alan jacobs md's blog

The Yin and Yang Relationship of Estrogen and Progesterone in the Brain.

I previously detailed 3 well-described patterns of catamenial symptoms that women report:  Type 1 - premenstrual, Type 2 - peri-ovulatory (mid-cycle), and Type 3 - luteal (throughout the 2 weeks from midcycle to menses).  Here I want to describe how and why the two reproductive hormones, estrogen (E2) and progesterone (P), have a yin / yang effect on the brain, so that these 3 patterns make sense.

Firstly, these hormones cause changes in our emotions and brain functioning by binding to specific docking sites (receptors) on specific brain cells in specific areas of the brain.  Estrogen is the yin.  When estrogen binds to its receptor on a brain cell, the brain cell fires faster and can use more glucose (sugar) and oxygen , its main fuels, faster.  Estrogen also increases the flow of blood to the brain cell so more fuel can be delivered faster.  These and many other similar effects make estrogen an energizing, mood elevating, "upper" hormone.  However, too much of a good thing is a problem here also, since too much estrogen effect ("unopposed" by progesterone) can bring anxiety, agitation and even seizures.  Progesterone is the yang.  It causes powerful restraints on a brain cell's activity and firing rates and also decreases the number of estrogen receptors on the cell, therefore directly blocking estrogen's effects.  These and many other related effects give progesterone calming, relaxing, anti-seizure even tranquilizing properties.  But, like we see in alcohol withdrawal (irritability, agitation, seizures), sudden withdrawal of progesterone can bring the same troubling symptoms.

The Type 1 (premenstrual)  pattern is the most potent and common because two things are happening that cause trouble as the menstrual cycle comes to an end:  1) progesterone withdrawals after 2 weeks of being at a high level and 2) estrogen remains high for a few more days once progesterone levels start going down, therefore leading to "unopposed" estrogen effects.  These  two conditions occurring at the same time pack a double wallop of over-excitement.  The Type 2 (mid-cycle) pattern is caused by one main event; the "unopposed" surge of estrogen that triggers the release of the egg (ovulation), a few days before progesterone levels rise to block the estrogen effects.  The Type 3  (luteal) pattern is less common but lasts for two or more difficult weeks.  Estrogen stays high after the mid-cycle surge, but the woman makes abnormally low levels of progesterone for the whole 2-weeks until menstruation.  This 14 to 16 days of high estrogen and low progesterone feels like "unopposed estrogen" the whole time.  the woman will report only one good week out of four (from day #3 to day #10) without agitating symptoms. 

In general, women are very good at noticing the specific pattern of their catamenial symptoms, whether they be seizures or mood changes or the like.  Our job as clinicians is to recognize these patterns and be able to listen and help.   

Why is anxiety more common in women with PCOS?

Researchers from the University of Pennsylvania Medical Center (Dokras, Anuja et al.) have published a new systematic review and meta-analysis in a November 29 online report in Fertility and Sterility investigating the prevalence of anxiety disorders in women with polycystic ovary syndrome (PCOS).  

They found 5 times as many women with PCOS having generalized anxiety symptoms compared with controls (prevalence - 20% vs. 4%) and a nearly sevenfold increase in the risk of generalized anxiety symptoms in women with PCOS (pooled odds ratio, 6.88).  They also found studies showing a higher prevalence of social phobia in women with PCOS and showing a higher percentage of obsessive compulsive disorder in women with PCOS.  

They ask clincians to begin screening all women with PCOS for both anxiety and mood disorders in order to refer them for appropriate evaluation and treatment.  They also ask for more studies to help better understand why anxiety is more prevalent in women with PCOS.

Neuroendocrinology provides a nice framework to understand why anxiety is more prevalent in women with PCOS.  PCOS is defined as chronic hyperandrogenic oligo-ovulation.  This translates to women being contiuously stuck in the first week of their menstrual cycles due to elevated androgens, like testosterone, mucking things up in the ovary and preventing them from ovulating except once in a while.  This then leads to a hormonal environment in the brain consisting of relatively normal levels of estrogen, but no progesterone.  If there is no ovulation, there is no progesterone production.  

