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The Comparison of Bleeding Patterns With High-Dose and Low-Dose Hormone Replacement Therapy in Postmenopausal Women

Posted on: Thursday, 28 October 2004, 03:00 CDT

Key words: CONJUGATED EQUINE ESTROGENS, CEE, MEDROXYPROGESTERONE ACETATE, MPA, BLEEDING PATTERN

Abstract

Our objective was to compare vaginal bleeding patterns with lower doses of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), in a randomized, double- blind, placebo-controlled trial. A total of 112 healthy, postmenopausal women were divided into three groups. Group A received CEE 0.625 mg/day plus MPA 2.5 mg/ day; group B received CEE 0.3 mg/day, plus MPA 1.25 mg/day; and another group received placebo. All medications were continued for 13 months and bleeding data were analyzed in each group. The percentage of patients who experienced no bleeding in cycle one was 45.2% in group B. These values were significantly greater than the figure for group A (18.2%) and lower than in the placebo group (66.7%). A linear trend between time since menopause and cumulative anienorrliea was observed in cases in group B and the placebo group in all cycles (p < 0.05). This finding was significant in only cycle 13 in group A. In conclusion, a higher rate of amenorrhea was observed with a lower-dose regimen of CEE/MPA, which may be the appropriate regimen.

INTRODUCTION

Hormone replacement therapy (HKT) in postmenopausal women has been associated with a significant relief of postnicnopausal symptoms and particularly a decreased risk of heart disease and improved exercise capacity . Postmenopausal HRT has been used for more than 25 years and combined estrogen-progesterone therapy has been widely used for at least the past 15 years2. One of the most complex and difficult health-care decision that women face is whether to use postmenopausal HRT3.

Despite the proven benefit of HRT, beliefs about side-effects and concerns about safety hinder acceptance of HRT among patients and even in some recent research4-6. The average women in the USA live nearly 30 years after menopause, a phase of life that is often accompanied by an increasing burden of chronic diseases3. HRT, once prescribed primarily for the relief of vasomotor symptoms, is increasingly viewed as a possible strategy for preventing or delaying some of these chronic diseases3.

The most commonly prescribed HRT regimen in the USA is a continuous combined regimen of conjugated equine cstrogens (CEE) 0.625 mg/day/ medroxyprogesterone acetate (MPA) 2.5 mg/day7 This regimen produces amenorrhea in many women in the first years of treatment8,9. However, irregular bleeding is not uncommon and despite the benefits and convenience of the continuous combined regimen, compliance with HRT is reported to be low8. It has been suggested that lower doses of HRT may reduce side-effects such as endometrial bleeding4,7,10,11.

This study was conducted to determine the effects of lower doses of estrogen and progestin on vaginal bleeding patterns in postmenopausal women.

PATIENTS AND METHOD

A double-blind randomized placebo-controlled study was conducted in gynecologic clinics of Shiraz University of Medical Sciences during a 13-month period. The protocol was reviewed and approved by the Ethical Committee and the Institutional Review Board at our university (Approval Number: 81-1541).

Patients

The study population included 112 healthy postmenopausal women who gave written informed consent prior to the initiation of the study. Each subject had an intact uterus and her last menstrual cycle was at least 6 month previously. The level of follicle stimulating hormone (FSH) in all cases was greater than 30 IU/1. Pre- study screening for all women included a complete medical and physical examination to ensure that all exclusion criteria were met. Exclusion criteria included abnormal uterine bleeding (before starting the study), abnormal transvaginal sonographic findings (endometrial thickness of ≥ 5 mm), an abnormal Pap smear or any type of abnormal sonographic findings which needed more investigation, any history of active gallbladder or liver disease, or any condition that was a contraindication to the use of estrogen therapy (such as active thrombophlebitis, cerebrovascular accident, history of uncontrolled hypertension or usage of drugs that influence estrogen metabolism).

Study design

Following the screening tests, in a double-blind design, women were randomly divided into three groups. In group A, CEE 0.625 mg/ day plus MPA 2.5 mg/day was given, while CEE 0.3 mg/day plus MPA 1.25 mg/day was given to cases in group B. The control group received only placebo. A computer-generated table determined randomization. Patients were instructed to take two tablets once daily. The pills all looked alike, including the placebo. The Department of Pharmacology of Shiraz University of Medical Sciences supplied both the medication and the placebo. Each patient was instructed to keep a daily diary card to record the dates on which they took or missed their medication. These cards were also used for recording any episode of vaginal bleeding. For analysis of data, 'amenorrhea' was defined as the absence of any vaginal bleeding or spotting in the entire period of the study.

Statistical analysis

The data were analyzed according to individual cycles and cumulatively. The cumulative rate of amenorrhea was defined as the proportion of women who experienced consecutive cycles of amenorrhea for a given period of time (e.g. cycles 1-13, cycles 7-13). Women who did not record taking study medication and filled out the days of their cycles incompletely were excluded from the analysis.

