Bioidentical Hormones

Achieving the Perfect Fit

By Sharon Campbell, NP

Continuing Education Offering: The goal of this article is to educate nurse practitioners about bioidentical hormones. Nurse practitioners may obtain 2 pharmacology credits by reading this article and earning a passing score on the test that follows. For immediate test results, take the quiz online at www.advanceweb.com/np.

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Objectives: The purpose of this article is to educate nurse practitioners about bioidentical hormone therapy. After reading this article, the nurse practitioner should be able to:

• Define menopause and discuss the long-term results of untreated menopausal symptoms.

• Discuss how to assess risk factors associated with menopause.

• Explain BHT, how it is prescribed, and how to individualize treatment protocols.

• Discuss how to analyze relevant laboratory data related to BHT and menopause.

Directions: On the registration form, check the box next to the best answer.

Today's menopausal women are educated, empowered and self-assured. They led the women's liberation movement, they used the first birth control pills, and they broke barriers in the political and corporate worlds. They found a way to get what they wanted then, and they are still doing so today.

Today's menopausal women are seeking health care choices that are in line with their personal values, philosophies and beliefs.1 These principles are leading thousands of them to consider bioidentical hormone therapy (BHT), an alternative to conventional synthetic hormone replacement that uses compounded or plant-derived substances to deliver individually matched hormone replacement. This article provides an introduction to this customized method of treatment.

Physiology of Menopause

Menopause has a major impact on a woman's health and quality of life. Despite the abundant information available, many women don't have a clear picture of what happens during this transition. Knowledge can empower women to make sensible, positive decisions about their health.

Menopause is not a disease state, and it is not always necessary to intervene medically to manage its symptoms. Menopause is defined as the cessation of menses for 1 calendar year. When ovarian function ends, follicle-stimulating hormone (FSH) production rises. At the same time, estrogen, progesterone and testosterone levels diminish — events that occur at varying rates. These variations, which are highly individualized, cause a wide range of symptoms.

What Is BHT?

Whether bioidentical or synthetic, all hormones are powerful chemicals that affect many systems of the body. Bioidentical hormones have a chemical structure that matches that of the hormones they are intended to replace. They are derived from wild yam (Dioscorea) and soybean plants, which contain precursor molecules chemically processed into a variety of steroid hormones. These hormones, produced by chemical conversion, are identical to those produced by the body. However, they are still hormones and must be prescribed with the same detail and caution as any other medication.

BHT has not been studied nearly as much as conventional drugs. More time and money must be invested in documenting the benefits and risks of this therapy. Unfortunately, the pharmaceutical industry seems uninterested in spearheading this research, probably because bioidentical formulations cannot be patented and have little potential for profit.

Bioidentical hormones are customized to each woman according to her particular hormonal variations. The goals of BHT are to relieve menopausal symptoms and restore hormone balance. To formulate effective dosages, determination of hormone levels is necessary. This can be done with blood or saliva tests. Five hormones are relevant to BHT for the treatment of menopause:

• estrogen (estriol [E-3], estradiol [E-2], estrone [E-1])

• progesterone

• testosterone

• dehydroepiandrosterone (DHEA)

• pregnenolone.

The goal of all forms of hormone therapy is not to reproduce the hormonal milieu of a menstruating woman. Rather, the goal is to optimize function and prevent morbidity with aging, without causing harm. Interventions should be made with caution. Hormone treatments should be modified and titrated in accordance with clinical and laboratory feedback.

Guidelines for Initiating BHT

Menopause management requires effective collaboration between the patient and provider. Collaborative decision making begins with clarification of the patient's values and priorities. Careful consideration, in-depth education and discussion are essential when initiating or continuing any form of hormone therapy. Even women in similar clinical situations make entirely different decisions about hormone therapy.

There is no magic formula for approaching this decision-making process. Patience, insight and care are necessary to recognize different perspectives and to have a respectful and balanced discussion.

