Topical estrogen therapy can be applied either as a transdermal patch, gel, or cream. It has potential advantages over other forms of parenteral estrogen administration, it can be conveniently self-administered by the patient, and readily discontinued if toxicities occur.55 In a small pilot study, Ockrim et al. used transdermal estrogen (estradiol skin patches) in 20 hormone-naïve patients with advanced PC. Castrate levels of testosterone were achieved within 3 weeks of treatment initiation and effective tumor response was obtained in terms of a decrease in PSA levels. With DES, CVS toxicity occurred in up to 35 % of patients with 15 % experiencing a thromboembolic event. This study with parenteral estrogen showed no significant cardiac toxicity.56 Results from another trial of transdermal estradiol as second-line therapy showed a PSA reduction of more than 25 % in 10 of the 24 patients and no thromboembolic complications were seen.57
Confirmatory evidence of the potential efficacy of transdermal estrogen therapy comes from the recently published first stage of the Prostate Adenocarcinoma Trans Cutaneous Hormones (PATCH) study (see Figure 2). PATCH is a large phase II randomized clinical trial comparing transdermal estrogen patches with LHRHa in locally advanced and metastatic PC. In a cohort of 254 men (randomized 2:1 to patches or LHRHa) with a median follow-up of 19 months, the rates of CVS events (the primary outcome measure) were similar in the two trial arms (see Table 1). Testosterone suppression rates were also similar in the two groups.58 An extension to this trial is ongoing and has recruited to date nearly 700 men (excluding the first 50 randomized before the initial patch dose regime change) and will provide further efficacy and toxicity data.
Potential Benefits of Androgen Deprivation Therapy with Parenteral Estrogen
Exogenous parenteral estrogen for ADT potentially offers two major therapeutic benefits. First, it appears to circumvent the CVS toxicity of oral estrogen by avoiding hepatic first-pass metabolism.56 Second, exogenous estrogen replaces endogenous estrogen, which would be lost through LHRHa administration.58 Thus exogenous estrogen as a single agent has the potential of being an effective and cost-effective therapy for PC, avoiding the need for further expensive treatment of conditions caused by LHRHa.
Estrogen preserves bone mass through its anti-resorptive actions mediated by estrogen receptors. It is known to inhibit osteoclastogenesis and increase osteoclast apoptosis. The life span of bone-resorptive osteoclasts is prolonged in estrogen deficiency, and the resultant imbalance between the bone-forming osteoblasts and osteoclasts increases the rate of bone thinning and heightens the risk for fracture. The protective effects of estrogen in bone health have been studied extensively in the context of the female menopause.59 In PC, two studies have reported the benefit of parenteral estrogen in preventing the skeletal side effects of ADT. In the pilot study of men treated with transdermal patches for newly diagnosed locally advanced or metastatic PC, of 12 baseline osteoporotic/osteopenic regions (in five patients), four showed improvement based on the World Health Organization grading after a year of therapy and bone mineral density increased at all measured sites over time.60 In the larger SPCG trial (n=910) with a follow-up of approximately 9 years, none of the patients on intramuscular PEP developed serious skeletal complications compared with 18 on combined androgen blockade (anti-androgen with either LHRHa or bilateral orchiectomy).59
Estrogen receptors are present throughout the brain, including the cerebral cortex, hippocampus, and amygdala. These regions mediate memory and other cognitive functions, which are impaired in sex hormone deficiency state such as the menopause. Studies in menopausal women suggest that women who use hormone replacement therapy (HRT), with estrogen alone or in combination, have better cognitive skills and memory compared with age-matched non-users.61,62 The data on cognitive effects of parenteral estrogen in PC treatment are limited. In a small study, Beer et al. suggested potential beneficial effects of transdermal estradiol on specific cognitive aspects (verbal memory) in patients with castration-resistant PC.57
It has been suggested that estrogen has a role in the protection from atherosclerosis as rates of CVS disease in premenopausal women are lower compared with men of the same age. Data from the nurses health study including over 29,000 women, also suggested early menopause increases the risk for CVS disease.63 In post-menopausal women CVS disease rates increase to attain similar rates as men of the same age. However, randomized data have not confirmed this association and HRT in postmenopausal women is not recommended for this indication.64 Beneficial arterial effects of estrogen may be mediated through an improved lipid profile as there is evidence that estrogen reduces low-density lipoprotein (LDL) and increases high-density lipoprotein (HDL).65 Similar favorable lipid changes have been observed with the use of parenteral estrogen as ADT for PC (see Table 1).21 Results from the PATCH trial showed that at 6 and 12 months, mean fasting cholesterol increased in the LHRHa arm but decreased in the estrogen arm, whereas HDL increased in both. Mean fasting glucose increased in the LHRHa group at 6 months and again further at 12 months but showed a decrease in the estrogen group at 6 months, which was maintained unchanged at 12 months. Whether these effects on exogenous hormones impact directly on cardiac risk is unclear, both for HRT and ADT.
Several studies have highlighted the role of estrogen in preventing and treating hot flashes.21 In one such study, a significant decline in hot flashes (77 % reduction; p<0.02) after 8 weeks in men receiving transdermal estradiol as second-line therapy for castration-resistant PC was observed.66
Long-term ADT is becoming increasingly common as men live longer with a diagnosis of PC. By creating both testosterone and estrogen deficiency, contemporary ADT with LHRHa causes a range of significant side effects. The large number of patients receiving LHRHa greatly amplifies the impact of this toxicity and have been under-estimated in the literature.67 The wide-ranging nature of these effects complicates discussion in clinical practice68 particularly if patients are older with multiple comorbidities.69 Understanding and preventing the consequences of contemporary ADT is vital to improve the QoL of these men. There are also significant financial implications for healthcare systems the world over. The re-emergence of estrogens, in parenteral form, offers an effective and inexpensive alternative to LHRHa. Parenteral estrogen avoids the thromboembolic and CVS toxicities associated with its oral counterpart. As a monotherapy, it has the potential to reduce or eliminate some of the serious complications of LHRHa, (osteoporosis, cognitive impairment, and hot flashes), which result in significant morbidity and mortality. Results from trials such as PATCH may establish parenteral estrogen as an important alternative to LHRHa in the management of PC. Until definitive results are available, effective monitoring is required so that timely prophylactic and/ or therapeutic interventions can be instituted to mitigate the toxicities associated with LHRHa.
Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer
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