Menopausal Symptom Relief and Side Effects – Part 3

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 3

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.

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

Part 3: The results and conclusion of this study.

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.

Results

Data Analysis and Interpretations

A convenience sample of women, age 35 and older, were recruited for this study to examine the differences in reported relief of menopausal symptoms and side effects experienced by women using compounded bioidentical hormone replacement therapy (BHRT) as compared to women using synthetic conjugated equine estrogen and/or progestin hormone therapy (HRT). Of the 216 surveys distributed (108 for each group), 123 were completed, which included 70 surveys from women using compounded BHRT (group one-bio) and 53 from women using synthetic conjugated equine estrogen and/or progestin HRT (group two-syn) A minimum response rate of 49% was proposed for this study, based on a similar research study conducted by¹ in which a total of 160 surveys were distributed; 78 surveys (49%,) were completed a11d returned over an eight-week period. In this study, Group one-bio had a response rate of 64.8% by the end of eight weeks., however, group two-syn required an additional 16 weeks in order to obtain a response rate of 49.1 % due to the declining number of women using conjugated equine estrogen and/or progestin HRT.² The overall response rates for both groups was 56.9%. Therefore, the minimum response rate of 49% was met for group two-syn and was exceeded for group one-bio.

Inferential and descriptive statistical procedures, including a paired difference t-test. two-sample t-test, f-test (ie., percentage, mean. standard de­viation, frequency), were run on Statistical Package for the Social Sciences (SPSS.14.0, 2005).

Sample Characteristics

Women in group one-bio were a mean age of 55.4 7 years, and women in group two-syn were a mean age of 59.43 years. A two-sample t-test revealed a significant difference in the means of the ages between group one-bio and group two-syn (t = -2.481, P = .013). Bonferroni’s correction (.0025) suggests the difference in the means of the ages between the two groups was not significant. Women in group one-bio had been taking HRT for a mean of 50.23 months (S.D. = 70.741). with a minimum of four months and a maximum of 360 months. Women in group two-syn had been taking HRT for an average of 145 months (S.D. = 123.758), with a minimum of 3 months and a maximum 420 months. A two-sample t-test revealed a significant difference in the mean duration of HRT usage between groups (t = -4.992. P =<.001). Women were also asked to indicate whether they used dehydroepiandrosterone (DHEA), testosterone or both, along with the type and form of HRT used. Women in group two-syn did not use additional HRT (i.e., DHEA, testosterone, or both products) as frequently as the women in group one-bio­­ (see Table 1). The topical cream form of the compounded BHRT which was applied to areas on the body where the skin is thin (e.g., inner arms, inner thighs, abdomen), was the most popular (n = 54,77%). Less than 25% of the participants used compounded BHRT in capsule form (n = 16, 22.9%). The form of HRT used most frequently by women in group two-syn was the opposite of the above: (n = 49, 92.5%) used capsules, and only three (4.2%) used vaginal cream. One person (1.9%) in group two-syn did not report what form of HRT they used.

Reason for initiating HRT and percentages are presented in Table 2. For both groups, the two most common reasons for initiation HRT were 1) relief of menopausal symptoms and 2) recommendation from a nurse practitioner of physician. Having a hysterectomy was the third most common reason for women initiating synthetic conjugated equine estrogen and/or progestin HRT. Both groups also ranked the prevention of bone loss as a significant reason for initiating HRT.

Research Question 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?

The participants reported a high occurrence of menopausal symptoms before beginning HRT of any type (Table 1). The participants who eventually initiated use of the compounded BHRT experienced all of the symptoms more frequently than did the women who used the synthetic conjugated equine estrogen and or progestin HRT, but for both groups the menopausal symptoms were moderate to severe. One month and more after initiation of HRT, both groups had dramatic decreases in the occurrence of all menopausal symptoms with the exception of dry skin for group two-syn. The women in group two-syn reported a greater increase in symptoms occurrence for the menopausal symptom of dry skin and hair.

The participants were also asked to rate the severity of their symptoms on a Likert scale in which zero = experiencing no symptoms and four = experiencing extreme symptoms. Frequencies and percentages for symptom severity before and after initiating HRT within each group are shown in Table 1.

