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 2

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.

Read Part 1

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

Read Part 2

Part 3: The results and conclusion of this study.

Read Part 3

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, large-scale 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. Included in part 1 is the introduction to the study conducted and the results of the literature review that was conducted for the purpose of examining the current data related to the topic of hormone replacement therapy. Part 2 provides a brief discussion on the significance of this study to nursing and provides the methods used in this study.

Menopausal Symptom Relief and Side Effects – Part 2

Significance of Compounded Bioidentical Hormone Replacement Therapy to Nursing

In the last several years, compounded bioidentical hormone replacement therapy (BHRT) has become very popular with perimenopausal and menopausal women due to safety concerns with traditional synthetic hormone replacement therapy (HRT).1-3 However, compounded bioidentical hormones, like their synthetic counterparts (conjugated equine estrogen and/or progestin hormones), are powerful substances that help relieve menopausal symptoms, but may also come with risks. Nurse practitioners should continue to evaluate the scientific evidence available when considering the most effective HRT solutions for their patients’ menopausal health. Unfortunately, there have not been enough large-scale studies conducted to assess the value and risks of compounded BHRT. Part 1 includes the results of the literature review that was conducted for the purpose of examining the current data related to the topic of hormone replacement therapy. In order to safely treat the varied health concerns of women at menopause, nurse practitioners need to be informed about the different types of HRT to be able to determine the best regimen with the fewest number of side effects for their patients. Since anecdotal “proof” is not enough to guarantee efficacy and low side-effect profile, the findings from this study are important for nurse practitioners who may be prescribing compounded BHRT, since their patient’s health should be of the utmost importance.

Methods

Statement of Purpose

The purpose of this proposed research was to examine the difference in reported relief of the unpleasant menopausal symptoms and side effects experienced by women using compounded BHRT as compared to women using synthetic conjugated equine estrogen and/or progestin HRT.

Research Design

This retrospective study utilized a two-group post-test comparative design. Group one-bio was comprised of women using compounded BHRT, and group two-syn consisted of women using synthetic conjugated equine estrogen and/or progestin HRT. Both groups completed the same survey at a single data collection point.

Sample

Power Analysis

A power analysis was con­ducted using G power with a two-tailed test to determine the sample size needed for this study5,6 and results of two studies similar to the current study3,7 for calculating the effect size. The effect size using the t-value [t(77) = -12.68] for the total survey in Vigesaa’s study was 0.82 (“Effect size,” n.d.).2 Only four questions from the satisfaction questionnaire in Fitzpatrick’s study were used to calculate the second effect size. The questions, which were similar to the questions in the current study, queried par­ticipants about their satisfac­tion with relief of menopausal symptoms and control of breakthrough bleeding for two different hormone products. Means for the two questions related to relief of menopausal symptoms with previous HRT and current HRT were 2.95 (S.D. = 1.50) and 1.97 (S.D. = 1.19). Using the parameters above, the effect size for these questions was 0.34. Similarly, the means for the two ques­tions regarding control of breakthrough bleeding were 2.66 (S.D. = 1.53) and 2.06 (S.D. = 1.27), yielding an effect size of 0.21. The effect sizes were aver­aged, yielding an overall effect size for the Fitzpatrick study of 0.28. Averaging the effect sizes for the two studies resulted in an effect size of 0.55 for this study. The minimum number of responses needed to achieve a power of .80 with an alpha of .05 and a moderate effect size of 0.55 was 53 in each group. Based on the 49% response rate achieved in the Vigesaa study, it was determined that 108 sur­veys needed to be distributed to each group in this study for a total of 216 surveys.

Setting

Surveys were distributed to a convenience sample of woman taking compounded BHRT or synthetic conjugated equine estrogen and/or progestin HRT at two pharmacies in West Central Florida. The first pharmacy used Medical Arts Pharmacy and Compound­ing Center located in Bradenton, Florida, owned by Thomas Moss III, RPh, and managed by David 0. Keener, RPh. Pelot’s Pharmacy located in Bradenton, Florida was the second pharmacy used in this study. Medical Arts Pharmacy and Compounding Center share a store front in Blake Park, a professional complex for several physi­cians and dentists. Medical Arts Pharmacy was established 32 years ago, and the Compounding Center was opened in 2001. Medical Arts Pharmacy and Compounding Center offers patients a full array of pharmaceutical services, including customized medications to meet specific patient needs. In front of the Medical Arts prescription area is the check-out counter. The physical layout of the pharmacy al­lows for the maximum use of space with the front end stocked with all categories of over-the-counter preparations, greeting cards, and some durable medical goods, which is used for picking up prescrip­tions and cashing out sales for both pharmacies. The Compounding Center is located in a separate enclosed area so that all chemicals are isolated from staff and customers. Pelot’s Pharmacy is a tradi­tional pharmacy located in a free-standing building in downtown Bradenton, Florida.

