Let me start this essay with an admission: I chose the title in part to attract your attention. A more technically correct title would be “Multifunctional usage of estrogen and testosterone and their pleiotropic effects when dosages are wrong”. That would be a more precise description but perhaps a little less, well, sexy? Nevertheless, I ask for your patience and to read on; the material is interesting.
Everyone has heard of the two main sex hormones, estrogen and testosterone, and has some idea of what they do. Estrogen promotes female development and testosterone promotes male development. Both are present from before birth in low amounts in every foetus and young child, but increase strongly but differentially in the two different sexes after puberty, promoting development of the gonads and reproductive cells and the so called secondary sexual characteristics of each sex, e.g. breasts in females and facial and body hair in males.1
However, this being a matter of biology, things are not simple. Both of these hormones do a lot more. To explain, here I will introduce a word that is not familiar to most people who know fairly little genetics and perhaps even some who are familiar with certain areas of biology but not biological development. The word is “pleiotropy”. It is from the Greek and literally translates as “many movements” but is often given as “many ways”, meaning “many uses”. Here it refers to a gene whose ultimate product does two or more (usually more) things in the cells of an organism. If that molecule is a hormone, those biological changes, in turn, can lead to other ones, in particular neurological traits, and then behavioral ones.
If a normal gene product, however, does more than one thing, then if it is subtracted from the body, in whole or in part, multiple changes can result. These are termed “pleiotropic effects”. Such multiple effects can also come about when the amounts are increased above the normal levels.
That last fact often has importance in medicine. When a gene product is being over-produced for some reason, and its increased amounts are causing one or more problems, medical practice is to treat it as a “target” and reduce its amounts in the places in the body where it is causing a problem. The potential problem with that strategy is that one can reduce its amount in other parts of the body that need it as well, to a level below those requirements, which can cause other problems.
A similar consideration can arise when the initial problem is the reverse, having not enough of that gene product in a tissue or organ. Here the therapy would be to increase it there by one procedure or another but if those increased amounts are too much for optimal functioning at those other sites, that can cause new problems.
It would be an exaggeration to say, concerning molecules that have a biological effect, that “dosage is everything” but it is very, very important in both normal biological functioning and in getting therapies to go well. We have encountered examples of its importance in a couple of earlier articles (see, in particular, How should we understand the effects of mutations?) In a future piece that I am planning for this series, dealing with serotonin, we will come to this issue again. I am stressing the importance of quantity, and getting it right for each context, because it is so often neglected in the popular press. This neglect is to the detriment of public understanding of how our bodies work normally and what has to be taken into account when therapies are needed.
Before getting into the biological specific complexities of estrogen and testosterone, one last point though this one concerns sociology and word usage, though it comes back to biology. One of these hormones has acquired some bad press, via some ugly associations. If your guess is that I am referring to testosterone, you are correct.
Bad press for a normal molecule is unusual: few of the body’s components have acquired some sort of moral stigma. Yet, testosterone has via the phrase “testosterone-fueled ranges.” Indeed, it is now linked, in many people’s minds, with some or all of the features of what is called “toxic masculinity”. Those behaviors are, indeed, egregious and should be eliminated or at least greatly reduced if we are to have healthy societies. However, it is quite unfair to blame them on a molecule that does a lot of valuable things (to be described). Higher testosterone levels may be associated with higher levels of aggression in some men but the data do not support a clear cause-and-effect relationship and certainly not that testosterone is the only factor in these bad behaviors.
Furthermore, one general biological fact that is forgotten in such thinking is that no hormone – any molecule that circulates through the bloodstream and which has significant effects on one or more cell types is a hormone – acts alone. It requires other specific molecules, called receptors, on the cells it acts on, to do its job. Take the relevant receptors away, as can happen with certain mutations, and the hormone is powerless to do anything. A hormone is a chemical messenger but if the message cannot be received (in this case, by strongly reducing or eliminating the number of its receptors) it will have no effect.
Let us now talk more specifically about estrogen and testosterone. A key point is that neither is strictly sex-specific. Both are found in females and males though in different amounts and do different things in the two sexes because their amounts differ. (Yes, we have just returned to the matter of quantity and its importance.) Another interesting facet of the situation is that they each exist in several forms, which have somewhat different activities in the body at different times. We can skimp on those details here but I will mention one: the predominant form of estrogen in the body of a woman who is pregnant is different from the one she had before she was pregnant or after she has given birth or the one she will have during menopause. The situation with respect to testosterone is comparable, in that different forms are synthesized and can have different activities, not all of which are appreciated, e.g. the derivative that often rises in older men, causing male pattern baldness.
Perhaps the most interesting generalization about additional roles for the sex hormones is that they are both crucial for optimal health, especially brain health though not only that. In both sexes, again, they perform these beneficent functions at different levels. As a recent headline in an article in The New York Times put it, concentrating on brain function: “Sex hormones are brain hormones. What does this mean for treating brain diseases?”2
The first indication that a sex hormone, specifically estrogen, was good for protecting neural cells came from the finding, in the late 1990s that women who had multiple sclerosis (MS) and who were pregnant, had many fewer bouts of suffering with MS during their last trimester and elevated levels of the estrogen form predominant in pregnancy, estriol, Soon, it was found that providing extra estrogen could be effective in therapy for MS in women, in whom it is much more common than men.
