Effects of hormone replacement therapy on postmenopausal uterine myoma

Maturitas 35 (2000) 167 – 173 www.elsevier.com/locate/maturitas

Effects of hormone replacement therapy on postmenopausal uterine myoma Nicola Colacurci a,*, Pasquale De Franciscis a, Luigi Cobellis a, Giovanni Nazzaro b, Giuseppe De Placido b a

Outpatient Menopausal Clinic, Institute of Gynaecology and Obstetrics, School of Medicine, Second Uni6ersity of Naples, Largo Madonna delle Grazie 1, 80134 Naples, Italy b Department of Emergency in Obstetrics and Gynaecology and Reproducti6e Medicine, Ultrasound Unit, ‘Federico II’ Uni6ersity, Via Pansini 5, 80100 Naples, Italy Received 9 November 1999; accepted 25 February 2000

Abstract Objecti6es: To evaluate the effects of sequential continuous hormone replacement therapy (HRT) on myoma size and on pulsatility index (PI) of uterine arteries and to verify the correlation between uterine artery flow impedance and the growth rate of myoma in women receiving HRT. Methods: In a prospective 1-year study 60 postmenopausal women were enrolled into three study-groups to receive continuous transdermal 17b-oestradiol 0.05 mg/day plus nomegestrolo acetate 5 mg/day sequentially added: 20 patients (group A) unaffected by uterine myomas, 20 patients (group B) with single asymptomatic myoma B3 cm/14 cm3, 20 patients (group C) with single asymptomatic myoma \3 cm/14 cm3. The changes in myoma volume and in PI were assessed by means of transvaginal ultrasonographic scan every 3 months. The patients with myoma were divided into two subgroups: quiescent myoma (B1, C1) and growing myoma (B2, C2). Results: No significant increase of uterine fibroids volume was found after 1-year HRT (24.14 920.02 “28.81 930.02 cm3). Six out of eight myomas growing during HRT belonged to group C. The uterine artery basal PI value of group A was significantly higher (PB 0.01) than the corresponding PI in group B and C. At 3 months follow-up, uterine artery PI was significantly higher (PB0.01) than the basal value in both group B (1.7090.22 “1.88 90.16) and C (1.59 90.28“1.9290.21). The baseline PI values in group B1 and C1 were significantly higher than the baseline values observed in group B2 and C2 (1.76 9 0.17 vs. 1.32 9 0.02, 1.769 0.16 vs. 1.24 90.08) and significantly lower than those observed in group A (2.399 0.47). After 3 months of HRT, the PI values were not significantly higher than the baseline values in groups B1 and C2 (1.769 0.17“ 1.909 0.17; 1.2490.08 “1.7490.16), while they were significantly higher in group C1 (1.769 0.16“2.019 0.17). Conclusions: Sequential continuous HRT does not increase the volume of the uterine myoma. The findings of very low resistance index in the uterine arteries of women with growing myoma may indicate the risk of growth of the neoplasia during HRT. The assessment of PI in the uterine arteries could be helpful in predicting the growth rate of the myomas before starting HRT. © 2000 Elsevier Science Ireland Ltd. All rights reserved.

* Corresponding author. Present address: Via Manzoni 88, 80100 Naples, Italy. Tel.: + 39-81-5665599; fax: +39-81-459908. E-mail address: [email protected] (N. Colacurci) 0378-5122/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 0 0 ) 0 0 1 1 5 - 8

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Keywords: Doppler; Hormone replacement therapy; Myoma; Postmenopause; Ultrasonography

