Vol. 10 Issue 11
Close-Up on Pharmacology
Bioidentical Hormone Replacement Therapy
The world of women's health hasn't been the same since two national studies determined that the risks of long-term hormone replacement therapy (HRT) apparently don't outweigh the benefits. The Women's Health Initiative and the Heart and Estrogen-Progestin Replacement Study follow-up (HERS II) studied oral conjugated equine estrogens (CEE) and oral medroxyprogesterone acetate (MPA), and determined that these forms of HRT may increase a woman's risk for heart disease, breast cancer and other diseases.1-3
Understandably, millions of menopausal women are concerned by these findings. Some are seeking alternative treatments, while others may decide to discontinue and never again touch any type of hormone replacement.
The WHI and HERS II studies focused on a combination of Premarin and Provera marketed as Prempro. Since Premarin is made of conjugated equine estrogen, a common belief is that the drug is safe because it is "natural." But the meaning of the term varies from person to person, rendering "natural" meaningless in terms of efficacy and safety. The WHI and HERS II studies make it more important than ever for health care professionals and patients to understand the true meaning of natural hormone replacement therapy.1-3 The term "bioidentical" more accurately describes substances that resemble the body's natural makeup.
Consumers tend to be comfortable with hormones that are obtained from plant sources and that resemble their own physiologic makeup. Because patients are often focused on the source of hormones rather than the effect produced by hormones, the term "natural" should not be used to describe any type of hormone replacement.
Types of Hormonal Therapies
The table accompaning this article lists the types of hormone replacement therapies available today.4 Phytoestrogens are plant extracts that exert hormonal activity but are not hormones themselves. Examples are soy extracts, black cohosh, red clover, etc. These products, which are available over the counter, are not hormones but do have some mild estrogen- or progesterone-like activity. When derived from plants, the extracts are the end product.4,5
Traditional hormone replacement represents a cluster of commonly prescribed hormones. Some examples of these manufactured hormones are Premarin, Provera, Vivelle patch, Prometrium, FemHRT and others. The term "conventional" or "traditional" hormone replacement therapy is used to describe these hormones instead of "synthetic" hormone replacement. In essence, all hormone replacement is synthetic or semi-synthetic. The word "synthetic" connotes a negative or harmful type of therapy, whereas the term "natural" suggests a positive or safe form of hormone replacement. These generalizations are not accurate, so the different types of HRT should not be labeled as natural vs. synthetic.4-7
Selective Estrogen Receptor Modulators
A medication marketed for hormone therapy that is not actually a type of hormone replacement is Evista. The drug is a selective estrogen receptor modulator (SERM), rather than a hormone. The name was derived from the drug's ability to bind to estrogen receptors and selectively modulate the effects of estrogen in different body tissues. Studies of Evista show that it can treat and prevent osteoporosis and has a positive effect on cholesterol by lowering total cholesterol through reduction of low-density lipoprotein (LDL). In general, Evista does not affect triglycerides or high-density lipoprotein (HDL). Another SERM is tamoxifen (Nolvadex). Tamoxifen, the most widely used SERM, is approved for the treatment of estrogen-receptor-positive breast cancer and as a preventive measure for women at increased risk for breast cancer. It reduces the risk of developing breast cancer in the remaining breast, as well as breast cancer recurrences and deaths. In addition, tamoxifen helps prevent bone loss and has a beneficial effect on LDL.4,6
Bioidentical Hormone Replacement
Bioidentical hormone replacement uses hormones containing the exact molecular structure as hormones made in the body. These hormones are chemically indistinguishable from endogenous hormones and exert the same physiologic response as endogenously produced hormones in the body. Among the many manufactured hormones prescribed, the majority are derived from plants but are chemically changed to make a unique molecule that can be patented. Manufacturers of bioidentical hormones may hold a patent on a specific delivery system, such as a transdermal patch or a unique sustained release. True bioidentical hormones are considered by the FDA to be "natural" regardless of source and are therefore not eligible for patent. As a result, few commercially available pharmaceuticals are truly bioidentical. Some examples are products that contain 17-estradiol, such as Estrace, and certain transdermal patches, such as Climara. The active ingredient in Prometrium is progesterone USP, which is also a bioidentical hormone. However, this does not stop other companies or compounding pharmacies from using the active ingredient.4-9
Many patients ask, "Why doesn't my health care provider prescribe bioidentical hormones?" The answer lies in the lack of information provided to health care professionals. Because bioidentical hormones cannot be patented, drug companies do not take on many of these products. These companies would rather hold a patent on a drug, which would give them exclusive marketing rights. Since few drug companies are promoting these products using advertising or a sales force, prescribers have limited opportunities to learn about them unless they are studied and reported in the literature.