There was more good news: it was soon found that estrogen could be used for treating menopause, often diminishing the symptoms, including the problems in cognition and memory and general brain fog that so often occur in it. It is now suspected that the menopausal shift that creates this special vulnerability in women to MS concerns a general shift in metabolism that a woman’s body undergoes at this time. That shift involves a move away from the brain’s reliance on glucose for its energy needs. Instead, it tends to shift to digesting the myelin, the fatty sheath material, that surrounds and protects many brain cells. Estrogen provides some protection against this.
About the same time, both statistical studies and animal studies indicated that estrogen might also be helpful in fighting dementia (Alzheimer’s disease) (see The terrible tangle of Alzheimer’s disease) in women, who are more prone to it. In the very early 2000s, indeed, it looked as if estrogen might be a sort of miracle drug.
And then, a setback occurred. An influential report published in 2003 showed that older women, that is women 65 and older, were more likely to develop Alzheimer’s if they were on estrogen therapy than if they were not. For awhile it looked as if this was not going to be the way forward for helping menopausal women. After all, while menopause is an unpleasant experience, who would want to trade it in for Alzheimer’s?
Then it was found that this was an effect on older women specifically, not on younger women going through menopause. (In other words, an older woman should not take estrogen as some sort of insurance or back-up mechanism.) Just as dosage of a drug is important, the time of its application is too. Currently, estriol therapy is being tested again as an anti-menopause symptom therapy on women of the appropriate age and apparently showing promise.
What about testosterone and its related hormones, termed “androgens”? Are these substances potentially important for health issues? There seems to be less information on this than for estrogen effects but, again, the results seem positive. Men, as they age, show lower testosterone levels with time. Furthermore, as they do so, they show various frailties, both physical, such as muscle weakness, and mental traits, such as poorer performance in memory and verbal tests. Appropriate doses of testosterone have a restorative effect. Animal experiments confirm this, in particular tests with older male rodents, who have been castrated and therefore deprived of their main source of this hormone, produce similar results.
Examination of these animals’ brains shows that testosterone treatment favored various signs of neural development, including richer dendritic morphology on neural cells and more new neurons (neurogenesis) in the hippocampus, a major site for memory formation. Furthermore, new synthesis of androgens is now known to take place in several male brain regions. Usually, such gene activity signifies the existence of an evolved trait, one that has a positive function. Additional research provides further evidence for improved neural function in the male brain in response to testosterone. 3
Furthermore, there is new evidence that implicates testosterone in the control of functions that have to do with mating but are not strictly reproductive ones. This is the property of “sexual selection”, discovered and first described by Charles Darwin. In a recent article, results were reported on the control of colouration in the plumage of male birds of the species the charismatic ruff (Calidris pugnax). There are three kinds of male plumage seen in this bird: 1) “independent males”, who are the showiest and the most aggressive in defending territory when courting; 2) “satellite males”, who are slightly toned down versions, in both plumage and behavior, but who hang around with first group and have more mating opportunities as a result and 3) so called “faeder” males, who look and act more like females, which allows them to blend in more and sneak in to mate with the real females. The genetic differences between these three kinds of male are all due to differences in levels of an enzyme that degrades testosterone in the blood, with the final levels determining both the plumage coloration and the behaviors. 4
This last example would seem to be more in line with the traditional notions of a sex hormone but the effects on behavior indicate additional roles in shaping neural circuitry. Since the estrogens and the androgens are found throughout the vertebrates, we can expect this to be a general finding: that sex hormones are not just about sexual development but have much broader roles in health and organ functioning, especially in the brain, quite possibly for all vertebrates but at least for birds and mammals.
There is a lot more that can be said about testosterone and estrogens, but I will end this piece with a more general comment on the phenomenon of pleiotropy. Can evolution account for it? Doesn’t evolution tend to select for one new trait at a time? Yes, it does but it always works from a precursor trait in doing so and that previous trait is usually not lost when the new one is acquired. In particular, every “new” gene has evolved from a preceding one. The over-all result is that, over long evolutionary time spans, genes tend to add jobs. They become multi-functional, thus pleiotropic. This often occurs when a gene duplicates itself, and the new copy then evolves to take on a new function. This almost certainly happened with estrogens and androgens, which are clearly chemically related, as one can see from their structures and the DNA sequences of the enzymes that synthesize them. Indeed, in the brain estrogen can be made from testosterone. This fact alone helps undermine the popular but false distinction between testosterone as the “bad” sex hormone and (by implication) estrogen as the virtuous “good” sex hormone.
For basic information about testosterone and estrogen, including their chemical nature and developmental and physiological effects, the Wickipedia entries are good.
See Gross, R.E. (2025). Sex hormones are brain hormones. What does this mean for treating brain diseases. The New York Times. http://www.nytimes.com/2025/04/22/health /neuroscience-estrogen-hormones.
Kuwahara, N., et al. (2021). Androgen effects on neural plasticity. Androgens: Clinical Research and Therapeutics 2.1: 216-218
The findings are reported in Loveland, J.L. et al. (2025). A single gene orchestrates androgen variation underlying male mating morphs in ruffs. Science 387: 406-412. A shorter account is given in “Perspectives” in that issue by K.A. Rosvall, “Adaptations in surprising places: testosterone is controlled while it circulates in the blood”, 387: 358-359.
Amazing and revealing article. This is the first time I read you and I wonder where I've been all this time. Thanks