Testosterone replacement therapy and the risk of prostate cancer. Is there a link?

Abstract

Substantial evidence supports the value of testosterone replacement therapy (TRT) in improving quality of life in men with proven aging male syndrome (AMS). Benefits of TRT include improved bone mineral density, reduced fracture risk, increased muscle mass, and improved mood, sense of well being, and libido, among others. There is currently a heated debate about the theoretical association between TRT and the initiation, progression, and aggressiveness of prostate cancer; however, this link has not been uniformly studied, and any results have been contradictory and nonconclusive. Although no clear evidence links TRT to prostate cancer, the possibility of increasing the risk of a clinical manifestation of a latent pre-existing malignancy can influence the decision about TRT use. Current recommendations are to exclude prostate cancer before initiating TRT in men over age 40 and to closely monitor men in the first year of testosterone replacement, followed by observation in subsequent years.

Introduction

Prostate cancer is a common disease that affects many men in the sixth and seventh decade of life. Historically, the development, differentiation, and maintenance of the prostate gland has been shown to be closely linked to the bioavailability of testosterone and other related sex hormones.1 Although the association between testosterone and cancer cell transformation in the prostate is well established, the mechanisms of this link and the role of androgen receptor (AR) transformation are less well described. It is postulated that these effects are mainly mediated via the activation of ARs by the ligand: testosterone from androstenedione in Leydig cells and dihydrotestosterone (DHT) by 5α-reductases from testosterone. However, these steroidal functions involve complex interactions of many other growth factors with different receptors affecting various cell types in the prostate. For example, the exact contribution of androgen-induced signaling via the AR to the carcinogenic transformation remains unknown. Several transgenic prostate cancer mice have demonstrated an oncogenic potential for ARs, implicating a mutation or hormone perturbation at the level of the AR as facilitating a malignant transformation in the prostate.2 There has been heated debate about the trigger for such transformation. In addition, the effect of testosterone levels on the complex interaction with other growth factors, including the steroid hormones estrogen and DHT, remains a mystery.3 Recent research partially indicates an indirect link between mutations of the AR gene and the initiation, amplification, and overexpression of prostate cancer.2 Regardless of the complexity and lack of full understanding of these mechanisms, there is a growing demand for testosterone replacement therapy (TRT) in men with symptoms suggestive of aging male syndrome (AMS), also known as late-onset hypogonadism (LOH). This is due in part to the recognition that many symptoms associated with aging, are similar to those characteristic of AMS, and well-publicized data have recently suggested a potential benefit of TRT on the overall quality of life in these men.4, 5 However, these benefits are offset by the potential side effects of TRT, which may include, the exacerbation of existing prostatic disease, hematological and cardiovascular events, plus possible negative effects on male reproduction. Perhaps the single greatest concern associated with TRT is the possibility that it may significantly increase the risk of developing prostate cancer or may contribute to the progression of the disease. This review focuses on the potential link between the use of TRT and the risk of prostate cancer, as reported in the literature.

The effect of testosterone level on prostate cancer risk

Since the landmark publication by Huggins and Hodges6 in 1941 showing the potential benefit of androgen deprivation for controlling prostate cancer growth, several long-term studies have failed to establish that the use of testosterone suppression provides a clear disease-specific survival advantage in men with early organ-confined prostate cancer and the current indications for hormonal therapy is preserved for patients with recurrent or metastatic disease. In fact, the inevitable occurrence of androgen-refractory prostate cancer after hormonal therapy suggests that androgens play a rather ‘permissive’ role in prostate cancer growth.7 This concept is supported by evidence that dependence on the androgen–AR binding process persists regardless of the oncogenic pathways triggered by the genetic instability of prostate cells, which is thought to be linked to the initiation of prostate cancer.8 Furthermore, an increase in prostate cancer incidence coincides with a gradual decrease in testosterone levels with advancing age, that is, the development of AMS.9 However, a causal relationship between hypogonadism and the risk of prostate cancer has not been established in controlled studies. Similarly, a definite correlation has not been shown between adjusted testosterone levels in hypogonadal men due to TRT and the initiation and/or acceleration of latent prostate cancer. Designing such studies would be difficult, due to a lack of consensus on what constitute a normal range of testosterone levels, the well-known inaccuracy of measuring serum bioavailable testosterone levels, and the considerable interindividual variation in the degree of testosterone decline associated with age. The decrease in bioavailable testosterone (i.e., a combination of free testosterone and the fraction weakly bound to albumin) with aging is reported to be considerably greater than the total testosterone decline.10 The Massachusetts Male Aging Study found declines of 0.8% in total testosterone and 2–3% in bioavailable testosterone and an increase of 1.6% in sex hormone binding globulin (SHBG) per year.11 Roberts et al.12 reported a significant decline in bioavailable testosterone levels with increasing cross-sectional age, which was associated with a significant increase in the ratio of estradiol to bioavailable testosterone. When these variations are coupled with the potential effects of cofactors such as obesity, diabetes, race, and family history, assessment of the potential role of testosterone in prostate cancer risk becomes increasingly complex.

