| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From the Department of Experimental Medicine, University of Catanzaro, Catanzaro; Department of Obstetrics and Gynecology, Department of Gynecology, Obstetrics, and Human Reproduction, University of Naples "Federico II," Naples; and University of Messina, Messina, Italy.
Address reprint requests to: Stefano Palomba, MD, Via Nicolardi 188, 80131 Napoli, Italy; E-mail: stefanopalomba{at}tin.it.
 |
ABSTRACT |
|---|
TOP
 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS: The required sample size was calculated to be 30 subjects per group to detect an effect on the size of one standard deviation (SD) with an 
value of 0.05 (two-sided) and a power 1 
= 0.8. At the end of the study, the power analysis showed a value of ß = 0.826. Seventy postmenopausal women with uterine leiomyomas were enrolled and treated for 12 cycles of 28 days each with transdermal 17 ß-estradiol (E2) patches plus oral medroxyprogesterone acetate continuously added (group A) or with calcium carbonate (group B). At entry and every three cycles, uterine and leiomyoma dimensions were measured by trans-vaginal ultrasonography. To evaluate the effect of trans-dermal HRT on the characteristics of uterine bleeding, 35 healthy postmenopausal women without uterine leiomyomas (group C) were enrolled and treated with the same regimen as group A. A daily diary was used to record the abnormal uterine bleeding episodes, and a rank scale was used to assess the severity of bleeding.
RESULTS: There were no significant changes in mean uterine or leiomyoma size between groups A and B, or in each group compared with basal values. No significant difference was detected between groups A and C in uterine bleeding patterns.
CONCLUSION: Transdermal HRT did not increase the size of uterine leiomyomas or affect uterine bleeding patterns in postmenopausal women.
Many gynecologists are hesitant to administer hormone replacement therapy (HRT) to postmenopausal women with uterine leiomyomas because of concern that the hormones might stimulate leiomyoma growth and induce abnormal uterine bleeding.
The increase of leiomyoma size during the fertile age and tumor regression after menopause or induction of a hypoestrogenic state by gonadotropin-releasing hormone (GnRH) analogues have led to the hypothesis that the pathogenesis of uterine leiomyomas might be related to estrogen and that leiomyoma growth is estrogen-dependent.1–4 This hypothesis of estrogen dependence is based on only a few in vitro studies. The estrogen plasma levels in women with uterine leiomyomas are usually in the normal range.1–4 In addition, there are many experimental and clinical studies3,5,6–11 of the role of progesterone in the pathogenesis of leiomyoma.
Although uterine leiomyomas have a high prevalence,1 there are only a few studies evaluating the effects of HRT on their size in postmenopausal women and on their symptomatology.12–18 At present, no valid conclusions can be drawn regarding the use of HRT, particularly the transdermal route, in cases of uterine leiomyomas.13,16–18
Sener et al13 showed a significant increase in uterine leiomyoma size in postmenopausal women treated with transdermal HRT, although no significant variation was detected in oral HRT users. Recently, Polatti et al16 observed a significant increase in leiomyoma dimensions in postmenopausal women treated with transdermal estradiol (E2) and oral medroxyprogesterone acetate in a sequential cyclic regimen. After 2 years of transdermal HRT treatment, onset of new leiomyomas was observed in 5% of women without leiomyomas.16 Fedele et al17 confirmed an increase in uterine volume and volume of largest leiomyoma and in the number of leiomyomas in postmenopausal women treated with transdermal E2 combined with oral medroxyprogesterone acetate in a sequential continuous schedule.
Conversely, Colacurci et al18 did not find any significant variation in leiomyoma dimensions after 1 year of continuous transdermal HRT in association with no-megestrolo acetate sequentially added. None of the published studies13,16–18 was designed to evaluate the real effect of transdermal HRT on leiomyoma volume using a valid control group.