When discussing treatment options with patients, it is important to address the many variations and gaps in our knowledge about menopause, including the Women's Health Initiative results (Table 1) and the most recent hormone therapy position statement from the North American Menopause Society (NAMS) (Table 2).^2-7

Table 3 outlines the history, diagnostic methods and physical exam I use when treating menopausal women in my practice. In conventional medicine settings, hormones are often prescribed without attention to blood levels. This approach can result in deficiencies of all hormones. Table 4 outlines the hormone levels that should be measured before initiating BHT.

Contraindications to BHT

The history and physical exam provide information that helps determine suitability for BHT. Contraindications to BHT include the following:

• unexplained vaginal bleeding

• pregnancy

• past history of breast or endometrial cancer (Although these cancers are usually considered contraindications to BHT, therapy may be considered with proper precautions and consultation with an oncologist.)

• past history of venous thromboembolism (VTE) (Some patients are at an increased risk for VTE recurrence, although it may be an overall low rate.)

• family history of perimenopausal breast cancer (This does not increase a woman's risk of breast cancer.)

• hypertriglyceridemia, chronic liver disease or gallbladder disease (Oral administration is contraindicated in these states because it may precipitate pancreatitis. Routes that avoid the first-pass hepatic effect, such as transdermal or sublingual, do not carry this risk.)

BHT is not contraindicated in the presence of endometriosis, fibrocystic breast disease, hypertension, mastalgia, migraines, obesity, tobacco use or uterine fibroids.⁸

Prescribing BHT

A full range of BHT is available by prescription from compounding pharmacies that make them to your specifications. These individualized hormone preparations can be taken orally, transdermally, vaginally or sublingually as a troche or lozenge — whichever is most effective and preferred by the patient.

The transdermal or sublingual route is more physiologically appropriate because the hormones go directly into the bloodstream. Oral capsules have to be absorbed from the gastrointestinal tract and transported to the liver, where they are further metabolized before being released to the bloodstream and organs. Research has shown that bioidentical transdermal therapy regimens provide adequate blood levels to protect the endometrium from hyperplasia.⁸

Compounding pharmacists and pharmacies must comply with regulations set by the boards of pharmacy in their respective states. Compounding pharmacies are inspected and monitored by these boards, not the Food and Drug Administration. Compounding pharmacies have access to United States Pharmacopeia (USP) bulk chemicals and to state-of-the-art equipment for accurate preparation of hormone formulations.⁹ Hormone compounding is a standardized process, so doses are consistent from batch to batch.

It is difficult to generalize how to prescribe BHT. There are no set protocols because each prescription is determined by the specific patient. Table 6 provides guidelines for calculating dosages, along with advice based on my experience with this treatment. The table also lists some of the reported side effects. The response to BHT can be wide-ranging, since absorption of the hormones can vary considerably from woman to woman.

The ever present, overriding goal of any treatment is to keep risk at a minimum. After you have gathered all relevant information and analyzed it, you are ready to prescribe individualized dosages and adjust them as treatment progresses.

The selection of hormone modulation is complex and based on the patient's personal philosophy, resources, time and perseverance. Philosophically, a woman must strive for personal balance between acceptable methods and outcomes. Choices involve types of hormones used, their sources (plant or chemical), costs, side effects, desired results, short- and long-term goals, and risks.

There is a choice to be made in terms of outcome priorities: Is reduction of symptoms sufficient, or is achieving optimal blood levels also required? These decisions have to be made by each woman with thoughtful guidance, education and instruction from you.

Follow-Up

When designing a menopause treatment plan, quality of life must always be considered. Proper balance cannot be achieved with a cookie-cutter approach. Although it is possible to take short cuts in hormone regulation, testing and fine tuning of various hormone-modulating agents is recommended because balance is the key to success. Adjustments can be achieved only by patient self-evaluation and testing before and after hormones are taken.

After BHT is initiated, I have my patients make a follow-up appointment in 6 weeks. At that time, I assess symptoms, evaluate efficacy, observe for side effects and provide further education. Six months after starting BHT, I recheck hormone blood levels to ascertain whether an adjustment is needed. I recommend more frequent appointments if a patient has any symptoms that warrant closer follow-up. After 1 year, I again check hormone levels — as well as lipids and a chemistry panel — unless there is a reason to do so earlier (such as with a history of elevated lipids).

