hysteroscopic findings in postmenopausal patients using tibolone

© 2002 Blackwell Science Ltd

Gynaecological Endoscopy

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ABSTRACT

Objective

To investigate the cause of uterine bleeding in tibolone users whowere referred to an endoscopy unit.

Design

Hysteroscopy followed by endometrial biopsy was carried out in allpatients. The endometrial echo was measured by transvaginal sonographyprior to hysteroscopy and compared with hysteroscopic findings.

Results

Endometrial polyps were the pathological lesions most frequentlydiagnosed by hysteroscopy in tibolone users. However, their diagnosis wasmissed by blind endometrial biopsy in all cases. The surroundingendometrium was always atrophic even when a polyp was present in theuterine cavity. There was one case of endometrial carcinoma which occurredin association with a polyp.

Conclusion

Tibolone does not exert any stimulatory effect on the normalendometrium. However, intrauterine lesions such as polyps can grow inresponse to this treatment. The presence of polyps is associated withabnormal uterine bleeding in these patients.

Correspondence

H. Maia Jr, Endoscopy Unit, CEPARH, Rua Caetano Moura, 35, Salvador 40.210–341 Bahia, Brazil.

Accepted for publication 10 January 2002

Blackwell Science, LtdOxford, UKGENGynaecological Endoscopy0962-1091Blackwell Science Ltd, 200211

Original Article

HYSTEROSCOPIC FINDINGS IN POSTMENOPAUSAL PATIENTS USING TIBOLONEH. MAIA et al.

Hysteroscopic findings in postmenopausal patients using tibolone

Hugo Maia,

1

Simone Machado,

2

Silvana Borges,

2

Ariane Chagas,

2

Amélia Maltez

3

and Elsimar M. Coutinho

1

1 Endoscopy Unit, CEPARH, Salvador, Bahia, Brazil 2 Hysteroscopy Unit, Hospital São Rafael, Salvador, Bahia, Brazil 3 Pathology Department, CEPARH, Salvador, Bahia, Brazil

Keywords

endometrial biopsy, endometrial polyp, HRT, hysteroscopy, menopause, tibolone.

INTRODUCTION

Tibolone (Org OD14) is one of the alternatives toconventional hormone replacement therapy (HRT)because of the low incidence of endometrial stimula-tion and bleeding observed in clinical trials.

1

The lackof proliferative effects on the endometrium is oneimportant advantage of tibolone over other forms ofHRT and is a consequence of its tissue-specific meta-bolism. In the endometrium, tibolone is preferentiallytransformed into its delta 4 metabolite, which showsaffinity to androgen and progesterone receptors butnot to estrogen receptors.

2

Indeed, studies have shownthat in most patients using tibolone the endometriumwas atrophic and endometrial hyperplasia was rarelyseen.

3

Although approximately 12–20% of patients on tibo-lone experience some episodes of vaginal bleeding,endometrial biopsies carried out in these cases have

shown that most such bleeding derives from an atrophicendometrium.

4

However, other studies using hystero-scopy to evaluate the uterine cavity have revealed that thepresence of intrauterine pathologies was responsible forthe occurrence of bleeding in tibolone users.

5,6

In thesepatients, endometrial polyps and submucous myomaswere the lesions detected most frequently by hystero-scopic examination. The discrepancy between biopsyand hysteroscopic findings may be caused by the inabilityof blind endometrial biopsies to correctly identify polypsand submucous myomas in the majority of patients.

7

In fact, in menopausal patients who were experiencingabnormal uterine bleeding during HRT, the diagnosisof endometrial polyp was missed by endometrial biopsyin most cases.

8

In the present study, the causes of uterine bleedingin postmenopausal patients using tibolone were investig-ated by means of hysteroscopy, endometrial biopsy andtransvaginal sonography (TVS).

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SUBJECTS AND METHODS

A total of 85 consecutive postmenopausal patients,referred either to CEPARH or to the Hospital São Rafaelwith abnormal uterine bleeding after using tibolone(Livial; Organon, São Paulo, Brazil), 2.5 mg d

−

1

, wereenrolled in this study. According to the medical recordsof these patients, routine TVS had been carried outbefore initiation of tibolone therapy to exclude patientsfrom treatment whose endometrial echo was alreadygreater than 5 mm.

