Erik Wibowo & Richard Wassersug. American Scientist. Volume 102, Issue 6. Nov/Dec 2014.
In 1889, French physician Charles Édouard Brown-Séquard injected himself with an experimental mixture of testicular blood, semen, and extract from dog and guinea pig testes. After just one day, the 72-year-old doctor claimed improvement in his forearm strength, mental ability, urinary stream, and strength of fecal expulsion. Once his account was published, numerous people sought rejuvenation with Brown-Séquard’s “elixir of life.” Soon various marketers offered similar concoctions. Many of the people who took these exotic infusions suffered inflammation and infection and received little or no therapeutic benefit. Nevertheless, the elixirs laid the groundwork for much of modern endocrinology, in particular for hormone therapies used to address a wide variety of disorders.
One especially famous treatment was developed by Eugen Steinach at the Institute of Experimental Biology in Vienna. This “organotherapy”called for a vasectomy and the implantation of testicular tissues. Endorsements spread quickly, and a number of public figures made their way to Vienna to be “Steinached.” Among Steinach’s clients was the famous poet William Butler Yeats, who made no secret of his satisfaction with the results. Yeats proclaimed that the procedure not only helped him recover his creative powers but “revived also sexual desire… that in all likelihood will last … until I die.” (Presumably he was not displeased, then, when newspaper reporters in his native Dublin labeled him “the gland old man.”)
Medicine has changed greatly in the 125 years since Brown Séquard first promoted a potion for rejuvenation, but the yearning for an elixir of life, or at least of youth, remains strong. Recently, this desire among men has been exploited with a marketing barrage of pills, shots, and topical gels all promising to treat the vaguely defined condition “low T”—a decline in the body’s levels of testosterone, the predominant androgen produced by the male testes.
Androgens can indeed make men feel energized, which is why modem synthetic androgens are often taken by contemporary athletes and body builders. Those drugs can help men build up muscle, but not without other consequences. The simple fact is that many androgens can be converted to other hormones in the body that have their own suite of effects. Those effects can be long term, deleterious, and irreversible. One study published recently in the journal Andrologia found that more than 15 percent of 382 men who had taken the drugs regretted having used testosterone analogs. Tinkering with the levels of androgens in one’s body has an effect on other, seemingly unrelated aspects of one’s health because of the biochemical way the gonadal hormones are interrelated.
In conversational terms, testosterone is frequently labeled “the male hormone” because it is the major sex steroid, or androgen, in males. We also know that the predominant gonadal hormone for women is the estrogen estradiol, produced primarily by the ovaries. In parallel to testosterone, estradiol is often referred to as “the female hormone.” What is less appreciated is that both males and females naturally have both testosterone and estradiol in their bodies. Hence, a dichotomy of male versus female hormones is misleading.
It was Eugen Steinach, together with his colleague Heinrich Kun, who in 1937 first demonstrated that the male body can produce estrogens. The Viennese scientists observed estrogens in the urine of male rats that had been injected with testosterone; they then confirmed this finding for humans by documenting an increase of estrogenic compounds in the urine of men who received testosterone injections. Steinach and Kun astonished colleagues when they published their data showing that “the male organism can convert male hormone into a substance with a female hormone effect.” In the field of endocrine research, Steinach’s work was highly valued, so much so that he was nominated half a dozen times for a Nobel Prize in physiology.
Why Do Men Have Estrogen?
After the initial surprise of learning that the normal male can produce an estrogen, it seems reasonable to wonder about the source of and function for a “female” hormone in men. The key to the production of estradiol in males is the enzyme aromatase. This enzyme transforms testosterone into estradiol by converting one of the four cycloalkane rings, which defines it as a steroid, into an aromatic state (that is, the state in which it has a phenyl group). Aromafization of testosterone takes place in many different types of tissues throughout the body; aromatase has been found in the brain, testes, adipose tissue, blood vessels, and skin. Furthermore, many cells have estrogen receptors, which means that the hormone likely has some real functions in the male body. But what are they?
The project of sleuthing out the role of a chemical messenger in the body usually follows some time-honored paths. One can compare, for example, subjects who have normal levels of the substance to subjects with abnormal levels, or who lack the substance altogether. Alternatively, one can manipulate the levels of the substance and note the changes that occur. In studies of estrogen in males, both approaches have helped us understand the role of this hormone.
