Reproductive senescence, the time in a woman’s life marked by the slowing and eventual cessation of reproductive function, frequently coincides with an increased risk of a host of neurodegenerative disorders from memory impairment to dementia and Alzheimer’s disease. Researchers have long postulated that the loss of ovarian hormones was responsible; estradiol, in particular, but likely others as well.
This begs the question, what happens to the brain when we abruptly and artificially derail ovarian hormone synthesis in young women using drugs such as Lupron (leuprolide) and the other GnRH agonists and antagonists or by removing the ovaries altogether as in surgical oophorectomy? Is it the same damage we see in aging, only expedited and perhaps magnified, or does it run a different course? Along those same lines, though perhaps a topic for another day, what happens when we chronically supplant endogenous ovarian hormone production with synthetic hormones such as those used in hormonal birth control or menopausal hormone replacement therapies? I suspect, and there is evidence to back up my suspicions, that in all cases brain function is altered, and not for the better.
Estrogens and the Brain
The mechanisms by which estradiol and other steroid hormones influence brain function are myriad and complicated. Beyond just reproduction, steroid hormones influence all aspects of neurological function, with estrogen, androgen, glucocorticoid (cortisol), and mineralocorticoid (electrolyte balance, blood pressure) receptors located throughout the brain. Steroid hormones produced in the body, because of their fat solubility, easily cross the blood-brain barrier where they bind to their receptors and regulate all sorts of processes. Perhaps even more remarkable, the brain has all of the machinery to synthesize its own steroid hormones and so when body concentrations fall, at least for a time, the brain can compensate. Eventually, however, brain synthesis declines and that is where we begin to have problems. Fortunately, natural reproductive senescence occurs later in life and the risk of neurodegenerative diseases is just that, a risk, not a foretold conclusion. This suggests that other variables are at play, ones that we may be able to modulate to improve health, offset and/or reduce the severity of the natural neurodegenerative processes. Again, however, we must ask, what happens when we induce reproductive senescence in young women? By all accounts, the effects are often devastating, leaving many to wonder if they will ever recover.
Estradiol and Mitochondrial Energy
Among the myriad of functions mitochondria control, perhaps the most important is energy production. That is, mitochondria take the nutrients supplied by diet and convert them into adenosine triphosphate (ATP), the energy currency that cells use to perform all of the functions that keep us alive. The loss or diminishment of ATP is deleterious to health and can ultimately be deadly, by invoking a series of complicated processes
Estradiol is a critical component of that process and directly impacts mitochondrial energy production. That’s right, estradiol is part of the mitochondrial bioenergetic machinery such that when estradiol wanes, so too does energy production or ATP. As one might suspect, waning ATP is deleterious to brain health. In previous posts, I detailed the research showing how the loss of estradiol deforms mitochondrial morphology essentially disabling mitochondrial membrane potential while turning the mitochondria into misshapen donuts and blobs ripe for a slow, messy necrotic death; a process that evokes all sorts of deleterious reactions.
The Lupron Brain and Ketosis
Just recently, I stumbled upon research showing yet another mechanism of damage. In the absence of estradiol, brain glucose transport diminishes significantly. This effectively starves the brain for energy inducing severe bioenergetic deficiencies with all of the concordant neuronal damage one might expect. The reduction in glucose affects the mitochondria severely. Recall that glucose is one of the major fuel substrates of the brain, particularly where the Western diet predominates. The decline of glucose transport, therefore, is significant, and alone, without any other changes to the mitochondria, elicits a cascade of deleterious reactions. Oxidative phosphorylation and associated enzymes are downregulated, ATP production wanes, and ultimately may initiate the deformation of the very shape of the mitochondria, as observed in the research cited above. The ensuing reduction of ATP starves the brain of critical energy but also induces a state of hypoxia with the mitochondria incapable of utilizing molecular oxygen. With that hypoxia, inflammatory pathways are initiated further cementing mitochondrial death spirals and associated neuronal damage.
Interestingly, this reduction in aerobic activity coincides with the emergence of a ketogenic phenotype. That is, with the loss of one fuel substrate, ketones become the dominant source of fuel and the associated enzyme machinery is upregulated. Unfortunately, the Western diet is highly dependent upon carbohydrates and so a woman experiencing this loss of estradiol is not likely to consume sufficient fats and proteins to effectively weather this shift. Nevertheless, it does provide an opportunity for recovery. What if women who have lost the ability to produce sufficient estradiol either because of surgically (oophorectomy) or chemically (Lupron and other GnRH analogs) induced menopause adopt a ketogenic diet? Could we maximize the preferred energy source of the post-menopausal brain and reduce the neurological symptoms? I do not know the answer to that question, but given the severity of the suffering with surgical and chemical menopause, it seems worth the try.
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This article was originally published on November 15, 2018.
I can confirm with my personal experience that a ketogenic diet helps a lot! I went “clean” or “paleo” keto (lots of veggies which were organic, clean meats, no processed foods, healthy fats, lots of coconut products), lost the 15 lbs. I had been hanging onto for 7 years past having my 1st and only kid at 45, and quit Lupron, which I was on for the better of 3 years for breast cancer. Within a month, most of my symptoms were gone or mostly gone – the fatigue, the brain fog, the lower leg pain, the allodynia I’d get with every hot flash, the hot flashes, even my eyesight started to clear up.
I was excited, feeling like maybe I can get back to “normal” – normal diet and exercise which for me was at least Paleo and I’m a Pilates instructor, so a pretty healthy normal. So, after 3 months off of Lupron, I relaxed my diet and with COVID19 and quarantining, it was hard to exercise enough.
Big, fat (litteraly) ALAS. Yeah. I gained 20 lbs in 4 months and I wasn’t really eating that badly – still Paleo which is good healthy clean food, just higher carbs and allowing a dairy which is a little inflammatory in my system. It was (is) horrible! I went through some terrible depression, and the brain-fog returned and the fatigue came back (not as bad as before but it’s still my evil company) and my eyesight is blurry and sensitive to light. The light sensitivity is new. My hot flashes and accompanying allodynia have increased, tho not to the level they were before.
So, I’m back on the wagon. I think Lupron has forced my hand. I have to be lifestyle keto. It seems to be the only thing that “works” and will keep me safe for a longer life than cancer treatment could give me. Keto is good against many cancers too btw. And against so many ailments.
Other things I learned in my little relaxation experiment: coffee can add to depression and weight gain and maybe even throw you off your keto game if you have too much (the burst of cortisol can cause you to seek carbs for energy as well as make you put on weight); dairy is more inflammatory than I like to admit; I wonder how much being fat has caused, or at least contributed to these symptoms.