ORIGINAL ARTICLE

Aromatase inhibitor letrozole versus progestin

norethisterone in women with simple endometrial
hyperplasia without atypia: A prospective cohort trial
M. El-shamy
*
, A. Gibreel, E. Refai, E. Sadek, A. Ragab
Department of Obstetrics and Gynecology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Received 6 September 2011; accepted 23 November 2011
Available online 12 January 2012
KEYWORDS
Endometrial hyperplasia;
Letrozole;
Progestin
Abstract Objective: To evaluate the effectiveness of the aromataze inhibitor letrozole to
progestin norethisterone for women with simple endometrial hyperplasia without atypia.
Subjects and methods: One hundred women with a histo-pathological diagnosis of simple endo-
metrial hyperplasia without atypia were divided into two groups: Groups A and B. Group A
included 50 patients who received a daily 5 mg dose of letrozole for three successive months. Group
B included the other 50 patients who received norethisterone 10 mg daily by non-stop regimen for
3 months. All patients in both groups were reevaluated after treatment. Women diagnosed with
progressive or persistent endometrial hyperplasia at the second curettage were asked to continue
on the same medication for another 3 months. Transvaginal sonography as well as serum estradiol
level measurement were performed before the start of treatment and 3 months after treatment.
Results: Despite that there was no statistically signicant difference between the two groups as
regards the proportion of women whose endometrial sample revealed resolution, regressing or per-
sistence after 3 months of treatment. However, endometrial thickness was signicantly thinner in
women who received letrazole than in women who received norethisterone (mean difference
*
Corresponding author. Address: Department of Obstetrics and
Gynecology, Faculty of Medicine, Elgomhoria Street, Mansoura
University Hospital, Mansoura, Egypt. Tel.: +20 127779106, +20
502232553; fax: +20 502267017.
E-mail address: dr_maged66@yahoo.com (M. El-shamy).
1110-5690 2011 Middle East Fertility Society. Production and
hosting by Elsevier B.V. All rights reserved.
Peer review under responsibility of Middle East Fertility Society.
doi:10.1016/j.mefs.2011.11.005
Production and hosting by Elsevier
Middle East Fertility Society Journal (2012) 17, 111115
Middle East Fertility Society
Middle East Fertility Society Journal
www.mefsjournal.com
www.sciencedirect.com
0.12 mm, 95% CI: 0.220.01, P = 0.02). Serum E2 level was signicantly lower in the Group A
compared to Group B (mean difference 9.1 pg, 95% CI: 13.744.45, P < 0.001).
Conclusion: Letrozole is as effective as norethisterone for women with abnormal uterine bleeding
due to endometrial hyperplasia without atypia.
2011 Middle East Fertility Society. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction
Endometrial hyperplasia (EH), particularly in the presence of
atypia, is a premalignant epithelial disease which is considered
a precursor to endometrial adenocarcinoma. Endometrial ade-
nocarcinoma is a disease of postmenopausal women. However,
women at any age, with unopposed endogenous or exogenous
estrogen, may be at a risk for developing endometrial hyper-
plasia (1).
Endometrial hyperplasia is an estrogen-dependent disease
which may present with abnormal uterine bleeding. Anti-estro-
genic medications such as progestin and gonadotropin-releas-
ing hormone agonists have been shown to reverse
endometrial hyperplasia (27).
Progestin appears to decrease glandular cellularity by trig-
gering apoptosis. However, several reports had highlighted
the potentially unfavorable vascular effects of progestin as well
as the deleterious elevation of lipid and lipoprotein levels,
weight gain and mood changes (8). Meanwhile, treatment with
gonadotropin-releasing hormone agonists has been found to
have the same vasomotor and osteoporotic effects (9).
Aromatase inhibitors (anastrazole and letrozole) inhibit
peripheral aromatization of androgen to estrogen, therefore,
suppresses estrogen biosynthesis and also has local action on
the endometrium because aromatase levels are higher in hyper-
plastic than in normal endometrial tissues (10,18). Letrozole is
a very potent, non-steroidal aromatase inhibitor that selectively
inhibits the aromatase enzyme which catalyzes the last step in
estrogen biosynthesis (11). This third-generation aromatase
inhibitor (AI) effectively blocks the production of estrogen
without exerting effects on other steroidogenic pathways (12).
Few publications had recently reported a benecial effect of
letrozole in women with endometrial hyperplasia (13,14).
The aim of this study was to evaluate the effect of letrozole
in women with simple endometrial hyperplasia without atypia
compared to progestin in a prospective cohort trial. Those
with atypia were excluded because they are very risky and pre-
ferred hysterectomy from the start.
