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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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
How do we know what we think we
know?
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Generations of Marketing
For $1 in R&D, $19 in marketing and advertising
(BMJ 2012;345:e4348)
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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)
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
For years on end
n = 924
Age OC use
begins:
Average Length of time used: 9.41 years, SD 6.33
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Political tug-of-war
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
What do we really know?
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
A Foundation for
Understanding
Hormones.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Disconnected
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Compartmentalized
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Everything is
connected
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Pregnancy Prevention
http://sitn.hms.harvard.edu/flash/2014/the-risks-of-control-assessing-the-link-between-birth-control-pills-
and-breast-cancer/
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Beyond Reproduction
Steroid hormones regulate everything.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Where there are receptors…
Hormones act.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Metabolites Matter
4-methyl-2,4-bis(4-
hydroxyphenyl)pent-1-ene
(MBP) has about 1000-fold
higher estrogenic activity
than BPA.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Under Hormonal Control
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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*
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
GABAA Receptors
• Primary inhibitory
neurotransmitter
• Progesterone: agonist
(↑ inhibition/sedation)
• Prog sulfate antagonist
(↓ inhibition↑ anxiety)
• DHEA: antagonist
• DHEAS: 1000X stronger
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
We need endogenous hormones
Estradiol regulates metabolic
flexibility – the ability to utilize
different fuel sources when needed.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Exogenous vs Endogenous
Hormones
Are they the same?
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Synthetic steroids are similar but not identical
to endogenous steroids.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Similar but not identical
• Shape
• Binding
• Patterns, affinities,
interactions with other cells
• Potency
• Metabolites (and their
actions)
• Elimination
Differences between synthetic and endogenous
hormones
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
What happens to
endogenous hormones
while on synthetics?
A mixed response.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Follicular Mid-Cycle Luteal
Estriol(pg/mL)
Phase in Cycle
Control High EE Low EE
Guillermo C, Marrs C, unpublished
data.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Progesterone and Testosterone
5.0
15.0
25.0
35.0
45.0
55.0
65.0
75.0
Follicular Mid-Cycle Luteal
Progesterone(pg/mL)
Phase in Cycle
Control High EE Low EE
15.0
20.0
25.0
30.0
35.0
40.0
45.0
50.0
Follicular Mid-Cycle Luteal
Testosterone(pg/mL)
Phase in Cycle
Control High EE Low EE
Guillermo C, Marrs C, unpublished
data.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
DHEAS and Cortisol
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
Follicular Mid-Cycle Luteal
DHEAS(ng/mL)
Phase in Cycle
Control High EE Low EE
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
Follicular Mid-Cycle Luteal
Cortisol(ng/mL)
Phase in Cycle
Control High EE Low EE
Guillermo C, Marrs C, unpublished
data.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Long Term Changes in
Endogenous Hormones
Significantly lower endogenous hormones.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
What happens to innate systems that rely on
endogenous hormones for adaptive regulation?
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Side Effects
Or perhaps, if we’re honest, the just effects.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Evaluating Dose-Response
• Hormonal reactions are:
• not always linear
• time dependent
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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?
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Altered Immune Function
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Deficient, Reactive, or
Exhausted Immune System
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Cost/Benefit
If hormonal contraceptives override innate and
adaptive immunity, increasing susceptibility to STDs,
autoimmune disease processes, cancers, is the
tradeoff worth it?
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Hormonal Contraceptives Alter
Nutrient Concentrations
• ↓riboflavin,
pyridoxine, folate,
vitamin B12, ascorbic
acid, zinc
• ↓ CoQ10, vitamin E,
antioxidants
• +/- vitamin K, iron and
copper, vitamin A
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Nutrients are Critical for
Mitochondrial & Cellular Functioning
Nutrient deficiency damage the mitochondria
Impair steroidogenesis
Increase inflammation (oxidative and cytokine)
Increase disease processes
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Medical Misuse
Menstrual normalization, endometriosis, PCOS, fibroids,
menorrhagia, depression, anxiety, bloating, fatigue.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Pill withdrawal bleeds are not
periods.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
Endometriosis, PCOS, Fibroids
• Induces tissue growth
• Impairs glucose tolerance
• Induces chronic inflammation
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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?