To start with, estradiol plays a crucial role in early sexual development. A single gene, sry (sex-determining region of Y) on the Y chromosome of males, determines whether the embryonic gonads develop into testes rather than ovaries. In the male embryo, the testes produce high levels of testosterone during fetal development, which then drives the development of the remaining male reproductive organs, such as the penis, scrotum, and the prostate gland. In the absence of testosterone, female external genitalia are formed by default.
During gestation, all fetuses—at least for rodents, the primary animal model studied so far—are exposed to estradiol from the mother’s placenta, regardless of their chromosomal sex. The developing brain is buffered from the effects of this hormone by a molecule known as a-fetoprotein, which locks onto estradiol in the blood and prevents it from passing through the blood-brain barrier. By contrast, testosterone in male fetuses is not bound to a-fetoprotein and can pass freely into the brain. Within the brain, though, testosterone is aromatized into estradiol; that locally derived estradiol, paradoxically, converts embryonic brain regions to the male morphology. Several features of the brain subsequently take on distinctly male characteristics, such as the preoptic area, which is larger in males than females, and which controls male sexual behavior.
There’s an important caveat here. This paradoxical role of estradiol as a masculinizing agent for the brain is not universal. Unlike in rodents, testosterone appears to be the primary hormone that masculinizes the brain of primates. Some data to support this come from the rare genetic males in our species who have a mutated aromatase gene and lack a functional aromatase enzyme. These individuals have normal levels of testosterone, but produce little or no estradiol. Their sex is that of males. However, they have reduced fertility, which suggests that some amount of estradiol during development is needed to produce a completely functional male reproductive system.
The sexual differentiation that occurs in the brain during embryonic development results in life-long changes that show little plasticity once individuals reach maturity. The first experiment to demonstrate this was performed in 1959 by Charles Phoenix and his colleagues at the University of Kansas. They wanted to explore how exposing embryos to high-dose testosterone would affect female sexual behavior. To do this, they injected pregnant guinea pigs with testosterone and then, when the female pups reached adulthood, removed their ovaries and afterward observed how their sexual behavior was affected by the hormonal shift. These guinea pigs displayed little female-type sex behavior, even when given addback estrogen, but they showed heightened male-type sexual behavior.
By contrast, when otherwise normal adult female guinea pigs had their ovaries removed and were then treated with testosterone, they continued to show female-type sexual behavior. This experiment demonstrated that gonadal hormone treatment in the adults does not produce the same effect as in embryos, and that sex steroid exposure in embryonic life can produce a permanent effect. Gradually scientific evidence accrued to suggest there was a “sensitive period” (at least for rodents) during late embryonic life when steroid hormone treatment most extensively influenced brain development. After this period, sexual differentiation in the brain is less plastic (except during puberty) and sex treatment has far less influence on the morphology of brain regions that control sex-specific behaviors.
Estradiol continues to influence development in other organs and tissues of males, however. Once again, key insights have come from aromatasedeficient males who lack normal levels of estradiol. Vincenzo Rochira and Cesare Carani in Italy recently reviewed clinical data on these men and confirmed the importance of estradiol on male skeletal development. Aromatasedeficient boys do not experience a distinct growth spurt during puberty, nor do their long bones stop growing. Instead, their skeletal growth continues into adulthood, giving them unusually tall stature and disproportionately long limbs. Many aromatase-deficient men suffer from bone pain and genu valgum (a knock-knee deformity).
Less conspicuous are abnormalities in metabolism and fertility, as noted above. These men are likely to have impaired sugar and fat metabolism as well as abnormal liver function, which increase their risk of diabetes and liver diseases. Additionally, they have low sperm count and poor sperm motility. Estradiol given to aromatasedeficient males can reverse some abnormalities, but not all. When estradiol is administered after puberty, sperm production does not improve, nor do disproportionately long bones shorten to normal size. However, estradiol therapy can change their skeletal structure in other ways: The long bones mature, become thicker, and eventually cease to grow. In addition, estradiol therapy improves the men’s cholesterol profiles, liver function, and sugar metabolism, thereby lowering their risk of metabolic-related diseases. One aromatase-deficient man even reported increased libido after starting estradiol therapy, which suggests that estradiol may promote sexual interest to some extent in males.
Clearly aromatase deficiency, and hence a lack of estradiol, influences male development and health in a variety of ways. Some of the abnormalities seen in these men match those observed in males who have had their testicles removed, because these men lack not just testosterone but the estrogen derived from it.