The aim of this study was to evaluate the effect of transdermal HRT in postmenopausal women with uterine leiomyomas on uterine volume and uterine leiomyoma volume, and on uterine bleeding patterns.
|
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Seventy postmenopausal women with uterine leiomyomas were enrolled. The inclusion criteria were spontaneous menopause for at least 1 year but less than 2, history of uterine leiomyomas, and presence of no more than two intramural or subserosal uterine leiomyomas measuring over 20 mm at transvaginal ultrasonography. The exclusion criteria were neoplastic, metabolic, and infectious diseases; history of acute or recurrent vascular thrombosis; body mass index (BMI, kg/m2) over 30; use of hormonal therapy during the previous 6 months; and endometrial abnormalities at transvaginal ultrasonography. To obtain a homogeneous population to evaluate the uterine bleeding pattern and the effects of HRT treatment, subjects with an endometrial thickness greater than 5 mm or hypoechoic or calcified leiomyomas were excluded.19
Thirty-five women (group A) were treated with transdermal E2 (50 µg/day) patches in association with oral medroxyprogesterone acetate (2.5 mg/day) continuously added. Thirty-five women (group B) with uterine leiomyomas who refused HRT for personal reasons were treated with elemental calcium in the form of an effervescent tablet composed of calcium carbonate (1 tablet per day). The duration of the treatments for both groups was 12 cycles of 28 days each.
The study was a nonrandomized trial, and each eligible woman was segregated according to the choice to use or not use HRT. At the beginning of the study and at every third cycle of treatment for a total of 12 cycles, uterine and uterine leiomyomata dimensions were measured by transvaginal ultrasonography in groups A and B. Ultrasonographic scans were performed by the same experienced operator (SP) using a Toshiba PowerVision 6000 (Toshiba Medical System, Rome, Italy) equipped with a 7.5-MHz transvaginal probe. The operator was masked to the treatment status. Uterine and uterine leiomyoma size were evaluated measuring the three diameters (D1, D2, D3) and applying the formula of the ellipsoid: D1 · D2 · D3 · 0.52. When the presence of two leiomyomas was detected, an arithmetic mean was used.
To evaluate the effect of uterine leiomyomas on bleeding patterns during transdermal HRT, 35 healthy postmenopausal women without uterine leiomyomas (group C) were enrolled using the same exclusion criteria. Group C was treated for 12 cycles of 28 days each with the same transdermal HRT regimen given to group A.
The subjects were instructed to report in a daily diary the appearance of any adverse effects and the number and severity of abnormal uterine bleeding episodes. The severity of the abnormal uterine bleeding episodes was carefully evaluated by every woman with a rank scale of 1–10.20–22 Any uterine bleeding not requiring a sanitary pad (score of 1) was defined as mild, menstruation-like bleeding requiring a sanitary pad (score of 5) was defined as moderate, and heavy bleeding (score of 10) was defined as severe.20–22
Using a previous study,13 the required sample size was calculated to be 30 subjects per group to detect an effect on the size of one standard deviation (SD) with an value of 0.05 (two-sided) and a power 1 - of 0.8. After evaluation of the dropout rate, 35 subjects per group were enrolled. At the end of the study, the power analysis showed a value of ß = 0.826.
At baseline, the Student t test for unpaired data was used to compare the differences between the two groups in age, time since menopause, BMI, parity, number of cigarettes smoked, serum follicle-stimulating hormone (FSH) and E2 levels, and endometrial thickness. Repeated-measures analysis of variance was used to evaluate differences in uterine and uterine leiomyoma size at baseline and every 3 months. The number and severity of abnormal uterine bleeding episodes after every 3 months were compared by using the Mann-Whitney U test and Wilcoxon signed rank test, respectively. Statistical analysis was performed using SPSS 9.0 software (SPSS Inc., Chicago, IL). Data were expressed as mean ± SD.
|
RESULTS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
There was no significant difference in adverse effects between the three treatment groups. In particular, breast tenderness was observed in two, one, and one women in groups A, B, and C, respectively; headache in one woman each in groups B and C; and abdominal cramps in one woman each in groups B and C. No serious adverse events were observed during the study.
