Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer

Oncology & Hematology Review, 2014;10(1):42–7

A recent study in healthy individuals without PC has attempted to identify which short-term metabolic effects of ADT are related to testosterone insufficiency and which are related to estrogen insufficiency.23 The study enrolled 400 patients, divided into two equal cohorts (198 patients in cohort 1; 202 patients in cohort 2). Patients in both cohorts received a LHRHa (goserelin) and were then randomized to varying levels of testosterone replacement (0, 1.25 g, 2.5g, 5 g, and 10 g of testosterone gel in 24 hours). The second cohort additionally received anastrazole (which prevents the aromatization of testosterone to estrogen). Thus, in cohort 1 the varying levels of testosterone replacement were physiologically converted into estrogen, whereas in cohort 2 estrogen levels were suppressed with anastrazole, irrespective of the level of testosterone replacement. The study showed that testosterone deficiency led to a decrease in lean body mass, muscle mass, and muscle strength. The dose of testosterone to avoid these adverse effects was wide ranging among both cohorts. Estrogen deficiency seen in cohort 2 accounted for increases in percentage body fat. Increased deposition of body fat is thought to be associated with decreased insulin sensitivity and an increased risk for diabetes.24 Both groups showed a decrease in sexual desire and function.

Bone Weakness
There is extensive evidence showing the detrimental effect of ADT with LHRHa on bone health.25 LHRHa decreases bone mineral density and promotes bone turnover26 and has been shown to increase fracture risk by two to four times with the resulting fractures associated with increased mortality and decreased QoL.27 A recent study utilizing the Surveillance, Epidemiology and End Results (SEER) – Medicare database of 76,000 men with localized PC showed that men with a high baseline risk for skeletal complications had a higher probability of receiving ADT than those with a low risk (52.1 % versus 38.2 %; p<0.001). Those more likely to receive ADT in this study were older men, with higher PSAs, higher Gleason grade, more advanced staged tumors, multiple comorbidities, and those who received bisphosphonates and radiotherapy. Higher fracture risk was associated with those who were treated with ADT as a single modality compared with those who received it concomitantly with radiotherapy, or after a radical prostatectomy. The increased likelihood of receiving ADT with a higher baseline fracture risk correlates with the fact that men identified in the cohort above would be less likely to receive treatment without ADT such as a prostatectomy and were more likely to have treatment initiated because of the higherrisk nature of the cancer. More than 58 % of men with a high risk of developing a fracture and 38 % of men with a low risk had at least one fracture after ADT during the 12-year follow-up and following a fracture, the mortality risk increased by 40 %.28

Vasomotor Symptoms and Sleep Disturbance
Vasomotor symptoms, such as hot flashes and night sweats, are common, affecting almost four out of every five patients receiving ADT. They are thought to be caused by changes in sex hormone levels (particularly estrogen), which disrupt the negative feedback of hypothalamic noradrenaline production leading to a resetting of the thalamic thermoregulatory mechanism.29–32 Hot flashes appear shortly after LHRHa administration, do not appear to subside with the end of treatment, and are associated with substantial psychological distress.21 Disturbance of sleep is also a common occurrence in patients treated for PC. A recent questionnaire-based study showed higher insomnia scores in patients receiving ADT with radiotherapy compared with radiotherapy alone. Hot flashes and night sweats appear to contribute to this sleep disturbance.29,33

Cognitive Impairment
A number of studies using neuropsychological assessments have linked ADT with LHRHa to cognitive impairment.34,35 A meta-analysis by Nelson et al. including nine studies of ADT in PC showed that between 47 and 69 % of men showed decline in at least one cognitive parameter following ADT for 6 to 9 months. The most commonly affected domains included visuospatial ability and executive function.36 Some studies, however, have not shown this effect, Alibhai et al. found no consistent evidence of cognitive decline in ADT users (type of ADT not specified) over a period of 1 year.37 Functional imaging studies are being used to investigate this further. Reduced activation in the parieto-occipital lobe on a mental rotation task (a test of visuospatial memory) with ADT was seen with functional magnetic resonance imaging (fMRI).38 A similar study showed reduced pre-frontal activation on fMRI, but no cognitive deficit,39 and a further study showed decreased cortical gray matter volume in ADT users.40