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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.
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
“You did then what you knew how to do,
And when you knew better,
You did better.”
Maya Angelou
Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends
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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Birth Control, Big Money and Bad Medicine: A Deadly Trifecta in Women’s Health

  • 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
  • 2. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends How do we know what we think we know?
  • 3. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Generations of Marketing For $1 in R&D, $19 in marketing and advertising (BMJ 2012;345:e4348)
  • 4. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 5. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 6. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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)
  • 7. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 8. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends For years on end n = 924 Age OC use begins: Average Length of time used: 9.41 years, SD 6.33
  • 9. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 10. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Political tug-of-war
  • 11. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends What do we really know?
  • 12. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends A Foundation for Understanding Hormones.
  • 13. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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.
  • 14. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Disconnected
  • 15. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Compartmentalized
  • 16. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Everything is connected
  • 17. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Pregnancy Prevention http://sitn.hms.harvard.edu/flash/2014/the-risks-of-control-assessing-the-link-between-birth-control-pills- and-breast-cancer/
  • 18. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Beyond Reproduction Steroid hormones regulate everything.
  • 19. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 20. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Where there are receptors… Hormones act.
  • 21. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 22. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Metabolites Matter 4-methyl-2,4-bis(4- hydroxyphenyl)pent-1-ene (MBP) has about 1000-fold higher estrogenic activity than BPA.
  • 23. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 24. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Under Hormonal Control
  • 25. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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.
  • 26. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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*
  • 27. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends GABAA Receptors • Primary inhibitory neurotransmitter • Progesterone: agonist (↑ inhibition/sedation) • Prog sulfate antagonist (↓ inhibition↑ anxiety) • DHEA: antagonist • DHEAS: 1000X stronger
  • 28. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 29. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 30. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 31. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 32. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends We need endogenous hormones Estradiol regulates metabolic flexibility – the ability to utilize different fuel sources when needed.
  • 33. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 34. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 35. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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.
  • 36. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Exogenous vs Endogenous Hormones Are they the same?
  • 37. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Synthetic steroids are similar but not identical to endogenous steroids.
  • 38. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Similar but not identical • Shape • Binding • Patterns, affinities, interactions with other cells • Potency • Metabolites (and their actions) • Elimination Differences between synthetic and endogenous hormones
  • 39. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 40. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 41. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends What happens to endogenous hormones while on synthetics? A mixed response.
  • 42. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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 Follicular Mid-Cycle Luteal Estriol(pg/mL) Phase in Cycle Control High EE Low EE Guillermo C, Marrs C, unpublished data.
  • 43. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Progesterone and Testosterone 5.0 15.0 25.0 35.0 45.0 55.0 65.0 75.0 Follicular Mid-Cycle Luteal Progesterone(pg/mL) Phase in Cycle Control High EE Low EE 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 Follicular Mid-Cycle Luteal Testosterone(pg/mL) Phase in Cycle Control High EE Low EE Guillermo C, Marrs C, unpublished data.
  • 44. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends DHEAS and Cortisol 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 Follicular Mid-Cycle Luteal DHEAS(ng/mL) Phase in Cycle Control High EE Low EE 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 Follicular Mid-Cycle Luteal Cortisol(ng/mL) Phase in Cycle Control High EE Low EE Guillermo C, Marrs C, unpublished data.
  • 45. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Long Term Changes in Endogenous Hormones Significantly lower endogenous hormones.
  • 46. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends What happens to innate systems that rely on endogenous hormones for adaptive regulation?
  • 47. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Side Effects Or perhaps, if we’re honest, the just effects.
  • 48. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 49. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 50. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Evaluating Dose-Response • Hormonal reactions are: • not always linear • time dependent
  • 51. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 52. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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?
  • 53. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Altered Immune Function
  • 54. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Deficient, Reactive, or Exhausted Immune System
  • 55. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Cost/Benefit If hormonal contraceptives override innate and adaptive immunity, increasing susceptibility to STDs, autoimmune disease processes, cancers, is the tradeoff worth it?
