Androgen Deprivation Therapy
Androgen deprivation therapy (ADT) is the first-line treatment for systemic PCa. It is also used in the short term as adjuvant therapy along with radiotherapy or chemotherapy to enhance effectiveness.
There are a variety of ways androgen deprivation (AD) can be achieved to treat PCa. The testicles can be surgically removed; i.e., an orchiectomy. However, AD is more commonly achieved pharmacologically and depending on the drugs used, a PCa patient can be: 1) androgen- and estrogen-deprived, 2) androgen-deprived only, with normal male estrogen levels achieved with supplemental estrogen or 3) androgen-deprived with supraphysiological estrogen levels, more in line with those of premenopausal women. The first scenario is the most common one for patients with PCa on ADT and is typically achieved with either LHRH agonist or LHRH antagonist drugs. The second scenario occurs when the patient is on anti-androgen monotherapy, which is an uncommon treatment protocol in North America, but used in some European countries and elsewhere in the world. The third scenario occurs when high dose estrogens are used to suppress testosterone.80,81 This variation means that various ADT protocols can provide insights into how gonadal hormones may influence sex and gender perception for PCa patients.
Tsang et al. compiled data from 42 peer-reviewed studies that explored the impact of PCa treatment on patient views of their own manhood and masculinity.3 The authors clustered all adversities the patients described as emasculating to better understand what they were experiencing. The top complaints were ED, reduced libido, and diminished physical strength. All of these features are recognized physiological consequences of AD.
Arguably, AD's greatest challenge to male performance and masculine identity centers on how severely it depresses libido. This loss is most extreme for patients who are both estrogen- and androgen-deprived and less severe for those on high dose estrogen since estrogens help somewhat to preserve libido.82,83 However, all forms of ADT cause ED as well as testicular and penile shrinkage.
Navon and Morag, in a small qualitative study, explored the impact of ADT on PCa patients’ gender identities.84,85 Their 2003 paper84 was enriched by quotes from patients, who reported feeling no longer fully male and, despite having acquired some physical features associated with females, not necessarily female either. Below are some condensed quotes from that paper that reveal the liminality associated with feelings of emasculation as a result of ADT:
“It makes me feel different from other people. I find it hard to look at my body.”
“I was doomed to living with a disability.”
“Whenever I saw my body, I wondered, “Who am I? A woman? A man?” It's a very confusing situation.”
“I believe I'm neither one thing nor another; that's the only way I can think about myself without becoming confused.”
“The treatment robbed me of what I loved best in life—sex.”
“A man without the urge and capacity for sex isn't a man.”
“Today I consider myself an asexual man.”
ADT has numerous side effects that can impair patients’ QoL. Some have been considered “feminizing”, notably loss of body hair, reduced lean muscle mass, a proportionate increase in subcutaneous and abdominal fat (predominantly in the waist and hips), plus hot flashes.86 AD has additional psychological effects that include fatigue and increased risk of depression.87 It may also be associated with mild cognitive impairment, though data supporting this is controversial.88-91 Collectively, however AD is achieved, it reduces the QoL of PCa patients.
If AD is achieved with anti-androgen monotherapy or with high dose estrogen, there is a shift in the side effect profile from what is listed above.92 Anti-androgens prevent prostate cells (and other cell types) from binding androgens, but they do not block the production of testosterone, which can then be aromatized to estradiol. AD achieved either with anti-androgens monotherapy or high dose estrogen decreases the risk of hot flashes (which are due to low estrogen), but promotes breast development.83 Many patients on ADT without estrogen find hot flashes stressful and some take some add-back estradiol to make up for the lack of endogenous testosterone-derived estradiol.93 With careful and proper dosing this can alleviate the hot flashes without stimulating much breast growth. For some on ADT, taking a ‘female’ hormone may seem unappealing or counter-intuitive for the side effects they are trying to alleviate (e.g., hot flashes) are typically associated with women.
