1. Natural and Synthetic Hormone Replacement
Western University College of Pharmacy
Jenny Vu, PharmD 2008

3. Objectives What are hormones? What is estrogen? What is its functions?
What is progesterone? What is its function?
Difference between a natural hormone replacement and synthetic hormone replacement
History of HRT
SEs, Contraindications, the risks of synthetic estrogens and progesterone medications (synthetic HRT).
Benefits of natural hormones replacement

4. What are hormones? Works as the “couriers” in your body
Deliver messages from your brain that tell your cells what to do- such as begin ovulation, go to sleep, or become aroused.
Keeps your body working all day.
Deal primarily with sexual functions, characteristics, and also have thousands of other functions
Estrogen, Progesterone, and Testosterone are sex steroid hormones that most affect women’s health, sexuality, and well-being.
Other hormones are DHEA, cortisol
They are constantly working with each other so that your hormonal makeup remains balanced.
Conrad Christine, et. al. A Woman’s Guide to Natural Hormones. A Perigee Book. Revised and Updated Edition

5. Estrogen Is not a single hormone
Is a family of hormones produced by your body, primarily by your ovaries
Three most important are estrone (E1), estradiol (E2), and estriol (E3)
E2 is the most active and is the one that most doctor prefer for controlling hot flashes and other menopausal Sxs.
E3 is the largest one in your body and is considered generally safe in term of breast cancer risk. It may protect against breast cancer
Conrad Christine, et. al. A Woman’s Guide to Natural Hormones. A Perigee Book. Revised and Updated Edition

6. Estrogen Estrogen has 400 crucial functions in your body:
Stimulates the production of choline acetyltransferase, an enzyme, which prevents Alzheimer’s disease
Increase your metabolic rate
Improve insulin sensitivity
Regulates body temperature
Helps maintain muscle
Helps you sleep deeply
Helps maintain the elasticity of your arteries
Dilates your small arteries
Inhibits platelet stickiness
Decreases blood pressure, LDL
Reduces the overall risk of Heart disease by 40% to 50%
Decrease wrinkles
Etc
Smith W. Pamela. HRT: The Answers A Concise Guide for Solving the Hormone Replacement Therapy Puzzle. Healthy Living Books Inc

7. Estrogen Sxs of Decreased estrogens: Thinner skin More wrinkles
Decrease in breast size
Stress incontinence
Acne
Decreased sex drive
Increase in insulin resistance and possible diabetes
Vaginal dryness
Decrease memory
Osteoporosis
Urinary tract infections
Increased cholesterol
Smith W. Pamela. HRT: The Answers A Concise Guide for Solving the Hormone Replacement Therapy Puzzle. Healthy Living Books Inc

8. Estrogen
Has many protective affects on your brain. Without estrogen, your memory usually declines.
A recent study conducted on 1889 older women in Utah revealed that women who had taken HRT were 40% less likely to develop Alzheimer’s disease. Furthermore, the longer they were on HRT the lower was their risk.
Researchers have concluded that estrogen use would decrease the rate of heart disease by almost 50%
You need estrogen for optimal health. The amount of estrogen you have is important. Too little or too much can cause symptoms or disease.
Smith W. Pamela. HRT: The Answers A Concise Guide for Solving the Hormone Replacement Therapy Puzzle. Healthy Living Books Inc

9. Progesterone
Is one of your sex hormones and is made in your ovaries before menopause
Plays a vital role in maintaining your health:
-improve sleep
-has a natural calming effect
-eliminate water retention
-improves the body’s ability to use and eliminate fats
-lower high blood pressure
-stimulates new bone formation
-protect against breast cancer
-normalizes your sex drive
-regrow scalp hair in women
Smith W. Pamela. HRT: The Answers A Concise Guide for Solving the Hormone Replacement Therapy Puzzle. Healthy Living Books Inc
Conrad Christine, et. al. A Woman’s Guide to Natural Hormones. A Perigee Book. Revised and Updated Edition

10. Progesterone Sxs of decreased progesterone: Anxiety Depression
Irritability
Mood swings
Insomnia
Pain and inflammation
Osteoporosis
Decreased HDL
Excessive menstruation
Remember that progesterone is natural hormone while progestin or MPA is a synthetic hormone. They are different.
Smith W. Pamela. HRT: The Answers A Concise Guide for Solving the Hormone Replacement Therapy Puzzle. Healthy Living Books Inc. 2003

