Menopausal Symptom Relief and Side Effects Experienced by Women Using Compounded Bioidentical Hormone Replacement Therapy and Synthetic Conjugated Equine Estrogen and/or Progestin Hormone Replacement Therapy – Part 1

This is an adaptation of a thesis written by Dr. Laura Deleruyelle and presented to the faculty of Frances Payne Bolton School of Nursing at Case Western University in partial fulfillment of the requirements for the degree of Doctor of Nursing Practice.

Part 1: Introduction to the study conducted and the results of that literature review that was conducted for the purpose of examining the current data related to the topic of hormone replacement therapy.

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Part 2: A brief discussion on the significance of this study to nursing and provides the methods used in this study.

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Part 3: The results and conclusion of this study.

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Abstract

The use of compounded bioidentical hormone replacement therapy by menopausal women has become a popular alternative to traditional synthetic conjugated equine estrogen and progestin hormone replacement therapy due to safety concerns raised by recent studies. However, due to the lack of randomized, largescale trials to evaluate the efficacy and side-effect profile of compounded bioidentical hormone replacement therapy many healthcare providers are reluctant to prescribe such therapy. The purpose of this study was to compare women’s menopausal symptom relief and side effects experienced when using compounded bioidentical hormone replacement therapy and traditional hormone replacement therapy. A descriptive comparative design was used. Inferential and descriptive statistical procedures including a paired difference t-test, two-sample t-test, and f-tests (percentage, mean, standard deviation, frequency) were run on the Statistical Package for the Social Sciences. The framework used to guide this study was Lenz and Pugh’s Theory of Unpleasant Symptoms. Surveys were distributed once to a convenient sample of women aged 35 and older when they dropped off or picked up their prescriptions at a pharmacy. Of the 216 surveys distributed, 70 were returned from those women taking compounded bioidentical hormone replacement therapy and 53 from traditional hormone replacement therapy. The survey contained 15 questions pertaining to age, duration of hormone replacement therapy, type and formulation of hormone replacement therapy, reasons for initiating hormone replacement therapy, symptoms before and one month after hormone replacement therapy, and side effects related to hormone replacement therapy. The results of this study will be summarized in forthcoming articles in this series.

Menopausal Symptom Relief and Side Effects – Part 1

Introduction

Background and Significance of the Problem

With an estimated 37.5 million women reaching midlife, the impact of menopause has become an important public health issue for nurse researchers.1 Menopause is the transition period in a woman’s life when her ovaries cease to function, her body produces less estrogen and progesterone, and menstruation becomes less frequent, eventually stopping altogether.2 Decreasing hormone levels can cause numerous symptoms including hot flashes, night sweats, insomnia, weight gain, decreased libido, genitourinary atrophy and skin changes, as well as psychological and somatic symptoms.2 These symptoms can result in distress and disruption to women’s lives. The presence of unpleasant symptoms are the main reasons why women choose hormone replacement therapy (HRT)3·4 Considering the fact that women spend approximately one third of their lives after menopause, nurse practitioners need to identify regimens that have minimal side effects, provide health benefits, encourage compliance, and relieve the unpleasant symptoms ofmenopause.5

Over the past several decades, synthetic conjugated equine estrogen and progestin HRT has been the traditional treatment for menopausal symptoms.6 Synthetic conjugated equine estrogen was developed in the 1940s and has had widespread success in managing the unpleasant symptoms of menopause. In the 1970s, progestin was added to unopposed estrogen replacement therapy for those women with intact uteri, setting the stage for its current use. However, in July 2002, findings from the 1998 Women’s Health Initiative (WHI) study indicated an increased risk for breast cancer, heart disease, stroke, and blood clots among menopausal women using conjugated equine estrogen and progestin replacement therapy.7 Additionally, results from the Postmenopausal Estrogen/Progestin Intervention (PEPI) tri- al (1987-1990) suggested that women with intact uteri who took conjugated equine estrogen without progestin had an increase in serum triglycerides and endometrial hyperplasia.8 As a result of these studies, a growing number of women are choosing to use compounded bioidentical hormone replacement (BHRT) to relieve the unpleasant symptoms of menopause.9 Bioidentical hormones are hormones usually extracted from plant sources that are made chemically identical to the human hormone molecule.10 Conversely, synthetic conjugated equine estrogen and progestin hormones are assembled in a laboratory and are not identical to the human hormone molecule.

