Table 1

Emerging drug treatments for polycystic ovary syndrome

Therapeutic class (references)DrugPhase of testingOutcome measuresMain findingsPotential clinical benefitsAdverse effects (observed or potential)
Native kisspeptin100 101 104 105 107 KP54, KP10Phase 1-2Phase 1 and 2 clinical studies:
Oocyte maturation (in women at high risk of ovarian hyperstimulation syndrome, including polycystic ovary syndrome)
KP54 triggered oocyte maturation without causing ovarian hyperstimulation syndrome. A second dose of KP54 improved oocyte yieldOocyte maturation with reduced risk of ovarian hyperstimulation syndrome.
Promotion of progesterone rich ovarian environment favouring ovarian implantation
Tachyphylaxis after repeated and long term dosing.
Follicle stimulating hormone deficiency in polycystic ovary syndrome
Pilot study in 12 women with polycystic ovary syndrome:
Hormonal (gonadotrophin, oestradiol, inhibin B) and ovulatory responses to repeated KP54 administration
Increases in luteinising hormone and oestradiol but not follicle stimulating hormone or inhibin B. Development of a dominant follicle and subsequent ovulation in 2 of 12 women
In women with infertility undergoing in vitro fertilisation:
Changes in gene expression in granulosa cells from women with infertility (most of whom had polycystic ovary syndrome)
Compared with human chorionic gonadotropin or gonadotrophin releasing hormone agonists, KP54 increased expression of gonadotropin receptors (follicle stimulating hormone receptor and luteinising hormone receptor) and steroidogenic enzymes (including aromatase CYP19A1, StAR, and HSD3B2) in ovarian granulosa cells
KP10 analogues108 MVT-602
Phase 1Pharmacokinetic and pharmacodynamic properties of MVT-602Compared with KP54, MVT-602 increased luteinising hormone with similar amplitude but later peak, resulting in greater AUC of luteinising hormone exposureOocyte maturation with less frequent dosing than native kisspeptinsNo serious adverse effects identified so far
KISS1R antagonist110 111 P234, P271, P354, P356, compound 15aPreclinicalBasal and kisspeptin stimulated secretion of luteinising hormoneIn female dogs, P234, P271, P354, and P356 did not affect basal or kisspeptin stimulated luteinising hormone secretion.
P234 inhibited gonadotrophin releasing hormone neuron firing in mice and inhibited pulsatile gonadotrophin releasing hormone secretion in female monkeys. P234 inhibited kisspeptin stimulated luteinising hormone secretion in rats and mice
Improvement in ovulatory dysfunction and fertility.
Improvement in biochemical and clinical hyperandrogenism
Oversuppression of luteinising hormone secretion leading to anovulation
Neurokinin 3 receptor antagonist116 117 150 FezolinetantPhase 2aFezolinetant v placebo:
Change in total testosterone. Change in gonadotrophins, oestradiol, progesterone, anti-müllerian hormone, ovarian function and volume
Reduction in total testosterone.
Reduction in luteinising hormone, reduction in luteinising hormone:follicle stimulating hormone ratio
Improvement in biochemical and clinical hyperandrogenism.
Improvement in ovulatory dysfunction and fertility.
Improvement in body weight and composition.
Improvement in insulin sensitivity
Thrombophlebitis, headache, and gastrointestinal symptoms
Dihydrotestosterone mouse model:
Oestrous cycle regularity.
Ovarian follicle count.
Adipocyte morphology and adipose tissue mass.
Serum adiponectin, leptin, cholesterol, triglyceride, fasting blood glucose levels.
Food intake, energy expenditure, locomotor activity (metabolic cage study).
Glucose homeostasis
Reduction in body weight.
Reduction in inguinal, mesenteric, parametrial, and retroperitoneal fat pad weights.
Reversal of adipocyte hypertrophy.
Increased respiratory exchange ratio.
Improvement in glucose tolerance
Opioid receptor agonists119 121 DifelikefalinPreclinicalPrenatally androgenised mouse model:
Oestrous cycle regularity.
Hypothalamic KISS1 expression.
Luteinising hormone basal and peak levels, luteinising hormone pulse frequency.
Testosterone levels
Oestrous cycle reversed to normal state.
KISS1 expression normalised in arcuate nucleus.
Reduction in luteinising hormone pulse magnitude.
Reduction of testosterone levels
Improvement in ovulatory dysfunction and fertility.