Estrogen excites brain cells and brings energizing and then anxiety provoking effects and can eventually bring epileptic seizures, in women predisposed to seizures.  Progesterone is relaxing, anti-anxiety in its properties and will prevent seizures.  I have described estrogen and progesterone's relationship as like "yin and yang" upon the emotions.  

Therefore, the brains of women with PCOS spend weeks or months bathed in "unopposed estrogen", and if their brains are, for whatever reason, sensitive to the emotonal modulating effects of estrogen and progesterone, this brings anxiety, irritability and mood volatility.   The good news is that treatment with natural progesterone counters this estrogen effect and brings soothing, calming relief.  

 

An Interesting Case of Glucocorticoid Resistance

I saw a patient who was referred because of low sodium levels (hyponatremia).  He had experienced a very mild blunt head trauma and his doctors thought this had led to the hyponatremia due to the hormonal disorder called the syndrome of inappropriate antidiuretic hormone (SIADH).  Antidiuretic hormone (ADH) is normally secreted from the pituitary gland when sodium levels in the blood get too high and water needs to be reabsorbed from the kidney's filtered blood to dilute the blood back to normal.  If you make too much AHD you retain too much water in the blood and the concentration of sodium drops.  My view was that the degree of head trauma that my patient had experienced was far too mild to damage the pituitary system.  And, measurements of his ADH activity in the blood and urine showed the opposite situation of too little ADH activity, not excess.  I took note of a completely separate set of clinical facts in the case.

He had persistently shown blood and urine tests indicating very high levels of cortisol, an adrenal hormone related to stress.  His high cortisol levels were considered to represent Cushing's syndrome, the name given to the condition where a person's body is exposed to excess cortisol on a continual basis.  This leads to weight gain, especially around the midsection and face, fat pads around the neck, thinning of the skin with red stretch marks, high blood pressure, high blood glucose, and high sodium levels and many other symptoms that this patient did not have.  In fact his symptoms painted the opposite picture, with generalized weakness, weight loss, fatigue and low sodium levels, consistent with deficiency of cortisol, sometime called Addison's disease depending on the cause.  

Finding symptoms and signs of low cortisol effect in the face of chemical measures of excess cortisol in the blood and urine is indicative of cortisol resistance.  This is a rare condition in which the various tissues in the body are not responsive to cortisol, even with levels that are elevated.  Cortisol resistance can be inherited or acquired in life. One example is that AIDS patients are known to develop cortisol resistance with low levels of adrenocorticotropin (ACTH), the pituitary hormone that directs the adrenal gland to make cortisol.  The inherited form of cortisol resistance is associated with high levels of ACTH, indicating that the pituitary gland is also resistant to cortisol.  

In the end the hyponatremia had nothing to do with the head trauma, or even SIADH.  It was a sign of my patient's glucocorticoid (cortisol) resistance.  It is important to be aware of hormone resistance syndromes.  I have seen cases of thyroid, testosterone and cortisol resistance in my practice.  Of course, diabetes is characterized by insulin resistance.  In the situation of high or normal hormone levels with clinical signs of the hormone's deficiency, resistance to the hormone should be considered.  A mysterious case can occasionally be solved by thinking of this mechanism of illness.  

More Evidence For A Protective Role of Estrogen on Women's Brains

There is growing scientific support for a neuroprotective role of estrogen in women as they age, even as the question still exists as to whether there are risks to brain function that could outweigh the benefits of postmenopausal hormal replacement. 

In a new study (Differences in regional brain metabolism associated with specific formulations of hormone therapy in postmenopausal women at risk for AD, Psychoneuroendocrinology (2011) 36, 502-513), Daniel H.S. Silverman et al. publish the results of a prospective, randomized longitudinal clinical trial in which postmenopausal women age 50-65 on different formulations of hormone replacement therapy and at increased risk for Alzheimer's disease were evaluated with cognitive tests and functional brain imaging with positron emmission tomography (PET) at baseline and after two years of either treatment with, or discontinuation of, hormone replacement therapy.