The characteristics of the subjects are reported in Table 1
. At the beginning of the study, there was no significant difference among the groups in age, time since menopause, BMI, parity, number of cigarettes smoked, serum FSH and E2 levels, and endometrial thickness (Table 1).
|
). In addition, mean uterine and leiomyoma volumes did not change significantly within each group compared with baseline values (Table 2).
|
shows the percentage change from baseline in uterine and leiomyoma size in postmenopausal women treated (group A) or untreated (group B) with transdermal HRT during 12 cycles of treatment.
|
).
|
). At the sixth, ninth, and 12th treatment cycles the bleeding pattern was not significantly different between the three groups (Table 3). |
DISCUSSION |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Successive studies13,14,16–18 have shown no significant increase in uterine and leiomyoma size in postmenopausal women treated with oral HRT. In particular, tibolone seems to be the HRT with the least effect on uterine and leiomyoma dimensions14,17 and uterine bleeding patterns.15 Our data21,22 confirmed that tibolone administration was safe in women with uterine leiomyomas. In fact, the addition of tibolone to GnRH analogue did not change the efficacy of the analogue alone in reducing uterine leiomyoma sizes over 2 years.22
More confusing are the data regarding the use of transdermal HRT on uterine leiomyoma dimensions in postmenopausal women.13,16–18 A significant increase in uterine leiomyoma size was detected in postmenopausal women using transdermal E2 plus medroxyprogesterone acetate 5 mg/day, whereas no change was reported in women using oral conjugated equine estrogens plus oral medroxyprogesterone acetate 2.5 mg/day.13 Nevertheless, that increase was probably a result of the higher dose of medroxyprogesterone used during transdermal HRT compared with oral HRT.
In a 2-year prospective randomized study of postmenopausal women with and without uterine leiomyomas that compared an oral E2 valerate plus cyproterone acetate (1 mg/day) with a transdermal E2 plus oral medroxyprogesterone acetate (10 mg/day), each in a cyclic sequential regimen, Polatti et al16 showed a significant increase in uterine and leiomyoma size only after transdermal HRT. Indeed, the percentage of subjects with new leiomyomas was significantly higher after transdermal HRT than oral HRT.16 However, in that study, a different progestinic balance was used.
Recently,17 an increase in leiomyoma dimensions in postmenopausal women was noted after 1 year of transdermal E2 plus oral medroxyprogesterone acetate (10 mg/day) administration in a continuous sequential schedule. A significant increase in uterine volume and in number and size of leiomyomas was shown, whereas no such increases were detected in patients who received tibolone.17 Conversely, it was shown18 that continuous transdermal E2 plus sequential nomegestrolo acetate (5 mg/day) did not increase significantly the leiomyoma dimensions in postmenopausal women after 1 year of treatment.
Previous studies13,16–18 of transdermal HRT administration in postmenopausal women with uterine leiomyomas have used confusing variables. Different doses,13 types of progestins,14 and administration regimens were used.17 In addition, no real control group was present in any study.13,16–18 Based on these considerations, to evaluate the effect of transdermal HRT on uterine leiomyoma dimensions, we enrolled a control group with uterine leiomyomas but who refused HRT and the women were treated with drugs that had no effect on them. To evaluate the effect of transdermal HRT on uterine bleeding patterns, a second control group, consisting of healthy postmenopausal women without uterine leiomyomas, was enrolled and treated with the same transdermal HRT as women with leiomyomas. Unfortunately, in our study randomization of the subjects was not possible for ethical reasons, but the three groups were similar in age, time since menopause, BMI, parity, number of cigarettes smoked, serum FSH and E2 levels, and, for groups A and B, uterine and leiomyoma sizes.
We found that, in the women treated with transdermal HRT, there was no significant increase in mean uterine and uterine leiomyoma size in comparison with baseline and control groups. In particular, no significant differences were detected between groups A and B in the percentage of women with a decrease (19.4% and 19.4% for groups A and B, respectively) or an increase (25.8% and 19.4% for groups A and B, respectively) in uterine leiomyoma size. In both groups the uterine and leiomyoma sizes were unchanged in more than half of the subjects (54.8% and 61.3% for groups A and B, respectively).
