Journal List > J Menopausal Med > v.19(3) > 1092677

J Menopausal Med. 2013 Dec;19(3):123-129. English.
Published online December 27, 2013.  https://doi.org/10.6118/jmm.2013.19.3.123
Copyright © 2013 by The Korean Society of Menopause
Effects of Menopausal Hormone Therapy on Uterine Myoma in Menopausal Women
IK Jin Chang, M.D.,1 Gi Youn Hong, M.D., Ph.D.,2, Young Lim Oh, M.D., Ph.D.,3, Byoung Ryun Kim, M.D., Ph.D.,2 Seong Nam Park, M.D.,2 Hae-Hyeog Lee, M.D., Ph.D.,4 Yong-Jin Na, M.D., Ph.D.,5 and Jeong Namkung, M.D., Ph.D.6
1Kosin University Graduate School, Busan, Korea.
2Department of Obstetrics and Gynecology, Wonkwang University College of Medicine, Iksan, Korea.
3Department of Obstetrics and Gynecology, College of Medicine, Kosin University, Busan, Korea.
4Department of Obstetrics and Gynecology, Soonchunhyang University College of Medicine, Bucheon, Korea.
5Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Yangsan, Korea.
6Department of Obstetrics and Gynecology, The Catholic University of Korea, Seoul, Korea.

Address for Correspondence: Gi Youn Hong, Department of Obstetrics and Gynecology, Wonkwang University College of Medicine, 895 Muwang-ro, Iksan 570-711, Korea. Tel: 82-63-859-1114, Fax: 82-63-858-3922, Email: hykyale@yahoo.com Co-correspondance: Young Lim Oh, Department of Obstetrics and Gynecology, College of Medicine, Kosin University, 34 Amnamdong, Busan 602-030, Korea. Tel: 82-51-990-6114, Fax: 82-51-990-3300, Email: hykyale@hanmail.net

Professor Hong and Oh equally contributed to this article for correspondance.

Received July 11, 2013; Revised July 30, 2013; Accepted September 29, 2013.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/).


Abstract

Objectives

The aim of the present study is to evaluate the long term effects of estrogen-progestogen therapy (EPT) on uterine myomas volume in postmenopausal women.

Methods

We performed a retrospective analysis on postmenopausal women with asymptomatic uterine myoma during the period between April, 2008 and September, 2012. Postmenopause was defined as amenorrhea for longer than a year or serum follicle stimulating hormone levels higher than 40 IU/L. The volume of the myoma was assessed by transvaginal ultrasonography for every 6 months after administration of EPT.

Results

Thirty-eight women were included in the study, with 32 in the EPT group and 6 in the control group. Overall, uterine myoma volume (mean ± standard deviation, cm3) in the EPT group was 19.5 ± 24.6 at baseline, and those at 6 and 12 months were 24.7 ± 35.1 and 28.5 ± 56.4, respectively. Myoma volume did not change significantly with EPT, and these changes were not significantly different from the control group. Myoma volume changes were not significantly different in the subgroups according to the route of estrogen administrations and the method of progestogen administrations. Clinically significant volume increases during one year of EPT was noted in 28.1% (9/32), however, only one showed transient increases.

Conclusion

Our results suggest that treating postmenopausal woman with EPT on a long-term basis does not increase the volume of uterine myomas.

Keywords: Estrogens; Myoma; Postmenopause; Progesterone; Uterus


Uterine myoma is the most common pelvic tumor in women, and its prevalence rate is 40-50% in women of childbearing age.1, 2 The prevalence rate in the general population in South Korea has not been reported. The prevalence rate of uterine myoma in hospitalized patients was found to be around 20%.3, 4 However, its prevalence rate in general population is assumed to be higher.

The favorable effects of hormone replacement therapy (HRT) on hot flushes, phosphorus and calcium metabolism, and involution of the urogenital and cardiovascular systems during postmenopause are well known. In addition, HRT has an outstanding effect on the prevention and treatment of osteoporosis. However, the clinical trial of the Women's Health Initiative (WHI) in 2002 reported that the combination of conjugate equine estrogen and medroxyprogesterone acetate increased the risk of cardiovascular disorders and breast cancer.5 Thus, the debate over the advantages and risks of HRT continues. However, a great number of menopausal women still undergo HRT to reduce menopausal symptoms and prevent osteoporosis. The increasing knowledge of the effects of HRT has progressively reduced some traditional contraindications, diabetes mellitus, arterial hypertension, diseases of lipometabolism, and previous cardiovascular diseases. In fact some of them are today considered as clear indications able to modify the approach to HRT in postmenopause and to extend its applications. However, the administration of HRT in women with uterine myoma is still debated since hormone-dependent pathologies represent relative contraindication to HRT. Uterine myoma growth is known to be promoted by estrogen.5~7 Thus, doctors and menopausal patients with uterine myoma have been concerned about HRT as a risk factor for the increase in size of uterine myoma, worsening of symptoms, and the fear of cancer. However, studies about the effects of HRT on uterine myoma in menopausal women have been insufficient and remain inconclusive8~15 this study investigated the effects of estrogen-progestogen therapy (EPT) on the volume of uterine myomas in a year period of administration in postmenopausal women.

