Hormone Replacement Therapy Updates

Many medications are prescribed for "off-label" use or an alternate route of administration in order to improve the therapeutic response, provide an economical alternative to solve a medication problem, or minimize the incidence of side effects, because the desired dosage form is not commercially available (for example, eye drops may be used to treat ear infections). In some cases (e.g., terminal illness), alternate routes of drug administration are used because patients simply cannot take needed medication by the intended route.

It is essential that consideration is given to the formulation and excipients as well as active ingredients, particularly when prescribing a route of administration that is different than the labeled use. For example, patients have been instructed to instill tablets and syrups rectally. Because syrups contain sugar, they can be very messy and sticky, and syrups may need to be diluted with water since their high sorbitol concentration may cause bowel evacuation (a problem that can be avoided by prescribing a properly compounded rectal formulation). Patients should always check with our pharmacist before making assumptions: for example, although eye drops may be used in the ears, ear (otic) drops can not be used in the eyes because otic preparations may not be isotonic, which means that significant problems can occur due to differences in concentration gradients, and ear drops may also contain preservatives that can be harmful to the eyes.

Many anticonvulsants, analgesics, and sedatives are given rectally when patients can't take oral meds. The dosage of medication must be individualized as drug absorption via the rectum can be highly variable, i.e., delayed or almost as fast as an intravenous bolus. Therefore, the dose or dosing interval may need to be adjusted when the route of administration is changed.

Our compounding pharmacy can obtain the necessary drug as a bulk chemical and prepare a customized medication in the most appropriate strength and dosage form to solve each patient’s specific medication problems. Please contact us for more information.

Four years ago, the Women’s Health Initiative (WHI) suggested that taking synthetic hormones, which are primarily manufactured by the “Big Pharma” company Wyeth, could lead to an increased risk of breast cancer and heart problems. In response, many physicians ceased to prescribe conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) and a combination of the two hormones. Wyeth’s sales of these products decreased significantly. Many women who feared the risks or had previously experienced side effects after taking commercially-manufactured hormones or sought individualized alternatives to “one size fits all” hormone replacement therapy (HRT) turned to Bio-identical HRT (BHRT). In response, Wyeth has filed a complaint with the federal Food & Drug Administration asking it to take action against small pharmacies that compound bio-identical hormones.

“While Wyeth clearly expected to improve its position in the multibillion-dollar market for women's hormonal products, the episode thus far shows signs of having the opposite effect. The FDA has yet to rule on Wyeth's complaint, but the huge corporation has stirred up a hornet's nest of opposition from women and doctors around the country, who see it as a classic case of Big Pharma throwing its weight around against small businesses and seeking to remove an important element of choice for suffering patients.”¹ The FDA has not made a decision on the Wyeth petition, but has provided a site where patients and health care professionals can post comments and express their desire to stop pharmaceutical manufacturers from limiting prescribing options. Visit www.iacprx.org for a link to the FDA to take action. The comment period is expected to end May 4, 2006.

The WHI reported that the use of CEE alone increases the risk of stroke, decreases the risk of hip fracture, and does not affect the incidence of heart disease in postmenopausal women with prior hysterectomy over an average of 6.8 years. More detailed analysis has concluded that treatment with CEE alone for 7.1 years does not increase breast cancer incidence in postmenopausal women with prior hysterectomy. However, the researchers recommended that women who take CEE should have more frequent mammography screening and short interval follow-up. The authors of the review noted that initiation of hormone replacement should be based on consideration of the individual woman's potential risks and benefits.²

The WHI trial of combined estrogen plus progestin was stopped early when overall health risks, including invasive breast cancer, exceeded benefits. Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.³

For more information about the benefits of individualized Bio-identical Hormone Replacement Therapy,

¹ Business Week Online, April 13, 2006, http://www.businessweek.com/print/smallbiz/content/apr2006/sb20060413_667219.htm (accessed 4/19/06)

Approximately 200 million people worldwide have thyroid disorders, and the risk increases with age. More than half of all Americans affected by thyroid disease are unaware of their condition. Thyroid disease affects many more women than men (possibly because women need higher levels of TH) but it has no age, gender, or ethnic barriers. Patients may have some or all of the above symptoms, but may not be diagnosed for years.