Inclusion Criteria

Inclusion criteria for this study were women 35 years of age and older who have been using either synthetic conju­gated equine estrogen and/or progestin HRT or compound­ed BHRT for at least 1 month, with no upper time limits. Dosage forms of compounded BHRT for this study included creams, suppositories, tablets, or capsules. Dosage forms for conjugated equine estrogen and/or progestin HRT included vaginal creams, tablets, or capsules.

Exclusion Criteria

Exclusion criteria included women taking commercially available bioidentical hormone products, as well as their inability to communicate, read, or write in English.

Recruitment

When a woman came by the pharmacy to pick up her prescriptions, the pharmacists or pharmacy technicians distributed the packets containing the survey, along with a postage-paid stamped envelope addressed to the investigator. Women on synthetic hormones (premarin, prempro, premphase, provera, cycrin, amen) received white packets, and women on compounded bioidentical hormones received yellow packets. All packets were labeled

“Hormone Replacement Survey.” The packets were placed in the shopping bag along with the hormone replacement medications, and the consent letter was stapled to the smaller bag containing the hormone replacement medications. The consent letter was also used to explain the study and invite the women to participate. The pharmacists and pharmacy technicians were not required to verbally invite women to participate in the study. To ensure confidentiality and participant anonymity, the investigator did not distribute or personally accept any surveys, and no names or identifying information appeared on the surveys or packets.8

Menopausal Symptom Relief and Side Effects – Part 2

Definitions of Menopausal Symptoms (Operational Definitions)

Decreased libido: A lowered desire for sexual activity and less sexual satisfaction reported by menopausal women due to a decrease in circulating hormone levels as measured by the hormone replacement survey.9

Dry skin and hair: loss of moisture and elasticity of the skin and brittleness of the hair due to a decrease in circulating estrogen levels reported by menopausal women as measured by the hormone replacement survey.10

Foggy thinking: The experience of losing one’s train of thought or thought blockade, forgetfulness, and an inability to concentrate as well as in the past reported by menopausal women due to declining circulating estrogen levels as measured by the hormone replacement survey.11

Hot Flashes: Intermittent feelings of warmth spreading over the body, followed by sweating and exhaustion as reported by menopausal women due to declining hormone levels as measured by the hormone replacement survey.9

Mood Swings: Feelings of well-being alternating with irritability and emotional lability as experienced by menopausal women due to fluctuating hormone levels as measured by the hormone replacement survey.12

Night sweats: Profuse sweating during sleep at night followed by chills as a consequence of hot flashes secondary to fluctuating hormones in menopausal women as measured by the hormone replacement survey.13

Sleep problems: Insomnia or a disruption in sleep due to vasomotor symptoms secondary to decreasing hormone levels in menopausal women as measured by the hormone replacement survey.14

Vaginal dryness: A decrease in vaginal lubrication in menopausal women secondary to decreasing estrogen levels as measured by the hormone replacement survey.9

Instrument

The original survey tool, titled The Apothecary Shop of Arizona, was intended to measure the presence and severity of women’s menopausal symptoms before and after treatment and side effects experienced with compounded BHRT and synthetic conjugated equine estrogen and progestin HRT. Permission to utilize this tool was obtained from Kristy A. Vigesaa, PharmD, who developed the survey as part of her residency project at Midwestern University in Arizona (KA Vigesaa, Personal communication, June 19, 2006).3 The tool consists of 18 questions and was originally used to determine if compounded BHRT relieved the symptoms of menopause and tolerance to the medication (low incidence of side effects). Secondarily, the tool was also used to compare menopausal symptom relief and tolerability with compounded BHRT to previously used synthetic prescription HRT. In the survey, relief was measured by asking participants to circle menopausal symptoms they had prior to taking compounded BHRT and the level of severity (none, mild, moderate, severe, extreme) of the symptom before and after initiation of HRT. Side effects of compounded BHRT and synthetic prescription products were measured by asking participants to circle the side effects listed that occurred with compounded BHRT, and then those previously experienced with synthetic prescription products.

