during the replacement therapy which is intended for maintaining testosterone levels in the physiological range. Associated disease should be accounted for as a possible factor worsening ADAM and could be relevant of a specific therapy.     

P450-dependent enzymes as targets for prostate cancer therapy

Metastatic prostate adenocarcinoma is a leading cause of cancer-related deaths among men. First line treatment is primarily aimed at blocking the synthesis and action of androgens. As primary endocrine treatment, androgen deprivation is usually achieved by orchidectomy or LHRH analogues, frequently combined with androgen receptor antagonists in order to block the residual adrenal androgens. However, nearly all the patients will eventually relapse. Available or potential second line therapies include, among others, alternative endocrine manipulations and chemotherapy.

Cytochrome P450-dependent enzymes are involved in the synthesis and/or degradation of many endogenous compounds, such as steroids and retinoic acid. Some of these enzymes represent suitable targets for the treatment of prostate cancer.

In first line therapy, inhibitors of the P450-dependent 17,20-lyase may achieve a maximal androgen ablation with a single drug treatment. Ketoconazole at high dose blocks both testicular and adrenal androgen biosynthesis but its side-effects, mainly gastric discomfort, limit its widespread use. A series of newly synthesized, more selective, steroidal 17,20-lyase inhibitors related to 17-(3-pyridyl)androsta-5,16-dien-3β-ol, may open new perspectives in this field.

In prostate cancer patients who relapse after surgical or medical castration, therapies aiming at suppressing the remaining adrenal androgen biosynthesis (ketoconazole) or producing a medical adrenalectomy (aminoglutethimide + hydrocortisone) have been used, but are becoming obsolete with the generalization of maximal androgen blockade in first line treatment. The role of inhibition of aromatase in prostate cancer therapy, which was postulated for aminoglutethimide, could not be confirmed by the use of more selective aromatase inhibitors, such as formestane.

An alternative approach is represented by liarozole fumarate (LIA), a compound that blocks the P450-dependent catabolism of retinoic acid (RA). In vitro, it enhances the antiproliferative and differentiation effects of RA in cell lines that express RA metabolism, such as F9 teratocarcinoma and MCF-7 breast carcinoma cells. In vivo, monotherapy with LIA increases RA plasma levels and, to a greater extent, endogenous tissue RA levels leading to retinoid-mimetic effects. In the rat Dunning prostate cancer models, it inhibits the growth of androgen-independent as well as androgen-dependent carcinomas relapsing after castration. Concurrently, changes in the pattern of cytokeratins characteristic of increased differentiation were observed. Early clinical trials show that LIA, in second or third line therapy in metastatic prostate cancer, induces PSA responses in about 30% of unselected patients. In some patients regression of soft tissue metastasis has been observed. In a subgroup of patients, an important relief of metastatic bone pain was also noted.     

Testosterone therapy is associated with reduced tactile sensitivity in human males

Responses to vibrotactile stimuli were examined in men as a function of chronic exposure to either exogenous or endogenous androgens. Psychophysical techniques were used to evaluate thresholds to stimulus detection and perceived stimulus intensities in response to mild vibration applied to either the finger or the penis. Normal men were compared to the following groups: (a) untreated hypogonadal men, (b) androgen-replaced hypogonadal men, or (c) infertile men with androgen levels in the low normal range. Among the four groups, untreated hypogonadal men perceived vibrotactile stimuli as most intense and were slightly more sensitive to touch than were men with higher levels of androgen. Chronic treatment with testosterone enanthate was associated with a decline in the perceived intensity of vibrotactile stimuli in hypogonadal men. The lowest levels of sensitivity to tactile stimuli were observed in the infertile men.     

Circulating testosterone and prostate cancer. A brief review

In vitro andin vivo studies show that androgens stimulate prostate cancer. However, evidence from epidemiological studies of an association between circulating levels of androgens and prostate cancer risk has been inconsistent, but most studies have likely been undersized given that the association may be relatively weak. We review prospective studies on the association of serum levels of free and total testosterone, the principal androgen in circulation with risk of prostate cancer.     

Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR)-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR) suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27^Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.     

