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Maturitas 66 (2010) 201205

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Maturitas

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m a t u r i t a s

Ultra low dose continuous combined hormone replacement therapy with 0.5 mg

17-oestradiol and 2.5 mg dydrogesterone: Protection of the endometrium andamenorrhoea rate

C. Bergeron a,, F.F. Nogales b, T. Rechberger c, T. Tatarchjuk d, L. Zipfel e

a Laboratoire Cerba, 95066 Cergy Pontoise Cedex 9, Franceb Department of Pathology, University of Granada, Spainc II Dept of Gynecology, Medical University, Lublin, Polandd Institute of Obstetrics and Gynecology, Kiev, Ukrainee Solvay Pharmaceuticals, Marietta, GA, USA

a r t i c l e i n f o

Article history:

Received 2 November 2009

Received in revised form 25 February 2010

Accepted 8 March 2010

Keywords:

Hormone replacement therapy

Endometrial safety

Bleeding

Estradiol

Dydrogesterone

Postmenopausal

a b s t r a c t

Objectives and study design:The aim of this open, multicentre study was to demonstrate the endometrial

safety and assess the bleeding pattern of ultra low dose continuous combined hormone replacement

therapy with 0.5mg 17-oestradiol and 2.5 mg dydrogesterone in 446 healthy, non-hysterectomised,postmenopausal women with symptoms of oestrogen deficiency.

Main outcome measure:Aspiration endometrial biopsies were performed at baseline and after 1 year of

treatment to assess the incidence of endometrial hyperplasia or a more serious endometrial outcome.

Results:The only adverse endometrial outcome at the end of the study was one case of simple hyper-

plasia. This gives an overall incidence of 0.27% (95% CI: 0.011.48%) in the per protocol sample ( n =395).

The overall rate of amenorrhoea in the full sample ( n =446) was 68% and 14% had only one or two

bleeding/spotting episodes. The rate of amenorrhoea in months 1012 (n = 413) was 88%. The number of

bleeding/spotting days per cycle fell during the study. The mean number of bleeding/spotting days was

5.8 and the mean number of days without bleeding was 358.2. Spotting alone was the most prevalent

bleeding intensity, whilst heavy bleeding was rare.

Conclusions:In conclusion, 2.5mg dydrogesterone continuously combined with 0.5mg 17-oestradioleffectively protects the endometrium in postmenopausal women in accordance with the guidelines of

the Committee for Medicinal Products for Human Use(CHMP). It hasa favourable amenorrhoea rate and

is well tolerated by the majority of women.

2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Hormone replacementtherapy(HRT) withoral continuouscom-

bined 1mg 17-oestradiol and 5 mg dydrogesterone has proved

to be effective in relieving climacteric symptoms and increas-

ing bone mineral density in postmenopausal women [1], whilst

demonstrating good endometrial safety and bleeding patterns[2,3].Nevertheless, current guidelines recommend the use of the

lowest effective dose of oestrogen for the management of climac-

teric symptoms [46]. For this reason, an ultra lowdose continuous

combined regimen of 0.5 mg 17-oestradiol and 2.5 mg dydroges-terone has been developed. The use of low dose oestrogen permits

lower progestogen doses to protect the endometrium. Such low

dose HRTcombinations mayreduce theincidence of adverse events

Corresponding author. Tel.: +33 0134 40 21 17; fax: +33 0134 40 20 29.

E-mail address: bergeron@lab-cerba.com(C. Bergeron).

such as breast tenderness, vaginal bleeding, cardiovascular dis-

ease, stroke or venous thromboembolism, whilst maintaining the

benefits on climacteric symptoms [711]. As well as improving

the overall safety profile, a reduction in bothersome side effects

achieved with low doses is likely to improve compliance with the

treatment regimen.

The main objective of this study was therefore to demonstratethe endometrial safety of ultra low dose continuous combined

HRT with 0.5mg 17-oestradiol and 2.5 mg dydrogesterone inpostmenopausal women in accordance with the guidelines of the

Committee for Medicinal Products for Human Use (CHMP). A sec-

ondary objective was to assess the bleeding profile.

2. Methods

2.1. Subjects

A 1-year, open, multicentre (6 centres in Romania, 5 in

Poland and 5 in Ukraine) study was carried out in healthy,

0378-5122/$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/j.maturitas.2010.03.007

http://www.sciencedirect.com/science/journal/03785122http://www.elsevier.com/locate/maturitasmailto:bergeron@lab-cerba.comhttp://localhost/var/www/apps/conversion/tmp/scratch_4/dx.doi.org/10.1016/j.maturitas.2010.03.007http://localhost/var/www/apps/conversion/tmp/scratch_4/dx.doi.org/10.1016/j.maturitas.2010.03.007mailto:bergeron@lab-cerba.comhttp://www.elsevier.com/locate/maturitashttp://www.sciencedirect.com/science/journal/03785122

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202 C. Bergeron et al. / Maturitas 66 (2010) 201205

non-hysterectomised, postmenopausal women (aged 45 years)

with symptoms of oestrogen deficiency who had been amenor-

rhoeic for 12 months or more and who had serum oestradiol and

follicle-stimulating hormone levels within the postmenopausal

range (1050 ng/l and 36157 U/l, respectively). All women were

required to have a baseline biopsy showing either atrophic, secre-

tory, menstrual type or proliferative endometrium or insufficient

available endometrial tissue for diagnosis (not due to an inac-

cessible cervix) with a double-layer endometrial thickness of

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Table 1

Baseline demographic characteristics (n = 454).