1. Introduction In spite of the numerous acknowledged benefits of hormone replacement therapy (HRT), the percentage of women undergoing treatment is still relatively low. The increasing knowledge of the effects of HRT has progressively reduced some traditional contraindications, i.e. diabetes mellitus, arterial hypertension, diseases of lipometabolism, and previous cardiovascular diseases. In fact some of them are today considered as clear indications [1] 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. Estroprogestin therapy could produce a proliferative stimulus [2] increasing the volume and enhancing the related symptoms. So far, in literature there are few large longitudinal studies regarding postmenopausal women with uterine fibroids undergoing HRT. Ultrasound enables performance of a morphologic study [3] of site, volume, echostructure of the myoma, and assessment of the intrauterine artery and intratumoral blood flow [4 – 6]. The aim of the present study was to evaluate the effects of sequential continuous HRT on myoma size and on uterine arteries hemodynamics in postmenopausal women. Furthermore, the study was also aimed to verify the correlation, if any, between uterine artery flow impedance and the growth rate of myoma in women receiving HRT.

2. Materials and methods Sixty patients referred to the Outpatient Menopausal Clinic of the Second University of Naples were recruited to the study protocol from January 1995 to January 1998. Patients were younger than 57 years with amenorrhoea lasting between 12 and 36 months. The

menopausal status was confirmed by serum FSH (\ 30 IU/l) and oestradiol levels (B 30 pg/ml) using commercially available standard enzymeimmunoassay and radioimmunoassay kits. None had previously taken HRT. Exclusion criteria were liver disease, heart disease, severe or familiar hypercholesterolemia, severe hypertension, and breast cancer or oestrogen-dependent cancer. High alcohol intake or cigarette smoking (\ 20/ day) and body mass index\28 also represented exclusion criteria. The study groups were as follows: group A: 20 patients unaffected by uterine myomas and other uterine or adnexal pathology who represented the control group; group B: 20 patients with single asymptomatic myoma B 3 cm/14 cm3; group C: 20 patients with single asymptomatic myoma \ 3 cm/14 cm3. Prior to being enrolled, all patients signed written informed consent. All the patients underwent ultrasonographic scan at admission and every 3 months for 1 year by means of a 5- and 6.5-MHz transducer. The equipment used was a Toshiba 270 Sonolayer A ultrasound system and it was set as previously described [7]. Myoma size was expressed as volume (cm3) calculated after measuring the three largest dimensions (D) using the formula D1× D2× D3× 0.523. In relation to the location, only women with subserosal (26) or intramural (14) myomas were enrolled; the patients with submucosal myomas were excluded because of the increased risk of irregular uterine bleeding or spotting and at once underwent hysteroscopic surgery. Myomas with ultrasound check featuring calcification, necrosis or degeneration were also excluded. The Doppler analysis of uterine arteries flow velocity waveforms was performed by pulsatility index (PI): the main branch of both uterine arteries was examined lateral to the cervix and the lowest index obtained was considered.

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All the patients were treated with continuous transdermal 17b-oestradiol 0.05 mg/day plus nomegestrolo acetate 5 mg/day (Lutenyl, Schering, Milan, Italy) added sequentially from day 17 to day 28 of each 28-day cycle. Ultrasonographic examinations repeated after 3 (T1), 6 (T2), 9 (T3) and 12 (T4) months of treatment during progesterone administration were carried out by the same observer (G.N.). We analysed the morphologic parameters (myoma growth rate) during HRT in both groups B and C and divided the study groups into two subgroups: patients with quiescent myoma (B1, C1) and patients with myoma growing more than 20% from baseline size (B2, C2). We compared the Doppler findings in the control group (group A), in the patients with myoma (groups B and C) and in the subgroups B1, B2, C1, C2. All data are presented as mean 9 S.D. and range or as mean percentage variation of baseline

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values. Statistical analysis was performed by Student’s t-test for unpaired data and Wilcoxon Matched Pairs test (Stat for Windows Release 4.5, Stat Soft Inc. 1993), when adequate. Statistical significance was set at P B 0.01.

3. Results The follow-up at 12 months was completed in 33 myomas out of 40 (82.5%), in 15 patients of group B and 18 patients of group C. No statistically significant differences were found in the basal clinical characteristics between the study groups (Table 1).

