alan jacobs md's blog

Premenstrual Syndrome - An example of normal hormones/anomalous brains

I had mentioned in a previous post that one way to become a neuroendocrine patient is to possess an anomalous brain in the setting of normal hormones (the other ways were -  normal brain, anomalous hormones and anomalous brain, anomalous hormones).  Here is a research study that demonstrates this idea in the context of premenstrual syndrome (PMS) from N Engl J Med. 1998 Jan 22;338(4):209-16.

PJ Schmidt et al. from the National Institute of Mental Health set out to induce a reversible chemical menopause in 40 women split into 2 groups - 20 with PMS and 20 without PMS(normal).  They gave 10 PMS women and 10 normal women a drug called leuprolide, which fakes the brain/pituitary gland into thinking there is more than enough estrogen and progesterone around and thus causes the pituitary to go quiet and stop stimulating the ovaries to make estrogen and progesterone.  The resulting absence of estrogen and progesterone mimics menopause.  They gave the other 10 PMS women and 10 normal women a placebo.  The 10 PMS women put into "menopause" with leuprolide saw a disappearence of their PMS symptoms.  The 10 PMS women on placebo did not. 

They then took the 10 PMS women whose PMS-symptoms went away on leuprolide  and the 10 normal women on leuprolide and added back estrogen alone for 4 weeks and then progesterone alone for 4 weeks, each time concealing from the women which hormone they were on or whether they were on placebo pills.  The women all rated their own symptoms and also had independent raters rate their symptoms.

Giving the PMS women on leuprolide estrogen or progesterone brought back their PMS symptoms where as giving back these hormones had no such effect on the moods of normal women on leuprolide.

The conclusion of the researchers was that women with PMS have an abnormal emotional response to normal hormone changes.  This abnormal emotional response is the "anomalous brain substrate" I have previously referred to.  Markers of anomalous brain substrate have been identified and consist of things such as a history of mild head trauma or mild abnormal electroencephalogram (EEG) findings, or asymmetrical reflexes on a neurological examination, a family history of major mood disorders, even left-handedness.  These sorts of markers are seen with significantly greater frequency in women with agitated PMS compared to women without PMS.  It is as if these conditions, or something underlying them, render the woman's brain sensitive to the emotional modulating effects of their own reproductive hormones.  Even in PMS women without such overt markers, scientists are actively looking for, and have begun to find, subtle genetic and acquired influences on brain chemistry and brain circuit excitability to explain this sensitivity. 

My only surprise with the results of this study was the seemingly similar negative effects of estrogen and progesterone on the moods of these PMS women.  In my own neuroendocrine practice I have almost universally seen estrogen and progesterone have opposite effects in women, both on the emotions of women with agitated PMS (estrogen bringing agitation and progesterone bringing calmness) and on brain cell excitability in women with seizures (estrogen pro-seizure and progesterone anti-seizure).

An Interesting Study Linking Estrogen, Cognition and Menopause

This week I am summarizing a recent interesting article concerning the relationship between menopause and cognition, as influenced by estrogen exposure.  I have long wondered whether the subset of women who experience cognitive changes/decline associated with the menopausal transition do so because of estrogen decline directly or because of an underlying risk profile relating decreased brain levels of estrogen to preclinical Alzheimer's disease.

 

Accelerated postmenopausal cognitive decline is restricted to women with normal BMI: Longitudinal evidence from the Betula project

Psychoneuroendocrinology, May 2010.  Vol. 35, Issue 4, Pages 516-524.

Petra P. Thilers, Stuart W.S. MacDonald, Lars-Göran Nilsson, Agneta Herlitz

 

The researchers sought to answer the important question of whether women experience systematic changes in cognition following the onset of menopause.  They also explored the interesting question of whether a woman’s body mass index (BMI) influenced any changes related to menopause.  Higher BMI is associated with higher levels of circulating estrogens, due to their increased production in fat tissue, and estrogen has been extensively researched in terms of its role in enhancing and protecting cognition and even in protecting the brain from Alzheimer’s disease (AD).  The study followed 193 women between ages 40-65 years with extensive cognitive testing and measures of BMI longitudinally in the transition from pre- to late stages of post-menopause over a 10-year period.  The results showed that, compared to performances premenopausally, postmenopausal women had a reduction in performance on measures of attention and visuospatial processing. Also, women with a normal BMI (18.5-25) had a more rapid decline than women with a BMI above 25 on measures of memory and visuospatial processing.  These results support the notion that reduced production of estrogen after menopause may have small negative influences on cognitive abilities, mainly in women within a normal BMI range, implying that the extra estrogen created in the extra fat tissue associated with a high BMI can mitigate this negative influence on cognition.  Of course, these results do not directly deal with the question of any potential long-term benefits of estrogen exposure in the 5-7 years following menopause on a woman's later risk of AD, which is also an active area of scientific research.

What Links Our Hormones And Our Behavior?

