[Antigonadotropic effects of a 19-nor-progesterone derivative: the example of nomegestrol acetate].
The antigonadotropic activity of progestins, progesterone and 19-norprogesterone derivatives, is generally used in clinical practice to treat hyperestrogenic symptoms and to provide a contraceptive effect in women with intolerance to exogenous estrogens. Our purpose was to review data from clinical pharmacological trials and from efficacy and/or safety clinical studies on progestin antigonadotropic properties with the example of nomegestrol acetate administered at the dose of 5 mg daily during 20 or 21 days per cycle. The antigonadotropic effect was shown by the effect on gonadotropins: in normally cycling premenopausal women, gonadotropin ovulatory peak was constantly inhibited, LH secretion was decreased and FSH increase at the end of the control cycle was inhibited by nomegestrol acetate (n = 5). Moreover, LH basal levels, LH response to exogenous GnRH and aeras under the curves (AUC) of LH pulsatile profile were decreased in the treated cycle (n = 11) compared to the control cycle. For both LH and FSH, the basal levels, the response to GnRH and the AUC of pulsatile profile were decreased by nomegestrol acetate compared to placebo in postmenopausal women; moreover, the frequency but not the amplitude of LH pulses was decreased. Depending on the woman's ovarian functional status, the effects of nomegestrol acetate on FSH were divergent (FSH increased before menopause and decreased at postmenopause), perhaps due to experimental conditions or a direct effect on the ovary. In postmenopausal women, the action of nomegestrol acetate on gonadotropin secretion was not modified by flutamide, a pure antiandrogen; this suggests that the antigonagotropic activity of the progestin is not mediated through the androgen receptor and it acts probably through the progesterone receptor. This antigonadotropic effect had an impact on ovarian function: in premenopausal women on nomegestrol acetate (n = 21), progesterone secretion was inhibited attesting to the absence of corpus luteum, the pre-ovulatory peak of estradiol was inhibited and plasma estradiol concentrations were decreased. The antigonadotropic activity of nomegestrol acetate results in reinforcement of its antiestrogenic activity, particurlarly on the endometrium and enables to treat the frequent clinical hyperestrogenic symptoms of the perimenopause without negative metabolic or hemostatic effects. In the efficacy and/or safety studies, no pregnancy was observed with nomegestrol acetate administered in antigonadotropic sequence, during 1355 treated cycles and the hormonal data (n = 205) were in agreement with the antigonadotropic effects of the progestin demonstrated in the clinical pharmacological studies.Furthermore, at the same dose and sequence, nomegestrol acetate, in addition to its inhibitory effect on ovulation, induces changes in the endometrium rendering it unable to implantation and in the cervical mucus to rendering it hostile to spermatozoa migration. However, it must be emphasized that data from experimental conditions required for the calculation of the Pearl Index are not available and therefore there is no legal claim for "contraception".
Jamin
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C
Service de gynécologie-obstétrique, hôpital Bichat-Claude-Bernard, 46, rue Henri-Huchard, 75018, Paris, France. cjamin@aol.com
Batallan
A
A
Madelenat
P
P
D000328:Adult; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006062:Gonadotropins / Q000037:antagonists & inhibitors*; D006801:Humans; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D008535:Megestrol; D008593:Menopause; D008875:Middle Aged; D009649:Norpregnadienes / Q000008:administration & dosage*; D010060:Ovulation / Q000187:drug effects; D010507:Periodicity; D011374:Progesterone / Q000378:metabolism; D011372:Progestins / Q000008:administration & dosage*
D006062:Gonadotropins; D009649:Norpregnadienes; D011372:Progestins; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D004958:Estradiol; C038501:nomegestrol acetate; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D008535:Megestrol