During the entire period of transdermal HRT administration, women with and without uterine leiomyomas had similar uterine bleeding patterns in terms of incidence of amenorrhea and number and severity of abnormal uterine bleeding episodes.
It is well established that leiomyomas are estrogen-dependent1–4 and that there are alterations in estrogen metabolism.23–26 The transcription of the estrogen receptor gene and translation of the protein are enhanced in leiomyomas.24,25 Cytosolic concentration of estrogens and estrogen receptors are higher in leiomyomas compared with normal myometrium,24,25 and a redistribution of estrogen receptor subtypes has been detected.26 Moreover, our recent data27 showed that raloxifene, a selective estrogen receptor modulator, induced a significant decrease in uterine and leiomyoma size in postmenopausal women with selective action on uterine leiomyomas. However, E2 action is not the only pathogenetic mechanism. Progesterone might play a pivotal role in the transformation of normal myometrial muscle to leiomyoma.5,6 High progesterone levels, as during the luteal phase, are associated with increased mitotic activity in leiomyomas.7 Oral medroxyprogesterone acetate administration is associated with increased mitotic activity in myomatous cells,8 and the addition of progestative agents to GnRH analogues as an add-back therapy induces a lack of regression in leiomyoma volume.10,11 Finally, RU486 administration, a compound with marked antiprogestative action, induces a reduction of progesterone receptors and leiomyoma volume without any effect on estrogen receptors, as determined by immunohistochemical assays.11 These data underline the pivotal role played by progestins on the growth of leiomyomas.
|
Footnotes |
|---|
Received April 30, 2001. Received in revised form July 26, 2001. Accepted August 9, 2001.
|
REFERENCES |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2. Chegini N, Rong H, Dou Q, Kipersztok S, Williams RS. Gonadotropin-releasing hormone (GnRH) and GnRH receptor gene expression in human myometrium and leiomyomata and the direct action of GnRH analogs on myometrial smooth muscle cells and interaction with ovarian steroids in vitro. J Clin Endocrinol Metab 1996;81: 3215–21.[Abstract]
3. Englund K, Blanck A, Gustavsson I, Lundkvist U, Sjoblom P. Sex steroids receptors in human myometrium and fibroids: Changes during the menstrual cycle and gonadotropin-releasing hormone treatment. J Clin Endocrinol Metab 1998;83:92–6.
4. Rein MS, Friedman AJ, Stuart JM, MacLaughlin DT. Fibroids and myometrial steroid receptors in women treated with gonadotropin releasing hormone agonist leuprolide acetate. Fertil Steril 1990;53:1018–23.[Medline]
5. Rein MS, Barbieri RL, Friedman AJ. Progesterone: A critical role in pathogenesis of uterine myomas. Am J Obstet Gynecol 1995;172:14–8.[Medline]
6. Tiltman AJ. The effect of progestins on the mitotic activity of uterine fibromyomas. Int J Gynecol Pathol 1985;4: 89–96.[Medline]
7. Kawaguchi K, Fujii S, Konishi I, Nanbu Y, Nonogaki H, Mori T. Mitotic activity in uterine leiomyomas during the menstrual cycle. Am J Obstet Gynecol 1989;160:637–41.[Medline]
8. Rein MS. Advances in uterine leiomyoma research: The progesterone hypothesis. Environ Health Perspect 2000; 108:791–3.
9. Thomas EJ. Add-back therapy for long-term use in dysfunctional uterine bleeding and uterine fibroids. Br J Obstet Gynaecol 1996;103:18–21.
10. Friedman AJ, Daly M, Juneau-Norcross M, Gleason R, Rein MS, Leboff M. Long-term medical therapy for leiomyomata uteri: A prospective, randomized study of leuprolide acetate depot plus either oetrogen-progestin or progestin "add-back" for 2 years. Hum Reprod 1994;9: 1618–25.
