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GnRH ANALUGUE PLUS AROMATASE INHIBITOR IN THE TREATMENT OF UTERINE

LEIOMYOMATOSIS. A CONTROLLED STUDY.
1Fabio Scarpellini, 2Marco Sbracia, 3Sergio Lecchini, 1Giammario Frigo, 4Luciano Scarpellini.
1Department of Internal Medicine and Medical Therapy, University of Pavia, Italy. 2CERM, Rome,
Italy. 3Laboratory of Pharmacology, University of Varese, Italy. 4II Institute of Obstetrics and
Gynecology “La Sapienza” University, Rome, Italy.

Summary:
We performed a controlled study on 378 women affected by symptomatic uterine leiomyomatosis in
order to assess the effectiveness of the combined treatment GnRH analogue (Goserelin) plus
aromatase inhibitor (Anastrozole) versus GnRH analogue (Goserelin) only. This study showed that
the combined therapy reduced the uterine dimensions faster than the GnRH analogue alone
treatment (three month versus six months), without significant side effects and bone mineral loss.

Corresponding author: Fabio Scarpellini, MD

Viale Liegi 28,
00198 Rome, Italy.
Phone: 39-06-8848013
Fax: 39-06-8848013
E-mail: [email protected]
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Uterine fibroids or leiomyomata uteri, are the most common tumors of the female genital tract.
These benign tumors occur in approximately 20% to 50% of women depending on their race, age,
and the method of assessment used1. The most common therapeutic procedure is surgery:
hysterectomy and myomectomy. The introduction of GnRH analogues, which pharmacologically
suppress the gonadotrophin secretion, in the treatment of this disease has been proven to be useful
to shrink myomas, but has not determined a significant reduction of surgery. It has been shown that
leiomyomata tissue expresses aromatase, the enzyme synthesising estrogens whose normal
myometrium is lacking2,3. Some recently developed drugs block the aromatase activity selectively
without showing major side effects previously observed with the earlier compounds of this class4.
We have tried to take advantage of the biological background of this pathology, joining the GnRH
analogue treatment with an aromatase inhibitor in order to obtain a major shrinkage of the myoma
in a shorter time.
We conducted a controlled pilot study on 378 patients with uterine myomas showing metrorrhagia

and pelvic pain and uterine size of more than 60 cm 3, comparing the use of a combined therapy of
GnRH analogue plus aromatase inhibitor in 198 patients (group A) and a GnRH analogue only in
189 patients (group B). We employed as a GnRH analogue Goserelin at a dosage of 3.75 mg every
28 days and as an aromatase inhibitor 1 mg daily of Anastrozole. Every month an ultrasound scan, a
complete blood count and serum estradiol titration were performed. In all patients before and after
therapy bone mineral density (BMD) assessment of lumbar spine (L2-L4) was performed using
dual-energy X ray absorptiometry. Patients were randomly assigned to one of the two groups: the
two groups were similar for clinical characteristics (Table I).
Estradiol levels were depressed in both groups during treatment (21.4+5.7ng/ml in group A and
23.3+6.4ng/ml in group B). Serum haemoglobin levels in patients of both groups was restored to
normal levels after treatment (in group A it was 9.8g/dL before therapy and 13.6 at the end; in group
B it was 9.7g/dL at the beginning of therapy and 13.4g/dL at the end ). Uterine volume in group A

had shrunk more than 60% after three months of treatment (281.7+221.8 cm3initial volume, and