Sexual Inactivity and Spousal Relations
Sexual activity has been shown to decline considerably in PC patients on ADT with up to 85 % of the patients reporting sexual side effects.12,31,41,42 This sexual inactivity is a consequence of diminished libido, physical changes (decreased strength, adiposity, genital shrinkage), and erectile dysfunction.12,43 Loss of masculine traits in PC patients negatively impacts their psychosocial and sexual life.42 In one small study (n=15), nearly half the men on ADT experienced an erosion of spousal relations.44 This may be related to a degree of estrogen deficiency, as estrogen replacement appears to alleviate some of these symptoms.45

Changes in Body Composition and Physical Function
Body composition changes considerably in men undergoing ADT with LHRHa therapy, with more extensive changes seen with a longer duration of treatment. These changes include increased fat mass (adiposity), loss of lean musculature (sarcopenia), and weight gain.11,46 Smith et al. prospectively measured lean body mass at three time points following the start of ADT and compared it with baseline measurements. A significant decline in mean lean body mass was seen at 1 year (1 % decrease; p<0.01), 2 years (2.1 % decrease; p<0.001), and 3 years (2.4 % decrease; p<0.001).47 Fatigue affects nearly half of the patients on ADT and decreased muscle mass and increased adiposity may be important factors contributing to this.18 Endurance, upper extremity strength, and physical activity are affected within 3 months of starting ADT.48

Acute Kidney Injury
A recent observational study of patients with newly diagnosed nonmetastatic PC has highlighted a potentially serious complication of ADT. Out of the 10,250 men studies, 232 new cases of acute kidney injury were identified. ADT included LHRHa, oral anti-androgens, combined androgen blockade (LHRHa plus anti-androgens), orchiectomy, estrogens, and combinations of these. Current ADT use was associated with an increased risk for acute kidney injury compared with no ADT use (odds ratio [OR] 2.48, 95 % confidence interval [CI] 1.61–3.82]).49

Metabolic Disturbances and Cardiovascular Risks
The relationship between CVS risk and LHRHa therapy appears complex. Treatment with LHRHa has been linked to hyperglycemia, insulin resistance, dyslipidemia, and the development of the metabolic syndrome suggesting an increased risk for diabetes and CVS disease in these patients.11,32 Observational data from Medicare databases suggest that men receiving ADT have an increased risk for coronary artery disease (hazard ratio [HR] 1.16, 95 % CI 1.10–1.21, p<0.001), myocardial infarction (HR 1.11, 95 % CI 1.01–1.21; p=0.03), and sudden death (HR 1.16, 95 % CI 1.05–1.27; p=0.004).50 In another cross-sectional study, the occurrence of type 2 diabetes and obesity was significantly greater (p<0.05) in patients receiving ADT (mean time of 15.37±2.48 months) compared with eugonadal men. Randomized data, however, have not supported these associations, for example, in a trial of 945 men, comparing prostate radiotherapy with LHRHa versus radiotherapy alone, after 9 years CV events occurred in 8.4 % in the concomitant treatment group versus 11.4 % in those receiving radiotherapy alone (p=0.17).51 Interestingly, in a recent study, a significantly higher risk for CVS events (p<0.002) was seen with LHRHa alone compared with LHRHa and Degarelix in men who had pre-existing CVS disease.52

Some of the toxicities associated with ADT are not directly attributable to either estrogen or testosterone deficiency alone. For example, gynecomastia is thought to result from a change in the ratio of estrogen to testosterone. Rates of gynecomastia differ between various forms of ADT, the highest rates are seen with estrogen (more than 50 % men affected). Rates are similar with surgical orchiectomy and LHRHa (10–15 %).11

Parenteral Estrogen as Androgen Deprivation Therapy
The route of administration of estrogen is thought to explain the CVS toxicity seen with the oral preparations. When estrogen is taken orally, enterohepatic first pass exposes the liver to high levels of estrogen resulting in upregulation of pro-coagulant proteins (increased clotting factors I, II, VII, IX, and X) and downregulation of anti-coagulant factors (decreased plasminogen activator and anti-thrombin III). This estrogen-induced hypercoaguable state in turn increases the risk for thromboembolic and CVS events.53

