Prevalence of Hypogonadism in Low-Risk Prostate Cancer Survivors

In the current study, the association between obesity and hypogonadism is consistent with epidemiologic evidence that suggests complex multidirectional interactions between testosterone, sex hormone-binding globulin, obesity, metabolic syndrome, and type 2 DM (T2DM), mediated by cytokines and adipokines. Several studies show that obesity adversely affects testicular function and is associated with a reduction in sex hormone-binding globulin, serum T, and free testosterone levels.^17,18 In addition, secondary hypogonadism has been shown to be higher in men who are overweight (25-29 kg/m2 BMI) and obese (≥ 30 kg/ m2 BMI) compared with normal weight men.^19,20 Hypogonadism has also been shown to increase insulin resistance, thereby increasing the risk for developing metabolic syndrome, which is a precursor for cardiovascular disease (CVD) and T2DM.²¹ Furthermore, low testosterone concentration may be associated with increased insulin resistance, incidence of CVD events, anemia, and low bone density.^19,22,23

The relationship between obesity, metabolic syndrome, and androgen deficiency remains unclear because of the complex mechanisms involved in this association. Impairment of hypothalamic-pituitary function by decreased LH pulse amplitude, inhibitory effects of estrogen at the
hypothalamus and pituitary, and the effects of leptin, ghrelin, and resistin, both centrally and on testicular Leydig cells, may explain lower testosterone level in obese males.^24,25 Recent studies have suggested a possible increased risk of  CV events among groups of men prescribed TRT.^26,27 However, other studies demonstrate beneficial effects of TRT on CVD risk factors, and research over several decades suggests a strong beneficial relationship between normal T and CV health.26 The evidence to suggest that TRT increases CV morbidity and mortality risks is poor,²⁸ but FDA is investigating the link between TRT and adverse CV outcomes.²⁹

Testosterone replacement therapy is recommended for symptomatic men with androgen deficiency to induce or maintain secondary sex characteristics and improve their sexual function, sense of well-being, muscle mass, strength, and bone mineral density. In a recent study supported by the National Institutes of Health (NIH) in men aged 65 years, increasing serum testosterone levels to mid-normal range for 1 year was associated with a moderate benefit in sexual function and improved mood, but there was no significant benefit in vitality (as measured by a fatigue scale) or walking distance.²⁸ In the NIH study, 4 men in the testosterone group and 1 in the placebo group received a diagnosis of PCa during or within the subsequent year of treatment, but the sample size was inadequate to reliably assess the effect of testosterone
on the risk of PCa.²⁸

With increasing direct-to-consumer marketing of branded pharmaceutical products in the U.S., there is widening interest in testosterone levels and hypogonadism symptoms in middle-aged and older men. Indeed, 2.3 million patients received a prescription for testosterone in 2013, up from 1.3 million in 2010.^29,30 This change has become important because whereas TRT is standard therapy in symptomatic hypogonadal men, it has long been considered taboo for men with a history of PCa, regardless of disease status. Transdermal testosterone is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate, according to the package insert.³¹ Androgens are contraindicated in men with known or suspected carcinoma of the prostate or breast, according to the testosterone cypionate injection package insert.³² Although TRT may increase serum PSA levels in some men, it often remains within clinically acceptable ranges and has not been shown to increase the risk for PCa. A recent observation from 3 registries of more than 1,000 hypogonadal men receiving TRT for up to 17 years concluded that TRT does not increase the risk for PCa.³³

Prostate cancer encompasses a heterogeneous collection of androgen-dependent and independent cells. Androgens have been known to play an important role in PCa biology, but this relationship is more complex than the traditional view that androgens stimulate PCa growth. More than 7 decades ago, Huggins and colleagues showed that disseminated PCa was inhibited by eliminating androgens by castration and activated by androgen injections.³⁴ Recently, the androgen hypothesis and the relationship of testosterone to PCa has been more clearly defined. Although it has been established that effective suppression of serum T levels with surgical or chemical castration remains an essential strategy in the management of advanced PCa, the assertion that testosterone causes growth of PCa has been challenged.^35,36

