The use of misoprostol prior to hysteroscopy in postmenopausal women

S.W. Ngai,1, Y.M. Chan and P.C. Ho

Department of Obstetrics and Gynaecology, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: This study examined whether oral misoprostol exerted a cervical priming effect in postmenopausal women prior to hysteroscopy. METHOD: Thirty-seven patients were randomized to receive either oral misoprostol (400 µg) or placebo (vitamin B6) 12 h prior to hysteroscopy. The resistance of the cervix to dilatation was objectively assessed by a cervical tonometer. RESULTS: The mean baseline cervical dilatation (4.2 mm in misoprostol group versus 4.4 mm in placebo group) was similar between the two groups. The mean cumulative force measured (27.7 N in misoprostol group versus 21.8 N in placebo group) was also comparable. None of the patients suffered from any significant side-effects. CONCLUSIONS: These data showed that there were no significant benefits from giving misoprostol pre-operatively in postmenopausal women, and it was concluded that oral misoprostol had no significant cervical priming effect in postmenopausal women.

Key words: cervical priming/misoprostol/oestrogen/postmenopausal women


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Postmenopausal bleeding is a common gynaecological problem. Endometrial biopsy is often necessary to exclude endometrial carcinoma. The procedure is sometimes difficult because of the small and tight cervical os in postmenopausal women. Sometimes the patients need to undergo hysteroscopy and endometrial sampling for a formal assessment.

Difficulty in negotiating through the cervical os is not uncommon. The procedure may be abandoned even when it is performed under general anaesthesia. Cervical injuries, uterine perforation, creation of a false tract or haemorrhage may occur. Unfortunately, data concerning the effectiveness of cervical priming agent in postmenopausal women are lacking. This is of particular importance, especially if office hysteroscopy is to be used.

The synthetic prostaglandin E1 analogue misoprostol (Cytotec; Searle, High Wycombe, UK) has been used successfully in the management of peptic ulcer. It is an effective cervical priming agent prior to suction evacuation (Ngai et al., 1995Go; Ngai et al., 1999Go). A previous study showed that it was also effective in pre-menopausal non-pregnant patients (Ngai et al., 1997Go). It is safe, well tolerated and inexpensive. As data for the use of this drug in postmenopasal women were lacking, a randomized study was performed to investigate the cervical priming effect of misoprostol in this group.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Ethical approval for the study was granted by the Ethics Committee, Queen Mary Hospital. A total of 37 women admitted for hysteroscopy and endometrial sampling were recruited for this double-blind, randomized trial in Queen Mary Hospital. Subjects participating in this trial were recruited from women who had a definite indication for hysteroscopy and endometrial sampling. The inclusion criteria included: (i) good general health; (ii) menopause (amenorrhoea for >12 months); and (iii) willingness to participate after the study had been explained. Women with a history of past ill health were excluded from the recruitment. None of the recruited patients was on hormonal replacement therapy.

Women were randomized into two groups: group 1, placebo (vitamin B6); group 2, 400 µg of oral misoprostol. The randomization schedule was produced as described by Meinert (Meinert, 1986Go). The tablets were put into a plastic bag labelled with subject number according to the randomization schedule at the pharmacy in Queen Mary Hospital.

Women who were recruited underwent a full medical, obstetrical and gynaecological history and physical examination. Subjects were admitted 1 day before the operation. The oral tablet (either misoprostol or vitamin B6) was given 12 h before the operation. All hysteroscopy and endometrial sampling was carried out under general anaesthesia by one of the two investigators (S.W.N or Y.M.C). The randomization schedule was unknown to the surgeon. A cervical tonometer (West of Scotland Health Board, Department of Clinical Physics and Bioengineering, UK) was used to measure the peak force required to enter the cervical os with successive dilators from 2–6 mm. The resistance of cervix to dilatation was objectively assessed using a series of tapered dilators attached to a force-sensing handle as described previously (El-Rafaey et al., 1994Go). Baseline dilatation was defined as the first dilator, which required a peak force >5 N to enter the internal os. The cumulative force required to dilate the cervix was calculated by summing the peak forces produced by each dilator up to 6 mm. Other parameters that were assessed during operation included the pre-operative side-effects and the complications during the procedure. The blood loss during the operation was assessed by subjective visual assessment. After hysteroscopy, women were observed for a further 6 h. The blood pressure and pulse rate were measured hourly. These observations were only recorded on the data forms if complications occurred. All women were followed up 6 weeks later.

