Rhythms and Regulation: Connections between Mood and Neuroendocrine Function in Women with PMS and PMDD Ginger Nash, ND OAND, November 2014 PMS and PMDD extremely common conditions 75-80% women experience PMS 5-8% of those women may have PMDD any race or class with PMS but higher rates of PMDD in women discriminated against Where endocrinology and neurology (or psychiatry) meet Neuro-endocrinology: involves both hormones, cortisol, estrogen and progesterone and neurotransmitters serotonin, GABA and endorphin. Other molecules too: dopamine, gonadotrophin-releasing hormone, sex-hormone binding globulin, melatonin, etc. PMS and PMDD: symptoms they share Sadness, hopelessness, or feelings of worthlessness Tension, anxiety, or "edginess" Variable moods with frequent tearfulness Irritability, anger, and conflict with family, coworkers, or friends Decreased interest in usual activities Difficulty concentrating Fatigue and/or lethargy Changes in appetite, which may include binge eating or craving certain foods Sleep disturbances Feelings of being overwhelmed or out of control Breast tenderness or swelling, headaches, joint or muscle pain, weight gain The female brain: “wired” for connectivity? mature earlier, changes in hormones and neurotransmitters earlier than males Pre-menstrual exacerbation (PME) of other existing conditions: irritable bowel syndrome, migraines, bipolar or unipolar major depression Symptoms should totally resolve for part of the month Mood as central feature of both conditions What role does estrogen and progesterone play in women’s moods? What systems are affected by disrupted sleep-wake cycle? What role does melatonin and cortisol play in mood for women? suprachiasmatic nucleus: regulates circadian rhythm hormone secretion core temperature sleep appetite retina registers light and sends signal to brain after brake (paraventricular nucleus) is released then the pineal gland begins to release melatonin diurnal rhythm (24-hour cycle) Feedback loop of hypothalamicpituitary-adrenal (HPA) axis Normally cortisol is secreted from adrenals in a diurnal rhythm Adrenals major gland of stress management the diurnal see-saw: as the levels of melatonin go up beginning around 9:00p.m. the levels of cortisol should be at their lowest conversely, as levels of melatonin drop to their lowest point, about 6:00 am levels of cortisol begin their dramatic incline reaching highest levels towards 7:00 am 24-hour rhythms the whole “shebang” numerous studies show that disrupted sleep cycle causes changes in mood over the course of one 24-hour cycle but also over longer periods of time with more prolonged insomnia insomnia is used here as trouble either initiating sleep or staying asleep for a 7.5-8 hour period of time lack of sufficient REM and slow-wave sleep can impact serotonin, dopamine and endorphins We know cortisol is major stress-response hormone Excess cortisol can cause anxiety and insomnia Deficient cortisol can cause depression and fatigue PMS associated with imbalances in cortisol Excessively low cortisol at night associated with PMS Anxiety and depression often go hand-in-hand Diurnal rhythm cortisol, melatonin and serotonin executive control function deficits in people with insomnia memory loss decreased efficiency switching attention and working memory affected far more than sustaining attention for sort periods of time transitions become more challenging Normal Menstrual Cycle Anterior Pituitary Hormones Ovarian Hormones Uterine Tissue Response Endorphins act on hypothalamus, hippocampus and pituitary gland Opioid peptides (endorphins are a class) play a role in emotion and motivation Changes in estrogen can attenuate the effects of endorphin Mood swings, behavioral disturbances, changes in body temperature (causing “hot flashes” or “night sweats”) A “hot flash” can occur anytime hormones shift dramatically and “confuse” the hypothalamus biggest changes are around Day 1215 and then again Day 25-28 Estrogen and cognitive function: estradiol has excitatory effect on hippocampus, amygdala and frontal cortex Estrogen has a role in neurotransmitter function of GABA, serotonin and catecholamines Estrogen also has a role in memory, certain cognitive and spatial tasks Differences in response to normal estrogen levels What makes the brain hypersensitive? The balance of estrogen and progesterone may be a key in the hormonal aspect of PMS and PMDD GABA: some paradoxical evidence but no question GABA is main inhibitory neurotransmitter in the brain GABA and sleep: GABA(a) receptors induce sleep and lessen effects of glutamate Disruption of circadian rhythm, disruption of monthly rhythm Insomnia, anxiety, irritability associated with PMS+PMDD Serotonin: sometimes called “the happiness hormone”, wellbeing, any disruption in production can effect mood Serotonin and estrogen: estrogen helps to produce serotonin and increase receptor levels More complex analysis needed with regards to adequate levels of estrogen despite depression, exact neural connections are unclear Endorphin and estrogen linkage Endorphin linked with joy and pleasure Estrogen linked in several studies to modifying the production of endorphin, higher levels of estrogen, higher levels of endorphin Once again, the balance of progesterone can be key in this equation Progesterone and Cortisol: pre-cursor pregnenalone, shunting away from progesterone when too much cortisol is being manufactured Melatonin/Cortisol rhythm and Serotonin: both crucial components of managing mood Both connected to fluctuating levels of estrogen and progesterone as well. Lowering stress