Table 2.

Mode of action and fertility-related side effects of current pharmacological agents * commonly used in anovulatory women with PCOS.

Medication	Mode of Action	Fertility-Related Side Effects
Clomiphene Citrate	-Induces ovarian follicular development [112]	-Due to its antiestrogenic effect, endometrial proliferation may be hampered [112,113] -May change cervical mucus characteristics with a consequent reduction in sperm penetration [112,113] -May impair endometrial receptivity [114] -May worsen subendometrial/endometrial vascularization as detected by power Doppler [114] -Its use is associated with an increased cardiac anomaly rate [115,116] -Resistance to CC is fairly common in women with PCOS (~ 15% of women with PCOS may not respond to the maximum dose of CC and are considered resistant to this medication) [78]
Gonadotropins (recombinant follicle-stimulating hormone (rFSH) or human menopausal gonadotropin (HMG))	-Stimulates endogenous peak of luteinizing hormone for oocyte maturation and ovulation triggering [117]	-Rate of clinical complications such as ovarian hyperstimulation ranges between 6.67 and 17.78% [118]; nonetheless, hCG therapy for PCOS-associated infertility is considered of high clinical curative value [118]
Letrozole	-Induces ovarian follicular growth and development and supports postovulatory corpus luteum without having a premature luteinizing effect on the developing follicles [119] -Supports endometrial proliferation through the stimulation of the Wnt/β-catenin pathway [107] -May improve endometrial receptivity and spiral artery resistivity indices [72,107,120] -Inhibits androgen-induced stimulation of E2 and aromatase p450 in endometrial cells [121]	-May result in elevated serum level of FSH [119] -May induce ovarian cyst formation [119] (not reported in CC-resistant women with PCOS [122]) -Can induce PCOS-like ovarian phenotype in experimental animals [123]
Metformin	-Improves glucose intolerance [87,88] -Modulates uterine/endometrial ER and PGR expressional irregularities [89] -Suppresses AR expression and normalizes the AR-mediated gene transcription [91,124] -May improve endometrial receptivity defects and improves uterine vascularity and subendometrial blood flow [125]	-Does not prevent the development of GDM [102] -May not improve live birth rate [126] -May not reduce the risk of PCOS-associated adverse pregnancy outcomes such as spontaneous abortion, gestational hypertension, preeclampsia and placental abruption [85] -Causes increased birth weight [103]

Abbreviations: CC: clomiphene citrate, FSH: follicle-stimulating hormone, GDM: gestational diabetes mellitus, ER: estrogen receptor, PGR: progesterone receptor, E2: estradiol, hCG: human chorionic gonadotropin. * Irrespective of current FDA-approval status.