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