They were able to show evidence of relative preservation of function in specific brain regions in all the women that was associated with longer esposure to bodily estrogen (age of menopause minus age of menarche).  Moreover, women taking bio-identical 17-beta estradiol (E) performed far superior to women on congugated equine estrogens (CEE) on tests of verbal memory, and had higher functional measures in language and verbal memory areas of their brains on the PET scans.  Women taking progesterone-plus-estrogen compounds had lower function scores compared to women on unopposed estrogen in other specific brain regions. 

These findings further support a neuroprotective role for estrogen, at least in middle age women at increased risk for the future development of AD.  How these results can be generalized to all women remains to be seen, however, this study supports the idea that current decisions about whether a woman should take hormone replacment therapy after menopause, how long she should take it for, and in what formulation she should take it, should consider her risk profile for future AD and should consider 17-beta estradiol as the estrogen to use.  Whether natural micronized progesterone mitigates these benefits less than synthetic medroxy-progesterone acetate remains to be determined by future studies.

The Stakes in the Race to Prevent Diabetes are Getting Bigger

Two recent articles offer us bookends around the topic of overweightness, prediabetes and diabetes, and brain dysfunction. At one end is a study by Laura Baker, PhD, et al. (Arch Neurol/vol 68 (No.1), Jan 2011 pp 51-7.), which showed that insulin resistance in cognitively normal adults around 70 years old with prediabetes or diabetes was associated with a pattern of decreased brain function on positron emission tomagraphy (PET) scans that mimicked the same pattern seen on PET scans of patients with early Alzheimer's disease (AD).  Moreover, when compared to healthy adults matched for age, education, body mass index and fasting blood sugar levels, the patients with insulin resistance showed subtle cognitive impairment on a memory task, as if their "normal aging" was somewhat accelerated. 

At the other end of the topic is an article by Traustadottir, PhD and Tsitouras, MD (in Clinical Geriatrics Nov/Dec 2010, pp 22-6.), which review evidence-based guidlines for exercise prescriptions for individuals at risk for diabetes because "The undisputed first line of management of prediabetes and type 2 diabetes is through diet and exercise, usually described as the "cornerstones" of treatment, management and prevention."  They give evidence for the clinical recommendation of a combination of moderate to vigorous aerobic exercise (3-5 days per week) and moderate to high intensity resistance training (2-3 days per week) to achieve increases in insulin sensitivity and control of blood sugar.

Insulin resistance occurs when insulin becomes less effective at lowering blood sugars.  It is associated with genetic factors, but also with a sedentary lifestyle, obesity, stress and many other conditions.  It is known to increases the risk of heart disease and vascular disease. It is also well known that physical fitness through diet and exercise brings with it improved health status and well-being and greatly reduces the risk of weight gain and insulin resistance.  Yet, two-thirds of the US population are either overweight or obese and prediabetes and diabetes, either accompanied or preceded by insulin resistance, occur in more than half of the US poulation over 60.  Now that studies are revealling that insulin resistance also increases the risk of brain dysfunction and that physical fitness through proper dieting, aerobic exercise and resistance training can help to prevent and control insulin resistance, we have a stronger arguement than ever that physical fitness and weight control should be adopted as a logical, low-tech way to help maintain cognition and prevent dementia, especially since "short-cut", high-tech ways to treat insulin resistance are not yet known.

Another Piece of the Post-Finasteride Hypogonadism Puzzle?

The persitence of male sexual side effects (hypogonadism) after discontinuation of finasteride is a serious problem for a significant subset of men who use the drug.  I  had previously written about whether the propensity of finasteride to cause lasting hypogonadism could be due to the development of partial androgen resistance and whether this relates to the number of CAG repeats in exon 1 of their androgen receptor genes.

