Neal Shore, MD,
Medical Director of the Carolina Urologic Research Center Myrtle Beach, South Carolina
and Stephen Freedland, MD
Urologist, Duke Prostate Center at Duke University
Durham, North Carolina
Edited from PCRI Insights May, 2009 v 12.2
Testosterone plays an integral role in the progression of prostate cancer1; consequently, androgen deprivation therapy (ADT) has long been recognized as a treatment option for patients whose disease has metastasized. Recently, ADT has been used more frequently in patients without radiographically measurable metastatic disease, such as in patients with recurring, elevated PSA levels after a locally curative procedure as well as in combination with radiation treatment.2
Although effective in lowering PSA levels and potentially improving prostate cancer control, ADT is associated with significant side effects. In a recent internet survey of 153 men undergoing ADT (ADT Habits and Practices Survey3, March 2007) 137 men (90%) reported at least 1 side effect (Tables 1 and 2). Of these 137 men, 57 (or 41%) reported being very concerned about ADT side effects.
Patients and clinicians may not realize that ADT side effects are caused not only by the decrease of testosterone but also by the relative increase of estrogen related to testerone.4 Estrogen is typically thought of as a female hormone, but because testosterone is converted to estradiol (Figure 1),5 it also plays a significant physiological role in men, and its reduction will contribute to multiple ADT side effects. Side effects associated with estrogen deficiency include increased fracture risk, hot flashes, gynecomastia (benign enlargement of the breasts), and unfavorable lipid changes.5 Notably, few patients from the ADT Habits and Practices Survey who reported experiencing side effects acknowledged receiving any corrective treatment for these complaints (Figure 2). An understanding of the mechanism of action regarding estrogen deficiency and its associated side effects is an important initial step toward increasing awareness of these side effects and providing subsequent corrective therapies. Thus, the mechanisms of action of the most common estrogen-related ADT side effects are reviewed in the following paragraphs.
Bone Loss: Potential for Increased Fracture Risk
Bone remodeling is the continuous process of bone removal and bone formation by cells known as osteoclasts and osteoblasts, respectively.6 Specifically, estrogen deficiency lengthens the life span of the osteoclasts and shortens the life span of the osteoblasts leading to more bone removal than formation6 and a subsequent loss of bone mineral density. It is this loss of bone mineral density that increases the risk of fractures. During the normal aging process, there exists a gradual reduction in testosterone7, and many men experience an age-related decrease in bone mineral density.8 However, the decrease in testosterone from ADT leading to estrogen deficiency is rapid and sustained and therefore distinguishes ADT-induced bone loss from that associated with normal aging.
Several recent studies have established an association between ADT and an increased risk of fracture. One U.S. study examined the risk of fracture associated with ADT in 50,613 men with prostate cancer, 15,741 (or 31.1%) of whom received ADT).9 A significantly greater number of patients who received ADT had a fracture (19.4%) compared with those who were not receiving ADT (12.6%). ADT was also associated with a significantly higher incidence of hospitalization due to fracture (5.2% vs 2.4%). In fact, the risk of fracture increased relative to the number of doses of gonadotropin-releasing hormone (GnRH) agonist administered compared with untreated patients over a 12-month period, from a 7% higher relative risk for patients who received up to four doses to a 45% higher relative risk for those who received more than nine doses.
A similar analysis performed in Denmark compared data from 15,716 men with fractures with 47,149 matched controls.10 Overall, 2.5% of patients in the fracture group were previously diagnosed with prostate cancer, 20% of whom received ADT. In the control group, 1.3% had been diagnosed with prostate cancer, and 15% of those patients received ADT. Based on these data, men with prostate cancer who had received ADT faced an overall risk of fracture that was nearly double that of their counterparts who also had prostate cancer but did not receive ADT (odds ratio, 1.7).
