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Testosterone supplementation after prostate cancer? - Harvard Health
The use of exogenous testosterone to treat hypogonadism in the men with a history of prostate cancer CaP remains controversial due to fears of cancer recurrence or progression.
Due to the detrimental impact of hypogonadism on patient quality of life, recent work has examined the safety of testosterone therapy TTh in men with a history of CaP. In this review, we evaluate the literature with regards to the safety of TTh in men with a history of CaP. TTh results in improvements in quality of life with little evidence of biochemical recurrence or progression in men with a history of CaP, or de novo cancer in unaffected men.
An insufficient amount of evidence is currently available to truly demonstrate the safe use of TTh in men with low risk CaP. In men with high-risk cancer, more limited data suggest that TTh may be safe, but these findings remain inconclusive. Despite the historic avoidance of TTh in men with a history of CaP, the existing body of evidence largely supports the safe and effective use of testosterone in these men, although additional study is needed before unequivocal safety can be demonstrated.
Male hypogonadism is defined as the presence of both low serum testosterone levels as well as symptoms that can include decreased libido, erectile dysfunction, loss of vitality, loss of lean muscle and bone density, fatigue, anemia and depression 1. The prevalence of hypogonadism has proven difficult to accurately determine, with the highest reported prevalence reported in when Mulligan et al. Importantly, these studies incorporated both the presence of low testosterone levels as well as symptoms as part of the definition of hypogonadism.
Prostate cancer CaP is also most common among older men and accounts for one of every five cancer diagnoses in men 5. Over the past decade, the use of testosterone therapy TTh has dramatically increased.
Between — the number of testosterone prescriptions tripled, with increases among all age groups. Baillargeon and colleagues found that 3. This increase in prescribing practices is in part due to the known benefits of therapy, which can decrease mortality, improve lipid parameters, decrease body fat, and improved sexual function 8 - The negative physiological sequelae of hypogonadism are also well established, and include bone reabsorption, which can lead to osteoporosis and osteopenia; TTh can normalize bone density 11 - Multiple studies have also shown that testosterone has important immunomodulatory effects, including regulation of neutrophils and monocytes 14 - Along with the benefits of TTh, several potential risks have been identified.
Among these, the most discussed are the potential adverse cardiovascular CV effects of TTh and the impact of testosterone on CaP. Numerous studies have reported a relationship between TTh and CV risk, with studies observing an increased risk of CV events in men with both low and high testosterone levels. Most recently, a handful of studies have observed a positive correlation between testosterone levels and CV events, especially in older men, and have ultimately led to changes in testosterone labeling 18 - More recently, Baillargeon and colleagues found that the risk of CV events was the same in both hypogonadal men treated and not treated with TTh.
Upon further examination, however, a modest decrease in CV risk was observed in the testosterone treated cohort 22 , For decades, the use of TTh in men with a history of CaP has been controversial. The seminal study by Drs. Charles Huggins and Clarence Hodges found that castration resulted in regression of metastatic CaP, implicating androgens in the CaP growth Subsequent work supported a role for testosterone in recurrence or progression of existing CaP, especially in the setting of advanced CaP 25 , However, clinical studies have failed to show a persuasive link between CaP and TTh that would limit the treatment of hypogondal men with a history of CaP.
With an aging population, increasing CaP survivorship and the quality of life that can be restored with TTh, TTh is worth considering in CaP survivors. In this review, we examine the literature with regards to the risk of CaP as a function of serum testosterone levels, as well as what is known regarding the safety of TTh in men with a history of CaP.
A literature search was conducted using PubMed to identify relevant, current studies as well as historical perspectives on the data and attitudes examining TTh in the setting of CaP. Search terms used included: The link between low endogenous testosterone levels and CaP has been extensively studied. Men with low endogenous testosterone levels have increased rates and severity of CaP at diagnosis, including extraprostatic invasion The first study to recognize this was published in by Morgentaler et al.
Though the small sample size limited the generalizability of these initial results, the relationship between endogenous testosterone levels has been examined repeatedly over the past two decades Table 1 In , Morgentaler et al. In , Shin et al. Using multivariate regression analysis to compare these groups, the authors found a significantly higher incidence of CaP in the low testosterone group In addition to low serum testosterone levels, the study identified increasing age, high PSA, and low prostate volume as factors associated with increased CaP risk Low serum testosterone has also been linked to more aggressive, higher-grade CaP.
In , Hoffman and colleagues retrospectively analyzed men with CaP. Recent prospective studies have also shown that low pretreatment testosterone level is a predictor of higher Gleason score. A study examining men found that low serum testosterone was not predictive of biochemical recurrence, tumor volume or disease progression, but that it was associated with Gleason 4—5 disease [odds ratio OR 2. While the literature mainly supports hypogonadism as a risk factor for CaP and increased severity of disease, controversy still remains in the absence of large prospective, controlled studies.
A retrospective analysis of men with CaP showed hypogonadism to only be predictive of seminal vesicle invasion and did not show a relationship between pretreatment hypogonadism and a higher incidence of CaP Studies examining the relationship between normal and high pretreatment serum testosterone levels and CaP have yielded often conflicting results Table 2.
A number of studies have reported an increased risk of CaP with high pretreatment serum testosterone levels. In , Gann et al. Similarly, a meta-analysis published in found that when stratified by pretreatment testosterone levels, men in the highest quartile were 2. While this meta-analysis adjusted for BMI, age and serum hormone levels, it only incorporated data from two studies The relationship between Gleason score and high serum testosterone levels has also been examined.