Recently, a patient of mine brought to my attention a research paper from Csoka, et al.(J Sex Med 2008;5:227-233) titled "Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors".  They added 3 well-characterized case reports to the half dozen or so that were already in the literature and cited studies probing underlying mechanisms for the problem.  Their fourth proposed mechanism relates to a growing field that has caught my attention in a big way, the field of epigenetics.   They note that antidepressants can cause complex changes in the expression of genes.  They cite animal research that has linked SSRI treatment during youth to permanantly decreased sexual behavior that persits into adulthood and that has explored underlying mechanisms for this including brain epigenetic changes at the molecular level. 

Epigenetics is a field that concerns the complex web of proteins that surround our DNA.  These proteins include histones, which help package and unpackage our genes to either turn on or turn off their function. "Acetylation" and "methylation" are chemical reactions that alter the histone's function, which in turn alters the expression of our genes.  Within this emerging field may lie a new mechanism by which a drug can cause persistent changes in gene expression that can influence sexual behavior.

This brings up the idea that there is a common epigenetic mechanism that may apply generally to medications that cause persistent sexual dysfunction.  It may be the case with finasteride that a common epigenetic effect interacts with a less common variant in the androgen receptor gene CAG repeat profile to cause its syndrome of crippling persistent post-finasteride hypogonadism.

Human research in this area has yet to be done, but holds promise for new therapies to treat this troublesome side effect of finasteride and other widely used medications.

Catamenial Epilepsy - "What To Expect When You Are Expecting".

In response to a recent question posed to me from a woman concerning what to expect in terms of the frequency of her seizures as she goes through a pregnancy and breastfeeds her baby, I though it would be useful to expand on this topic in a blog post - a sort of "what to expect when you are expecting" from a catamenial epilepsy/neuroendocrinology perspective.  

Recall that estrogen provokes epileptic seizures and progesterone inhibits them.  When a woman becomes pregnant the cyclic production of estrogen and progesterone that brought the catamenial onset of seizures  comes to an end and the levels of both hormones rise steadily for the next nine months until birth.  Because of the sky-high progesterone ('promote-the-gestation') levels, women with catamenial epilepsy almost always report a decline in seizure frequency throughout the 3 trimesters, often they are seizure-free (even though estrogen is high also). 

As labor and birth occur the levels of both hormones decline dramatically.  From the seizure perspective this is also a relative seizure-free hormonal environment.  And if a woman breastfeeds, the levels of estrogen and progesterone remain suppressed (so that another pregnancy does not occur too soon).  Once nursing is done and the menstrual cycle returns, then the catamenial pattern of seizure occurrence typically returns and cyclic progesterone therapy will again be needed for seizure control. 

One important issue to consider is when women with catamenial epilepsy experience a post-partum mood drop or depression.  This is triggerred by the drop in estrogen and treating with estrogen will help, but if the estrogen is not pared with natural progesterone, then seizures will be provoked.  Of course, there will need to be a careful balancing of the two hormones, since progesterone will not raise mood (though it will reduce anxiety very effectively in this setting).

Incremental Progress In Defining the Proper Use of Testosterone As Therapy

The wealth of recent public interest in, and scientific investigation of, testosterone as a neuroprotective hormone that can increase brain cell defenses against Alzheimer's disease(AD)-related insults in men and the rising demand to test optimal ways of using androgens in men to delay, prevent, and or treat AD has reintroduced the idea of giving elderly men testosterone therapy. 

Two recent articles from June 2010 in the New England Journal of Medicine have looked directly at the issue of testosterone and its safety and proper use in older men and attempt to further our larger understanding of how to incorporate hormone therapy in the promotion of successful aging. 