Severity of each symptom was significantly decreased in both groups. The one exception to the symptom relief was dry skin among those women in group two-syn. This symptom actually worsened slightly after initiation of HRT (Table 3).

Eight two-sample t-tests were used to measure the differences in menopausal symptom relief between women currently using compounded BHRT compared to women currently using conjugated equine estrogen and/or progestin HRT (Table 4). There were statistically significant differences noted between groups for the relief of five menopausal symptoms:

1. Sleep problems
2. Dry skin/hair
3. Foggy thinking
4. Decreased sex drive
5. Weight gain

Bonferroni’s procedure would require a more stringent alpha of 0.0025, which suggests that the t-tests for the following three symptoms were not significant:

1. Foggy thinking
2. Decreased sex drive
3. Weight gain

However, the women in group one-bio reported more relief of menopausal symptoms and less weight gain than the women in group two-syn. In fact, the women in group two-syn reported worsening dry skin/hair after starting treatment, with a mean of -.10. The -.10 refers to the average reported increase in the menopausal symptom severity scale of O to 4, none to extreme, respectively. However, results from the two-sample t-test suggest there were no statistically significant differences noted between groups for the relief of menopausal symptoms including the following:

1. Acne
2. Anxiety
3. Depression
4. Fatigue
5. Hot flashes
6. Migraine
7. Mood swings
8. Nausea
9. Night sweats
10. Vaginal dryness

It should be noted that the following symptoms were reported as “other symptoms”:

1. Acne
2. Anxiety
3. Depression
4. Fatigue
5. Migraine
6. Nausea
7. Weight gain

However, the number of women with the “other” symptoms was a very small and net enough to meet statistical assumptions. Some of the women in group one-bio reported the following symptoms. Also shown are the number of participants who experienced them:

Acne = 1
Depression = 3
Fatigue = 5
Migraine = 4
Nausea = 1

None of the women in group two-syn reported the symptoms listed above, however, both groups reported weight gain (9) and anxiety (6) under “other symptoms”.

Both groups rated the overall relief of all of their menopausal symptoms “together” after initiating HRT on a scale of 0 to 4:

No relief = 0
Little relief = 1
Moderate relief = 2
Lot of relief = 3
Complete relief = 4

A two-sample t-test was used to calculate the difference in the means. For overall relief of menopausal symptoms after initiating HRT, the mean for group one-bio was 2.70 and the mean for group two-syn was 2.00. Results of t-test (t = 4.045, P = 0.000) revealed a statistically significant difference between groups with more overall relief of menopausal symptoms noted in group one-bio.

Research Question 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?

The most commonly reported side effects by women in group one-bio using compounded BHRT were (Table 5):

Difficulty sleeping (37%)
Weight gain (35%)
Breast tenderness (28.6%)
Bloating (27.1%)

For the women in group two-syn, the most commonly reported side effect were:

Weight gain (67.9%)
Bloating (56.6%)
Breast tenderness (47.2%)
Headaches (43.4%)

Overall, the women in group one-bio experienced fewer side effects and they occurred less frequently.

Participants were asked to rate how much the side effects of HRT bother them (question 12) and interfered with their daily lives (question 13) on a scale of 0 to 4 (not at all to extremely) (Table 6). Results revealed a mean of .61 for group one-bio and 1.55 for group two-syn, indicating a significant difference between groups t-test results were -6.73 for question 12 and -3.997 for question 13. These results suggest that the women in group one-bio were less bothered by the side effects of their HRT than those women in group two-syn. Participants in both groups reported minimal interference in their daily life from the side effects of HRT. Group one-bio reported less interference in their daily lives than group two-syn and there was a significant difference between the two groups.

