Erik Wibowo

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

PURPOSE Patients with prostate cancer on androgen deprivation therapy with luteinizing hormone-releasing hormone agonists experience deleterious side effects, including sexual dysfunction, hot flashes and osteoporosis. Estrogen may relieve or reduce some of these side effects. We explore the role of estrogen in normal male function, emphasizing sexual interest and performance. MATERIALS AND METHODS We reviewed the literature on androgen deprivation therapy, estrogen and sexual function in males using PubMed® and other sources. RESULTS Estrogen receptors are present in tissues involved in sexual behavior including several brain centers and pelvic floor muscles. Exogenous estrogens can restore some sexual interest to greater than castrate level in castrated animals. This has also been reported for certain androgen deprived patients (eg voluntarily castrated men, male-to-female transsexuals) who take exogenous estrogens and others who are on high dose antiandrogens which increase endogenous estradiol levels. Estrogen also helps prevent hot flashes and bone mineral loss, which commonly occur with luteinizing hormone-releasing hormone agonist treatment. However, estrogen may cause gynecomastia and increases the risk of breast cancer. Thus, patients with prostate cancer should be informed about the pros and cons of estrogen therapy before starting androgen deprivation therapy. Based on these data estrogen is likely to have maximal benefits in men if initiated simultaneously with androgen deprivation therapy. Because estrogen autoregulates its own receptors, a constant dose of estrogen will not likely produce a constant serum concentration, suggesting that its effectiveness could be optimized if administered cyclically. CONCLUSIONS Prospective studies on the ability of parenteral estrogen to preserve sexual interest at greater than castrate level in patients with prostate cancer are warranted.

Impact of androgen deprivation therapy on sexual function: a response.

Dear Editors, We appreciate the growing interest in sexual health for cancer patients and survivors. Mazzola and Mulhalls 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 India3 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 18+ 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, differences in the type and dose of estrogen used and in the pathways used for estrogen administration. Estrogen can also preserve libido to some extent in cancer patients on ADT. Studies by Ellis and Grayhack (1963)6, Bergman et al. (1984)7, Davidson et al. (1983)8 and Brett et al. (2007)9 (all cited in Wibowo et al.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.7 Wassersug and Gray12 independently noted that male-to-female transsexuals, who are castrated and take supplemental estrogen, are more likely to be sexually active than are androgen-deprived prostate cancer patients, who typically take no supplemental estrogen. These studies support the hypothesis that estrogen can elevate libido in androgen-deprived men. We recognize that this estrogenic effect is not as strong as androgens in promoting sexual interest. Additionally, as with testosterone itself, it is likely to be confounded by factors such as age and also whether the person was sexually active prior to ADT treatment. In addition, regardless of erectile functioning, androgen-deprived cancer patients need not be anorgasmic. Warkentin et al.13 published a case study of an androgen-deprived male who reported being orgasmic. We have recently obtained physiological data from the patient discussed in Warkentin et al.13 which confirm that there are spastic contractions in the patients pelvic floor synchronous with his reports of orgasm. It is noteworthy that patient uses an external penile prosthesis and his ability to achieve orgasms appears to be dependent on the multisensory integration of total body and not just genital stimulation. A discussion of this method for maintaining a satisfying sex life was unfortunately overlooked in both Mulhalls 2010 book Saving Your Sex Life: A Guide for Men with Prostate Cancer, and the current paper. Other studies have reported some prostate cancer couples maintaining a sex life while on ADT.14 The sample, although small, suggests that maintaining some level of sexual intimacy is both possible and satisfying. It should be acknowledged that humans are motivated to engage in sexual activity for a variety of reasons, not because of sexual urges alone.15 For example, despite a lack of libido, some patients remain sexual for the benefit of their partners. Assessments of libido do not necessarily equate with ability and/or motivation for maintaining sexual activity. In sum, there is far more to male sexuality than erectile function and libido, and lack of testosterone needs not inevitably eliminate pleasurable sexual experiences. Impressions, like the one made by Mazzola and Mulhall,1 about the hopelessness of maintaining a rewarding sex life may in fact contribute to the finding that many couples do abandon their sex lives after being told to expect failure.14 Sadly, none of the papers mentioned above are discussed by Mazzola and Mulhall.1 To ignore this literature is, we believe, a disservice to the many couples who are trying to maintain a rewarding sexual life in the presence of ADT.

