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