The Role of Reproductive Hormones, Birth Control and Hormone Replacement

1
The Role of Reproductive Hormones, Birth Control
and Hormone Replacement in Female Pathophysiology
by
John S. Green, Ed.D., Ph.D., FACSM. Brittany
Klepac, M.S., Kristen Brown, B.S.
Applied Exercise Science Laboratory Huffines
Institute for Sports Medicine
Department of Health Kinesiology
Texas AM University
2
The Female Menstrual Cycle
3
Regulation of Female Reproductive Function
Hypothalamus
LHRH (GNRH)
Anterior Pituitary
LH
FSH
Ovulation
Follicle
Corpus Luteum
Progesterone
Estrogen
Inhibin
4
Introduction of Exogenous Estrogen
Progesterone
Hypothalamus
LHRH
Estrogen
Progesterone
Anterior Pituitary
FSH
LH
Ovulation
Follicle
Corpus Luteum
Progesterone
Estrogen
Inhibin

• Ovulation is prevented
• Cervical mucus is thickened - helps prevent
  sperm from entering uterus (progestins)
• The uterine wall lining is usually thinned to
  prevent implantation
• in the difficulty of sperm penetrating the
  mucous surrounding the egg (progestins)

5
Birth Control Pills (oral contraceptives or
OCs)

• 1960 Frank B Colton (1923-2003) introduced
  Envoid
• 30-50 mcg of E2 progesterone r d LH r no
  ovulation
• Ushered in the era of oral contraception
• Most socially significant medical advance in
  history ??
• Early pills (lt 1975) u E2 and progesterone r u
  risks side effects
• Most pills now contain 25 mcg of estrogen or less
• 2002 introduction of Ortho-Tricyclen-Lo
• Produced distributed by Ortho-McNeil
  Pharmaceuticals
• Primary producer of oral contraceptives in this
  country since 1960
• Currently the nations most widely prescribed
  birth control pill
• The progesterone in this pill is less likely to
  cause side effects

6
Risks Concerns Associated with the pill

• u Risk of blood clots, heart attack, stroke
• Risk substantially increased by smoking, being
  over 35, and having a family history
• Women who have a familial history of thrombolic
  events should consult a gynecologist to screen
  for pro-thrombotic state before using the pill
• Slight chance of u risk of breast cervical
  cancer - ???
• Risk for breast cancer is less than 1 in 1000 in
  women of all races under age 35
• This has not been proven or supported by all
  studies
• Women who have a family history and used OC prior
  to 1975 r u risk
• Breast cancer important factor is total estrogen
  exposure
• Early menarche and late menopause r u breast
  cancer risk
• Women who have a genetic history and used OC
  prior to 1975 r u risk
• Family history not linked to genetic defect is
  not a strong risk factor
• Slight u risk of CAD in women over 40 - ???
• This has not been proven or supported by all
  studies
• Possible link between oral contraception and
  carotid plaque development
• u Stroke risk (for every 10 yr use, plaque u by
  20 - 30 (AHA Study 2007)
• d contraception effectiveness if taking certain
  antibiotic

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Benefits of the Pill Besides Contraception

• Bigger Boobs!!! water retention and u breast
  tissue growth
• Not seen in all woman and with all types of
  pills may be transient
• 40 - 50 d in risk of ovarian endometrial
  cancer, and ovarian cysts
• Decreased risk of pelvic inflammatory disease
• Menstrual cycles or more regular
• Lighter blood flow during menses
• Possible reduction in menstrual cramping
• Some pills may improve complexion ( reduced acne
  )

Possible Side Effects of Taking the Pill

• Nausea
• Bleeding
• Mood changes

• Weight gain
• Fluid retention
• Breast tenderness

8
New Choices and Routes of Administration

• Injectable estrogen progesterone (DEPO
  PROVERA)
• Deep intramuscular Injection every 23 to 33
  days
• Transdermal patch (ORTHO EVRA)
• Patch applied about anywhere but boobs
• One patch weekly for three weeks followed by a
  patch free week
• Contraceptive Vaginal Ring (NUVARING)
• Ring is used for 3 weeks continuoulsy followed
  by a ring free weak
• Ring may or may not be taken out during sex
• Intrauterine Device (IUD) (MIRENA)
• Implantable Contraceptives (NORPLANT II,
  JADELLE, IMPLANON)
• Emergency Contraception (PREVIN, PLAN B)
• Large doses of estrogen progesterone or
  estrogen alone
• Pregnancy is the only contraindication