Materials and Methods

A retrospective study was performed among the women who visited the menopausal clinic in a university hospital from April 2008 to September 2012; subjects were menopausal women in whom an asymptomatic uterine myoma had been identified by ultrasound before starting HRT. Postmenopause was defined as amenorrhea for longer than a year or serum follicle stimulating hormone level higher than 40 IU/L. The location of uterine myoma in this study was not limited, but the maximum diameter of uterine myoma was over 2 cm, and the number of uterine myoma was less than 3 by ultrasonography. Women who had contraindications for HRT and those with a past or currently taking oral contraceptives or HRT were excluded. The control group included menopausal women who had uterine myoma without HRT.

The size of the uterine myoma was measured by transvaginal ultrasound (5 MHz probe, Aloka SSD-1700; Toshiba, Tokyo, Japan) at baseline, 6 and 12 months after treatment. The volume of uterine myoma was calculated by the formula 0.521 × D1 × D2 × D3, which used the diameters of 3 dimensions. A clinically significant change in volume was defined as a greater than 30% increase compared with baseline data.

All data are shown as mean ± standard deviation and then A Mann-Whitney U test was used to analyze baseline data. The size change of uterine myoma was compared by a Wilcoxon two-sample test because the number of subjects was small, distribution of the data was wide, and the data did not follow normal distribution. A chi-square test was used to compare clinically significant changes in the size of uterine myoma. P < 0.05 was considered statistically significance.

Results

The study included 38 menopausal women. The number of members of the case with HRT was 32, and the control group without HRT was 6. All 32 cases took an EPT. The case was compared by estrogen taking methods.

The numbers in the case with oral estrogen was 22, transdermal estrogen was 10. As an oral estrogen, 12 patients has conjugate equine estrogen 0.625 mg and 8 patients has estradiol-17-valerate. As a transdermal estrogen, A 50-µg 17 β-estradiol patch a day was prescribed to 5 patients, and 1.5 mg 17 β-estradiol gel a day was prescribed to 5 other patients. The continuous combined method was administered to 16 patients, and the sequential cyclic method, which adds medications for 12 days a month, was used in 16 patients. In the use of progestogen, 2 patients took medroxyprogesterone acetate 5 mg and 20 patients micronized progesterone 200 mg.

There were no significant differences among groups. The mean age was 55.5 ± 4.9, the age for menarche was 15.6 ± 1.7, the age for menopause was 51.8 ± 3.4, and the postmenopausal period was 3.9 ± 3.6 years. There were also no differences between the oral estrogen and the transdermal estrogen groups (Table 1).


Table 1
Baseline characteristics of the study patients
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The volume increase was not statistically significant compared to the baseline value between the case with hormone therapy and the control groups. And also there were no differences in the size of uterine myoma on baseline to 6 months, 6 months to 12 months, or baseline to 12 months. In addition, there were no differences in the change of the size of uterine myoma according to the prescription method of estrogen, or the progestogen protocol (Table 2).


Table 2
Changes in the volume of uterine myoma with estrogen-progestogen therapy
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However, there was a significant difference in the change of size of uterine myoma between baseline and 6 months in the oral estrogen and the transdermal estrogen groups (Table 3).


Table 3
Distribution of myoma volume change according to the route of estrogen administration
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The number of cases with a significant change in the size of uterine myoma between baseline and 12 months was 9 (28.1%) (Table 4A). In 11 cases, the size of uterine myoma had significantly increased at 6 months; however, the size was unchanged or decreased after 6 months in 10 patients. Oral estrogen group in which the size of uterine myoma had increased after 6 months, was no change or decrease in size after 12 months (Table 4B, 4C, 4D). The size of uterine myoma continued to increase in the 1 remaining patient who was prescribed transdermal estrogen. A hysterectomy was performed at patient's request, and a benign uterine myoma was confirmed by pathological study.


