Nomegestrol acetate, a novel progestogen for oral contraception

doi:10.1016/j.steroids.2011.02.002

Steroids

Volume 76, Issue 6, May 2011, Pages 531-539

https://doi.org/10.1016/j.steroids.2011.02.002 Get rights and content

Abstract

Nomegestrol acetate (NOMAC) is a potent, highly selective progestogen, which is structurally similar to 19-norprogesterone and characterized as a full agonist at the progesterone receptor, with no or minimal binding to other steroid receptors, including the androgen and glucocorticoid receptors. In animal models, NOMAC demonstrated moderate antiandrogenic activity and strong antiestrogenic activity. In clinical studies, the progestogen was associated with effective suppression of gonadotropic activity and ovulation in premenopausal women, and a neutral impact on hemostasis, lipids, and carbohydrate metabolism. In normal and cancerous human breast tissue, NOMAC has shown favorable effects on estrogen metabolism, and in human breast cancer cell lines in vitro, it does not stimulate cell proliferation. The pharmacologic profile of NOMAC suggested that it would be well suited for combination with a physiologic estrogen in a combined oral contraceptive (COC), with the aim of achieving effective contraception with good cycle control and a favorable safety profile. A monophasic COC containing NOMAC 2.5 mg and 17β-estradiol (E2) 1.5 mg, administered in a 24/4-day regimen, is currently under clinical investigation. In a phase III study, NOMAC/E2 provided consistent and robust ovulation inhibition, with contraceptive effects that compared favorably with those of drospirenone 3 mg/ethinyl estradiol (EE) 30 μg. Investigators for a second phase III study reported less overall impact with NOMAC/E2 on hemostatic, lipid, inflammatory, and carbohydrate metabolism parameters than with levonorgestrel 150 μg/EE 30 μg. These clinical findings are promising; however, full publication of results from the pivotal phase III trials of NOMAC/E2 is pending.

Research highlights

► NOMAC is a highly selective progestogen, structurally similar to 19-norprogesterone. ► It has strong antiestrogenic effects, without androgenic or glucocorticoid effects. ► NOMAC characteristics suggest usefulness if combined with E2 for oral contraception. ► NOMAC/E2 provides robust contraceptive efficacy with minimal cardiometabolic impact. ► Clinical findings from pivotal phase III trials of NOMAC/E2 are pending.

Introduction

Since the introduction of the first combined oral contraceptive (COC) in 1960, a half century ago, COCs have become one of the most popular modern family planning methods used worldwide [1]. Early formulations of the “pill” differed dramatically from current formulations. The first generation of COCs contained high doses of estrogen and progestogen, several times greater than those found in current formulations, and were administered exclusively in a 28-day cycle. An initial 3 weeks of continuous combined fixed-dose contraceptive hormone pills were followed by 1 week off treatment or 1 week of placebo pills, which allowed for a monthly withdrawal bleeding that mimicked normal menses and minimized women's concerns about potential pregnancy. Early COCs offered very effective contraception and other benefits, including improvements in menstrual bleeding, but were also associated with relatively high rates of side effects and an increased risk of cardiovascular events, especially venous thromboembolism (VTE) [2].

Over the past several decades, COCs have undergone substantial changes intended primarily to improve tolerability, safety, and compliance without compromising contraceptive efficacy. These changes have included the reduction of hormone doses, the development of new pill-dosage regimens and administration schedules, and the incorporation of new estrogens and progestogens. The synthetic estrogen ethinyl estradiol (EE) has been used almost exclusively in COCs since their introduction. The 17-α ethinyl group found in EE elevates the oral bioavailability of this hormone but slows down its hepatic metabolism, increasing the risk of metabolic changes and adverse events. Early attempts to replace EE with a form of the natural estrogen estradiol, used in combination with progestogens such as cyproterone or norethisterone acetate, were unsuccessful due to inadequate cycle stability [3], [4], [5], [6]. However, systematic research has recently focused on the development of progestogens that are more suitable for combination with physiological estrogen in COCs with the aim of achieving contraceptive efficacy, an improved safety profile, and good cycle control.