Avoiding this first-pass effect through parenteral estrogen administration (intramuscular, intravenous, subcutaneous, topical) for PC treatment is a logical deduction. This was first tested in a series of studies conducted by the Scandinavian Prostate Cancer Group (SPCG) using polyestradiol phosphate (PEP) administered intramuscularly. In the earlier SPCG studies a monthly PEP dose of 160 mg was given. Rates of CVS morbidity and mortality were not different from surgical orchiectomy or LHRHa but castrate levels of testosterone were not achieved. Reduction in serum testosterone to castrate levels was achieved in subsequent studies at a dose of 240 mg PEP given monthly. No added CVS toxicity was observed with this higher dose. The largest SPCG trial randomized PC patients (n=910) to receive either combined androgen blockade (LHRHa/orchiectomy plus anti-androgen) or intramuscular estrogen (PEP 240 mg). No significant difference was observed between the groups in terms of progression-free survival, overall, or disease-specific survival, and CVS mortality.54

References:
  1. Siegel R, Naishadham D, Jemal A, Cancer statistics, 2012, CA Cancer J Clin, 2012;62:10–29.
  2. Silberstein J, Pal SK, Lewis B, Sartor O, Current clinical challenges in prostate cancer, Transl Androl Urol, 2013;2:122–36.
  3. Rehman Y, Rosenberg JE, Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer, Drug Des Devel Ther, 2012;6:13–8.
  4. Turo R, Smolski M, Esler R, et al., Diethylstilboestrol for the treatment of prostate cancer: past, present and future, Scand J Urol, 2013;32(October):1–11.
  5. Bosset P-O, Albiges L, Seisen T, et al., Current role of diethylstilbestrol in the management of advanced prostate cancer, BJU Int, 2012;110(11 Pt C):E826–9.
  6. Byar DP, The Veterans Administration Cooperative Urological Research Groups Studies of cancer of the prostate, Cancer, 1973;32:1126–30.
  7. Thomas BC, Neal DE, Androgen deprivation treatment in prostate cancer, BMJ, 2013;346:e8555.
  8. Gomella LG, Effective testosterone suppression for prostate cancer: is there a best castration therapy? Rev Urol, 2009;11:52–60.
  9. Bourke L, Kirkbride P, Hooper R, et al., Endocrine therapy in prostate cancer: time for reappraisal of risks, benefits and costeffectiveness?, Br J Cancer, 2013;108:9–13.
  10. Oudard S, Progress in emerging therapies for advanced prostate cancer, Cancer Treat Rev, 2013;39:275–89.
  11. Sharifi N, Gulley JL, Dahut WL, An update on androgen deprivation therapy for prostate cancer, Endocr Relat Cancer, 2010;17:R305–15.
  12. Mazzola CR, Mulhall JP, Impact of androgen deprivation therapy on sexual function, Asian J Androl, 2012;14:198–203.
  13. Ockrim JL, Abel PD, Long term androgen deprivation therapy in prostate cancer, BMJ, 2008;337:a1361.
  14. Beebe-Dimmer JL, Freedland SJ, Androgen deprivation therapy: further confirmation of known harms, BJU Int, 2013;111:690–1.
  15. Walker LM, Tran S, Robinson JW, Luteinizing hormone-releasing hormone agonists: a quick reference for prevalence rates of potential adverse effects, Clin Genitourin Cancer, 2013;11:375–84.
  16. Trost LW, Serefoglu E, Gokce A, et al., Androgen deprivation therapy impact on quality of life and cardiovascularhealth, monitoring therapeutic replacement, J Sex Med, 2013;10(Suppl. 1):84–101.
  17. Saylor PJ, Smith MR, Adverse effects of androgen deprivation therapy: defining the problem and promoting health among men with prostate cancer, J Natl Compr Canc Netw, 2010;8:211–23.
  18. Ahmadi H, Daneshmand S, Androgen deprivation therapy: evidence-based management of side effects, BJU Int, 2013;111:543–8.
  19. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. The Leuprolide Study Group, N Engl J Med, 1984;311:1281–6.
  20. Garnick MB, Leuprolide versus diethylstilbestrol for previously untreated stage D2 prostate cancer. Results of a prospectively randomized trial, Urology, 1986;27(Suppl. 1):21–8.
  21. Freedland SJ, Eastham J, Shore N, Androgen deprivation therapy and estrogen deficiency induced adverse effects in the treatment of prostate cancer, Prostate Cancer Prostatic Dis, 2009;12:333–8.
