No Adverse Endometrial Effects Seen With Ospemifene

SAN DIEGO – A year of using the experimental drug ospemifene for vulvar and vaginal atrophy produced no clinically significant estrogenic or adverse endometrial effects, compared with placebo in a study of 180 women.

Patients from an initial 12-week efficacy and safety study at 51 sites continued on the same blinded courses of 30 mg or 60 mg of ospemifene or placebo daily for up to 52 weeks in the long-term safety extension study.

After a year, endometrial thickness decreased slightly in the placebo group and increased slightly in the ospemifene groups by approximately 1 mm on average, Dr. Steven R. Goldstein and his associates reported at the annual meeting of the American College of Obstetricians and Gynecologists.

Endometrial biopsies in the 30-mg ospemifene group after 1 year showed atrophic, inactive, or insufficient endometrial tissue in approximately 95% of patients; weakly proliferative tissue in 2%; and atypical epithelial proliferation in 2%. In the 60-mg ospemifene group, 96% had atrophic, inactive, or insufficient endometrial tissue; 2% had weakly proliferative tissue; and 2% showed atrophic-type polyps. All biopsies in the placebo group showed atrophic, inactive, or insufficient endometrial tissue, said Dr. Goldstein, professor of ob.gyn. at New York University Langone Medical Center.

The category of "weakly proliferative" basically represents inactive atrophic endometrium with a few mitotic figures, and can be considered clinically to be in a category with atrophic, inactive, or insufficient tissue, he said.

Two patients in the 30-mg group and one in the 60-mg group developed vaginal bleeding or spotting. One had intermittent spotting, one had 2 days of bleeding, and the third had 4 days of bleeding. Endometrial biopsy results for all three were reported as atrophic.

The patients had no endometrial pathology at baseline biopsy. Forty patients discontinued treatment before 1 year, including 17% of the 60-mg group, 21% of the 30-mg group, and 31% of the placebo group, usually because of withdrawal of patient consent to continue. "This probably represents people who were upset with failure of efficacy" on placebo or low-dose ospemifene, he said.

There were no cases of endometrial hyperplasia or carcinoma. Although 2% of endometrial biopsy results were proliferative in the drug treatment groups, "the overwhelming majority of all endometrial tissue was atrophic or inactive," Dr. Goldstein said.

The findings echo results from a similar previous study in Europe that also found minimal endometrial impact – a 2% incidence of proliferative endometrium after 1 year, he noted (Menopause 2010;17:642-53).

Ospemifene is an investigational selective estrogen-receptor modulator (SERM). The incidence of proliferation with ospemifene (2%) compares favorably with a 3% rate of proliferation seen after 1 year in studies of raloxifene, another SERM, he said.

Only estrogens are approved in the United States for the treatment of moderate to severe vulvar or vaginal atrophy. The package insert for one clinically available low-dose estrogen vaginal tablet (Vagifem 10 mcg) lists the incidences of endometrial carcinoma and complex hyperplasia as approximately 1% each, he said.

Different SERMs have been shown to have different effects on the endometrium. Previous studies have reported estrogenic action in the vaginal epithelium from ospemifene use, prompting the current study.

Dr. Goldstein reported financial associations with Shionogi, which has applied for Food and Drug Administration approval for ospemifene, and with Amgen, Bayer, Cook Ob.Gyn., Eli Lilly, Novo Nordisk, Merck, Pfizer, Philips Ultrasound, and Warner Chilcott.

SAN DIEGO – A year of using the experimental drug ospemifene for vulvar and vaginal atrophy produced no clinically significant estrogenic or adverse endometrial effects, compared with placebo in a study of 180 women.

Patients from an initial 12-week efficacy and safety study at 51 sites continued on the same blinded courses of 30 mg or 60 mg of ospemifene or placebo daily for up to 52 weeks in the long-term safety extension study.

After a year, endometrial thickness decreased slightly in the placebo group and increased slightly in the ospemifene groups by approximately 1 mm on average, Dr. Steven R. Goldstein and his associates reported at the annual meeting of the American College of Obstetricians and Gynecologists.

Endometrial biopsies in the 30-mg ospemifene group after 1 year showed atrophic, inactive, or insufficient endometrial tissue in approximately 95% of patients; weakly proliferative tissue in 2%; and atypical epithelial proliferation in 2%. In the 60-mg ospemifene group, 96% had atrophic, inactive, or insufficient endometrial tissue; 2% had weakly proliferative tissue; and 2% showed atrophic-type polyps. All biopsies in the placebo group showed atrophic, inactive, or insufficient endometrial tissue, said Dr. Goldstein, professor of ob.gyn. at New York University Langone Medical Center.

The category of "weakly proliferative" basically represents inactive atrophic endometrium with a few mitotic figures, and can be considered clinically to be in a category with atrophic, inactive, or insufficient tissue, he said.

Two patients in the 30-mg group and one in the 60-mg group developed vaginal bleeding or spotting. One had intermittent spotting, one had 2 days of bleeding, and the third had 4 days of bleeding. Endometrial biopsy results for all three were reported as atrophic.

