Transdermal Estradiol Therapy for Prostate Cancer

August 11, 2005 -- Can a hormonal therapy for men with advanced prostate cancer move forward by going "back to the future"? As an alternative to standard androgen suppressing drugs like Lupron and Zoladex, some doctors and patients in the US and the UK are looking at estradiol patches.

Tomasz Beer in Oregon and Paul Abel and Jeremy Ockrim in the UK have shown that estradiol patches are effective. Because transdermal estradiol enters the bloodstream through the skin, without passing through the liver, the patches cause fewer cardiovascular side effects than oral estrogen. And compared with Lupron and Zoladex, estradiol patches seem to reduce andropause symptoms and protect against osteoporosis.

Men treated with Lupron and Zoladex experience acute onset andropause ("male menopause"). Most men experience hot flashes, and some report emotional changes and loss of libido, or sex drive.

Osteoporosis, a silent side effect, which can lead to hip or spinal fracture, is another problem with the conventional drugs, especially for white men and men who arenot overweight.

Estradiol dose can be controlled by number of patches used, placement on the body and how often patches are changed. Some men use dispenser-measured doses of estradiol gel. The gel method has not yet been tested in clinical studies, but studies have been done using estradiol patches and results look positive.

Dr. Beer at Oregon Health and Science University and Portland Veterans Affairs Medical Center tested the safety and efficacy of transdermal estradiol (TDE) and the effect on hot flashes, sex hormones, the procoagulant cascade, and bone turnover in patients with androgen independent prostate cancer (AIPC).

In the Oregon study, patients progressing after primary hormonal therapy received transdermal estradiol at a rate of 0.6 mg per 24 hours (administered as six 0.1 mg per 24-hour patches replaced every 7 days). Serum prostate-specific antigen (PSA) and hormone levels, coagulation factors, markers of bone turnover, bone density measurements, and a hot flash diary were collected at regular intervals. Median time to disease progression was 12 weeks.

Three of 24 patients (12.5%) had a confirmed PSA reduction of greater than 50 per cent. Estradiol levels in the blood increased from mean starting level of 17.2 pg.mL to 460.7 pg/mL (range, 334.6-586.7 pg/mL). Total testosterone remained suppressed to castrate levels during treatment, "but the free testosterone level decreased as a result of increased sex hormone binding globulin." Toxicity was "modest" Beer says, "and no thromboembolic complications occurred."

Jeremy Ockrim and Paul Abel At Hammersmith Hospital, London, say transdermal estradiol patches are an effective alternative to current androgen deprivation therapy. In a small pilot study men were given transdermal estradiol patches for 1 year with follow up of 15 months.

The patches produced "an effective tumor response" Abel says. Cardiovascular toxicity was substantially reduced compared with that expected of oral estrogen."The changes in the coagulation parameters suggest down regulation of the hypercoaguable state inherent to advanced prostate cancer," Abel says.

"Transdermal estradiol therapy prevented andropause symptoms" and "improved quality of life scores and increased bone density," Ockrim and Abel say. A common side effect of androgen suppression, gynecomastia (breast enlargement and soreness) was "negligible."

Estradiol levels above 1,000 pmol./l. were achieved using 2 patches and higher levels were obtained by increasing the number of patches. All patients achieved castrate levels of testosterone within 3 weeks and had biochemical evidence of disease regression. However, one patient died of disease at 14 months and 1 cardiovascular complication occurred.

The patches avoided the clotting problem (hypercoaguable state) associated with estrogen therapy (This is especially important because blood clots are associated with prostate cancer as such). Vascular flow improved. Bone mineral density was significantly increased. Mild or moderate gynecomastia occurred in 80% of patients but no patient had hot flushes. All other functional and symptomatic quality of life domains improved.

The effect on bone mineral density looks especially impressive. Ockrim measured patients for bone bone mineral density of the lumbar spine and the proximal femur with dual-energy x-ray absorptiometry, and correlated with computerized tomography and isotope bone scan findings at 6-month intervals. He found that transdermal estradiol patches improved bone mineral density of men with prostate cancer.

In 20 patients treated with transdermal estradiol patches, in all measured regions bone mineral density increased with time. By 1 year mean bone mineral density had increased by 3.60% +/- 1.6% in the lumbar spine, 2.19% +/- 1.03% in the femoral neck, 3.76% +/- 1.35% in the Ward's region and 1.90% +/- 0.85% in the total hip, respectively. Of 12 osteoporotic sites 4 had improvement based on World Health Organization grading. All other sites improved toward a better classification.

Signs of osteoporosis have been seen in some men's bone density scans within 6 months of their first shot of Lupron, although not all men develop it.

"Patients with prostate cancer treated with androgen suppression are at risk for skeletal fracture," Martin Resnick at Case Western Reserve reported in 2001, "and risk increases with the duration of therapy. Slender white men are at greatest risk. Conversely, black men and those with body mass indexes greater than normal (greater than 25 kg/m(2)) are at minimal risk despite a prolonged duration (10 years) of androgen suppression."