Cumulative amenorrhea was analyzed between treatment groups and placebo for cycles 1-13, cycles 7-13 and cycle 13 by using the Fisher exact test for paired comparison (α = 0.05). Subgroup analysis of cumulative amenorrhea was performed by using two categories: ≤ 3 and > 3 years since menopause. The McNemar test was used to evaluate the significant change in the pattern of bleeding for each participant for cycles 1-13. A Cochran- MantelHaenszel test was also used to assess the linearity of the relationship between cumulative amenorrhea and years since menopause.

RESULTS

Among the 112 women who participated in this study, 18 women were excluded for the following reasons: 11 refused to continue the treatment cycle because of vaginal bleeding and/or spotting in the first month of the treatment cycle (four women from the placebo group and seven women from group A); and seven did not fill out the dairy cards completely. Therefore, 33, 31 and 30 women were included in groups A, B and placebo, respectively. The characteristics of all participants are depicted in Table 1. The mean age of all study groups was 51.87 0.35 years, the mean age since menopause was .55 0.1 years and the mean parity was 3.36 0.28.

As shown in Table 2, the highest rate of cumulative amenorrhca in cycle 13 was observed in the placebo group (93.4%). This figure was 09.7% and 87.1% for groups A and B, respectively. Table 2 also depicts the frequency and percentage of patients in each treatment group with cumulative amenorrhca for cycles 1-13, 713 and 13. The group with the lower dose of CEE/MPA (group 13) had a significantly higher rate of cumulative amenorrhea than cases in group A (CEE 0.625 mg/day plus MPA 2.5 mg/ day) in all treatment cycles (p < 0.03), but it was significantly less than the placebo group (p < 0.05).

The cumulative rates of amenorrhea in participants who were ≤ 3 and > 3 years postmenopause are shown in Table 3. There were no differences in the rate of cumulative amenorrhea between treatment groups and placebo in the groups at ≤ 3 years postmenopause (p=0.09, 0.2 and 0.4 in cycles 1 13, 7-13 and 13, respectively). Among the groups at > 3 years postmenopause, there were significance differences for cycles 1-13 and 7-13 between group A and the placebo group at the same cycle. Also, there were significant differences in the rate of amenorrhea in each study group between cycles 1 13 and cycle 13 (cumulative rate of amenorrhea were higher in cycle 13 of each study group) (Table 3). Thus, all treatment groups as well as the placebo group demonstrated a significant linear trend at cycles 1-13 (p < 0.05).

Table 1 Characteristics of patients for cumulative analyses of bleeding patterns

Table 2 Patients with cumulative amenorrhea by treatment and placebo

DISCUSSION

Various studies have assessed the efficacy of lowdose HRT in the prevention of rnenopausal symptoms 12-15. The Women's Health Osteoporosis Progestin Estrogen Study (HOPE) was the first large randomized trial for evaluation of the effects of lowdose HRT on postmenopausal symptoms4,7,11 Several doses of CEE/MPA were evaluated and it was finally concluded that a lower dose of HRT could produce the same results on menopausal symptoms as the traditional dose. An earlier study suggested that lower doses of estrogen replacement therapy may reduce side-effects, such as endometrial bleeding. The population of that study was smaller to that of the HOPE. In the present study we also found that the highest rates of cumulative amenorrhea were in both the placebo group and women who had used a lower dose of HRT.

Table 3 Patients with cumulative amenorrhea, by treatment group and years since menopause

The ratio of estrogen to progestin may be an important determinant of vaginal bleeding. The need for adding a progestin for prevention of the occurrence of endometr\ial cancer with a lower dose of CEE (0.3 mg) is obvious. Cushing and colleagues in 1998(16) in a case-control study corroborated the endometrial effects of 0.3 mg/day of CEE. These authors reported that the risk of endometrial cancer was increased in women who used this low-dose estrogen without progestin. One year later (1999), Weiderpass and co- workers17 confirmed the protective effect of the addition of progestin even in low-dose estrogen. Therefore, in our study we also added progestin to all regimens and used a combined method of HRT.

In another study, Xing and asociates18 compared the two different dosages of CEE and MPA in postmenopausal hormone therapy. They concluded that there was a higher rate of vaginal bleeding in the groups who used CEE at 0.625 mg/day than in those using CEE at 0.3 mg/day. This was confirmed by Simon and colleagues19.

The present study showed that in all groups who were > 3 years postmenopause, there was a higher rate of cumulative amenorrhea by cycle 13 than in women, who were ≤ 3 years postmenopause. With all regimens of HRT in women at > 3 years or ≤ 3 postmenopause, there was some improvement in the rate of bleeding, but this rate was higher in patients who were > 3 years postmenopause (42.5% versus 27.3% in group A, and 38.7% versus 48.3% in group B). Therefore, in contrast to the women's HOPE study, we found a consistent relationship between the rate of cumulative amenorrhea and years since menopause in both groups (CEE 0.625 mg/ day plus MPA 2.5 mg/day, and lower doses of CEE/MPA). Archer and Picar, in a previous study, reported similar findings to ours in women taking CEE 0.625 mg/day plus MPA 2.5 mg/day in a continues daily combined regimen20.

