Effective Post-Laparoscopic Treatment of Endometriosis With Dydrogesterone

Written By: Sam Savage

Published Date: December 14, 2007 Last Edited: December 14, 2007

By Trivedi, Prakash Selvaraj, Kamala; Mahapatra, P Das; Srivastava, Saroj; Malik, Sonia

Abstract An open, prospective, multicenter study was designed to assess the efficacy and safety of dydrogesterone in the post- laparoscopic treatment of endometriosis in Indian patients. Ninety- eight patients suffering from minimal, mild, moderate or severe endometriosis, with or without infertility, who had undergone laparoscopy, were treated with dydrogesterone 10 mg/day (or 20 mg/ day in severe cases) orally from day 5 to day 25 of each cycle for 3- 6 months. Pelvic pain, dysmenorrhea and dyspareunia improved significandy (p

Keywords: Endometriosis, fertility, dydrogesterone, progestogens, dysmenorrhoea, dyspareunia, menstrual bleeding, pelvic pain

Introduction

Endometriosis is a complex and perplexing gynecological disorder that affects the fertility potential of women. It has been estimated that 25-50% of infertile women seeking treatment have evidence of endometriosis, and that 30-50% of women with endometriosis are infertile [1]. Reasonable clinical approaches in the infertile patient found to have mild to moderate endometriosis include watchful waiting, ablation using either laser or electrosurgery if laparoscopy is performed, one of the medical treatments and/or intrauterine insemination. If, at the time of laparoscopy, the surgeon is not satisfied that all the disease has been identified or if it cannot safely be destroyed, the choice remains between watchful waiting and medical therapy. Symptomatic patients always receive medical therapy [2], which can include any of the progestational agents, such as dydrogesterone (Duphaston(R)), medroxyprogesterone acetate (MPA) or danazol, or the gonadotropin- releasing hormone (GnRH) analogs. The choice of drug therapy, especially in post-laparoscopic patients, is very important as this is the best available fertile window and any drug that inhibits ovulation and causes amenorrhea should preferably be avoided in these patients. A review of the available drugs for the post- laparoscopic treatment of endometriosis is therefore essential.

The function of GnRH analogs, which may be useful for extensive endometriosis, is to render the patient markedly hypoestrogenic and to produce a pseudomenopause. The major side-effects associated with long-term use of GnRH analogs are hot flushes, vaginal dryness, headaches and superficial dyspareunia; there is also a potential for the development of osteoporotic changes [2]. Patients will not conceive while on GnRH analog therapy. Pregnancy rates after treatment with GnRH analogs are similar to those achieved with watchful waiting [3].

Danazol has not demonstrated any benefit in the treatment of endometriosis-related infertility [4]. Moreover, we advise that even infertile patients receiving danazol also take contraceptive measures in order to avoid harmful effects on the fetus. The most common side-effects reported with danazol are weight gain, edema, decrease in breast size and irreversible deepening of the voice. Amenorrhea has been reported in 84% patients on danazol [2]. Published data on MPA do not suggest a statistically significant benefit with regard to pregnancy [5], and varying lengths of time are required for ovulation to resume after discontinuation of therapy [6].

Dydrogesterone is a retroprogesterone derivative that is similar in structure and pharmacology to endogenous progesterone. Publications have reported the efficacy of dydrogesterone in relieving symptoms of endometriosis, with regression of lesions and improved pregnancy rate in infertile patients [2,6]. There are several striking features of dydrogesterone. First, while it causes atrophy of ectopic endometrium, it does not suppress the normal endometrium [7] and inhibits the development of new endometriotic areas. Second, it does not inhibit ovulation, and regular menstruation is seen in patients using cyclic dydrogesterone therapy. This means that patients can conceive while using dydrogesterone, if they so desire. Finally, side-effects like weight gain and edema are not observed with dydrogesterone. However, although dydrogesterone is an effective drug with the least side- effects [2], it is under-utilized. The present study was designed to assess the efficacy of dydrogesterone in the post-laparoscopic treatment of endometriosis in Indian patients.

Patients and methods

This was an open, prospective, multicenter study conducted at five centers throughout India. Female patients suffering from minimal, mild, moderate or severe endometriosis, with or without infertility, who had undergone laparoscopy, were included in the study. Endometriosis was staged according to the revised American Fertility Society (AFS) classification [8] as follows: stage I (minimal) – score 1-5; stage II (mild) – score 6-15; stage III (moderate) – score 16-40; or stage IV (severe) – score >40. Written consent was obtained from all of the patients. Exclusion criteria included severe endometriosis (stage IV of the revised AFS classification) in the case of repeat surgery; a history of treatment with danazol, progestins or other sex hormones, corticosteroids, GnRH analogs or gestrinone in the 6 months prior to study entry; menopause or premature ovarian failure; known hypersensitivity to dydrogesterone; severe concomitant medical illness; and hepatic or renal dysfunction.

Patients were given dydrogesterone 10 mg/day, or 20 mg/day in severe cases, orally from day 5 to day 25 of each cycle for a period of 3 to 6 months depending on their response to therapy.

