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

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


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:

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

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Keywords: Prostate cancer, estrogen, testosterone, LHRH agonist, PATCH trial, androgen deprivation therapy (ADT)