MENOPAUSAL HORMONE

THERAPY: Putting Talk Shows into

Perspective

Janice Werbinski, MD, Medical Director

Borgess Women’s Health
WomenSense Lecture Series
June 2009
A $SIGN OF THE TIMES
“Who ARE these people??”
Christiane Northrup
Lauren Hutton
Sally Field
Patty LaBelle
Oprah Winfrey
Robin McGraw
Suzanne Sommers
MENOPAUSE AND WOMEN’S
HEALTH PROVIDERS
Wulf Utian, MD
Holly Thacker, MD
Elizabeth Lee Vliet, MD
Wendy Klein, MD
Nancy Teaff, MD
Jan Werbinski, MD
 REPUTABLE RESOURCES
(See Bibliography)
 National Women’s Health Network
 Cleveland Clinic – Holly Thacker
 Susan Love
 North American Menopause Society
 Harvard Women’s Health Watch
 DHHS (4Woman.gov)
 Our Bodies Ourselves
 WebMD.com
 MENOPAUSE DEFINITION
 Cessation of Menses for 12 months or more
 Laboratory Values - Serum (or Saliva?)
 FSH > 40 Units

 Estradiol < 25 Picograms/Deciliter

 Progesterone drops earlier

 Invalid if Taking any hormones at all

 If NON-Menopausal, hormone levels vary
hour-to-hour, depends on day of the cycle.
 ESTROGEN RECEPTORS
 Brain  Bladder
 Mood
 Frequency
 Urge Incontinence
 Memory
 Bone
 Hot Flashes*
 Density/Fracture risk
 Breast
 Colon
 Fibrocystic Density
 Carcinoma
 Uterus  Liver
 Hyperplasia/Carcinoma
 Coagulation Factors
 Vessels  Lipids
 Hot Flashes*  Heart
 Hemorrhagic Stroke  Palpitations
 Ischemic Stroke  Atherosclerosis
 Deep Vein Thrombosis  Ischemic MI
HT Through the Ages
 Nazi Germany
 Feminine Forever 1950
 Endometrial Ca (1971)
 MPA (1980)
 “Designer” Estrogens
 Micronization (Prog)
 NHS, WHI and HERS
 “Natural Hormones”
 Back to Basics
 New NAMS Statement
MENOPAUSAL THERAPIES
 Pharmaceutical Hormones
 FDA Approved after intense study on large numbers
 Prospective, Double Blind, Crossover, Placebo
 Interesting History

 Bioidentical Hormones
 Identical to the ovarian hormones produced during
reproductive years
 Some are FDA Approved
 Some are “Compounded” by Pharmacists
 Some are sold on the Internet without a prescription
MENOPAUSAL THERAPIES
 Herbals
 Eastern Medicine, Alchemy, Witchcraft
 Can be helpful and safe

 Not many studied extensively

 Alternative Modalities
 Massage, Acupuncture, Relaxation exercises,
Chiropractic, Nutritional Medicine, Stellate
Ganglion Injection
 HT TERMINOLOGY
 ET – Estrogen Therapy
 EPT – Combined Estrogen-Progestogen Therapy
 HT – Hormone Therapy (Encompassing both ET and
EPT
 Progestogen – Encompassing both progesterone and
progestin
 Systemic Therapy – HT administration that results in
absorption in the blood high enough to provide
clinically significant effects
 Local Therapy – Vaginal ET that does not result in
systemic absorption
 WHAT ABOUT FDA
APPROVAL?
 What does it take to get approval?
 How does a Patent influence
approval?
 What does it mean to use a drug
“Off Label”?
 What is informed consent?
 ADDITIONAL TERMINOLOGY
 Spontaneous/Natural Menopause
 Induced Menopause-surgical/chemorx

 Perimenopause (8 years around LMP)

 Premature Menopause (<age 40)

 Premature Ovarian Failure

 Early Menopause (at or <age 45)