Increased fracture risk is an important concern, because skeletal fracture associated with ADT has been correlated with decreased survival. In an analysis of 195 men receiving ADT (24 of whom reported skeletal fracture), the median overall survival was 121 months for those with a history of fracture compared with 160 months for those without (P=0.04).11 Despite this risk, recent data suggest that only one-third of patients with ADT-treated prostate cancer received recommended management for increased fracture risk, including any of the following: diagnostic dual-energy x-ray absorptiometry (DEXA) scan, oral or intravenous bisphosphonate, calcitonin, calcium, and/or vitamin D.12
Hot flashes have been defined as “a sudden rush of warmth in the face, neck, upper chest, and back, which is sometimes associated with facial flushing and/or nausea, and which lasts for a few seconds to an hour.”5 Although the biology of ADT-related hot flashes is not fully understood, it has been postulated that they are related to estrogen deficiency. The decline in estrogen may affect the hypothalamus and cause an increase in norepinephrine and serotonin release, which ultimately triggers the heat loss mechanisms that lead to hot flash symptoms.13
Hot flashes are among the most common side effects induced by estrogen deficiency, with an estimated incidence of 55% to 80% in men receiving ADT.5 Not only is the initial incidence rate high, but the occurrence of hot flashes appears to continue over time. In one study of 63 patients receiving ADT, nearly 70% reported hot flashes during treatment, 48% reported them five years after treatment, and 40% reported them eight years after treatment.14 In fact, although only three patients remained in the study 11 years after treatment, two of them still reported experiencing hot flashes.14
The significance of hot flashes is not only physical, but may be psychological as well. A recent study examined the relationship between hot flashes and cancer distress during the first three months of ADT and found that hot flashes had a significant influence on patients’ psychological well-being.15 Specifically, men who did not have hot flashes had a significant decrease in total cancer-related stress over the three months (P=0.01), whereas those with hot flashes experienced no change.15 Furthermore, after accounting for age and baseline levels of distress, the hot flash score (frequency × severity) was a significant contributor to total cancer-related distress as well as feelings of intrusion (e.g. unwanted or inescapable thoughts regarding their cancer) (P≤0.02).15
Gynecomastia, the benign proliferation of breast tissue in men, is frequently associated with pain. It is an estrogen-related side effect of ADT and is thought to result from an increased estrogen-to-testosterone ratio.16 The incidence of gynecomastia varies widely depending on the selected method of ADT. For example, although the use of GnRH agonists reduces gonadal testosterone, androgens are still produced by the adrenal gland and converted to estrogens, thereby resulting in an increased estrogen-to-androgen ratio.16 However, when using non-steroidal anti-androgens (e.g. flutamide, bicalutamide) as monotherapy, testosterone levels are not reduced, but rather, the effects of testosterone are inhibited in the body. This increases the amount of testosterone available for aromatization and conversion to estrogen, resulting in a dramatic increase in the estrogen-to-testosterone ratio.17
Despite the frequency of gynecomastia (reported by 66% of patients who experienced side effects in the ADT Habits and Practices Survey), few studies have examined the impact of this side effect on patients’ physical and psychological well-being. However, in the aforementioned survey, one-third of ADT patients who had experienced side effects viewed gynecomastia as a major problem. Furthermore, a follow-up telephone interview with 12 men from the survey demonstrated that gynecomastia can have both physical and psychological effects as evidenced by the following patient quotes:
• “It [the pain] can wake me up…two times a week”
• “It weighs on me a bit. You’re a man… I was concerned I would be more feminine.”
• “I associate breasts with a feminine look.”
Serum lipid changes as a consequence of estrogen deficiency predominantly result from estrogen–receptor-mediated changes in hepatic genes.18 In a recent study, men with prostate cancer receiving ADT for at least 12 months had significantly higher levels of total cholesterol and LDL cholesterol compared with age-matched healthy men (P≤ 0 . 0 4).19 Regarding specific changes within ADT patients, a one-year study of asymptomatic men with non-metastatic prostate cancer treated with GnRH agonists also showed adverse changes in serum lipid levels with an average increase in total cholesterol of 9.0% (P<0.001), an increase in LDL cholesterol of 7.3% (P=0.05), and an increase in triglycerides of 26.5% (P=0.01).20 However, there were also positive changes, such as an average increase in HDL cholesterol of 11.3% (P<0.001).20
Recent epidemiological data suggest that ADT, through the use of GnRH agonists, is associated with an increased risk of coronary heart disease, acute myocardial infarction, and sudden cardiac death.21 Although this may be related to testosterone-deficiency-induced side effects of ADT, such as increases in body weight and fat mass and decreases in lean body mass,22 it may also be due to the aforementioned lipid changes plus loss of the potential protective effects of estrogen. Some of these estrogenic protective effects include increases in vasodilation (widening of blood vessels), inhibition of response to vascular injury, and prevention of atherosclerosis.23
Although epidemiologic data suggest an increased risk of cardiovascular death associated with ADT, some clinical data suggest otherwise. For example, a recent randomized Phase 3 study found that long-term adjuvant treatment with GnRH agonists does not increase the risk of cardiovascular mortality in men with locally advanced prostate cancer.24 Clearly, the disparity between epidemiologic and clinical data regarding an increased risk of cardiovascular death warrants further study. However, it is established that ADT can negatively impact serum lipid levels, a known risk for cardiovascular disease.
