The paradigm of norgestimate: a third-generation testosterone-derivative progestin with a peripheral anti-androgenic activity and the lowest risk of venous thromboembolism

Abstract

Introduction: Norgestimate (NGM) is a testosterone derivative with peculiar receptor activities.Areas covered: This is a narrative review of the available data on the pharmacotherapy of NGM in combined hormonal contraceptives (CHCs) in terms of contraceptive efficacy, venous thromboembolism (VTE) risk, safety, tolerability and bleeding patterns. A comprehensive literature review was conducted in August 2020 using PubMed with the keyword 'norgestimate'. Expert Opinion: NGM shows a mild estrogenic activity associated with anti-mineralocorticoid and antiandrogenic properties, largely responsible for the cardiovascular safety profile. The anti-androgenic property depends on the androgen receptor (AR) nuclear translocation (AR trafficking and its subnuclear distribution), the inhibition of 5α-reductase activity (it possesses higher activity compared to other available progestins), and the increase on sexual hormone binding globulin (SHBG) levels if combined with an estrogenic counterpart. NGM is one of the molecules that best modulates the power of ethinyl-estradiol on the thromboembolic risk, being associated with the lowest VTE risk between different CHCs. NGM has the advantage of retaining peripheral anti-androgenic activity, demonstrated by the impact on lipid and glucose metabolism, and it should be preferred if compared with other similar progestins of the same class of risk which are much more androgenic, such as levonorgestrel.

Postpartum contraception: A matter of guidelines

“…Until now, the commercial intravaginal and transdermal contraceptives exclusively contained ethinyl estradiol, with devices containing E2 having also been studied in recent years. 32,33 Some physiologic hematologic changes occurring during pregnancy are the increase in levels of coagulation factors and fibrinogen, the decrease in the concentrations of natural anticoagulants such protein S and activated protein C status, and the shift in coagulation and fibrinolytic systems towards hypercoagulability.…”

“…Furthermore, the non‐oral administration of E2 (intravaginal or transdermal) could allow the use of smaller quantities of E2 necessary to give satisfactory control of the menstrual cycle. Until now, the commercial intravaginal and transdermal contraceptives exclusively contained ethinyl estradiol, with devices containing E2 having also been studied in recent years 32,33 …”

La balance bénéfices-risques des contraceptions hormonales estroprogestatives

“…De plus, le niveau de cette interaction est statistiquement différent selon le type de COP qui ont souligné l'effet du norgestimate sur le système rénine-angiotensine et l'importance de prendre en compte l'ensemble des impacts sur les récepteurs des différents stéroïdes (androgénique, des gluco-corticoïdes, des minéralocorticoïdes, estrogénique, etc.) [24].…”

Breast cancer and progestins in menopausal hormone therapy: a literature review

“…Anyhow, this is just something to acknowledge when thinking about the potential risks regarding its pharmacodynamic profile, but it has not been associated with BC-risk. 92,93 Two multicenter, double-blind parallel group studies, which included a total of 1252 women compared the use of estradiol alone, intermittent estradiol + norgestimate and continuous estradiol + norgestimate. Only 3 cases of malignant breast neoplasms were diagnosed after 1 year, all of them in the subgroups receiving intermittent estradiol and norgestimate in different doses.…”