Age (years)

Mean (SD) 53.54.6

Range 4073

Weight (kg)

Mean (SD) 72.312.1

Range 45.0114.6

Body mass index (kg/m2)

Mean (SD) 27.44.4

Range 17.243.7

Height (cm)

Mean (SD) 162.45.8

Range 138181

Duration of amenorrhoea (months)

Mean (SD) 59.753.1

Range 12330

FA sample therefore consisted of 446 women. A flow chart of the

samples analysed is shown inFig. 1.

3.1. Endometrial safety

Of the 446 women in the FA sample, 34 had no baseline biopsy

and a further 17 women had no end-of-treatment biopsy. The

endometrial-PP sample therefore consisted of 395 women (Fig. 1).

Endometrial histology at baseline and at the end of treatment is

shown inTable 2.There was one case of simple hyperplasia after 1

year of treatmentamongthe women in theendometrial-PPsample,

resulting in an overall incidence of adverse endometrial outcomes

Fig. 1. Flow chart of samples analysed.

Table 2

Endometrial histology at baseline and end of treatment: endometrial-PP sample

(n =395).

Baseline:n(%)

No tissue 12 (3.0%)

Tissue insufficient for diagnosis 149 (37.7%)

Atrophic endometrium 198 (50.1%)

Secretory endometrium 11 (2.8%)

Menstrual type endometrium 5 (1.3%)

Proliferative endometrium 16 (4.1%)

Simple hyperplasia 1 (0.3%)Atrophic polyps 3 (0.8%)

End of treatment:n(%)

No tissuea 15(3.8%)

Tissue insufficient for diagnosisb 129(32.7%)

Atrophic endometrium 203 (51.4%)

Secretory endometrium 11 (2.8%)

Menstrual type endometrium 4 (1.0%)

Proliferative endometrium 30 (7.6%)

Simple hyperplasia 1 (0.3%)

Atrophic polyps 1 (0.3%)

Hyperplastic polyps without atypia 1 (0.3%)

a Excluded from the final analysis.b Histological assessment not possible in n = 6 biopsies; excluded from the final

analysis.

of 0.27% (95% CI: 0.011.48%). The initial biopsy taken at the end

of treatment was assessed as tissue insufficient for diagnosis, with

TVUS showing an endometrial thickness of 11.8mm. Subsequent

curettage of the endometrium showed simple hyperplasia.

Of the 395 women in the endometrial-PP sample, 21 were

excluded from the final analysis. In 6 women the TVUS revealed an

endometrial thickness5 mm; the biopsy material attained never-

theless did not allow any histological assessment. In the remaining

15 women with an endometrial thickness 5 mm as assessed by

TVUS, the technical approach to attain tissue failed. The women

refused a second biopsy, therefore no histological diagnosis could

be performed. There was no evidence from the TVUS or physi-

cal examination of an adverse endometrial outcome in these 21

women.

3.2. Bleeding profile

Bleeding profile was assessed in the 446women included in the

FA sample.

The mean number of days with bleeding/spotting per standard-

ised 28-day cycle decreased during the treatment period (Fig. 2).

The cycle effect evaluated by repeated measures of ANOVA was

statistically significant (p = 0.0045). As the data did not meet the

assumptions of a normal ANOVA, each bleeding variable was

replaced by its rank and a standard ANOVA calculation was per-

formed on the rank-transformed data. The cycle effect remained

statistically significant (p = 0.0027). Overall, 68.4% of the women

hadno bleeding or spotting (amenorrhoea) and83.0% hadno bleed-ing throughout the study. One, two and three bleeding/spotting

episodes were recorded in 7.6%, 6.5% and 2.7% of women, respec-

tively, whilst less than 3% of the women had more than 10

bleeding/spotting episodes. The rate of amenorrhoea in the 413

women who completed months 1012 of the study was 87.6%.

The number of days with particular bleeding intensities during a

standardised 364-day period is shown inTable 3.The mean num-

ber of bleeding/spotting days was 5.8 (range 0130) and the mean

numberof days without bleeding was358.2 (range234364). Spot-

ting accountedfor most of thebleeding/spottingdays,whilstheavy

bleeding was uncommon. The majority of women were bleed-

ing free for the duration of the study (median 363 days). The

meanbleeding-free interval was 253.7 days(range 7364). Adverse

events associated with bleeding problems included metrorrha-

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204 C. Bergeron et al. / Maturitas 66 (2010) 201205

Fig. 2. Mean (95% confidence interval) number of days with bleeding/spotting per cycle (FA sample).

gia (designated as an adverse event by the investigator amongst

women reporting their bleeding intensityas heavy) in 31 women

and uterine haemorrhage (reported as an adverse event) in 29

women, the majority of which were considered mild. Only one

woman withdrew from the study prematurely due to bleeding

problems (uterine haemorrhage).

