Taurine Levels in Human Aqueous Humour MEDICAL SCIENCES (2000), 2, 33−35 © 2000 SULTAN QABOOS UNIVERSITY 1Department of Obstetrics & Gynaecology, Sultan Qaboos University, P O Box 35 Al-Khod, Muscat 123, Sultanate of Oman. *To whom correspondence should be addressed. 33 Minimal stimulation protocol: a cheap and effective method of ovulation induction *Mathew M, Al-Busaidi F, Krolikowski A طريقة رخيصة : األدنىالتنبيهنظام .وفعّالة إلحداث اإلباضة آروليكوسكي. ، أ البوسعيدي. ماثيو ، ف. م تسجيل معدالت اإلباضة ، الحمل : الطريقة. منضبط للمبايض تنبيهوهو نظام جديد من العالج الهرموني إلحداث " األدنى للمبايض التنبيه"ية وتكلفة نظام تحديد فعال :الهدف: الملخص وآانت نسبة % . 7، ونسبة الحمل بأآثر من جنين % 2 ، نسبة الحمل % 82 نسبة اإلباضة آانت :النتائج. إمرأة تم عالجها بهذا النظام 67، اإلجهاض إلى جانب التكلفة الدوائية في نظام التنشيط األدنى :النتائج. منشط القند أألنسان األدنى للمبايض ثلث تكلفة نظام إستخدام هرمون لتنبيهآما بـلغ معدل تكلفة نظام ا . من إجمالي حاالت الحمل % 36اإلجهاض التلقائي وعليه فإن هذا النظام يستحق الدراسة . وله نفس المفعول ، وهو يتطلب متابعة أقل ولذلك فهو أآثر راحة للمريض ن منشط القند أألنسا ني رموللمبايض أرخص بكثير من نظام العالج به .آعالج للعقم ABSTRACT:�������� � – To determine the effectiveness and cost of Minimal Stimulation Protocol (MSP), a new combination of human menopausal gonadotrophin (hMG) and clomiphene citrate (CC), for controlled ovarian hyperstimulation. ���� �– The ovulation rates, pregnancy rates, abortion rates and the cost of medication were assessed in respect of 67 women who underwent MSP. ������� – Ovulation rate in the study group was 82%, pregnancy rate 21% and multiple pregnancies 7%. Spontaneous abortion occurred in 36% of the pregnancies. The average cost of MSP stimulation was one-third of hMG protocol. ���������� – MSP protocol, while substantially cheaper than hMG, gives comparable pregnancy rates with less need for monitoring and better patient comfort. These justify further evaluation of its role in the treatment of infertility. Key words: clomiphene citrate, human menopausal gonadotrophin, minimal stimulation protocol varian stimulation has been established to be a reasonably effective treatment for non- ovulatory infertility. Clomiphene citrate (CC), a cheap and easy-to-administer drug, was the first one used for ovarian stimulation. For women failing to conceive after four to six cycles of CC, gonadotrophins are the accepted alternative.1,2 However, the medi- cation and monitoring expenses are higher than those of CC. Cost reduction has been achieved without sacrificing efficacy by using a combination of CC and human menopausal gonadotrophin (hMG).3,4 In 1993, Corfman6 described a novel ovarian sti- mulation protocol termed minimal stimulation (MSP). When used in in-vitro fertilization program (IVF), this protocol gave a clinical pregnancy rate comparable to pure hMG stimulation at lower expense.6 Although MSP has been reported to be effective for ovulation induction, a widespread search of the literature shows only a few studies using it.6,7 Our retrospective study describes the experience with MSP in a non-IVF population over two years and aims to confirm its effectiveness and to ascertain the costs involved. Our results are compared with those for patients treated with a standard hMG ovarian stimulation protocol as described by others.7 METHOD From April 1996 to March 1998, patients presenting to the infertility clinic of Sultan Qaboos University Hos- pital, Muscat, were offered a stimulation protocol com- bining CC & hMG. This retrospective study involved 221 minimal stimulation cycles in 67 infertile women. O M A T H E W E T A L 34 The mean age of the treatment group was 28.7 years and the average duration of infertility, 6.1 years. The majority (66%) of the women suffered from primary infertility. The causes of infertility included anovulation (in some cases combined with male factor), tubal dis- eases or endometriosis and unexplained infertility. Most of them had failed CC therapy before. Intra- uterine insemination was