To establish content validity, Vigesaa submitted a blueprint of the survey to a panel of four experts who were selected based on their expertise in the areas of clinical pharmacy and research, instrument content and development and menopause education relevant to her study. The experts reviewed the blueprint to determine the appropriateness, accuracy, and representativeness of the selected items (KA Vigesaa, personal communication, March 11, 2007). The items in the survey were reviewed for the consistency in relationship to the studies primary and secondary purposes. Appropriate reading level was established using the Classroom Reading Inventory.

The survey described above was used for the study. Questions regarding menopausal symptoms relief and side ef­fects for participants who had previously used commercially available HRT and were now using BHRT and questions regarding satisfaction with customer service at the Apothecary Shop were removed. Three questions were added for the purpose of obtaining more general information from participants regarding their overall hormone symptom relief and how much the side effects of HRT bothered them or interfered with their daily lives.

Background information collected for this study included age, length of time on HRT, and the type of hormone formulation used. The survey also included questions about the participant’s reasons for initiating HRT, the symptoms they experienced before and after taking HRT, as well as side effects related to HRT. In addition, participants were asked to list any prescription medications and herbal/vitamin supplements they were taking since some medications such as selective serotonin reuptake inhibitors, anxiolytics, sleep aids, and some over-the-counter herbal remedies may relieve some menopausal symptoms.15,16 The hormone therapy survey included the variables shown in the table below.

TABLE 1: Hormone Therapy Survey Variables (Symptoms and Side Effects)

SYMPTOMS SIDE EFFECTS BACKGROUND VARIABLES
Hot flashes Breast tenderness Length of hormone therapy use
Night sweats Breakthrough bleeding Type of hormone therapy
Sleep problems Weight gain Additional hormones
Dry skin/hair Mood swings Form of hormone therapy
Vaginal dryness Bloating Reasons for taking hormone therapy
Foggy thinking Difficulty sleeping Other medicines
Mood swings Headaches Vitamin supplements
Decreased libido Fluid retention Herbal supplements
Other symptoms Upset stomach

Drowsiness

Leg pain

Other side effects

Age

Procedure

A list of all the possible brands of synthetic conjugated equine estrogen and/or progestin HRT were provided to pharmacists and the pharmacy technicians who were responsible for collecting prescriptions and dispensing medications at the front counter, so they gave surveys only to women meeting the inclusion criteria. The pharmacists or pharmacy technicians were responsible for distributing the packets containing the surveys and postage-paid envelopes addressed to the investigator, along with the consent letter inviting the women to participate. Also, if participants asked, they were instructed by the pharmacists or technicians that they had the option of completing the survey at the pharmacy and returning it to the pharmacists. Based on similar research in the past, data acquisition was expected to take approximately 6 to 8

weeks between the time needed to distribute 216 surveys and for the surveys to be returned to the investigator.3 The requisite number of surveys from the group one-bio was collected within this timeframe. However, due to the declining number of women using synthetic conjugated equine estrogen and progestin products, distribution of 108 surveys to the women in the group two-syn took an additional 18 weeks.17 The 15-item survey was estimated to take participants approximately 20 to 30 minutes during one data collection point. When returned, completed surveys were immediately stored in a locked file cabinet in the investigators home. Data were entered into the Statistical Package for the Social Sciences (SPSS 14.0, 2005) after all the surveys were reviewed for completeness.

Statistical Analysis

Prior to entering the data into the computer, the surveys were checked by the investigator for missing data, items to which the participant provided more answers then was required, and items for which the answer marked was unclear.8 There were a few surveys with only one missing value for each survey period these surveys were included in the statistical analysis for the study. The value 99 was entered into the SPSS to characterize missing values and 77 for “don’t know” for question five.

Demographic Data

A mean was reported for age (years) and duration (months) of HRT usage for both groups. Frequency (number of participants) was reported for those participants using the additional hormones dehydroepiandrosterone and testosterone in question one. In question one, participants had the option choices of dehydroepiandrosterone, testosterone, none, both, or don’t know. Frequencies were reported for the form (capsules/tablet, cream, suppository, vaginal cream) of HRT used in each group. In question three, participants circled all of the reasons why they initiated HRT, and these reasons are reported as proportions for each group in the Data Analysis and Interpretations section. Finally, in questions 14 and 15, participants were required to list other medicines, over-the-counter, and/or herbal supplements they were currently taking. Frequency of concurrent medications was calculated. Consequently, f-tests and Levene’s test were conducted between participants with concurrent medication usage and those who did not take concurrent medications to determine if significant differences exist between the two groups.19 An a priori [alpha] = 0.05 was set, which is the predetermined risk of making a type I error. In order to strengthen the meaning of the findings of this study, a power of .80 was used to lower the risk of making a type of II error. A power of .80 is the standard used when conduction a power analysis to determine sample size.8

Planned Analysis by 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?

