Though GnRHa suppress LH concentration, higher number of follicles during stimulation is an adverse effect. GnRH antagonists have some advantages over agonists. Since the antagonist suppress LH immediately, it can be administered in the late follicular phase when the LH peak is expected thereby reduce premature LH surge in PCOS patients.
Ultrasound assessment of the ovary can be performed at baseline before the initiation of each cycle. Serial ovarian ultrasound is an excellent method of determining follicle growth and development in response to gonadotropin stimulation. In particular, documentation of all follicles greater than 10 mm may be helpful to predict the risk of multiple pregnancies. Adherence to the chronic low-dose regimen of FSH administration in women with PCOS should markedly reduce the likelihood of excessive ovarian stimulation and OHSS. However, before ovulation induction with gonadotropins, it is mandatory to counsel the patient about the risks associated with higher-order multiple pregnancies after polyovulation.
Overall, low-dose regimens result in a monofollicular ovulation rate of approximately 70%, a pregnancy rate of 20%, and a multiple live birth rate of 5.7%. Correspondingly, there is a low incidence of multiple pregnancies (<6%) and OHSS (<1%) . These results compare favorably to the unacceptable high risk of multiple follicular development, multiple pregnancies (36%), and severe OHSS (4.6%) reported for conventional dose protocols
i). Insulin sensitizers
At least five different modalities have been used to lower insulin levels in PCOS. These include weight loss, diazoxide, metformin, thiazolidinedeones (pioglitazone, rosiglitazone, troglitazone is no longer available for use) and D-chiro inositol. Among all drugs metformin is the most comprehensively evaluated drug. Both metformin and the thiazolidinediones effect reductions in insulin levels but they do so by fundamentally different mechanism. None of the insulin sensitizing drugs have Food and Drug administration (FDA) approval for use in PCOS. Nonetheless the scientific evidence supporting their salutary effects in PCOS is substantial and progressively mounting and their use for this purpose by clinicians is already established. Although troglitazone is effective in resulting ovulation in PCOS due to need of liver transplantation and death from hepatic failure it is withdrawn from the market. Much published data assessing rosiglitazone and pioglitazone and D-chiro inositol in PCOS are not available. Moreover, D-chiro inositol is not yet commercially available.
Metformin is a biguanide antihyperglycemic that is approved for the management of type 2 diabetes mellitus. The mechanism by which metformin enhance insulin sensitivity are not fully characterized. At a molecular level, metformin may increase the activity of the enzyme adenosine monophosphate-activated protein kinase. Metformin appears to suppress hepatic glucose output, decreased intestinal absorption of glucose, increased insulin mediated glucose utilization in peripheral tissues and has an antilypolytic affect on fatty acid concentration reducing gluconeogenesis . It does not produce hypoglycemia in either normal subjects or patients with type 2 diabetes. It is rapidly absorbed from the small intestine and without metabolism largely excreted in the urine. It is available in a generic form as 500 mg, 850mg and 1000 mg tablets. The target dose of metformin is in the range of 1500 mg to 2550mg . Metformin is given with meals to reduce the gastrointestinal side-effects. The most common side-effects of metformin are diarrhea, nausea, vomiting, flatulence, indigestion and abdominal discomfort. The gastrointestinal side-effects may be caused by high intestinal metfromin concentration that cause builds up of lactic acid in the bowel. A rare problem caused by metformin is lactic acidosis, which is fatal in as many as 30%-50% of cases . Chances of lactic acidosis is increased when patients have renal insufficiency. So it should not be prescribed if serum creatinine level is greater than 1mg/dL. Liver disease, congestive heart failure and previous history of lactic acidosis are other contraindications of metformin therapy. Metfromin should be temporarily suspended for all major surgical procedures that involve restriction of fluid intake. Among metformin users in 10% of cases lactic acidosis occurred after the intravenous administration of iodinated contrast agents. So most authorities recommend that metformin should be discontinued 48 hours before any radiologic procedure that involves intravenous administration of iodinated contrast material. Though some authorities believe that it is safe to give contrast media to person taking metformin as long as renal function is known to be normal.