performed in women with male factor infertility. The procedure for MSP was started with administration of 100 mg of CC daily orally from cycle day 3 to 7. A single injection of hMG 150 iu i.m. was given on the 9th cycle-day. Transvaginal ultrasono- graphy was done on the 12th cycle-day to assess follicle size and endometrial thickness. If the leading follicle was seen to be ≥14 mm, its diameter could be ex- pected to increase by 1–2 mm/day, and accordingly, the day of hCG injection was projected. When leading follicle had grown to >18 mm, 10,000 iu hCG was given intramuscularly. If follicle size remained <14 mm, vaginal ultrasound was repeated on the 15th cycle day. If even then there was no follicle ≥ 16 mm, the treatment was considered failed. Criteria for ovulation induction failure were ultra- sonic finding of a leading follicle <19mm and/or an endometrial thickness <8mm. Criterion for treatment failure was inability to become pregnant during 4 courses of treatment. A clinical pregnancy was defined as visualization of the gestational sac by transvaginal ultrasound performed 4 weeks after hCG administra- tion. We follow the criteria published by Lu et al.7 RESULTS A total of 67 women who completed 221 ovarian stimulation cycles were included in the analysis. Ovulation occurred in 82% of treatment cycles and each patient received 10,000 i.u. hCG. The treatment was cancelled in 18% of cycles mainly because of inadequate follicular growth. Only ovulatory dysfunc- tion was found in 63% of the patients. The other causes for infertility included male factor, tubal diseas- es, endometriosis and unexplained infertility (table 1). In the study group, 21% patients (14 out of 67) became pregnant. Table 2 summarizes the outcome of these pregnancies. Abortion rate was high at 36%, and all except one occurred before 10 weeks gestation. One woman aborted triplets at 20 weeks gestation. There were 9 successful pregnancies, resulting in live babies. Table 3 shows the number of pregnancies in each cycle. Maximum pregnancy rate was noticed in the first cycle. Although the original protocol advocates 4 cy- cles of treatment, 17% of our patients received more than 4 cycles and 14% of our pregnancies occurred during the 5th and 6th cycles. TABLE 1 Characteristics of 67 women treated with MSP No. % Ovulatory dysfunction 42 63 Male factor 12 18 Tubal diseases 10 15 Endometriosis 9 13 Unexplained 8 12 N.B. The total number is > 100% because some of the patients appear more than once due to combined factors of infertility. TABLE 2 Outcome of 14 pregnancies achieved with MSP No % Completed pregnancy 9 64 Abortion rate 5 36 Total 14 100 Singleton pregnancy 13 93 Multiple pregnancy 1 7 Total 14 100 TABLE 3 Number of pregnancies in each treatment cycle Cycle Pregnancy % 1st 5 36 2nd 4 29 3rd 0 0 4th 3 21 THE COST FACTOR SQU Hospital pharmacy charges were (approxi- mately) Rials Omani (RO) 2.200 (US $5.70) for 5 days’ treatment with CC at 100 mg per day, RO 3.200 M I N I M A L S T I M U L A T I O N P R O T O C O L 35 ($8.30) for 150 i.u. hMG, and RO 3 ($7.80) for 10,000 i.u. hCG. Thus, the average medication expenses for MSP is RO 8.400 ($22), one-third of the RO 25.500 ($66) required for hMG stimulation. Also to be noted is MSP’s lower monitoring requirements: whereas monitoring of hMG cycle usually requires several transvaginal scans and serum Estradiol estimations, MSP needs only one, or at the most, two transvaginal scans. (Due to the variability of the number of serum estradiol estimations in monitoring of HMG-only pro- tocol, and the difficulty in calculating the cost of trans- vaginal ultrasound examinations, the exact savings on monitoring requirements could not be worked out.) DISCUSSION Our study shows that MSP may be used for achieving late follicular growth. Patients who fail to ovulate or do not conceive with CC therapy may benefit from this CC-cum-hMG regime before hMG- alone therapy is administered. Majority of the patients in this study had previous unsuccessful CC cycles. MSP was