Statement of the Problem

In the last several years, many women and nurse practitioners have revised their opinion of synthetic conjugated equine estrogen and progestin as a treatment for the unpleasant symptoms ofmenopause.6 Due to adverse side effects such as weight gain, uterine bleeding, breast tenderness, bloating, and safety concerns, a considerable number of women have discontinued the use of synthetic conjugated equine estrogen and progestin HRT. In fact, recent findings suggest growing dissatisfaction with synthetic conjugated equine estrogen and progestin HRT and an increasing number of women choosing alternative treatments.11

However, synthetic conjugated equine estrogen alone or in combination with progestin is still considered to be a very effective treatment for the unpleasant symptoms of menopause.1 Alternately, in light of the findings from the WHI and PEPI trials and changes in women’s healthcare attitudes and expectations, compounded BHRT is now being promoted as an effective alternative to traditional conjugated equine estrogen and/or progestin HRT.12 In fact, compounded BHRT has become so popular that in January 2009, a record number of women joined in the audience for a two-part compounded BHRT debate on The Oprah Winfrey Show.13 Dr. Phil’s wife, Robin Mc-Graw. a compounded BHRT patient, along with Dr. Christine Northrop, author of the book The Wisdom of Menopause, joined part one of the conversation with Oprah. Robin McGraw, author of the book What’s Age Got to do with it? Living your Happiest and Healthiest Life, shared her experience with menopause on the show. She explained that before using compounded BHRT she felt tired and lifeless and after treatment she felt vibrant again. Robin credits Prudence Hall, MD and Howard Liebowitz, MD for starting her on compounded BHRT. In her book, she devotes an entire chapter to compounded BHRT.13

Suzanne Somers, author of the book Ageless, the Naked Truth about Bioidentical Hormones, shared her story with Oprah during part two of the compounded BHRT debate.13 Suzanne credits getting her life, her figure, her health, and her happiness back after replacing low or missing hormones with compounded BHRT. But despite the press coverage and numerous books touting the praises of compounded BHRT, many healthcare providers are still reluctant to prescribe them. This is largely due to the lack of largescale randomized controlled trials to evaluate the effective-ness of compounded BHRT in relieving menopausal symptoms.14,15 In fact, the concern about the risks of compounded BHRT is the basis for the recent U.S. Food and Drug Administration (FDA) action to halt compounding of the hormone estriol.16 The FDA stated that pharmacy operations were violating federal law when they made claims of the safety and effectiveness of compounded BHRT that were not sup-ported by medical evidence.17 However, numerous small studies support the use and efficacy of compounded BHRT.

Statement of Purpose

The purpose of this study was to examine the differences in reported relief from the unpleasant symptoms of menopause and the side effects experienced among women currently using compounded BHRT as compared to women currently using synthetic conjugated equine estrogen and/ or progestin HRT. the effect symptoms have on performance, but also how performance affects symptoms and the entire menopausal symptom experience.19 Therefore, the relationship of the performance outcome to the other components of the theory (antecedent factors and symptoms) is considered reciprocal. In this study, the performance outcome was not only dependent on the efficacy of the HRT, but also on the side effect profile of the treatment. Unwanted side effects of HRT may cause women to prematurely discontinue treatment which could result in a relapse of menopausal symptoms and disruption in their lives. According to the TOUS, this would be a poor performance outcome. Therefore, nurse practitioners need to suggest an effective hormone treatment with a low incidence of side effects in order to successfully treat women’s menopausal symptoms.

