Introduction
Polycystic ovary disease is one of the most common endocrinopathy among women of reproductive age. Stein and Levanthal described masculanised women with ammenorrhoea, sterility and enlarged ovaries containing multiple follicles/cysts. The syndrome was placed in the gynaecologic realm for control of chronic anovulation, abnormal menstrual bleeding and infertility.1
The French physicians Achard and Thiers, way back in 1921, provided the first description of the relationship between androgen excess in women and disturbances in carbohydrate metabolism, which was dubbed “diatbeticdes femme a barbe” (diabetes of the bearded lady). By early 1980s, evidence regarding association between hyper-insulinaemia and impaired glucose tolerance started emerging. The connection to an insulin post-receptor defect was isolated in women with polycystic ovarian disease in the early 1990s. As a result of these recent developments, attention is now focused on treating the central deficits and fundamental problems of hyperandrogenism, hyper-insulinaemia, abnormal serum lipid levels, and obesity that has broader health implications.1,2
As our knowledge regarding this rather mysterious and enigmatic condition evolved, newer therapeutic modalities come to light and sometimes even fall by the wayside later on. Numerous questions have baffled and continue to baffle researches over time.
Is hyperinsulinaemia the backbone of polycystic ovarian disease?
Does hyperandrogenisum cause hyper-insulinaemia or is it vice-versa?
Is obesity an essential feature or is it only an aggravating factor?
Have we found the treatment for polycystic ovarian disease?
As association of hyperinsulinaemia and insulin resistance with hyperandrogenic polycystic anovulation has become more apparent, it was logical for drug like metformin to find place in treatment of this syndrome. In this study, we have tried to assess effect of metformin in sensitizing resistant ovaries to the treatment by ovulation inducing drugs like clomiphene citrate.
Primary objective of our study was to assess effect of ‘Metformin’ in sensitizing ovaries for causing optimum follicular maturation (17-18 mm) followed by ovulation after therapy clomiphene, in women with diagnosis of polycystic ovarian disease.
Secondary objectives were to see the changes in the various parameters like body mass index, ratio of LH and FSH, menstrual pattern and hirsutism in these women after administration of metformin.
Material And Methods
This was a prospective study carried out within a single working unit at a major tertiary teaching institute over a period of 3 years.
Sixty women of infertility with Polycystic Ovarian Disease diagnosed on ultra-sonography, that failed to respond on 50 and 100 mg of clomiphene citrate for two to three cycles were included in this study.
Sonographic Diagnostic Criteria for Polycystic Ovarian Disease
- Bulky ovary;
- Thickened theca;
- Necklace pattern of follicles.
Detailed history and examination were carried out in all these women.
The parameters evaluated were Type/ duration of infertility
- History of menstrual pattern
- Hirsutism
- Weight of the patient
- Body mass index
- Blood sugar level
- Serum FSH and LH levels and LH/FSH ratio study group, tablet Metformin 500 mg three times a day was started, while in placebo group, women were given Calcium lactate, 500 mg three times a day
Next cycle onwards, all these women were started on 100 mg clomiphene citrate from D2 - D6 of the cycle.
Follicular studies by transvaginal sonography were started from D10 onwards
Injection human chorionic gonadotropin (hCG) 5,000-10,000 IU was given when the dominant / largest follicle achieved the size of 18-20 mm.
Ultrasonography was repeated after 36 hrs to check the signs of ovulation.
The disappearance of dominant follicle along with free fluid in pouch of Douglas was considered as signs of ovulation.
The effect of clomephene in inducing optimum follicular maturation followed by ovulation was assessed and compared in study and placebo group.
The dose of clomiphene was increased by 50 mg per day in subsequent cycle in cases of failure to achieve follicular maturation. The maximum dose of clomiphene given per day was 250 mg (fourth cycle). During this period of ovulation induction, metformin (Study Group) and calcium lactate (Placebo Group) was continued. After the period of six months, all basic parameters were revaluated and percentage change was calculated and also compared in two groups.
Observations and Results
It was seen that majority of women in our study were in the age group of 19-39 years, the average age being 27.4 years.
In study group, 24 women had primary infertility while six women had secondary infertility. In placebo group, 25 women complained of primary infertility.
The distribution of various parameters in two groups is summarized in Table 1. The mean Body Mass Index in study group was comparable to that in control group. The disease was seen in both obese and lean women. Abnormal LH /FSH ratio of more than two was observed in total number of 25 patients.