  22. Elliott S, Latini DM, Walker LM, et al., Androgen deprivation therapy for prostate cancer: recommendations to improve patient and partner quality of life, J Sex Med, 2010;7:2996–3010.
  23. Finkelstein JS, Lee H, Burnett-Bowie S-AM, et al., Gonadal steroids and body composition, strength, and sexual function in men, N Engl J Med, 2013;369:1011–22.
  24. Raji A, Seely EW, Arky RA, Simonson DC, Body fat distribution and insulin resistance in healthy Asian Indians and Caucasians, J Clin Endocrinol Metab, 2001;86:5366–71.
  25. Smith MR, Androgen deprivation therapy for prostate cancer: new concepts and concerns, Curr Opin Endocrinol Diabetes Obes, 2007;14:247–54.
  26. Morrison BF, Burrowes IE, Aiken WD, et al., Bone mineral density in Jamaican men on androgen deprivation therapy for prostate cancer, Infect Agent Cancer, 2011;6(Suppl. 2):S7.
  27. Greenspan SL, Wagner J, Nelson JB, et al., Vertebral fractures and trabecular microstructure in men with prostate cancer on androgen deprivation therapy, J Bone Miner Res, 2013;28:325–32.
  28. Shao Y-H, Moore DF, Shih W, et al., Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications, BJU Int, 2013;111:745–52.
  29. Nishimura K, Yamaguchi Y, Yamanaka M, et al., Climacteric-like disorders in prostate cancer patients treated with LHRH agonists, Arch Androl, 2005;51:41–8.
  30. Yamaguchi N, Okajima Y, Fujii T, et al., The efficacy of nonestrogenic therapy to hot flashes in cancer patients under hormone manipulation therapy: a systematic review and metaanalysis, J Cancer Res Clin Oncol, 2013;139:1701–7.
  31. Grunfeld EA, Halliday A, Martin P, Drudge-Coates L, Andropause syndrome in men treated for metastatic prostate cancer: a qualitative study of the impact of symptoms, Cancer Nurs, 2002;35:63–9.
  32. Bagrodia A, Diblasio CJ, Wake RW, Derweesh IH, Adverse effects of androgen deprivation therapy in prostate cancer: Current management issues, Indian J Urol, 2009;25:169–76.
  33. Savard J, Hervouet S, Ivers H, Prostate cancer treatments and their side effects are associated with increased insomnia, Psychooncology, 2013;22:1381–8.
  34. Janowsky JS, The role of androgens in cognition and brain aging in men, Neuroscience, 2006;138:1015–20.
  35. Jamadar RJ, Winters MJ, Maki PM, Cognitive changes associated with ADT: a review of the literature, Asian J Androl, 2012;14:232–8.
  36. Nelson CJ, Lee JS, Gamboa MC, Roth AJ, Cognitive effects of hormone therapy in men with prostate cancer: a review, Cancer, 2008;113:1097–106.
  37. Alibhai SMH, Breunis H, Timilshina N, et al., Impact of androgen-deprivation therapy on cognitive function in men with nonmetastatic prostate cancer, J Clin Oncol, 2010;28:5030–7.
  38. Cherrier MM, Borghesani PR, Shelton AL, Higano CS, Changes in neuronal activation patterns in response to androgen deprivation therapy: a pilot study, BMC Cancer, 2010;10:1.
  39. Chao HH, Uchio E, Zhang S, et al., Effects of androgen deprivation on brain function in prostate cancer patients – a prospective observational cohort analysis, BMC Cancer, 2012;12:371.
  40. Chao HH, Hu S, Ide JS, et al., Effects of androgen deprivation on cerebral morphometry in prostate cancer patients – an exploratory study, PLoS One, 2013;8:e72032.
  41. Corona G, Gacci M, Baldi E, et al., Androgen deprivation therapy in prostate cancer: focusing on sexual side effects, J Sex Med, 2012;9:887–902.
  42. Casey RG, Corcoran NM, Goldenberg SL, Quality of life issues in men undergoing androgen deprivation therapy: a review, Asian J Androl, 2012;14:226–31.
  43. Higano CS, Sexuality and intimacy after definitive treatment and subsequent androgen deprivation therapy for prostate cancer, J Clin Oncol, 2012;30:3720–5.
  44. Navon L, Morag A, Advanced prostate cancer patients’ relationships with their spouses following hormonal therapy, Eur J Oncol Nurs, 2003;7:73–80; discussion 81–2.
  45. Wibowo E, Wassersug R, Warkentin K, et al., Impact of androgen deprivation therapy on sexual function: a response, Asian J Androl, 2012;14:793–4.