Improvement in biochemical and clinical hyperandrogenism
Diarrhoea, dizziness, and vomiting
11β-HSD1 inhibitors37 BVT.2733PreclinicalDHEA rodent model:
Insulin sensitivity.
Ovulatory function
Improvements in insulin resistance, ovulatory dysfunction, reproductive hormone dysfunction, and polycystic ovarian morphologyImprovement in insulin sensitivity.
Improvement in ovulatory dysfunction and fertility
Yet to be tested in humans
GLP-1 agonists*132–140 Exenatide, liraglutide, dulaglutide, semaglutidePhase 2-3Systematic review of GLP-1 agonists v metformin:
Changes in body weight and anthropometric parameters.
Insulin sensitivity
GLP-1 agonists produced greater improvements in body weight, waist circumference, and insulin sensitivityImprovement in weight and body composition.
Improvement in cardiometabolic risk
Nausea, vomiting, and diarrhoea; safety in pregnancy unclear
Liraglutide v placebo:
Body weight.
Ovarian morphology.
Changes in menstrual pattern (bleeding ratio).
Reduction in body weight.
Improvement in bleeding ratio.
Reduction in free androgen index, sex hormone binding globulin and free testosterone.
Reduction in ovarian volume
Markers of cardiovascular risk:
Serum endothelial markers (ICAM-1, P-selectin, E-selectin).
Changes in endothelial function.
Lipid levels
Exenatide improved serum markers of endothelial function without a change in endothelial function.
Liraglutide improved thrombin generation test parameters.
Liraglutide improved triglyceride levels and triglyceride:high density lipoprotein ratio
SGLT2 inhibitors†144 146 147 Canagliflozin, dapagliflozin, empagliflozinClinicalEmpagliflozin v placebo in humans:
Changes in anthropometric parameters and body composition.
Hormonal (total testosterone, androstenedione, sex hormone binding globulin, DHEAS) and metabolic (HOMA-IR, fasting lipids) parameters
Reduction in body weight, and hip and waist circumference.
Reduction in fat mass.
Reduction in basal metabolic rate.
No change in hormonal and metabolic parameters
Improvement in weight and body composition.
Improvement in cardiometabolic risk
Urinary tract infection and ketoacidosis
Combination canagliflozin-metformin v metformin in humans:
Anthropometric parameters, gonadotrophins, androgen levels, menstrual pattern, glucose and lipid homeostasis
Compared with metformin alone, combination canagliflozin-metformin produced greater reductions in total testosterone, AUC for glucose, and AUC ratio for insulin to glucose
Markers of cardiovascular risk in humans:
Changes in serum endothelial markers (ICAM-1, E-selectin, VCAM-1, PECAM-1).
Endothelial function
Empagliflozin reduced ICAM-1, E-selectin, and VCAM-1 but not PECAM-1, without a change in endothelial function
SGLT1-2 inhibitor148 LicogliflozinPhase 2Licogliflozin v placebo:
Androgen levels.
Insulin sensitivity (HOMA-IR).
Hyperinsulinaemia (maximum (insulin), insulin AUC)
Reduction in androstenedione and DHEAS.
Reduction in HOMA-IR and fasting glucose.
Reduction in maximum (insulin) and insulin AUC.
No change in free testosterone, total testosterone, sex hormone binding globulin, free androgen index, or DHEA
Improvement in insulin resistance.
Reduction in androgen excess.
Improvement in weight and cardiometabolic risk
Urinary tract infection, ketoacidosis, diarrhoea, and nausea
  • AUC=area under the curve; CYP19A1=cytochrome P450 family 19 subfamily A member 1; DHEA=dehydroepiandrosterone; DHEAS=dehydroepiandrosterone sulphate; GLP-1=glucagon-like peptide 1; HOMA-IR=homeostatic model assessment of insulin resistance; HSD3B2=3β-hydroxysteroid dehydrogenase; ICAM-1=intercellular adhesion molecule 1; KISS1=gene encoding kisspeptins in humans; KISS1R= KISS1 receptor; KP=kisspeptin; PECAM-1=platelet endothelial cell adhesion molecule; SGLT=sodium-glucose co-transporter; StAR=steroidogenic acute regulatory protein; VCAM-1=vascular cell adhesion molecule 1; 11β-HSD1=11β-hydroxysteroid dehydrogenase type 1.

  • *Clinical trial in progress: NCT03919929, Treating PCOS With Semaglutide vs Active Lifestyle Intervention (TEAL).

  • †Clinical trials in progress: NCT04213677, Dapagliflozin Efficacy and Action in PCOS (DEAP); NCT05200793, Efficacy of Empagliflozin or Linagliptin as an Alternative to Metformin for Treatment of Polycystic Ovary Syndrome.