11. Difference Between Nature vs. Synthetic Hormones
Nature Hormones (NH) are the same chemical structure as the ones that your body made
NH is also called bio-identical hormones
NH are synthesized from wild yam or soy and match your own hormones exactly
NH work in your body in the same manner as your own hormones
NH don’t interfere with your body’s own hormone production
Natural progesterone is synergistic and increases the protective affects of estrogen on your heart
Natural HR don’t have the same SEs and long-term risks like synthetic HR

12. Difference Between Nature vs. Synthetic Hormones
Synthetic estrogens are artificial, or not found in nature, and are created from various sources, such as horse urine, or plants
Premarin: most commonly prescribed HR, is a mixture of estrone, sodium equilin sulfate, contains horse estrogens, equilin and equilenin, and additives that are synthetic. These additives cause some SEs including: burning in the urinary tract, allergies, joint aches, and pains.
Premarin contains many form of estrogen that do not fit into the estrogen receptors in your body. Your own estradiol are eliminated from your body within a few hours. Conversely, equilin (estrogen derived from the urine of horses) has been shown to stay in your body for up to13 weeks. This is due to the fact that your enzymes are designed to metabolize your own estrogen and not equilin
Premarin can cause endometrial cancer

13. Difference Between Nature vs. Synthetic Hormones
Synthetic progesterone is called progestin. It is very different from natural progesterone since it does not have the same chemical structure as the progesterone that your body makes on its own.
Progestins were designed to mimic the actions of natural progesterone, but it don’t reproduce the actions of natural progesterone
Progestins are contained in Provera, and Prempro/ Premphase.

14. Difference Between Nature vs. Synthetic Hormones
Recent study has shown that the use of synthetic progesterone increase the risk of breast cancer by 800% as compared to the use of estrogen alone. Furthermore, an article cancer that was predicted to rise by nearly 80% after 10 years of use of estrogen-progestin (synthetic) HRT and 160% after 20 years [6]

15. Difference Between Nature vs. Synthetic Hormones
Dr. Stephen Sinatra, a well-known cardiologist, states in his book, Heart Sense for Women, “I have found that synthetic progestins can lead to serious cardiac side effects in my patients, including shortness of breath, fatigue, chest pain, and high blood pressure.
Progestin has many side effects and doesn’t function the same way in your body as natural progesterone. Progestins stop the protective effects of estrogen on your heart
Smith W. Pamela. HRT: The Answers A Concise Guide for Solving the Hormone Replacement Therapy Puzzle. Healthy Living Books Inc. 2003

16. History of HRT
Menopause was considered to be a disease needing treatment
Early 1940s, Russell Marker, chemist, discovered a way to replicate human hormones by synthesizing the plant substance diosgenis, found in yam.
He wanted to make the substance available to anyone.
No U.S. drug company would decide to market the natural hormones because of limiting potential profit.
1960s, doctors began prescribing estrogen therapy for women, and millions of women began using the synthesized estrogen (Premarin).
1977, studies done at Kaiser Permanente Hospital in San Franciso showed that women on Premarin had a rate of endometrial cancer five times higher than that of non-users.

17. History of HRT
To fix this problem, many doctors began prescribing the progestin Provera along with Premarin to protect the uterus from endometrial cancer. Also, Prempro (Premarin and Provera) drug was introduced to many women.
1996, Postmenopausal Estrogen/Progestin Intervention (PEPI) trial revealed that women on estrogen daily had high risk of endometrial cancer
1998, Heart and Estrogen/Progestin Replacement Study (HERS) found that women on estrogen/progestin Prempro had 4-5 times increase the risk of breast cancer with 5-10 year use.
2002, Women’s Health Initiative found that women on Prempro: ↑breast cancer after 5 years, ↑ coronary heart disease events, ↑VTE.

18. Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial 1996
Randomized, double-masked, placebo-controlled with 3 yrs of follow-up conducted to assess the influence of estrogen with or without progestin
N= 596 healthy postmenopausal women
Mean age 53 (range 45 to 64)
Drug:0.625mg CEE; 0.625mg CEE with 2.5mg MPA; 0.625mg CEE with 10mg MPA; 0.625mg CEE with 200mg MP
Note: Conjugated equine estrogens (CEE)
Medroxyprogesterone (MPA)
Micronized progesterone (MP)
JAMA. 1996; 275:
Conjugated equine estrogen (CEE)

19. PEPI Results
Women assigned to estrogens only had 11% to 27% of increased risk of endometrial cancer.
Women on placebo and women on CEE and MPA or MP had less chance of developing endometrial cancer.
JAMA. 1996; 275:

20. HERS Trial 1998 Heart and Estrogen/Progestin Replacement Study (HERS)
Randomized, blinded, placebo-controlled secondary prevention trial
N=2763 postmenopausal women with established CHD
Mean age 66.7 yrs ( less than 80 yo)
Drug: CEE mg/2.5mg MPA for 4 yrs
JAMA ; 280:

21. HERS Trial Results No benefit overall after4.1 years
Did not reduce overall cardiovascular risk
Increase risk for VTE: 3-Fold
Increase risk for gallbladder disease 40%
4-5 times ↑ risk of breast cancer with ≥ 5-10 year use
JAMA ; 280:

22. Women’s Health Initiative (WHI) 2002
Randomized, placebo controlled primary prevention trial (planned duration 8.5 yrs)
N=16,608 healthy women with intact uterus
40 Us centers from
Mean age 63 yrs (range 50-79)
Drug: Prempro (CEE 0.625mg/2.5mgMPA)
Duration: 5.2 yrs (early termination due to increased invasive breast cancer)
JAMA ; 288:

23. WHI Results Risks: 26% ↑ in invasive breast cancer
29% ↑ in coronary heart disease events (CHD)
41% in CVA (stroke, MI)
Double risk of venous thromboembolic (VTE)
Benefits:
37% ↓ in colorectal cancer
33% ↓ in hip fracture
24% ↓ in total fracture
JAMA ; 288:

24. WHI: Clinical Implication
Long-term estrogen plus progestin therapy failed
to preserve health and prevent common disease in postmenopausal women
Combination HRT increases breast cancer and
cardiovascular disease events
Combination HRT is NOT a viable intervention
for primary prevention of chronic diseases

25. Synthetic Estrogen (Premarin): SEs
Breast Tenderness
Weight Gain
Fluid Retention
Headache – some migraines are estrogen related
Nausea
GI upset
Heavy withdrawal/bleeding
Decreased libido

26. Synthetic Estrogen (Premarin): SEs
Increased risk of gallstones
Blood clots– Increase clotting factors
ACHES:
– Abdominal pain (severe)
– Chest pain
– Headache
– Eye problems (vistual disturbance)
– Severe leg pain

27. Synthetic Estrogen: SEs
Risk of breast cancer in postmenopausal
women:
– No increased risk < 5 years use
– > 35% increased risk > 5 years use
– Increase risk with E+P combination

28. Synthetic Estrogen (Premarin): Contraindications
Hypersensitivity to estrogens
Venous thromboembolic disorders (DVT, PE)
Arterial thromboembolic disease (Stroke, MI)
Estrogen-dependent cancer
Breast cancer
Undiagnosed abnormal genital bleeding
Hepatic dysfunction or disease
Pregnancy (Category X)

29. Synthetic Estrogen: US Boxed Warning
Estrogens with or without progestin should not be used to prevent coronary heart disease
The risk of dementia may be increased in postmenopausal women
Unopposed estrogens may increase the risk of endometrial carcinoma in postmenopausal women

30. Sythetic Progesterone (Progestin/ Provera): SEs
Central nervous system: dizziness, HA, nervousness
Decrease libido
Menstrual irregularities
Abdominal pain/ discomfort, bloating, nausea
Edema
Depression, fatigue, insomnia

31. Synthetic Progesterone (Progestin/ Provera): Contraindications
Hypersensitivity to MPA
VTE (deep vein thrombosis (DVT) or pulmonary emboli (PE))
Cerebral vascular disease
Severe hepatic dysfunction
Carcinoma of the breast or genital organs
Undiagnosed vaginal bleeding
Pregnancy

32. Sythetic Progesterone (Progestin/ Provera): Black Boxed Warnings
Prolonged use of Provera may result in a loss of bone mineral density
Long-term use (ie, ≥2 yrs) should be limited
Use caution with cardiovascular disease
Progestin and estrogen combination may increase the risks of HTN, MI, stroke, PE, DVT
May cause glucose intolerance in DM pts