 Early postmenopause – the 5 years

subsequent to the LMP.
ESTROGENS
Bioidentical Term:
17Beta Estradiol
Estrone
Estriol
ESTROGEN THERAPY OPTIONS
ORAL PATCH TDERMAL VAGINAL
Cenestin Alora Divigel Estrace
Enjuvia Climara Elestrin Estring
Estrace Esclim EstroGel Femring
Estratab Estraderm Estrasorb Premarin
Femtrace Menostar Vagifem
Ortho-Est Vivelle
Menest Vivelle-Dot
Premarin
 Risk of VTE (blood clot) by Route
and Type of Hormone
Cases Controls RR
(259n) (603n)
Nonuse 146 384 1
PO Estrogen 45 39 4.2
TD Estrogen 67 180 0.9
No Prog 14 40 --
Micronized 19 63 0.7
Pregnanes 39 79 0.9
Norpregnan 40 37 3.9
 PROGESTERONE
PROGESTIN
Micronized Progesterone: BHT
Pregnane
NorPregnane
 PROGESTERONE
PROGESTIN
 The “Natural” Product
 Corpus Luteum
 USP Progesterone
 Prometrium
 MedroxyProgesterone Acetate-Provera
 Progestins
 Norethindrone Acetate (NETA)
 Norgestimate
 Desogestrel
 Levonorgestrel
 Norethindrone
 Breast Cancer Risk Varies by
Type of Progestin
Progestin Route # RR
Progesterone Transdermal 35,513 1.08
MPA (Provera) Oral 7,035 1.48
Norethindrone Oral 7,401 2.11
Acetate
Dydrogesteron Transdermal 25,405 1.18
Nomegestrol Transdermal 18,826 1.6
Acetate
Promegestone Transdermal 14,910 1.52
Fournier,A et.al Breast Cancer Res Treatment. 2008; 107:103-111.
 TESTOSTERONE
 Available Products
 Historically for Men (Orchiectomy, Male
Menopause)
 Potential for Women (Libido, Energy,
Potentiation of Estrogen Therapy)
 BioIdenticals and Transdermals – Patch
coming
 Safety and Effectiveness Research
 Black Box Warning
 DHEA
 Data – Interesting
 Possibility
of Several Uses
 No FDA Approval

 Health food stores

 Compounding Pharmacies

 Sports Ban

 Congressional Bill Pending

 OTHER HORMONES
 Serotonin
 NorEpinephrine
 Dopamine
 Melatonin
 Pituitary
 Growth
 Thyroid
 Cortisol/Adrenalin
 Insulin
 Use of Nonhormonal Therapies
for Vasomotor Symptoms
AGENT DAILY % PLACEBO
DOSE REDUCED % REDUC
Paroxetine 25 mg 50% 27%

Venlaxafine 75 mg 51% 15%

Gabapentin 900 mg 45% 29%

Clonidine 0.1 mg 38% 20%

 Benefit:Risk Ratio of PremPro
(Women’s Health Initiative)

Condition Change in Risk Cases per Year

Invasive Breast Ca 26% increase 8 more
Stroke 41% increase 8 more
Clots in veins 107% increase 10 more
Clots in lungs 113% increase 8 more
Heart attacks 29% increase 7 more
Hip fractures 34% less 5 less
Colorectal Cancer 37% less 6 less
 Where Does The
WHI Leave Us Now?
2.5

1.5

1 RR

0.5

0
MI CVA DVT FX Colon Breast
 What Else Can We Use?
 Hot Flashes
 Bone Density
 Cardiovascular Disease
 Colon Cancer
 Incontinence
 Breast Cancer
 Libido
 Mood Changes
 Memory Deficits
 Individualize, New Drugs
 SSRI’s, Catapres, Bellergal -FLASHES
 Fosamax, Actonel, Boniva, Forteo-BONE
 Detrol, Ditropan, Hyoscyamine-INCONT.
 Topical Estrogen-BLADDER,VAGINA
 Testosterone, DHEA -LIBIDO
 Progesterone-MOOD, BLEEDING,SLEEP
 Tamoxifen, Evista-BREAST DISEASE
 Injections of Neck Nerves-FLASHES
 Lifestyle Influences
(Diet, Exercise, Nutriceuticals
Meditation, Stress Management)
 Soy, Black Cohosh-FLASHES
 Cruciferous (Indole-3-Carbinol)-BREAST
 Calcium/Vitamin D-BONE
 Folic Acid-MEMORY
 B Vitamins-MOOD
 Antioxidants-CANCER
 Soluble Fiber-COLON
 Melatonin-SLEEP
 What Do the Experts Now Say?