Several other observations are worth consideration in assessing the risk of TRT on prostate cancer. Since concentrations of testosterone, SHBG, and DHT are substantially higher in prostate tissue than in serum, the modest increase in androgens in the peripheral circulation resulting from TRT supplementation may not accurately reflect the androgenic environment within the prostate. The effect of exogenous supplementation on the ratio of testosterone to DHT within the prostate is still unknown. DHT, which is the most potent intraprostatic androgen, appears to play a significant role in the initiation of prostate cancer. Based on the 24% decrease in the risk of prostate cancer observed in men treated with a selective 5α-reductase inhibitor in the Prostate Cancer Prevention Trial (PCPT),13 it can be postulated that a reduction in tissue DHT level may prevent cancerous transformation in the prostate or delay its clinical manifestations. However, other factors may play a role, taking into account that men in the 5α-reductase inhibitor arm had a statistically significant proportion (37%) of men with high Gleason score (7, 8, 9, or 10), when compared to the placebo group (22.2%). The clinical significance, of which, is still debatable.13

The effect of testosterone replacement on PSA and prostate volume

Based on immunoprofile studies, there are three distinct functional compartments of the prostate epithelium.14 The first compartment consists of androgen-independent cells that secret prostate-specific antigen (PSA) and form most of the prostate epithelium. The proliferation compartment, which primarily consists of basal cells located in the basal cell layer, regulates the differentiation of pluripotent stem cells into endocrine or secretory cells, a process that requires the presence of androgen-receptive cells.15 The function of the third compartment, which consists of endocrine-paracrine cells, is less well defined. Based on this description, there is a relationship between testosterone levels and the proliferative potential of PSA-secretory cells, which is reflected in the mixed results of reports on the clinical correlation between testosterone and PSA levels in men with normal and pathological prostates. Several studies have demonstrated significantly lower PSA levels in hypogonadal men, while others have shown a similar trend but failed to reach statistical significance. Using a PSA level of 4 ng/dl and a sextant biopsy as criteria for diagnosis, Morgentaler et al.16 suggested that men with low testosterone levels might have higher rates of undetectable occult prostate cancer. There are several difficulties in interpreting these reports, including the significant variation in volume between the studies, inaccuracies in testosterone assay, and, most importantly, the different serum testosterone cutoffs used to diagnose hypogonadism. Although TRT can increase prostate size and subsequently elevate PSA levels in hypogonadal men, the prostate size and PSA levels observed in hypogonadal men treated with TRT typically do not exceed those in untreated eugonadal individuals.4, 17, 18 It is postulated that TRT normalizes the growth of the prostate by balancing the underdeveloped gland secondary to the hypogonadal state.

