We are witnessing an explosion of interest in endocrinology in psychiatric illness. This interest is two-fold. Psychiatric illness is profoundly influenced by the endocrine milieu. This includes normal and cyclical changes in hormone levels as well as abnormal hormone levels such as occurring under conditions of profound stress. Secondly, classic endocrine disorders are a cause of psychiatric illness. Perhaps more interestingly, subtle endocrine alterations can lead to subtle to profound psychiatric symptoms. How may we influence neuroendocrine states to alter the outcome of psychiatric illness.? My initial study of endocrinology and the emerging field of hormone receptors kindled my interest in psychiatry in the 1970s. While on the faculty at the University of Iowa , I discovered that many patients were poorly served by psychiatry because they presented with subtle endocrine abnormalities and psychiatric illness that was poorly understood and therefore poorly treated by specialists in endocrinology and psychiatry. This led me to pursue a career in psychiatry and endocrinology and ultimately psychoneuroendocrinology. This field now includes an international society, The International Society of Psychoneuroendocrinology and a monthly journal, Psychoneuroendocrinology. What can be learned from seeing a psychoneuroendocrinologist? Why should you see this specialist? What is Psychoneuroendocrinology? Psychoneuroendocrinology is the clinical study of hormone fluctuations and their relationship to psychiatric illness. It is subtle blend of endocrinology and psychiatry. The brain is increasingly viewed as an organ secreting hormones. This observation cements the relationship between hormones and behavior.
Bioidentical hormones or so-called “natural hormones” are plant-derived hormones which are identical in structure to endogenous hormones produced by the body. Because bioidentical hormones have low absorption with oral administration, they are frequently formulated as a gel to be applied topically to the skin. They include estradiol, estriol, estrone, and progesterone. They are usually formulated by compounding pharmacies. Bioidentical hormone replacement therapy (BHRPT) is typically used to relieve symptoms of menopause, but is also prescribed for its alleged anti-aging effects. Bioidentical hormones have been promoted usually, by people outside the conventional medical community, as a safer alternative to traditional hormone replacement therapy. The US Food and Drug Administration, however, has warned multiple compounding pharmacies that the claims they make about the efficacy of bioidentical hormones are misleading and are not supported by medical evidence. (The FDA letter can be read here.)
The Endocrine Society’s October 2006 Position Statement says, “…many ‘bioidentical hormone’ formulations are not subject to FDA oversight and can be inconsistent in dose and purity. As a result of unfounded but highly publicized claims, patients have received incomplete or incorrect information regarding the relative safety and efficacy of hormone preparations that are referred to as ‘bioidentical.’” The American Association of Clinical Endocrinologists shares a similar perspective, “…AACE believes that potentially serious dangers of BH [Bioidentical Hormones] use have not been sufficiently exposed. The primary concern about bioidentical hormone use is patient safety. These substances have not been shown within the medical community to be clinically effective. In addition, utilization of these formulations may be associated with various risks inherent in the compounding process.”
Essentially, the assertions made by the scientific community about BHRT condense into four criticisms: there is no medical evidence to support the claims about the increased effectiveness and safety of BH; the majority of compounded products have not undergone rigorous testing; there are significant concerns about the purity, potency and quality of BH; and “hormone therapy does not belong to a class of drugs with an indication for individualized dosing.” (Stephen Barret of Pharmwatch.com). Unfortunately, clinical testing of bioidentical hormones may never be done because the pharmaceutical industry has no economic interest in their promotion. Since recent studies using traditional oral hormone replacement therapy have shown negative consequences with long term use, it is reasonable to further study bioidentical hormones in menopausal women to possibly make them more generally available as prescription drugs.