Table 4
Pattern of myoma volume changes with estrogen-progestogen therapy (EPT)
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Discussion

Little has been published referring to the effect of HRT on uterine myomas in postmenopausal women. However, it is assumed that uterine myoma is strongly related with the physiological changes of ovarian hormone in the blood because uterine myoma has not been reported in women who have not started menarche, and the size of uterine myoma decreases after menopause.5 The presence of oestrogen and progesterone receptors in fibromatous tissue has now been confirmed by several studies. It is well known that uterine myoma occurrence and growth is dependent on estrogen.16 Furthermore, the role of progesterone in the proliferation of uterine myoma has been proposed. The effect of estrogen and progesterone on the occurrence and growth of uterine myoma has been reported to be strongly related with the increase of hormone receptors on uterine myoma tissue.17~19 The size of uterine myoma decreases after menopause, which is thought to be associated with decreasing levels of estrogen and progesterone in the blood. However, the effect of exogenous hormone on uterine myoma in menopausal women has not been definitively concluded. In this study, there was no significant change in the size on uterine myoma by HRT in menopausal women. In addition, there were no differences according to the prescription methods of estrogen and progestogen protocols.

The use of HRT in women with myomas has so far received scant attention in the literature, although the high prevalence of this disease. Various studies have reported effects of HRT on uterine myoma after menopause.8~15 It is thought that the size of uterine myoma can be affected by various prescription methods of estrogen, doses of estrogen, and the types and doses of combined progestogen. The size of uterine myoma is not affected by oral estrogen type in most studies.9, 12, 13, 20 However, the effects of transdermal estrogen is debated.8, 11~13 Some reported that the size of uterine myoma is not increased by using the transdermal 17 β-estradiol patch.8, 11 On the other hand, there are other agreement that the size of uterine myoma did increase in the transdermal estrogen group relative to the oral estrogen group.12, 13 However, in this studies, it is not clear that the increase of the size of uterine myoma is caused by the prescription method of estrogen or the progestogen protocol because different protocols of progestogen were used in the oral estrogen and the transdermal estrogen groups. However, Sener et al.13 argued that the increase in the size of uterine myoma was caused by the different progestogen doses (5 mg medroxyprogesterone acetate vs. 2.5 mg) rather than the different methods of estrogen because there was no difference in estrogen level in the blood. Based on the results of a randomized study in 30 menopausal women, the size of uterine myoma had been significantly increased in the group prescribed 5 mg medroxyprogesterone acetate when 2 mg micronized estradiols were combined with 2.5 mg and 5 mg medroxyprogesterone acetate in each group.21

In this study, similar protocols of progestogen were used in the oral estrogen and the transdermal estrogen groups; nevertheless, there was a significant difference in the size of uterine myoma between baseline and 6 months. Remarkably, the results of the present study are uneven and inconsistent, including increases, maintenance, and decreases in the size of uterine myoma. Thus, it is suggested that the direct effect of HRT on uterine myoma is not minimal in menopausal women. HRT should be discontinued if an increase in the size of uterine myoma occurs during HRT. Attentive size follow-up are important in case with uterine myoma during HRT. Colacurci et al.8 reported that follow-up ultrasounds performed once every 3 months are helpful to evaluate changes in the size of uterine myoma. And also, the decrease in the resistance of the uterine artery by the Doppler test is related to an increase in the size of uterine myoma after HRT.

Continuous growing uterine myoma causes doctors and patients anxious during HRT because it is difficult to diagnose uterine myoma and uterine sarcoma differently with only diagnostic radiologic studies including ultrasound. Uterine sarcoma is a rare malignant tumor which occurs as less than 1% of all malignant tumors, and has poor prognosis.22 Less than 0.5% patients who were diagnosed with uterine myoma before surgery are found as the sarcoma after surgery.23 In addition, it is unknown whether uterine sarcoma originates from uterine myoma or uterine muscle cells. Besides, there is no evidence that exogenous estrogen increases the incidence rate of uterine sarcoma. If the size of uterine myoma increases continuously, medications should be changed, or medications should be discontinued temporarily and then check up the change of size.

This study has some limitations. It is a retrospective study that depends on medical records, and the number of the subjects is small. Another limitation is that the ultrasounds were performed by different radiologists. In addition, various hormone medications could have interactions with one another. Therefore, various prospective randomized studies are needed with a sufficient number of subjects.

In conclusion, HRT did not affect the size of uterine myoma significantly in menopausal women. There were no differences by used methods of estrogen or progestogen protocols. Our results appear to encourage the use of HRT in menopausal women with uterine myomas. However, attentive follow-up is needed in case of a continuous increase in the size of uterine myoma.

