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Beyond the Abstract - Role of estrogen in normal male function: Clinical implications for patients with prostate cancer on androgen deprivation therapy, by Richard J. Wassersug, et al

BERKELEY, CA (UroToday.com) - The most common treatment for advanced prostate cancer (PCa) is androgen deprivation therapy achieved with luteinizing hormone-releasing hormone agonists (LHRHa).

These are expensive drugs with many adverse side effects such as osteoporosis, hot flashes, and sexual dysfunction. The sexual side effects include loss of libido, which reduces the quality of life (QoL) of not just the patients but also their partners.1

As an alternative to LHRHa, estrogen (E) can be used for androgen suppression. In our paper we review previous studies on the effect of E on the sexual function and/or sexual interest of androgen-deprived males. There are estrogen receptors (ERs) in abundance in brain regions that control sexual behaviour in mammals. This suggests that E plays a role in normal male sexual function.

We revisited the literature, some of it going back more than 70 years, to show that E can increase the sexual interest of castrated male rats, hamsters, horses, rabbits, deer, guinea pigs, quail, and even a lizard. Since the publication of our paper we have added boars,2, 3 rams,4, 5 and bulls6 to the list. Regarding humans, we review evidence that men who are androgen-deprived (and thus E-deprived too), such as male-to-female transsexuals,7 surgically castrated men,8, 9 aromatase-deficient men,10 and PCa patients in at least two studies, have better sexual interest when they are on E-therapy. In fact, older studies show that PCa patients on oral E (diethylstilbestrol) were more likely than patients who were surgically castrated to report continuing sexual activity despite erectile and orgasmic dysfunction.11, 12 Furthermore, a significantly higher proportion of PCa patients on anti-androgen monotherapy (which results in elevated plasma E levels) retain their libido than those who are surgically castrated.13 In sum, E can elevate sexual interest in men above castrate levels. It is important to note that E may not restore the libido to a eugonadal level. However, even if E can only partially restore the libidos of PCa patients, this may improve both theirs and their partners’ QoL.

What isn’t clear is when it is best to administer E to maximally preserve libido in androgen-deprived males. We suggest that the time from the initiation of androgen suppression to E-treatment may be crucial and that E may increase libido best when administered early rather than late after the beginning of androgen suppression. This is at variance with current clinical practice where patients receiving LHRHa are only offered transdermal E sometime later in their course of therapy if they subsequently experience severe hot flashes.

E-therapy has both pros and cons, which should be considered by PCa patients prior to starting treatment. The beneficial effects of E include the avoidance of osteoporosis14 and fewer hot flashes15 as compared to men who are on LHRHa. Fewer hot flashes may lead to less sleep disturbance and fatigue, both of which are common for patients on LHRHa. Better sleep and less fatigue, in turn, may help reduce the cognitive impairment that many patients with LHRHa treatment report. However, oral E has been associated with increased thromboembolytic risk, but this can be avoided by parenteral administration of estradiol through intramuscular injection16 or cutaneous application.17

One of the most common side effects of E-therapy is gynecomastia, which is of no consequence to some men and severely distressing to others. Gynecomastia can be reduce by prophylactic radiation or with subcutaneous mastectomy.18

Other concerns with E are PCa progression19 and breast cancer20, 21 risk. Breast cancer risk can be monitored as it is for women. The concern about disease progression is derived from the fact that in androgen independent Pca, E may bind to and activate aberrant steroid receptors. This would be analogous to the situation with anti-androgen drugs that first block but then activate androgen receptors in castrate resistant PCa. To extend the analogy, in that situation E’s withdrawal might also temporarily slow disease progression—an idea that has yet to be explored. Interestingly, in the same issue of the Journal of Urology that our article appeared in, there was a paper showing that the 17α form of estradiol significantly inhibited tumor growth in vitro making it “a potential therapeutic agent for androgen independent prostate cancer due to androgen receptor mutation.”22 Meanwhile the risk that E may accelerate disease progression when the disease is androgen independent must be weighed against the potential to improve the QoL of patients with androgen dependent PCa.

In our review, we raise two hypotheses related to maximizing the benefit of E therapy for PCa patients on ADT. First we hypothesize that E is likely to be most beneficial to these patients if initiated as early as possible following the commencement of ADT. This is based on Sherwin’s “Critical Period” hypothesis which states that E-replacement therapy in menopausal women gives the greatest benefit when administered early, around the perimenopausal period, rather than years later.23 Secondly, cyclically administered E may provide greater benefits to PCa patients than continuous E-therapy. This is based on the fact that ERs are capable of autoregulating their own expression and thus a constant dose of E many not lead to constant serum concentration. Research is warranted to test both hypotheses.

Clearly more research on E treatment for PCa is in order. Unfortunately, since estradiol is a natural hormone, no drug company could profit much from the research. This simple economic fact means that many hundreds of thousands of men on LHRHa cannot expect research to move quickly in this important area that affects their QoL. Thankfully some research is underway. There is, for example, the PATCH study being run out of the Medical Research Council in the UK, which is comparing transdermal estradiol (tE2) patches with conventional LHRHa in terms of QoL and disease progression.