The effect of estrogen on the sexual interest of castrated males: Implications to prostate cancer patients on androgen-deprivation therapy.

Androgen deprivation therapy (ADT) for prostate cancer (PCa) treatment causes sexual dysfunction. We review here the effects of estrogen on the sexual performance of androgen-deprived males. The major findings are: 1. Estrogen receptors are present in brain centers that are important for sexual behavior; as well as in male reproductive organs, in a pattern suggesting that estrogen may have some role in orgasmic function and genital skin sensitivity. 2. Estrogen restores sexual interest above castrate levels in many vertebrates including reptiles, birds and mammals; but multiple factors contribute to the magnitude of this effect. 3. Data from castrated men, aromatase-deficient men, male-to-female transsexuals, and men on antiandrogens all suggest that estrogen can maintain some libido in androgen-deprived men. We discuss the general benefits of estrogen therapy to quality of life of men on ADT, the potential risks of this treatment, and possible treatment regimes for estrogen therapy in males. Unless contraindicated, we propose that PCa patients on ADT would benefit from supplemental parenteral estrogen.

Estradiol treatment modulates spontaneous sleep and recovery after sleep deprivation in castrated male rats.

Exogenous estradiol (E) is used occasionally to treat the side effects associated with androgen-deprivation in men, but its effects on sleep patterns have received little attention. We examined whether E modulates sleep patterns and recovery from sleep loss in castrated male rats. Adult male rats were castrated and implanted subcutaneously with Silastic tubes containing either oil (Cast+Oil) or E (Cast+E). Sham-operated male rats (Intact) were implanted with oil-filled tubes. All rats were also implanted with EEG and EMG electrodes for sleep/wake recordings. After two weeks, polysomnographic recordings were made before, during, and following 6h of sleep deprivation (SD). At baseline, the Cast+Oil group showed sleep and EEG patterns similar to those in the Intact group. Compared to these groups, the Cast+E group spent more time awake during the dark (active) phase, and showed higher EEG theta power (a measure of cortical activation) during wake and rapid eye movement (REM) sleep in both the light and dark phases. Following SD, the Cast+E group showed a larger increase from baseline in REM sleep amount, compared to the Cast+Oil group. The Cast+Oil group showed prolonged rebound in non-REM sleep and EEG delta power, and reduced REM sleep rebound, compared to the other two groups. These results indicate that E treatment in castrated male rats promotes baseline wakefulness during the active phase, and facilitates recovery of REM sleep after acute sleep loss. The possible benefit of E treatment for improving sleep quality in androgen-deprived men remains to be investigated.

Does the timing of estrogen administration after castration affect its ability to preserve sexual interest in male rats? — Exploring the critical period hypothesis

Loss of libido is a major side effect that reduces the quality of life of prostate cancer patients on androgen-deprivation therapy. Estrogen restores sexual interest to some extent in castrated male mammals; however, the beneficial effects of estrogen vary greatly among different studies. We investigated whether the timing of estrogen treatment after castration affected its ability to restore sexual interest in male rats. For each rat, sexual behavior was tested with receptive female rats before castration, and after 2 weeks of either oil alone (as a control) or oil plus estradiol (E2) treatment administered via Silastic tubes implanted immediately, at 1 month (Short-Term), or at 3 months (Long-Term) after castration. Intromission frequency decreased and genital sniffing frequency increased significantly after castration compared to pre-castration levels, regardless of the testing time post-castration. E2 treatment at any time point did not reverse these changes. However, more E2-treated than control rats exhibited mounting behavior, with a significant difference between the Long-Term groups. Mounting frequency did not differ from pre-castration levels for either E2 or control rats under the Immediate condition, but declined significantly in rats treated with oil only under both the Short- and Long-Term conditions. In contrast, E2 treatment elevated mounting frequency above the castrate levels to a similar extent in both the Short and Long-term groups. In conclusion, E2 administration partially restores sexual interest in castrated male rats, and the length of post-castration delay in E2 administration does not affect the ability of E2 to restore mounting behavior.