I provide support, encouragement, accessibility and close follow-up. I also regularly evaluate each woman's need for ongoing hormone therapy. A woman's reasons for using hormones may change, as can her risk factors. Stopping hormones altogether may be appropriate for some women. The goal should be to use the lowest dose for the shortest amount of time. An important part of follow-up is to be constantly aware of changes in clinical understanding and standards of care associated with hormone therapy. Any changes must be communicated to patients.

Putting It Into Practice

To incorporate BHT into your practice, you need to be a researcher, inquisitor and confidante. You need to be able to analyze data, effectively and objectively communicate information to patients, and think outside the box while applying science that is still evolving.

It is essential to work closely with a compounding pharmacist. These pharmacists are formally trained and licensed and can provide detailed information about how to prescribe bioidentical hormones.

The use of BHT is controversial, mainly because there is so little definitive research about it. Even with questions remaining, many providers have been prescribing BHT regimens for more than 20 years. Anecdotally, they report several benefits associated with BHT:^10-12

• reduced osteoporosis and restoration of bone strength

• reduced hot flashes and vaginal dryness

• better maintenance of muscle mass and strength

• improved cholesterol levels

• reduced risk of endometrial and breast cancer

• reduced risk of depression

• improved sleep

• better mood, concentration and memory

• improved libido

• fewer side effects than with synthetic hormones.

To provide BHT in your practice, you must respect the concerns of consumers and health professionals who question its efficacy.¹⁰ If you are not confident in the benefits of this therapy, it may not be an appropriate choice for your practice. Some providers feel more comfortable sticking with traditional, conventional approaches. Even if you do not want to provide BHT, you should be able to discuss it with your patients.

Your duty is to give patients information about all options, even the treatments you don't provide.

References

1. Astin JA. Why patients use alternative medicine: results of a national study. JAMA. 1998;279:1548-1553.

2. Manso JE, et al. Estrogen plus progestin and the risk of coronary artery disease. JAMA. 2003;349:523-534.

3. Chlebowski RT, et al. Influence of estrogen plus progestin on breast cancer and mammography in a healthy postmenopausal woman. JAMA. 2003;289:3243-3253.

4. Wassertheil S, et al. Effect of estrogen plus progestin on stroke in postmenopausal women. JAMA. 2003;289:2673-2684.

5. Cushman M, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580.

6. Cauley J, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density. JAMA. 2003;290:1729-1738.

7. North American Menopause Society. Recommendations for estrogen and progesterone use in peri- and post-menopausal women. Menopause. 2004;11(6):589-600.

8. Institute for Clinical Systems Improvement. Working Group on Health Care Guidelines, Menopause and Hormone Therapy & Management. Menopause and Hormone Therapy: Collaborative Decision Making and Management. 6th ed. Bloomington, Minn.; 2004:1-57.

9. Ford G, et al. Using serum hormone analysis to develop hormone replacement regimens, Part 2. International Journal of Pharmaceutical Compounding. 2001;5(1):52-54.

10. Reed KD. Natural hormone replacement therapy: what it is and what consumers really want. International Journal of Pharmaceutical Compounding. 2001;5(5):332-335.

11. Drusko J. Natural isomolecular hormone replacement: an evidence-based medicine approach. International Journal of Pharmaceutical Compounding. 2000;4(6):414-442.

12. Boothby L, et al. Bioindentical hormone therapy: a review. Menopause. 2004;11(3):356-367.

Sharon Campbell is a women's health nurse practitioner who is the owner of A New Creation Women's Clinic in Tucson, Ariz.

Table 1: The Women's Health Initiative: What Is the Bottom Line?

The Women's Health Initiative (WHI) was conducted to determine the effects of hormone therapy on heart disease, cancer and osteoporosis — the major causes of death and disability in older women.^2-6

The study included more than 16,000 women between the ages of 50 and 79. Many of them were overweight and smoked, which placed them at high risk for heart disease and stroke. Considering the older age of the women studied, the increased number of reported cases of breast cancer and chronic diseases was small.

