Clinical evidence of the minimal androgenic activity of norgestimate.
The goal in improving the progestational component of oral contraceptives (OCs) is to enhance the selectivity of the progestin by achieving a high degree of contraceptive efficacy while decreasing undesirable side effects associated with existing progestational agents. The androgenic activity of current progestins results in changes in lipid metabolism, particularly decreased levels of high-density lipoprotein cholesterol (HDL), which have been associated with an increased risk of coronary heart disease (CHD). A progestin with high antiovulatory activity and minimal androgenicity would offer a clear therapeutic advantage in oral contraception. Norgestimate (NGM) is a new progestin with a unique profile of biological activity that has demonstrated a high level of selectivity in preclinical assays. The present studies were conducted to confirm clinically the low androgenic activity of NGM. Norgestimate (0.25 mg) in combination with 0.035 mg ethinyl estradiol (NGM 0.25/35) was compared with 0.30 mg norgestrel combined with 0.030 mg ethinyl estradiol (Lo/Ovral) in two multicenter clinical studies. In the first study (1,261 women), HDL levels were significantly increased from baseline levels in NGM 0.25/35 subjects but were significantly decreased in Lo/Ovral subjects. Increases in low-density lipoprotein cholesterol (LDL) levels were moderate in the NGM 0.25/35 group and pronounced in the Lo/Ovral group. A favorable lipid profile in NGM 0.25/35 subjects was also reflected in the LDL/HDL ratios, which were significantly lower in the NGM 0.25/35 subjects than in the Lo/Ovral subjects. Sex hormone binding globulin (SHBG) binds androgens, preventing clinical expression of androgenic activity. As a result, elevations in SHBG levels reduce bioactive (unbound) androgen levels and decrease the potential for androgenic side effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Chapdelaine
A
A
Hôpital Maisonneuve Rosemont, Montreal, Quebec, Canada.
Desmarais
J L
JL
Derman
R J
RJ
D000152:Acne Vulgaris / Q000139:chemically induced; D000328:Adult; D000727:Androgen-Binding Protein / Q000032:analysis; D000728:Androgens; D003277:Contraceptives, Oral, Combined / Q000009:adverse effects / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D015337:Multicenter Studies as Topic; D009644:Norgestrel / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D016032:Randomized Controlled Trials as Topic; D015430:Weight Gain
D000727:Androgen-Binding Protein; D000728:Androgens; D003277:Contraceptives, Oral, Combined; D008074:Lipoproteins; D009644:Norgestrel; D004997:Ethinyl Estradiol; C017576:norgestimate