The patients underwent at least one more TVS within1 month prior to hysteroscopy. The endometrial thick-ness measured under these circumstances was comparedwith the hysteroscopic findings. Hysteroscopy wascarried out using CO

2

as the distension medium (

n

= 60)or saline in continuous flow (

n

= 25), after a paracervicalblock had been established with the injection of 5 mL oflidocaine 1% precisely at the junction of the vaginalmucosa with the cervix, at the 4 and 8 o’clock positions.After completion of the hysteroscopic examination, theuterine cavity was deflated and a 4-mm plastic Karmancurette (IPAS, Carrboro, NC, USA) was then introducedin order to carry out a blind endometrial biopsy. Thecurette was attached to a 10-mL syringe to produce avacuum and the uterine cavity was aspirated for approx-imately 1 minute. Tissue fragments were fixed in formalinand sent for pathological examination.

The hysteroscopic findings were compared with thepathology reports for biopsy specimens. Statistical analysiswas carried out using Student’s

t

-test, with significanceset at

P

< 0.05.

RESULTS

The hysteroscopic findings in the postmenopausal patientswith episodes of uterine bleeding after tibolone use areshown in Table 1. In 61 patients (72%), hysteroscopyidentified the presence of endometrial polyps in theuterus. The surrounding endometrium in these patientswas always atrophic, showing areas of active haemorrhagewith capillary fragility (Fig. 1). The endometrial echo meas-ured by TVS was 8

±

2 mm in these patients (Table 2).

In 21 patients (25%), hysteroscopy failed to revealthe presence of any intrauterine pathology that could beresponsible for the occurrence of abnormal bleeding. Inthese patients, the endometrium displayed only featuresof atrophy with areas showing haemorrhagic foci. Thecapillaries also showed fragility, which resulted in bleed-ing at the slightest contact between the hysteroscope andthe atrophic mucosa (Fig. 2). The endometrial echo was3.1

±

1.2 mm in these patients. There was only one caseof atrophic endometrium in which the endometrialecho was >4 mm and this occurred in a patient who hadsynechia in the uterine cavity.

The mean duration of tibolone use was significantlygreater in patients with endometrial polyps than in thosewith atrophic endometrium. In patients with atrophicendometrium, the onset of bleeding occurred duringthe first months of tibolone use, while in the patientswith endometrial polyps bleeding occurred much laterin treatment, with mean durations of 3

±

2 and17

±

11 months of tibolone use, respectively. In twopatients, the cause of bleeding was the presence of asubmucous myoma surrounded by an atrophic mucosa.

The comparison between hysteroscopic and endo-metrial biopsy findings is summarized in Table 3. In allthe cases of endometrial polyps and submucous myomas,the pathology findings from blind biopsy specimensrevealed only atrophic endometrium. Concordancebetween these two diagnostic methods occurred only incases of endometrial atrophy and in the only patient withendometrial carcinoma. In the latter, an endometrialcarcinoma was found in a polyploid outgrowth occupyingthe fundal region of the uterine cavity. This patient had

Table 1 Hysteroscopic findings in women with uterine bleeding whilst using tibolone

Findings n %

Endometrial polyp 61 72Atrophic endometrium 21 25Submucous myoma 2 2Endometrial carcinoma 1 1Total 85

Table 2 Duration of use, age and endometrial echo in tibolone users, according to endometrial pathology

Atrophic endometrium Endometrial polyp Significance

Age (range), years 59.6 ± 6 (48–70) 61 ± 7 (49–67) NSDuration of use (range), months 3 ± 0.6 (2–4) 17 ± 11 (2–48) <0.01Endometrial echo (range), mm 3 ± 1 (2–7) 8 ± 2 (4–14) <0.01

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undergone a diagnostic hysteroscopy 2 years previously,at another institution, which had revealed the presenceof an endometrial polyp in the uterine cavity. Anendometrial biopsy carried out at that time showed only

atrophic endometrium. The patient continued to usetibolone on her physician’s advice because the biopsyresults were negative, but 2 years later she started to haveprofuse bleeding and a second hysteroscopy with

Figure 1 Hysteroscopy in a 65-year-old patient with bleeding after using tibolone. Note the presence of an endometrial polyp and the atrophic mucosa.

Figure 2 Hysteroscopic view of an atrophic uterine cavity in a 52-year-old patient with bleeding after using tibolone.

Endometrial biopsy

Endometrial polyp Atrophy Myoma Carcinoma

HysteroscopyEndometrial polyp 0 61 0 0Atrophy 0 21 0 0Myoma 0 2 0 0Carcinoma 0 0 0 1

Table 3 Comparison between hysteroscopic and endometrial biopsy findings in tibolone users with bleeding



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endometrial biopsy confirmed the diagnosis of endo-metrial carcinoma (Fig. 3). TVS showed an endometrialecho of 14 mm.