Although in the present study we did not consider the dose of progestin, the observation of similar bleeding profiles in previous studies have shown a dose-response relationship between bleeding and progestin dose, with a higher dose resulting in less bleeding2,9,21. Archer and colleagues21 studied three doses of norethindrone acetate administrated with 17β-estradiol, and the Menopause Study Group reported a dose-response relationship when higher doses of CEE (0.625 mg) and MPA (2.5 and 5 mg) were used. An important determinant of vaginal bleeding may be the ratio of estrogen to progestin, which was shown in the HOPE study7. Those authors suggested that a lower estrogen dose could be opposed by a lower progestin dose for optimal reduction of vaginal bleeding. As mentioned previously in our study, the dose of CCE was concurrently decreased with the progestin dose. Thus, the effect of changes in the dose of progestin versus the fixed dose of estrogen could not be evaluated, and further research is needed.

In conclusion, low doses of estrogen and progestin produced higher rates of amenorrhea than the traditional doses, and this higher rate of amenorrhea become more significant with time.

ACKNOWLEDGMENTS

We thank Dr F. Handjani for his revision of this article. The protocol was reviewed and approved by the Ethical Committee and the Institutional Review Board at our university (Approval Number: 81- 1541).

REFERENCES

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2. Glazier MG, Bowman MA. A review of the evidence for the use of phytoestrogens as a replacement therapy. Arch Int Med 2001;161:1161- 71

3. Manson JE, Martin KA. Post menopausal hormone replacement therapy. N Engl J Med 2001;345:34-40

4. Utian WH, Shoupe D, Bachmann G, et al. Relief of vasomotor symptoms and vaginal atrophy with lower dose of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001;75: 1065-75

5. Anderson G-L, Judd HL, Kaunitz AM, et al. Effect of estrogen plus progestin on gynecologic cancer and associated diagnostic procedures: the Women's Health Initiative randomized trial. J Am Med Assoc 2003;290:1739-49

6. Janssen TL, Rosser WW, Weel CV. Breast cancer and hormone replacement therapy. Lancet 2003; 362:1332

7. Archer DF, Dorin M, Lewis V, et al. Effect of lower dose of conjugated equine estrogen and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril 2001;75:1080-7

8. Hammond CB. Women's concerns with hormone replacement therapy - compliance issues. Fertile Steril 1994;62:157S-60S

9. Archer DF, Pickar JH, Bottiglioni F. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Menopause Study Group. Obstet Gynecol 1994:83:686-92

10. Ettinger B. Personal perspective on low-dose estrogen therapy for postmenopausal women. Menopause 1999;6:273-6

11. Pickar JH, Yeh IT, Wheeler JE, et al. Endometrial effects of lower doses of conjugated equine estrogen and medroxyprogesterone acetate. Fertil Steril 2001; 76:25-31

12. Gambacciani M, Ciaponi M, Cappagli B, et al. Effects of lower- doses conjugated estrogen and medroxyprogesterone acetate on menopausal symptoms, body weight, bone density and metabolism in postmenopausal women. Am J Obstet Gynecol 2001; 185:1180-5

13. Weiss SR, Ellman H, Dolker M. A randomized control trial of four doses of transdermal estradiol for preventing postmenopausal bone loss. Obstet Gynecol 1999;94:330-6

14. Welnstein L, Bewtra C, Gallagher JC. Evaluation of a continuous combined low-dose regimen of estrogen-progestin for treatment of the menopausal patient. Am J Obstet Gynecol 1990;162:1534-42

15. Genazzani AR, Gambacciani M. Hormone replacement therapy: the perspective for the 21st century. Maturitas 1999;32:11-7

16. Cushing KL, Weiss NS, Voigt LF, et al. Risk of endometrial cancer in relation to use of low-dose, unopposed estrogens. Obstet Gynecol 1998;91:35-9

17. Weiderpass E, Baron JA, Adami HO, et al. Low potency estrogen and risk of endometrial cancer: a case-control study. Lancet 1999;353:1824-8

18. Xing S, Wu Y, Liu J, et al. A comparison of two different dosages of conjugated equine estrogen in continuous combined hormone replacement therapy with progestin. Chin Med J (Engl) 2003;116: 584- 7

19. Simon JA, Liu JH, Speroff L, et al. Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low dose ethinyl estradiol therapy versus combined conjugated equine estrogen and medroxyprogesterone acetate therapy. Am J Obstet Gynecol 2003;188:92-9

20. Archer DF, Picar JH. Hormone replacement therapy: effect of progestin dose and time since menopause on endometrial bleeding. Obstet Gynecol 2000;96:899-905

21. Archer DF, Dorm MH, Heine W, et al. Uterine bleeding in postmenopausal women on continuous therapy with estradiol and norethindrone acetate. Endometrium Study Group. Obstet Gynecol 1999; 94:323-9

T. Kazerooni and J. Zolghadri

Department of Obstetrics and Gynecology, Shiraz University of Medical Sciences, Shiraz, Iran

Correspondence: Dr T. Kazerooni, P.O. Box: 71345-1111, Shiraz, Iran Fax No: +98-711-6288427. E-mail: kazeront@sums.ac.ir

Copyright CRC Press Aug 2004

Source: Gynecological Endocrinology

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