Estrogen, Hypothalamus Hormones and Brain Function – Part 1

By: Dr. Michael Lam, MD, MPH; Justin Lam, ABAAHP, FMNM


Hypothalamus hormones coming from the hypothalamusEveryone interested in Adrenal Fatigue Syndrome (AFS) is aware of the importance of the hypothalamic-pituitary-adrenal (HPA) hormonal axis in the body’s natural response to stress. This HPA axis sets in motion the cascade of responses that results in the adrenal glands releasing cortisol to fight the effects of stress on the body. In the brain, hypothalamus hormones start the sequence of other hormones being brought into play in the stress response.

High Importance of Hypothalamus Hormones

Ultimately, if stress is unresolved, adrenal fatigue can result. Once this fatigue sets in, not enough cortisol is released to deal with the effects of stress. Thus begins the set of symptoms frequently seen in AFS.

These symptoms are vague at first and not often seen as being connected by traditionally trained physicians during their evaluation of patients presenting with them. Symptoms such as continuing fatigue even after sleeping well all night, gaining weight around the middle of the body, not able to go to sleep, feeling anxious and depressed, suffering from allergies easily, difficulty concentrating, and brain fog.
Biochemically, as AFS progresses, cortisol levels tend to first rise but eventually fall. Your body responds to the lower level of cortisol in several ways. Stress will lead to your gut system developing what is called leaky gut, in which toxins, bacteria, and viruses leak from the gut into your bloodstream and throughout your body. This leads to increased inflammation and an overactive immune response.

In women, estrogen dominance begins playing a role in health, as cortisol precursors (such as progesterone) may be shunted towards cortisol synthesis. The reduction of progesterone can lead to a relative increase in estrogen, or a state called estrogen dominance. Symptoms include PCOS, endometriosis, fibrocystic breasts​, fibroids​, and even estrogen driven cancers.This overabundance of estrogen sets them up for very significant chronic illnesses.

Estrogen also may play a vital role in protecting women from some of these very chronic illnesses that can be brought on by an excess of the same hormone.

The Women’s Health Initiative Study

The Women’s Health Initiative (WHI) was an ambitious study designed to investigate effects of synthetic hormone replacement therapy with estrogen on women’s health. Its negative findings were significant enough to stop the study early. A major finding of this study was an increased risk of several serious medical conditions including heart attack, stroke, and breast cancer in women taking a specific combination of hormones.

These findings encouraged women to stop synthetic hormone replacement therapy and encouraged physicians to consider whether they would recommend this therapy to their patients. Unfortunately, the recommendations were not specific to the estrogens used in the research. Perhaps, this may have resulted in some women coming off needed hormone replacement therapy when they may not have needed to do so.
Several shortcomings in this study suggest the findings may not be as generalizable as they have been considered.

One significant shortcoming had to do with the choice of hormones investigated. Premarin is a conjugated equine estrogen made up of hormones and hormone metabolites from pregnant mare urine. Prempro is an estrogen-containing medroxyprogesterone acetate, a substance known to cause birth defects. Both of these are synthetic hormones and are not natural to the human body.

Estrogen can affect your hypothalamus hormonesEstradiol is the preferred naturally occurring estrogen for replacement therapy. Using a synthetic hormone or hormones from other species such as Premarin won’t give the desired results in a human female as compared​ to natural estrogens such as estradiol or estriol.

Another shortcoming in the WHI research was the dosage amount utilized. Low doses on a continuing basis with no consideration of the physical needs of the women regarding estrogen simply were not sufficient for the desired purpose. Estrogen fills many roles in the female body and levels vary, sometimes considerably, during a woman’s monthly cycle. Disregarding this changing need at different times in women’s physiology, even women going through or post-menopause, was a confounding factor in this research.

Yet another factor that limited the validity of results in this research was the delivery system.

This may have been the most serious limitation of the study because of some of the potential results of taking estrogen by mouth. These potential results include an increase in clotting factors that may bring about increased risk of blood clots, DVTs, pulmonary embolism, and stroke.

There could also be an increase in hormone binding proteins, such as SHBG, that could lead to significant detrimental physical results. An increase in mediators of inflammation, such as pro-inflammatory cytokines, could also result from orally administered estrogen. Increased blood pressure and weight gain are possible as well. One very significant, even critical, problem with orally administered estrogen therapy is the inhibition and reduction of human growth hormone.

These very significant problems with the WHI research may have led to the findings that prompted so many women to stop synthetic hormone replacement therapy on their own or to go to their physicians and request a stop in replacement therapy. Current research suggests strongly that estrogen is a necessary hormone for a number of reasons and that women whose estrogen levels are low due to menopause or other reasons may do well with replacement therapy – if administered correctly.

Relationship Between Hypothalamus Hormones and Estrogen

Hypothalamus hormones play several roles in women’s health. In general, hypothalamus hormones affect metabolism and the autonomic nervous system. While these hormones regulate body systems that operate within all people, there are specific connections with women’s reproductive systems and estrogen and these hormones controlled in part by the hypothalamus.

Estrogen and progesterone have an effect on gene expression and on activating protein synthesis through the estrogen and progesterone receptors in neurons in the anterior and mediobasal areas of the hypothalamus, respectively. These estrogen-sensitive neurons in the hypothalamus respond differently in males and females.