PTSD is a fairly common disorder that occurs after exposure to major and often terrifying events, threatened or actual, with physical, mental or sexual harm. It is considered to be an anxiety disorder, with symptoms including flashbacks, memories, nightmares, obsessive and intrusive thoughts related to the trauma and perpetrator(s). There are also frequently symptoms of dissociation, anxiety, anger, irritability and depression. PTSD can also masquerade as an eating disorder with symptoms of bulimia and/or anorexia. The usual treatment of this disorder includes cognitive therapy, exposure therapy, group therapy, and psychotropic medications. PTSD is commonly associated with neuroendocrine changes including low cortisol and high norepenephine levels. This is in contrast to major depression which is frequently associated with high cortisol levels. In my experience, a combination of hypnosis and EMDR (Eye Movement Desensitization and Reconstruction) facilitates treatment. Under hypnosis, the subject re-experiences the original past trauma(s) and this traumatic experience is brought from the past into the present consciousness with EMDR. This leads to a release of traumatic memories with all sensory modalities including visual, emotional, body, and even olfactory (smell) memories. Often following the hypnosis-EMDR session(s), a reworking of the original traumatic experience occurs. This progresses to a healing of the original trauma. In my practice, the symptoms of PTSD often recede following sessions of hypnosis and EMDR, thus shortening the overall treatment.
In recent years it has become increasingly clear that vitamin D is an extremely novel and important prohormone. Not only is vitamin D involved in calcium and bone metabolism including the prevention of osteoporosis, but it has several other functions of equal import. It was discovered by Dr. Michael Holick that vitamin D is converted to 1,25-dihydroxy vitamin D3 (calcitriol) in the liver and kidneys, and this latter hormone is an important factor in inhibiting cancer cell growth. Epidemiological evidence strongly suggests that maintaining adequate vitamin D levels in the blood markedly decreases the incidence of colon, breast, prostate and other cancers. Receptors for vitamin D are found throughout the body. Vitamin D may also play an important role in preventing heart disease. There are receptors for vitamin D in pancreatic islet cells involved in insulin secretion. In fact low vitamin D levels are associated with type I and type II diabetes mellitus. Vitamin D is important in cellular immunity and prevention of the autoimmune diseases. It is actively involved in brain metabolism with links to depression. Fibromyalgia is a musculoskeletal syndrome characterized by muscle pain and fatigue of unknown origin. It has been found that a majority of patients presenting with symptoms of fibromyalgia are deficient in vitamin D. Treatment with vitamin D3 is successful in relieving the symptoms of fibromyalgia in these cases.
In northern latitudes in the United States as well as in Canada, it is very common to develop vitamin D deficiency during fall, winter and spring due to decreased ultraviolet radiation (UVB) from the sun. This is especially true in northern California. Nutritionally there are few sources of vitamin D in the diet, so supplementation with vitamin D in capsule form may be necessary to prevent deficiency of this vitamin. Vitamin D is present in certain fish and fish oils and is synthesized in the skin from exposure of a cholesterol derivative to UVB. Milk products are supplemented with low levels of vitamin D. It is also in egg yolk. The level of vitamin D in the body is assayed by a blood test measuring serum 25- hydroxy vitamin D. This can be used to determine an adequate intake of vitamin D. Vitamin D supplementation is also extremely important during pregnancy to ensure proper development of the fetus and to prevent later life diseases. Forty percent of the American population is vitamin D deficient. A high percentage of pregnant women are also deficient in vitamin D. Consult your physician for advice regarding proper supplementation with vitamin D.
Update: recently conducted research suggests that ingesting a vitamin D supplement during pregnancy may reduce the risk of the child developing schizophrenia later in life. See the abstract for the article: Relation of Schizophrenia Prevalence to Latitude, Climate, Fish Consumption, Infant Mortality, and Skin Color: A Role for Prenatal Vitamin D Deficiency and Infections?
Reference: Vitamin D Deficiency, M. F. Holick, NEJM, 257, 266-281, 2007.
ADHD in children is a well-defined disorder that has been carefully researched and documented in the literature for many decades and is listed as a specific disorder in the DSM-IV-TR (American Psychiatric Association, 2000). On the other hand, ADHD in adults has only recently been described and separated from childhood ADHD by its differing symptom list and associated dysfunctions. Adult ADHD is described as a specific disorder in DSM-V (APA, 2013).