hormones, increasing natural balance of female hormones and proper production of neurotransmitters This is all to show the connections between various substances in the regulation of mood and the menstrual cycle It’s all connected! One place is the amygdala The circadian rhythm is “super-imposed” on the female menses rhythm, or monthly cycle LH & FSH are not controlled by circadian rhythm but rather they are under control of female menstrual rhythm (FMR) The notion of a mobile, when one aspect of the endocrine system is out of balance, off homeostasis, all other aspects must adjust/compensate In addition, when production or receptor activity of one neurotransmitter is imbalanced, consequences occur that may cross-over to endocrine system Bipolar or unipolar depression vs. PMS? Reaction to fluctuating hormone levels Estrogen usually exhibits protective effect against depression Traditional/allopathic treatment usually entails suppression of cycle (through estradiol, GnRH agonists or oral contraceptives) Women are more different epigenetically than genetically This means the genes may be be identical but they way they are epigenetically modified may be quite different No clear linkage of particular gene and PMS/PMDD Formation of epigenetic metabolic types can effect hormone regulation through liver function, tendency toward overweight and inflammatory markers The regulation of gene expression or silencing is accomplished by epigenetic mechanisms of methylation, histone acetylation and ubiquitylation Transcription of DNA, proper copying of cells, is largely affected by these mechanisms Various single-nucleotide polymorphisms (SNPs) factor into the ability of the cell to alter it’s epigenetic settings, or modifications SNPs mean one or more base pair has a mutation, degree of phenotypic expression varies Binding of enzymes, primary drivers of cellular metabolism, relates to SNPs and the activity of their respective genes SNPs will effect the ability of enzymes to catalyze reactions that then in turn methylate or modify the histone Promoter portions of the genes are where methylation and histone acetylation exert their effects For example, the ESR1 gene Two main components of epigenetics DNA methylation/ histone acetylation CpG Sites and Islands ESR1 gene has a somewhat common polymorphism associated with it Research indicates it may be a variable in diminished ovarian reserve, polycystic ovarian disease, bone density, endometriosis, pre-term rupture of membranes, endothelial dysfunction, insulin resistance and early changes in breast tissue cells Most “famous” SNP are probably those in the MTHFR genes which affect the metabolism of folate Folate plays a role in critical neurotransmitter production, as well as the regulation of female hormones Irregular menses normalized with proper supplementation of active folate and B-vitamins Methylation patterns are affected by SNPs in the MTHFR gene Melatonin receptor SNP plays role in glucose metabolism, cortisol balancing and therefore overall hormonal regulation Would we bother to do genetic testing? How would we measure levels of melatonin? Trial with administering melatonin best? Hx of PMS in adolescence? Periods irregular around menarche? Abatement of depression in pregnancy? FHx of depression or bi-polar disorder? Stretches of 5-20 euthymic days per month? Differentiate from bi-polar by asking about manic or hypomanic sxs? Does mood improve 24 hours prior to or immediately with beginning of menses or not until Day 2-3? Depression re-emerges after onset of menses postpartum? Pre-menstrual depression worsens with age, blending into menopausal transition and becoming less cyclical thereafter? Concomitant sxs such as mastalgia, intestinal bloating or migraine? Keys to evaluation to test or not to test? must assess sleep habits and hygiene assess menses from menarche assess epigenetic inheritance and metabolic tendencies assess miasm and ways patient will eliminate, bring into balance Salivary testing a reliable way to evaluate cortisol diurnal rhythm in women with PMS and PMDD Quest and other major labs will run but I set my own normals ranges as follows: o 6:00a.m.-7:00a.m. 0.4-0.6 o 11:00a.m.-12:00p.m. 0.3-0.15 o 4:00p.m.-5:00p.m. 0.05-0.09 o 11:00p.m.-12:00a.m. 0.01-0.06 When the case is complex, start by simplifying the cure Back up, do the basics When those things are in place, hit key areas for each individual woman Which pathways need the most help? Which interactions are key and how do they tend to rebalance from stressors? Sleep and light effects Sleep hygiene and timing Spending time outdoors each day Meditation and deep breathing Computer-free days (that includes smart phones) Amino acid support GABA dl-Phenyalanine Taurine L-theanine N-acetyl cysteine Herbs and Nutrients Essential Fatty Acids Active B-vitamins Dong Quai, Vitex and Gymnema Di-indole methane (DIM) Rhodiola, Ashwaganda and Holy Basil Rotating menses protocol Day 1 (menses begins) Hypophysinum Day 7 (estrogenic phase) Folliculinum Day 14 (ovulation) Ovarinum Day 21 (progesterogenic phase) Luteinum All in 200K (or medium) potency Single homeopathics and homeopathic hormones Various according to miasmatic, metabolic tendencies Hp pregnenalone Hp DHEA Iodine-rich organisms (homeopathically-prepared) Essential oils: various that affect pituitary and brain function, modulate mood, depression or anxiety Frankincense Citrus like lemon, lime or grapefruit Lavender Wintergreen Pay attention to the clinical side, the symptoms and the history with regards to stressors Many variables, all of which contribute to overall hormone health