Summary and Conclusions
The original indication for ADT was men with metastatic prostate cancer; however, ADT is being used more frequently for patients whose PSA levels have begun to rise despite prior localized treatment.5 Additionally, the use and length of time on ADT has increased due to earlier diagnoses and increased patient survival from prostate cancer.25 While patients and clinicians may be aware of the side effects of ADT induced by testosterone deficiency26, many are unaware that there are also side effects induced by estrogen deficiency, including increased fracture risk, hot flashes, gynecomastia, and adverse lipid changes (Table 3). While hot flashes and gynecomastia may be the most physically or psychologically distressing side effects for patients, increased fracture risk and adverse lipid changes have the greatest effect on morbidity and mortality. Unfortunately, as seen by the results of the ADT Habits and Practices Survey, patients are frequently not treated for these estrogen deficiency induced side effects.
Although treatment options exist to manage individual effects, there is currently no single treatment option that can manage multiple side effects. However, improved awareness is the first step toward managing these problems and providing clinicians with the background knowledge needed to keep their patients informed and openly communicating their needs. As noted by a patient from the ADT Habits and Practices Survey:
“He [my urologist] gave me peace of mind. He actually told me about the hot flashes and the swelling of the breasts. [He told me] the bones could become very soft…”
By discussing and treating side effects induced by estrogen deficiency, clinicians can reduce some patient concerns and help them with prevention of these complications and avoidance of a reduction in their quality of life.
1. Heinlein CA, Chang C: Androgen receptor in prostate cancer. Endocr Rev 25:276-308, 2004.
2. Isbarn H, Boccon-Gibod L, Carroll PR, et al: Androgen deprivation therapy for the treatment of prostate cancer: Consider both benefits and risks. Eur Urol 55:62-75, 2009.
3. ADT Habits and Practices Survey. Data on file: GTx, Inc.; 2007.
4. Guise TA, Oefelein MG, Eastham JA, et al: Estrogenic side effects of androgen deprivation therapy. Rev Urol 9:163-180, 2007.
5. Higano CS: Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology 61:32-38, 2003.
6. Manolagas SC: Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115-137, 2000.
7. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR: Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86:724-731, 2001.
8. Hannan MT, Felson DT, Anderson JJ: Bone mineral density in elderly men and women: results from the Framingham osteoporosis study. J Bone Miner Res 7:547-553, 1992.
9. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154-164, 2005.
10. Abrahamsen B, Nielsen MF, Eskildsen P, et al: Fracture risk in Danish men with prostate cancer: a nationwide register study. BJU Int 100:749-754, 2007.
11. Oefelein MG, Ricchiuti V, Conrad W, Resnick MI: Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 168:1005-1007, 2002.
12. Yee EF, White RE, Murata GH, Handanos C, Hoffman RM: Osteoporosis management in prostate cancer patients treated with androgen deprivation therapy. J Gen Intern Med 22:1305-1310, 2007.
13. Shanafelt TD, Barton DL, Adjei AA, Loprinzi CL: Pathophysiology and treatment of hot flashes. Mayo Clin Proc 77:1207-1218, 2002.
14. Karling P, Hammar M, Varenhorst E: Prevalence and duration of hot flushes after surgical or medical castration in men with prostatic carcinoma. J Urol 152:1170-1173, 1994.
15. Ulloa EW, Salup R, Patterson SG, Jacobsen PB: Relationship between hot flashes and distress in men receiving androgen deprivation therapy for prostate cancer. Psychooncology 2008.
16. Chen AC, Petrylak DP: Complications of androgen-deprivation therapy in men with prostate cancer. Curr Urol Rep 6:210-216, 2005.
17. Flaig TW, Glode LM: Management of the side effects of androgen deprivation therapy in men with prostate cancer. Expert Opin Pharmacother 9:2829-2841, 2008.
18. Mendelsohn ME, Karas RH: The protective effects of estrogen on the cardiovascular system. N Engl J Med 340:1801-1811, 1999.
19. Braga-Basaria M, Muller DC, Carducci MA, Dobs AS, Basaria S: Lipoprotein profile in men with prostate cancer undergoing androgen deprivation therapy. Int J Impot R es 18:494-498, 2006.
20. Smith MR, Finkelstein JS, McGovern FJ, et al: Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 87:599-603, 2002.
21. Keating NL, O’Malley AJ, Smith MR: Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24:4448-4456, 2006.
22. Smith MR, Lee H, McGovern F, et al: Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: differences from the classic metabolic syndrome. Cancer 112:2188-2194, 2008.
23. Mendelsohn ME: Protective effects of estrogen on the cardiovascular system. Am J Cardiol 89:12E-17E; discussion 17E-18E, 2002.
24. Efstathiou JA, Bae K, Shipley WU, et al: Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. J Clin Onc ol 27:92-99, 2009.
25. Eastham JA: Bone health in men receiving androgen deprivation therapy for prostate cancer. J Urol 177:17-24, 2007.
26. Guess B: Preventing and treating the side effects of testosterone depravation therapy in men with prostate cancer. PCRI Insights Vol. 10, No. 4, 10-16, 2007.