33. Premphase/ Prempro (Combination of E+P Products): SEs
CNS: HA, dizziness, pain, depression
Breast pain, dysmenorrhea
Abdominal pain, nausea
Back pain
Infection, flu-like syndrome
Peripheral edema
Vaginitis, vaginal hemorrhage
Weakness, leg cramps
Adnormal vaginal bleeding, amenorrhea
Hypertension, triglycerides increased
Libido changes
Pancreatitis, cholelithiasis

34. Premphase/ Prempro (Combination of E+P Products): Contraindications
Hypersensitivity to conjugated Estrogen, MPA
Undiagnosed abnormal vaginal bleeding
VTE
Arterial thromboembolic disease
Breast cancer
Estrogen-dependent tumor
Hepatic dysfunction
Pregnancy

35. Premarin/ Provera and Synthetic Hormones: Long-term risks
Breast cancer
Endometrial cancer
Ovarian cancer
Gallbladder disease
Liver disease
Stroke
Blood clots
Conrad Christine, et. al. A Woman’s Guide to Natural Hormones. A Perigee Book. Revised and Updated Edition

37. Greater Benefits of Natural Hormone Replacement
Match your own hormones exactly
Leave the body more quickly than synthetics, thereby not posing the same health risk like synthetic HR
Don’t have the side effects of synthetic HRT drugs if used at the proper dosage
Natural mood enhancers (progesterone provide this benefit, while progestin can’t)
Don’t have long-term risks as synthetics

38. Greater Benefits of Natural Hormone Replacement
Are much safer than synthetic HR
Don’t inhibit the benefits of estrogen on lowering cholesterol, as does a progestin
Natural progesterone will not cause you to bleed for duration of use of HRT, as can progestin
Natural progesterone may protect against breast cancer

39. Greater Benefits of Natural Hormone Replacement
Natural progesterone affects not seen with progestins:
Helps balance estrogen
Leaves your body quickly
Helps you sleep
Natural calming effect
Lowers high BP and cholesterol
May protect against breast cancer
Increases scalp hair
Normalizes libido
Increases the beneficial effects of estrogens on blood vessel dilation in atherosclerotic plaques
Decrease the rate of cancer
Natural antidepressant
Natural progesterone offers a safer approach to HRT than synthetic progesterone

40. Natural Hormone Replacement
5 reasons you should consider NHR:
relief of Sxs (PMS, hormonal imbalance, menopause)
Prevention of memory loss (Alzheimer’s disease)
Protection against heart disease
Bone production (prevention of osteoporosis)
Growth and repair (anti-aging benefits)

41. Natural Hormone Replacement Therapy
Is a better and safer therapy
Has received increasing attention since the results of the WHI studies were announced
Will become more and more the standard hormone treatment through compounding pharmacies

42. Natural Hormone Replacement Therapy
Emphasis on topical administration; avoids problems such as blood clotting that are caused by the rapid metabolism of orally administered hormones[4]
Individualized compounded doses may be prescribed, rather than "one dose fits all" approach of conventional hormone replacement therapy[5]

43. Conclusions
Your hormones function as a web. The right levels of all of your hormones are needed for you to achieve optimal health.
If you are going to use hormone replacement, than natural hormone replacements are in every sense a better choice.

44. References
Smith W. Pamela. HRT: The Answers A Concise Guide for Solving the Hormone Replacement Therapy Puzzle. Healthy Living Books Inc
Conrad Christine, et. al. A Woman’s Guide to Natural Hormones. A Perigee Book. Revised and Updated Edition
Wright V. Jonathan and Morgenthaler John. Natural Hormone Replacement for Women Over 45. Smart Publication, Petaluma, CA
Scarabin, PY; Oger E, Plu-Bureau G (2003). "Differential association of oral and transdermal estrogen-replacement therapy with venous thromboembolism risk". Lancet 362:  
Romero, M (2002). "Bioidentical hormone replacement therapy. Customizing care for perimenopausal and menopausal women". Advance for Nurse Practitioners 10 (11): 51-2.
Schairer C. et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000;283:
No author. Effects of Hormone Replacement Therapy on Endometrial Histology in Postmenopausal Women The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial JAMA. 1996; 275:
No author. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women Principal Results from the Women’s Health Initiative Randomized Controlled Trial JAMA ; 288:
Hulley Stephen, Grady D. and et. al. For HERS Group. Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women JAMA ; 280:
Access PDA Lexi.com on November 21, 2007.