Significance to Nursing

Providers should continue to evaluate the scientific evidence available when considering the most effective HRT solutions for their patients’ menopausal health. The significance will be discussed further in part 2.

Research Questions

  1. Are there differences in menopausal symp­tom relief between women currently using compounded BHRT as compared to women currently using synthetic conjugated equine estrogen and/or progestin HRT?
  2. Are there differences in side effects expe­rienced between women currently using compounded BHRT as compared to women currently using synthetic conjugated equine estrogen and/or progestin HRT?

Conceptual Definitions

Bioidentical hormones: Hormones that are made chemically identical to the hu­man hormone molecule.10

Synthetic hormones: Conjugated equine estrogen is derived from the urine of pregnant horses that is physiologically different from human serum estrogen. It consists of mainly estrone sulfate, equilins, equilenins, and alpha estradiol, all of the estrogens that occur naturally in horses.2,6 Progestin is a synthetic drug with a progesterone-like effect on the uterus used to mimic the human hormone molecule. 2,6

Side effects: An action or undesirable effect of a drug other than that desired.21

Symptom relief: The alleviation or reduc­tion of a distressing psychological or painful physiological feature of a condition.21

Synthetic: A unique structure that has been artificially prepared in a laboratory.6

Synthetic Conjugated Equine Estrogen

The synthetic estrogen and progesterone replacement most healthcare providers prescribe today are known generically as conjugated equine estrogen and medroxyprogesterone acetate.22 Synthetic conjugated equine estrogens are derived from the urine of pregnant mares and consist of approximately 75% to 80% estrone, 6% to 15% equilin, and 5% to 19% of estradiol and two other equine estrogens.22 This is in stark contrast with the estrogen combination found in the human female reproductive system, which includes ap­proximately 90% estriol, 3% estrone, and 7% estradiol. In addition to the larger proportions of estrone and estradiol found in synthetic conjugated equine estrogens, these estrogens also contain equilin and two other forms of estrogen found exclusively in horses. Some synthetic estrogen hormone products are also derived from plants such as yams or soy but contain equilin and estrone as primary in­gredients and still mimic conjugated equine estrogen in the human body.23 While the human body has enzymes and cofactors to process human estrogens, the body has none of the necessary enzymes and cofactors required to break down equilin and the other horse estrogens, equilenin and alpha estradiol. 2,6 The difference between horse and human estrogen compounds and the body’s ability to metabo­lize the compounds may explain why synthetic equine estrogens in the female body can induce a hormonal imbalance resulting in undesired side effects.

Synthetic Progesterone

Progesterone was first used in 1934 and was originally procured by methods of extraction from animal placenta.2,6 However, when given orally, progesterone was rapidly destroyed in the gastrointestinal tract.2,6 As a result, synthetic progestins such as medroxyprogester­one acetate were developed from progesterone to mimic the human hormone molecule.2,6 Progestins have similar protective effects on the endometrium and decrease vasomotor symptoms as does human progesterone, but the progestins have been linked to adverse side effects such as depression, breakthrough bleeding, and breast cancers.24,25

An abundance of research exists supporting the use of synthetic conjugated equine estrogen and progestin HRT to maintain bone health, prevent endometrial cancer, and provide relief from menopausal symptoms.1,3,4,7,26,27 However, due to fear of breast cancer and bothersome side effects, approximately 40% only of the women using synthetic HRT continue treatment beyond one year.6 For example, Caucasian women aged 45 to 64 in Norway started HRT to relieve climacteric symptoms, but 43% of the sample reported adverse side effects such as weight gain, breast tenderness, and irregular bleeding, which lead them to discontinue HRT.28 Weakness of this study include limitations on generalizability and possibly selection bias. Only women between 45 and 64 years of age participated in this study, and there were a higher proportion of well-educated women who responded. Therefore, the results cannot be generalized to those women older than 64 years of age and to those women less educated.