9

• Low Dose Pills (ALESSE)
• The lowest overall dosage of levonorgestrel
  (progestin) and ethinyl estradiol (estrogen)
  marketed in the United States
• 20 mcg ethinyl estradiol (estrogen) 100 mcg
  levonorgestrel (progestin)
• Less control over ovulation due to lower hormone
  dosage)
• Higher risk of breakthrough bleeding
• Less risk of cancer, stroke, blood clots, and
  other cardiovascular diseases
• Similar to most monthly oral contraceptives, but
  the user is given 2 options
• 28 Pill Pack
• Take 21 active pills and the 7 provided reminder
  pills (placebos) to begin menstruation
• 21 Pill Pack
• Take 21 active pills followed by a week with no
  pills to begin menstruation
• Long term effects of ALESEE have not been
  determined

10

• Trans-dermal Patch (ORTHO EVRA)
• Weekly patch applied to the body (anywhere except
  the breasts)
• Left on for 3 weeks on the 4th week, no patch
  is worn
• 60 more estrogen than in other contraceptive
  methods
• Pros
• Do not have to remember to take a pill each day
• Cons
• Higher estrogen dosage ? higher risks of blood
  clots
• Some studies have shown a two-fold increase in
  blood clot risk
• Obstetrics Gynecology

11
Intrauterine Device a.k.a. IUD (MIRENA)

• T-shaped piece of plastic placed in the uterus
  by a healthcare professional
• It is Estrogen Free Levonorgestrel is the
  active hormone
• Pros
• Shorter periods due to thinning of the uterus
• Less weight gain
• Nearly immediate return of fertility upon
  removal
• Up to 90 reduction in menstrual bleeding
• May be left in for up to 5 years
• Cons
• Substantially increased risk of uterine
  perforation
• Increased risk of Pelvic Inflammatory Disease
• Increased risk of ovarian cysts

Canadian Journal of Rural Medicine, 2008
12

• Estrogen-Free Injection (DEPO PROVERA)
• Progesterone-only hormone injection every 3
  months
• Requires visiting a healthcare professional every
  3 months for reinjection
• Can take 6-18 hours for excess hormones to
  completely be expelled from the body upon
  stopping this method
• Menstruation usually returns up to 6 months after
  cessation of use
• No extensive research regarding Depo Provera and
  heart disease
• Amenorrhea may occur
• Risk of irreversible bone density loss with
  prolonged use of Depo Provera
• Estrogen reduces bone resorption (more calcium
  and bone density)
• Progestins reduce estrogen levels ? decreased
  bone formation ( osteoperosis risk)
• Recommended as a long term contraceptive method
  (at least 2 years)

13

• Contraceptive Vaginal Ring (NUVA RING)
• Ring inserted and left in for 3 weeks at a time
• Contains estrogen and progesterone
• Lower estrogen dosage than most other
  contraceptive methods
• Pros
• Can be removed for up to 3 hours without losing
  contraceptive effectiveness
• Can be left in during sex
• Insertion only once a month
• Cons
• Vaginitis is a common side effect
• Vaginal discomfort upon insertion

14

• Implantable Contraceptives (IMPLANON)
• Contains progestin only estrogen-free
• This type of birth control originated as a set of
  6 silicon capsules inserted subdermally in the
  upper arm
• Implanon is one rod inserted into the arm by a
  healthcare professional
• Pros
• Effective for up to 3 years
• Cons
• Higher risk of an ectopic pregnancy than with no
  contraception
• Complications with insertion can lead to minor
  surgeries
• The American College of Obstetricians and
  Gynecologists

15

• Continuous Contraception (LYBREL)
• Birth control pills taken every day suppress
  menstrual cycle for a full year
• Low dosage of hormones released with each pill
• 90 mcg levonorgestrel and 20 mcg ethinyl
  estradiol
• Doctors in disagreement about whether it is safe
  for a woman to completely stop having her
  monthly period
• Some doctors feel that preventing the uterus from
  undergoing monthly menstrual changes may prove
  to reduce endometrial cancer
• Not enough published data regarding long term
  effects
• Fertility possibly affected?
• Risks of cancer, blood clots, heart attacks
  increased without menstruation?
• Pros
• Stabilization of hormonal levels
  reduction/elimination of monthly PMS
• Save money no longer buying feminine products
  each month
• Elimination of menstruation linked to decreased
  endometriosis and anemia
• Cons
• Hard to determine if you become pregnant
  (menstrual cycle eliminated)
• Irregular, unplanned, unscheduled bleeding

16

• Mini-Pills NORGESTIN CERAZETTE
• Mini-Pills do not contain estrogen, only
  progesterone
• Taken daily
• Pros
• Ideal method for women who have migraines, high
  blood pressure, or who are breastfeeding
• Cons
• Found to be one of the less effective methods in
  prevention of pregnancy
• Only relies on progestin to thicken the cervical
  mucus
• Increased risk of developing ovarian cysts