An important piece of the neuroendocrine puzzle that brings together our hormones and our behavior, leading to conditions such as premenstrual syndrome (PMS), catamenial epilepsy and stress related menstrual disorders is the area of our brains called the temporal lobes.  We each have a right and left temporal lobe on each side of our brain.  They point forwards on each side like very large thumbs, with the tips pointing forwards towards the backs of our eyes.  The lateral side of the temporal lobe could be seen directly if one were looking at a brain from the side.  The inner or medial side of the temporal lobe faces the center of the brain and would be hidden from view from the side.  This medial portion of the temporal lobe is where our emotions, our hormones and epileptic seizures meet and interact.

The medial temporal regions are home to two central parts of the limbic system.  The limbic system is a group of interconnected brain areas that are related to experiencing emotions and deploying the right emotion in the right way at the right time.  The two central parts of the medial temporal lobe are the hippocampus and the amygdala.  The hippocampus is our "organ of short term memory" and the amygdala is where emotional relevance is mapped onto our memories.  If we receive a painful bite by a snake, the fear memory that will arise the next time we see the snake is a product of the amygdala and the hippocampus working together to protect us. 

Importantly, the limbic system is also the region of our brain where all the estrogen and progesterone binding sites or receptors are.  These receptors are like tiny locks on the surface of our brain cells and the hormones serve as the key that fits in the lock and causes the cell to do something.  An example of how this hormone/limbic system connection helps us is shown when a woman who is under great emotional and physical stress loses her periods and becomes temporarily infertile.  Her brain seems to know it would be a poor time to support a pregnancy when so much of the woman's resources must be used for her own survival.  The medial temporal lobes can shut down the woman's menstrual cycle by their connections directly to the lower hormone centers, the hypothalamus and pituitary gland, which can suppress their functions until a time when all the emotional and physical stress has gone away.  Then the woman's periods and her fertility will return.

The medial temporal lobes, especially the hippocampal regions, are also very prone to epileptic seizures.  One reason is their position right behind the "windshield" or front inner part of the skull, behind the face.  When our moving heads hit a stationary object in traumatic brain injury, the temporal lobes crash into this "windshield" and get bruised and scarred in these limbic regions.  This is one reason why temporal lobe epilepsy is so prevalent.  There are also reasons specific to the circuitry of the hippocampus that render it so seizure prone. 

Therefore, because of its affiliations with our emotions and our memories and our hormones and with the lower brain centers that control their secretion, the medial temporal lobe and its limbic system is in a perfect position to link our emotions and behavior with our hormones and our seizures (when present) to cause PMS, catamenial epilepsy and stress-related menstrual disorders.     

 

A Neuroendocrine Approach To Finasteride Side Effects In Men

I have recently seen an increasing number of men who have developed significant degrees of clinical hypogonadism - low sex drive, erectile dysfunction, reduced sexual sensations and listlessness, fatigue and/or "brain fog" - while either taking finasteride or after stopping the medication, even long after stopping it.  Finasteride is a medication approved by the FDA to treat benign prostate enlargement and testosterone-related hair loss.  It does so by blocking the function of an enzyme called 5-alpha reductase.  This enzyme normally converts testosterone to dihydrotestosterone (DHT), which is a more potent hormone that acts at the prostate and the hair follicles.  The occurrence of these symptoms in the setting of being on, or even after stopping, the medicine presents a compelling neuroendocrine problem.  And it is reasonable to assume that not all men suffer from the exact same cause.

The investigation of this problem begins with measuring blood levels of the testicular hormone testosterone, DHT and luteinizing hormone (LH) and follicle stimulating hormone (FSH), which are the pituitary gland's hormones that stimulate the testicles to make testosterone, and also estradiol, a "female" hormone that is present in men, but in much smaller amounts than in women.  Small elevations in estradiol  in men can have noticeable anti-testosterone effects. 

If testosterone is low and LH and FSH are high, then the problem is testicular.  If testosterone is low and LH and FSH are low or even normal, then the problem is "upstairs" either in the pituitary gland or in higher brain centers that control hormones.  Depending on the outcome of this evaluation, treatment first and foremost involves giving enough testosterone to bring high normal levels (by gels or intramuscular shots), while blocking the conversion of some of the testosterone to estrogen, which happens naturally in fat tissue.  There is a pill for this. 

If high normal levels of testosterone, combined with low estrogen levels, does not relieve the hypogonadal symptoms, then the possibility that the man has some resistance to testosterone must be considered.  This would be akin to the insulin resistance seen in diabetes and would be treated in a different manner.   An MRI of the pituitary gland would be indicated if LH and FSH are low or normal, at the same time that testosterone is low, to exclude the possibility of a benign tumor impairing the pituitary's ability to respond to the low testosterone. 

Finally, other brain hormones can be effected by finasteride.  These are called neurosteroids and their decline can bring anxiety and depression.  These neurosteroids cannot yet be measured commercially with blood tests, but the "brain fog" some men experience on finasteride may result from disturbances in attention caused by anxiety or mood changes.  

Finasteride certainly helps men fight hair loss and prostate enlargement.  However, a considerable number of men have intolerable and sometimes persistent side effects from the medicine.  A systematic neuroendocrine approach to this problem should shed light on the cause in a majority of cases and bring relief.