Role of Estrogen in Normal Male Function: Clinical Implications for Patients With Prostate Cancer on Androgen Deprivation Therapy

Wibowo, Erik; Schellhammer, Paul F.; Wassersug, Richard J.

doi:10.1016/j.juro.2010.08.094

Cited by 75 publications

(55 citation statements)

References 43 publications

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“…Estrogens, including the synthetic estrogen diethylstilbestrol, have previously been used in prostate cancer treatment; however, adverse effects limited their use (8,56). These undesirable effects of estrogenic drugs are probably mediated in part by the transactivation of ERs (classical pathway) (57).…”

Section: Discussionmentioning

confidence: 99%

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

Nakajima

Osakabe

Waku

et al. 2016

Molecular and Cellular Biology

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h Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17␤-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor ␤ (ER␤) or Krüppel-like zinc finger transcription factor 5 (KLF5). ⌱n addition, E2 suppressed KLF5-mediated transcription through ER␤, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ER␤-KLF5 pathway and regulated prostate tumor growth without ER␤ transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ER␤ and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation.

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Section: Discussionmentioning

confidence: 99%

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

Nakajima

Osakabe

Waku

et al. 2016

Molecular and Cellular Biology

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“…Animal studies suggest an important role for estradiol in male sexual behaviour (Davidson 1969, Ogawa et al 2000, Wibowo et al 2011. However, case reports of men with congenital aromatase deficiency have generally reported normal sexual function, and whether there is improvement with estrogen replacement is controversial (Jones et al 2007).…”

Section: Effect Of Estradiol On Sexual Symptomsmentioning

confidence: 99%

Estradiol for the mitigation of adverse effects of androgen deprivation therapy

Russell

Cheung

Grossmann

2017

Endocrine-Related Cancer

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Prostate cancer (PCa) is the second most commonly diagnosed cancer in men. Conventional endocrine treatment for PCa leads to global sex steroid deprivation. The ensuing severe hypogonadism is associated with well-documented adverse effects. Recently, it has become apparent that many of the biological actions attributed to androgens in men are in fact not direct, but mediated by estradiol. Available evidence supports a primary role for estradiol in vasomotor stability, skeletal maturation and maintenance, and prevention of fat accumulation. Hence there has been interest in revisiting estradiol as a treatment for PCa. Potential roles for estradiol could be in lieu of conventional androgen deprivation therapy or as low-dose add-back treatment while continuing androgen deprivation therapy. These strategies may limit some of the side effects associated with conventional androgen deprivation therapy. However, although available data are reassuring, the potential for cardiovascular risk and pro-carcinogenic effects on PCa via estrogen receptor signalling must be considered.

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“…Studies by Ellis and Grayhack (1963) 10 ) collectively indicate that patients taking high-dose estrogen were more sexually active than those who were surgically castrated and receiving no supplemental hormones. Furthermore, libido is better preserved in prostate cancer patients on anti-androgen monotherapy (who subsequently have elevated estradiol levels from the aromatization of testosterone) than those who are surgically castrated.…”

Section: Dear Editorsmentioning

confidence: 99%

Impact of androgen deprivation therapy on sexual function: a response

Wibowo¹,

Wassersug²,

Warkentin³

et al. 2012

Asian J Androl

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Dear Editors,We appreciate the growing interest in sexual health for cancer patients and survivors. Mazzola and Mulhall's recent paper, 1 however, creates the impression that rewarding sex is not possible for prostate cancer patients on androgen deprivation therapy (ADT). This impression, we believe, is not scientifically justified, and may be a disservice to prostate cancer patients and their partners in that it could act as a negative placebo, i.e., the opposite of an aphrodisiac. It was unfortunate that the authors did not use their paper to explore positive pathways for sexual interaction and arousal among ADT patients. Instead, readers may be left with a rather discouraging outlook on the prospect of sexual intimacy and pleasure for androgen-deprived cancer patients.Historically and culturally, there are data to show that castrated males are not obligatorily asexual. While most historical eunuchs were castrated before puberty, they were considered to be everything from asexual to hypersexual depending on the culture. 2 Postpubertal eunuchs, whether the one million Hijra of India 3 or the contemporary Westerners castrated (frequently by self-surgery) as treatment for Male-to-Eunuch gender dysphoria, 4 continue to display both sexual interest and ability.Our data show that many modern-day voluntary eunuchs maintain not only sexual interest, but also sexual activity (manuscript in prep.). Of 203 adult males who were voluntary castrated (chemically or physically) and either used no hormone supplementation or took minimal estrogen to prevent osteoporosis and hot flashes, 4% reported an increase in sexual activity, either masturbation or with a partner, 24% reported no change and 45% reported some reduction in sexual activity. Only 27% reported becoming asexual, a result that many of them had sought. As reported previously, 5 these men ranged in age from 181 to their 80s, with a mean age in the mid-forties. Sexual function was self-reported in a brief questionnaire that we designed to acquire data on sexual fantasies, sexual attraction and sexual activity in the months before and after castration. Based on the information that the respondents provided us, we could assume that the vast majority of these men were functionally intact before being androgen-deprived.One contributing factor for androgen-deprived males to maintain sexual interests is likely to be estrogen supplementation. Wibowo et al. 6 recently reviewed a wealth of animal studies showing that estrogen in androgen-deprived males raises libido above castrate levels. Furthermore, Wibowo et al. have now expanded this review to include castrated males of 27 species ranging from amphibians to mammals. Of these, 14 (13 mammalian) species exhibit elevated sexual interest following exogenous estrogen administration. This further strengthens the notion that androgen deprivation needs not terminally eradicate libido. We acknowledge, though, that this effect is not universal and differences between species could be attributable to innate species differences, diff...

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Role of Estrogen in Normal Male Function: Clinical Implications for Patients With Prostate Cancer on Androgen Deprivation Therapy

Abstract: Prospective studies on the ability of parenteral estrogen to preserve sexual interest at greater than castrate level in patients with prostate cancer are warranted.

Cited by 75 publications

References 43 publications

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

Estradiol for the mitigation of adverse effects of androgen deprivation therapy

Impact of androgen deprivation therapy on sexual function: a response

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