Decoding androgen excess in polycystic ovary syndrome: Roles of insulin resistance and other key intraovarian and systemic factors

Table 1 Phenotypes for the classification and diagnosis of polycystic ovary syndrome

Phenotype	Synonym	Diagnostic criteria
Phenotype A	Classic phenotype (full-blown PCOS)	Hyperandrogenism + oligo-ovulation + polycystic ovaries
Phenotype B	Classic phenotype (non-polycystic ovaries)	Hyperandrogenism + oligo-ovulation
Phenotype C	Ovulatory phenotype	Hyperandrogenism + polycystic ovaries
Phenotype D	Non-hyperandrogenic phenotype	Oligo-ovulation + polycystic ovaries

PCOS: Polycystic ovary syndrome.

Table 2 Pharmacological interventions for polycystic ovary syndrome: Efficacy, side effects and safety

Drug class and treatment	Clinical benefits	Mechanism of action	Adverse effects	Safety considerations	Ref.
Hormonal regulators (combined oral contraceptives): Ethinylestradiol + drospirenone	Menstrual regulation, androgen suppression, reduces hirsutism and acne	Inhibits ovarian androgen production by suppressing gonadotropin, primarily, LH	Nausea, bloating, and mood changes	Weight gain, alterations in cardiometabolic parameters and venous thromboembolism risk	[38,39]
Insulin sensitizers (biguanides): Metformin	Improves insulin sensitivity, menstrual regularity, and ovulation	Inhibits hepatic gluconeogenesis and improves peripheral glucose uptake	GI upset	Caution with persistent use, increases homocysteine levels and increase risk of CVD	[12,37,40]
Insulin sensitizers (thiazolidinediones): Pioglitazone	Improves IR, ovulation, and excess androgen regulation	Decreases hepatic and peripheral IR through the activation of the nuclear hormone receptor (PPARα)	Weight gain and peripheral edema	Liver toxicity, not a first-line treatment option due to cardiovascular concerns	[37,41]
GLP-1 agonists: Liraglutide	Improves metabolic profile, including weight loss	Binds to insulin receptors on beta cells, stimulates insulin secretion, reduces glucagon secretion, inhibits hunger centers and delays gastric emptying	Nausea and emesis	Avoid during pregnancy; effective contraception is required and a washout period prior to pregnancy	[2,42,43]
SGLT2 inhibitors: Empagliflozin	Weight loss, improves insulin sensitivity, and reduces androgen levels	Renal glucose reabsorption is inhibited, promoting glycosuria	Increased urination, urinary tract infections, and dehydration	Monitor hydration and renal function; limited long-term data in PCOS	[44,45]
Anti-androgens: Spironolactone	Reduces hirsutism and acne	Reduces androgen production by blocking AR	May cause menstrual irregularity	Teratogenic; requires effective contraception; potassium monitoring advised due to hyperkalemia risk	[46]
Ovulation inducers: Clomiphene citrate	Ovulation induction	Selective estrogen receptor modulator	Mood swings, hot flashes	Risk of multiple pregnancies, endometrial thinning and thickening of cervical mucus	[47]
Ovulation inducers: Letrozole	Enhances ovulation and pregnancy rates	Aromatase inhibitor, reduces estrogen feedback to increase FSH	Fatigue, dizziness, hot flashes	Possibly teratogenic effects	[48]

LH: Luteinizing hormone; GI: Gastrointestinal; CVD: Cardiovascular disease; IR: Insulin resistance; PPARα: Peroxisome proliferator-activated receptor alpha; GLP-1: Glucagon-like peptide-1; SGLT2: Sodium-glucose cotransporter 2; PCOS: Polycystic ovary syndrome; AR: Androgen receptor; FSH: Follicle-stimulating hormone.