Once a prescriber has located a compounding pharmacist and established a relationship to discuss individual patient dosing, a successful regimen can be determined. Compounding pharmacists can source chemicals from licensed chemical supply companies and obtain various hormones in their purest form. Compounding pharmacists must comply with regulations of the state board of pharmacy when preparing any medication for a patient. These pharmacists have access to the highest grade of United States Pharmacopoeia (USP) and national formulary (NF) bulk chemicals and use state-of-the-art equipment with which they can accurately prepare individualized formulas.
How does customizing medication fit into the HRT landscape? Individualizing hormone replacement addresses the No. 1 problem with HRT: compliance. Many women tire of taking numerous medications a day. A compounding pharmacist has the ability to combine the medications into one capsule, encouraging compliance through ease of dosing. Transdermal creams provide immediate onset to relieve symptoms such as hot flashes and night sweats.
A compounding pharmacist can customize hormone replacement therapy to meet a patient's specific need. Customizing options include making the hormone replacement in a variety of dosage forms, such as transdermal creams or sustained release capsules. An unlimited number of dosage strengths and different hormones can be combined into one dosage form.
Compounding pharmacists have been in practice for hundreds of years. In 1920, 80% of all prescriptions were compounded. With the industrial revolution, large pharmaceutical manufactures took over the role of preparing medications. These companies were able to mass produce medication in large volumes to make dispensing easier and quicker, reducing the amount of prescriptions compounded. Today, only 1% of all prescriptions require a compounding pharmacist to help individualize productseven though research shows that HRT patients benefit from individualized treatments.
In the wake of the WHI results, Morris Notelovitz, MD, PhD, noted in an issue of Contemporary Issues in Gynecology, Obstetrics and Women's Health that providers should not treat menopause generically. "One needs to prescribe hormone therapy to treat menopause-related conditions in exactly the same way as one prescribes thyroid therapy for a woman with hypothyroidism or diabetic medications for the diabetic," he wrote. "So the message I want to convey is this: Hormone therapy, if indicated, if individualized, and if monitored, is safe."10 Notelovitz is a noted researcher who is the founder and president of Emeritus Women's Medical and Diagnostic Center in Gainesville, Fla.
In the article, Notelovitz offered some specific advise: When estrogen therapy is indicated for an older woman with established heart disease, a low dose of transdermally delivered estrogen is prudent because it has minimal effect on the stimulation of coagulation factors, C-reactive protein and other pro-inflammatory factors.10 For a woman with an intact uterus who is at risk for breast cancer, natural micronized progesterone is a prudent choice, since it is the form of progesterone that naturally occurs before menopause.10
Compounding pharmacists work with the patient and health care provider to formulate a treatment based on the patient's individual health profile. Symptom assessment is crucial to determine hormonal needs. Along with the patient's symptoms and the tools of serum or saliva testing, the pharmacist and health care provider can collaborate and choose the proper combination of bioidentical hormones. The lowest effective dosage of identified hormones should be prescribed. Specific hormones can be increased in minute increments with monitoring of the patient's symptoms. It is vital that the prescribing provider understand the unique role and benefits of estrogen, progesterone and testosterone.
