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.
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.
