Department of Obstetrics and Gynaecology of the University FedericoII, Naples Italy
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology of the University FedericoII, Naples Italy. e-mail: fmercorio{at}libero.it
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Abstract |
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Key words: desmopressin/IUD-related menorrhagia/uterine artery resistance
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Introduction |
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Several factors have been suggested to explain IUD-related bleeding, including increased vascularity of the endometrium and capillary permeability (Hillier and Kasonde, 1976), reduced platelet aggregation (Moncada et al., 1976
) and enhanced fibrinolytic activity of uterine fluid (Larsson et al., 1974
). A direct correlation between the uterine artery pulsatility index (PI) and amount of menstrual blood loss has suggested that vascular factors might be involved in the pathogenesis of IUD-related menorrhagia (Momtaz et al., 1994
). Indeed, one hypothesis is that menorrhagic women may have decreased uterine artery resistance due to a lack of balance between the vasoconstrictor and vasodilator effects of prostaglandins (Smith et al., 1981
). The above-mentioned derangement of the haemostatic process, as well as the altered uterine haemodynamics, suggest a novel approach to the treatment of IUD related menorrhagia by means of vasopressin
Besides its well-known antidiuretic properties, vasopressin is known for its ability to enhance the haemostatic process by mediating the release of von Willebrand factor (vWF) from endogenous storage sites, thereby increasing plasma levels of Factor VIII and platelet adhesiveness, as well as reducing bleeding time (Mannucci, 1998). These properties have made this drug effective also for the treatment of bleeding disorders in women (Lethagen, 1999
; Edlund et al., 2002
). A further action of vasopressin, which is similar to that of its counterpart oxytocin, is the powerful uterine muscle-contracting and vasoconstricting actions which occur as a result of direct excitatory effects on the specific receptor sites that cause vascular spasms (Townsend, 1991
; Frederick et al., 1994
). This latter action may have some interesting therapeutic implications on the basis of the pathogenesis of IUD related menorrhagia, as suggested by the above-mentioned studies.
Indeed, the oxytocic effectas well as the purported increase in vascular tone of the uterine artery with consequent reduction in uterine flow due to both vasopressin and the known haemostatic effect of the drugcould produce a particularly useful synergic mechanism for the treatment of IUD-related menorrhagia.
The aim of the present study was to assess the effects of vasopressin on menstrual blood loss among women fitted with copper IUDs, and to compare the efficacy of treatment with that of mefenamic acid, an antiprostaglandin drug considered by many authors to be first-line treatment in IUD-related menorrhagia. A secondary objective of the study was to evaluate in both treatment groups the changes, if any, in uterine blood flow impedance as measured using transvaginal colour Doppler.
This study evaluated the effect of vasopressin in the form of its structural analogue obtained by deamination at the N-terminal 1-position and replacement of 8-L-arginine with 8-D-arginine; this compound is known as desmopressin acetate and is characterized by a longer duration of activity. The drug was administered in high concentrations as an intranasal spray. The safety and efficacy of both the drug and this novel administration route were documented previously in healthy volunteers (Lethagen et al., 1987).
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Materials and methods |
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Twenty-four women with a menstrual blood loss objectively judged as menorrhagic were invited to participate in the study. Those patients with menorrhagia caused by pelvic pathologies evaluated by gynaecological examination and transvaginal ultrasonography were excluded, as were patients with a family or personal history of bleeding. None of the patients had previously taken mefenamic acid or any other drug to treat this pathology.
The mean age of the women was 28.9 (median 31; range 2040) years. All women were parous (mean parity 2.3; range 24) and all were using an IUD (No-Gravid; Irmet Verona-Italia). The device had a copper surface area of 384 mm2 and released 100 µg Cu over a 24-h period.
Patients provided their fully informed consent, and the study was approved by the hospital ethics committee.
Treatments and investigations
The subjects were allocated to either the desmopressin or mefenamic acid group according to a schedule provided by an envelope system developed using computer analysis.
Each patient in the desmopressin group received a single daily dose of high-concentration intranasal desmopressin (HCIN-DDAVP; Minirin; Ferring s.p.a, Milan, Italy) administered as a morning 300 µg dose (one intranasal spray in each nostril) for the first 5 days of menstruation, irrespective of the duration of the menstrual period.
Patients in the mefenamic acid group were instructed to take one 500 mg tablet every 8 h for 5 days from the onset of menstrual bleeding, irrespective of the duration of the menstrual period.