Estrogen is not a single hormone. Rather, it is a group of different but related hormones that perform functions we normally attribute to estrogen.4,6,9
The three estrogens that predominate in an adult woman are:
• Estrone (E1), which constitutes approximately 10% to 20% of circulating estrogens11
• Estradiol (E2), which constitutes approximately 10% to 20% of circulating estrogens11
• Estriol (E3), which constitutes approximately 60% to 80% of circulating estrogens.11
The other estrogens are estrone, estradiol and estriol. Estrone is a weak estrogen produced by oxidation of estradiol and is the primary estrogen present after menopause.6,9,11 Estradiol is the most potent estrogen and the major secretory product of the ovary. It is the primary estrogen throughout the reproductive years and before menopause.6,8,9,11 Estriol is a weak estrogen that also has anti-estrogenic properties. It is the major estrogen produced during pregnancy and is primarily produced via metabolism by hydration of estrone. It is an end product of sex hormone metabolism. Thought to be protective against breast cancer, estriol causes little or no build-up of the endometrium and offers a potential option for symptomatic women at high risk for breast cancer. It is very effective in alleviating vaginal and urinary symptoms in postmenopausal women.6,9,11-15
No manufactured product mimics the body's production of the hormones mentioned. Some commercially available products contain one of the three estrogens the body produces, but not a combination of the three. By using a formulation that closely mimics a woman's hormone production, we can reduce the incidence of side effects if used properly. A combination of bioidentical hormones will produce side effects if patient symptoms are not monitored and modification is not made accordingly.7
Progesterone is a hormone produced by the ovaries, predominately after ovulation. This hormone has many effects on the body not limited to the uterus. In fact, it affects nearly every cell in the body. Some of the main functions of progesterone are:
• anti-depressive effect16,17
• improved sleeping pattern18
• builds bone density16,19,20
• normalizes blood clotting16
• precursor to other sex hormones, such as estrogens and testosterone6
• protects against fibrocystic breasts16,21
• helps normalize blood sugar levels16
• decreases the number of estrogen receptors, accounting in part for its anti-estrogenic effects or protective properties against endometrial cancer. The same process appears to provide protection against breast cancer.4,7,16,21,22
Progesterone is often confused with the synthetic progestins. Progestins are a synthetic class that are analogs to progesterone. One of the most common progestins prescribed for perimenopausal or menopausal women is Provera. It was developed to reduce the increased risk of endometrial and uterine cancer associated with estrogen therapy alone in postmenopausal women with intact uteruses.6
Provera should not be confused with bioidentical micronized progesterone because it does not have the same effect in the body.6
Some women believe that testosterone is a male hormone, but the ovaries produce this substance for much of a woman's life. The ovaries continue to secrete testosterone following menopause, though at a slowing rate. This decline in testosterone is not as rapid or substantial as the decline estrogens and progesterone.4,16
At physiologic doses, testosterone improves many menopausal symptoms related to the physical and psychological changes inherent in this time of life.4,6-8,23-27
Testosterone replacement can be beneficial for menopausal women because it can:
• protect the heart
• improve mental alertness
• improve bone strength and density by increasing calcium retention
• revive a lagging sex life
• improve sexual response
• stimulate sexual desire
• increase sexual fantasies
• raise a woman's general level of sexual arousal
• provide an overall feeling of well-being
• improve a woman's energy level
• improve muscle tone.
Prescribing Bioidentical HRT
This section outlines tips for prescribing bioidentical hormones. There are three formulas for estrogen replacement in perimenopausal and menopausal women: tri-estrogen, bi-estrogen and estriol (USP only).
Tri-estrogen (often called "Triest") contains a combination of the three bioidentical estrogens in different combinations. The most commonly prescribed combination is 80% estriol, 10% estradiol and 10% estrone. An alternative is 70% estriol, 10% estradiol and 10% estrone.
Bi-estrogen (often called "Biest") contains a combination of two of the three bioidentical estrogens in combination. The most commonly prescribed combination is 80% and 20% or 70% and 30%.
Estriol (USP only) is mainly prescribed for patients who may be at high risk for breast cancer or other hormone-dependent cancer, or for patients with very mild estrogen deficiency symptoms.
