Journal of Regional Section of Serbian Medical Association in Zajecar

Year 2011     Vol 36     No 2
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      UDK 618.173-085.357

ISSN 0350-2899, 36(2011) br.2 p.79-84

Original paper

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)

Terezija Mošković
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

Napomena: sažetak rada na srpskom jeziku
Note: abstract in Serbian



Estrogen replacement therapy provides benefits to women with respect to menopausal symptoms [1,2], and prevention of osteoporosis. [3,4].
The addition of progestin to estrogen replacement therapy in cyclic or continuous regimens has been shown to significantly decrease the incidence of endometrial pathology [5,6]. Cyclic HRT regime results in reasonably predictable withdrawal of bleeding [7].
However many postmenopausal women reject to use HRT because of the continuation of regular menstrual bleeding with sequential combined regiments. In order to minimize this inconvenience, a continuous combined regime has been developed [8].


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.
After finishing the first year of the therapy, the total of 624 cycles or 52 women were analyzed.
During the first year of the therapy, 38 women (73.1%) had at least one bleeding episode, 34 (65.4%) of them had bleeding episodes in the first 3 months of the therapy. The percentage of women with bleeding episodes declined from 55.8% in 1st cycle to 40.4% in 2nd cycle, to 26.9% in 3rd cycle and 1.9% in 12th cycle (Table 1).

Table 1. Bleeding frequency

Ordinal number of cycles in 1st year 1 2 3 4 5 6 7 8 9 10 11 12
No of women with bleeding 29 21 14 9 8 5 6 7 8 2 3 1
Percentage 55.8 40.4 26.9 17.3 15.4 9.6  11.5 13.5 9.6 3.8 5.8 1.9

Table 2. Distribution of bleeding patterns according to the No of bleeding cycles(1st year)

No of bleeding cycles 1 2 3 4 5 6 7
No of women 17 6 8 3 2 1 1
Percentage 44.7 15.8 21.1 7.9 5.3 2.6 2.6

Table 3. Distribution according to the duration of bleeding - 1st year

Duration of bleeding (days) No of bleeding episodes Percentage
1-2 16 17.4
3-5 40 43.5
5-10 23 25.0
>10 13 14.1

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.
Of all patients who experienced bleeding in the first year of the therapy 23 (60.5%) had bleeding episodes in one or two cycles and only 1 (2.6 %) had bleeding episodes in 7 cycles (Table 2).
Bleeding onset was found in 88 cycles (14.1%) in the first year of the therapy. In 73.4% of bleeding cycles in the first year of the therapy irregular bleeding was found and 26.6% were cyclic bleeding episodes.
In 62% of bleeding cycles there was one bleeding episode and in 22.0% of bleeding cycles there were two bleeding episodes.
60.9% of bleeding episodes lasted for less than 5 days and 14.1% of bleeding episodes lasted for more than 10 days (Table 3).
Only 11.8% of bleeding episodes were menstrual like bleeding and all the others were light and spotting.
After 24 months of the therapy, 50 patients or 600 cycles were analysed. In the second year of the therapy 1 patient discontinued the therapy after 17 months because of an orthopedic surgery, and 1 was afraid of therapy risks and discontinued the therapy after 14 months. They were not included in the second year analysis of bleeding pattern. Of all 60 patients who initiated the therapy, 50 or 83.3% finished the second year of the therapy.
Of all 50 patients who completed the second year of the therapy only 8 (16 %) had bleeding episodes: 6 patients in one cycle and 2 patients in 2 cycles.
Of all 600 cycles in the second year of the therapy bleeding onset was found in 10 or 1.7% of cycles.
In all bleeding cycles there was only one bleeding episode.
All bleeding episodes were very light, irregular and spotting.
4 (40.0%) bleeding episodes lasted for less than 5-10 days, and 6 (60.0%) episodes lasted for more than 10 days.
The average endometrial thickness before therapy was 3.8 mm and between 8-12 months of the therapy it was 3.5mm. The average endometrial thickness after 18 to 24 months was 3.2 mm.
Endometrial thickness of more than 5 mm was noticed neither in the first nor in the second year of the therapy. No differences in endometrial thickness between the patients with or without bleeding episodes were found in the first and in the second year.


The endometrium is target tissue for both endogenous and exogenous sexual hormones [9]. 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 [8] 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 [12].
In the first year of the therapy 73.1% patients had at least one bleeding episode, and only 16% in the second year of the therapy. Continuous combined therapy results in 85.9% amenorrheic cycles in the first year of the therapy and 98.3% amenorrheic cycles in the second year of the therapy. At the end of the third and sixth therapy cycles 73.1% and 90.4% of patients were amenorrheic respectively. At the end of 24th cycle of the therapy all patients had amenorrhea. The results were more or less similar to other authors [13, 14].
The incidence of amenorrhea increased and irregular bleeding decreased with longer duration of treatment. 8.4 % of treated women discontinued the therapy because of undesirable bleeding in the first year. It is less than other authors reported [9], and may be due to good motivation for the therapy as well as good support of their gynecologists. None of the women discontinued the therapy in the second year. Very few bleeding episodes and increased percentage of amenorrhea may be one of the reasons for excellent acceptance of the therapy in the second year. Women satisfied with positive effects of the therapy on menopausal symptoms may ignore undesirable bleeding.
We expected to find out atrophic endometrium in case of irregular bleeding due to progestagen effect [8]. There was not need for D&C in all cases of bleeding because the endometrium was not ticker than 4-5mm [14].
Although available data indicate no relation between bleeding and endometrial histology during the treatment with continuous combined HRT [15] there remains concern that such bleeding may be a sign of endometrial pathology; that is why close follow up and monitoring must be performed [16]. Gynecologists must be well trained to find out the cause of bleeding, especially in a long lasting therapy and try to avoid unnecessary D&C as an invasive procedure. Endometrial thickness up to 4 mm can be regarded as completely normal finding in patients on continuous combined HRT [17].
The question is: why women bleed from an atrophic endometrium or why do they not bleed if they have atrophic endometrium? The factors or mechanisms involved in bleeding during continuous combined HRT are not well understood. Steroidal regulation of angiogenesis and the growth factor expression is not fully understandable. The key to understanding endometrial bleeding may be in the endometrial vasculature [18] and stoma [19]. Combined estrogen-progestagen hormone therapy may maintain an underdeveloped endometrium that remains inactive with low mitotic activity in glands and stoma, which results in amenorrhea for years [20].
Some authors believe that bleeding during the initial year of continuous combined HRT reflects the endometrial adaptation to therapy rather than the presence or development of endometrial abnormalities [21].


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.


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      Corresponding Address:
Terezija Mošković
Sinđelićeva 40, 11000 Beograd
Phone 063 348 180; Fax. 011 308 99 44;
Paper received: 18.04.2011
Paper aaccepted: 08.07.2011
Paper Internet issues: 21.10.2011
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Timočki medicinski glasnik, Zdravstveni centar Zaječar
Journal of Regional section of Serbian medical association in Zajecar
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