3.1. Morphologic parameters At the beginning of the study, fibroids mean volume (group B+ group C) was 24.149 20.02 cm3 (range 1.56–70.43). On the whole, the volume

Table 1 Basal clinical characteristics of the study groupa Parameter

Group A

Group B

Group C

P-value

Age (years) Time since menopause (months) FSH (IU/l) 17b-oestradiol (pg/ml)

51.29 2.26 (47–56) 24.39 7.1 (12–36) 63.0 9 16.4 (40–90) 14.2 9 5.9 (5–23)

51.4 92.87 (48–57) 23.299.11 (12–36) 67.9 921.75 (46–92) 12.2 96.22 (4–25)

51.39 2.59 (47–56) 25.6 9 6.08 (14–35) 61.9 9 16.44 (39–92) 12.1 9 3.51 (7–21)

\0.01 \0.01 \0.01 \0.01

a

Values are mean 9 S.D. with range in parentheses.

Fig. 1. Changes of myoma size during hormone replacement therapy (groups B and C). Box and whisker plot. Open square, mean value; box, 9S.E.; whiskers, 9 S.D.

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Fig. 2. Individual data on myoma size during hormone replacement therapy. Open circle, T0; open square, T1; open lozenge, T2; open triangle, T3.

3.2. Doppler findings

0.08 in C2). The baseline PI values in group B1 (1.769 0.17) and C1 (1.769 0.16) were significantly higher than the baseline values observed in group B2 (1.32 9 0.02) and C2 (1.24 9 0.08), and significantly lower than those observed in group A (2.399 0.47) (Fig. 4). After 3 months of HRT, the PI values in groups B1 and C2 were not significantly higher than the baseline values (1.769 0.17“ 1.909 0.17; 1.249 0.08“ 1.749 0.16), while they were significantly higher in group C1 (1.769 0.16“ 2.019 0.17) and not comparable in group B2. A statistically significant difference was also found between PI in group C1 and PI in group C2 (Fig. 4).

The uterine artery basal PI value of group A was 2.399 0.47, significantly higher (P B 0.01) than the corresponding PI in groups B and C (Table 2). At 3 months follow-up, uterine artery PI mean value of group A showed a reduction (2.39 9 0.47“ 2.2490.31) with no significant differences when compared with the baseline value, while in the patients with myoma, PI showed a significant increase (P B 0.01) both in group B (1.70 90.22“1.8890.16) and C (1.599 0.28 “ 1.92 90.21). No further considerable variations in PI values occurred at the subsequent followup. The basal PI values in both groups of patients with quiescent and with growing myoma showed no significant differences (1.769 0.17 in B1 vs. 1.76 90.16 in C1; 1.3290.02 in B2 vs. 1.249

Fig. 3. Changes of myoma volume during hormone replacement therapy in groups B and C. Light stipple, T0; moderate stipple, T1; dark stipple, T2; solid, T3; cross-hatch, T4.

of uterine leiomyomas was unchanged or not significantly increased (28.819 30.02 cm3) during 1-year hormonal treatment (Figs. 1 and 2) without significant differences between groups B and C (Fig. 3). After 3 months of HRT an increased volume was observed in eight fibroids, two from group B and six from group C; a further increase of a few millimetres (B5 mm) was observed in five patients by the end of the study, without significant differences in relation to the location: three subserosal and five intramural myomas grew during HRT.

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Table 2 Uterine artery pulsatility index during hormone replacement therapya Time of follow-up

Group A

Group B

Group C

P-value

Basal After After After After

2.399 0.47 2.2490.31 2.279 0.29 2.2590.31 2.25 9 0.30

1.70 90.22 1.88 90.16** 1.91 90.16 1.90 9 0.16 1.90 90.17

1.59 9 0.28 1.92 9 0.21** 1.94 9 0.23 1.93 9 0.21 1.94 9 0.21

B0.01* B0.01 \0.01 \0.01 \0.01

(T0) 3 months (T1) 6 months (T2) 9 months (T3) 12 months (T4)

a Values are mean 9 S.D. * PB0.01 when comparing basal values between groups A and B, and between groups A and C. ** PB0.01 when comparing values between T0 and T1.