Additional Analysis

Both groups listed prescription medications as well as over-the-counter (OTC) and herbal products they were taking. Prescription medications were used for the following conditions:

• Allergic rhinitis
• Asthma
• Coronary artery disease
• Constipation
• Depression
• Gastroesophageal reflux disease
• Generalized anxiety disorder
• Hyperlipidemia
• Hypertension
• Hypothyroidism
• Insomnia
• Migraines
• Osteoarthritis
• Osteoporosis
• Seizure disorder
• Urinary stress incontinence

In group one, nine women reported using antidepressants, six used anxiolytics and eight used sleep aids. Six women reported using antidepressants in group two-syn, six used anxiolytics and four used sleep aids. There were numerous OTC and herbal supplements listed in both groups. One woman in group one-bio reported using Estroven, and two reported using primrose oil. In group two-syn, two women reported using primrose oil.

F-tests were conducted to determine if those women taking concurrent medications as compared to those who were not on concurrent medications differed in their report of menopausal symptoms relief after initiating HRT.³ In group one-bio, f-tests revealed there were no significant differences between women taking concurrent medications and those who did not while using HRT. In group two-syn f-tests results suggest there, were no significant differences between women on concurrent medication usage and those who were not while on HRT, except for the way women responded on the survey to the question about sleep difficulties (Table 7). As a result, an additional statistical test (Levene’s test) was conducted on group two in order to determine if there were differences in women who were concurrently take medications and those who were not in terms of reporting sleep problems. Results of the Levene’s test suggested that there were no significant differences between variances for women on concurrent medications and women who were not on concurrent medications and the way they responded in terms of reporting sleep difficulties on the survey.

Discussion

Introduction

In the past several years, more women have been using compounded BHRT rather than synthetic conjugated equine estrogen and/or progestin HRT for menopausal symptoms due to the adverse side effects of the latter treatment.^4,5 However, due to the small number of studies completed to determine the effectiveness and side-effect profile of compounded BHRT. many nurse practitioners are reluctant to prescribe them. Results of this study provide further evidence for the efficacy and low side-effect profile of compounded BHRT.

Sample Characteristics

Previous studies^6-11 have reported that the participants of those studies were Caucasian and were well educated from higher socioeconomic backgrounds. Thus, it is assumed, based on the aforementioned studies, that the participants for this study were Caucasian and well educated from higher socioeconomic backgrounds and therefore data were not collected on race, educational level, or socioeconomic background. The mean age for women In Group one-bio was 55.47 years, with a mean duration of HRT usage of 50.23 months. The mean age for women in group two-syn was 49.3, with a mean duration of HRT usage of 145 months. A two-sample t-test with Bonferonni’s correction was conducted that suggests there was not a statistically significant difference between groups with regards to the age of the women. However, there was a statistically significant difference in duration of HRT usage between groups with two-syn having used HRT for a longer duration. The longer duration HRT noted in group two-syn was not surprising based on the review of the literature that suggests conjugated equine estrogen and/or progestin HRT has been the traditional treatment for menopausal symptoms for the past several decades.⁴ The majority of women in group one-bio used HRT in the form of topical cream while the group two-syn used the more traditional capsule form. Both groups reported that the most common reason for initiating HRT was for the relief of menopausal symptoms.

Instrument Reliability and Validity

The tool for this study was chosen based on its ease of use, demonstrated validity and reliability for the measurement of the presence and severity of women’s menopausal symptoms before and after HRT, and side effects experienced with compounded BHRT compared to previously used commercially available synthetic HRT. Vigesaa et al, who designed the original survey, made the comment in her published paper that “the next step in this process would be to use a similar instrument to survey patients taking commercially available products separately from those taking compounded bioidentical hormones.¹ In this study, albeit with some alterations in the survey and study design, the process was taken to the next level by surveying two groups of women on the two different HRT products in order to reinforce her findings and strengthen the findings from this study. However, in order to determine reliability of the survey tool used in this study, Cronbach’s alpha coefficient was carried out. Based on the operational HRT survey variables (symptoms and side effects). Cronbach’s alpha coefficient was computed using SPSS (14.0, 2005), resulting in a value of .766, which suggests an acceptable level of reliability for the survey tool used in this study.¹²

