Gonadotropins and Their Analogs: Current and Potential Clinical Applications

The gonadotropin receptors LH receptor and FSH receptor play a central role in governing reproductive competency/fertility. Gonadotropin hormone analogs have been used clinically for decades in assisted reproductive therapies and in the treatment of various infertility disorders. Though these treatments are effective, the clinical protocols demand multiple injections, and the hormone preparations can lack uniformity and stability. The past two decades have seen a drive to develop chimeric and modified peptide analogs with more desirable pharmacokinetic profiles, with some displaying clinical efficacy, such as corifollitropin alfa, which is now in clinical use. More recently, low-molecular-weight, orally active molecules with activity at gonadotropin receptors have been developed. Some have excellent characteristics in animals and in human studies but have not reached the market-largely as a result of acquisitions by large pharma. Nonetheless, such molecules have the potential to mitigate risks currently associated with gonadotropin-based fertility treatments, such as ovarian hyperstimulation syndrome and the demands of injection-based therapies. There is also scope for novel use beyond the current remit of gonadotropin analogs in fertility treatments, including application as novel contraceptives; in the treatment of polycystic ovary syndrome; in the restoration of function to inactivating mutations of gonadotropin receptors; in the treatment of ovarian and prostate cancers; and in the prevention of bone loss and weight gain in postmenopausal women. Here we review the properties and clinical application of current gonadotropin preparations and their analogs, as well as the development of novel orally active, small-molecule nonpeptide analogs. (Endocrine Reviews 39: 911 -937, 2018) G lobally, many couples desiring children expe- rience problems with infertility (). With the global demand for assisted reproductive technologies (ARTs), there has been a drive toward the discovery and development of effective therapeutic modulators of human reproduction. Central to this is the use of gonadotropins [FSH, LH, and human chorionic gonadotropin (hCG)] and their analogs. Here, we provide an up-to-date review of the development, properties, and activities of peptide and nonpeptide gonadotropin analogs and their current and potential clinical uses. The authors searched PubMed and Google Patents databases for original articles, appropriate reviews, and patent applications focused on gonadotropin receptors, gonadotropins, gonadotropin analogs, and ARTs published until February .