History provides many examples of castration, carried out for various purposes. In the Western world, the best-known examples were the castrati singers of church choirs and opera. These individuals, castrated before puberty, retained higher-pitched voices because the deepening of the male voice at puberty is directly due to enlargement of the laryngeal cartilage and lengthening of the vocal folds brought on by the adolescent surge in testosterone. Castrati also had greater lung capacity and more powerful voices, owing to the continued growth of their rib cage. As adults, they were often taller and had longer limbs than normal males. Their anatomy was similar to that of aromatase-deficient males, a trait that suggests it was predominantly the lack of estradiol and not testosterone deprivation that gave them their unusual skeletal structure.
Hormone Therapy for Men Today
The castrati dominated European vocal music for 300 years, beginning in the middle of the 16th century. (The practice was banned in the late 19th century.) Long before that, boys had been castrated to serve as functionaries in imperial courts across Eurasia. In the modern world, many people presume that this barbaric-sounding practice has been largely abandoned. On the contrarycastration is more common now than at any time in the past, although its rationale and the methods used have changed greatly.
A common assumption in North America nowadays is that men undergoing castration must be either recidivist sexual predators or male-to-female transsexuals. Both groups are tiny, however, compared to the number of men who undergo androgen deprivation to treat prostate cancer. This practice is euphemistically called “hormonal therapy” and can be achieved either by surgical castration or with pharmaceuticals that shut down testosterone production. Although not curative, androgen deprivation can slow the growth of prostate cells.
About half of all prostate cancer patients in the industrial world take androgen-suppressing drugs at one time or another; some 600,000 men are on this regime in North America alone, according to an estimate by Harvard University oncologist Matthew R. Smith. Androgen deprivation is now more often achieved with drugs than by the surgical removal of the testicles, but the psychological and physical effects of the treatments are similar. Whereas the effect of surgery is permanent, that of drug treatment is usually reversible if the drugs are taken for only a short term. Prolonged use can lead to permanent effects, however, and many advanced prostate cancer patients who receive this treatment can expect to stay on it for the remainder of their lives.
Most male features acquired at puberty, such as full stature, shoulder width, and the facial bone structure, remain unaffected by androgen suppression in adults, because bones do not change their shape once they have matured. Similarly, androgen deprivation after puberty has little or no effect on the voice, because the cartilage in the male throat has reached full growth and does not regress with castration.
As noted earlier, castration depletes both testosterone and estradiol in men, resulting in numerous side effects that may take a toll on a patient’s quality of life. Testosterone-deprived adult males commonly experience reduced libido, erectile dysfunction, loss of muscle mass, hot flashes, loss of body hair, weight gained as fat, mood changes, fatigue, and possibly some effects on mental processing. Many of these side effects, such as hot flashes and an increased risk of osteoporosis, are identical to what women experience at menopause, and they arise for the same reason. The cause is a large decline in levels of estradiol, and in both sexes those side effects are diminished when the individuals are given some supplementary estradiol.
As for the mental processes of castrated males, estradiol may help preserve libido. Although it is not nearly as potent as testosterone, there is growing evidence that estradiol can elevate sexual interest in males above the castrate level. Some notable eunuchs in history, as well as anecdotal reports from contemporary transsexuals and some prostate cancer patients on androgen deprivation therapy, collectively show that complete loss of libido is not inevitable with castration. Recently, in a well-designed, properly controlled, and blinded study, Joel Finkelstein and his colleagues at Harvard University confirmed that estradiol plays a positive role in male sexual desire. In their study, testosterone-deprived men received supplemental testosterone with or without an aromatase-inhibiting drug. Those who received the aromatase inhibitor, and therefore had low estradiol levels, experienced less sexual desire than those who did not receive the aromatase inhibitor.
Sex Hormones in Concert
Long-term studies of the gonadal hormones are yielding increasing evidence that testosterone and estradiol often function in concert and with similar rather than opposing functions. Two groups of patients that have provided data on this point are men treated for prostate cancer with androgen-suppressing drugs and individuals treated for male-to-female transsexualism. In both populations, individuals can have testosterone at castrate levels, but some may be receiving supplemental estrogen and others are not. Studies in these populations help distinguish the effects of emasculation from feminization.
Given their different reasons for undergoing androgen deprivation, it is not surprising that prostate cancer patients and transsexuals perceive the effects of their treatment quite differently. Whereas low sex drive can be distressing to prostate cancer patients and their partners, some transsexuals report a sense of relief with the depressed libido they experience in the course of androgen deprivation. Similarly, loss of body hair after castration can be construed as an undesired loss of a masculine trait by prostate cancer patients and as a desired feminizing trait by transsexuals.