4. Discussion Few papers have been published on HRT and myomas and its effects on Doppler and ultrasonographic features. By means of morphologic parameters, Schwartz et al. [8] failed to show an increase in myoma size during HRT; also Sener et al. [9] found no significant increase of myoma volume after 1 year of sequential continuous HRT with conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (MAP), but a significant increase was observed with transdermal oestradiol 0.05 mg plus MPA 5 mg. Because of the dose-equivalence of the oestradiol regimens, the doubled dose of progestin should be the cause of the increased size of the fibroids. This is consistent with other reports [10,11] showing progestin receptors and serum progesteron levels more critical than estrogens in the regulation of postmenopause fibroid growth. The relevance of a hormonal milieu of high progesteron levels is confirmed by the studies carried out in women undergoing long-term therapy with gonadotropin releasing hormone agonists: the administration of estrogens and progestins as add-back therapy did not cause an increase of myomas size [12], while only progestin regimen did [13]. During tibolone treatment the volume of the fibroids remained constant [14]. We administered transdermal oestradiol 0.05 mg/day plus progestogen with reduced androgenic activity (nomegestrolo acetate 5 mg) sequentially added in all the patients. No significant change of uterine fibroids volume was found during the

1-year treatment. Only eight fibroids out of 33 (24.1%) showed significant increased volume (\ 20% from baseline size) during HRT, and the observed increase was not statistically significant when compared with the baseline values on the whole. The increase size was already recorded at the first follow-up in two out of 15 myomas (13.3%) from group B and in six out of 18 myomas (33.3%) from group C: five of these myomas showed a further non-significant increase. This suggests that a short-term ultrasonographic follow-up could be useful to identify myoma at high risk of growth, while the location does not seem to have any predictive value. As regards Doppler features of uterine arteries, our data are in agreement with international literature [15–17] and showed that vascular effects of HRT are obtained within 3 months. HRT reduces vascular resistance and improves the uterine artery perfusion in patients with normal uterus. The findings of our study also indicate that uter-

Fig. 4. Pulsatility index (PI) values according to the growth rate of the myoma. Light stipple T0; moderate stipple, T1. *P B0.01.

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ine myomas affect uterine artery blood flow with low baseline PI values recorded, as reported by other authors [3,5,6,18]. The patients with uterine myoma showed a significant swift increase of uterine artery resistance due to modified hormone/receptor equilibrium achieved during HRT: however this condition is typical of any neoplasia supplied by a local vascularization. Colour Doppler ultrasonography was used [6,19] to predict the growth rate of the myomas measuring both uterine artery blood flow and intratumoral blood flow. The assessment of uterine artery blood flow seems to have a predictable value higher than intratumoral blood flow that does not correlate with cell proliferation or angiogenesis [20]. The reason for this may be either due to extrinsic factors such as missed visualisation of flow because of technical limitations or the equipment is not sensitive enough to detect intratumoral blood flow, or to intrinsic factors such as vessel structure or neoplasia degeneration. We correlated the uterine artery flow impedance with the growth rate of myoma in women receiving HRT. The most part of myomas growing during HRT (six out of eight) belonged to the group with basal large volume (group C); when divided according to the growth rate, they were characterised by very low basal PI values (group B2 and C2). During HRT, PI values increased in all the subgroups but the increase was statistically significant only in patients of group C1 who showed PI values significantly higher than those recorded in group C2; no significant difference was observed between group B1 and B2. The findings of very low resistance index in the uterine arteries of women with myomas may indicate the risk of growth of the neoplasia during HRT. Therefore, the assessment of PI in the uterine arteries may be helpful in predicting the growth rate of the myomas and could be used as a screening parameter before starting HRT. References [1] Birkhauser MH. Contraindications today, indications tomorrow. In: Birkhauser MH, Rozenbaum H, editors. Menopause: European Consensus Development Conference. Montreux, Switzerland: Eska, 1996:283–91.

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