Thyroid Hormone (TH) is produced by the thyroid gland in response to the release of thyroid stimulating hormone (TSH) from the pituitary gland. TH helps the body convert food into energy and heat, regulates body temperature, and impacts many other hormonal systems in the body.

Slowed metabolism and slowed heart rate
Cold and heat intolerance – cold hands and feet
Fatigue
Fluid retention - face, legs, eyelids and abdomen
Dry skin, eyes and/or hair
Yellowed skin
Loss of eyebrows
Constipation
Headaches, migraines
Depression, apathy and anxiety
Irritability - low self esteem
Low sexual desire
Infertility
Memory and concentration impairment
Enlarged tongue, deep voice and swollen neck
PMS, Irregular menstrual periods
Lack of exercise tolerance
Weight gain (especially in the stomach)
Hypoglycemia (low blood sugar)

Thyroxine (T4), an inactive form that is produced exclusively by the thyroid gland.
Triiodothyronine (T3), the active form of thyroid hormone. About 20 percent of T3 is produced by the thyroid gland, with the remainder produced through conversion of T4 in various tissues of the body when more T3 is needed.

Researchers have attempted to provide appropriate thyroid hormone replacement since 1892, when the Armour meat company began to provide desiccated thyroid extract from the thyroid glands of animals. Beginning in the 1970s, the use of desiccated thyroid for the treatment of primary hypothyroidism was gradually replaced by a synthetic form of T4 known as levothyroxine sodium. Physicians note that despite apparently adequate replacement therapy with levothyroxine, some hypothyroid patients remain symptomatic. Studies suggest that replacement therapy for hypothyroidism with levothyroxine alone does not ensure normal thyroid hormone levels in all tissues, and that a combination of levothyroxine and T3 may be required for optimal thyroid replacement therapy. However, the only commercially available form of T3 for replacement therapy is synthetic liothyronine sodium, an immediate release formulation which is rapidly absorbed, may result in higher than normal T3 concentrations throughout the body, and may cause serious side effects, including heart palpitations. Research indicates there is a need for sustained-release T3 preparations in order to avoid adverse cardiac effects due to high serum T3 levels which can result if the hormone is absorbed too rapidly.

A study published in the New England Journal of Medicine reported that treatment with T4 plus T3 improved the quality of life for most hypothyroid patients. The researchers also recommended that the ideal thyroid hormone replacement program for someone without a thyroid gland, or whose thyroid gland is nearly non-functioning, should include daily T3 in sustained-release form, along with enough T4 to ensure normal levels of thyroid hormone. Partial substitution of the T4 dose with T3 improved cognitive performance, mood, physical status, and neuropsychological function in hypothyroid patients.

For more information about thyroid hormone replacement using sustained-release T3 formulations, please contact our compounding pharmacist.

Copyright 2006, Storey Marketing - Monthly Website Updates. Reproduction prohibited. Subscription available through Storey Marketing (814-337-3441). Questions regarding this article should be directed to the compounding professionals at Market Compounding Pharmacy.

Since the Women’s Health Initiative report, millions of women have discontinued post-menopausal hormone replacement therapy (HRT), raising some concerns. The National Osteoporosis Risk Assessment (NORA) evaluated the association between HRT cessation and hip fracture risk in 140,584 postmenopausal American women. Hip fractures are the most devastating, costly, and reliably reported events to measure osteoporosis.