Heart Disease

The researchers determined that estrogen plus progestin (E+P) does not protect the heart and may increase coronary heart disease risk. In the overall analysis, six more heart attacks occurred annually per 10,000 women using E+P.

Breast Cancer

E+P therapy was linked with an additional eight cases of breast cancer for every 10,000 women treated with E+P for 1 year.

Strokes

For every 10,000 women followed for 1 year, 31 expected strokes occurred in those taking E+P compared with 24 on placebo (seven additional cases).

Venous Thrombosis

After 5.6 years of E+P therapy, researchers documented 18 additional cases of venous thromboembolism (VTE) for every 10,000 women who developed VTE.

Osteoporosis

Researchers documented a 24% reduction in all fractures and a 33% reduction in hip fractures in women who took E+P.

Table 2: North American Menopause Society Statement on Hormone Therapy⁷

The author uses this excerpt from the NAMS statement to educate patients and obtain informed consent.

In October 2004, the North American Menopause Society (NAMS) published recommendations for estrogen and progesterone use in peri- and postmenopausal women.

The statement summarized 21 recommendations for clinical practice. An expert panel appointed by NAMS reached consensus in four areas of clinical practice but could not reach consensus on other areas. Panel members used evidence-based data and clinical experience to reach the conclusions they could.

What Does the Report Say?

The report strongly endorses the use of estrogen therapy and combined estrogen-progestogen therapy for treating moderate to severe menopause symptoms such as hot flushes. This remains the primary indication for this therapy.

NAMS stated that hormone therapy (HT) is acceptable as long as there is a clear indication for use, the woman is under medical supervision, she is aware of the potential risks and benefits, and she is motivated to continue with HT.

As for the duration of HT, the statement said it should be "for the lowest effective dose and time consistent with treatment goals."

The paper reaffirmed earlier conclusions that there are probably differences among the various estrogens, progestins, combinations and doses of HT. The panel noted that "specific compounds, doses and routes of administration may have different outcomes." But without clinical trial data for each product, "clinical trial results for one agent should be generalized to all agents within the same family."

What About BHT?

One of the NAMS panelists said that this conclusion applies to bioidentical hormones. "We believe that these are active hormones and in the absence of safety and efficacy data, they still fall under the same proviso as any other product," said Wulf H. Utian, MD, in an interview when the NAMS statement was released.

His statement confirms that BHT formulations are considered active hormones and can be included in the "family" of agents used in HT.

NAMS does not recommend custom compounded BHT over well-tested, FDA-approved products for the majority of women.

"Custom compounded hormones may provide certain benefits, such as individualized doses and mixtures of products and dosage forms that are not available commercially," NAMS said in the statement. "However, there may be risks to the consumer. These compounds do not have government approval because individually mixed recipes have not been tested to prove that they are absorbed appropriately or provide predictable levels in the blood and tissue.

"There is no scientific evidence about the effects of these hormones on the body É Although there is a long history of pharmacies providing a wide range of compounded products, the fact that preparation methods vary means that patients may not receive consistent amounts of medication. Inactive ingredients may vary and there can be batch-to-batch differences."

Table 3: Health Evaluation of Women in Menopause Transition

This recommendation for evaluation was developed by the author for use in her women's health practice.

History

Family History:

• cardiovascular disease • osteoporosis

• cancer • other — Alzheimer's, mental illness, obesity

• diabetes

Personal History:

• health status

• dietary/nutritional assessment

• medical history

• history of mental illness or depression

• medications

• psychological issues

• supplements

• marital and family status

• fracture

• substance use or abuse, past or present

• smoking history

• abuse or family violence

• physical activity

• history of STDs, sexual practices

Diagnostic Evaluations:

• Pap test

• DEXA scan

• mammography

• fasting chemistry panel

• lipid profile

• hormone levels — TSH (full panel, if indicated),

• colonoscopy FSH (if indicated), E-1, E-2, E-3, free testosterone,

DHEA, DHEAS, pregneninolone

Table 4: Hormone Levels To Be Measured Before BHT Treatment

Serum hormone analysis provides useful information in determining BHT regimens. While blood tests are important, they should always be evaluated in a clinical context.