17

• BC That Treats Menstrual Mood Problems (YAZ)
• 24 active pills followed by 4 placebo pills
  (rather than 7)
• Shorter, lighter periods
• Used for treatment of premenstrual dysphoric
  disorder (PMDD)
• Drospirenone, the progestin in Yaz, is the active
  hormone that treats PMDD
• Studies have shown success in treatment of acne
• Drospirenone has anti-androgenic effects
• Binds to aldosterone receptors ? blocks
  aldosterone action in the kidneys
• ? sodium and water excretion
• ? retention of potassium ? hyperkalemia ? risk of
  heart arrhythmia

18

• Birth Control Methods of the Future
• The Pill for men
• Synthetic hormones to reduce sperm count
• Vaccinations (for men and women)
• Suppression of sperm production in men
• Reduction of pregnancy hormones in women
• Active immunization against antigens
  specific
  for reproduction

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Definitions

• Menopause Permanent cessation of menstruation
  resulting from loss of ovarian function
• Average age at menopause 51.4 years
• Average life expectancy gt 80 years
• Perimenopause (Climacteric) the period
  immediately before menopause and at least 5 years
  after the initial onset of symptoms (menses
  seldom ceases abruptly)
• Postmenopause the period dating from the
  menopause, which can only be assessed in
  retrospect

World Health Organization
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How do I know if Im going through menopause ?

• Surgical Menopause - hysterectomy (total vs.
  partial)
• Blood Tests
• d circulating estrogen inhibin concentrations
• u LH and FSH concentrations
• Irregular Menstruation
• Vaginal or abdominal pain
• Vaginal dryness
• Autonomic Vasomotor Disturbances
• Hot flashes, sweating, heart palpitations,
  headaches, dizziness
• Psychological Manifestations
• Depression, loss of libido, insomnia,
  irritability

21
Estrogen Changes with Menopause Carr McDonald,
Advances in Internal Medicine, 1983
Androstenedione
Androstenedione
22
Primary Killers of Women in 2001 2004

Source National Center for Health Statistics,
AHA, CDC
23
Cardiovascular Disease (CVD) Differences in
Men vs. Women

• CVD incidence is lower in fertile women lt 50 than
  in men lt 50
• 1 3 ratio
• CVD incidence in women pulls even with men at age
  70 - 90
• CVD incidence in women is u with early / surgical
  menopause
• oophorectomy causes greater risk than uterus
  excision alone
• for each year the menopause is delayed, death
  risk d 2

Thrombosis Research 84 (1) 1996
24
CVD Risk Markers and Cardiovascular Function
Negatively Affected by Menopause

• u LDL-Cholesterol (the Bad cholesterol)
• d HDL-Cholesterol (the Good cholesterol)
• u Triglycerides (circulating blood fats)
• u Lipoproteina (similar to LDL promotes
  thrombi)
• u Fibrinogen (promotes thrombus formation)
• u Coagulation Factor VII (promotes thrombus
  formation)
• u Coagulation Factor VIII (promotes thrombus
  formation)
• u Plasminogen Activator Inhibitor (promotes
  thrombi)
• u Vascular wall dysfunction and arterial
  stiffness
• u Left ventricular dysfunction

25
CVD Risk Markers and Cardiovascular Function
Positively Affected by Hormone Replacement
(Estrogen Progesterone)

• d LDL-Cholesterol (the Bad cholesterol)
• u HDL-Cholesterol (the Good cholesterol)
• d Triglycerides (circulating blood fats)
• d Lipoproteina (similar to LDL promotes
  thrombi)
• d Fibrinogen (promotes thrombus formation)
• d Coagulation Factor VII (promotes thrombus
  formation)
• d Plasminogen Activator Inhibitor (promotes
  thrombi)
• d Circulating insulin levels
• d Vascular wall dysfunction and arterial
  stiffness
• d Left ventricular dysfunction

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CVD Risk and Hormone Replacement

• Almost all studies prior to 2002 show HRT to
  reduce the risk of CV disease
• decrease in relative risk approaches 50

HRT and CV Disease Risk - Study Results
Stampfer et al, 1985 Bush et al, 1987 Henderson
et al, 1988 Petitti et al, 1987 Folkbebom,
1992 Psaty et al, 1994 Folsom et al, 1995
0 .5
1.0 2.0
Relative Risk (1.0 - average risk)
27
CVD Risk, Breast Cancer, and Hormone Replacement
The New and Current Controversy

