Trimegestone

Description

Trimegestone was launched in Sweden in combination with 17 beta-estradiol as hormone replacement therapy (HRT) for the oral treatment of menopausal vasomotor symptoms and the prevention of osteoporosis. Trimegestone can be synthesized in a multistep process starting with 3,3-(ethylenedioxy)estra-5(10),9(11)-dien-17-one and involving a final key regio- and enantioselective reduction of the 17beta-2-oxopropionyl side chain with Saccharomyces cerevisiae in sodium acetate buffer. The norpregnane progestin, trimegestone, exhibited high specificity and affinity for the progesterone receptor, no affinity for the estrogen receptor, and weak affinity for androgen, glucocorticoid and mineralcorticoid receptors. The relative binding affinity of trimegestone for the progestin receptor was 7 times that of progesterone, 4.5 and 1.5 times greater than norethindrone and medroxyprogesterone acetate, respectively. The decrease in circulating estrogen associated with menopause is thought to contribute to a variety of diseases in women, including osteoporosis, cancers, cardiovascular disease, stroke and cognitive dectine. Estrogen conserves bone mass by reducing bone turnover. Estrogen replacement therapy (ERT) is recommended for all women at high risk for osteoporosis. However, estrogen therapy alone has been linked to an increase risk of endometrial cancer; thus progestin (such as trimegestone) is often prescribed in combination with estrogen for women who have not had a hysterectomy. The progestin blocks the estrogenic activity in the endometrium, thereby reducing the potential unwanted cell proliferation in response to estrogen administration. This action of progestin occurs without compromising the beneficial effects of estrogen on hot flashes and bone loss. A study in rats with osteopenia showed that treatment with trimegestone in combination with 17beta-estradiol for 2 months was superior to norethisterone in preventing bone loss. Treatment with trimegestone also more effectively prevented estradiol-induced uterine atrophy as compared to norethisterone. In clinical trials, trimegestone was found to be a highly effective oral progestone for endometrial protection and beneficial effects have been observed on anxiety, depression, somatic, and vasomotor menopausal symptoms. The combination provides improved and predictable cycle control and a better lipid profile in comparison with existing products. Minimal progestogenic adverse events (i.e. mastalgia, acne, nausea, leg cramps, seborrhea and bloatedness) were reported. Totelle Sekvens employs a cyclic regimen of 14 days of 2mg of 17beta--estradiol alone and 14 days in combination with 500 μg of trimegestone.

Originator

Aventis (France)

Uses

Trimegestone causes an increased risk for uterine sarcomas and endometrial cancers with prolonged use. Used in hormone replacement therapies and the treatment of post-menopausal diseases.

Definition

ChEBI: Trimegestone is a 20-oxo steroid.

brand name

Totelle Sekvens, Ondeva

General Description

Trimegestone, 17β-(S)-lactoyl-17-methyl-estra-4,9-dien-3-one, is a highly modified norprogesteronederivative. The key structural differences are a17β-lactoyl group in place of the typical acetyl group, a17α-methyl, and a C9-C10 double bond. Trimegestonelacks androgenic action and has little to no affinity for theER and GR. Although already approved for treating HRTin Sweden in combination with estradiol, it is still in developmentin the United States for its use in HRT and as a componentof oral contraceptives.