DISCUSSION

The present study showed that endometrial polyps wasthe most frequently found intracavitary lesion in post-menopausal patients with abnormal uterine bleedingafter using tibolone. Endometrial hyperplasia, on theother hand, was not observed in any of the cases. Thisconfirms previous reports that tibolone does notprovoke proliferation of the normal endometrium.

9

Thelack of proliferative effects of tibolone may be accountedfor by its transformation in the endometrium to a delta4 metabolite which is devoid of any estrogenic action.

2

This explains why the endometrium was atrophic, show-ing no signs of proliferation even when endometrialpolyps were present.

The high incidence of endometrial polyps in tiboloneusers which was seen in the present study confirms pre-vious observations carried out with hysteroscopy; theserevealed that the presence of uterine intracavitarylesions accounts for a large number of the bleeding epis-odes reported during tibolone treatment.

5,6

The higherincidence of endometrial polyps in menopausal patientsusing HRT has also been observed in previous studies.

8,10

Our findings that endometrial polyps are missed byblind biopsy suggest that this pathology may be under-diagnosed in studies in which endometrial biopsies areused to evaluate the uterine cavity, making it difficult toestimate the real incidence of endometrial polyps inthese patients. In fact, in the present report, atrophic

endometrium was indeed the most frequent patholog-ical finding in biopsy specimens taken from patientswith hysteroscopically diagnosed endometrial polyps.

Although hysteroscopy is more costly and difficultto carry out than blind endometrial biopsies, its useshould be encouraged as part of the diagnostic work-upof symptomatic postmenopausal patients using HRT,particularly when an endometrial echo of >4 mm isencountered at TVS examination. Our finding thatpatients with endometrial polyps had been using tibolonefor longer periods of time than those with anatrophic endometrium suggests an association betweenprolonged tibolone use and the growth of endometrialpolyps. However, it is not possible to determine fromthis study the percentage of patients who were alreadyharbouring clinically undetected endometrial polypsat the beginning of HRT. Although these patients wereasymptomatic, and had an endometrial echo of <5 mm asmeasured by TVS prior to HRT use, this does not excludewith certainty the presence of endometrial polyps. Indeed,a recent study using sonohysterography has revealed thepresence of endometrial polyps, and other focal intra-cavitary lesions, in otherwise asymptomatic menopausalpatients whose endometrial echo measured <5 mm.

11

Although the high incidence of endometrial polypsobserved in this study may suggest an associationbetween tibolone use and the ultimate growth of polypsin the uterine cavity, this is far from being completelyunderstood. It is not yet clear, for instance, why end-ometrial polyps grow during tibolone use while thesurrounding endometrium shows only atrophic changesconsistent with a lack of estrogenic stimulation. It isdoubtful whether tibolone or other forms of HRT can

Figure 3 Hysteroscopy in a case of endometrial carcinoma detected in a patient using tibolone.




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HYSTEROSCOPIC FINDINGS IN POSTMENOPAUSAL PATIENTS USING TIBOLONE 135

cause the appearance of endometrial polyps, since theselesions show associated chromosomal abnormalitieswhich are unrelated to hormone use.

12

It is thereforemore reasonable to assume that tibolone may have stim-ulated the growth of pre-existing endometrial polypswhich had gone undetected by routine TVS.

Routine hysteroscopy in asymptomatic postmeno-pausal patients prior to HRT was not a standard diagnosticprocedure in the present study, and although thesepatients had normal TVS findings prior to treatment,this does not exclude with certainty the presence of smallpolyps in the uterine cavity. The development of anendometrial carcinoma in one of our patients, in whomdiagnosis of a benign polyp in the uterine cavity hadbeen made 2 years previously, suggests that the removalof these pathological lesions may be necessary in post-menopausal patients using HRT. This is also in agree-ment with findings from a previous large study whichshowed that patients with endometrial polyps had ahigher risk of later developing an endometrial carcin-oma.

13

Ginsburg & Prelevic

5

have also reported theoccurrence of endometrial carcinomas in tibolone userswith bleeding, and in one patient the carcinomaoccurred in association with a cervical polyp. The pres-ence of endometrial carcinomas associated with uterinepolyps has also been observed in postmenopausalpatients who had been using other forms of HRT.

10

In conclusion, the present study has shown that ina non-selected population of postmenopausal patientswith abnormal uterine bleeding after using tibolone,there is a high likelihood of encountering intracavitarypathological lesions such as endometrial polyps, particu-larly if the endometrial echo is >4 mm. Therefore, theuse of hysteroscopy should be encouraged in the diag-nostic work-up of these patients, since blind endometrialbiopsies were found to be inaccurate for the diagnosis ofendometrial polyps.

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