All participants were at least 50 years old, were postmenopausal, and had no previous diagnosis of osteoporosis. Baseline and 12-month follow-up questionnaires assessed use of HRT and incident hip fractures. Hip fractures were reported by 269 women. Consistent with the WHI, women in NORA who were currently on HRT had a 40% lower incidence of hip fractures compared with those who never used HRT. Women who stopped using HRT more than 5 years earlier had similar hip fracture risk to “never users”, as expected. However, surprisingly, women who had discontinued HRT within the previous 5 years had an increased hip fracture odds ratio of 1.65 relative to never users of HRT.

Estrogen use initially increases, and later maintains, bone mass, reducing the incidence of fractures, including hip fractures, even in a population not selected for low bone mass. This study showed that rapid bone loss follows estrogen discontinuation, such that bone mineral density approached the pretreatment level within 2 years after estrogen withdrawal. In addition, because during the early phase of estrogen withdrawal, the rate of bone resorption substantially exceeds that of bone formation, not only are individual trabeculae at high risk of loss from osteoclastic resorption, but repair of partly transected trabeculae may be incomplete.

Please contact our compounding pharmacy for more information on Bio-identical Hormone Replacement Therapy.
We work together with prescribers and their patients to customize therapy to meet each woman’s specific needs.

Suzanne Somers’ book and interviews on Larry King Live, The Today Show, and other programs have generated many questions about the benefits of Bio-identical Hormone Replacement Therapy (B-HRT). The Sexy Years: Discover the Hormone Connection: The Secret to Fabulous Sex, Great Health, and Vitality, for Women and Men (© 2004, Crown Publishing Group) is a culmination of Suzanne’s years of research to find an alternative to and avoid the side effects of synthetic hormones for relief of menopausal symptoms, and to restore her vitality. After being thin and fit and full of energy, Suzanne herself encountered the “Seven Dwarfs of Menopause-Itchy, Bitchy, Sweaty, Sleepy, Bloated, Forgetful, and All-Dried-Up”. Instead of living out the rest of her life cranky, sleep-deprived, and with no libido, Suzanne set out to discover how she could get her mind, body, and life back and found the solution in bio-identical hormones. She claims she has discovered her “fountain of youth” and feels 30 years old again. She describes her personal bout with breast cancer, and shares personal insight, patient stories, and testimonials. The book also discusses andropause and how men can take bio-identical hormones and regain the strength and energy they had in their youth. Suzanne supports her own research and experiences with the expertise of leading doctors in the field of women’s and men’s health.

Diana Schwarzbein, M.D., an endocrinologist, advocates cycling progesterone, because “continuously combining an estrogen with a progestin on a daily basis makes the patient more insulin resistant.” She blames both the use of synthetic hormones and continuous combined therapy for the problems reported by the Women's Health Initiative: an increased incidence of heart attack, stroke, and blood clots. Dr. Schwarzbein works with compounding pharmacies and attempts to mimic normal physiology with the use of bio-identical hormones, recommends bio-identical hormones for life, and monitors therapy with blood levels.

Uzzi Reiss, M.D., is board certified in obstetrics-gynecology and anti-aging medicine, and author of Natural Hormone Balance for Women. He has an innovative medical practice specializing in anti-aging medicine for men and women, and a gynecological practice based on nutritional and hormonal approaches. He also advocates cyclic bio-identical hormone replacement therapy, blood tests, and working with compounding pharmacies. He believes that an imbalance of estrogen and progesterone creates disease, and that cancer results from a lack of progesterone. Dr. Reiss also discusses the importance of testosterone, DHEA, thyroid, and adrenal hormones.

The final interview was with sisters Dr. Jennifer and Dr. Laura Berman, founders of the Female Sexual Medicine Center at UCLA and the Berman Center in Chicago, hosts of the The Berman and Berman Show: For Women Only on Discovery Health, and authors of For Women Only: A Revolutionary Guide to overcoming Sexual Dysfunction and Reclaiming Your Sex Life. Dr. Laura Berman is a female sex therapist and Dr. Jennifer Berman is a urologist, and both discuss the use of testosterone in various dosage forms for the treatment of female sexual dysfunction.