In order to assess the effect of treatments on menstrual blood loss measured by the PBAC score, patients were seen monthly for 3 months during the treatment period, and asked to complete a new menstrual chart every month before each follow-up, when a gynaecological examination and evaluation of their PABC score and of any adverse reaction was carried out.
In order to evaluate possible haemodynamic uterine changes during the 3-month period, transvaginal colour Doppler was conducted in each patient in order to measure flow impedance of the uterine arteries; the data obtained were compared with the two monthly pretreatment values.
An ultrasound scan was carried out during each menstrual phase of the cycle (days 34), measuring uterine blood flow indices using a transvaginally directed pulsed colour Doppler system (POWER VISION 8000; Toshiba, Tokyo) equipped with a 6.5 MHz vaginal probe. All examinations were performed by one gynaecologist, who was blinded to the clinical purpose of the study. Examinations were conducted between 08:00 and 10:00 in order to reduce the effect of circadian variation on the PI (Zaidi et al., 1995).
Blood flow velocity waveforms were evaluated in the main branch of the uterine artery on either side at the level of the inner cervical os. The PI was calculated electronically according to the formula [(AB)/mean], where A is the peak systolic Doppler shift frequency, B the end-diastolic shift frequency, and mean the mean maximum Doppler shift frequency. When adequate colour signals were obtained, three similar and optimal consecutive waveforms of the left and right uterine arteries were analysed, and the mean value was obtained for statistical analysis.
Statistical analysis
All data processing and statistical analyses were carried out using SPSS 9.0 (SPSS Inc., Chicago, IL, USA) and a personal computer. For each variable, the arithmetic mean of the two pretreatment periods, as well of the three treatment periods, was calculated. A linear analysis of variance (ANOVA) model was then fitted to the difference in mean values. If the overall F-test was significant, tests for differences between treatment groups were carried out.
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Results |
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No serious adverse effects were reported during the study, and none of the patients discontinued treatment. Three patients (25%) in the desmopressin group reported headache and insomnia during treatment, but these were mild in intensity and not considered to be related to desmopressin administration.
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Discussion |
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These results suggest that in women fitted with an IUD, altered local coagulation factors are the major determinants of menorrhagia, and that desmopressin has an important selective activity in restoring the altered coagulation pattern caused by increased prostaglandin synthesis.
The mechanism by which desmopressin promotes haemo stasis in women with presumably normal haemostatic function is unclear. It has been suggested that such an effect might be mediated by the attainment of supranormal plasma concentrations of the von Willebrand factor (vWF)/Factor VIII involved in fibrin formation, though others have suggested that vWF is not involved in this process (Cattaneo et al., 1989).
Although the results of the present study demonstrated the effectiveness of desmopressin in promoting haemostasis, confirmation should be sought in a larger series of patients as, in the present authors opinion, this drug is potentially of major clinical value, despite its well-known fibrinolytic action which is exerted through the release of plasminogen activator from the vascular endothelium (Lethagen et al., 1990). This (theoretically) untoward action not only diminishes the ultimate therapeutic effect of the drug, but also casts some doubts on the role of fibrinolysis in the pathogenesis of IUD-related menorrhagia (Rybo et al., 1981
).
No significant changes in flow impedance of the uterine arteries was demonstrated during treatment with either desmopressin or mefenamic acid; therefore, the therapeutic action of both drugs in reducing menstrual blood loss is not mediated through changes in uterine vascular tone.
It has been shown (Momtaz et al., 1994) that some women are more prone to develop IUD-induced menorrhagia than others, and this tendency might be due to a decreased vascular resistance in the uterine artery. In this respect, it has been suggested that vasoactive substances such as prostaglandins might play an important role in regulation of uterine blood flow and menstrual blood loss.
The limitations of the present study were clear, in that uterine artery PI is not a precise indicator of the endometrial vascular bed. However, two subordinate conclusions may be drawn in that: (i) there is no association between the impedance of uterine arteries and the successful reduction of menstrual loss; and (ii) further evidence is needed to place in perspective the relationship between diminished uterine vascular tone and menorrhagia.
The results of the present study confirmed previous reports that drugs believed to inhibit prostaglandin synthetase would significantly reduce menstrual blood loss in women fitted with IUDs (Guillebaud et al., 1978). The results also supported the use of desmopressin as a therapeutic tool in many women with IUD-related menorrhagia, even if larger case series are needed to provide a solid basis for recommending the use of one drug over another. It is possible that the mechanism of action of desmopressin lies in its ability to enhance local haemostasis, without imparting any haemodynamic effect on uterine blood flow.
