Infertility is inability to conceive after 1 year of unprotected intercourse which can be due to ovarian factors (30-40%), pelvic factors (30-40%), cervical factors (5%), male factors (25-40%), and unexplained causes (10-15%).

Polycystic ovarian syndrome (PCOS) is a complex metabolic syndrome and the foremost ovarian factor that leads to infertility in the general population due to the increasing incidence of obesity and diabetes [1]. According to Rotterdam ESHRE/ASRM sponsored PCOS consensus workshop group, the presence of two of three of the following criteria are required for the diagnosis of PCOS: (i) oligo and/or anovulation, (ii) clinical and/or biochemical signs of hyperandrogenism and (iii) polycystic ovaries defined as the presence of 12 or more follicles in each ovary(with one ovary being sufficient for the diagnosis) measuring 2-9mm in diameter and/or increased ovarian volume (>10 ml) [2],

Pathophysiology of Infertility caused by PCOS

The inability of women with PCOS to produce and release ovum is due to complex interplay of multiple hormonal imbalances. The hormones involved are insulin, androgens, estrogen, progesterone, luteinizing hormone, follicle stimulating hormone, adrenal androgens, thyroid hormone, prolactin and many others. In addition to infertility, women with PCOS are at higher risk of insulin resistance, impaired glucose tolerance, metabolic syndrome, obesity, cardiovascular disease, etc. All the above conditions are complexly inter-related and forerunners of one another.

Insulin resistance and PCOS

Insulin resistance is defined as reduced insulin response to a given amount of insulin. It occurs in 25 – 70% of infertile patients with PCOS [3]. Insulin resistance can be due to reduced number of insulin receptors, altered insulin to receptor interaction or post receptor failure. In PCOS, it is mainly the post receptor defect which is due to increased serine phosphorylation of beta chain of insulin receptor and adrenal and ovarian cytochrome P450 enzyme. Increased phosphorylation causes increased 17-hydroxylase and 17-20 lyase action that leads to hyperandrogenemia. Also, there is increased conversion of androstenedione to estrone, yet ovarian estrogen production is sparse. Estrone level causes increased prolactin level in 30-40% of patients.

Increased insulin levels reduce sex hormone binding globulin which in turn increases testosterone and estrogen level. Estrogen rise causes increased LH and decreased FSH level. Suboptimal FSH action leads to follicular stimulation but no maturation or ovulation; as a result numerous small follicles with hyperplastic and luteinized theca cells form. These immature follicles when undergo atresia, lead to increase in stromal component that secretes androstenedione and testosterone which further prevents normal follicular growth and causes premature follicular atresia [Figure 1].



Role of ‘insulin sensitizing agents’ in PCOS related infertility

Use of insulin sensitizing agents is a recent therapeutic strategy adopted for women with PCOS to reduce insulin resistance and induce regular menstrual cycles and fertility. Candidate drugs that are used for the purpose include metformin and thiazolidinediones (rosiglitazone and pioglitazone).

Metformin

It is a biguanide, originally used as oral glucose lowering agent to treat type 2 diabetes mellitus. This drug acts by improving sensitivity of peripheral tissue and liver to insulin thus improving insulin resistance in type 2 diabetes. It also decreases basal hepatic glucose output thereby decreasing fasting glucose level [4]. Metformin also helps to increase insulin sensitivity of peripheral cells by increasing GLUT1 and GLUT4 receptor translocation [5]. Decrease in fatty acid oxidation by 10-20% also reduces glucose via glucose–fatty acid cycle. Metformin also has other beneficial actions viz. decreasing androgenemia, improving lipid profile, and increasing fibrinolytic action [6,7]. Metformin causes 3-4 kg of weight loss and 1-2 kg/m² decrease in BMI [8]. The effect on central adiposity is maximum at dose of 2500 mg/day [9].

Major side-effects of this drug are gastrointestinal discomfort leading to nausea, abdominal pain, flatulence, abdominal bloating, vitamin B12 deficiency etc [10]. The gastrointestinal side-effects can be minimized by gradually increasing the dosage and by taking the drug after meals. A major side effect is lactic acidosis and hence this drug is contraindicated in hepatic and renal failure; however, phenformin and not metformin has been the culprit on most occasions.

Contraindications for metformin include renal dysfunction (a serum creatinine level >1.4 mg/dL), hepatic dysfunction, severe congestive heart failure, or a history of alcohol abuse.

