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Title of Thesis

Nasim Karim
Institute/University/Department Details
University Of Karachi/ Department of Pharmacology
Number of Pages
Keywords (Extracted from title, table of contents and abstract of thesis)
metformin, carbohydrate, ovulation, polycystic ovary, syndrome, infertility, sterility, functional ovarian hyperandrogenism, hyperinsulinemia, insulin, oligomenorrhoea

Infertility (Sterility) is an absolute state of inability to conceive. T affects approximately 10-15% of the reproductive age couples in the ( US. Numerically important broad categories causing infertihty (either alone or in combination) are ovulation disorders, tubal obstructions pelvic adhesions, endometriosis and semen abnormalities.

Polycystic ovary syndrome (PCOS) is a form of functional ovarian hyperandrogenism and affects approximately 5-10% women of reproductive age. Insulin resistance and hyperinsulinemia appear to be almost universal features of the PCOS.

It is now 50 years since Stein and Leventhal first described this baffling syndrome. The classical picture is of an obese, hirsute, infertile female with oligomenorrhoea, ovaries although polycystic may not always be enlarged. The most constant endocrinological change is an absolute increase in the levels of LH and a high LH/ FSH ratio. Plasma testosterone is frequently slightly above the normal range.

As insulin has a direct effect on the ovarian androgen production in vitro, insulin resistance may play a crucial role in the physiopathology of the PCOS. Although the molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive insulin independent serine phosphorylation of the β-subunit of the insulin receptor has put forward as a new mechanism for insulin resistance.

Insulin influence steriodogenesis via its own receptor arid notIGF-I to stimulate testosterone, estrogen and progesterone production by increasing C17, 20 lyase activity. The action of insulin at the oval}in polycystic ovary syndrome is preserved despite the co-existence of peripheral insulin resistance as it is mediated by pathways distinct from those which regulate the peripheral glucose disposal. Only the pathway regulating carbohydrate metabolism is impaired in PCOS WomeJ1 with PCOS exhibit elevated fasting insulin levels and are increased insulin response to an oral glucose tolerance test.

Levels of low' density lipoproteins and triglycerides are .elevated while high density lipoprotein cholesterol levels are reduced compared with those of controls. Insulin resistance is associated with alterations that accentuate thrombosis by increasing coagulation and inhibiting fibrinolysis. Elevated levels of both P AI-l and fibrinogen have beer documented in PCOS.

Obesity may be an important pathogenefic factor involved in the development of hyperandrogenism in women with PCOS. Among several other mechanisms hyperinsulinemia plays a fundamental role due to its gonadotrophic function which has been demonstrated both in vitro and vivo. Weight loss appears to be associated with a significant improvement in menses abnormalities, ovulation and fertility rates and with a reduction of . hyperandrogenism, hyperinsulinemia and altered gonadotropin pulsatile secretion.

Exercise via mechanisms independent of weight loss, also reduces insulin resistance reducing abdominal fat, increasing muscle capillarity and restoring both the level and function of glucose transporter-4 and. there is a well recognized association between PCOS and eating disorders.

Therapeutic efforts have focussed on agents that could treat or modify the clinical manifestations of these disorders. Antiandrogens as a sale treatment or combined with oral contraceptives are considered the treatment of choice for the manifestations of hyperandrogenemia, but there is no agreement about their efficacy on the metabolic sequclae of PCOS (insulin resistance, hyperinsulinemial dyslipidemia). Furthermore the improvement of insulin sensitivity by insulin sensitizers may be of therapeutic value directly and or indirectly in the management of clinical manifestations of hyperinsulinemia and hyperandrogenemia.

With this background in view a total of one hundred and eleven patients of peas were enrolled from an infertility clinic of Karachi in accordance to a set pattern of inclusion and exclusion criteria. A total of 100 patients completed the study while 11 patients left the study at different times due to their own reasons. Patients were divided into two groups each group having 50 patients. Finally Group A was given tablet metformin HCl 500 mg TDS for 90 days (12 weeks) after gradual build up (within 2 weeks) while Group B was the conservatively l1umaged group and was advised to have 30-60 minutes walk daily along with the. avoidance of excess sugars, oily food and red meat from their diet for a period of 90 days (12 weeks). The patients were evaluated at day 0 and day 90 of the study for: .

1. The effects of metformin HCl on the carbohydrate metabolism (fasting serum glucose and fasting serum insulin levels).

2. The effects of metformin HCl on the ovulation (serum progesterone level > 4 ng/ml was considered to be consistent with ovulation). .

OBSERVATIONS: S.No.ParametersDays ZeroDay 90 1Weight of Patient (kg)√√ 2Height (m)√√ 3Body mass index (BMI)√√ 4Blood pressure √√ 5Fasting serum glucose level√√ 6Fasting serum insulin level√√ 7Serum LH level√√ 8Serum FSH level √√ 9Serum testosterone level √√ 10Serum progesterone level √√ 11Serum prolactin level√√ 12Ultrasound pelvis√√

In group A weight (Kg) of the patients showed a decrease from a mean ±SD of 69.4±11.8 to 65.85±9.0. Body mass index (BMI in Kg/m2) decreased from 27.5±4.8 to 26.l±3.7. Systolic blood pressure (mmHg) reduced from a mean ±SD of 128±14.9 to 122±11.1. Diastolic blood pressure (mmHg) reduced. from 83±9.0 to 82±6.8. Fasting serum glucose (mg/dl) showed a reduction from 92.74±13.0 to 86±8.7. Fasting serum insulin (μU/ml) reduced from 20.6±11 to 9.8±5.6 and serum progesterone (ng/ml) increased from 1.3±0.3 to 9.5±5.1 from day 0 to day 90. All the parameters were found to be statistically significant with the exception of diastolic blood pressure which showed non-significant results. Whereas in group B weight (Kg) of the patients reduced significantly from a mean ±SD of 75.4±8.8 to 74.3±9.1. BMI (Kg/m2) reduced from a mean ±SD of 30±4.8 to 29.5±4.3. On statistical evaluation this was, also significant. Other parameters of systolic and diastolic blood .pressure, fasting serum glucose, fasting serum insulin and serum progesterone showed non-significant results.

When group A was compared with group B, group A showed significant reduction in fasting serum glucose, fasting serum insulin and body mass index while significant increase in serum progesterone level whereas in group B fasting serum glucose, fasting serum insulin levels and serum progesterone showed non-significant results while body mass index showed significant reduction. Although patients of group B showed significant reduction in their weights and' accordingly in their body mass index but they failed to produce improvement in their metabolic and endocrine parameters significantly. In group A 41 (82%) patients ovulated (serum progesterone> 4 ng/ml) while in group B only 2 (4%) patients ovulated (serum progesterone> 4 mg/ml).

Thus it is concluded that metformin treated patients showed significant improvement in. all parameters (except diastolic blood pressure) while conservatively managed group showed significant improvement only in BMI indicating on balance that metformin is of benefit in improving reproductive function and reducing insulin resistance independent of weight loss. It seems that metformin has a direct effect on the human ovarian sterioidogenesis in addition to reduction of the weight and body mass index.

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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
286.21 KB
2 1 Introduction 1
859.58 KB
3 2 Subjects, Materials and Methods 75
132.6 KB
4 3 Results 89
575.14 KB
5 4 Discussion 148
190.95 KB
6 5 Atlas Photogarphs 165
245.67 KB
7 7 Anexures 212
162.08 KB