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

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

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. 2005.

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. 2005.

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. 2003.

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. 2003.

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. 2003.

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. 2003. Conrad Christine, et. al. A Woman’s Guide to Natural Hormones. A Perigee Book. Revised and Updated Edition. 2005.

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

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

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

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.

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]

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

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.

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.

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; 275:370-375 Conjugated equine estrogen (CEE)

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; 275:370-375

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 0.625 mg/2.5mg MPA for 4 yrs JAMA. 1998; 280: 605-613

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. 1998; 280: 605-613

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 1993-1998 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. 2002; 288:321-333

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. 2002; 288:321-333

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

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

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

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

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)

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

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

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

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

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

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

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. 2005.

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

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

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

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)

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

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]

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.

References Smith W. Pamela. HRT: The Answers A Concise Guide for Solving the Hormone Replacement Therapy Puzzle. Healthy Living Books Inc. 2003. Conrad Christine, et. al. A Woman’s Guide to Natural Hormones. A Perigee Book. Revised and Updated Edition. 2005. Wright V. Jonathan and Morgenthaler John. Natural Hormone Replacement for Women Over 45. Smart Publication, Petaluma, CA. 1997. 4. Scarabin, PY; Oger E, Plu-Bureau G (2003). "Differential association of oral and transdermal estrogen-replacement therapy with venous thromboembolism risk". Lancet 362: 428-32.  5. Romero, M (2002). "Bioidentical hormone replacement therapy. Customizing care for perimenopausal and menopausal women". Advance for Nurse Practitioners 10 (11): 51-2. 6. Schairer C. et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000;283: 485-491. 7. No author. Effects of Hormone Replacement Therapy on Endometrial Histology in Postmenopausal Women The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996; 275:370-375. 8. 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. 2002; 288:321-333. 9. 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. 1998; 280: 605-613. 10. Access PDA Lexi.com on November 21, 2007.