3.3. Safety and tolerability

Treatment was well tolerated. Adverse events considered at

leastpossiblyrelatedto studytreatment occurredin 72/446 women

(16.1%). The most common adverse events were metrorrhagia

(n = 31; 7.0%) and uterine haemorrhage (n = 29; 6.5%). Breast pain

was reported by 7 women (1.6%) and breast discomfort by 4 (0.9%).Three women experienced serious adverse events (rectal polyp,

renal stone removal and exacerbation of chronic calculous chole-

cystitis) and one woman withdrew due to an adverse event (pelvic

pain). There were no clinically significant changes in vital signs or

laboratory parameters.

4. Discussion

The results of this study confirmed the endometrial safety of

ultra low dose continuous combined oral HRT with 0.5 mg 17-oestradiol and 2.5 mg dydrogesterone in postmenopausal women.

After 1 year of treatment, one woman (0.27%; 95% CI: 0.011.48%)

developed an adverse endometrial outcome in the form of sim-

ple hyperplasia. This is within the range of the CHMP guidelinesfor the conclusion of endometrial safety for new HRT regimens,

which requires that the upper limit of the two-sided 95% CI for the

incidence of adverse endometrial outcomes does not exceed 2%.

Table 3

Number of days with particular bleeding intensities during a standardised 364-day

period: FA sample (n = 446).

Mean Range

No bleeding 358.2 234364

Spotting 3.9 0130

Slight bleeding 1.2 061

Normal bleeding 0.6 024

Heavy bleeding 0.1 012

Bleeding or spotting 5.8 0130

The endometrial safety observed with thisultra low dosecombi-

nation is comparable to that seen with higher doses. One previous

study investigated the endometrial effects of continuously com-

bining 1 or 2mg 17-oestradiol with 2.520 mg dydrogesterone in960 postmenopausal women [3]. A dydrogesterone dose of 5 mg or

above effectively protected the endometrium from either dose of

17-oestradiol. The latter study used a particularly cautious defi-

nition of endometrial protection, with proliferative endometrium,

endometrial polyp and endometrial hyperplasia and cancer all

being considered as inadequate. Among women given 1 mg 17-oestradiol combined with 5, 10 or 20mg dydrogesterone for

52 weeks, success was observed in 165/170 (97.06%, lower 95%

CI 93.92), 160/165 (96.97%, 93.73) and 147/150 (98.00%, 94.91)

women, respectively. There were no cases of endometrial hyper-plasiaor cancer. Inthose given 2 mg17-oestradiol combined with

5, 10 or 20 mg dydrogesterone for 24 weeks, success was observed

in 40/42 (95.24%, lower 95% CI 85.76), 42/43 (97.67%, 89.44) and

21/23 (91.30%, 75.07) women, respectively. One case of hyperpla-

siaoccurredin the2/5 mg group.A subsequent study assessed 1 mg

17-oestradiol continuously combined with 5 mg dydrogesteronein 290 postmenopausal women[2].After 1 year, one woman had

developed simple hyperplasia resulting in a failure rate of 0.36%

(upper 95% CI 1.71).

The administration of a progestogen reduces the risk of

endometrial hyperplasia and carcinoma associated with unop-

posed oestrogen, but may cause unacceptable bleeding and

spotting that can influence adherence to treatment [13,14]. It is

therefore important that any vaginal bleeding is minimised as faras possible. The majority of women in the current study remained

amenorrhoeic (absence of bleeding or spotting) (68%) or had no

bleeding episodes (83%) and a further 14% of women had only

one or two bleeding/spotting episodes. The rate of amenorrhoea

in months 1012 was 88%. Spotting alone was the most prevalent

bleeding intensity and heavy bleeding was rare. The overall inci-

dence of bleeding/spotting also declined steadily over time. This

bleeding profile is better than that observed with higher doses of

continuous combined 17-oestradiol and dydrogesterone[2].Theopen design of the current study and the inclusion of only a single

treatment arm should be noted as a possible limitation.

In conclusion, ultra low dose continuous combined HRT with

0.5mg 17-oestradiol and 2.5mg dydrogesterone demonstratesendometrial safety in postmenopausal women according to CHMP

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C. Bergeron et al. / Maturitas 66 (2010) 201205 205

guidelines, is associated with a favourable amenorrhoea rate and is

well tolerated in the majority of women.

Contributors

C. Bergeron and F.F. Nogales participated in the assessment of

endometrial biopsies andhave seen andapprovedthe final version.

T. Rechberger and T. Tatarchjuk participated in the conduct of the

studyas investigators andhaveseen andapproved thefinalversion.

L. Zipfel participated in the statistical design and analysis of the

study and has seen and approved the final version.

Competing interest

C. Bergeron, F.F. Nogales, T. Rechberger and T. Tatarchjuk have

no conflict of interest. L. Zipfel is an employee of Solvay Pharma-

ceuticals.

Funding

The study was sponsored by Solvay Pharmaceuticals.

Acknowledgements

We would like to thank Jane Irons for the technical, linguistic

and style editing of the manuscript.

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