The best recent source for the characterization of adult ADHD is, ADHD in Adults: What the Science Says, by Russell Barkley, Kevin Murphy, and Mariellen Fischer, The Guilford Press 2008. This important book is a result of a carefully conducted research study using excellent control populations to characterize ADHD in adults, their symptoms, their evaluation by various psychological tests, and treatment options. The study shows the profound implications of having ADHD relative to the educational and occupational functioning of the adult, as well as with drug use and driving/antisocial behavior. Of particular interest is that the study concluded that easy distractibility is a seminal feature of the disorder. The book lists nine best symptoms for the diagnosis of ADHD in adults. The book also concluded that neuropsychological tests were not necessarily recommended nor particularly informative in the diagnosis of ADHD in adults, but could instead be used to assess specific cognitive impairments.
Treatment options include evidence that specific medications (such as some stimulants and atomoxetine) are sometimes effective in reversing some of the deficits in executive functioning that are present in adults with ADHD. Adderall (mixed amphetamine salts) has been supplanted by the newer drug Vyvanse (lisdexamfetamine) as the most popular psychostimulant for the treatment of ADHD. A comparison of these two drugs can be found here.
Quantitative EEG (also known as QEEG) has been used as part of the evaluation and treatment of ADHD. (www.q-metrx.com). This diagnostic test can demonstrate defects in the frontal lobes of the adult and child ADHD. QEEG also is sometimes useful in defining treatment modalities for use of brain wave neurofeedback. Some studies have concluded that neurofeedback is effective in the treatment of childhood ADHD. It is less clear if it is effective in treating adult ADHD.
The issue regarding testosterone replacement therapy in men, associated with middle age and later, has become increasingly controversial because of the link between testosterone and prostate cancer. This is reminiscent of the association between estrogen and breast cancer in women. However, the two may not be comparable. In men, there seems to be a relationship between dihydrotestosterone (DHT) and prostate cancer. This association was confirmed in recent studies showing that Proscar and Avodart (both of which block the conversion of testosterone to dihydrotestosterone) decrease the incidence of prostate cancer in long-term controled studies. However it is unclear whether testosterone itself is linked to prostate cancer. In a seminal book, Testosterone for Life, by Abraham Morgentaler, the author points out the benefits of testosterone therapy in middle age and older men and debunks the prostate cancer risk. He even shows that low testosterone levels may predispose to prostate cancer. However, he does not answer the question regarding why dihydrotestosterone appears to be a risk factor for prostate cancer. Men suffering from low libido, depression and erectile dysfunction deserve to have a complete evaluation, including measurement of testosterone levels and appropriate pituitary hormones that may influence testosterone levels. If a man is found to have low testosterone levels on repeated testing, replacement therapy may be indicated with a patch or gel as appropriate to that individual.
The issue of testosterone replacement in women is more controversial than that of men because there are no long-term studies of using testosterone replacement therapy in women. The issue of breast cancer is certainly raised and it is unclear what role testosterone may play in either preventing or accelerating breast cancer. Testosterone does appear to influence libido in women as well as men. However, it also stimulates the growth of excess hair on the face, as well as contributing to increased acne. It is often incorporated into hormone replacement preparations. The appropriate dosing in women is unclear, although blood testing is helpful in preventing excess hormone replacement levels.
Major depressive disorder (MDD) and other mood disorders may share some overlapping features with neurodegenerative diseases like Alzheimer’s disease. For example, recurrent or treatment resistant depression confers an increased risk of later developing dementia. Conversely, dementia is frequently accompanied by depression and mood instability.
Moreover, neuroimaging studies conducted on patients suffering from a mood disorder has revealed hippocampal atrophy, where the number of major depressive episodes correlates with volumetric and morphological changes in the hippocampus. (The hippocampus is a brain structure that plays important roles in working memory, mood, and higher cognitive function.) These observations suggest that changes in mood and behavior may be reflected in brain structure. Antidepressants, independent of class (SSRI, tricyclic or MAOI), all appear to enhance the rate of hippocampal neurogenesis, and thereby reverse depression-related cognitive deficits and synaptic wear-and-tear.
Emerging evidence suggest that healthy dietary choices also play a role in both resilience to depression and susceptibility to neurodegenerative disease. In particular, blueberries, wild salmon, curry (curcumin), and cacao have been identified as brain-healthy foods that reverse brain aging and restore cognitive function.