Inferential statistical procedures using a two-sample t-test were used to measure the differences in each menopausal symptom relief between women currently using compounded BHRT compared to women currently using synthetic conjugated equine estrogen and/or progestin HRT.8 Relief from menopausal symptoms was measured at the ordinal-scale level. In order to measure relief, participants ranked the level of severity of their menopausal symptoms prior to HRT and at least one month after initiation of HRT in both group one-bio and group two-syn. Level of severity were ranked for each symptom as none, mild, moderate, severe, and extreme (scored 0 to 4). In addition, a paired difference t-test was used to determine if there was significant improvement within each group for each menopausal symptom. A two-sample t-test was used to determine if one group offered more significant relief from menopausal symptoms than the other group. To measure severity and occurrence of menopausal symptoms, frequencies and means were obtained for each group. Frequency was obtained for each menopausal symptom rated as moderate to extreme before HRT and then after HRT. The difference in the means were obtained using a severity scale of O (no symptoms) to 4 (extreme) for before HRT and after HRT for each group. Question 10 asked participants to rank overall relief of all menopausal symptoms; no relief, a little relief, moderate relief, a lot of relief, or complete relief (scored O to 4). Relief of menopausal symptoms was then calculated based on results from the two-sample t-test.

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

A comparison of the most commonly reported side effects of compounded BHRT and conjugated equine estrogen and/or progestin HRT were discussed as frequencies. Side effects were measured at the nominal level with numerical values assigned for coding purposes and data entry only. A two-sample t-test was used to analyze results from questions 12 and 13. In questions 12, participants were asked to rank the level of how much the side effects of HRT bothered them. In question 13, participants were asked to rank how much side effects interfered with their daily life. Participants ranked the level of how much their HRT bothered them or interfered with their daily lives as (scored O to 4):

0 = Not at all
1 = Severely
2 = Somewhat
3 = Extremely
4 = Moderately

Severity of side effects was measured at the ordinal-scale level.

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References

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  3. Vigesaa KA, Downhour NP, Chui MA et al. Efficacy and tolerability of compounded bioidentical hormone replacement therapy. IJPC 2004; 8(4): 313-319.
  4. Deleruyelle L J. 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. IJPC 2016; 20(5):359-364.
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  6. Institute for Digital Research and Education UCLA. G* Power Data Analysis Examples: Power Analysis for Two-group Independent Sample t-test. [IDRE Website.] Available at: www.ats.ucla.edu/stat/gpower/indepsamps. htm. Accessed March 15, 2007.
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  10. The North American Menopause Society. Menopause Practice Textbook. Menopause Practice: A Clinician’s Guide. 5th ed. [NAMS Website.] Available at: www.menopause. org.publications/profesional-publications/-i-menopause. practice-i-menopause/-i-menopause-practice-i-textbook. Accessed January 20, 2007.
  11. Warga CL. Menopause and the Mind: The Complete Guide to Coping with the Cognitive Effects of Perimenopause and Menopause -Including Memory Loss, Foggy Thinking and Verbal Slips. New York, NY: Simon & Schuster, Inc.; 1999: 1-375.
  12. Cutter B, Vail J. Natural or bioidentical hormone replacement: What makes the difference? An interview with Christopher B. Cutter, MD. IJPC 2003; 7(1): 24-26.
  13. The Mayo Clinic. Womens Health. Menopause. [The Mayo Clinic Website.] Available at www.mayoclinic.comhealth/ menopause/D500119/DSECTION =2. Accessed January 20, 2007.
  14. Penckofer S, Schwertz D. Hormone replacement therapy: Primary and secondary prevention. J Cardiovasc Nurs 2001; 15(3): 1-25.
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  16. Soares CN, Poitras JR, Prouty J. Effect of reproductive hormones and selective estrogen receptor modulators on mood during menopause. Drugs Aging 2003; 20(2): 85-100. Francisco L. Is bio-identical hormone therapy fact or fairy tale? Nurse Practice 2003; 28(7 Pt 1): 39-44.
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