 NAMS (North American Menopause Society)

 ACOG (American College of Ob/Gyn)
 NIH (National Institutes of Health)
 AHA (American Heart Association
 USPTF (US Preventive Task Force)
 NCI (National Cancer Institute)
 NWHN (National Women’s Health Network)
 Consensus 2008
 ERT or HRT for severe climacteric symptoms
(<5 years) unless symptoms persist
 Calcium, Exercise, Bisphosphanates, SERMs,
PTH for osteoporosis
 Tamoxifen, Raloxifene for Breast Cancer
Prevention
 Low Fat, High Fiber, Low Carb diet
 Kegel Exercise, Vaginal HT for Incontinence
 Stress Management, SSRI for Moods
 Exercise, Exercise, Exercise
 2008 NAMS Position Statement
Recent data support the initiation of HT
around the time of menopause to treat
menopause-related symptoms; to treat or
reduce the risk of certain disorders, such as
osteoporosis, diabetes, colon cancer or
fractures in select postmenopausal women;
or both. Benefit-risk ratio is favorable close
to menopause, but decreases with aging and
with time since menopause.
Menopause Vol.15;4:2008, p.584-602
 Timing of HT and CVD
 Women <70 at the time of initiating HT
have no increased risk of CHD for up to 8
yr.
 HT may possibly be associated with an
increase in CHD risk if initiated at a more
distant time from menopause
 Long term use of HT is associated with less
coronary artery calcium (hardening of the
arteries)
 Women <60 after 7 yr treatment had less
 NAMS 2008 Recommendations
(CardioVascular)
 HT is not recommended as a sole or
primary indication for coronary protection
@ any age

 Initiation @ age 50-59 or within 10 yr. of

LMP does not seem to increase CHD risk

 Initiation in early postmenopause may

actually reduce CHD risk
 NAMS 2008 Recommendations
(Diabetes)
 Large RCTs suggest that HT use
reduces the new onset of type 2 DM
 21% reduction in the WHI ET arm of
study
 20% reduction in the HERS trial

 Meta analyses data suggest HT is

associated with improvement in
insulin resistance
 NAMS 2008
(Invasive Breast Cancer Risk)
WHI-EPT use
> 5 years: 4-6/10,000 woman-years
Significantly related to EPT use prior to
study
WHI-ET use
No increased risk after 7.1 years of use
6 fewer cases per 10,000 woman years
This observed in all 3 age groups
(50-59; 60-69; 70-79)
Both may increase pain and density and
impede interpretation of mammograms
 UPCOMING STUDIES
 ELITE STUDY (National Institute on
Aging)
 2004-2009
 Early vs Late Intervention Trial with Estrogen
 Measuring Carotid Artery Thickness with Estradiol
 504n, <6 or >10 yrs. menopausal
 KEEPS STUDY
 Kronos Early Estrogen Prevention Stugy
 720n, age 42-58
 Oral Premarin, TD Climara, Progesterone
 Bottom Line
Provider and Patient must Decide together
on Best Course of Action, Considering:
 Risks

 Benefits

 Desires

 History (Family and Personal)

 Continuing Research
 Protective Levels

Depending on what one wants to protect:

 Heart?

 Flushes

 Vulvovagina

 Uterus

 Bone

 Breast

 Colon
 Duration of Treatment
 SHORT TERM PROTECTION
 To manage immediate flushes, palpitations,
sleep disorders, usually <5 yr. needed
 INTERMEDIATE PROTECTION
 To manage intermediate vulvovaginal
dryness, dyspareunia, libido, incontinence
 LONG TERM PROTECTION
 For cardiovascular?, skeletal, colon, CNS
 Changed with WHI Study
Goal
Choices which
will allow us to
live the longest
time without
disability or loss
of function
 Case Presentation
48 y.o. MWF. LMP 18 months ago.

30 Flushes daily. Sweats and Insomnia at

Night. Cries easily and has labile moods.

Great Aunt with history of Breast Cancer.

Grandmother had a Hip Fracture. Father
had CABG at age 49 for CHD.
 Oral vs Transdermal Estrogen
(pg/ml)
180
160
140
120
PO Estradiol
100
TD Gel
80
TD Patch
60
40
20
0
Day Day Day Day Day Day Day Day
11 11.5 12 12.5 13 13.5 14 14.5
 PHARMACEUTICAL
INFLUENCE

 Number one in sales in US, 2000 (Premarin)

 Based on Observational Studies
 HERS Study
 Healy, NIH, WHI
 Only NIH Prospective HRT Study
 Early Release of Results and Discontinuation