Nomegestrol acetate (NOMAC) is a potent, highly selective synthetic progestogen that is derived from 19-norprogesterone. NOMAC is used alone and in combination with estradiol as hormone replacement therapy in menopause [7]. In clinical trials, this progestogen, which is characterized by a high antigonadotropic activity, provided effective ovulation inhibition in normally cycling women and consistently suppressed luteinizing hormone, follicle growth, and progesterone levels [8], [9], [10], [11], [12]. To restore suppressed estrogen levels, it has been combined with 17β-estradiol (E2) for use in a monophasic COC that is currently in development [13], [14], [15].

In this review, an overview of the use of progestogens in COCs is presented, including a description of the pharmacologic profile of the new progestogen NOMAC.

Section snippets

Classification of progestogens

Progestogens have traditionally been classified by the steroidal structure to which they relate (Table 1) [16], [17]. Most older progestogens were related to testosterone (19-nortestosterone derivatives). The structures of testosterone-related progestogens were modified to decrease the frequency of undesirable androgenic side effects such as acne, oily skin, and hair growth, as well as the negative effect on high-density lipoproteins (HDL), and to increase progestational potency, i.e., to allow

Progestogenic properties

NOMAC, a highly selective progestogen derived from 19-nor-progesterone, is a very strong agonist at the PR [20]. In rats, NOMAC has been shown to have moderate antiandrogenic activity, without androgenic activity [21], [22]. This progestogen is devoid of significant agonistic or antagonistic activity for the ER [23]. In studies of the modulatory effects of NOMAC on rat uterine steroid receptors, NOMAC displayed higher antiestrogenic activity than medroxyprogesterone, megestrol, norethisterone,

Clinical investigations of the COC NOMAC/E2

Combinations of progestogens with E2 in postmenopausal women have been far more extensively studied than such combinations in younger women of fertile age. Initial investigations of COCs containing estradiol were unsuccessful because these pills were associated with inadequate cycle control [3], [4], [5], [6]. Although the progestogen components of these COCs proved effective in preventing pregnancy, oral estradiol was less effective than EE in preventing intracyclic bleeding. The progestogen

Conclusions

NOMAC is a highly selective progestogen that is derived from 19-nor-progesterone. Several characteristics suggest its usefulness in combination with E2 for oral contraception, including the specificity of its binding to the PR and lack of binding to other steroid receptors; its highly antiestrogenic effects, without androgenic or glucocorticoid effects; potent antigonadotropic action when given as a single agent; and its favorable impact on the metabolic profile and proliferative activity in

Acknowledgments

Editorial assistance was provided by Donna McGuire of Evidence Scientific Solutions, Philadelphia, PA, USA. This assistance was funded by Schering Corp., a division of Merck & Co. The authors received no compensation or honoraria in association with this article.

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ReviewNomegestrol acetate, a novel progestogen for oral contraception

Abstract

Research highlights

Introduction

Section snippets

Classification of progestogens

Progestogenic properties

Clinical investigations of the COC NOMAC/E2

Conclusions

Acknowledgments

Maturitas

Exp Toxicol Pathol

Fertil Steril

Gynecol Obstet Fertil

Fertil Steril

Maturitas

Steroids

J Steroid Biochem Mol Biol

J Steroid Biochem Mol Biol

Contraception

Contraception

Contraception

Lancet

Contraception

Contraception

J Am Coll Cardiol

Am J Obstet Gynecol

Steroids

J Steroid Biochem Mol Biol

Mayo Clin Proc

J Steroid Biochem Mol Biol

Eur J Pharmacol

J Steroid Biochem Mol Biol

J Steroid Biochem Mol Biol

J Steroid Biochem Mol Biol

Maturitas

J Steroid Biochem Mol Biol

Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs

Br Med J

A randomized, double-blind study of two combined oral contraceptives containing the same progestogen, but different estrogens. World Health Organization Task Force on Oral Contraception

Contraception

New progestogens: a review of their effects in perimenopausal and postmenopausal women

Drugs Aging

Effect of nomegestrol acetate, a new 19-nor-progesterone derivative, on pituitary-ovarian function in women

Br J Obstet Gynaecol

The antigonadotropic activity of a 19-nor-progesterone derivative is exerted both at the hypothalamic and pituitary levels in women

J Clin Endocrinol Metab

Pharmacology of estrogens and progestogens: influence of different routes of administration

Climacteric

Synergistic effect of 17 β-estradiol and nomegestrol acetate used in a new monophasic oral contraceptive

Comparison of two regimens of new monophasic oral contraceptive combining 17 beta-estradiol and nomegestrol acetate

Review
Nomegestrol acetate, a novel progestogen for oral contraception