Although properly controlled studies in this area are still scarce, a large array of effects on personality and mood has been reported for androgen-deprived genetic males. To say that men become less aggressive with androgen deprivation is too simplistic, for eunuchs in history were often military leaders and even assassins. Modern androgendeprived men report being more emotional (in particular, tearful) than they were before treatment-an effect that can be embarrassing, but for transsexuals can be an affirmation of their newly acquired femininity. Along the same lines, with colleagues in Canada and the United States we have published some data suggesting that estrogen therapy increases agreeability in androgen-deprived males. In addition, Gomez-Gil and colleagues reported that estradiol treatment reduces social distress, anxiety, and depression in male-to-female transsexuals, although it is not clear to what extent that is a placebo effect.
Other, more subtle effects have been difficult to measure, let alone treat. As with many menopausal women who report sleep disturbance (which leads to daytime fatigue and may impede cognitive function to some extent), prostate cancer patients, who are testosterone-deprived, commonly suffer from fatigue that is sometimes severe enough to impede daily activities. Studies with women after menopause, such as those done by Barbara Sherwin at McGill University, suggest that estradiol can improve cognitive function. Data to show this effect in androgendeprived males given supplemental estradiol are fewer and more anecdotal.
Evidence from our lab indicates that estradiol promotes wakefulness in castrated male rats during their active period. In that same study, we found that estradiol treatment helped the rats recover normal sleep patterns after sleep deprivation. If estrogen can help androgen-deprived men (as well as postmenopausal women) to be more alert during the day, it may potentially alleviate the fatigue associated with androgen deprivation therapy. Furthermore, supplemental estradiol may reduce cognitive impairment in these androgen-deprived patients by improving their sleep.
Only recently have researchers begun using the powerful tool of functional magnetic resonance imaging (fMRI) to visualize how sex hormones affect brain function in genetic males. The advantage of fMRI is its ability to reveal which brain areas are activated by specific stimuli or tasks while the subjects receive various drug treatments. A couple of recent, but small, fMRI studies (one by Herta Chao and colleagues at Yale University and another by Monique Cherrier and colleagues at the University of Washington) confirm that a loss of testosterone alters brain function in areas associated with memory and cognitive processing. We are not aware of any studies that have taken the next step and looked at changes in brain activity for androgen-deprived men who are then given enough supplemental estradiol to bring their levels into the range for normal males. Such studies should help us understand precisely how estradiol versus testosterone affects brain function in genetic males.
In addition, by using analytical tools like fMRI to study how hormonal manipulations affect brain activity we should be able to sort out placebo effects from genuine endocrinological responses. At present, many prostate cancer patients may wish to believe that their hormonal treatments have little effect on their mood, personality, and general mental processing. At the other extreme, some male-to-female transsexuals consider supplemental estrogen a miracle elixir, the sine qua non of sexual reassignment. To be sure of what is really happening in the nervous system, the participants in future studies will need to be blind to the hormonal manipulation. Paradoxically, the most profound mental and metabolic effects seem to come from castration, and some supplemental estrogen appears in many ways to normalize the androgen-deprived genetic male as much as it feminizes him.
The most conspicuous effect of highdose estradiol therapy in adult males is gynecomastia, or breast enlargement. Many prostate cancer patients who believe that breast development is a key signifier of the female gender despair at gynecomastia; at the same time, transsexual women are often disappointed by the limited amount of breast development they experience with this treatment. Some male-to-female transsexuals opt for breast implants; many prostate cancer patients find even modest amounts of gynecomastia intolerable, and some seek cosmetic mastectomies. To sort out what exogenous estrogen does in the adult human male will clearly require blinded studies and objective, analytical data.
This point leads us to the next question: Are there any major risks to men taking supplemental estrogens? The concern is valid whether one is a prostate cancer patient on androgen deprivation therapy taking low-dose estrogen to control, say, hot flashes, or a male-to female transsexual taking highdose estrogen to promote breast growth.
In the earliest form of nonsurgical hormone therapy for prostate cancer, patients were given high doses of a synthetic estrogen, diethylstilbestrol (DES), to depress their testosterone production. This approach worked by means of an endocrinological feedback loop in which high concentrations of either androgens or estrogens in the brain shut down the normal signal from the pituitary gland to the gonads to make sex hormones. High-dose DES can thus lead to castrate levels of testosterone.