The infographic below organizes brain foods that have been identified in the literature as conferring cognitive benefits into a food pyramide. Tentative evidence also suggests that, in addition to psychopharmacology and therapy, a healthy diet enriched in these foods are an important part of a comprehensive mental health plan.
The Brain Food Pyramid
An association between thyroid function and mood disorders has been appreciated for many decades. Thyroid imbalance affects mental health, and the biological basis of this connection is well characterized. Even in euthyroid individuals, iiodothyronine (T3) has been noted to improve mood. T3 enhances neurogenesis (the birth of new neurons) in the hippocampus – a brain region linked to mood and memory. Enhanced neurogenesis may restore hippocampal atrophy observed in depressed patients.
Thyroid hormones directly regulate the metabolism of every cell in the body. Specifically, thyroxine (T4) is converted to the more biologically active form, triiodothyronine (T3), which binds to nuclear receptors inside the cell, upregulating the transcription of genes related to metabolism.
Hypothyroidism (too little thyroid hormone) suppresses cellular metabolism. The brain is the most energetically demanding organ in the body. Hence, the brain is very sensitive to the impairments of metabolism that results from a hypothyroid state. Profound hypothyroidism can even result in coma. Conversely, hyperthyroidism can cause anxiety and even a sympathomimetic toxidrome with psychosis.
Implications For Patients
Levothyroxine has been the most prescribed drug in the US for many years in a row. Levothyroxine is synthetic thyroxine (T4) used for thyroid replacement in deficient patients with hypothyroidism.
However, a subset of patients suffering from thyroidal illness have complained that levothyroxine (T4) therapy alone is insufficient to resolve symptoms. Endocrinologists could not reconcile these complaints with the fact that test results often showed normalized TSH results after levothyroxine therapy. (TSH or thyroid-stimulating hormone is a sensitive indicator of thyroid levels). These patients responded better to combination T4/T3 therapy, as is found in products like Armour Thyroid.
Websites like Stop The Thyroid Madness were started to give a voice to patients whose hypothyroid symptoms failed to resolve in spite of thyroid replacement therapy with levothyroxine (T4).
The recent paper Scope and Limitations of Iodothyronine Deiodinases in Hypothyroidism explicitly addresses the limitations of treatment with levothyroxine alone. The paper discusses a genetic variation (Thr92AlaD2) or polymorphism that affects the gene encoding deiodinase iiodothyronine 2. This enzyme converts thyroxine (T4), to the more biologically active form, iiodothyronine (T3). Patients with this genetic variation are much more likely to respond to combination T3/T4 therapy, raising the question about whether genetic testing for this variation should be part of the standard thyroid workup.
The paper also emphasizes that type 2 iodothyronine deiodinase in the hypothalamus is less sensitive to degradation. In contrast, type 2 iodothyronine deiodinase in the periphery is very sensitive to local T4 concentrations. (In the periphery, T4 inactivates and marks the enzyme for destruction so that it has a very brief half-life). This finding challenges the assumption that tissue levels of T3 and TSH can be fully restored by administration of levothyroxine by itself. This is because the levothyroxine dose that normalizes serum levels of TSH is lower than the dose that normalizes serum T3, which explains the increased T4:T3 ratio observed in patients treated with levothyroxine.
These studies underscore the importance of remaining receptive to patient feedback. For many years endocrinologists dismissed patient experience about levothyroxine vs combined T4/T3 therapy because laboratory TSH values were almost dogmatically used to assess thyroid function at the exclusion of other information. Many patients have insisted that they felt better on combination T4/T3 or Armour thyroid therapy, and recent studies now provide a biological basis for this phenomenon.
Hashimoto’s thyroiditis is one form of hypothyroidism. It occurs when one’s immune system assaults the thyroid gland. The autoimmune destruction of the thyroid gland results in the failure to produce adequate thyroxine (also known as T4 or thyroid hormone).
The body responds by increasing thyroid-stimulating hormone (which does exactly what its name suggests). But escalating thyroid-stimulating hormone is unable to normalize thyroid in patients with Hashimoto’s thyroiditis because the thyroid gland is itself damaged.
Autoimmunity and Neuroinflammation
Automimmune diseases have been a hot topic in psychiatry and neurology in the last decade.