There is now convincing evidence that non-bio-identical hormone replacement therapy increases the risk for breast cancer. Dimitrakakis et al. of the National Institutes of Health, had previously shown that ovarian androgens normally protect mammary epithelial cells from excessive estrogenic stimulation, and therefore hypothesized that the addition of testosterone to non-bio-identical hormone therapy might protect women from breast cancer. A retrospective, observational study followed 508 postmenopausal women in South Australia receiving testosterone (implant, average 100mg every 5 months) in addition to synthetic hormone therapy with conjugated estrogens or estrone, in some cases with the addition of a synthetic progestin (medroxyprogesterone acetate or norethisterone). Breast cancer status was ascertained by mammography at the initiation of testosterone treatment and biannually thereafter. The average age at the start of follow-up was 56.4 years, and the mean duration of follow-up was 5.8 years. There were seven cases of invasive breast cancer in this population of testosterone users, for an incidence of 238 per 100,000 woman-years. The rate for non-bio-identical estrogen/synthetic progestin and testosterone users was 293 per 100,000 woman-years--substantially less than women receiving non-bio-identical estrogen/synthetic progestin in the Women's Health Initiative study (380 per 100,000 woman-years) or in the "Million Women" Study (521 per 100,000 woman-years). The breast cancer rate in these testosterone users was closest to that reported for hormone therapy “never-users” in the latter study (283 per 100,000 woman-years), and their age-standardized rate was the same as for the general population. These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population.

Ask us about the benefits of Bio-Identical Hormone Replacement Therapy (BHRT).

Copyright 2006, Storey Marketing - Monthly Website Updates. All rights reserved. Questions regarding this article should be directed to the compounding professionals at Market Compounding Pharmacy.

According to the American Dental Association: “Women have special oral health needs and considerations that men do not have. Hormonal fluctuations have a surprisingly strong influence on the oral cavity. Puberty, menses, pregnancy and menopause all influence women’s oral health and the way in which a dentist should approach treatment.”

Osteoporosis and periodontitis represent two highly prevalent diseases associated with advancing age. There is evidence that a patient with systemic osteoporosis is likely to have decreased oral bone density, which may impact the success of dental implants and prosthetic devices, and affect other treatment decisions. Further, a patient with decreased bone mineral density may be at a higher risk for progression of periodontitis.

On dental examination, clinical findings of postmenopausal problems may include decreased saliva production, increased dental caries, irritation of the gums, and mouth sores. Menopausal women often report discomfort (pain, burning sensation), xerostomia, and altered taste sensations (salty, peppery or sour).

One study noted the prevalence of oral discomfort in postmenopausal women was 46%, compared to 6% for premenopausal women. Eighty percent of burning mouth syndrome patients are women whose pain began from 3 years before to 12 years after onset of menopause. Most menopausal women who complained of oral discomfort experienced relief with estrogen therapy.

Hormone replacement therapy (HRT) is consistently associated with greater tooth retention. Brigham and Women's Hospital and Harvard Medical School conducted a study of 42,171 postmenopausal women and concluded the risk of tooth loss was 24% lower in women who were currently using hormones.

Our professional staff recommends the use of individualized doses of bio-identical hormones when hormone replacement therapy is indicated. Bio-identical hormones have exactly the same chemical structure as endogenous human hormones, and therefore are able to follow normal human metabolic pathways and provide the full range of active hormones that are required by humans.

We are also able to compound a variety of preparations that may help to relieve some of the oral problems associated with menopause. Examples include electrolyte lozenges and saliva stimulants to help with dry mouth, and various medications for burning mouth syndrome. Please call for more information on these customized medications.

Appropriate Hormone Replacement Therapy should optimize function and minimize health risks due to aging, without causing harm.