Estrogen also plays a major signaling role in hypothalamus hormones. It affects signaling in the major neuroendocrine and autonomic cellular groups of the hypothalamus. In this way, it plays a part in the releasing of the hypothalamus hormones as well.

Hypothalamus hormones also affect reproduction in females. Estrogen and luteinizing hormones operate in a positive feedback loop to prepare the uterus for implantation of a fertilized egg. Once an egg is released, progesterone inhibits the hypothalamus and anterior pituitary to stop this feedback loop.

If there is no conception, levels of progesterone decrease, stimulating the hypothalamus to secrete GnRH, gonadotrophin releasing hormone, to start the woman’s cycle over again.

This relationship between the hypothalamus hormones and estrogen is important for another reason, also. Recent research has shown estrogen to have a neuroprotective function in regard to protecting the brain and its neurons from inflammation and in the repair and remodeling of the brain. Appropriate levels of the correct types of estrogen will assist in the function of the hypothalamus through its protection of neurons.

Estrogen’s Neuroprotective Function

Hypothalamus hormones can affect your brainWith the rapidly increasing incidence of serious chronic health conditions – such as Alzheimer’s Disease, Parkinson’s Disease, and stroke – researchers and clinicians are eagerly seeking ways to prevent or lessen the severity of these conditions. The increasing length of human life spans makes these kinds of conditions more likely in the future.

Alzheimer’s affects roughly 4 million people in the U.S. Nearly half of those over 85 suffer from this condition. It is the most common cause of dementia in the U.S. for people over age 65. The number of people with this condition doubles for every five years of age over 65.
Parkinson’s affects about 1 million people in the U.S. One in 20 people over the age of 80 have Parkinson’s Disease.

These numbers indicate the severity of just two of the serious chronic health conditions that can be helped by estrogen of the right kind and in the right dose at the right time. Significant research has shown this hormone to help protect women from these aging conditions.

Animal research has shown estrogen to reduce the amount of neuronal death in rodents with stroke-like symptoms, traumatic brain injury, and Parkinson’s-like symptoms. Estrogens thus appear to have direct effects on neurons, although the exact mechanisms are just now being investigated and defined.

Some of these mechanisms may involve activated nuclear estrogen receptors, some of which are located in the hypothalamus, altering the expression of some proteins, activating the mitogen-activated pathway, and direct antioxidant activity.

Estradiol, the primary estrogen in humans, has been shown to delay onset or decrease the risk of Alzheimer’s and other neurological illness conditions. It also lessens the amount of cell death in conditions like stroke or brain injury.

Two mechanisms appear to be at work when estradiol lowers the amount of injury in these brain conditions. It may directly attack the neurotoxic stimulus that results in the illness conditions, or it may increase the ability of the brain to regenerate and repair itself after the injury or illness condition.

Estrogen and Stroke

One factor that increases the importance of estrogen’s neuroprotective function is the increasing age of women in the U.S. As more women age, their risk of stroke and other neurological disorders increases. One reason for this increase is that the age of menopause remains roughly the same.

Therefore, more postmenopausal women are living longer, meaning without the protective effects of naturally-occurring estrogen on their brain functions. They also will have more years without estrogen’s protection of the neurons of the hypothalamus. This will lower the amount of hypothalamus hormones available for these women.

Hypothalamus hormones can be affected by strokePrior to the time of menopause, women appear to be more protected from the risk of cerebrovascular accidents than men, likely due to the influence of a higher level of estrogen and other hormones controlled by the hypothalamus in their bodies. During and following menopause – as the levels of estrogen decrease – the incidence of stroke in women increases.

Clinical studies have shown the outcomes of these strokes in postmenopausal women to be worse than those of men. Disability and fatality rates are significantly higher for these women. Thus it appears the lower levels of estrogen and possibly other hypothalamus hormones decrease the protective factor enjoyed by women of pre-menopausal age.

In support of this contention, animal studies have shown estrogen to dramatically decrease the severity of stroke damage. This result does not appear to be due to any effect of estrogen on blood flow in the brain, but rather to its effect directly on the brain.

One of the hypothalamus hormones, the ovarian hormone 17beta estradiol (E2), performs a crucial role in many physiological functions. It operates through the estrogen receptors found throughout the brain. The most active form of estrogen, E2 may even work independently of the estrogen receptors in the brain. This would make the time for its effects much shorter, thus decreasing the effects of stroke faster.

Among the many effects of E2 on the brain are significant influences on memory formation, cognition, and motor coordination. All of these are detrimentally affected by the loss of function due to stroke. The application of E2 would appear to decrease the loss of function in these areas through its neurocognitive effects and the increased ability of the brain to repair and remodel itself following a stroke.

Read Part 2 | Part 3

© Copyright 2018 Michael Lam, M.D. All Rights Reserved.


Dr. Lam’s Key Question

Estrogen and other hypothalamus hormones have been labeled as dangerous by the researchers associated with the Women’s Health Initiative. Current research strongly refutes these results. This current research indicates estrogen replacement to be safe and very effective in alleviating menopausal symptoms and those of AFS.


hypothalamus hormones