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ISSN 0350-2899, 36(2011) br.2 p.79-84
Bleeding as a side effect in the first versus second year of continuous combined hormone replacement therapy
(Razlika u pojavi krvarenja kao sporednog efekta u prvoj i drugoj godini kontinuirane kombinovane hormonske supstitucije)
Gynecology and Obstetric Outpatient Clinic "Mošković" Belgrade, Serbia
INTRODUCTION: Continuous combined hormone replacement therapy (HRT) has been introduced in an attempt to increase patients’ compliance by eliminating withdrawal of bleeding which is one of the most significant and troublesome side effects of sequential HRT.
AIM: to analyse the onset, frequency and duration of bleeding during the first and second year in postmeno-pausal women receiving continuous estrogen-progestagen therapy.
METHODS: a prospective study of postmenopausal women who came to the clinic seeking help for menopausal symptoms. Patients received oral hormone replacement therapy: 1 tablet containing 2mg estradiol + 1mg norethisterone acetate daily in a continuous regime.
RESULTS: after 12 and 24 months of the therapy bleeding patterns were evaluated in 52 patients or 624 cycles and 50 patients or 600 cycles respectively. 73.1% patients had at least one bleeding episode during the first year of the therapy and 65.4% of them in the first 3 months of the therapy. In the second year 16 % of the patients had bleeding episodes or bleeding in 1.7% of cycles. In the first year of the therapy 73.4% bleeding episodes were irregular and 26.6% were cyclic. All bleeding episodes in the second year of the therapy were irregular and light. The average endometrial thickness before the therapy was 3.8 mm, after 12 months of the therapy it was 3.5 mm and after 24 months it was 3.2 mm.
CONCLUSION: continuous estrogen-progestagen therapy protects endometrium from proliferation thus the majority of women experienced amenorrhea. Even irregular bleeding episodes were mostly light and of short duration, but may be the reason for the discontinuation of the therapy. A long lasting therapy is much better tolerated and accepted.
Key words: Continuous combined estrogen-progestagen therapy, bleeding, postmenopause
Estrogen replacement therapy provides benefits to women with
respect to menopausal symptoms [1,2], and prevention of
The aim of the study is to analyse the onset, frequency and duration of bleeding during the first and second year in postmenopausal women receiving continuous estrogen-progestagen therapy. The aim of the study is also to study the difference in bleeding pattern and acceptance of therapy between the first and second year of therapy
An open prospective study was conducted in Gyne-cology and Obstetrics Outpatient Clinic "Moškovic" in Belgrade. Postmenopausal women who came to the G/Ob Clinic seeking help for menopausal symptoms from January 2005 to November 2007 were recruited for study. There were 84 postmeno-pausal women (last menstrual period more than 12 months earlier), with intact uterus and at least 12 months without any hormonal replacement therapy in this period. Some of them came for the first time to our clinic. Prior to initiating the therapy, general medical anamnesis, gynecological bimanual exam, colposcopy and PAP smear, vaginal ultrasound (vaginal probe 5.7Mhz) and breast ultrasound (linear probe 7Mhz) were performed. Patients were informed about the therapy: effects, risks and side effects and asked to complete written data about the onset and duration of bleeding for each therapy cycle. All women who were candidate for the therapy were given prescription for oral therapy of 1 tablet daily, containing 2mg estradiol + 1mg nore-thisterone acetate in a continuous regime. All patients were asked to come after 3 months for consultations and the revision of effects and side effects of the therapy. This is a policy of our G/Ob Clinic for any hormonal therapy. Endometrial thickens was evaluated before the therapy and after 12 and 24 months of the therapy. After 12 months and after 24 months the patients come for regular check up and evaluation of the therapy as at the beginning of the therapy.
Symptomatic postmenopausal women who entered the study were 39-57
years old. 54 (64.3 %) of them had been in postmenopause for less
than 5 years, and 30 (35.7%) of them had been in postmenopause for 5
and more years. From all women who were candidate for the therapy,
24 (28.6%) were excluded from the study. At the basic ultrasound
exam we found out endometrial thickness 7 to 9 mm in 7 (8,8%)
patients . They were given progestagen therapy and after bleeding
they were suggested sequential replacement therapy. In 3 (3.6%)
cases endometrial thickness was 14 -16 mm and D&C with histological
examination of endometrium was performed. Nothing but endometrial
hyperplasia was found. These patients were also suggested sequential
replacement therapy. One patient was excluded due to previous vein
thrombosis. There were no patients with previous unopposed estrogen
therapy, undiagnosed vaginal bleeding, uncontrolled hypertension or
previous malignancy in this group. 13 (15.5%) patients were afraid
of hormones and asked for some other more natural therapy. Of all
patients who were candidates for the therapy 60 (71.4%) otherwise
healthy patients started continuous combined estrogen progestagen
therapy. Of all 60 patients who initiated the therapy, 5 patients
(8.4%) got discontinued therapy due to irregular bleeding: 2 women
after 1st cycle, 1 women after 2nd cycle, 2 women after 7th
and 8th cycles. 3 patients did not come for a check up
visit after twelve months.
Table 2. Distribution of bleeding patterns according to the No of bleeding cycles(1st year)
Table 3. Distribution according to the duration of bleeding - 1st year
28 (87.5%) patients who had been in postmenopause for less than 4
years had at least one bleeding episode. 12 (60%) patients who had
been for more than 4 years in postmenopause had bleeding episodes.
Bleeding episodes were more often in early postmenopause
independently of the women’s age.
The endometrium is target tissue for both endogenous and
exogenous sexual hormones . Increasing our understanding of the
effects of exogenous hormones on the endometrium may help to avoid
risks and to optimize patient satisfaction with hormone replacement
therapy [10, 11]. Sequential hormone replacement therapy results in
cyclic bleeding pattern  thus continuous combined therapy is
introduced to avoid bleeding in postmenopausal women. In a long
lasting therapy atrophy of endometrium and amenorrhea depend on the
kind and dose of progestagen .
Women in postmenopause, especially in late meno-pause, do not tolerate restoring of regular bleeding while in sequential regime of hormone replacement therapy; that is why continuous estrogen-progestagen therapy is more appreciable for them. The majority of women who receive continuous estro-gen-progestin therapy experience bleeding episodes in the first 12 months of the therapy, but only few in a long lasting therapy. Continuous estrogen-progestagen therapy protects endometrium from pro-liferation and hyperplasia thus bleeding episodes are mostly due to endometrium atrophy. Even irregular bleeding is mostly light and of short duration; but may be the reason for the discontinuation of the therapy in 8.4% of the women in the first year but none of the women discontinued the therapy in the second year. A long lasting therapy is much better tolerated and accepted with a few bleeding episodes as a side effect.
Sinđelićeva 40, 11000 Beograd
Phone 063 348 180; Fax. 011 308 99 44;
Paper aaccepted: 08.07.2011
Paper Internet issues: 21.10.2011
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