Hyperandrogenism and Insulin Resistance in PCOS

Table of Content

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 Resistance4,6

 

  • 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

Study design

Patient population

Intervention

Results

Prospective

clinical study8

 

Patients diagnosed

with PCOS (n = 50)

 

2 mg CPA + 35 mcg EE for over 6 consecutive cycles

 

• Improvement in the levels of serum FSH, LH and LH/FSH ratio and free testosterone

• Decrease in hirsutism and acne scores

• Improvement of menstrual disturbances

• Ovarian morphology reverted to normal in 42% patients.

Randomized

clinical study9

Patients diagnosed

with PCOS (n = 36)

EE 30 mcg / desogestrel 150 mcg + spironolactone 25 mg /day v/s 2 mg CPA + 35 mcg EE for 3 treatment

cycles

Both groups showed:

• Decreased acne score and free androgen index

• Increase SHBG levels.

• Regular withdrawal bleedings CPA + EE showed increase in HDL levels

Clinical study10

Patients diagnosed

with PCOS (n = 66)

 

2 mg CPA + 35 mcg EE for 36 cycles

• Significant decrease in LH/FSH ratio and in

adrenal and ovarian androgens

• Significant increase in SHBG

• Progressive decrease of the total androgenic

activity: at the 36th cycle of therapy, acne

disappeared in 100% of the cases, seborrhoea

in 76.4% and hirsutism in 75%.

Randomized,

double-blind,

control study11

Patients diagnosed

with PCOS (n = 171)

 

30 mcg EE + 150 mg desogestrel, 2 mg CPA + 35

mcg EE, and EE 30 mcg + drospirenone 3 mg for 12 months

CPA + EE -

• Significantly decreased modified Ferriman

Galwey score compared with both desogestrel

and drospirenone

• Significantly increased SHBG compared with desogestrel

• Showed strongest antiandrogen activities at 12 months

Targeting Metabolic Profile in PCOS

Role of inositols in PCOS management12,13,14

  • 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

Study design

Patient population

Intervention

Results

Randomized

study15

 

Patients diagnosed

with PCOS (n = 140)

 

MI 550 mg + DCI 13.8 mg twice daily v/s MI 1 gm twice daily for 6 months

 

• MI + DCI provides statistically

significant decreased BMI, W:H ratio,

diastolic BP, fasting blood sugar at the end of both 3rd and 6th month

• MI + DCI also increased the HDL level significantly in both the occasions.

Randomized

study16

 

Obese patients

(BMI>30) diagnosed

with PCOS (n = 140)

 

MI 550 mg + DCI 13.8 mg v/s placebo (folic acid

200 mcg) twice daily for 6 months

• LH and free testosterone levels decreased after the combined treatment,

downregulating the hyperandrogenism,

and even HOMA index and fasting insulin, markers of insulin resistance, resulted to be significantly reduced.

• E and SHBG significantly increased,

showing restoring in ovulation capability

• MI plus DCI significantly rebalanced

the endocrine and metabolic profiles of

these patients, ameliorating their insulin

resistance and the ovulatory function.

Randomized

study17

Patients with PCOS

(BMI > 27 kg/m2,

mean age 28 years

old, n = 50)

MI 550 mg + DCI 13.8 mg twice daily v/s MI 2 gm twice daily for 6 months

MI + DCI:

• significant reduction in both plasma glucose and insulin concentrations

• more relevant decrement of total

testosterone and increment of the serum SHBG

• Striking improvement of ovulation function

Prospective,

randomized,

comparative

study18

Patients of

reproductive age

group (15-45 years),

diagnosed with

PCOS (n = 200)

MI 550 mg + DCI 13.8 mg twice daily v/s

metformin 500 mg thrice daily for 24 weeks

MI + DCI

• Improved insulin sensitivity in PCOS women.

• Was effective in controlling the

hormonal profiles (LH/FSH ratio and

free testosterone)

• Associated with improvement in insulin sensitivity in HOMA-IR defined insulin resistant patients.

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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