Effects of low testosterone levels and of adrenal androgens on growth of prostate tumor models in nude mice

Two transplantable, androgen dependent prostate tumor models of human origin, PC-82 and PC-EW, were used to study the effect of low androgen levels and adrenal androgens on prostate tumor cell proliferation. Tumor load of the PC-82 and PC-EW tumors could be maintained constant when plasma testosterone levels were 0.8 and 0.9 nmol/l, respectively, corresponding with an intratissue 5-dihydrotestosterone level of 3–4 pmol/g tissue. This critical androgen level for prostate tumor growth stimulation amounted to 2–3 times the castration level and proved to be similar for both tumor models. Relatively high levels of androstenedione resulted in physiological levels of plasma testosterone causing androgen concentrations in PC-82 tumor tissue exceeding the critical level for tumor growth. These results indicate that submaximal suppression of androgens can stop tumor growth in these prostate tumor models.     

CYP17 inhibitors for prostate cancer therapy

Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues' androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17,20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development. Article from the special issue on Targeted Inhibitors.     

Effective Testosterone Suppression for Prostate Cancer: Is There a Best Castration Therapy?

Achieving and maintaining effective suppression of serum testosterone levels in men treated with androgen ablation is one of the essential strategies in the management of prostate cancer. Historically, a serum testosterone below 50 ng/dL was considered to be the castrate level. Current data suggest that the new target for either surgical or chemical castration is a serum testosterone level of lower than 20 ng/dL in an attempt to maximize therapeutic outcomes. Testosterone breakthrough and the acute-on-chronic effects of administration of a luteinizing hormone-releasing hormone analogue may cause testosterone levels to periodically rise, sometimes to noncastrate levels. The goal of androgen ablation is to identify those agents that will most consistently achieve and maintain the lowest testosterone levels possible.Key words: Prostate cancer, Androgen ablation, LHRH analogues, LHRH antagonists, TestosteroneThe cornerstone of understanding the basic biology of prostate cancer relies upon the important discovery that prostate cancer is a hormonally responsive tumor. The current use of androgen ablation therapy in prostate cancer includes treatment based on serum prostate-specific antigen (PSA) only or local recurrence; neoadjuvant or adjuvant treatment of high-risk disease, usually in combination with radiation therapy; and treatment of patients with metastatic disease regardless of symptoms. The American Society of Clinical Oncology (ASCO) 2007 guidelines and National Comprehensive Cancer Network (NCCN) 2009 guidelines recommend either luteinizing hormone-releasing hormone (LHRH) agonists or bilateral orchiectomy as first-line therapy for men with advanced prostate cancer.^1,2Medical or chemical castration is almost exclusively performed by the use of injectable LHRH analogues, with a minor role for estrogen and limited experience with LHRH antagonists. Surgical castration through bilateral orchiectomy is infrequently used today.Intermittent hormonal therapy (IHT) is being investigated as an alternative to continuous hormonal therapy with a potential for reduced morbidity and a delay of the progression to hormone-refractory disease.³ Although intermittent therapy may rely upon restoring a normal testosterone level, it is believed that the testosterone level should be as low as possible when the patient is on treatment, thus generating the lowest serum PSA level possible and likely improving outcome.⁴ Although the data on IHT are promising, trials reported thus far are relatively small and somewhat underpowered, and it is likely that its use will increase in the future as trials mature.There is growing recognition that many men may not achieve acceptable levels of testosterone using androgen ablation. This has led to a renewed interest in the significance of the testosterone level in the modern era of prostate cancer management. Can we define the best castration therapy for prostate cancer? Is this the therapy that provides the lowest and most consistent levels of testosterone suppression? To quote Dr. Claude Schulman in a recent editorial: “less is more.”⁵     

Androgen receptor action in hormone-dependent and recurrent prostate cancer

The importance of androgens and androgen receptors (AR) in primary prostate cancer is well established. Metastatic disease is usually treated with some form of androgen ablation, which is effective for a limited amount of time. The role of AR in prostate cancers that recur despite androgen ablation therapy is less certain. Most of these tumors express prostate specific antigen (PSA), an androgen-regulated gene; moreover, AR is generally highly expressed in recurrent prostate cancer. We propose that AR continues to play a role in many of these tumors and that it is not only the levels of AR, ligands, and co-regulators, but also the changes in cell signaling that induce AR action in recurrent prostate cancer. These pathways are, therefore, potential therapeutic targets.     

Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity

The effects of androgens on cardiovascular disease (CVD) risk in men remain unclear. To better characterize the relationship between androgens and HDL, we investigated the effects of testosterone replacement on HDL protein composition and serum HDL-mediated cholesterol efflux in hypogonadal men. Twenty-three older hypogonadal men (ages 51-83, baseline testosterone < 280 ng/dl) were administered replacement testosterone therapy (1% transdermal gel) with or without the 5α-reductase inhibitor dutasteride. At baseline and after three months of treatment, we determined fasting lipid concentrations, HDL protein composition, and the cholesterol efflux capacity of serum HDL. Testosterone replacement did not affect HDL cholesterol (HDL-C) concentrations but conferred significant increases in HDL-associated paraoxonase 1 (PON1) and fibrinogen α chain (FGA) (P = 0.022 and P = 0.023, respectively) and a decrease in apolipoprotein A-IV (apoA-IV) (P = 0.016). Exogenous testosterone did not affect the cholesterol efflux capacity of serum HDL. No differences were observed between men who received testosterone alone and those who also received dutasteride. Testosterone replacement in older hypogonadal men alters the protein composition of HDL but does not significantly change serum HDL-mediated cholesterol efflux. These effects appear independent of testosterone conversion to dihydrotestosterone. Further research is needed to determine how changes in HDL protein content affect CVD risk in men.     

Does Testosterone Therapy Increase the Risk of Prostate Cancer?

ObjectiveTo review factors affecting use of testosterone therapy for hypogonadism including the persistent controversial link between testosterone therapy and prostate cancer.MethodsWe reviewed studies investigating the relationship between testosterone therapy and prostate cancer progression and summarized strategies for hypogonadism management and prostate monitoring.ResultsTrials of up to 36 months in length and longitudinal studies consistently fail to demonstrate an increased prostate cancer risk associated with increased testosterone levels. No evidence of an associated relationship between exogenous testosterone therapy and prostate cancer has emerged from clinical trials or adverse event reports. It does not appear that exogenous testosterone accumulates in the prostate or provokes major biologic change in the prostate gland. In addition, preliminary evidence indicates that low endogenous testosterone may confer an increased risk of prostate cancer.ConclusionsMounting evidence demonstrates that there is a lack of association between testosterone therapy and prostate cancer progression. Testosterone therapy may be prescribed for men for whom it was once not considered. Careful monitoring of patients with hypogonadism who are receiving testosterone therapy is imperative. Well-designed, large-scale prospective clinical trials are necessary to adequately address prostate safety in hypogonadal men receiving testosterone therapy. (Endocr Pract. 2008;14:904-911)     

Androgens in women

The role of androgen treatment in women remains controversial. The proposed “Female Androgen Insufficiency Syndrome” (Fertility and Sterility, April 2002) describes a number of non-specific symptoms including unexplained fatigue, decreased well being/dysphoric mood and/or blunted motivation and diminished sexual function. An estimated 40% of women experience sexual dysfunction, highlighting the need for ongoing research into this field in order to fully define the possible contribution of androgen insufficiency. The increasing availability of products, such as dehydroepiandrosterone (DHEA) supplements also points to the need for controlled studies to assess the safety of these and other preparations.

Measurement of androgens in women requires sensitive assays with the ability to detect low levels and a narrow range with precision. Normal ranges of androgens for women of reproductive and post-reproductive age remain poorly defined. Debate exists as per importance of measurement of free versus total testosterone, with the ‘free androgen index’ offering an alternative method of assessment of testosterone availability.

Testosterone treatment is being developed for women in the form of transdermal patches, gels or cream, with percutaneous implants in common usage in some countries. Recent research has highlighted alternative means of administration, such as oral inhalation or buccal lozenge. DHEA is widely available in some countries. Research to date has demonstrated improvements in libido and sexual function, mood and well being. Evidence points to other potential benefits of androgen treatment, including preservation of bone mass, a possible protective role in breast cancer and beneficial effects on cognition.

Adverse effects of androgen treatment in women are dose-dependent and include virilisation, mood disturbance and acne. These are uncommon if appropriate doses are administered and highlight the need for treatment to be closely monitored clinically and biochemically. Beneficial effects of testosterone treatment in post-menopausal women with lowered androgen levels have been well documented, and preliminary evidence suggests a role for treatment in pre-menopausal women with symptoms and lowered testosterone levels.