The calculation of the sample size was based on the following assumptions: (i) type 1 error of 0.05 and power of 0.8 were acceptable and (ii) it was assumed that the baseline cervical dilatation was 1 mm in the postmenopausal women and a change of 2 mm in baseline dilatation would be significant in clinical management. The ideal sample size in each group was calculated as 17, and to allow for ~10% of the data being unusable, the number in each group was set at 19. Therefore, the total sample size was 38.

The characteristics of the subjects, the indication for dilatation and curettage, the incidence of side-effects and the baseline cervical dilatation between the two groups were compared. The difference in discontinuous variables was analysed by {chi}2 test and Fisher's exact test. The difference of continuous variables was analysed by the Student's t-test for normally distributed data and Mann–Whitney U-tests for skewed data.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
There was a change in treatment policy in our department after recruitment of 37 women and nearly all the hysteroscopy procedures were performed under local anaesthesia. Therefore, the project was terminated when a total of 37 postmenopausal women had been recruited. Three women did not have cumulative force and baseline cervical dilatation recorded because (i) the machine malfunctioned (n = 1), (ii) the operation was changed to local anaesthesia (n = 1), and (iii) the procedure was delayed and performed by another surgeon (n = 1). All of the study subjects underwent the operation without suffering from any complication.

Patients' characteristics are shown in Table IGo. The median age of subjects in the misoprostol group was significantly lower than that of the placebo group (55.6 versus 66.9 years, P = 0.01). In the placebo group, the patients' ages ranged from 47 to 86 years whereas in the misoprostol group, they ranged from 49 to 67 years. Other demographic parameters, including body weight, height and body mass index, were comparable between the two groups. Operative findings are summarized in Table IIGo. The mean baseline cervical dilatation was similar between the two groups (4.2 mm in misoprostol group versus 4.4 mm in placebo group). Cumulative force required for the procedure was also comparable (27.7 N in misoprostol group versus 21.8 N in placebo group).


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Table I. Patients' characteristics, mean ± SD
 

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Table II. Intra-operative findings in misoprostol and placebo groups
 
As the patients in the placebo group were significantly older when compared with the misoprostol group, we have compared the cumulative force within the former group. There was no significant difference in cumulative force between those whose age was <=65 years (median age) versus >65 years within the placebo group (26.9 N versus 19.2 N respectively). Similarly, there was no difference in baseline dilatation and duration of the operation between the two groups. Therefore, age differences between the misoprostol and placebo groups probably would not affect the ease of dilatation. The duration of the procedure as well as the blood loss was comparable between the two groups. No operative complications were encountered in any subjects. The pre-operative side-effects are shown in Table IIIGo. Gastrointestinal symptoms were uncommon and mild in both groups. The incidence was low and comparable between the two groups.


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Table III. Pre-operative side-effects in misoprostol and placebo groups. Values are shown as number (%)
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Cervical ripening is a complicated process, being mediated by hormones, cytokines, growth factors and other biochemical compounds (Barclay et al., 1993Go; Norman et al., 1993Go). Misoprostol had been shown to be effective for cervical priming in pregnant women (Ngai et al., 1995Go, 1996Go, 1999Go). Information on the use of prostaglandins in non-pregnant cervix was scanty. With the introduction of various hysteroscopic procedures, it was considered worthwhile to explore the role of cervical priming in this group of women.

We have previously demonstrated that 400 µg oral misoprostol, when given 12 h prior to hysteroscopy, reduced cervical resistance significantly when compared with placebo (Ngai et al., 1997Go). In that study, subjects suffered from infertility and were admitted for laparoscopy and hysteroscopy.

