Does loss of sexual fertility trigger Alzheimer's disease?

n recent years, it's become fashionable to talk about “testosterone poisoning.” Feminists think it's funny to say it, and last week James Cameron, the Hollywood director of Terminator, complained that he suffered from it. He should be careful what he wishes for. We have treatments for that. Boy, do we have treatments!

Let us assume he doesn't want the dreaded surgical option. Fine. We have seven different types of drugs that can fix him: steroidal anti-androgens, non-steroidal anti-androgens, androgen synthesis inhibitors, 5α-reductase inhibitors, androgen receptor antagonists, GnRH agonists, and GnRH antagonists.

What makes all this interesting is that there's a big debate in science as to whether these treatments cause Alzheimer's disease, or AD. The evidence is not yet conclusive, but it appears that for both sexes a decline in fertility, whether natural or artificially induced, may serve as a trigger for dementia. It also raises questions about the long-term safety of puberty blockers.

For women, the evidence is now pretty strong. It is now well understood that the reason twice as many women as men have AD is not related to their longer lifespan. (In any case, the lifespan difference has continually decreased since women entered the workforce in large numbers.) The higher rate of AD among women is due to the same factor that increases their susceptibility to autoimmune disorders: differences in the immune system between the two sexes.

After years of confusion, it was finally realized that ERT, or estrogen replacement therapy, doesn't protect women from AD if it's started more than five years after menopause. Only if started immediately, providing a continuous supply of the hormone, does ERT protect.

A big paper just came out showing that females with AD have as much as ten-fold higher levels of S-nitrosylated C3 ^[1]. This was discovered by a technique called SNO-TRAP, which is an acronym for protein S-nitrosylation with a triaryl phosphine probe. C3 is a protein that's an important part of the innate immune system, which is known to be involved in AD. When C3 gets nitrosylated, it triggers synaptic pruning, which causes depression, loss of neurons, and probably dementia. β-estradiol prevents S-nitrosylation, which suggests a mechanism by which HRT might work.

Likewise, men given testosterone blocking drugs after being convicted of sex crimes—a treatment known as chemical castration—have a higher incidence of AD. Low testosterone is one of the biggest, and least publicized, risk factors for Alzheimer's disease. It doesn't necessarily follow that watching Terminator II or going hunting will protect you. It's not even clear whether taking supplements would help either. But it's almost as if, for both men and women, the end of their reproductive life in many cases signals the beginning of the end.

This makes sense from a behavioral genetics point of view: as far as nature is concerned, the end of reproductive life means the end of an animal's value for the species, so a programmed death for the individual almost makes sense. Individual cells undergo programmed death. Is it possible that there is some unknown death program for the individual that is triggered by a loss of fertility?

In mice, depletion of endogenous androgens increases tau phosphorylation, a sign of neuronal death ^[3]. It's not clear how this relates to humans. While total testosterone remains stable in men from 40–69 unless they suffer from obesity and ill health ^[2], testosterone binds to SHBG (sex hormone-binding globulin), which increases with age. This means the calculated free testosterone, or cFT, decreases with age more than total testosterone. In a small postmortem study of 22 men aged 60–89, cFT was lower in AD. Even so, cFT did not correlate with PiB retention, which is to say it wasn't correlated with β-amyloid brain levels indicated by PET scan ^[4].

It might seem ironic that higher estradiol in men is also associated with increased risk ^[5], but it must be kept in mind that sex hormones have entirely different functions in the brain than in the periphery. While testosterone replacement therapy causes an improvement in sexual function, it doesn't restore cognitive function, so Yeap et al. ^[6] concluded that testosterone is a biomarker, not a therapeutic target. Their hypothesis is that testosterone loss occurs along with cardiovascular events and diabetes, both of which are thought to be risk factors for AD (along with air pollution, lower education, smoking, obesity, alcohol consumption, traumatic brain injury, hypertension, physical inactivity, and low social contact). In another study, testosterone treatment reduced or reversed type 2 diabetes, a risk factor for AD, in high-risk men, but other studies found no effect on cognitive ability or memory. So the evidence for benefit from hormone replacement therapy for men is so far inconclusive.

Most of these risk factors are controversial. The air pollution theory was recently challenged in a big clinical study ^[7], and the definitive word is not out. Another study found that air pollution increased AD in non-smokers but had no effect in smokers, suggesting that either (a) nicotine protects or (b) smokers inhale so much crap already that any pollution from the air makes no difference.^[18]

Androgen deprivation therapy (ADT)

The strongest evidence of a link between androgens and AD comes from a big statistical analysis of 23,651 men with prostate cancer, which is commonly treated with antiandrogens to block testosterone production or function. They found that 6.4% of patients treated with antiandrogen monotherapy got dementia ^[8]. Another study showed that GnRH agonists ^[9] lead to increased risk of cardiovascular disease with 33% having death, MI, CVA, TIA, or other cardiac-related hospitalization ^[10] but found no difference for GnRH agonists in dementia ^[11]. A meta-analysis ^[12] confirmed these findings, so maybe GnRH has a temporary reprieve. However, many studies are hampered by the reliance of β-amyloid and phospho-tau as the only accepted biomarkers ^[13].

Thus, it's not yet clear how anti-androgen therapy could induce AD, as it has numerous side effects including weight gain and insulin resistance that can result in type 2 diabetes ^[14]. One enormous observational study of 1,238,879 Medicare beneficiaries, 35% of whom got ADT, showed no effect ^[15]. But such “big data” studies are known to have many limitations due to heterogeneous data and other factors ^[16]. As with most current cancer treatments, patients initially respond to ADT but develop resistance, called castration-resistant prostate cancer (CRPC), which has a very poor prognosis ^[17].

Puberty blockers

The question few scientists are asking is: some of these same drugs used to chemically castrate sex offenders and prostate cancer sufferers are now being given to teenagers and even children who, it is claimed, have gender dysphoria. What will happen to these children? Are they being condemned to a lifetime of poor health and possibly even an early death from dementia? I guess we'll find out in forty or fifty years.

dec 16 2022, 6:51 am