The patients had no endometrial pathology at baseline biopsy. Forty patients discontinued treatment before 1 year, including 17% of the 60-mg group, 21% of the 30-mg group, and 31% of the placebo group, usually because of withdrawal of patient consent to continue. "This probably represents people who were upset with failure of efficacy" on placebo or low-dose ospemifene, he said.

There were no cases of endometrial hyperplasia or carcinoma. Although 2% of endometrial biopsy results were proliferative in the drug treatment groups, "the overwhelming majority of all endometrial tissue was atrophic or inactive," Dr. Goldstein said.

The findings echo results from a similar previous study in Europe that also found minimal endometrial impact – a 2% incidence of proliferative endometrium after 1 year, he noted (Menopause 2010;17:642-53).

Ospemifene is an investigational selective estrogen-receptor modulator (SERM). The incidence of proliferation with ospemifene (2%) compares favorably with a 3% rate of proliferation seen after 1 year in studies of raloxifene, another SERM, he said.

Only estrogens are approved in the United States for the treatment of moderate to severe vulvar or vaginal atrophy. The package insert for one clinically available low-dose estrogen vaginal tablet (Vagifem 10 mcg) lists the incidences of endometrial carcinoma and complex hyperplasia as approximately 1% each, he said.

Different SERMs have been shown to have different effects on the endometrium. Previous studies have reported estrogenic action in the vaginal epithelium from ospemifene use, prompting the current study.

Dr. Goldstein reported financial associations with Shionogi, which has applied for Food and Drug Administration approval for ospemifene, and with Amgen, Bayer, Cook Ob.Gyn., Eli Lilly, Novo Nordisk, Merck, Pfizer, Philips Ultrasound, and Warner Chilcott.

SAN DIEGO – A year of using the experimental drug ospemifene for vulvar and vaginal atrophy produced no clinically significant estrogenic or adverse endometrial effects, compared with placebo in a study of 180 women.

Patients from an initial 12-week efficacy and safety study at 51 sites continued on the same blinded courses of 30 mg or 60 mg of ospemifene or placebo daily for up to 52 weeks in the long-term safety extension study.

After a year, endometrial thickness decreased slightly in the placebo group and increased slightly in the ospemifene groups by approximately 1 mm on average, Dr. Steven R. Goldstein and his associates reported at the annual meeting of the American College of Obstetricians and Gynecologists.

Endometrial biopsies in the 30-mg ospemifene group after 1 year showed atrophic, inactive, or insufficient endometrial tissue in approximately 95% of patients; weakly proliferative tissue in 2%; and atypical epithelial proliferation in 2%. In the 60-mg ospemifene group, 96% had atrophic, inactive, or insufficient endometrial tissue; 2% had weakly proliferative tissue; and 2% showed atrophic-type polyps. All biopsies in the placebo group showed atrophic, inactive, or insufficient endometrial tissue, said Dr. Goldstein, professor of ob.gyn. at New York University Langone Medical Center.

The category of "weakly proliferative" basically represents inactive atrophic endometrium with a few mitotic figures, and can be considered clinically to be in a category with atrophic, inactive, or insufficient tissue, he said.

Two patients in the 30-mg group and one in the 60-mg group developed vaginal bleeding or spotting. One had intermittent spotting, one had 2 days of bleeding, and the third had 4 days of bleeding. Endometrial biopsy results for all three were reported as atrophic.

The patients had no endometrial pathology at baseline biopsy. Forty patients discontinued treatment before 1 year, including 17% of the 60-mg group, 21% of the 30-mg group, and 31% of the placebo group, usually because of withdrawal of patient consent to continue. "This probably represents people who were upset with failure of efficacy" on placebo or low-dose ospemifene, he said.

There were no cases of endometrial hyperplasia or carcinoma. Although 2% of endometrial biopsy results were proliferative in the drug treatment groups, "the overwhelming majority of all endometrial tissue was atrophic or inactive," Dr. Goldstein said.

The findings echo results from a similar previous study in Europe that also found minimal endometrial impact – a 2% incidence of proliferative endometrium after 1 year, he noted (Menopause 2010;17:642-53).

Ospemifene is an investigational selective estrogen-receptor modulator (SERM). The incidence of proliferation with ospemifene (2%) compares favorably with a 3% rate of proliferation seen after 1 year in studies of raloxifene, another SERM, he said.

Only estrogens are approved in the United States for the treatment of moderate to severe vulvar or vaginal atrophy. The package insert for one clinically available low-dose estrogen vaginal tablet (Vagifem 10 mcg) lists the incidences of endometrial carcinoma and complex hyperplasia as approximately 1% each, he said.

Different SERMs have been shown to have different effects on the endometrium. Previous studies have reported estrogenic action in the vaginal epithelium from ospemifene use, prompting the current study.

Dr. Goldstein reported financial associations with Shionogi, which has applied for Food and Drug Administration approval for ospemifene, and with Amgen, Bayer, Cook Ob.Gyn., Eli Lilly, Novo Nordisk, Merck, Pfizer, Philips Ultrasound, and Warner Chilcott.