offered as a ‘next step’ after CC failure. Its reduced cost and monitoring were attractive to the patients. Single leading follicle of size >18 mm was considered as ovulatory in our study compared to 2 or more follicles of 20mm size in original MSP.5-7 It is our practice to cancel the treatment cycle in the presence of a thin endometrium.8,9 Endometrial thickness ≥ 8mm occurred in 87% of ovulating cycles. Only 30% of non-ovulating cycles had endometrial thickness > 8mm, and none of the patients in this group conceived, thus confirming the results achieved by the other authors.10 Ovulation and pregnancy rates were comparable to hMG stimulation reported by Lu.7 However, the abortion rate of 36% in our group was significantly higher than in the MSP group reported by the above author. The reason for this variation is not clear. The treatment cycle were cancelled in 18% due to poor follicular growth compared to the cancellation rate of 26% in the MSP and 14% in the hMG protocol reported by Corfman6. Although the original protocol suggests a maximum of 4 cycles5-7, 17% of our patients received up to 6 cycles and 14% of pregnancies occurred in this group. Combined infertility factors were the reason for extending the therapy. CONCLUSION From the above, MSP appears to be an effective protocol for controlled ovarian stimulation in infertile women. It is easy to administer, requires less intense monitoring, fewer medications, and is cheaper. On drug costs alone, MSP protocol is 1/3rd cheaper than hMG protocol. In addition to this are the savings on monitoring. These factors make minimal stimulation protocol a reasonable therapeutic option to a pure hMG treatment. REFERENCES 1. Welner S, DeCherney AH, Polan ML. Human Meno- pausal Gonadotrophins: A justifiable therapy in ovulatory women with long-standing idiopathic infertility. Am J Obstet Gynecol 1988, 158, 111–7. 2. Diamond et al. Comparison of human menopausal gonadotrophin, Clomiphene Citrate and combined human menopausal gonadotrophin-Clomiphene Citrate stimulation protocols for invitro fertilization. Fertil Steril 1986, 46, 1108–12. 3. March CM, Tredway D, Mishell D Jr. Effect of Clomiphene Citrate upon amount and duration of human menopausal gonadotrophin therapy. Am J Obstet Gynecol 1976, 125, 699–704. 4. Jarrell J, McInnes R, Cooke R, Arronet G. Observations on the combination of clomiphene citrate –human menopausal gonadotrophin– human chorionic gonadotrophin in the management of anovulation. Fertil Steril 1981, 35, 634–7. 5. Rose BI. A Conservative low-cost superovulation regi- men. Int J Fertil 1992, 37, 339–42. 6. Corfman RS, Milad MP, Bellavance TL, Ory SJ. A novel ovarian stimulation protocol for use with the assisted reproductive technologies. Fertil Steril 1993, 60, 864–70. 7. Lu YP, Chen AL. Minimal stimulation achieves pregnancy rates comparable to human menopausal gonodotrophins in the treatment of infertility. Fertil Steril 1996, 65, 583–7. 8. Randal JM, Templeton A. Transvaginal sonographic assessment of follicular and endometrial growth in spontaneous and Clomiphene Citrate cycles. Fertil Steril 1991, 56, 208–12. 9. Gonen Y, Casper RF, Jacobson W, Blankier J. Endometrial thickness and growth during ovarian stimulation: A possible predictor of implantation in in- vitro fertilization. Fertil Steril 1989, 52, 446–9. 10. Shoham Z, D Carlo C, Patel A. Is it possible to run a successful ovulation induction program based solely on ultrasound monitoring? The importance of endometrial measurements. Fertil Steril 1991, 56, 836–41. Minimal stimulation protocol: �a cheap and effective method of ovulation induction *Mathew M, Al-Busaidi F, Krolikowski A ???? ??????? ??????: ????? ????? ?. ????? ? ?. ????????? ? ?. ?????????? METHOD RESULTS Table 1 Characteristics of 67 women treated with MSP N.B. The total number is > 100% because some of the patients appear more than once due to combined factors of infertility. Table 2 Table 3 Number of pregnancies in each treatment cycle The cost factor DISCUSSION CONCLUSION REFERENCES