The effect of combined conjugated equine estrogen and medroxyprogesterone acetate HRT on health-related quality of life was assessed by Welton and associates.29 Researchers utilized a randomized, double-blind, placebo study design. They recruited postmenopausal women with intact uteri or subtotal hysterectomy aged 50 to 69, at random, from general practices in the United Kingdom, Australia, and New Zealand. Women were randomized to receive combined oral estrogen 0.625 mg plus progestogen or matched oral placebo daily for one year. Health related quality of life and psychological well-being were measured using the Women’s Health Questionnaire (WHQ), European quality of life instrument, and Visual Analogue Scale (VAS). Also, emotional and physical changes were measured with a symptoms questionnaire by the Centre for Epidemiological Studies Depression Scale. The study was originally meant to treat women for an average of 10 scheduled visits, but the study was closed early in October 2002. Early termination of the study was due to the announcement of the finding from the WHI study which indicated an increased risk for breast cancer, heart disease, stroke, and blood clots among menopausal women using conjugated equine estrogen and progestogen HRT. The findings from this study were limited to data collected in one year due to the fact that the information on health-related quality of life was available on less than half of the original study participants by the end of the second year.

After one year, results were small but significant for observed improvements in vasomotor symptoms, sexual functioning, and sleep problems for the women on combined HRT compared to those taking placebo.29 Significantly fewer women taking combined HRT compared to placebo reported insomnia (P<0.001), hot flashes (P<0.001), night sweats (P<0.001), aching joints and muscles (P<0.001), and vaginal dryness (P<0.001). However, greater proportions of women taking combined HRT compared to placebo reported breast tenderness or vaginal discharge. Hot Flashes were reported as 30% and 29% by the combined group and placebo groups, respectively, at baseline and 9% and 25% at one year. The findings suggest that women on combined HRT started several years after menopause had improved health-related quality of life. Weaknesses of this study included substantial discontinuation of study medication and loss to follow-up which may have introduced selection bias.

Breast Cancer

In contrast, data from the French E3N cohort study were used by researchers to assess and compare the association between three different estrogen HRT combinations (estrogen alone, combined with progesterone or dydrogesterone, or with other synthetic progestogens) and the number of women with breast cancer at follow-up.24 The E3N was a prospective study initiated in 1991 to investigate risk factors for cancer in women aged 40 to 65 years and living in France. Participants were mostly teachers insured by the Mutuelle Generale de l’Education Nationale insurance company. A total of 98,995 women consented to participate and complete self-administered questionnaires, which inquired about medical history, menopausal status, and numerous lifestyle characteristics at regular intervals. The questionnaires were sent over an eleven-year period from 1991 to 2002. The E3N study was approved by the French National Commission for Data Protection and Privacy and was an integral part of the European Prospective Investigation into Cancer and Nutrition (EPIC). For the study by Fournier and colleagues, 24 breast cancer cases were identified from the E3N studies’ self-report questionnaires and a small amount from the Mutuelle Generale de I’Education Nationale insurance company files or information on deaths. Data analysis was limited to postmenopausal

women (n = 87,936). Exclusion criteria included those women who reported cancer other than a basal cell carcinoma before the start of follow-up questionnaires in 1992 (n = 5,849). Further exclusion included women for which no age was identified when HRT was initiated (n = 1,710). A total of 80,377 postmenopausal women were left for analysis. Of the 88.7% of the 80,377 women who completed the last survey in 2002, 2,354 cases of invasive breast cancer were identified, 2,243 (95.3%) of which were confirmed by pathology reports. Results yielded relative breast-cancer risks compared with HRT never-use as 1.29 (95% confidence interval 1.02 to 1.65), 1.00 (0.83 to 1.22), 1.16 (0.94 to 1.43), and 1.69 (1.50 to 1.91) for estrogen alone, estrogen-progesterone, estrogen-dydrogesterone, and other synthetic progestogens, respectively. The findings from this study may suggest that progesterone, when combined with estrogen, may have a safer risk profile on the breast than other synthetic proges­togens. A weakness of this study was the limited power to examine breast cancer risk among past users of HRT since most women were still using HRT at the end of follow-up.