Arguably, apart from ED, gynecomastia is the most conspicuous feminizing side effect associate with AD. Its occurrence is linked to elevated estrogen titers and is most common in patients on anti-androgen monotherapy or high dose estrogens for ADT. Patients vary greatly in how they tolerate this side effect94 ranging from considering it intolerable to inconsequential to finding it appealing in an auto-erotic, autogynephilic fashion. We hypothesize that the stronger a PCa patient adheres to a gender hierarchy that considers women inferior to men, the less tolerant he will be of iatrogenic gynecomastia.94 However, this hypothesis has yet to be tested.
Patients, who have an orchiectomy or start on an LHRH agonist or antagonist drug for AD, often make behavioral adjustments that are predominantly associated with menopausal women. One such behavior is fanning themselves to get relief from hot flashes while another is sitting down to urinate.95 Due to the combination of penile shrinkage and abdominal fat, AD can make it difficult for men to see their own penis and direct the urine stream appropriately when they urinate while standing. As a result, patients on ADT find it more manageable to urinate sitting down. Data confirm that patients on ADT sit significantly more often to urinate compared to those not on ADT.3 This postural shift toward one normally associated with women may be demoralizing for some PCa patients. As with gynecomastia, we suspect that men, who more strongly adhere to a gender hierarchy in which women are inferior to men, are more likely to consider experiencing hot flashes or sitting to urinate as demeaning. Again, we know of no existing data that test these hypotheses.
No longer a man…
As previously discussed, PCa treatments negatively affect male sexual performance and self-perception vis à vis one's manhood in terms of gender displays. AD makes most patients largely asexual in terms of both erectile function and sexual interest. These effects on sexuality are noted physiologically by the prolonged absence of erections leading to penile shrinkage. Many PCa patients express fear that the iatrogenic changes they experience due to ADT might be discovered by others. Navon and Morag explore this concern and have shown how patients use disguises, diversion, and avoidance strategies in social settings to project, as best they can, an image of masculine normalcy.84 They concluded that ADT subjects patients, “…to a liminal state, that is, the inability to classify themselves into culturally available categories.” We believe that this liminality is similar, if not identical, to Ussher et al.’s “disqualification” for men, who have lost erectile function and their sex drive following PCa treatments.60
Neither Navon and Morag, nor the men they quote, distinguish sex from gender in their discussion of the liminal sex/gender space in which patients on ADT find themselves. The absence of this distinction is meaningful on several counts. First, it suggests that men view loss of sexual functionality as a loss of masculinity, without distinguishing one as sex and the other as gender. Fergus et al. similarly found in a qualitative study of men treated for PCa that patients perceived their manhood as affirmed by their bodily form and functions.96 For those men, loss of biological function, seen most overtly in ED, poses a, if not “the”, major threat to their masculinity. If a patient declares himself “no longer a man”, this is first and foremost understood as a shift in biological functionality. This grounds gender identity in biology and belies claims that gender is solely a social construct. Tsang et al., in their review of how men report PCa treatments affecting their sense of their manhood, determined it to be most commonly expressed as a loss in biological function and control.3
These observations have been further endorsed by a recent study by Peel et al. 2020 that correlated testosterone titers with how men perceive their masculinity.97 The study involved a sample of over 1000 men in Australia, who provided testosterone data and filled in the Masculinity in Chronic Disease Inventory (MCD-I).98 That questionnaire was designed to assess self-perceived masculinity and has been validated for PCa patients. The researchers found that the men most likely to avoid answering questions about their erectile function were those with low MCD-I scores indicative of feelings of emasculation. Indeed, the most significant factor they related to a low self-perceived masculinity score was moderate to severe ED. The authors bluntly concluded that “masculinity is most strongly related to physical and psychological health, rather than to social constructs.”97
All this begs the question—Is there a pathway out of the sex/gender liminality brought on by the emasculating effects of ADT?97