Before choosing a formula for your patient, consider a few issues. If the patient is at risk for cancer, avoid prescribing high doses of estrone or estradiol. Bi-estrogen may be a better choice than tri-estrogen. In addition, take into account the current hormone regimen the patient is taking. If the patient has been taking Premarin for a while, it may be better to give more estradiol in the formulation, such as the 70/20/10 tri-estrogen formula. Patients who have been on conjugated estrogens for a long time need estrone as well. If they have not been on such a regimen, prescribe estrone initially. This may produce hot flashes or night sweats, however. Again, it is all depends on the patient's individual response. Some patients may do better without estrone in the formula.4,7-9
Progesterone is a necessary hormone in women who have an intact uterus and have chosen to use estrogen replacement therapy. However, progesterone's list of benefits does not stop in the uterus. As a matter of fact, all women with hormonal imbalances, including the ones who have had a hysterectomy, can benefit from the use of progesterone. Women who have PMS, migraine headaches, irregular bleeding, hot flashes, night sweats or breast tenderness need progesterone.
Progesterone can be delivered through many routes of delivery, such as oral sustained-release capsules, sublingual drops, transdermal creams, troches, vaginal suppositories, etc. The most common delivery systems for progesterone are oral sustained-release capsules and transdermal creams.4,6,7,16
A few things to remember about oral sustained-release progesterone capsules:
• any strength can be compounded
• the most common increments are 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 300 mg and 400 mg
• 100 mg is the lowest acceptable dosage for a woman with a uterus who is taking estrogen replacement
• oral progesterone is helpful for insomnia
• oral progesterone can be dosed more than once daily in a continuous or cyclic manner.
• oral progesterone is absorbed orally, but only about 10% to 15% remains after metabolism.
A few things to remember about transdermal progesterone cream:
• any strength or concentration can be compounded
• the most common concentrations are 1%, 2% and 4% (10 mg, 20 mg and 40 mg, respectively)
• the minimal dosage for women with an intact uterus who are taking estrogen has not been established
• progesterone applied to the skin via a water-based cream can be packaged in a calibrated delivery device to ensure accurate doses
• does not have the same effect as oral progesterone on sleep
• does not metabolize to alpha-pregnenolone to the magnitude of oral progesterone
• can be dosed more than once daily without regard to drowsiness
• can be given in a continuous or cyclical manner
• the exact amount absorbed through the skin is not known, but it is far more absorbed than oral progesterone according to salivary testing.
Testosterone Replacement Dosing
In women, testosterone replacement therapy is mainly prescribed to treat sexual dysfunction.6 Oral testosterone is not a good choice due to high first-pass metabolism in the liver. Transdermal, sublingual or transmucosal (mouth) delivery are superior to oral delivery. Testosterone should be given in small doses and the dosage should be gradually titrated until symptoms are relieved. Transdermal testosterone is highly effective and readily absorbed, therefore only a small dosage is required. A recommended starting dosage would be 0.5 mg to 1 mg daily, given in the morning or at night. Titrate the dosage in 0.25 mg or 0.5 mg increments. The therapy is most effective if the patient applies the cream to the clitoris for the first 7 to 14 days and then to other areas, such as the forearm or inner thigh.4,6,8,23
Because the latest research casts significant doubt on the wisdom of using HRT, it is important to clearly define terms in your mind and the minds of your patients. Prempro, a combination of equine estrogen and manufactured medroxyprogesterone acetate, was the only medication studied. These hormones are not bioidentical and should not be compared to bioidentical hormone replacement.
With any combined hormone regimen, the levels of hormones and any symptoms associated with therapy should be monitored. Your patient's health and quality of life are of primary concern. By working together as a collaborative team, health care professionals, compounding pharmacists and patients can be creative with bioidentical hormone therapy and bypass compliance issues, which may in turn improve therapeutic outcomes.
1. Grady D, Herrington D, Bittner V, et al, for the HERS Research Group. Heart and Estrogen/progestin Replacement Study follow-up (HERS II): Part 1. Cardiovascular outcomes during 6.8 years of hormone therapy. JAMA. 2002;288:49-57.