Standard dosage of metformin is 500-1000 mg/day as a starting dose. It is advisable to increase the dose by 500 mg every week till the required dose. If side-effects appear, the dose should be reduced or stopped for next 2-3 weeks. US guidelines suggest maximum of 2500 mg/day, others use maximum of 3 gm/day.

Ovulation induction and metformin

Metformin is the most commonly used insulin sensitizing agent for ovulation induction. Following are the indications for starting metformin therapy [11]-

1) fasting insulin level >25 IU/L
2) post prandial insulin levels >100 IU/L
3) PCOS women with raised androgens
4) failure of ovulation induction after clomiphene with BMI >25 kg/m2.
5) patient has Metabolic Syndrome
6) genetic predisposition to type 2 diabetes or cardiovascular diseases

Metformin is initiated in the follicular phase as 500 mg/day for 5 – 7 days. Dosage is increased weekly by 500 mg till 1500-2000 mg/day and is continued for 2-3 months to show results [12]. If after 3 months of therapy, serum insulin is still high then one can add other drugs like rosiglitazone or pioglitazone etc.

Optimum results of the therapy noticed are regularization of menstrual cycle in 60-95% of patients within 4 to 6 months of treatment and improved ovulation by decreased hyperandrogenemia and insulin resistance.

Better results are seen when metformin therapy is combined with clomiphene; ovulation rates with clomiphene alone are lower (76% vs 46%) [13]. Similar results are seen when rosigliatazone is combined with clomiphene.

Also, effect of metformin to improve FSH-induced ovulation in women with clomiphene resistant PCOS is still investigational. Yet, it decreases intraovarian androgens which leads to reduced estradiol and causes orderly follicular growth in response to exogenous gonadotropins [14].

It is also notable that combined treatment with rosiglitazone and metformin improved the number of ovulatory cycles in non-obese patients with PCOS although definitive trials are still awaited [15,16,17,18,19].

Reduced hyperandrogenemia and insulin resistance in PCOS women by insulin sensitizing agents facilitates FSH stimulation; and therefore parallel administration of metformin before and during IVF cycle decreases the requirement of FSH and increases pregnancy rates. In a trial, both the fertilization (64% vs 43%) and pregnancy rate (70% vs 30%) were increased in metformin and FSH treated cycles as compared to only FSH treated cycles. Nevertheless, role of metformin is still investigational as regards use with FSH and in IVF cycle and further studies are awaited [20,21,22].

Rosiglitazone

It is a thiazolidinedione derivative. It mainly activates nuclear peroxisome proliferator activated receptor gamma (PPAR-gamma) and sequesters lipids in adipocytes, thereby decreasing lipid accumulation in muscle and increasing insulin sensitivity [23]. It also decreases LH, testosterone, androstenedione, DHEAS, and leptin level. It increases ovulation rate by 50% [24]. It is taken as 4-8 mg/day [25].

Pioglitazone

Pioglitazone belongs to the same thiazolidinedione family. Only difference is that it activates PPAR-g leading to regulated glucose and lipid metabolism by amplifying post-receptor action of insulin in liver and peripheral tissue. Standard dosage is 30-45 mg/day.

Newer Drugs-

D- chiroinositol- It increases phosphoglycan that mediates insulin action. It takes 6- 8 weeks to show its effect. According to some studies it has 86% ovulation rate [26].

Acarbose
It is alfa-glucosidase inhibitor which slows down carbohydrate digestion and absorption in the body. Its role in ovulation is still investigational.

Somatostatin analogue

It is an endogenous hypothalamic peptide that besides blunting LH response to gonadotropin releasing hormone and decreasing GH, it inhibits pancreatic insulin release. According to studies, 7-day administration of octreotide, a synthetic somatostatin, decreases fasting and glucose stimulated insulin [27]. It also improves pulsatile gonadotropin pattern, reduces LH, androgen, increases spontaneous and stimulated ovulation [28,29,30]. To overcome its short half life, octreotide-LAR has been devised. Role of this drug is still investigational.

Needless to stress is the importance of diet, exercise and life style measures. It has been reported that 10% weight loss is followed by improvement in hormonal profile, menstrual regularity, ovulation and improved pregnancy rates [31].

Dietary management with modification of sedentary lifestyle is recommended to be initially adopted; and pharmacological and other interventions should be reserved for use when weight loss regimens and life style measures have proved unsuccessful. It is important to realise that 10-13% of PCOS women are lean in whom weight loss is not effective, thereby arising need for other therapeutic strategies [16]. Use of insulin-sensitising agents is a recent therapeutic strategy and a lot of work is being done in this field, but definitely, it opens up new vistas for management of the infertile PCOS patient.

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