2. Subjects and methods
The protocol of this study was approved by Mansoura Univer-
sity Ethics Committee and all participants were provided with
the patients information sheet, counseled before being consid-
ered eligible for inclusion, and also a written consent was
sought from them before starting the treatment.
Women underwent endometrial sampling for abnormal
uterine bleeding, or those in whom histopathology revealed
simple or complex endometrial hyperplasia without atypia
were asked to participate. On the other hand women with
atypical endometrial hyperplasia were excluded as well as
women treated with hormones in the previous 6 months and
those with associated pathologies of the endometrial cavity.
Premenopausal status was dened by ongoing menstrual cycle
for at least 6 months before inclusion.
The study included 100 women who accepted to participate
and was conducted between December 2006 and February
2011 at the Obstetrics and Gynecology Department, Mansoura
University Teaching Hospital. Pretreatment and follow-up
ultrasound scans were performed by an independent ultraso-
nographer.
At baseline, transvaginal ultrasound (TVS) was performed
to determine the uterine size, endometrial thickness (ET) and
any uterine or adnexial pathology. Endometrial thickness
was measured at the widest point across the hyperechoeic area
in a longitudinal section of the uterus along the sagittal plane.
Thereafter, participants were then divided into two groups:
Group A included 50 patients who received letrozole (Femara;
Novartis pharma services, Basel, Switzerland) in a dose of
2.5 mg twice daily for 3 months, while Group B included 50
patients who received norethisterone by non-stop regimen in
a dose of 10 mg daily (Cidolut-Nor; Chemical Industries
Development (CID), Giza, Egypt) for 3 months. Women were
given a sealed envelope containing one of both lines of the sug-
gested treatment. Three months from the start of treatment, all
participants were subjected to TVS, serum estradiol level mea-
surements, endometrial sampling. Endometrial specimens were
obtained as an outpatient procedure using a fractional curet-
tage technique. Response to treatment based on histopathol-
ogy of the curettage was dened as follows: (1) if secretory-,
inactive- or atrophic endometrium pattern, this was classied
as resolution; (2) if proliferative endometrium pattern, this
was classied as proliferative; (3) a diagnosis of persistence if
the follow-up curettage showed simple EH without atypia
and (4) a diagnosis of progression was made, if the specimen
showed complex EH and/or atypia (15).
Women with resolution discontinued progestin therapy and
were asked to attend for follow-up every 3 months. Women
diagnosed with proliferative or persistence in the follow-up
curettage were offered the same medication they were using,
norethisterone or letrozole, for another 3 months and were
then reevaluated. Treatment was to be stopped and hysterec-
tomy was to be offered if there was histo-pathological evidence
of progression of EH to atypia after 3 months of initial treat-
ment or persistence of uterine bleeding following a total of
6 months treatment without any further biopsies.
3. Statistical analysis
Data were analyzed using SPSS 16.0 (SPSS Inc., Chicago, IL,
USA) statistical program and unpaired t-test and Chi-square
tests were used to examine group differences as appropriate.
112 M. El-shamy et al.
4. Discussion
As shown in Table 1, the mean age, BMI, parity and meno-
pausal status in both groups show no signicant difference
P value 0.29, 0.30, 0.53, 0.60, respectively.
This prospective cohort trial demonstrates no difference be-
tween letrozole and norethisterone in the management of
endometrial hyperplasia without atypia. However, letrozole
may be superior over the conventionally used norethisterone
as regards the ET and serum E2 level following 3 months of
treatment as shown in Tables 2 and 3.
The price of letrozole, in the Egyptian market, is 15 times
more expensive than most available progestin. This huge dif-
ference in price may have an impact on the uptake of this
new treatment modality among different patient socioeco-
nomic groups. This is particularly important in countries
where health insurance or national free health service may
not be well-implemented. Health economic studies are war-
ranted to reveal the cost-effectiveness of this treatment.
The favorable effect of letrozole might be mediatedthrougha
direct inhibitory effect on the endometrium or through a sys-
temic pathway that reduces the amount of circulating estrogen
(1618). Recent data have shown more sustainable effects of
aromatase inhibitors compared to progestin (13,14). In one
study, administering up to 5 mg of letrozole per day produced
marked suppression of estradiol, estrone, and estrone sulfate
production with very few adverse effects. as shown in Table 3,
Our results strongly agreed with reports from a number of pre-
viously published trials which demonstrated a desirable effect of
aromatase inhibitors as shown in Tables 2 and 3 (13,20,21).
Endometrial hyperplasia usually affects either postmeno-
pausal women or women in their late reproductive age. Wo-
men in this age group might be at higher risk of other
cancers such as breast cancer. Aromatase inhibitors have been
approved as adjuvant therapy in the treatment of cancer breast
(25,26).