11. Murphy AA, Kettel LM, Morales AJ, Roberts VJ, Yen SSC. Regression of uterine leiomyomata in response to the antiprogesterone RU 486. J Clin Endocrinol Metab 1993; 76:513–7.[Abstract]
12. Schwartz LB, Iazer S, Mark M, Natchticall LE, Horan C, Goldstein SR. Does the use of postmenopausal hormone replacement therapy influence the size of uterine leiomyomata? A preliminary report. Menopause 1996;3:38–43.
13. Sener AB, Seckin NC, Ozmen S, Gokmen O, Dogu N, Ekici E. The effects of hormone replacement therapy on uterine fibroids in postmenopausal women. Fertil Steril 1996;63:354–7.
14. Gregoriou O, Vitoratos N, Papadias C, Konidaris S, Costomenos D, Chryssikopoulos A. Effect of tibolone on postmenopausal women with myomas. Maturitas 1997; 27:187–91.[Medline]
15. De Aloysio D, Altieri P, Pennacchioni P, Salgarello M, Ventura V. Bleeding patterns in recent postmenopausal outpatients with uterine myomas: Comparison between two regimens of HRT. Maturitas 1998;29:261–4.[Medline]
16. 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.[Medline]
17. Fedele L, Bianchi S, Raffaelli R, Zanconato R. 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; 88:91–4.[Medline]
18. Colacurci N, De Franciscis P, Cobellis L, Nazzaro G, De Placido G. Effects of hormone replacement therapy on postmenopausal uterine myoma. Maturitas 2000;35: 167–73.[Medline]
19. Zullo F, Pellicano M, Di Carlo C, De Stefano R, Marconi D, Zupi E. Ultrasonographic predictor of the efficacy of GnRH agonist therapy before laparoscopic myomectomy. J Am Assoc Gynecol Laparosc 1998;5:361–6.[Medline]
20. Nand SL, Webster MD, Baber R, O’Connor V, for the Ogen/Provera Study Group. Bleeding pattern and endometrial changes during continuous combined hormone replacement therapy. Obstet Gynecol 1998;91:678–84.[Abstract]
21. Palomba S, Affinito P, Tommaselli GA, Nappi C. A clinical trial on the effects of tibolone association with gonadotropin-releasing hormone analogues for the treatment of uterine leiomyomata. Fertil Steril 1998;70:111–8.[Medline]
22. Palomba S, Affinito P, Di Carlo C, Bifulco G, Nappi C. Long term administration of tibolone plus gonadotropin-releasing hormone agonist for treatment of uterine leiomyomas: Effectiveness and effects on vasomotor symptoms, bone mass, and lipid profile. Fertil Steril 1999; 72:889–95.[Medline]
23. Pasqualini JR, Cornier E, Grenier J, Vella C, Schatz B, Netter A. Effect of decapeptyl, an agonost analog of gonadotropin-releasing hormone on estrogens, estrogen sulfates, and progesterone receptors in leiomyomata and myometrium. Fertil Steril 1990;53:1012–7.[Medline]
24. Yamamoto T, Takamori K, Okada H. Estrogen biosynthesis in leiomyomata and myometrium of the uterus. Horm Metab Res 1984;16:678–9.[Medline]
25. Bulun SE, Simpson ER, Word RA. Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissue and cells in culture. J Clin Endocrinol Metab 1994;78:736–43.[Abstract]
26. Benassayag C, Leroy MJ, Rigourd V, Robert B, Honore JC, Mignot TM, et al. Estrogen receptors (ERalpha/ER-beta) in normal and pathological growth of the human myometrium: Pregnancy and leiomyoma. Am J Physiol 1999;276:1112–8.
27. Palomba S, Sammartino A, Di Carlo C, Affinito P, Zullo F, Nappi C. Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women. Fertil Steril 2001; 76:38–43.[Medline]
This article has been cited by other articles:
|
|
 |
|
  Postmenopausal HT Does Not Increase Size of Leiomyomas Journal Watch Women's Health, February 5, 2002; 2002(205): 8 - 8. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
