Emerging drug treatments for polycystic ovary syndrome
| Therapeutic class (references) | Drug | Phase of testing | Outcome measures | Main findings | Potential clinical benefits | Adverse effects (observed or potential) |
| Native kisspeptin100 101 104 105 107 | KP54, KP10 | Phase 1-2 | Phase 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 yield | Oocyte 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 (TAK-448) | Phase 1 | Pharmacokinetic and pharmacodynamic properties of MVT-602 | Compared with KP54, MVT-602 increased luteinising hormone with similar amplitude but later peak, resulting in greater AUC of luteinising hormone exposure | Oocyte maturation with less frequent dosing than native kisspeptins | No serious adverse effects identified so far |
| KISS1R antagonist110 111 | P234, P271, P354, P356, compound 15a | Preclinical | Basal and kisspeptin stimulated secretion of luteinising hormone | In 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 | Fezolinetant | Phase 2a | Fezolinetant 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 | Difelikefalin | Preclinical | Prenatally 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.2733 | Preclinical | DHEA rodent model: Insulin sensitivity. Ovulatory function | Improvements in insulin resistance, ovulatory dysfunction, reproductive hormone dysfunction, and polycystic ovarian morphology | Improvement in insulin sensitivity. Improvement in ovulatory dysfunction and fertility | Yet to be tested in humans |
| GLP-1 agonists*132–140 | Exenatide, liraglutide, dulaglutide, semaglutide | Phase 2-3 | Systematic 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 sensitivity | Improvement 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). Hyperandrogenism | 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, empagliflozin | Clinical | Empagliflozin 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 | Licogliflozin | Phase 2 | Licogliflozin 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.