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

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

Abstract:

Androgen deprivation therapy (ADT) resulting in testosterone suppression is central to the management of prostate cancer (PC). As PC incidence increases, ADT is more frequently prescribed, and for longer periods of time as survival improves. Initial approaches to ADT included orchiectomy or oral estrogen (diethylstilbestrol [DES]). DES reduces PC-specific mortality, but causes substantial cardiovascular (CV) toxicity. Currently, luteinizing hormone-releasing hormone agonists (LHRHa) are mainly used; they produce low levels of both testosterone and estrogen (as estrogen in men results from the aromatization of testosterone), and many toxicities including osteoporosis, fractures, hot flashes, erectile dysfunction, muscle weakness, increased risk for diabetes, changes in body composition, and CV toxicity. An alternative approach is parenteral estrogen, it suppresses testosterone, appears to mitigate the CV complications of oral estrogen by avoiding first-pass hepatic metabolism, and avoids complications caused by estrogen deprivation. Recent research on the toxicity of ADT and the rationale for revisiting parenteral estrogen is discussed.

Keywords: Prostate cancer, estrogen, testosterone, LHRH agonist, PATCH trial, androgen deprivation therapy (ADT)
Disclosure: Paul Abel, MB ChB, FRCS, and Ruth E Langley, MBBS, MRCP, are co-chief investigators of the PATCH trial, which is an academic study funded by Cancer Research UK sponsored by the MRC Clinical Trials Unit at UCL. Iain Phillips, MBBS, MRCP, Syed I A Shah, MBBS, and Trinh Duong, MSc, have no conflicts of interest to declare.
Received: January 23, 2014 Accepted March 10, 2014 Citation Oncology & Hematology Review, 2014;10(1):42–7
Correspondence: Ruth E Langley, MBBS, MRCP, Oncologist/Senior Scientist, MRC CTU at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK. E: ruth.langley@ucl.ac.uk

An erratum to this article can be found below.

This review describes strategies for producing castrate levels of testosterone in men with androgen-sensitive prostate cancer (PC) and the associated toxicities, with particular focus on the re-emergence and potential benefits of parenteral estrogen. In the developed world, PC is the commonest malignancy and second commonest cause of cancer death affecting men. Its incidence is increasing with an aging population and frequent prostate-specific antigen (PSA) testing.1 Almost 240,000 new cases of PC are diagnosed each year in the US and nearly 30,000 American men die from PC annually.2

Androgen Deprivation Therapy
The androgen dependence of PC has been recognized since the 1940s and remains a major component of the strategies used to manage PC today.

Surgical Orchiectomy and Oral Estrogen
Androgen deprivation therapy (ADT) was initially achieved by surgical orchiectomy, as the testes produce nearly 95 % of circulating androgens; the remaining 5 % is produced by the adrenal glands.3 As surgical castration is invasive and can cause significant psychological trauma it became less common following the introduction of medical (also called chemical) ADT. Diethylstilbestrol (DES), a synthetic oral estrogen, was the first pharmacological agent used as ADT for PC. The primary mechanism of action of DES involves a negative feedback loop affecting the hypothalamic–pituitary–testicular axis.4,5 The pulsatile secretion of hypothalamic luteinizing hormone-releasing hormone (LHRH) stimulates the release of follicle stimulating hormone (FSH) and LH from the anterior pituitary, which then stimulates testicular Leydig cells to produce testosterone. DES remained an effective and low-cost option for ADT from the 1950s up to the 1980s, but its use was discontinued following findings of adverse cardiovascular system (CVS) outcomes from the Veterans Administrative Cooperative Urological Research Group (VACURG) trials. Initiated in the early 1960s, this series of randomized clinical trials compared DES with orchiectomy, placebo, DES plus orchiectomy, and placebo plus orchiectomy. Although DES improved PC outcomes, the DES groups were shown to have increased CVS toxicity (36 % increase in noncancer- related deaths mostly CVS) with the highest risk in the first year of starting therapy.6

Luteinizing Hormone-releasing Hormone Agonists and Anti-androgens
Luteinizing hormone-releasing hormone agonists (LHRHa), also called gonadotrophin-releasing hormone analogs (GnRHa), were introduced in the 1980s for ADT. Unlike the pulsatile action of hypothalamic LHRH, synthetic LHRHa continually stimulate pituitary receptors, causing downregulation of the receptors and central hypogonadism. Initial exposure to LHRHa leads to a surge in androgen production, termed ‘testosterone flare’, which in some patients can exacerbate symptoms, such as bone pain from skeletal metastasis, increase the risk for aggravating nerve compression (e.g. spinal cord compression), or worsen urinary outflow obstruction. Short courses of anti-androgens that compete with androgens for receptor binding are given to avoid these complications.7,8

ADT with LHRHa is a mainstay of contemporary PC treatment. It is used alone to control PC or in the neoadjuvant/adjuvant setting with radical surgery or radiotherapy. It is also used for advanced PC, which can be incurable at presentation or as a result of disease recurrence following the failure of radical therapy. Estimates suggest that more than half of the men diagnosed with PC will be treated with ADT at some point during the course of their disease, remaining on it for a decade or even more.9

Novel Agents
Degarelix, an LHRH antagonist, is another form of ADT that binds competitively to pituitary LHRH receptors.10 It reduces LH and testosterone levels without causing testosterone flare. Other newer agents include abiraterone (an inhibitor of androgen biosynthesis) and enzalutamide (an inhibitor of nuclear translocation of the androgen receptor) that are currently reserved for use in castration-resistant PC, when the cancer no longer responds to ADT despite castrate levels of testosterone.3,7

Toxicities of Androgen Deprivation Therapy
In the last decade there has been a growing recognition of the need to understand the nature and impact of the toxicities from contemporary ADT with LHRHa. This becomes more salient when considering the everincreasing and widespread use of LHRHa, as the incidence of PC and overall survival with PC increases. LHRHa toxicity has a large impact on the health economy and overall cost of treating PC. LHRHa are associated with multiple adverse effects (see Figure 1) including osteoporosis and associated fractures, hot flashes, imbalances in lipid and glucose homeostasis, diminished libido, erectile dysfunction, depression, cognitive decline, loss of musculature, adiposity, anemia, increased susceptibility to CVS events, and decreased physical strength.11–19 Some toxicities of LHRHa can be attributed to low testosterone levels. These include loss of libido, erectile dysfunction, and low muscle mass. Others, such as osteoporosis, fracture risk, hot flashes, and dyslipidemia are thought to be due to the accompanying estrogen deficiency (80 % reduction in estrogen levels by LHRHa), as testosterone is required for synthesis of estrogen through aromatization.19–21 Collectively these toxicities are labeled as ‘castration syndrome’ or ‘androgen deprivation syndrome,’ and greatly impact upon quality of life (QoL). ADT also affects the intimate partners of those receiving ADT and studies suggest that partners often experience more distress than the patients themselves.22

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)