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References |
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Cattaneo, M., Moia, M., Della Valle, P., Castellana, P. and Mannucci, P.M. (1989) DDAVP shortens the prolonged bleeding time of patients with severe von Willebrand disease treated with cryoprecipitate: evidence for a mechanism of action independent of released von Willebrand factor. Blood, 74, 19721975.[Abstract]
Edlund, M., Blomback, M. and Fried, G. (2002) Desmopressin in the treatment of menorrhagia in women with no common coagulation factor deficiency but with prolonged bleeding time. Blood Coag. Fibrinol., 13, 225231.[CrossRef][ISI][Medline]
Frederick, J., Fletcher, H., Simeon, D., Mullings, A. and Hardie, M. (1994) Intramyometrial vasopressin as a haemostatic agent during myomectomy. Br. J. Obstet. Gynecol., 101, 435437.[ISI][Medline]
Guillebaud, J., Anderson, A.B.M. and Turnbull, A.C. (1978) Reduction by mefenamic acid of increased menstrual blood loss associated with intrauterine contraception. Br. J. Obstet. Gynecol., 85, 53.
Higham, J.M., OBrien, P.M.S. and Shaw, R.W. (1990) Assessment of menstrual blood loss using a pictorial chart. Br. J. Obstet. Gynaecol., 97, 734739.[ISI][Medline]
Hillier, K. and Kasonde, J.M. (1976) Prostaglandin E and F concentrations in human endometrium after insertion of intrauterine contraceptive devices. Lancet, 1, 1516.[CrossRef][Medline]
Janssen, C.A.H., Sholten, P.C. and Heintz, A.P.M. (1995) A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss. Obstet. Gynecol., 85, 977982.
Larsson, B., Liedholm, P., Sjoberg, N.O. and Asted, B. (1974) Increased fibrinolytic activity in the endometrium of patients using copper IUD. Contraception, 9, 531.
Lethagen, S. (1999) Desmopressin in the treatment of womens bleeding disorders. Haemophilia, 5, 233237.[CrossRef][ISI][Medline]
Lethagen, S., Harris, A.S., Sjorin, E. and Nilsson, I.M. (1987) Intranasal and intravenous administration of desmopressin: effect on FVIII/vWF pharmacokinetics and reproducibility. Thromb. Haemost., 58, 10331036.[ISI][Medline]
Lethagen, S., Rugarn, P., Aberg, M. and Nilsson, I.M. (1990) Effects of desmopressin acetate (DDAVP) and dextran on hemostatic and thromboprophylactic mechanisms. Acta Chir. Scand., 156, 597602.[ISI][Medline]
Mannucci, P.M. (1998) Hemostatic drugs. N. Engl. J. Med., 339, 245.
Momtaz, M., Zayed, M., Rashid, K. and Idriss, O. (1994) Doppler study of the uterine artery in patients using an intrauterine contraceptive device. Ultrasound Obstet. Gynecol., 4, 231234.[CrossRef][ISI][Medline]
Moncada, S., Gtyglewski, R.J., Bunting, S. and Vane, I.R. (1976) An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature, 262, 663.
Reid, P.C., Coker, A. and Coltart, R. (2000) Assessment of menstrual blood loss using a pictorial chart: a validation study. Br. J. Obstet. Gynecol., 107, 320322.[ISI]
Rybo, G., Nilsson, S., Sikstrom, B. and Nygren, K.G. (1981) Naproxen in menorrhagia. Lancet, 1, 608609.[CrossRef][Medline]
Smith, S.K., Abel, M.H., Kelly, R.W. and Baird, D.T. (1981) A role of prostacyclin (PGI2) in excessive menstrual bleeding. Lancet, 1, 522524.[Medline]
Townsend, D.E. (1991) Vasopressin pack for treatment of bleeding after myoma resection. Am. J. Obstet. Gynecol., 165, 14051407.[ISI][Medline]
Zaidi, J., Jurkovic, D., Campbell, S., Okokou, E. and Tan, S.L. (1995) Circadian variation in uterine blood flow during the follicular phase of menstrual cycle. Ultrasound Obstet. Gynecol., 5, 406411.[CrossRef][ISI][Medline]
Submitted on May 27, 2003; accepted on July 12, 2003.