Estradiol: Levels less than 50 pg/mL are considered menopausal.

Total Estrogen: 67 pg/mL to 437 pg/mL

(Women whose estradiol levels are between 50 pg/mL and 150 pg/mL feel the best and have fewer symptoms.)

Serum Progesterone: The normal serum progesterone for women in the luteal phase is 6.3 to 14.5. Women who have an intact uterus require progesterone to oppose the effect of the estrogen on the endometrium.

(Menopausal women have fewer symptoms of progesterone deficiency if their levels are in the luteal phase range.)

Testosterone: Testosterone for women in the reproductive years ranges between 20 ng/mL and 80 ng/mL. Levels of circulating testosterone decline with age. For testosterone to be effective in restoring libido, it must be increased to at least the upper end of the normal range found in ovulating women.

DHEA: Use lab reference range.

DHEAS: Use lab reference range or 65 mcg/dL to 380 mcg/dL.

Pregnenolone: Use lab reference range or 10 ng/ dL to 230 ng/dL.

Table 5: Guide to Prescribing BHT

This guide was created by the author.

Because bioidentical hormones are replaced in a customized, per-patient dose, no standard dosing schedule exists. The conversion chart provided here is meant to be used as reference only. It does not constitute a recommendation for any product or clinical situation. The conversions are approximations for reference only. In women, estrogens normally exist in approximately the following ratio:

• estriol: 60% to 80%

• estradiol: 10% to 20%

• estrone: 10% to 20%

Dosages

Dosages are determined by individual needs. Each prescription is preceded by a thorough evaluation of the patient's blood levels.

The goal of BHT is to mimic normal physiology as much as possible, putting the hormones back to levels where they are beneficial for relief of symptoms.

Starting with a low dose and titrating up helps achieve results at the lowest effective dose.

I often include progesterone with estrogen in the preparations I prescribe, whether or not the woman has an intact uterus. This frequently balances the effect of estrogen. I also add testosterone if the levels are low and the patient's symptoms warrant it.

While remembering that each patient is unique, I have discovered through trial and error that the correct dosing often starts with these levels:

• biest (estriol 80% and estradiol 20%) 2.5 mg

• progesterone 100 mg

• Testosterone at 2.5 mg is also a common addition.

• If the DHEA level is low, I often add 10 mg to 25 mg to the regimen, in a separate capsule.

• Some providers use triest, which includes estrone, and the ratio of that can be estriol 80%, estradiol 10% and estrone 10%. I often exclude estrone because it is the dominant circulating estrogen after menopause and many of my patients have adequate levels.

Routes of Administration

Sublingual troche (lozenges) are clinically effective as well as cost effective, since the dose can be doubled and the troche cut in half, often for the same price as a full troche.

Transdermal creams are often well accepted by patients, but in the climate where I practice (desert), absorption rates can vary.

Oil capsules in sustained-release forms are also popular. Patients may need a 20% to 30% increase in hormone amounts to accomplish the same results as the other routes of administration because of metabolic effects of the first pass in the liver.

Some patients prefer continuous combined therapy. Others take cyclic progesterone 14 days of the month.

Side Effects and Usage Issues

The side effects associated with BHT vary according to patient and are mostly anecdotal. They occur primarily in the first 1 to 2 months of therapy and include breast tenderness and vaginal spotting. Some of my patients have reported feeling "revved up" when taking testosterone and prefer to take it in the morning. Some have had an increase in oily skin and acne and feelings of aggressiveness. Some have noticed increased muscle strength and stamina.

If uncomfortable side effects occur or symptoms do not improve, dose changes can be made easily.

All hormone levels vary significantly due to daily life. During times of stress, anxiety or illness, hormones may be depleted more rapidly. One of the benefits of BHT is that deviations can be quickly addressed with a dose adjustment.