Introduction

Polycystic ovary syndrome (PCOS) is a multifaceted disease affecting not only women of childbearing age, but also adolescents and postmenopausal women. PCOS adversely influences the fertility and reproductive health of the affected women. Also, due to its association with other lifestyle diseases, it is also the cause of significant cardiovascular and metabolic morbidity.¹

Clinical presentation can vary widely but, in general, PCOS is characterised by irregular menses, hyperandrogenism and polycystic ovary morphology, after excluding differential diagnosis such as pregnancy, hypothyroidism, hyperprolactinemia, late-onset congenital adrenal hyperplasia, ovarian tumor, hyperthecosis, adrenal tumor and Cushing’s syndrome.^2,6

When diagnosing PCOS, extension of the Rotterdam criteria to phenotypic definitions, will not only help with clinical research and practice but also aid the identification of women with PCOS who are at long-term metabolic risk (Table 1).²

Pathogenesis

Hyperandrogenism in PCOS

Hyperandrogenism is characterized by excessive production and/or secretion of androgens, which is usually manifested by acne, hirsutism or frontal alopecia. Hyperandrogenism remains the main feature of PCOS, because up to 70–80% of PCOS women exhibit clinical manifestations of hyperandrogenism.⁴

Insulin Resistance in PCOS

Insulin sensitivity is decreased by an average of 35% to 40% in women with PCOS, as compared to matched controls. Most women with PCOS are insulin resistant and develop compensatory hyperinsulinemia, which seems to play a critical role in the syndrome’s pathogenesis.⁴

GLUT-4: Glucose transporter type 4; IRS-1: Insulin receptor substrate 1; PI-3K: Phosphoinositide 3-kinases; T2DM: Type 2 diabetes mellitus

Androgen Excess and Insulin Resistance^4,6

• Insulin resistance and compensatory hyperinsulinism contribute to androgen excess in PCOS because, insulin acts as a co-gonadotropin on the ovary, facilitating androgen secretion from the adrenal glands and modulating LH pulsatility.
• Multiple studies have shown that insulin stimulates androgenesis in normal ovarian in vitro models.
• PCOS thecal cells show increased androgen responsiveness to insulin and LH when compared to normal thecal cells.
• There is a possibility that increased insulin action on androgen production may co-exist with normal or reduced metabolic activity of insulin in PCOS.

Long-Term Consequences of PCOS²

Management Strategies

Since there are no universal treatment available for PCOS, therapy must always be individualized and adapted to the actual needs of the individual patient. Targets for pharmacological treatment might include androgen excess, oligo-ovulation and insulin resistance, but lifestyle counselling should be provided in all cases in order to prevent or treat obesity.⁶

Targeting Androgen Excess in PCOS

Role of Cyproterone Acetate/Ethinylestradiol (CPA/EE) Combination in PCOS Management2

The main pharmacological aim is to reduce the levels of circulating androgens and control their effect at tissue level to improve symptoms such as hirsutism and acne and reduce the risk of long-term metabolic consequences. Combinations of ethinylestradiol and antiandrogenic progestogens, such as cyproterone acetate, drospirenone, etc., have traditionally been the first choice for management of PCOS.

Clinical Benefits²

• Improvement in androgenic symptoms of PCOS – hirsutism, acne, seborrhea and alopecia
• Decrease in hyperandrogenemia and hyperinsulinemia
• Reduction in long-term risks (metabolic disorder, endometrial cancer)
• In women who want to avoid pregnancy:
  • improvement of irregular bleeding patterns
  • contraception as additional effect

The antiandrogenic effects of combined oral contraceptives, such as CPA+EE, is achieved via a number of different mechanisms:²

• Increase in hepatic sex hormone-binding globulin (SHBG) production achieved is much stronger using ethinyl estradiol compared with the use of estradiol.
• When used in ovulatory inhibition dosage, progesterone component brings about suppression of LH secretion and thereby ovarian androgen production
• Competition for the 5-alpha-reductase and androgen receptors by progestogens; effect is strongest when using cyproterone acetate
• CPA can block action of testosterone by competitive action on androgen-receptor at tissue level
• CPA also directly acts on ovarian androgen production.

Clinical Efficacy

Targeting Metabolic Profile in PCOS

Role of inositols in PCOS management^12,13,14

• Two specific inositol stereoisomers, myo-inositol (MI) and D-chiro-inositol (DCI), both function as insulin second messengers and mediate different actions of insulin.
• In the ovary, Myo-inositol phosphoglycan mediator is involved in FSH signaling, whereas D-chiroinositol phosphoglycan mediator is involved in insulin-mediated androgen production.
• Thus, disorders in the ovarian MI-DCI ratio might impair FSH signaling and worsen oocyte quality
• Combination inositol therapy (MI and DCI) has the potential to improve all symptoms, signs, and laboratory anomalies of PCOS.
• Both inositols, prescribed together, should be able to improve the required inositol concentrations in both systemic circulation and the ovary, thus addressing the ovary inositol paradox.
• The correction of systemic insulin resistance by MI will treat the metabolic features of PCOS.
• Simultaneously, adequate DCI levels will create a healthy intra-ovarian milieu, which will correct hyperandrogenism, improve menstrual regularity, and promote ovulation and fertility.
• Inositol is generally regarded as safe. Gastrointestinal symptoms can occur but are rare.

Clinical Benefits¹⁴

• Inositols MI and DCI can reduce insulin resistance, improve ovarian function, and reduce androgen levels in women with PCOS.
• The effect of MI on ovarian function and oocyte quality is independent of its concentration in circulation.
• Serum levels of DCI are reported to be lower in women with PCOS, both at baseline and after administration of glucose loads. DCI treatment has been found to reduce insulin levels, lipids, and blood pressure, in women with PCOS.

Clinical Efficacy

Summary

• Insulin resistance and hyperinsulinemia are the major pathophysiological mechanisms underlying PCOS.⁵
• Cyproterone acetate/ethinylestradiol shows improvement in the symptoms of hyperandrogenism, such as acne and hirsutism, which commonly present in women with PCOS.²
• Inositols act as second messengers for insulin, and hence correction of their deficiencies may help in alleviating metabolic, menstrual/ovulatory, and cutaneous hyperandrogenic features of PCOS.¹⁴

References

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