In , Porcaro et al. In contrast to the above findings, several studies have found no relationship, or even a protective relationship, between high testosterone levels and CaP risk. The Endogenous Hormones and CaP Collaborative Group used conditional logistic regression to assess 18 prospective studies that included 3, men with incident CaP and 6, controls. No associations between the risk of CaP and serum testosterone concentrations were identified A handful of studies have observed a decreased risk of CaP in the setting of high testosterone levels.
In , Stattin et al. Two similarly designed studies also reported that men with higher testosterone levels had a lower risk of CaP 50 , A lower risk of biochemical recurrence and better prognosis for both localized and metastatic CaP after radical prostatectomy have also been observed in men with higher pretreatment testosterone levels 52 - As such, androgen deprivation remains a major component of advanced CaP treatment However, changes in PSA in vivo do not linearly correlate with serum testosterone levels.
A study found no significant change in PSA levels in 31 healthy volunteers 21—39 years old after administration of either , or mg testosterone for 15 weeks at any dose, supporting an androgen receptor AR saturation point, above which no further increases in PSA or CaP growth are observed Among men with castrate serum testosterone levels, a rise in testosterone levels correlates with a rise in PSA, but only until the androgen receptor is saturated Studies aimed at correlating androgen levels and PSA have had limited success.
Testosterone level was identified as an independent predictor of CaP risk, as both a continuous and binary variable with sensitivity and specificity varying as a function of testosterone thresholds established in the analysis. As a result of the findings of Huggins and Hodges in , treatment of hypogonadal men with a history of CaP has remained controversial. Work over the past two decades has yielded conflicting results and has shown that the relationships between androgen levels, healthy prostate tissue and CaP is more complex than originally thought.
Two recent models that have been proposed to explain the more recent clinical findings are the prostate saturation and time-dependence models. The prostate saturation model was first alluded to in by Fowler and Whitmore, who concluded that normal serum testosterone levels may not be correlated with maximal CaP growth and that growth only varied with androgens at sub-physiologic levels Morgentaler and Traish sought to reconcile why low testosterone levels resulted in regression of CaP but high levels could not consistently be linked to CaP growth or spread.
They postulated that because tumor growth varied with testosterone levels only in the setting of castrate testosterone levels, and not in eugonadal men, that this may be related to the saturation point of the AR, and that any stimulation of prostate tissue would cease when the AR saturation point had been reached Overall, however, there are a few studies that support the prostate saturation model A similar study enrolling men found comparable results and concluded that physicians should exercise caution when treating hypogonadal men with very low testosterone levels There is also support for this prostate saturation model in vitro using the androgen-responsive CaP tumor cell line, LnCaP.
Using the same cell line, Arnold et al. The time-dependence model was initially presented in by Salonia et al. This model was developed based on the observation that an increased risk of CaP was observed both at near-castrate as well as high serum testosterone levels. The authors concluded that the relationship between CaP and androgen levels followed a non-linear u-shaped distribution.
Broad support for the time-dependence theory does not currently exist, in large part because the relationship between high endogenous testosterone levels and CaP remains unclear.
Both the prostate saturation and time-dependence models account for the observation that CaP growth in culture is androgen-dependent at low levels. This is clinically relevant because these levels 0. This is thought to explain CaP recurrence after androgen deprivation therapy ADT as the androgen levels normalize from castrate levels after treatment In men with androgen-sensitive cancers, keeping androgen levels low is the standard of care despite the tradeoff of hypogonadal symptoms Many cellular mechanisms have been attributed to this phenomenon including: While cells can adapt to androgen deprivation well, even CRPC cells are inhibited by supraphysiologic androgen levels 75 , Mechanistically, supraphysiologic androgen levels facilitate nuclear stabilization of ligand-bound AR, which leads to apoptosis by inhibiting DNA relicensing 78 , This in vitro finding led to a pilot study using bipolar androgen therapy BAT to treat metastatic CaP.
Fourteen patients with metastatic CRPC were given testosterone cypionate mg intramuscular and etoposide mg oral daily to rapidly bring them from castrate to supraphysiologic testosterone levels; this cycle was repeated three times.
Astonishingly, 7 of 14 patients had PSA decline in response to AR-directed therapy such as abiraterone, enzalutamide, or bicalutamide given after BAT, suggesting that BAT could re-sensitize patients to therapy Additional in vitro evidence supports the efficacy of BAT therapy. While many studies have examined the relationship between testosterone and CaP, there are many ongoing limitations including: Radical prostatectomy remains the preferred treatment modality in CaP patients under 70 years old with an aging population and increase in CaP survivorship, TTh after radical prostatectomy is an important area of investigation Recent studies support the conclusion that TTh in men with a history of CaP is effective in treating hypogonadism without having a significant impact on CaP recurrence or progression.
A study by Kaufman and Graydon followed seven hypogonadal men started on TTh with a history of CaP treated with radical prostatectomy. After following the patients for 1—12 years, no CaP recurrence was observed, though the small sample size was a significant limitation of the work In , Agarwal and Oefelein followed ten men post radical prostatectomy recently started on TTh and found significant improvements in quality of life attributed to decreases in hot flashes and increases in energy without CaP recurrence or detectable increase in PSA after 19 months More recently, Pastuszak et al.
Of the hypogonadal men, 77 had non-high risk and 26 had high risk CaP.