46.7+ 21.3cm3 after treatment). In group B a similar shrinkage was observed after 6 months of

treatment, 276.9+.211.4cm3 initial volume, 126.3+72.8cm3(P<0.01) after three months of treatment

and 56.8+19.5 cm3 at the end of treatment. The BMD screening showed no appreciable loss of
calcium bone density in the women of group A after treatment, whereas there was a significant loss
of calcium bone density in the patients of group B after treatment (1.014+0.12 vs
0.911+0.16;P<0.01). The cost per patient for treatment in group A was 1180 Euro and in group B it
was 1270 Euro. The date are reassumed in Table II
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It has been estimated that in USA hysterectomy is the most common surgical procedure performed,
and mostly of them are made for uterine leiomyomatosis5. It is a disease with an important social
impact not only for the number of patients interested, but also for the costs of the therapy either
surgical or medical in such a large number of patients. Consequently, the possibility of avoiding
surgery and reducing the costs of medical treatment in these women is a relevant issue. We showed
that the use of a combined therapy with GnRH analogue plus Anastrazole, an aromatase inhibitor
significantly reduces the time of treatment and also the costs when compared to GnRH analogue
alone. Furthermore, women treated with the combined therapy did not show loss of bone calcium
density, probably due to the shorter time of hypoestrogenism, whereas women treated with just the
GnRH analogue had a significant loss of bone calcium density.

1) Stewart EA: Uterine fibroids. Lancet 2001, 357: 293-8.

2) Folkerd EJ, Newton CJ, Davidson K, Anderson MC, James VH. Aromatase activity in uterine
leiomyomata. J Steroid Biochem. 1984 May;20(5):1195-200.

3) Liehr JG, Ricci MJ, Jefcoate CR, Hannigan EV, Hokanson JA, Zhu BT. 4-Hydroxylation of
estradiol by human uterine myometrium and myoma microsomes: implications for the mechanism
of uterine tumorigenesis. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9220-4.

4) Dukes M, Edwards PN, Large M, Smith IK, Boyle T. The preclinical pharmacology of
"Arimidex" (anastrozole; ZD1033)--a potent, selective aromatase inhibitor. J Steroid Biochem Mol
Biol. 1996 Jul;58(4):439-45.

5) Vessey MP, Villard-Mackintosh L, McPherson K, Coulter A, Eates D. The epidemiology of

hysterectomy: findings in a large cohort study. Br J Obstet Gynecol 1992; 99: 402-7.
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Table I Clinical characteristics of patients underwent randomization.

____________________________________________________________
Patient characteristics GnRH-a/arim GnRH-a P
____________________________________________________________

Age 39.7+4.8 39.5+5.0 NS

BMI 23.4+1.9 23.6+2.1 NS
Full term pregnancy 1.4(0-3) 1.3(0-3) NS
Abortion 1.8(0-4) 2.0(0-5) NS
Infertility 13.5% 12.9% NS

Symptoms:
menorrhagia 81.6% 83.0% NS
urinary urgens 25.3% 24.8% NS
pelvic bulk 49.5% 50.2% NS
pain 37.1% 34.3% NS
duration 19.5+9.0 20.2+8.9 NS
haematocrit 9.8+0.8 9.7+0.6 NS
uterine volume 281.7+221.8 276.9+211.4 NS
____________________________________________________________

Table II Clinical results of patients with myomas in the controlled study.

_________________________________________________________
Patient characteristics GnRH-a/arim GnRH-a P
_________________________________________________________

N of patients 50 50
Time of treatment 4.3+0.3 6.2+0.6 0.01
Myoma shrink 2months 23.5+ 7.9 12.3+ 6.1 0.05
Myoma shrink end tratment 52.6+10.3 42.2+11.4 0.01
BMD 2.1+0.8 10.1+ 1.8 0.05
N relapses 3(6.0%) 9(18.0%) 0.01
_________________________________________________________
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Table II. Clinical data after treatment in the two groups of patients.
__________________________________________________________________
Characteristics group A Group B
after before after before
____________________________________________________________________
uterine volume 281.7+221.8 46.7+21.3 276.9+211.4 56.8+19.5
haematocrit 9.8+0.8 13.6+0.6 9.7+0.9 13.4+0.5
BMD 1.010+0.13 0.991+0.12 1.014+0.15 0.911+0.16*
____________________________________________________________________
* P<0.01 (group B after vs before)