In the present study, using the same dosage and route of administration as our prior study (Ngai et al., 1997Go), we failed to demonstrate any beneficial effect. The only difference between the two studies was that we recruited postmenopausal women in this study, whereas women of reproductive age were recruited in the previous study. Endogenous oestrogen may be essential for the cervical priming induced by prostaglandin, and therefore women in a hypo-oestrogenic state would show no response to prostaglandins.

This theory is supported by findings from laboratory and animal studies on cervical priming. The final, rapid cervical softening that occurs just before the onset of labour corresponds to the connective tissue remodelling characterized by an increased turnover of both collagen and proteoglycans (Norman et al., 1993Go). Several hormones, such as prostaglandins, gonadal steroids and relaxin, are involved in the process. Administration of oestrogen promotes, and of progesterone at high concentrations inhibits, neutrophil migration into rodent uterine tissue (Stites and Siiteri, 1983Go). Human studies have further demonstrated that there is an upregulation of gene expression as well as protein concentrations of interleukin-8, interleukin-6 and granulocyte colony-stimulating factor during the final cervical priming process, which is similar to an inflammatory process (Sennstrom et al., 2000Go). The effect of hormones on cervical priming may be related to the regulation of pro-inflammatory cytokines.

Our knowledge of the molecular basis for the ripening of the human cervix has increased substantially since the pioneering reports by Danforth 40 years ago (Danforth, 1960). Expanded knowledge of the biochemistry and ultrastructure of the human cervix will most likely be of practical importance in the near future. Further laboratory basic research on the local concentration, action and interaction of gonadal steroids and prostaglandins, and their effects on collagenase and non-collagenolytic proteases in the cervical ripening process are awaited to confirm or refute the speculation stated above.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was supported by the Committee on Research and Conference Grants, University of Hong Kong.


    Notes
 
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Tsan Yuk Hospital, Hong Kong SAR, China. E-mail: cora{at}hkucc.hku.hk Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Barclay, C.G., Brennand, J.E. and Calder, A.A. (1993) Interleukin-S production by the human cervix. Am. J. Obstet. Gynecol., 169, 625–632.[ISI][Medline]

Danforth, D.N., Buckingham, J.C. and Roddick, J.W. (1960) Connective tissue changes in the pregnant cervix during pregnancy and labor. Am. J. Obstet. Gynecol., 80, 939.[ISI][Medline]

El-Rafaey H., Calder, L., Wheatley, D.N. and Templeton, A. (1994) Cervical priming with prostaglandin E1 analogues, misoprostol and gemeprost. Lancet, 343, 1207–1209.[ISI][Medline]

Meinert, C.L. (1986) Randomization and the mechanics of treatment masking. In Meinert, C.L. and Tonaseia, S. (eds), Clinical Trials, Design, Conduct and Analysis. Oxford University Press, New York, Oxford, pp. 90–112.

Ngai, S.W., Tang, O.S. and Lao, T. (1995) Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy. Hum. Reprod., 5, 1220–1222.

Ngai, S.W., To, W.K., Lao, T. and Ho, P.C. (1996) Cervical priming with oral misoprostol in pre-labour rupture of membranes at term. Obstet. Gynecol., 87, 923–926.[Abstract/Free Full Text]

Ngai, S.W., Chan, Y.M. and Liu, K.L. (1997) Oral misoprostol for cervical priming in non-pregnant women. Hum. Reprod., 5, 1220–1222.

Ngai, S.W., Chan, Y.M., Tang, O.S. and Ho, P.C. (1999) The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial. Hum. Reprod., 14, 2139–2142.[Abstract/Free Full Text]

Norman, M., Ekman, G. and Malmstrom, A. (1993) Prostaglandin E2 induced ripening of the human cervix involves changes in the proteoglycan metabolism. Obstet. Gynecol., 82, 1013–1020.[Abstract]

Sennstrom, M.B., Ekman, G., Thorsson, W.G. et al. (2000) Human cervical ripening, an inflammatory process mediated by cytokines. Mol. Hum. Reprod., 6, 375–381.[Abstract/Free Full Text]

Stites, D.P. and Siiteri, P.K. (1983) Steroids as immunosuppressants in pregnancy. Immunol. Rev., 75, 117–138.[ISI][Medline]

Submitted on November 22, 2000; accepted on March 22, 2001.