A study done at Beth Israel Deaconess Medical Centre and Harvard Medical School reported that postmenopausal women who choose hormone replacement therapy (HRT) often discontinue this therapy within one year, most frequently due to side effects such as bloating and breast swelling/tenderness.1 At the Research Triangle Institute in North Carolina, researchers concluded that clinicians may influence HRT continuation rates through initial drug choice or modifications in drug type or regimen over the course of therapy.2 If hormone-related problems could be solved without using replacement hormones that produce intolerable side effects, it would be reasonable to expect long-term compliance to increase.

When a physiologic balance is restored using bio-identical hormones such as estriol, estradiol, progesterone, and testosterone, many symptoms attributed to hormone decline can be eliminated. Based on results of laboratory tests, symptoms, and response to therapy, doses of individual bio-identical hormones can be adjusted and administered in the most appropriate dosage form to meet each woman’s specific needs, while minimizing the risk of side effects.

In “A Perspective on HRT for Women: Picking Up the Pieces After the Women’s Health Initiative Trial”, George R. Gillson, MD, PhD, and David T. Zava, PhD conclude “there is a lot of evidence supporting BHRT [Bio-identical Hormone Replacement Therapy], but no big trials… Regarding BHRT and conventional HRT (conjugated estrogens/progestin), each practitioner has to consider all of the evidence and decide whether the small trials that show benefits outweigh the large trials that conclusively demonstrate harm, since there is no longer any clear standard of care.”3

Risks vs. Benefits of Hormone Replacement Therapy and The Advantages of Bio-Identical HRT

The Women’s Health Initiative study was designed to identify the potential risks and benefits of Hormone Replacement Therapy (HRT). A portion of the clinical trial was stopped early after results showed that a synthetic hormone combination increased the women’s risks of developing invasive breast cancer, heart disease, stroke, and blood clots. The data and safety monitoring board concluded that the risks of using a synthetic estrogen - synthetic progestin drug combination outweighed the benefits.

It is interesting that the researchers considered this finding to be “news”. In fact, many published clinical trials have already reported that the risk of breast cancer is increased by long-term use of conjugated equine estrogens, and further increases when the synthetic progestin medroxyprogesterone acetate is added to the regimen.

At our pharmacy, we compound customized bio-identical hormones including estriol, estrone, estradiol, progesterone, and testosterone, using the exact dose of the specific bio-identical hormones needed by each woman in the most appropriate dosage form for that individual. This customization allows the prescriber to maximize the therapeutic benefits that can be obtained through the use of bio-identical hormones, while minimizing the potential for adverse effects.

Bio-identical hormones were NOT used in the WHI study. Bio-identical hormones are structurally identical to hormones that are naturally produced by the human body, and intended to replace these hormones when their levels decline either as a consequence of aging, disease, or surgery. Research has shown that bio-identical hormones can effectively control symptoms of menopause, including hot flashes, insomnia, vaginal dryness, and frequent urinary tract infections. Women's experiences and clinical outcomes of HRT differ vastly depending on whether the hormones are synthetic or bio-identical, the dose, dosage form, and route of administration. For years, physicians have been prescribing bio-identical HRT for women who have experienced problems or have other concerns about the use of synthetic hormones.

Progesterone is a term that is incorrectly used interchangeably to describe both natural bio-identical progesterone and synthetic substitutes. Synthetic progestins (also called progestogens or progestational agents) are derivatives of bio-identical progesterone, and have been developed because they are longer-lasting, more potent, and patentable. Although synthetic progestins such as medroxyprogesterone acetate are clearly beneficial in preventing estrogen-induced overgrowth of the uterine lining and endometrial cancer, their other effects are much less desirable. Medroxyprogesterone can negate the beneficial effects of estrogen on lipid profiles, atherosclerosis and vascular reactivity. Natural progesterone, on the other hand, maintains all the benefits of estrogen on cholesterol without any of the side effects associated with synthetic progestins.