Additional Analysis

In order to ensure women’s concurrent medication usage did not affect the outcomes of this study, women listed all prescription, OTC, and herbal remedies they were concurrently taking. Some concurrent medications, specifically anti-depressants, anxiolytics, sleep aids, and some herbal remedies, may help to alleviate some menopausal symptoms such as hot flashes, mood swings, and insomnia. Some antidepressants, such as selective serotonin re-uptake inhibitors (SSRI’s), may help to alleviate hot flashes and mood swings by affecting serotonin levels. In addition, anxiolytics and sleep aids may help to alleviate mood swings an insomnia.¹⁰ Some of the OTC herbal remedies such as Estroven and primrose oil can also help to alleviate menopausal symptoms. A total of 26 women in group one-bio and 18 women a group two-syn were taking these products. F-tests suggest that there were no statistically significant differences between women concurrently on medications and those who were not in group one-bio. In group two-syn, there were no statistically significant differences noted between women concurrently on medications and those who were not, with the exception of how women responded on the survey to sleep problems. However, further statistical analysis using Levene’s test revealed there were no statistically significant differences for women in group two-syn who were concurrently taking medications and those who were not with regard to their response to the survey questions referencing sleep problems. Results suggest that women’s concurrent medication usage combined with the compounded BHRT or synthetic conjugated equine estrogen and/or progestin did not appear to have a synergistic effect and, therefore, did not influence the outcome of this study. The results of this study are similar to those of the study by Vigesaa et al, suggesting that there were no significant differences no did in their study between women on concurrent medications and those who were not in how they responded to the survey items.¹⁰ Therefore, women on concurrent medications were included in the study by Vigesaa et al.

Study Limitations

Limitations to the study included nonrandom sampling: survey distribution took place at the pharmacy counter of two specific pharmacies which could imply a problem of selection bias. Another possible weakness of this study may lie with the inclusion criteria: women who were currently taking HRT for at least one month with no upper time limits. Women taking HRT for long periods of time may have trouble with recall. For example, a woman who has been taking HRT for 20 years may have trouble recalling the effectiveness of her menopausal symptom relief or lack thereof. Additionally, women were not asked if they had previously taken HRT before they were surveyed about their current use of compounded BHRT or synthetic conjugated equine estrogen and/or progestin HRT. The results from this study may have been affected if women had been asked if they switched HRT products from compounded biological to synthetic conjugated equine estrogen and/or progestin, or the reverse situation. Another limitation was the small number of women reporting “other symptoms.” In group one-bio for “other symptoms” only three reported the following:

Depression = 3
Migraine = 4
Acne = 1
Fatigue = 5
Nausea = 1

Both groups reported weight gain (9) and anxiety (6), which may have affected generalizability of the findings. Lastly, missing values can be a problem in surveys that are returned by mail. However, the missing data rates for this study are very low and the missing values were assumed to be randomly distributed.

Implications for Nursing Practice

Part 2 discussed the significance of this study to nursing. The results from this study suggest that compounded BHRT was more effective at relieving the symptoms of menopause, with a lower incidence of side effects, than synthetic conjugated equine estrogen and/or progestin HRT. The information obtained from this study can be useful to nurse practitioners who are unfamiliar with compounded BHRT when counseling patients on various HRT products. Nurse practitioners can use the findings from this study and previous research to lay out the pros and cons of both types of HRT so the patients can make informed decisions.