  46. Cleffi S, Neto AS, Reis LO, et al., Androgen deprivation therapy and morbid obesity: do they share cardiovascular risk through metabolic syndrome?, Actas Urol Españolas, 2011;35:259–65.
  47. Smith MR, Saad F, Egerdie B, et al., Sarcopenia during androgen-deprivation therapy for prostate cancer, J Clin Oncol, 2012;30:3271–6.
  48. Alibhai SMH, Breunis H, Timilshina N, et al., Impact of androgendeprivation therapy on physical function and quality of life in men with nonmetastatic prostate cancer, J Clin Oncol, 2010;28:5038–45.
  49. Lapi F, Azoulay L, Niazi MT, et al., Androgen deprivation therapy and risk of acute kidney injury in patients with prostate cancer, JAMA, 2013;310:289–96.
  50. Keating NL, O’Malley AJ, Smith MR, Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer, J Clin Oncol, 2006;24:4448–56.
  51. Efstathiou JA, Bae K, Shipley WU, et al., Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31, J Clin Oncol, 2009;27:92–9.
  52. Albertsen PC, Klotz L, Tombal B, et al., Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist, Eur Urol, 2014;65:565–73.
  53. Von Schoultz B, Carlström K, Collste L, et al., Estrogen therapy and liver function—metabolic effects of oral and parenteral administration, Prostate, 1989;14:389–95.
  54. Hedlund PO, Damber J-E, Hagerman I, et al., Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5, Scand J Urol Nephrol, 2008;42:220–9.
  55. Wassersug RJ, Extending the case for oestradiol in androgensensitive prostate cancer, Lancet Oncol, 2013;14:e252–3.
  56. Ockrim JL, Lalani E-N, Kakkar AK, Abel PD, Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism, J Urol, 2005;174:527–33; discussion 532–3.
  57. Beer TM, Bland LB, Bussiere JR, et al., Testosterone loss and estradiol administration modify memory in men, J Urol, 2006;175:130–5.
  58. Langley RE, Cafferty FH, Alhasso AA, et al., Cardiovascular outcomes in patients with locally advancedand metastatic prostate cancer treated with luteinising hormone-releasinghormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09), Lancet Oncol, 2013;14:306–16.
  59. Frenkel B, Hong A, Baniwal SK, et al., Regulation of adult bone turnover by sex steroids, J Cell Physiol, 2010;224:305–10.
  60. Ockrim JL, Lalani EN, Banks LM, et al., Transdermal estradiol improves bone density when used as single agent therapy for prostate cancer, J Urol, 2004;172(6 Pt 1):2203–7.
  61. Genazzani AR, Pluchino N, Luisi S, Luisi M, Estrogen, cognition and female ageing, Hum Reprod Update, 2007;13:175–87.
  62. LeBlanc ES, Janowsky J, Chan BK, Nelson HD, Hormone replacement therapy and cognition: systematic review and metaanalysis, JAMA, 2001;285:1489–99.
  63. Parker WH, Broder MS, Chang E, et al., Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study, Obstet Gynecol, 2009;113:1027–37.
  64. Yang X-P, Reckelhoff J, Estrogen, hormone replacement therapy and cardiovascular disease, Curr Opin Nephrol Hypertens, 2011;20:133–8.
  65. Bracamonte MP, Miller VM, Vascular effects of estrogens: arterial protection versus venous thrombotic risk, Trends Endocrinol Metab, 2001;12:204–9.
  66. Bland LB, Garzotto M, DeLoughery TG, et al., Phase II study of transdermal estradiol in androgen-independent prostate carcinoma, Cancer, 2005;103:717–23.
  67. Phillips JL, Wassersug RJ, McLeod DL, Systemic bias in the medical literature on androgen deprivation therapy and its implication to clinical practice, Int J Clin Pract, 2012;66:1189–96.
  68. Tran S, Walker LM, Wassersug RJ, et al., What do Canadian uro-oncologists believe patients should know about androgen deprivation therapy? J Oncol Pharm Pract, 2013 [Epub ahead of print].
  69. Cheung AS, Pattison D, Bretherton I, et al., Cardiovascular risk and bone loss in men undergoing androgen deprivation therapy for non-metastatic prostate cancer: implementation of standardized management guidelines, Andrology, 2013;1:583–9.
Keywords: Prostate cancer, estrogen, testosterone, LHRH agonist, PATCH trial, androgen deprivation therapy (ADT)