During the 1960s, over 2,000 prostate cancer patients at 14 Veterans Administration hospitals in the United States participated in a study that showed surgical and chemical castration (with DES) to be equally effective in treating prostate cancer. However, about one in five patients taking DES died from some form of cardiovascular disease, with blood clots being particularly common. This significant risk led investigators to search for alternative drugs for androgen suppression, and in the 1980s another class of synthetic hormones (known as the luteinizing hormone-releasing hormone agonists) came to market. These drugs were equally effective in controlling prostate cancer, and, because they carried a lower risk of blood clots, they have been the primary drugs used to treat advanced prostate cancer in the industrial world for the last quarter century.
Many physicians, remembering the history of DES, are reluctant to prescribe estrogens to men under almost any circumstances, but the newer forms of estrogen therapy that are prescribed today pose a significantly lower risk. We now know that the high risk of blood clots from DES was in part due to its method of administration, which was oral. Once swallowed, DES was carried to the liver before passing into the general circulatory system. The surge of estrogen in the liver increased the level of clotting factors, raising the risk for dangerous blood clot formation. Nowadays, with estrogens applied to the skin or by injection into muscle, the risk of blood clots is greatly diminished.
Even so, nonoral estrogen therapy is not absolutely without risk. Certain studies, such as those done in both tissue culture and transgenic animals by Gail Risbridger and colleagues at Monash University in Australia, have given rise to the concern that estrogen may itself promote the growth of prostate or breast cancer cells. For this reason, some physicians are concerned that estrogen given to men, regardless of how it is administered, may exacerbate the risk of either prostate or breast cancer.
To date there is little evidence that estradiol administered to genetic males directly causes prostate cancer. Even among the thousands of male-to-female transsexuals known to have taken high-dose estrogens, we are aware of only nine individual reports of prostate cancer. Admittedly, estradiol can promote the growth of cancer cells in tissue culture by activating one type of estrogen receptor, ERa. In contrast, there is evidence that estrogen can suppress prostate cell growth by activating another receptor, ERß. Thus, estrogen may have a dual effect on prostate cancer cells in culture. How this plays out in vivo may also depend on how advanced the cancer is.
Breast cancer is another potential concern, particularly because some aggressive forms of breast cancer are stimulated by estradiol. Men as well as women can develop breast cancer, although the incidence in men is quite low, about 1 in 100,000. To date, there are few reports of breast cancer among estrogen-treated men, or even among male-to-female transsexuals, who typically take high doses of estrogen. Prostate cancer patients do, however, have a higher probability of developing breast cancer than other men, with an incidence rate of 1 in 7,000. For this reason, regular breast screening is recommended for any genetic males on long-term estrogen therapy.
Emerging Questions
How estrogen supplementation affects adult human males may be further complicated by the issue of timing. About a decade ago, the Women’s Health Initiative study assessed the safety and effectiveness of hormone replacement therapy in postmenopausal women. The study was terminated early when preliminary findings showed that postmenopausal estrogen did not benefit the women and might even be harmful. More recently, however, reanalysis of the Women’s Health Initiative data has indicated that if the therapy is started when estradiol levels first decline-at the beginning of menopause or immediately on the removal of the ovaries in premenopausal women-then hormone replacement therapy may attenuate memory decline and limit cardiovascular risk.
By contrast, when estrogen therapy is initiated years after menopause, the beneficial effect is reduced or lost. This is another example of a “critical period.” The effectiveness of estrogen treatment depends on how soon it is administered after hormone deprivation. Laboratory studies on female rats further confirmed this result by showing that estrogen therapy is protective of memory when the treatment begins soon after surgical removal of the ovaries. Prompt estrogen treatment after ovarian removal also raised the level of sexual behavior and improved cardiovascular health in these female rodents.
But does the “critical period” hypothesis apply to males as well? Two studies on male rodents have shown that estradiol treatment initiated at different times after castration raised sexual interest about equally well, suggesting that the timing of the estrogen treatment was not as important in males. However, the time gap between castration and the beginning of estrogen treatment in those studies was less than in the studies in female rodents. In general we do not yet know whether estrogen therapy can benefit either androgen-deprived prostate cancer patients or male-to-female transsexuals equally well, independent of when the estrogen therapy is started after androgen suppression.
Much work lies ahead for anyone who wants to contribute to a clearer understanding of the complex way that sex hormones interact in males and females. From a clinical perspective, androgens and estrogens do much more than simply make individuals either male or female. Yes, testosterone is important for male normality and vitality-but as we now understand, so is estradiol. We have come a long way from the days of Brown-Séquard and his single “elixir of life.”