Our results showed no signicant difference in the rate of
endometrial regression between letrozole and norethisterone
Table 3 Endometrial thickness (ET) as measured by transvaginal sonography (TVS) at the start of treatment and 3 months later.
Letrozole Progestin P value
Endometrial thickness (cm) mean SD
Before treatment 1.11 0.42 1.15 0.33 0.68
Three months after treatment 0.83 0.14 0.95 0.24 0.03
a
Estradiol level (pmol/L) mean SD
Before treatment 90.5 13.1 95.2 12.3 0.15
Three months after treatment 75.3 7.3 84.4 10.4 <0.001
a
a
Statistically signicant: ET was signicantly thinner, after 3 months of treatment, in the group treated by letrozole than the group treated by
gestagens (mean difference 0.12, 95% CI: 0.230.01, P = 0.03). Serum E2 level was signicantly low in Group A compared to Group B after 3
months of treatment (mean difference 10.8, 95% CI: 14.467.13 and P < 0.001).
Table 1 Patients characteristics, with no signicant differences between Groups A and B as regards the age, parity, body mass index
(BMI) or menopausal status.
Letrozole (50 women) Progestin (50 women) P value
Age (mean SD) 52 3 51 9 0.29 = NS
BMI (mean SD) 33 8.1 34 5.2 0.30 = NS
Parity (mean SD) 2.1 1.2 2.2 1.1 0.53 = NS
Menopausal status
Premenopausal 20 (40%) 24 (48%) 0.60 = NS
Postmenopausal 30 (60%) 26 (52%)
The mean age, BMI, parity and menopausal status in both groups show no signicant difference P value 0.29, 0.30, 0.53, 0.60, respectively.
NS: non-signicant.
Table 2 Outcome of both treatments according to the results of endometrial histopathology obtained 3 months post treatment.
Treatment group Resolution Regression Persistence P value
Letrozole (Group A) 19 (38%) 30 (60%) 1 (2%) 0.29 = NS
Progestins (Group B) 20 (40%) 29 (58%) 1 (2%)
NS: non-signicant.
Aromatase inhibitor letrozole versus progestin norethisterone in women with simple end 113
after 3 months of treatment as shown in Table 3. The manage-
ment of these cases has been almost left at gynecologists dis-
cretion. There are no clear established guidelines for a
specic treatment modality. Extending the treatment with the
same dose seems a valid option (21). Ninety-nine percent
(99%) of cases were subjectively cured following six months
of initial treatment. We did not feel it is necessary to obtain an-
other endometrial sample as a test for cure.
Although estrogen and progesterone receptors are present
at high levels in hyperplastic endometrium (22), the question
of whether response to hormonal therapy would be predicted
by the receptor status has not been solved yet (23,24).
However, in our study we followed-up patients for a shorter
duration so we are not able, currently, to compare the long
term effects of letrozole.
Letrozole is a relatively new medication in the market and
its long term side effects have yet to be unveiled though most
available data showed a high degree of safety and compliance.
Unlike progestin that carries slight but sometimes very serious
risks of vascular and metabolic side effects, letrozole seems to
be more tolerable with fewer adverse effects such as headache,
muscle pain and dizziness (13,19).
Although we detected statistically signicant thinning of the
endometrial lining and lower E2 levels in the blood, in the pa-
tients receiving letrozole compared to progestin, there was no
signicant difference between the two medications as regards
the endometrial pattern as shown in Tables 2 and 3.
We admit that our study was not a randomized one. It in-
cluded a small number of participants without a prior sample
size calculation that may make it prone to type alpha statistics
error where a signicant difference is observed and it disap-
pears when sufcient number of participants is recruited.
We, therefore, call for a larger randomized trial to elucidate
the validity of this intervention in women with endometrial
hyperplasia. We would like to see more trials testing the effect
of letrozole on patients with early stage endometrial carcinoma
or as a postoperative adjuvant therapy to minimize rate of
recurrence as well as improving survival rates.
5. Results
After treatment by either medication for 3 months, none of the
cases had progression as evidenced by histopathology. There
was no statistically signicant difference between the two
groups as regards the proportion of women whose endometrial
sample revealed resolution, regressing or persistence after
3 months of treatment.
At the 6-month follow-up, only two women (4% in Group
B) in the norethisterone group continued to suffer from uterine
bleeding versus one woman (2% in Group A) in the letrozole
group. These women chose to undergo hysterectomy after
being counseled. Histopathology revealed complex endome-
trial hyperplasia with atypia in one of them and simple endo-
metrial hyperplasia without atypia in two of them.
6. Conclusion
To conclude, letrozole may be as effective as norethisterone for
women with abnormal uterine bleeding due to endometrial
hyperplasia without atypia.
Conict of interest
None.
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Aromatase inhibitor letrozole versus progestin norethisterone in women with simple end 115