  • 56. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Hormonal Contraceptives Alter Nutrient Concentrations • ↓riboflavin, pyridoxine, folate, vitamin B12, ascorbic acid, zinc • ↓ CoQ10, vitamin E, antioxidants • +/- vitamin K, iron and copper, vitamin A
  • 57. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Nutrients are Critical for Mitochondrial & Cellular Functioning Nutrient deficiency damage the mitochondria Impair steroidogenesis Increase inflammation (oxidative and cytokine) Increase disease processes
  • 58. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 59. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Medical Misuse Menstrual normalization, endometriosis, PCOS, fibroids, menorrhagia, depression, anxiety, bloating, fatigue.
  • 60. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Pill withdrawal bleeds are not periods.
  • 61. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends Endometriosis, PCOS, Fibroids • Induces tissue growth • Impairs glucose tolerance • Induces chronic inflammation
  • 62. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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?
  • 63. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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
  • 64. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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.
  • 65. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends “You did then what you knew how to do, And when you knew better, You did better.” Maya Angelou
  • 66. Lucine Health Sciences, Inc. | Hormones Matter I Heal with Friends 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

Notas del editor

  1. In much the same way that mind body dualism has pervaded medical thinking
  2. This compartmentalized approach to contraception and indeed reproduction has pervaded women’s health research for decades.
  3. We need to disabuse ourselves of the notion that the reproductive organs can somehow be separated from the totality of women’s health. The reproductive organs are no more separate and no less important than other organs within the human body. The health of these organs, the health of the hormones that impact these organs is connected to all of health.
  4. So while we have successfully figured out that when we override endogenous hormone production in the female ovary and subsequently eliminate ovulation and prevent pregnancy, we shouldn’t be so naïve to think that this action is limited solely to it’s target tissue – the ovary. No, far from it. By the 1940s scientists had figured out the importance of hormones in the female reproductive cycle. They established that once a woman becomes pregnant, her fertility is suspended. A woman cannot conceive again while pregnant, because her ovaries secrete the hormones estrogen and progesterone. The secretion of estrogen tells the pituitary gland to withhold the hormones necessary for ovulation. The secretion of progesterone also helps to inhibit ovulation by suppressing the lutenizing hormone known as LH. http://upload.wikimedia.org/wikipedia/commons/1/1d/Pilule_contraceptive.jpg Pituitary Gland: http://commons.wikimedia.org/wiki/File:Pituitary_gland_image.png Ovulation: http://en.wikipedia.org/wiki/Human_fertilization Uterus: “Blausen 0404 Fertilization” by BruceBlaus – Own work. Licensed under Creative Commons Attribution 3.0 via Wikimedia Commons – http://commons.wikimedia.org/wiki/File:Blausen_0404_Fertilization.png#mediaviewer/File:Blausen_0404_Fertilization.png
  5. I want to take you on a trip that goes beyond reproduction b/c steroid hormones regulate everything.
  6. Just to give you and idea about the breadth and depth of steroid influence, did you know that they can synthesized in other tissues – like the brain.
  7. And if they can be synthesized in these other tissues, doesn’t it make sense that they might perform a function there as well. And so, from here we can see the distribution of the two primary types of estrogen receptor, Era and ERB, notice they are all over the body and the brain suggesting that when we manipulate these hormones or there balance is disrupted in any way, there will be broad based effects. And this is just the estrogen receptors, there are similar distributions for the progesterone receptors, the androgen receptors, the glucocorticoids and mineralocorticoids. Steroid hormones and their receptors are distributed throughout the brain and body http://iovs.arvojournals.org/article.aspx?articleid=2122996
  8. Once upon a time, not too long ago, and even today, the notion of one-ligand > one receptor, single lock/single key pervaded. We now know that is not true. While there are specific estrogen, androgen, glucocorticoid and mineralocorticoid receptors that preferentially bind to their cognate ligand, it’s not that simple. Everything crossbinds. Progesterone has a very high affinity of mineralocorticoid and glucocorticoid receptors, for example. And depending upon the balance of power – one’s internal chemistry – can evoke changes consistent with aldosterone or cortisol binding. And they don’t need their own receptors, they can cross bind. adrenaline