Depression

Several previous studies had suggested that mood symptoms can be part of the menopausal syndrome and are thought to be caused by some of the unpleasant symptoms of menopause; vasomotor symp­toms, low libido, and insomnia.30 In a study by Rudolph et al that looked at a specific symptom of menopause, researchers conducted a randomized, double-blind, placebo-controlled study to investigate the effects of combined estradiol and dienogest treatment on post­menopausal depression.31 In that study, 31129 patients with mild to moderate depression in the context of a postmenopausal syndrome were recruited from gynecologists in private practice. The main target variable was the change in depression as measured by the Hamilton Depression Scale. To assess depression as secondary to the unpleasant symptoms of menopause, researchers used the Ger­man version of the WHQ. The participants in the treatment group were treated with 2-mg estradiol valerate and 2-mg dienogest every day for 24 weeks.

Results revealed that 43.1 % of those on HRT responded to treat­ment very well in the sense of a final score on the Hamilton Depres­sion Scale, and the effect seemed to be independent of the improve­ment in vasomotor symptoms and insomnia, thus indicating a direct mood-enhancing effect.31 Of the participants treated with placebo, 64.1% did not respond to treatment. This finding may suggest that there is a significant difference in the change of depression severity between HRT and placebo. Therefore, combination estradiol and dienogest may be an effective treatment option for depressed, post­menopausal women.

Functional Status

The association between HRT use and functional status in meno­pausal women was examined by Cohen and colleagues4 in a cross­sectional survey, population-based study of 682 Israeli women aged 50 to 70 years of age registered with six family physicians. The women in the study were required to have been on any type or form of HRT that contained estrogen, with or without progesterone, in any dose for at least one month. Functional status was assessed in the following domains:

  • Physical fitness
  • Emotions
  • Daily activity
  • Social activity
  • Pain
  • Sleep
  • General health status
  • Change in health status

The researchers found the contribution of HRT to be significant in the domains of general health status, sleep, physical activities, and feelings, but not significant for daily activities, social activities, change in health status, and pain. Results suggest that HRT may improve emotional and social function in menopausal women. A major weakness of this study was its cross-sectional design, and, therefore, only association between variables but not causation could be presented.4

Menopausal Symptom Relief and Side Effects – Part 1

The Impact of Exercise, Smoking, and Body Weight with Hormone Replacement Therapy

Another area researchers were interested in was not only in the association between the prevalence and severity of symptoms dur­ing menopause and HRT use, but also the prevalence of exercise, smoking, and body weight through the postmenopausal period. 3 They decided to conduct a prospective, longitudinal study. The study sample consisted of 5990 Swedish women aged 46, 50, 54, 58, and 62 years who were selected at random from the population register in the city of Goteborg. HRT with low-to-medium-potency estrogen was used by 46% of the women at the start of the study. The women were sent a 45-item postal questionnaire in 1992 and in 1998. The questionnaire included data on sociodemographic variables, general health, and reproductive history and presence of menopausal symptoms and their severity. The participants were asked to assess their quality of life and morbidity using a VAS. The researchers found that body weight increased over the six-year pe­riod from 66.3 to 68.9 kg while height remained the same. Body mass index (BMI) was the same for HRT users and non-users in 1992, however, BMI was higher for nonusers than current users.

Summary

The purpose of this study was to compare women’s menopausal symptom relief and side effects experienced when using compounded BHRT. This article includes the introduction to the study and the results of the literature review conducted by the author for the purpose of examining the current data related to the efficacy of compounded bioiden­tical hormone therapy compared to synthetic conjugated equine estrogen and progestin hormones.

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