Hyperinsulinaemia and PCO

What is HAIR-AN Syndrome, polycystic Ovary and its relation to Infertility??

High circulating insulin concentration has been noted in some forms of PCO. The association of hyper-androgenism, extreme insulin resistance and acanthosis nigricans (HAIR-AN syndrome) is recognized as one extreme end of the spectrum of PCOS. These patients show signs of ovarian hypertrophy with hirsutism, clitoromegaly and elevated androgen levels. Many such individuals show extreme obesity. But some workers have shown hyperinsulinemia in 30 percent of lean PCOS patients and 65 to 70 percent of obese patients.

  It is not known whether the defect in glucose metabolism causing hyperinsulinemia is congenital or acquired. The popular belief is that it is gene-related because several families are identified where, majority of siblings in the family are affected. In order to achieve a euglycemic state, there will be a rebound activity of islet cells of pancreas leading to hyperinsulinemia.

 While some PCO women show an uncompensated picture of hyperglycemia along with hyperinsulinemia (non-insulin dependent diabetes) most women show euglycemia with hyperinsulinemia. There are some women who are even hypoglycemic due to overcompensation. Such women with untreated hyperinsulinemia can eventually go to pancreatic failure and insulin deficiency diabetes.

Mechanism of hyperinsulinemia may be due to several factors. It may be due to increased pancreatic sensitivity to hyperglycemia, decreased hepatic clearance of insulin and peripheral target tissue resistance. The last is probably the most accepted hypothesis. The resistance may be caused by three possibilities. In type A syndrome, hyperinsulinemia is due to decrease in number of insulin receptors in target tissue due to mutation of insulin receptor gene. In type B syndrome, hyperisulinemia is due to autoantibodies to insulin recetors. In type c syndrome, which is the largest group of hyperinsulinemia, it is due to post receptor defect caused by interference with signal transduction.

 The relationship between insulin and insulin-like growth factor I (IGF-1) and ovaries

Receptor for insulin and IGF-I have been demonstrated in human ovaries. Both hormones have a mitogenic effect on granulose cells in culture. They augment the ovarian steroidogenic capacity in vivo by potentiating the effects of gonadotropins. They stimulate FSH induced estradiol (E2) and progesterone (P) synthesis in granulose cells and LH induced androstenedione (A) and testosterone (T) synthesis in theca and stromal cells. The serum concentration of testosterone decreases when serum insulin level is reduced. Insulin receptors have been demonstrated in pituitary. The increase in LH: FSH ratio in PCOS is partly attributed to increase in LH hormone production by pituitary due to the effect on insulin.

  Normally under physiological circumstances, insulin does not play any important role in steroid production in ovary. IGF-1 is the molecule active at physiological concentrations, which helps in regulation of ovarian function in vivo. Insulin and IGF-1 receptors share many structural and functional properties allowing a certain degree of cross-reactions at supraphysiological concentrations.

  Increased insulin is said to module the production of sex hormone binding globulin (SHBG) in the liver. There is a strong negative correlation between rising levels of insulin and falling levels of SHBG produced by liver. Increase in SHBG reduces free testosterone level. Likewise fall in SHBG (which occurs) in hyperinsulinemia can result in increase in free testosterone level and this appears to be the most important factor that determines the feature of hirsutism in PCO women.

Follicular Development and Insulin: Insulin may disrupt normal folliculogenesis:

1   insulin can act as a mitogenic factor and can stimulate other growth factors like IGF-I and IGF-II which can affect ovarian follicular development and cause multiple ovarian cysts and ovarian enlargement.

2   Insulin can interfere with orderly function of gonadotropins by releasing LH out of turn. It has been shown that at the time of puberty, young girl show evidence of insulin resistance and hyperinsulinemia at a time when they produce multiple cysts in the ovaries. Hyperinsulinemia, multicystic ovary (MCO) and onset of menarche seem to be intimately connected. Multicystic ovaries resolve in course of time. On occasions, the MCO can persist and may later on take the appearance of PCO. It has been found that circulating insulin levels are directly proportional to ovartian volume in both PCOS and women with multi follicular ovaries (MFO) thus promoting the hypothesis that insulin contributes to genesis of both PCO and MFO.

Therapy in PCO:  the goal of thereapy in women with PCOS  is to

·    Reduce serum androgen levels- particularly important in women seeking treatment for hirsutism

·    Improve ovulatory function and regulate menses-of importance in infertile women enhance weight loo-important in obese PCOS.

·    Halt metabolic disturbance that follow hyperinsulinemia, such as glucose intolerance, dyslipidemia, hypertension and atherosclerosis in elderly women.

·    To prevent onset of complication due to unopposed action of estrogen like endometrial hyperplasis, carcinoma of the breast etc.

Treatment of hyperinsulinemia seems to reduce most of the adverse effects of PCOS. But treatment of hyperinsulinemia can only be an adjuvant to other types of therapy immediately required to alleviate the patients’s problems of infertility.