2. Hulley S, Furberg C, Barrett-Connor E, et al for the HERS Research Group. Heart and Estrogen/progestin Replacement Study follow-up (HERS II): Part 2. Non-Cardiovascular outcomes during 6.8 years of hormone therapy. JAMA. 2002;288:58-66.
3. Writing Group for the Women's Health Initiative Investigators. 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.
4. Northrup C. The Wisdom of Menopause. New York: Bantam Books; 2001.
5. Reed-Kane D. Natural hormone replacement therapy: what it is and what consumers really want. International Journal of Pharmaceutical Compounding. 2001;Sept-Oct:332-335.
6. Fraser IS, Jansen RPS, Lobo RA, Whitehead MI, eds. Estrogens and Progestogens in Clinical Practice. London: Churchill Livingstone; 1998: 215-220.
7. Lorentzen J. Hormone replacement therapy: part 1. The evolution of hormone treatment. The International Journal of Pharmaceutical Compounding. 2001;5(5):336-338.
8. Hargrove J, Osteen K. An alternative method of hormone replacement therapy using the natural sex steroids. Infertility and Reproductive Medicine Clinics of North America. 1995;6(4):653-674.
9. Lorentzen J. Hormone replacement therapy: part 2. Estrogen defined. The International Journal of Pharmaceutical Compounding. 2001;5(6):460-461.
10. Notelovitz M. Why individualizing hormone therapy is crucial: putting the results of the WHI Trial into perspective. Contemporary Issues in Gynecology, Obstetrics and Women's Health. 2002;7(4):125-136.
11. Wright J, Schliesman B, Robinson L. Comparative measurements of serum estriol, estradiol, and estrone in non-pregnant, premenopausal women: a preliminary investigation. Alternative Medicine Review. 1999;4(4):266-270.
12. Lemon H, et al. Reduced estriol excretion in patients with breast cancer prior to endocrine therapy. JAMA. 1966;3:112-120.
13. Tzinqounis VA, Aksa MF, Greenblatt RB. Estriol in the management of menopause. JAMA. 1978;239(16):1638-1641.
14. Follingstad AH. Estriol–the forgotten estrogen? JAMA. 1978;239:29-30.
15. Head KA. Estriol: safety and efficacy. Alternative Medicine Review. 1998;3:101-113.
16. Lee JR, Hopkins V. What Your Doctor May Not Tell You About Menopause. New York: Warner Books; 1996.
17. Schechter D. Estrogen, progesterone, and mood. The Journal of Gender Specific Medicine. 1999;2:29-36.
18. Arafat E, Hargrove J, Maxson W. Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites. Am J Obstet Gyn. 1988;159:1203-1209.
19. Prior JC. Progesterone as a bone-trophic hormone. Endocrine Reviews. 1990;11(2):386-398.
20. Lee JR. Osteoporosis reversal. The role of progesterone. International Clinical Nutrition Review. 1990;10(3):384-390.
21. Chang KJ, Tigris TY, Gustavo LC. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertility and Sterility. 1995;63(4):785-791.
22. Cowan LD, et al. Breast cancer incidence in women with a history of progesterone deficiency. American Journal of Epidemiology. 1981;114(2):209-217.
23. Shifren J. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. NEJM. 2000;343:682-688.
24. Young RL. Androgens in postmenopausal therapy? Menopause Management. 1993;volume(issue):21-24.
25. Laughlin G, Barrett-Conner E, Kritz-Silverstein D, von Muhlen D. Hysterectomy, oophorectomy and endogenous sex hormone levels in older women: the Rancho Bernardo study. Journal of Clinical Endocrinology & Metabolism. 2000;85(2):645-651.
26. Miller K. Androgen deficiency in women. Journal of Clinical Endocrinology & Metabolism. 2001;86(6):2395-2401.
27. Casson P, Elkind-Hirsch K, Buster J, et al. Effect of postmenopausal estrogen replacement on circulating androgens. Obstetrics & Gynecology. 1997;90(6):995-998.
Mandie Romero is a doctor of pharmacy who specializes in compounded HRT at Professional Arts Pharmacy in Lafayette, La.