References

1. Vigesaa KA, Downhour NP, Chui MA et al. Efficacy and tolerability of compounded bioidentical hormone replacement therapy. IJPC 2004; 8(4): 313-319.
2. 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.
3. Porkess R. Collins Web-linked Dictionary Statistics. New York, NY: HarperCollins; 2005.
4. Francisco L. Is bio-identical hormone therapy fact or fairy tale? Nurse Practice 2003; 28(7 Pt 1): 39-44.
5. Santoro F. Satisfaction of patients using bioidentical hormones for hormone replacement therapy. IJPC 2002; 6(5): 377-378.
6. Kjersti Bakken 1, Anne Elise Eggen, Eiliv Lund (2004) Side-effects of hormone replacement therapy and influence on pattern of use among women aged 45-64 years. The Norwegian Women and Cancer (NOWAC) study 1997. Acta Obstet Gynecol Scand . 2004 Sep;83(9):850-6.
7. Davis A, Gilbert K, Misiowiec Pet al. Perceived effects of testosterone replacement therapy in perimenopausal and postmenopausal women: An Internet pilot study. Health Care Women Int 2003; 24(9): 831-848.
8. E R Lenz 1, L C Pugh, R A Milligan et al. The middle-range theory of unpleasant symptoms: an update. ANS Adv Nurs Sci . 1997 Mar;19(3):14-27.
9. Fitzpatrick LA, Pace C, Wiita B. Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: A cross-sectional survey. J Womens Health Gend Based Med 2000; 9(4): 381-387.
10. Anne M McGinley. Health beliefs and women’s use of hormone replacement therapy. Holist Nurs Pract . Jan-Feb 2004;18(1):18-25.
11. Narisa Y Holt-Waldo, Kenna Stephenson. The lived experience of perimenopausal and menopausal women undergoing treatment with bioidentical human hormones. Int J Pharm Compd . Jul-Aug 2007;11(4):292-6.
12. Burns N, Grove SK. The Practice of Nursing Research: Conduct, Critique, and Utilization. 5th ed. St. Louis, MO: Elsevier/Saunders; 2005.
13. Penckofer S, Schwertz D. Hormone replacement therapy: Primary and secondary prevention. J Cardiovasc Nurs 2001; 15(3): 1-25.
14. Sandra Lookinland, Renea L Beckstrand. HRT: decide based on the evidence. Nurse Pract. 2003 Sep;28(9):46-54.
15. Jose Ness, Wilbert S Aronow, Erin Newkirk, Deanna McDanel. Use of hormone replacement therapy by postmenopausal women after publication of the Women’s Health Initiative Trial. J Gerontol A Biol Sci Med Sci . 2005 Apr;60(4):460-2.
16. L Thunell, E Stadberg, I Milsom, L A Mattsson. A longitudinal population study of climacteric symptoms and their treatment in a random sample of Swedish women. Climacteric . 2004 Dec;7(4):357-65.
17. Karin H. Humphries, Sabrina Gill. Risks and benefits of hormone replacement therapy: The evidence speaks. CMAJ. 2003 Apr 15; 168(8): 1001–1010.
18. Jörgen Nathorst-Böös, Maria Jarkander-Rolff, Kjell Carlström, Angelique Flöter, Bo von Schoultz. Percutaneous administration of testosterone gel in postmenopausal women–a pharmacological study. Gynecol Endocrinol . 2005 May;20(5):243-8.
19. Helene B Leonetti, Jennifer Landes, David Steinberg, James N Anasti. Transdermal progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med . Nov-Dec 2005;11(6):36-8.
20. Agnès Fournier, Franco Berrino, Françoise Clavel-Chapelon. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat . 2008 Jan;107(1):103-11.
21. I Rudolph, E Palombo-Kinne, B Kirsch, U Mellinger, H Breitbarth, T Gräser. Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression. Climacteric . 2004 Sep;7(3):301-11.
22. O Cohen, S Vinker, J Yaphe, E Kitai. Hormone replacement therapy and WONCA/COOP functional status: a cross-sectional population-based study of women in Israel. Climacteric . 2005 Jun;8(2):171-6.
23. J Montplaisir, J Lorrain, R Denesle, D Petit. Sleep in menopause: differential effects of two forms of hormone replacement therapy. Menopause . Jan-Feb 2001;8(1):10-6.
24. Kenna Stephenson, Pierre F Neuenschwander, Anna K Kurdowska, Barbara Pinson, Carol Price. Transdermal progesterone: effects on menopausal symptoms and on thrombotic, anticoagulant, and inflammatory factors in postmenopausal women. Int J Pharm Compd. Jul-Aug 2008;12(4):295-304.
25. Jason Yen-Ping Ho, Ming-Jer Chen, Wayne Huey-Herng Sheu, Yu-Chiao Yi, Andy Chi-Wei Tsai, Hwa-Fen Guu, Esther Shih-Chu Ho. Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women. Hum Reprod . 2006 Oct;21(10):2715-20.