  9. Lupron, ovary removal, etc.
  10. Imagine if there were no options or if you had to respond to each and every stressful event in your life using exactly the same behaviors or response patterns. You would not get very far. The same holds true for cell behavior, and more specifically, mitochondrial behavior. The mitochondria need options to respond to the differing needs of the cells that they supply with energy. If those options become limited in any way, the mitochondria become less effective. They produce less energy, scavenge fewer oxidants (toxicants) and when stressors present, cannot easily adapt. In fact, the more inflexible the mitochondria are forced to become, the less likely they, and the cells, tissues, organs, and organism within which they reside, will survive. Estradiol upregulates the expression of the enzymes that make up the PDC (in the brain). If estradiol is reduced or blocked, mitochondrial ATP production will take a hit. If estradiol is blocked in an already nutrient depleted woman, the first step in mitochondrial fuel conversion would take a double hit.  I’ve written about this research previously, not fully understanding the implications. Estradiol allows cardiomyocytes (heart cells) to switch from their preferred fuel of fatty acids to glucose during stressors such as heart attack (and theoretically during any stressor like exercise). That ability to switch fuel types is protective and allows the cells to survive and heal. It may explain why women are more susceptible to heart damage post menopause, when endogenous estradiol declines. This may also point to a pathway for post oophorectomy and post Lupron declines in normal heart function.
  11. Steroid hormones and their receptors are distributed throughout the brain and body
  12. So while we have successfully figured out that when we override endogenous hormone production in the female ovary and subsequently eliminate ovulation and prevent pregnancy, we shouldn’t be so naïve to think that this action is limited solely to it’s target tissue – the ovary. No, far from it. By the 1940s scientists had figured out the importance of hormones in the female reproductive cycle. They established that once a woman becomes pregnant, her fertility is suspended. A woman cannot conceive again while pregnant, because her ovaries secrete the hormones estrogen and progesterone. The secretion of estrogen tells the pituitary gland to withhold the hormones necessary for ovulation. The secretion of progesterone also helps to inhibit ovulation by suppressing the lutenizing hormone known as LH. http://upload.wikimedia.org/wikipedia/commons/1/1d/Pilule_contraceptive.jpg Pituitary Gland: http://commons.wikimedia.org/wiki/File:Pituitary_gland_image.png Ovulation: http://en.wikipedia.org/wiki/Human_fertilization Uterus: “Blausen 0404 Fertilization” by BruceBlaus – Own work. Licensed under Creative Commons Attribution 3.0 via Wikimedia Commons – http://commons.wikimedia.org/wiki/File:Blausen_0404_Fertilization.png#mediaviewer/File:Blausen_0404_Fertilization.png
  13. BPA research --
  14. Aromatase activity is negligible in the ectopic endometrium, whereas the activity of estrogen sulfatase is high though not different between ectopic, eutopic and control endometrium. The activity of 17β-hydroxysteroid dehydrogenases (17β-HSDs) converting estrone into 17β-estradiol is higher in the ectopic compared to the eutopic endometrium in patients. The activity of 17β-HSDs converting 17β-estradiol back to estrone is significantly lower in the ectopic compared to the eutopic endometrium of both patients and controls. To evaluate the net metabolic capacity of tissues to synthesize 17β-estradiol, we calculated the activity ratio between 17β-HSDs synthesizing versus 17β-HSDs inactivating 17β-estradiol. This ratio is significantly higher in the ectopic compared to the eutopic endometrium of patients and controls, indicating a high synthesis of 17β-estradiol in the ectopic locations. This is further supported by the elevated mRNA levels of the estrogen-responsive gene TFF1in all ectopic compared to eutopic endometria. Conclusion: Endometriotic lesions have higher production of 17β-estradiol than the eutopic endometrium of patients and controls. This is mostly the result of impaired metabolism. Endometriosis lesions have increased activity of 17β-hydroxysteroid dehydrogenases synthesizing active 17β-estradiol compared to the eutopic endometrium.