trifectapresentation (1)

Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Birth Control, Big Money
and Bad Medicine
A Deadly Trifecta in Women’s Health
Chandler Marrs, PhD
Lucine Health Sciences
Hormones Matter
Heal with Friends

How do we know what we think we
know?

Generations of Marketing
For $1 in R&D, $19 in marketing and advertising
(BMJ 2012;345:e4348)

More Sophisticated Advertising
67.4% of retractions were attributable to
misconduct, including fraud or suspected
fraud
“Journals have devolved into information laundering operations for the
pharmaceutical industry."
Richard Horten, Editor-in-Chief – Lancet, 2004

Big Influence
Center for Responsive Politics.
https://www.opensecrets.org/
Lobbying dollars spent 1998-2015
FDA funded by fees from drug
companies
• FY 2010: $573,258,400
(http://blogs.plos.org/workinprogress/2012/01/25/how-much-
money-do-drug-companies-pay-the-fda/)
• ~80% of all filed applications will
eventually be approved
• Consumer Reports (2006), 12 types of
drugs sold in 140 prescription
medications had "rare but serious side
effects" that went unnoticed prior to
their market approval from the Food
and Drug Administration (FDA).
• CDC foundation funding
from drug companies
(BMJ 2015;350:h2362)
• Pharma single largest
government lobbyist

Big Money
Top 20 health products for women in the U.S. based on revenue
in 2013
Total oral
contraceptive
market
expected to
reach $17B
annually 2015
(reported in
Financial Times,
citing GIA)

Almost every woman uses
hormonal contraceptives
88.2%
35.4%
69.1%
89%
97.7%99.1% 97.5%
99.6% 99% 99.2%
0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
120.0%
All women, 15-44 years 15-17 years 18-19 years 20-24 years 25-44 years
Percentageofwomen
All women Sexually experienced women
Percentage of sexually experienced U.S. woman aged 15-44 who
ever used contraception in the period 2006-2010

For years on end
n = 924
Age OC use
begins:
Average Length of time used: 9.41 years, SD 6.33

Provided she survives the
side-effects
Percentage of U.S. women aged 15-44 years who
discontinued the use of selected contraceptive
methods in 2006-2010

Political tug-of-war

What do we really know?

A Foundation for
Understanding
Hormones.

A persistent notion in contraceptive research is that
progesterone and estradiol are singularly involved
with reproduction.
What follows is a presumption that these hormones
have no impact on other tissues and altering them
affects nothing but the intended target.

Disconnected

Compartmentalized

Everything is
connected

Pregnancy Prevention
http://sitn.hms.harvard.edu/flash/2014/the-risks-of-control-assessing-the-link-between-birth-control-pills-
and-breast-cancer/

Beyond Reproduction
Steroid hormones regulate everything.

Beyond the Ovaries
Where steroids are synthesized
Peripheral Tissue
In man and higher primates active sex steroids are in large part or wholly
synthesized locally in peripheral tissues. Labrie, 2005

Where there are receptors…
Hormones act.

Hormones are Promiscuous
• Never one-to-one
relationship
• Cross bind with multiple
receptors, different
affinities and different
activities
• Metabolites bind and
cross bind, sometimes
more strongly than the
original hormone

Metabolites Matter
4-methyl-2,4-bis(4-
hydroxyphenyl)pent-1-ene
(MBP) has about 1000-fold
higher estrogenic activity
than BPA.

Operate within exceedingly complex
feedback systems
Figure 3 Human steroidogenic and steroid-inactivating enzymes in peripheral intracrine tissues. 4-DIONE, androstenedione; A-DIONE, 5-alpha-
androstane-3,17-dione; ADT, androsterone; epi-ADT, epiandrosterone; E1, estrone; E1-S, estrone sulfate; 5-DIOL-FA, androst-5-ene-3alpha,17beta-
diol fatty acid; 5-DIOL-S, androst-5-ene-3alpha,17beta-diol sulphate; HSD, hydroxysteroid dehydrogenase; TESTO, testosterone; RoDH-1, Ro
dehydrogenase 1; ER, estrogen receptor; AR, androgen receptor; UGT2B28, uridine glucuronosyl transferase 2B28; Sult2B1, sulfotransferase 2B1;
UGT1A1, uridine glucuronosyl transferase 1A1.
F Labrie et al. J Endocrinol 2005;187:169-196

Under Hormonal Control

Hormones and the Brain
• Hormone receptors co-localized on neurons
• GABAA, DA, 5HT, NE, Glutamate
• Regulate mood, cognition, and other functions
The brain is a major target for and source of
steroid hormones.