Medroxyprogesterone reduces the dilatory effect of estrogens on coronary arteries, increases the progression of coronary artery atherosclerosis, increases the clot-forming potential of atherosclerotic plaques, promotes insulin resistance and consequent hyperglycemia (high blood sugar), and can significantly lower high density lipoproteins (HDL, “good cholesterol”), thereby decreasing the cardioprotective benefit of estrogen therapy. Studies at Wake Forest University School of Medicine have concluded that synthetic medroxyprogesterone, in contrast to bio-identical progesterone, increases the risk of coronary vasospasm. This narrowing of major blood vessels surrounding the heart could potentially lead to a heart attack. On the contrary, bio-identical progesterone plus estradiol protected against vasospasm.

The benefits of progesterone are not limited to prevention of endometrial cancer in women who are receiving estrogen replacement. Progesterone can build bone density, promote glucose utilization, and improve sleep patterns. Mayo Clinic researchers surveyed 176 women taking natural micronized progesterone who had previously taken synthetic progestins. After one to six months, the women reported an overall 34% increase in satisfaction on micronized progesterone compared to their previous HRT, reporting these improvements: 50% in hot flashes, 42% in depression, and 47% in anxiety. Micronized progesterone was also more effective in controlling breakthrough bleeding.

When considering treatment options for preventing heart disease and osteoporosis and relieving menopausal symptoms, it is important to address not only benefit-versus-risk ratios but also quality-of-life. A woman’s need for HRT may transcend statistics of heart disease, osteoporosis, and cancer. Without HRT, many women (and consequently, their families) feel totally miserable, exhausted, and unable to cope. Yet, only 20% of women continue to take synthetic hormones after two years, mainly due to the development of side effects. The quality of many women’s lives has been dramatically improved through the use of bio-identical HRT.

Statistics and fear abound, yet the absolute risk of cancer attributable to HRT remains low, and the risk of some forms of cancer is reduced. For example, an analysis of 18 studies involving thousands of women concluded that the risk of developing colorectal cancer is reduced by 34% in current estrogen users.

Decisions about whether to stop, start, or change your HRT should made on an individual basis only after consulting your physician and a knowledgeable pharmacist. Our goal is to work together with physician and patient to solve medication problems and optimize each patient’s health and well-being.

Studies and the media continue to provide conflicting and confusing information. We are here to help clarify the issues that surround HRT. Your questions are welcome.

Low serum testosterone (clinically referred to as hypogonadism) is commonly associated with erectile dysfunction (ED). There are merits to treating hypogonadism versus prescribing oral phosphodiesterase (PDE-5) inhibitors (such as Viagra™, Cialis™, and Levitra™) for sexual dysfunction. Testosterone-replacement therapy (TRT) may be the best treatment for men with ED when the presentation includes diminished libido or other sexual symptoms or when non-sexual symptoms such as depressed mood, decreased sense of vitality, and increased fatigue also exist. The health benefits of TRT also include improvements in body composition, bone density, cognition, and sense of well-being. Thus, there may be good reasons to use TRT as first-line therapy for the man with ED. Concerns regarding prostatic and cardiovascular risks of TRT have not been supported by the medical literature. Nevertheless, men receiving TRT must be monitored at regular intervals with digital rectal examination and blood testing for prostate-specific antigen. Hematocrit or hemoglobin also should be obtained regularly due to the risk of erythrocytosis. Awareness of the benefits of TRT in the man with ED may improve clinical outcomes.

According to the Department of Urology, Columbia University, New York, NY, there are benefits to using a combination of testosterone and PDE-5 inhibitors. A recently published multicenter, randomized, placebo-controlled study evaluated the safety and efficacy of testosterone gel 1% plus sildenafil (Viagra™), vs. placebo gel plus sildenafil, in producing an erectile response in men with low serum testosterone who had not responded to treatment with sildenafil alone for ED. Therapy with testosterone gel significantly improved erectile function in response to sildenafil. The combination therapy also significantly improved orgasmic function and patient satisfaction.

HORMONE REPLACEMENT THERAPY UPDATES