The first, titled "Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men" (NEJM June 16, 2010) defines evidence-based criteria for identifying which symptoms in the general aging male population are to be considered due to low testosterone as opposed to aging itself, and what level of testosterone in an aging man should rightly be labeled as low.  Their conclusion was that at least 3 sexual symptoms (poor morning erections, low sexual desire and erectile dysfunction) in the presence of a total testosterone level of less than 320 ng/mL and a free testosterone level below 64 pg/mL defines the minimum criteria for diagnosing late-onset hypogonadism as opposed to nonspecific symptoms of male aging.

The second study titled "Adverse Events Associated with Testosterone Administration" (NEJM June 30, 2010) asked whether giving testosterone to 65 + - year old men with evidence of limitations in mobility (e.g. difficulty walking 2 level blocks or climbing 10 steps) and low total testosterone levels between 100 and 350 ng/mL would be safe and would increase their strength and performance.  The study had to be stopped early due to an increased risk of cardiovascular adverse events (e.g. arrythmia, stroke, cardiac stenting procedures) in the testosterone group compared to the placebo group.  There was a high prevalence at baseline of high blood pressure, diabetes, obesity and high cholesterol in all participants.  Interestingly, the men in the testosterone group that could be tested showed significant improvements in leg and chest strength and in the ability to carry a load while climbing stairs. 

Obviously, a lot of work lies ahead to teach us the safest and best use of hormone therapies in aging men and women, and these studies are an important part of that work.

A Proposed Mechanism For Prolonged Sexual Side Effects From Finasteride

Several young men seen for hypogonadism (low libido, erectile dysfunction, low energy, etc) after using finasteride have been found to have low-normal levels of bio-available testosterone and LH.  This leads to the question of whether partial androgen resistance is at play.  It has been shown that androgen insensitivity can occur even without mutations in the genes coding for the androgen receptor¹.  How then to connect finasteride use to the development of partial androgen resistance, especially outlasting the use of the drug?

In recent years many scientists have looked at the androgen receptor gene with an eye towards a variable length of its structure in one particular region called exon-1.  In this region the number of CAG repeats, which code for glutamine (an amino acid-building block for the protein that becomes part of the receptor), vary between approximately 10-25 in different individuals and this variability has been linked to variable effectiveness or potency of androgens (testosterone(T) and dihydrotestosterone (DHT)) in these individuals. In other words, the number of these CAG repeats in the gene for the androgen receptor will effect the functionality of androgens in a man in various tissues in his body and even in his psychological traits².  This variability can cause hypogonadism in men with normal levels of testosterone, which is what androgen resistance is.

Many recent studies have looked at the CAG-repeat length of the androgen receptor in the setting of various clinical settings and found a causal relationship:  in mediating the expression of testosterone deficiency on depressive symptoms, on personality traits (neuroticism, extraversion), amygdala reactivity to threat-related facial expression, body composition (muscle and fat) and circulating levels of sex hormones in young and aging men,  on memory function in women, and even to solitary sexual desire in male-to-female transexuals.  One study in 2005³ linked the effectiveness of finasteride on men with baldness with the number of these CAG triplet repeats; the smaller the repeat number, the higher the improvement with finasteride.  

I am wondering whether the propensity of finasteride to cause lasting partial androgen resistance in a subset of men relates to the number of CAG repeats in exon 1 of their androgen receptor genes, perhaps those with the greatest number of repeats are at highest risk.  I cannot even guess how finasteride would do this after the drug is discontinued, but it is certainly a testable hypothesis.  Take 2 groups of men, one group without any post-finasteride hyposexuality and one group with, and measure the androgen receptor gene CAG repeat length in both groups and compare.  If it is the case, then men could be assessed, by a blood test prior to using finasteride, as to the risk of developing prolonged hypogonadism from the drug.  

1. Clin Endocrinol (Oxf). 1996 Dec;45(6):733-9.

2. Int J Androl. 2003 Apr;26(2):76-83.

3. J Investig Dermatol Symp Proc. 2005 Dec;10(3):293-4.

 

Healthy Brain Aging? Not Only Estrogen, But Testosterone Too.