It was recently discovered that narcolepsy (the irresistible propensity to sleep at inappropriate times) is actually an autoimmune disease. An overzealous immune system attacks orexinergic neurons in the brain. These neurons are important for the maintenance of wakefulness, and so their destruction increases sleep pressure.
Neuroinflammation refers to inflammation of nervous tissue. For a long time, the brain was thought to be immunologically privileged, like the eyes. This is mostly true because peripheral immune cells are blocked by the blood-brain barrier. But a compromised blood-brain barrier can let peripheral immune cells into the brain, unhindered.
Neuroinflammation is increasingly linked to schizophrenia, depression, and dementia. Even obesity may have a neuroinflammatory component. Excess consumption of sugar and fat promotes an inflammatory milieu, particularly in adipose tissue but also possibly the brain. Obesity-related neuroinflammation may then impair hormones that regulate appetite like leptin and ghrelin, leading to a vicious cycle.
The textbook example of a neuroinflammatory disease is multiple sclerosis, where the myelin sheath surrounding axons is damaged by inappropriate immune activation in the brain.
Hashimoto’s Thyroiditis and Autoimmunity
It’s well known that hypothyroidism negatively impacts mood, cognitive function, and general well-being. Hashimoto’s thyroiditis is no different, and produces this same pattern of symptoms.
But Hashimoto’s thyroiditis is indicative of a deeper underlying pathology: automimmunity and immunological hyperactivity.
The immune system is programmatically calibrated because of the inherent trade offs. If the the immune system is too weak, an individual will be susceptible to infection. But an overzealous immune system can damage tissues and contribute to autoimmune diseases like Hashimoto’s thyroiditis.
The biochemical markers of the disease are thyroid peroxidase, in addition to thyroglobulin antibodies. Twin concordance studies have revealed that Hashimoto’s has a strong genetic component. Genes encoding leukocyte antigen, cytotoxic T lymphocyte antigen-4, thyroglobulin and the vitamin D receptor are specifically implicated.
The most important risk factors for the development of Hashimoto’s are female gender and pregnancy with postpartum depression. Excess iodine intake, infections, exposure to chemicals and certain drugs are all significant risk factors.
Autoimmune thyroiditis encephalopathy is an example of a consequence of how autoimmunity can unfold to harm the brain. It should be better recognized that patients with Hashimoto’s are at-risk for the development of other diseases with an immunological aspect.
Zaletel K, Gaberšček S. Hashimoto’s Thyroiditis: From Genes to the Disease. Curr Genomics. 2011;12(8):576-88.
Li Y, Nishihara E, Kakudo K. Hashimoto’s thyroiditis: old concepts and new insights. Curr Opin Rheumatol. 2011;23(1):102-7.
Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0025658/. Accessed January 17, 2016.
Perimenopause is a midlife transition state experienced by women that leads to reproductive senescence (loss of reproductive cells in the body).
As a psychoneuroendocrinologist, I’m interested in perimenopause because it affects mood and behavior. Perimenopause can contribute to depression and cognitive changes. It’s increasingly recognized that sex hormones like estrogen and testosterone are neuroprotective, i.e., protect the brain against insult and deterioration .
Women usually transition through perimenopause at an average age of 51.4 years. The process through to menopause, the final stage of perimenopause, takes 1–5 years from start to completion. This occurs after 12 months of amenorrhea (the absence of menstruation). Although primarily viewed as a reproductive transition, many symptoms of perimenopause are neurological in nature and occur as a result of estrogen depletion.
Functional Changes Observed in Perimenopause
The clinical definition of perimenopause focuses on functional changes in the reproductive system.
Reproductive senescence in women is defined by the depletion of oocytes (cells in the ovary). This is a process that begins at birth and continues until menopause is achieved.
The relatively wide age range (40–58 years) for menopause suggests that women either have a highly variable number of oocytes or that the rate of oocyte loss varies greatly between individuals. Perimenopause is characterized by increased variability in the length of the menstrual cycle and levels of circulating hormones. This is because there are fluctuations in the levels of hypothalamic, pituitary and ovarian hormones, resulting in ovulatory irregularities.
Estrogen is the primary female sex hormone and is a master regulator that functions in a number of key regions throughout the brain.
