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Therapy Insight: parenteral estrogen treatment for prostate cancer—a new dawn for an old therapy

Abstract

Oral estrogens were the treatment of choice for carcinoma of the prostate for over four decades, but were abandoned because of an excess of cardiovascular and thromboembolic toxicity. It is now recognized that most of this toxicity is related to the first pass portal circulation, which upregulates the hepatic metabolism of hormones, lipids and coagulation proteins. Most of this toxicity can be avoided by parenteral (intramuscular or transdermal) estrogen administration, which avoids hepatic enzyme induction. It also seems that a short-term but modest increase in cardiovascular morbidity (but not mortality) is compensated for by a long-term cardioprotective benefit, which accrues progressively as vascular remodeling develops over time. Parenteral estrogen therapy has the advantage of giving protection against the effects of andropause (similar to the female menopause), which are induced by conventional androgen suppression and include osteoporotic fracture, hot flashes, asthenia and cognitive dysfunction. In addition, parenteral estrogen therapy is significantly cheaper than contemporary endocrine therapy, with substantive economic implications for health providers.

Key Points

  • Oral estrogens were abandoned as first-line hormone therapy for CaP because of their cardiovascular and thromboembolic toxicity

  • Thromboembolic toxicity during first pass absorption of estrogens from the gut necessitates the need for parenteral routes of administration, which reduce thromboembolic risk

  • Cardiovascular toxicity is related to estrogen-mediated vascular effects, which are both dose-dependent and time-dependent. Whilst short-term estrogen therapy has an increased risk of cardiovascular toxicity, long-term estrogen therapy may be associated with a cardiovascular benefit

  • Current conventional androgen deprivation therapy is associated with considerable morbidity (castration syndrome/andropause) resulting in osteoporosis, hot flashes, cognitive dysfunction, asthenia and anemia

  • Estrogen therapy is protective against the andropausal side effects of current hormone therapies

  • Estrogen therapy is cheap with substantial health-care economic implications

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Figure 1: Pituitary–testicular response to transdermal estradiol therapy and the PSA response (mean and standard error mean) over 12 months.
Figure 2: Improved levels of prothrombin fragments F1 and F2, fibrinogen and D-dimer during transdermal estradiol therapy.
Figure 3: Arterial blood and capillary filtration increase during transdermal estradiol therapy, a possible explanation for increased risk of edema and cardiac decompensation.
Figure 4: Changes in bone mineral density in men treated with transdermal estradiol patches over 1 year.
Figure 5: Change in cognitive function and overall quality of life during 12 months of transdermal estradiol therapy as measured by EORTC QLQ-C30 and PR25 CaP-specific QOL questionnaires.

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Correspondence to Paul Abel.

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Competing interests

P Abel is the principal investigator on a Cancer Research UK grant for a phase II randomized control trial of estrogen patches versus luteinizing hormone-releasing hormone. The other authors declared they have no competing interests.

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Ockrim, J., Lalani, EN. & Abel, P. Therapy Insight: parenteral estrogen treatment for prostate cancer—a new dawn for an old therapy. Nat Rev Clin Oncol 3, 552–563 (2006). https://doi.org/10.1038/ncponc0602

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