• RCT studies show different findings - study
  stopped after 5.2 yrs
• Subjects in older studies may have been healthier
  to begin with

http//www.nhlbi.nih.gov/whi/
Results from the Womens Health Initiative ( E2
Progesterone )
16,608 women
Coronary Artery Disease Breast Cancer Stroke Pulmo
nary Embolism Colorectal Cancer Endometrial
Cancer Hip Fracture Dementia Alzheimers (in
women gt65 yrs)
1.29
1.26
1.41
2.13
.63
.83
.66
1.49
(E2 alone)
JAMA, 2002, vol 288, 3
0 .5
1.0 2.0
Relative Risk (1.0 - average risk)
28
CVD Risk, Breast Cancer, and Hormone Replacement
The New and Current Controversy
Results from the HERs Trials ( E2 P in 2,763
Women with CVD )
.99
Coronary Artery Disease Breast Cancer Any
Thromboembolic Event All Cancer Hip Fractures All
Fractures Overall Mortality
1.27
2.08
1.19
1.61
1.04
1.1
JAMA, 2002, vol 288, 3
0 .5
1.0 2.0
Relative Risk (1.0 - average risk)
29
Osteoperosis and Hormone Replacement

• Studies show HRT to d risk of bone density loss
• d Osteoporosis r d Hip Fracture Risk
• The risk of hip fracture mortality and morbidity
  d
• Is HRT worth the risk a decision for you and
  your Dr.

HRT and Hip Fracture Risk - Experimental Study
Results
Weiss, 1980 Johnson, 1981 Paganini-Hill,
1981 Kiel, 1987 Naessen, 1990
0 .5
1.0 2.0
Relative Risk (1.0 - average risk)
30
The Fallout from the WHI and HERs findings

• In 2000 the New York Times published a warning
  to all HRT users
• From 2001 -2003 there was a 68 reduction in the
  use of HRT in the US
• Women often stopped HRT without consulting their
  doctor!!!
• This reduction in HRT use was positively linked
  with a 8-10 d in breast cancer
• New England Journal of Medicine
  20073561670-1674

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Further Analysis r New Thinking!!!!

• Researches in the WHI study and other RCT
  studies began looking at .
• The age at which HRT was initiated
• WHI and HERs women were 13 14 years past
  menopause!!!
• The differences between estrogen alone and
  estrogen progesterone
• Their findings
• HRT taken soon after menopause (lt60 years of
  age) associated with
• 39 reduction in cardiovascular events (heart
  attacks, etc.)
• Estrogen only regimens show a stronger
  protective effect
• JAMA 2007 Vol 297 pp 1465-1477
• Estrogen only HRT may not increase risk for
  breast cancer in women initiating HRT for the
  first time and at a young age (lt60 years) and
  may even reduce the risk.
• JAMA 2004 Vol 291 pp 1701-1712
• Thromboembolic events remain the most serious
  side effect of HRT
• These risk increases with age of initiation of
  HRT
• JAMA 2004 Vol 292 pp 1573 - 1580

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Conclusions

• Birth control pills (low estrogen pills
  manufactured after 1975) are safe for most women
  with a low incidence of negative side effects.
  Other routes of estrogen and estrogen
  progesterone administration are viable
  alternatives with similar side effects and
  efficacy rates.
• Hormone replacement therapy (especially estrogen
  plus progesterone) is associated with potential
  risks and benefits with the risks becoming
  greater when the medication is started at a later
  age past menopause.
• Estrogen only hormone replacement therapy started
  soon after menopause may prove beneficial in
  reducing cardiovascular risk and helping to
  prevent osteoperotic fractures without causing an
  increase in breast cancer risk. Further studies
  are needed to confirm this.
• Each woman should consult with a gynecologist to
  determine when, if, and how long she should take
  hormone replacement therapy.

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• Post Menopausal Systemic Hormone Therapy
• Menopause serves as a milestone where health can
  be re-evaluated
• Most frequent causes of death Heart Disease
  increases rapidly over the age of 45
• Menopause can cause vasomotor symptoms (hot
  flashes, night sweats), vaginal thinning
  (infections, painful intercourse), dry eye
• Atrophic vaginitis pH increase epithelial
  lining thins due to loss of estrogen, dryness,
  less elasticity
• Bone loss, osteoporosis, heart disease, skin
  thin, tooth and gum disease, weight gain
• FDA Labels
• Prescribe hormone therapy to fit the woman
• To treat vaginal atrophy, use topical cream
• Last resort for osteoporosis treatment alone
• Hormone Therapy (Benefits and Risks)
• Symptom relief if necessary
• Hot flashes stop w/o treatment etiology unknown
• Endometrial cancer reduced
• Therapy in younger women (50-59) associated with
  less CVD
• Risks related to baseline disease risks, age,
  cause of menopause, prior exposure to HT
• Blood clots increase with age, but 2 fold
  increase with combined therapy
• Breast cancer risk varies by type and duration of
  therapy
• The current thought is that Hormone Therapy can
  be used in post-menopausal treatment, but it
  should be stopped as soon as possible since long
  term effects are inconclusive