Acknowlegement

This paper was supported by Wonkwang University in 2012.

References
1. Marshall LM, Spiegelman D, Barbieri RL, Goldman MB, Manson JE, Colditz GA, et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol 1997;90:967–973.
2. Schwartz SM. Epidemiology of uterine leiomyomata. Clin Obstet Gynecol 2001;44:316–326.
3. Hee LC. Uterine myoma : review of 247 cases. Korean J Obstet Gynecol 1968;11:65–73.
4. Sue HS, Nam C, Kim CS, Jang BK, Yang HD, Park SJ. A clinico-statstical study on the myoma of the uterus. Korean J Obstet Gynecol 1996;39:1047–1057.
5. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–333.
6. Ang WC, Farrell E, Vollenhoven B. Effect of hormone replacement therapies and selective estrogen receptor modulators in postmenopausal women with uterine leiomyomas: a literature review. Climacteric 2001;4:284–292.
7. Stewart EA. Uterine fibroids. Lancet 2001;357:293–298.
8. Colacurci N, De Franciscis P, Cobellis L, Nazzaro G, De Placido G. Effects of hormone replacement therapy on postmenopausal uterine myoma. Maturitas 2000;35:167–173.
9. de Aloysio D, Altieri P, Penacchioni P, Salgarello M, Ventura V. Bleeding patterns in recent postmenopausal outpatients with uterine myomas: comparison between two regimens of HRT. Maturitas 1998;29:261–264.
10. Fedele L, Bianchi S, Raffaelli R, Zanconato G. A randomized study of the effects of tibolone and transdermal estrogen replacement therapy in postmenopausal women with uterine myomas. Eur J Obstet Gynecol Reprod Biol 2000;88:91–94.
11. Palomba S, Sena T, Noia R, Di Carlo C, Zullo F, Mastrantonio P. Transdermal hormone replacement therapy in postmenopausal women with uterine leiomyomas. Obstet Gynecol 2001;98:1053–1058.
12. Polatti F, Viazzo F, Colleoni R, Nappi RE. Uterine myoma in postmenopause: a comparison between two therapeutic schedules of HRT. Maturitas 2000;37:27–32.
13. Sener AB, Seckin NC, Ozmen S, Gökmen O, Doğu N, Ekici E. The effects of hormone replacement therapy on uterine fibroids in postmenopausal women. Fertil Steril 1996;65:354–357.
14. Simsek T, Karakus C, Trak B. Impact of different hormone replacement therapy regimens on the size of myoma uteri in postmenopausal period: tibolone versus transdermal hormonal replacement system. Maturitas 2002;42:243–246.
15. Yang CH, Lee JN, Hsu SC, Kuo CH, Tsai EM. Effect of hormone replacement therapy on uterine fibroids in postmenopausal women--a 3-year study. Maturitas 2002;43:35–39.
16. Maruo T, Ohara N, Wang J, Matsuo H. Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum Reprod Update 2004;10:207–220.
17. Chrapusta S, Sieinski W, Konopka B, Szamborski J, Paszko Z. Estrogen and progestin receptor levels in uterine leiomyomata: relation to the tumour histology and the phase of menstrual cycle. Eur J Gynaecol Oncol 1990;11:381–387.
18. Rein MS. Advances in uterine leiomyoma research: the progesterone hypothesis. Environ Health Perspect 2000;108 Suppl 5:791–793.
19. Tamaya T, Fujimoto J, Okada H. Comparison of cellular levels of steroid receptors in uterine leiomyoma and myometrium. Acta Obstet Gynecol Scand 1985;64:307–309.
20. Schwartz SM, Weiss NS, Daling JR, Gammon MD, Liff JM, Watt J, et al. Exogenous sex hormone use, correlates of endogenous hormone levels, and the incidence of histologic types of sarcoma of the uterus. Cancer 1996;77:717–724.
21. Palomba S, Sena T, Morelli M, Noia R, Zullo F, Mastrantonio P. Effect of different doses of progestin on uterine leiomyomas in postmenopausal women. Eur J Obstet Gynecol Reprod Biol 2002;102:199–201.
22. Giuntoli RL 2nd, Metzinger DS, DiMarco CS, Cha SS, Sloan JA, Keeney GL, et al. Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol 2003;89:460–469.
23. Leibsohn S, d'Ablaing G, Mishell DR Jr, Schlaerth JB. Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol 1990;162:968–974.
discussion 74-6.