In first cycle of follicular induction with 100 mg of clomiphene, 15 women had optimum follicular maturation in women taking metformin as compared to only three women of placebo group. The follicular maturations related to day of cycle are shown in Table 2.
The dose of clomiphene was increased by 50 mg per day in subsequent cycle in women who did not respond to previous dose.
| Table 1: Distribution of various parameters |
Table 2: Follicular maturation and ovulation with 100 mg of clomiphene |
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| Table 3: Follicular maturation and ovulation with 150 mg of clomiphene |
Table 4: Follicular maturation and ovulation with 200 mg of clomiphene |
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| Table 5: Follicular maturation and ovulation with 250 mg of clomiphene |
Table 6: Comparison of percentage change in various parameters two groups |
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The maximum dose given per day was 250 mg per day. The follicular maturations as related to higher doses of clomiphene i.e. 150 mg, 200 mg and 250 mg per day are shown in Table 3, Table 4 and Table 5 respectively.
Overall rate of successful optimum follicular development was 90% in study group as compared to 53.4% in placebo group. Also, maturation occurred on earlier days of cycle in metformin group as compared to control group.
At the end of six months, all parameters were reevaluated and compared with baseline values. In study group, majority of women had significant beneficial change in Body Mass Index, LH/FSH ratio and menstrual cycle pattern. The percentage change in all these parameters in two groups with ‘p’ value is compared in Table 6. At the end of six months, seven women in study group had conception as compared to one in placebo group.
Discussion
Polycystic Ovarian Disease is interplay of genetic factors, obesity and post-receptor insulin defect leading to insulin resistance. It is a heterogenous syndrome complex characterized by persistent hyperandrogenic chronic anovulation, hyperinsulinaemia and insulin resistance, resulting in menstrual irregularity, infertility and hirsutism.
There is no accepted theory regarding aetiopathogenesis of this syndrome and no single factor that can be held responsible for the causation of this condition. This is a condition, which, once established is, chronic and self-perpetuating. Hyperandrogenism in the ovarian microenvironment is a cardinal feature of Polycystic Ovarian disease. There is now definite appreciation of the role of hyperinsulinaemia in the development of Polycystic Ovarian disease. It is characterised by insulin resistance accompanied by compensatory hyperinsulinaemia.1 These women also have impaired glucose tolerence.2
Hyperinsulinaemia causes hyper-androgenism in Polycystic Ovarian Disease by the following mechanism:
- Increased insulin bind to type II GF receptors leading to activation of IGF-II and IGF-I factors which cause increased androgen production in theca cells in response to Luteinising hormone.
- Insulin inhibits hepatic synthesis of sex hormone binding globulin and IGFBP-I leading to free levels of testosterone and androstenedione.
Women with Polycystic Ovarian Disease are at risk of developing android obesity, abnormal lipid profile and associated cardiovascular diseases along with insulin dependant diabetes mellitus.3 Though, obesity was commonly implicated with pathogenesis of this syndrome, it is now evident that Polycystic Ovarian disease, though common in obese patients, is also seen in lean women.4 In our study also, almost 40% of women with Polycystic Ovarian Disease were lean.
The traditional treatment with clomiphene citrate and other hormones for chronic anovulation associated with Polycystic Ovarian Disease is associated with high failure rates.
Surgical methods such as ovarian drilling, electrocoagulation, and, wedge resection of ovary have been tried for this condition since the age old times. These methods are nowadays mostly used in cases of failure of the medical management. Also, these methods are associated with their own surgical risks along with formation of postoperative adhesions.5
Since hyperinsulinaemia and insulin resistance has been linked with Polycystic ovarian disease, it is logical that treatment with insulin sensitizing drugs like metformin may play a vital role in management of this disease. Metformin, insulin sensitiser, when used along with clomiphene citrate in women not responding to clomiphene alone has proven useful.
Metformin is a biguanide, which acts principally by suppression of gluconeogenesis in the liver. It enhances the binding of insulin to its receptors and also increases GLUT4, which improves the peripheral uptake of glucose.