Another interesting Mens' issue in Neuroendocrinology has recently been in the scientific news concerning testosterone and Alzheimer disease (AD).  Testosterone's brain protective properties have been suggested based on observations linking low blood levels of testosterone with increased risk for AD in older men.  There is ample evidence from population-based and animal-based studies that testosterone protects brain cells, even from beta-amyloid, the protein thought to be a major player in causing AD.  However, many scientists thought testosterone's benefits came indirectly from its conversion to estrogen in brain cells.  As I have blogged about before, the enzyme aromatase does this conversion.

Now researchers at the Banner Sun Health Research Institute in Sun City, AZ have taken a strain of mice genetically modified to get Alzheimer brain changes as they age and have genetically modified them further to completely lack the gene for aromatase, such that these 'Alzheimer mice' cannot convert testosterone to estrogen at all (Li, R. et al. J. Neursci 2010 May 26; 30:7326-34.). What they found in the males mice was that they had higher levels of testosterone in their blood and brains, that they were more protected from the Alzheimer-like brain changes and that they performed better on 'cognitive' tasks.  And of course all of this was due to testosterone's direct effects, not by conversion to estrogen. 

The researchers went out of their way to point out that their studies do not exclude a beneficial role for estrogen in the male brain also.  They do not yet advise giving men existing medications that block aromatase (aromatase inhibitors) to prevent AD.  But, they provide more evidence to support the development of drugs called selective androgen receptor modulators (SARMs) that will stimulate only brain testosterone sites and leave sites such as the prostate gland alone.  There are already selective estrogen receptor modulators (SERM's) available to women and there is a race to develop brain-specific SERMs. (Female double gene-modified mice get accelerated AD brain changes!)  Apparently, the government is currently sponsoring a study that will examine the benefits of testosterone with an aromatase inhibitor in older men at risk for AD.

The Plot Thickens, Along With The Hair, When You Mess With Dihydrotestosterone

As I involve myself in the biology underlying the finasteride and post-finasteride-associated hypogonadal syndrome and parallel "brain fog" syndrome many men experience, I have focused on the metabolism of dihydrotestosterone (DHT), the hormone that finasteride inhibits by virtue of its blockage of the 5-alpha reductase enzyme that normally converts testosterone to DHT (along with several other reactions it normally does that form potent neuroactive anti-anxiety and seizure preventing hormones in the brain).  Moreover, I have written here about the role of estrogen in the brains of women (e.g. cognition, neuroprotection) and the fact that we men need estrogen in our brains also.  We get it by converting testosterone to estrogen in brain cells by a different enzyme called aromatase.  One might think these two pathways for testosterone conversion, one to DHT and one to estrogen, are separate and distinct.  Interestingly, several brain areas important for controlling male sexual behavior use estrogen derived from testosterone.  

When a man takes finasteride to block DHT and save his hair, he is likely unaware of the complexity of this hormone's actions involving sexual behavior, stress responses, cognition and more.  However, a study I recently read, Handa, RJ et al. Hormones and Behavior 53 (2008) 741-752, describes an alternative pathway for androgen regulation of brain function by estrogen receptors triggered by metabolites of DHT.  In other words DHT, 10 times more potent than testosterone, can itself be converted to compounds that bind estrogen receptors (ERbeta) but are not estrogen.  One of these, called 3-alpha Diol, is also a neuroactive steroid that enhances the inhibitory compound GABA in the brain (like benzodiazepines and barbituates).  Another, called 3-beta Diol, can act through estrogen receptors to decrease anxiety and regulate the cortisol system's response to stress.  Without going into too much detail here, the important point is that DHT is involved in a number of metabolic pathways in the brain that create androgen-related and estrogen-related compounds that have effects on all these areas of behavior, some as promoters and others as inhibitors, some at androgen sites and others at estrogen sites, and, in at least a subset of men, interfering with this complex web of reactions by blocking DHT, may bring a lot of unwanted extra effects along with the preservation of hair.