Epidemiological evidence of a correlation between testosterone and prostate cancer

Several epidemiological studies have reported that low testosterone levels have an adverse effect on men with newly diagnosed prostate cancer. Schatzl et al.19 suggested an enhanced malignant potential associated with low serum testosterone, describing higher AR density and a more aggressive tumor. Massengill et al.20 reported a significant association between low serum testosterone and an increase in the likelihood of extraprostatic disease in men with localized disease.20 Imamoto et al.21 recently reported that low pretreatment serum testosterone levels had a significant predictive value for higher stage prostate cancer in 82 patients with clinically localized prostate cancer. Some controlled studies have reported that, compared with men with normal testosterone levels, men with low testosterone have a significantly shorter interval to disease progression and a worse prognosis after hormonal manipulation in metastatic disease.22 On the other hand, the effect on downstream testosterone metabolism of TRT increasing low levels of testosterone to levels that are above normal may contribute to the effect of TRT on prostate cancer risk. Shaneyfelt et al.23 conducted a meta-analysis that found a two-fold increase in the risk of prostate cancer in men with testosterone levels in the upper quartile of the population. Conversely, Chen et al.24 found no correlation between the incidence of prostate cancer and testosterone levels in a sub-analysis of 300 men from the Carotene and Retinol Efficacy Trial. In a study involving 486 men with clinically localized prostate cancer treated by radiation, Zagars et al.25 reported a markedly higher metastatic rate in men with a testosterone level 500 ng/dl. The study by the Finnprostate Group, however, found no correlation between pretreatment testosterone levels and metastatic prostate cancer.26 These seemingly conflicting reports of the effect of serum testosterone levels on the risk of clinical progression of prostate cancer suggest a U-shaped relationship between prostate cancer and androgens, in which extremes in testosterone levels may adversely affect the risk of prostate cancer.

Whether or not men on longterm TRT have an increased incidence of prostate cancer, several prospective studies have reported that these men have a low frequency of disease that is comparable to the general population.4, 27 Nevertheless, it is important to note that a causal relationship cannot be established based on observational epidemiological studies, and these correlations should be viewed with caution.

Does racial background matter?

In the United States, African-American men have the highest incidence of prostate cancer and are known to have more aggressive disease when compared with other racial groups. Although young healthy African-American men have consistently been reported to have higher levels of total and free serum testosterone,27 a correlation between these observations and prostate cancer risk remains theoretical at best. Kubricht et al.28 reported similar serum testosterone levels in 189 African Americans and 264 Caucasian men undergoing biopsy for prostate cancer. They concluded that men from different racial groups appear to have comparable testosterone levels beyond the age of 40 years, regardless of the presence of prostate cancer.28 Furthermore, after adjusting for clinical stage, Mohler et al.29 found similar tissue levels of testosterone and DHT in 36 African American and 59 Caucasian men undergoing radical prostatectomy; however, SHBG was significantly higher in the African-American men, indicating lower levels of bioavailable testosterone and the possibility of an alternative AR activation pathway. The epidemiological evidence of a higher incidence of diabetes and obesity in African-American men may also affect the overall correlation between testosterone levels and the risk of prostate cancer.

Future trends in reducing the risk of prostate cancer in men receiving TRT

Several studies have utilized the combination of a chemoprevention agent with TRT to reduce the risk of prostate cancer. Page et al.30 conducted a 36-month trial in which they randomized 70 men with low serum testosterone (<350 ng/dl) to receive one of three regimens: intramuscular testosterone enanthate 200 mg every 2 weeks plus daily placebo pills; intramuscular testosterone enanthate 200 mg every 2 weeks plus finasteride 5 mg/day; or placebo injections plus pills. The study rationale was to try and decrease the level of DHT while achieving the benefits of TRT on overall quality of life. The investigators reported no increase in prostate cancer risk in any of the groups. In an earlier study in the same men, Amory et al.31 reported that, compared with TRT alone, TRT plus finasteride had an attenuating effect on prostate volume and PSA. It is difficult to draw strong conclusions based on the small number of patients and the relatively short follow-up duration in these studies. Furthermore, the PCPT suggested that the use of finasteride may be associated with more aggressive cancer. Nevertheless, a recent review suggests a benefit to reducing death, factoring in the potential risk of higher Gleason scores in men receiving finasteride.33 Its widespread use as a chemoprevention agent is not currently recommended. Future larger trials need to be performed to assess the use of dietary manipulation (e.g. lycopene, vitamin E, selenium) and other chemopreventive agents. Until the association between testosterone and prostate cancer risk has been further clarified in large, long-term, controlled studies, caution should be exercised and rigorous selection and monitoring guidelines should be adhered to before initiating TRT in older men.