It improves insulin sensitivity and causes significant reduction in gluconeogenesis. It reduces level of insulin, LH and testosterone thus helping in spontaneous ovulation.6,7 It also significantly reduces risk of ovarian hyperstimulation.8 It helps in restoring regular cycles and fertility.9 Metformin facilitates weight loss and reduction in excess body hairs. However, Nestler et al found metformin ineffective in reducing Body Mass Index suggesting the role of other factors like leptins.10 The effect of metformin on hirsutism was insignificant in study by Agarwal.11
Metformin also reduces long term risk of heart disease, stroke and diabetes mellitus by lowering triglyceride and LDL levels and elevating HDL levels.
Though various dosage regimens are suggested for metformin, 500 mg three times a day is most accepted protocol used in treatment of Polycystic ovarian disease. In study by Gada N12 using similar regimen, follicular maturation occurred in more than 95% cases with pregnancy rate of 40%. Metformin is well tolerated with minimal side effects of nausea and vomiting and diarrhoea.
Conclusion
Polycystic Ovarian Disease is one of the most enigmatic and controversial entities. Hyperandrogenism associated with insulin resistance is cardinal feature of polycystic ovarian disease. Metformin is safe, cheap and effective treatment for restoring ovulation and fertility in such patients. It also has beneficial effect in decreasing body mass index, correcting carbohydrate metabolism and regularizing menstrual cycles.
Although, metformin does seem to be most logical solution, it may not provide perfect answers to all our questions.
References
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- Diamanti-Kandarakis E, Kauli C, Tsianteli C, Bergiele A. European J Endocrinol 1998; 138 : 269.
- Lefebvre P, Bringer J, Renard E, et al. Influences of weight, body fat pattering and nutrition on the management of polycystic ovarian disease. Hum Repord 1997; 12 Suppl 1 : 73-81.
- Insler V, Shoham Z. Human Reprod 1993; 8 : 378.
- Naether OG, hamer T, Utiger RE. Fertil Steril 1993.
- Beata Kolodziejczyk, Antoni J Duleba, Robert z, et al. Metformin therapy decreases hyper-androgenism and hyperinsulinemia in woken with polycystic ovary syndrome. Fertil Steril 2000; 73 : 1149-54.
- Jean – Charles Crave, Sylvie Fimbel, Harve, et al. Effects of diet and metformin administration on sex hormone- binding globulin, androgens, and insulon in hirsute and obese women. J Clin Endocrinol Metab 1995; 80 : 2057-62.
- Vincenzo De Leo, Antonio La Marca, Antonino Ditto, et al. Effects metformin on gonadotropin induced ovulation in women with polycystic ovary syndrome. Fertil Steril 1999; 72 : 282-5.
- Pasquali R, Casimirri F, Vicennati V. Weight control, and its beneficial effect on fertility in women with obesity and polycystic ovary syndrome. Hum Repord 1997; 12 Suppl 1 : 83-7.
- John E Nestler, Daniela J Jakubowicz, William S Evams, et al. Effects of metformin on spontaneous and clomiphene – induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998; 338 : 1876-80.
- Agarwal R, Kumar P. Polycystic ovarian disease- The role of obesity, hyperinsulinemia and metformin therapy. J Obstet Gynecol India 2003; 53 : 264-8.
- Gada NJ, Purandare CN, Lopez JA, Salunkhe R. Role of metformin in polycystic ovarian disease: A Comparative study. J Obstet Gynecol India 2001; 51 : 107-9.
HELICOBACTER PYLORI AND ANTIMICROBIAL RESISTANCE
‘In view of the large number of individuals colonised with H pylori, the proportion of individuals who develop disease, and the relative difficulty to treat the infection, it is not surprising that a lot of effort has been spent on understanding the mechanisms of antibiotic resistance’
Helicobacter pylori is the causative agent of several gastroduodenal disorders, ranging from chronic active gastritis and peptic ulcer disease to gastric cancer. In vitro, H pylori is suspectible to most antimicrobials but in vivo only a few antimicrobials can be used to cure infected patients. The frequent indication for anti-H pylori therapy, together with the lack of novel treatment options, has resulted in the development of antibiotic resistance in the bacterium. In the November issue of The Lancet Infectious Diseases, Monique Gerrits and colleagues analyse the treatment of H pylori infection and the clinical relevance, mechanisms, and diagnosis of antimicrobial resistance, which the authors predict could lead to serious problems for the treatment of H pylori - associated disorders in the near future.
Lancet Infect Dis 2006; 6 : 699.
*Associate Professor; **Registrar; ***Head of Unit, Department of Obstetrics and Gynaecology, LTMG Hospital, Sion, Mumbai 22.
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