Front. Neurosci., 20 February 2015 | http://dx.doi.org/10.3389/fnins.2015.00037
Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Claudia
Barth1, Arno Villringer1,2,3,4,5 and Julia Sacher1,2*

GABAA Receptors
• Primary inhibitory
neurotransmitter
• Progesterone: agonist
(↑ inhibition/sedation)
• Prog sulfate antagonist
(↓ inhibition↑ anxiety)
• DHEA: antagonist
• DHEAS: 1000X stronger

Morphological Changes
• Hippocampal neurons
• Estradiol (E2):
excitatory
• Mediates dendritic
growth
• Elicits DA
hypersensitivity
• E2 + PROG = ↑growth
• When both removed
abrupt retraction of
new dendrites
Woolley, C. S., and McEwen, B. S. (1993). Roles of estradiol
and progesterone in regulation of hippocampal dendritic
spine density during the estrous cycle in the rat. J. Comp.
Neurol. 336, 293–306. doi: 10.1002/cne.903360210

Engines within our cells
• Mitochondria
• Convert food fuel to cell fuel (ATP)
• Bi-product ROS
• Regulate immune signaling
• Apoptosis
• Control steroidogenesis
Cycle of Ill-Health
Toxicants ± insufficient
nutrients ► dysfunctional
mitochondria ►
↓ATP ► ↑ROS ►
mitochondrial damage ►
cell damage ► disease

Hormones and Mitochondria
• Steroidogenesis
begins in the
mitochondria
• Ends there too
with membrane
receptors
• Mitochondria are
dependent upon
estradiol
Front Neuroendocrinol. 2014 Jan; 35(1): 8–30.; Published online 2013 Aug
29. doi: 10.1016/j.yfrne.2013.08.001; Estrogen: A master regulator of bioenergetic systems in the brain and
body; Jamaica R Rettberg,
a
Jia Yao,
b
and Roberta Diaz Brinton
a,b,c

Mitochondria on Estradiol
Schematic
representation
of presynaptic
mitochondria
in the
mammalian
brain and their
effect on
synaptic
remodelling.
Martin Picard, and Bruce S. McEwen PNAS 2014;111:7-8
©2014 by National Academy of Sciences

We need endogenous hormones
Estradiol regulates metabolic
flexibility – the ability to utilize
different fuel sources when needed.

So far
• Steroid hormones synthesized pretty much everywhere
• Not just in the gonads and adrenals
• Bind to all sorts of different receptors to modulate health
• Cognate receptor
• Receptors of other steroids
• Neurotransmitters
• Immune cells
• Hormones fluctuate across the lifecycle, menstrual cycle,
pregnancy/postpartum
• Sensitive to endocrine disrupting chemicals,
environmental and pharmaceutical

Affect more than reproduction
• CNS
• Synaptogenesis
• Dendritic growth
• Neurotransmitters
• Nerve myelination
• Vascularization
• Vasoconstriction
• Dilation
• Tumorogenesis
• Metabolic flexibility
• Mitochondrial fuel
usage, structure and
function
• Insulin signaling
• Immune function
• Cytokine cross talk
• Connective tissue,
muscle, bone
• GI Motility

Overly simplistic notion
http://sitn.hms.harvard.edu/flash/2014/the-risks-of-control-assessing-the-link-
between-birth-control-pills-and-breast-cancer/
We cannot override one system by substituting two
synthetic hormones and not impact everything else.

Exogenous vs Endogenous
Hormones
Are they the same?

Synthetic steroids are similar but not identical
to endogenous steroids.

Similar but not identical
• Shape
• Binding
• Patterns, affinities,
interactions with other cells
• Potency
• Metabolites (and their
actions)
• Elimination
Differences between synthetic and endogenous
hormones

Progestin Shape ►Receptor
Activity ► Side Effect Profile
• Most are derived from testosterone or progesterone
• Bind to AR, GR, PR, MR to varying degrees
• Most more strongly than endogenous progesterone (10-100X)
• Androgenic side effects: hair, acne, BP, lipid changes
• Glucocorticoid side effects: BP, weight gain
• Drospirenone derived from spirolactone (anti-
mineralocorticoid)
• No androgenic effects (why it’s prescribed for acne)
• Blocks, mineralocorticoid receptors, reduce swelling, BP (not in all
women)
• Binds 500X to AR than progesterone

Side Note: Progesterone & Blood
Pressure
• Gain-of-function mineralocorticoid receptor mutation
• Increased progesterone binding
• Constitutively activated
• Early onset, high BP relative to cycle, pregnancy and
contraceptives, especially drospirenone
• Possible epigenetic and functional changes too

What happens to
endogenous hormones
while on synthetics?
A mixed response.

Estradiol and Estriol
0.6
0.9
1.2
1.5
1.8
2.1
2.4
2.7
3.0
Follicular Mid-Cycle Luteal
Estradiol(pg/mL)
Phase in Cycle
Control High EE Low EE
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
Estriol(pg/mL)
Phase in Cycle
Guillermo C, Marrs C, unpublished
data.

Progesterone and Testosterone
5.0
15.0
25.0
35.0
45.0
55.0
65.0
75.0
Progesterone(pg/mL)
Phase in Cycle
15.0
20.0
25.0
30.0
35.0
40.0
45.0
50.0
Testosterone(pg/mL)
Phase in Cycle
data.

DHEAS and Cortisol
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
DHEAS(ng/mL)
Phase in Cycle
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
Cortisol(ng/mL)
Phase in Cycle
data.