Suggested monitoring guidelines

A digital rectal examination (DRE) and PSA levels should be used to exclude prostate cancer before initiating TRT in hypogonadal men. The role of DRE in detecting early, clinically significant, prostate cancer is substantially hampered by the high false negative rate, which, largely reflects in contradictory reports for its value as a screening tool.32, 33 In a recent large review study, DRE findings did not correlate with biopsy findings and pathological stage.34 However, DRE is still mandatory in all men with PSA >2.5 ng/dl and may play a role in target biopsy of the prostate. The use of validated nomograms35 (based on age, PSA, %fPSA, and DRE) is recommended when in doubts, to aid in the decision for recommending biopsy of the prostate before TRT initiation in some patients. DRE and PSA should be performed every 3 months in the first year and then semiannually.34 It is important to note that, such recommended regimen for screening, is arbitrary, and not supported by published data. However, in our opinion it represents a sensible clinical practice that can be applied at our current knowledge. PSA velocity (rate of change in PSA level over time) can be utilized to monitor the dynamic risk of prostate cancer overtime and the need for prostate biopsy.36 A suggested PSA doubling time of <12 months in men with initial PSA levels of >1 ng/dl, may indicate exclusion of prostate cancer by extended biopsy.36

Little evidence exists on the safety of TRT initiation after treatment for primary prostate cancer. Agarwal et al.37 treated 10 hypogonadal men, treated for organ-confined prostate cancer, with TRT for a median of 18 months. They reported no PSA recurrence in all men with associated significant symptomatic improvement in quality of life indices. However, there are no documented large and long-term studies proving that the risk of recurrence is not affected by TRT in men treated with definitive therapy. A known risk of recurrence or biochemical failure after radical prostatectomy is estimated to be 10–20% within 15 years indicating that the possibility of micrometastasis at the time of diagnosis is real and substantial.38 In our opinion, until the true association between TRT and the risk of prostate cancer is established, the recommendations for TRT after radical prostatectomy should be contraindicated in the mainstream urological practice and probably only practiced under strict research protocols.

After TRT is initiated, a rigorous follow-up should be employed, including the monitoring of T levels. According to the recent EAU, ISA recommendations, symptomatic men with total T levels of <231 ng/dl or free T of <52 pg/ml should be offered TRT.39 Monitoring of treatment should aim at maintaining total T levels between 346 ng/dl (free T>72 pg/ml) and 500 ng/dl, by adjusting route and dosage of TRT regimens. It is theoretically inadvisable to recommend higher doses of TRT and the dose should reflect an improvement in LOH symptoms, with the lowest possible dosage. DHT levels are not routinely recommended to be monitored during TRT.

Other adverse events linked to TRT but unrelated to prostate cancer risk include the aggravation of Lower urinary tract symptoms (LUTS), that may occur in older men with existing benign prostatic hyperplasia-related symptoms and should be monitored on regular intervals in these men. Other potential adverse events in men treated with TRT for prolonged periods is erythrocytosis and sleep apnea. Hemoglobin (HCT), should be monitored semiannually and baseline determination of sleep apnea is recommended and should be monitored at each visit.

Conclusion

In spite of the theoretical increase in prostate cancer risk following TRT, there is currently no evidence that testosterone administration can initiate or promote a de novo or pre-existing prostatic malignancy in hypogonadal men.40 In fact, there are strong indications that normal testosterone levels play a protective role in the natural history of prostate cancer. Many studies have demonstrated that a low testosterone level prior to treatment is an independent predictor of a more aggressive, high-grade cancer,20 an increased likelihood of extraprostatic disease at the time of diagnosis,41 and a decreased likelihood of a favorable treatment response.42 Nevertheless, most of these trials are limited in sample size and duration of therapy. Therefore, until the true risk of TRT has been established in long-term studies, it is crucial to carefully screen and closely monitor these men for occult prostate cancer.

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Barqawi, A., Crawford, E. Testosterone replacement therapy and the risk of prostate cancer. Is there a link?. Int J Impot Res 18, 323–328 (2006). https://doi.org/10.1038/sj.ijir.3901418

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Keywords

  • testosterone
  • prostate cancer
  • testosterone replacement therapy

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