The role of estrogen in the brain – and its impact on mood and behavior – has been underappreciated until the last decade.
Estrogen affects specific neural circuits, those which (unsurprisingly) express a high number of estrogen receptors.
Although this distributed network of estrogen receptors forms the basis of the remarkable effects of estrogen in the brain, it can also be a point of vulnerability for the female brain.
During perimenopause, changes in levels of estrogen or its receptors networks result in a reduction in activity in key brain regions.
In many women, the brain compensates for these changes in estrogen levels during perimenopause. However, for some women this adaptive compensation is diminished, lacking or only expressed in some estrogen-regulated neural networks. Evidently, the main brain regions affected in the perimenopausal transition are heavily dependent upon estrogen to function effectively and, therefore, estrogen deficiencies give rise to a specific constellation of neuropsychiatric symptoms.
A substantial proportion of women (80%) are vulnerable to the neurological shifts that can occur during the perimenopausal transition.
Most women transition through perimenopause without long-term adverse effects. Yet some women emerge from this transition with an increased risk of neurological decline. Therefore, the presence, variability, intensity and duration of neurological perimenopausal symptoms could be warning signs for an increased risk of neurodegenerative diseases later in life. Neurological symptoms include:
The most frequent (often defining) feature of the perimenopausal transition is the hot flush.
This involves a disturbing and intense rise in body temperature, which is often sudden and short-lived, but can also last up to 60 minutes. It occurs in 75–80% of women in the perimenopausal phase and can continue for several decades (in less than 5% of women).
Hot flushes are generally caused by disruption to estrogen-regulated regions in the hypothalamus, which is the area of the brain that controls thermoregulation. This is a part of the brain with a high number of estrogen receptors.
Hot flushes can also cause severe stress and anxiety in many women, and can co-occur with the neurological symptoms outlined below.
Insomnia is a prevalent symptom of the perimenopausal transition and is frequently associated with the other symptoms.
The hypothalamus is the part of the brain that regulates sleep–wake cycles and relies heavily upon estrogen to function. A reduction in estrogen results in disruption of the regulation of sleep and circadian rhythms. Studies reveal that the prevalence of sleep disturbance is 28%-40% and sleep difficulties are maximal during late perimenopause and persist into postmenopause.
Subjective and objective memory deficits during the perimenopause have been well documented. Estrogen results in low activity in brain regions required for learning and memory function (e.g. prefrontal cortex, hippocampus, cingulate cortex).
These estrogen decrements affect verbal learning, verbal memory, working memory and fine motor skills. Such reduction in activity in the brain is associated with neurodegenerative diseases in later years.
There is an increased risk of depression in perimenopausal women, which can occur early in the perimenopausal transition. This even applies to women with no previous history of affective symptoms. The function of brain regions that regulate depression is byzantine.
Depression is also linked to a reduction of activity in the pons (which is affected by estrogen).
The experience of the perimenopausal transition can be highly variable. For some women intervention is necessary, and failing to intervene would be negligent.
When evaluating patients, I will identify the best strategy to maintain mood and neurological functioning in women during the perimenopausal and menopausal transition states.
Estrogen replacement therapy
Given that estrogen regulates key systems in the brain that contribute to perimenopausal symptoms, Estrogen replacement therapy is a logical choice.
Therapy has been shown to preserve activity in brain regions with estrogen-dependent neurological functions. It has also been shown to prevent a reduction in activity in cognitive brain regions and preserve memory function.
With regards to depression, the timing of the administration of estrogen therapy appears to be critical to the effectiveness of treatment, as treatment after perimenopause (5-10 years later) may be less effective.
Furthermore, in perimenopausal women with depression, estrogen replacement often has an antidepressant effect.
Nonetheless, many women do not choose Estrogen Replacement Therapy because the data on the benefits and risks of estrogen replacement therapy are complicated, controversial and confusing. The importance of seeking advice from qualified professionals so that therapy can be optimized and personalized remains paramount. This will allow for the best decision over how to deal with the symptoms of perimenopause.
 Behl C. Sex hormones, neuroprotection and cognition. Prog Brain Res. 2002;138:135-42.