Non-pharmacological and non-surgical strategies to promote sexual recovery for men with erectile dysfunction

Erectile dysfunction (ED), the most commonly reported sexual problem for men, reduces the quality of life for both patients and their partners. Even when physiologically effective, long-term adherence to ED treatments is poor. We review here the implication of having patients’ partners involved in ED treatment, starting with treatment selection. We suggest that having partners engaged from the outset may promote an erotic association of the treatment with the partner, i.e., conceptually linking the aid to the sexual pleasure that the partner provides. We hypothesize that this erotic association should enhance the sexual aid’s effectiveness and might potentially help improve long-term adherence. The primary focus of this review, though, is non-pharmacological and non-surgical options for maintaining sexual activity for men with ED. Though not ED treatments per se, anecdotal data suggest that these options may be effective for some patients and their partners in regaining a satisfying sex life. The aids discussed include external penile prostheses, penile sleeves, and penile support devices. These devices can allow men to participate in penetrative sexual intercourse despite moderate to severe ED. External penile prostheses can be personalized so they match in size and shape a man’s normal full erection. Penile sleeves can similarly be customized with a lumen that fits best a patient’s penis for optimal tactile stimulation. We review how multi-sensory integration can enhance sexual arousal for men who use such devices, allowing them to achieve orgasm despite intractable ED. Patients are not always advised within ED clinics about these options nor why and how they can facilitate non-erection dependent sexual recovery. Clinicians need to be aware of these devices and their positive attributes, so they can objectively counsel and encourage couples to explore their use as an alternative to more invasive treatments. The most commonly promoted non-medical ED aid offered to patients is the vacuum erection device. We discuss how erections achieved with the vacuum erection device have a “hinge effect”, that is an underappreciated barrier to the effectiveness of the erection. With a hinged erection, the penis points downward rather than upward. We show how the normal kinematics of the penis during coitus is not strictly linear (i.e., not uniaxial; not just in-and-out), and is impeded by hinging. Positional adjustment, such as the receptive partner being on top, may help overcome this problem for some couples. Lastly, we suggest that, in the case where ED can be anticipated from a pending medical treatment, such as a prostatectomy, pre-habilitative approaches may potentially improve adherence to sexual aid use in the long-term. In conclusion, non-pharmacological and non-surgical options for sexual recovery are available. Scientific studies on the effectiveness of these interventions in restoring satisfying sex are warranted.

Successful implementation of a disease-specific survivorship program for men with prostate cancer (PC) and their partners.

31 Background: Treatment for localized PC can adversely impact the quality of life for the patient (pts) and his partner. Addition of androgen deprivation therapy (ADT) to treat biochemical relapse or metastatic disease can result in further symptoms. We hypothesized that PC pts and partners would benefit from a clinical, educational, research-based approach to care that would focus on their specific needs. METHODS Funding from government agencies and philanthropic sources were used to establish a survivorship program in the urology clinic at the Vancouver Prostate Centre. A multi-disciplinary management team was formed to oversee the program. The Prostate Cancer Supportive Care (PCSC) Program is organized around 5 thematic modules 1) information about PC and primary treatment options (TX), 2) sexual health and intimacy (SH), 3) lifestyle changes in diet and exercise (DE), 4) managing the side effects of ADT, 5) incontinence and pelvic floor physiotherapy (PT). Group educational sessions (ED) are held 1-2 times monthly. Individual clinic appointments with SH and PT clinicians are also available. A program manager, clinic coordinator, and research assistant run PCSC on a day-to-day basis. RESULTS PCSC was initiated in January 2013. Urologists, nurses, pharmacists, and radiation oncologists referred patients to PCSC. Of 802 pts who enrolled (167 in 2013, 369 in 2014, and 266 in 2015 to date), to receive the quarterly newsletter, 626 (78%) chose to actively participate in at least one module (summarized in table). Feedback from couples, participating clinicians, and allied health personnel has been overwhelmingly positive. In addition, the PCSC population is proving to be a rich source of patients for research projects and training opportunities for young MDs. CONCLUSIONS The results demonstrate that implementation of a disease specific survivorship program is feasible, well received and has other unanticipated benefits. Outcomes research and intervention protocols are in progress to address our hypothesis. [Table: see text].

‘Should I get a PSA test?’ - the question is not that simple: Prostate Disease

PSA screening for prostate cancer is a controversial issue around the world. In this article the authors describe the situation in North America where screening is not being advised. They argue that patients should be tested and that men will adapt and learn to live with the results as active surveillance becomes more acceptable.