If parenteral estradiol proves, due to direct cytotoxic potential, to be as good as (or better than) LHRHa in controlling PCa while preserving libido and overall QoL, there will still be a need for further research to see what form of delivery (e.g., tE2 patches, tE2 gels, depot injections) is most convenient and acceptable to patients.

 

References:

  1. Elliott, S., Latini, D. M., Walker, L. M. et al.: Androgen deprivation therapy for prostate cancer: recommendations to improve patient and partner quality of life. Journal of Sexual Medicine, 7: 2996, 2010
  2. Booth, W. D.: Development of some male characteristics supported by oestrone but not dehydroepiandrosterone in the boar. Journal of Reproduction and Fertility, 68: 9, 1983
  3. Parrott, R. F., Booth, W. D.: Behavioural and morphological effects of 5 alpha-dihydrotestosterone and oestradiol-17 beta in the prepubertally castrated boar. Journal of Reproduction and Fertility, 71: 453, 1984
  4. D'Occhio, M. J., Brooks, D. E.: The influence of androgens and oestrogens on mating behaviour in male sheep Theriogenology, 6: 614, 1976
  5. Mattner, P. E.: Effects of androgens and oestradiol on libido and aggressiveness in rams castrated as adults. Theriogenology, 6: 612, 1976
  6. Dykeman, D. A., Katz, L. S., Foote, R. H.: Behavioral characteristics of beef steers administered estradiol, testosterone and dihydrotestosterone. Journal of Animal Science, 55: 1303, 1982
  7. Klein, C., Gorzalka, B. B.: Sexual functioning in transsexuals following hormone therapy and genital surgery: a review. Journal of Sexual Medicine, 6: 2922, 2009
  8. Brett, M. A., Roberts, L. F., Johnson, T. W. et al.: Eunuchs in contemporary society: expectations, consequences, and adjustments to castration (part II). Journal of Sexual Medicine, 4: 946, 2007
  9. Davidson, J. M., Camargo, C., Smith, E. R. et al.: Maintenance of sexual function in a castrated man treated with ovarian steroids. Archives of Sexual Behavior, 12: 263, 1983
  10. Rochira, V., Granata, A. R., Madeo, B. et al.: Estrogens in males: what have we learned in the last 10 years? Asian Journal of Andrology, 7: 3, 2005
  11. Ellis, W. J., Grayhack: Sexual function in aging males after orchiectomy and estrogen therapy. Journal of Urology, 89: 895, 1963
  12. Bergman, B., Damber, J. E., Littbrand, B. et al.: Sexual function in prostatic cancer patients treated with radiotherapy, orchiectomy or oestrogens. British Journal of Urology, 56: 64, 1984
  13. Iversen, P.: Quality of life issues relating to endocrine treatment options. European Urology, 36 Suppl 2: 20, 1999
  14. Guise, T. A., Oefelein, M. G., Eastham, J. A. et al.: Estrogenic side effects of androgen deprivation therapy. Reviews in Urology, 9: 163, 2007
  15. Engstrom, C. A.: Hot flashes in prostate cancer: state of the science. American Journal of Men's Health, 2: 122, 2008
  16. Hedlund, P. O., 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. Scandinavian Journal of Urology and Nephrology, 42: 220, 2008
  17. Ockrim, J. L., Lalani el, N., Kakkar, A. K. et al.: Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism. Journal of Urology 174: 527, 2005
  18. Wassersug, R. J., Oliffe, J. L.: The social context for psychological distress from iatrogenic gynecomastia with suggestions for its management. Journal of Sexual Medicine, 6: 989, 2009
  19. Bonkhoff, H., Berges, R.: The evolving role of oestrogens and their receptors in the development and progression of prostate cancer. European Urology, 55: 533, 2009
  20. Schoenberg, B. S.: Multiple primary malignant neoplasms. The Connecticut experience, 1935-1964. Recent Results in Cancer Research, 58: 1, 1977
  21. Sobin, L. H., Sherif, M.: Relation between male breast cancer and prostate cancer. British Journal of Cancer, 42: 787, 1980
  22. Qiao, Y., Wang, L., Cai, L. Q. et al.: Inhibition of aberrant androgen receptor induction of prostate specific antigen gene expression, cell proliferation and tumor growth by 17alpha-estradiol in prostate cancer. Journal of Urology, 185: 305, 2011
  23. Sherwin, B. B.: Estrogen therapy: is time of initiation critical for neuroprotection? Nature Reviews. Endocrinology, 5: 620, 2009

 

Written by:
Erik Wibowo,a Paul Schellhammer,b and Richard J. Wassersugc as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

  1. Department of Anatomy & Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada. Email:
  2. Professor, Department of Urology, Eastern Virginia Medical School. Norfolk, Virginia, USA. Email:
  3. (corresponding author): Department of Anatomy & Neurobiology. Sir Charles Tupper Medical Building. 5850 College Street. Dalhousie University. Halifax, Nova Scotia, B3H 1X5, Canada. Telephone: 1-902-494-2244. Email:

 

Role of estrogen in normal male function: Clinical implications for patients with prostate cancer on androgen deprivation therapy - Abstract

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