Ginger Nash, NDOAND, November 2014

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Rhythms and Regulation: Connections between Mood and Neuroendocrine Function in Women with PMS and PMDD

Introduction

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

Introduction

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.

Introduction 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

Introduction

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?

Introduction

Anatomy

suprachiasmatic nucleus:

regulates circadian rhythmhormone secretion core temperature sleep appetite

Anatomy

Sleep-wake cycle

after brake (paraventricular

nucleus) is released then the pineal gland

begins to release melatonin

retina registers light and sends signal to

brain

diurnal rhythm (24-hour cycle)

Sleep-wake cycle

Anatomy

Feedback loop of hypothalamic-pituitary-adrenal (HPA) axis

Normally cortisol is secreted from adrenals in a diurnal rhythm

Adrenals major gland of stress management

Anatomy

Cortisol and melatonin

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

Cortisol and Melatonin

Cortisol and melatonin

Coritsol and Melatonin

24-hour rhythms

Sleep-Wake Clock

the whole “shebang”

Sleep-wake clock

Sleep and mood

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

Sleep and Mood

Cortisol and mood

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

Cortisol and Mood

cortisol, melatonin and serotonin

Diurnal rhythm

Sleep and cognitive function

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

Estrogen and endorphin

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”)

Estrogen and Endorphin

When hormones shift

A “hot flash” can occur anytime hormones shift dramatically and “confuse” the hypothalamus

When hormones shift

When hormones shift

biggest changesare around Day 12-

15 and thenagain Day 25-28

When hormones shift

Female hormones

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

Female Hormones

Female hormones

Differences in response to normal estrogen levels

What makes the brain hyper-sensitive?

The balance of estrogen and progesterone may be a key in the hormonal aspect of PMS and PMDD

Female hormones

Neurotransmitters

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

Female hormones

Neurotransmitters

Neurotransmitters

Neurotransmitters

Serotonin: sometimes called “the happiness hormone”, well-being, 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

Neurotransmitters

Neurotransmitters

Neurotransmitters

Neuroendocrinology

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

Neuroendocrinology

Neuroendocrinology

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.

Neuroendocrinology

Neuroendocrinology

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

Neuroendocrinology

Layering of rhythms

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

Layering of Rhythms

What are we treating?

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)

What are we treating?

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

Epigenetics

Epigenetics

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

Epigenetics

Epigenetics

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

Epigenetics

Two main components of epigeneticsDNA methylation/ histone acetylation

Two main components of epigenetics DNA methylation/histone acetylation

CpG Sites and Islands

Methylation and estrogen

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

Methylation and Estrogen

Methylation and SNPs 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

Methylation pathway

SNP and Melatonin

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?

10 key questions Hx of PMS in adolescence?

Periods irregular around menarche?

Abatement of depression in pregnancy?

FHx of depression or bi-polar disorder?

10 key questions Stretches of 5-20 euthymic days per month?

Differentiate from bi-polar by asking about manic or hypo-manic sxs?

Does mood improve 24 hours prior to or immediately with beginning of menses or not until Day 2-3?

10 key questions

Depression re-emerges after onset of menses post-partum?

Pre-menstrual depression worsens with age, blending into menopausal transition and becoming less cyclical thereafter?

Concomitant sxs such as mastalgia, intestinal bloating or migraine?

Patient Evaluation

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

Cortisol Rhythm

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

Clinical Support

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 re-balance from stressors?

Natural Support

Sleep and light effects

Sleep hygiene and timing

Spending time outdoors each day

Meditation and deep breathing

Computer-free days (that includes smart phones)

Natural Support

Amino acid support

GABA

dl-Phenyalanine

Taurine

L-theanine

N-acetyl cysteine

Natural Support

Herbs and Nutrients

Essential Fatty Acids

Active B-vitamins

Dong Quai, Vitex and Gymnema

Di-indole methane (DIM)

Rhodiola, Ashwaganda and Holy Basil

Natural Support

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

Natural Support

Single homeopathics and homeopathic hormones

Various according to miasmatic, metabolic tendencies

Hp pregnenalone

Hp DHEA

Iodine-rich organisms (homeopathically-prepared)

Natural Support

Essential oils: various that affect pituitary and brain function, modulate mood, depression or anxiety

Frankincense

Citrus like lemon, lime or grapefruit

Lavender

Wintergreen

In conclusion

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