A detailed medical history was obtained prior to inclusion in the study and the patients underwent a physical and gynecological examination. Parameters assessed at baseline and at monthly intervals thereafter were pelvic pain, dysmenorrhea, dyspareunia, and duration and amount of menstrual bleeding. Pelvic pain (assessed by the doctor), dysmenorrhea and dyspareunia were scored on a 4- point scale (0 = absent; 1 = mild; 2 = moderate; 3 = severe). The amount of bleeding was determined by weighing the pad before and after use. A 4-point scale was used to score the amount of menstrual bleeding (1 = light; 2 = normal; 3 = moderate; 4 = heavy). Normal bleeding was defined as

The data were assessed using the Kruskal-Wallis test for analysis of variance.

Results

A total of 98 patients were enrolled and 90 completed the study. The reasons for withdrawal were loss to follow-up (n = 5) and conception (n = 3). The patients’ demographic details are shown in Table I. The patients’ age ranged from 20 to 51 years, and the majority (53.1%) was suffering from severe endometriosis. Vital signs were within normal limits.

Pelvic pain improved significantly (p

Table I. Demographic parameters of the patients at baseline (n = 98).

Table II. Scores for pelvic pain, dysmenorrhea and dyspareunia (mean +- SD).

At baseline, the mean score for the amount of menstrual bleeding was 2.6 and the mean duration of bleeding was 4.45 days. As shown in Table III, the mean score for the amount of bleeding had fallen significantly (p

Overall, after between 3 and 6 months of treatment, 21.1% of the patients were considered cured (symptom-free) and 66.7% showed improvement (in symptoms). Of the patients who were keen to conceive, 16.7% were pregnant within 6 months of finishing treatment.

The global assessment of treatment is shown in Table IV. According to the patients, 74.4% considered the treatment to be good or excellent, with only 5.6% rating it as poor. Similarly, the physicians rated 70.0% of the cases as good or excellent, and only 4.4% as poor. No adverse events were reported by any of the patients.

Discussion

The ideal treatment for endometriosis should offer relief from the associated symptoms, such as pelvic pain, dysmenorrhea and dyspareunia; regularization of the amount and duration of menstrual bleeding; and regression or cure of endometriosis. Post-laparascopy is a good period for patients who wish to conceive. Hence, drugs that do not inhibit ovulation are particularly promising in the post- laparascopic treatment of endometriosis.

Table III. Score for the amount of menstrual bleeding and the duration of bleeding (mean +- SD).

Table IV. Overall global assessment of the treatment by patients and physicians.

In this study of dydrogesterone for the treatment of post- laparoscopic endometriosis, statistically significant reductions in the symptoms pelvic pain, dysmenorrhea and dyspareunia were seen after the first treatment cycle. By the end of the sixth treatment cycle, the reduction in pelvic pain, dysmenorrhea and dyspareunia as compared with baseline was 95%, 87% and 85%, respectively. The amount and duration of menstrual bleeding was also significantly reduced, and from the end of the third month onwards, bleeding was considered normal in the majority of patients. Improvement of endometriosis was observed in 71% of patients and cure in 21%. Around a fifth of patients who wished to conceive became pregnant during the study. Overall, dydrogesterone therapy was rated as excellent to good by 74% of patients and 70% of physicians. No adverse events were reported.

Previous studies have also reported that dydrogesterone improves pain in patients with endometriosis. Among 60 women who had undergone coagulation of endometriotic foci during laparoscopy, only five experienced pain (as assessed by the investigator) after 6 months of treatment with dydrogesterone [9]. A lasting absence of pain combined with a regular bleeding cycle was achieved in 40 women. A number of other studies, in which pain was either assessed by the investigator or scored by the patient using a diary card and predefined severity scales, also showed marked improvement or disappearance of pain after treatment with dydrogesterone [10,11].

It is concluded that, for post-laparoscopic treatment of endometriosis, a good improvement or cure rate is seen with dydrogesterone therapy. Also, the post-laparoscopic period is immunologically suitable for conception and, since dydrogesterone does not inhibit ovulation and allows conception while on treatment with simultaneous clomiphene citrate or gonadotropin, it is the most appropriate therapy during this period. Good early conception rates were observed in the present study and it is hence concluded that dydrogesterone is a very effective drug for the treatment of post- laparoscopic endometriosis. In addition, the lack of adverse effects with dydrogesterone, in contrast to danazol and the GnRH analogs, makes dydrogesterone a particularly suitable option in these patients.

Acknowledgements

The authors wish to thank Mr Kailas Gandewar for the statistical analysis of the data.

References

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PRAKASH TRIVEDI1, KAMALA SELVARAJ2, P. DAS MAHAPATRA3,

SAROJ SRIVASTAVA4, & SONIA MALIK5

1 National Institute of Laser and Endoscopic Surgery, AAKAR IVF Centre, Mumbai, India, 2 Fertility Research Centre,

Chennai, India, 3 Spectrum Clinic & Endoscopy Research Institute, Calcutta, India, 4 Mahanagar, Lucknow, India, and

5 Southend Clinic & Fertility Services, New Delhi, India

(Received 17 May 2007; accepted 5 September 2007)

Correspondence: P. Trivedi, National Institute of Endoscopic and Laser Foundation, AAKAR IVF Centre, 1-3 Gautam Building, Tilak Road, Ghatkopar, Mumbai 400 077, India. Tel: 91 22 25158875. Fax: 91 22 25135913. E-mail: [email protected]

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