Long Term Changes in
Endogenous Hormones
Significantly lower endogenous hormones.

What happens to innate systems that rely on
endogenous hormones for adaptive regulation?

Side Effects
Or perhaps, if we’re honest, the just effects.

Hormonal Contraceptive Side
Effects
• Depend upon
• Characteristics of the drug
• Shape
• Binding affinity to hormone receptors
• Actions at those receptors
• Metabolites
• Dose and duration of use
• Route of administration
• Inter-individual variability
• Genetic, epigenetic, environmental, nutritional, medical and
pharmaceutical interactions

Delivery Method
Determines bioavailability.
Affects rapidity with which acute side effects develop
and, to some degree, the location.
Order of bioavailability of EE
Patch, Ring, Oral

Evaluating Dose-Response
• Hormonal reactions are:
• not always linear
• time dependent

Contraceptive Side Effects
• Systemic changes
• Where there are receptors, the drug will evoke an effect
• Compensatory reactions
• Short-term
• Acute and emergent reactions
• Longer-term
• Changes in enzymes, binding proteins and hormone
concentrations
• Epigenetic changes
• Potentially transgenerational

Mood and Cognitive Changes
• Great animal research on hormones and learning
• Contradictory finding with the human studies
• Vast methodological differences
• Must measure symptom changes across the menstrual cycle
relative to each hormone individually and to the hormone
pathway
• Patterns differ with oral contraceptives
• Would be great to measure synthetic concentrations relative to
symptoms
• Cannot test symptoms at cycle phase
We know hormones affect the brain, how do hormonal
contraceptives affect mood or cognition?

Altered Immune Function

Deficient, Reactive, or
Exhausted Immune System

Cost/Benefit
If hormonal contraceptives override innate and
adaptive immunity, increasing susceptibility to STDs,
autoimmune disease processes, cancers, is the
tradeoff worth it?

Hormonal Contraceptives Alter
Nutrient Concentrations
• ↓riboflavin,
pyridoxine, folate,
vitamin B12, ascorbic
acid, zinc
• ↓ CoQ10, vitamin E,
antioxidants
• +/- vitamin K, iron and
copper, vitamin A

Nutrients are Critical for
Mitochondrial & Cellular Functioning
Nutrient deficiency damage the mitochondria
Impair steroidogenesis
Increase inflammation (oxidative and cytokine)
Increase disease processes

Blood Clots
Drugs exert a pro-thrombotic
state by a variety of
mechanisms--those affecting
the vessel wall, the blood
flow, and/or different blood
constituents.
Cumulative, additive or
synergistic; immediate or
delayed reaction.
Genetic/epigenetic predisposition
• Clotting factors
• Endothelial damage
Pharmacological/medical
• Hormonal contraceptives (HRT too)
• Contrast media
• SSRIs, haloperidol
• Fluoroquinolones
• NSAIDs (PGI2 inhibition, AFIB)
• Med/vax induced vasculitis
• Lupron (E2/mito damage)
Lifestyle
• Smoking
• Diet (mito dysfunction)
• Intense exercise or prolonged sitting

Medical Misuse
Menstrual normalization, endometriosis, PCOS, fibroids,
menorrhagia, depression, anxiety, bloating, fatigue.

Pill withdrawal bleeds are not
periods.

Endometriosis, PCOS, Fibroids
• Induces tissue growth
• Impairs glucose tolerance
• Induces chronic inflammation

Hormonal contraceptives more likely to
• Evoke depression and/or anxiety
• Induce negative metabolic changes (weight gain, insulin
resistance, ↑ BP)
• Induce endometrioitic and fibroid growth
• Induce or exacerbate autoimmune conditions
Why then do we prescribe them for these conditions?

Contraceptives in the Real World
• Hormonal contraceptive
• Monthly NSAIDs
• SSRI (21% of females >20 on SSRIs)
• Periodic antibiotics, regular vaccines,
asthma or allergy medication
• Western diet
• Low nutrient content
• Athletic
• Trains hard
• Injuries (contrast media)
• Travels – long periods of sitting
 Impaired mitochondrial
functioning by multiple
mechanisms
 Oxidative stress
 Inflammation
 Impaired immune function
 Increased risk of
• Autoimmune disease
• Thrombosis
• Metabolic dysfunction
• Injury (athletic)
Polypharmacy – even in ‘healthy’ women

Final thoughts
Adverse events and side effects do not happen in a
vacuum, and thus, cannot be evaluated singularly.
We underestimate the risks of synthetic hormones
significantly by ignoring the vast reach hormones have
on health.
Reproductive health is but one component of women’s
health.

“You did then what you knew how to do,
And when you knew better,
You did better.”
Maya Angelou

Reach out
o Websites
o LucineHealthSciences.com I Business
o HormonesMatter.com I online journal, medication adverse
events surveys
o HealwithFriends.com I Social health
o Social Media
o Facebook pages: Hormones Matter, Lucine Women
Community
o Twitter: @chanatlucine, @lucinewoman,
@hormonesmatter, @healwithfriends

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