Recent studies have shown that there may be a more complex relationship between serum T and PCa risk than was previously established.³⁷ Although PCa cells have been shown to become androgen-independent as they progress into the castrate-resistant phase,⁹ several studies have indicated that low-serum T is associated with greater PCa risk and more worrisome features of PCa.^38,39 Hence, a saturation model has been proposed: Changes in serum T concentrations below the point of maximal androgen-androgen receptor (AR) binding will elicit substantial changes in PCa growth, as seen with castration or with serum T administration to castrated men.⁴⁰ However, once maximal androgen-AR binding is reached, the presence of additional androgen produces little further effect, suggesting that there is a limit to the ability of androgens to stimulate growth of PCa.⁴⁰

A meta-analysis of 45 articles studying the relationship between serum T and PCa risk has reported conflicting results.⁴ Eugonadal testosterone levels, whether physiologically or pharmacologically replaced, do not seem to promote PCa growth. It is unclear whether the timing of sex hormone exposure affects PCa or whether the cancer may influence blood levels of sex hormones. Since 2004, there have been case series totaling almost 150 men treated with prostatectomy, brachytherapy, or external beam radiation who have been safely treated with TRT.^6-9 These case studies suggest that after a thorough discussion of risks and benefits, TRT may be safer than previously thought for men who have been successfully treated for PCa, are deemed low risk for recurrence, and are monitored closely. However, no randomized controlled trials are available, and published guidelines recommend against starting TRT in patients with a history of breast or PCa.¹

Limitations

This study has limitations. The sample size is small and, therefore, it may not have had enough power to show differences in prevalence by subgroups. In addition, the population may not be representative of all male veterans who seek care in the VA or of men in other health care settings, because this was a convenience sample of VA patients who received most of their care in the VA. However, the prevalence of hypogonadism, in this outpatient population is very similar to that found among men seen in primary care clinics.¹⁴ Finally, because pretreatment serum T levels were lacking, the authors were unable to assess whether hypogonadism was present before surgery or radiation therapy, and unable to determine whether treatment had any effect on serum T levels.

The study has several strengths. First, to the authors’ knowledge, this is the first study to assess the prevalence of hypogonadism after patients with low-risk PCa have received treatment with curative intent. Second, the authors assessed hypogonadism in every patient by measuring serum T levels in the early morning when levels are known to be at their highest. Third, differentiating primary and secondary hypogonadism helped provide insight into the possible etiology of the low serum T levels. Fourth, this study was performed at a single institution that uses electronic medical records, with almost complete data on patient demographics, PCa treatment, and receipt of TRT or androgen deprivation therapy. Fifth, because this study had the participation of endocrinologists and urologists, the study design helped answer questions pertinent to both medical and surgical specialties.

Conclusion

As life expectancy increases, many survivors of treated PCa present with symptoms of hypogonadism associated with low serum T levels and request TRT. The prevalence of hypogonadism before or after treatment for PCa in this population is not known. This study suggests that many low-risk PCa survivors have hypogonadism. Because hypogonadism negatively impacts quality of life by increasing the risk for sexual dysfunction, mood disturbances, bone fracture, development of metabolic syndrome, frailty, and decline in the feeling of general well-being and may have significant deleterious effects on other body systems, consideration for treatment is warranted.

Patients with PCa may be untreated because the safety of TRT in this population is unknown. Clinical practice guidelines caution against using TRT in this population, and recent literature questions the benefits and risks associated with the long-term safety of TRT, particularly in older men.^28,41 Although further studies are necessary before definitive conclusions can be drawn, increasing evidence, albeit small, suggests that TRT can be cautiously considered in selected hypogonadal men treated with curative intent for PCa and without evidence of active disease. However, because obese patients are at higher risk for aggressive PCa and mortality, it is unclear whether obese PCa survivors have an additional risk in regard to TRT.^42,43 To help clinicians provide information and care for their patients, appropriately designed prospective randomized studies using a collaborative approach and long-term follow-up are urgently needed to determine the safety of TRT in hypogonadal men with a history of low-risk PCa.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the Edward Hines Jr. VA Hospital. Dr. Silva’s work was carried out while she was a postdoctoral fellow supported by the VA Office of Academic Affiliations (TPP 42-013). The authors thank Ahmer V. Farooq, DO, Department of Surgery, Division of Urology, for his help in planning the design of the study. Dr. Agrawal affirms that all coauthors contributed significantly to the work and had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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