[17][18][7][16] It was also previously available alone in Italy and as a combined injectable contraceptive in Portugal and Spain, but has been discontinued in these countries.

[30] Side effects of the combination of DHPA and estradiol enantate have reportedly included dysmenorrhea, breast tenderness, headache, edema, bloating, changes in libido, depression, anxiety, and injection site pain.

[30][4] The half-dose formulation of DHPA and estradiol enantate retains contraceptive effects but causes severe disruption of menstrual bleeding patterns.

[1][31] Likewise, the formulation of DHPA in combination with estradiol benzoate butyrate has been associated with poor control of menstrual bleeding.

[26][4] DHPA has been studied at high doses of 900 mg/week by intramuscular injection in women with endometrial cancer.

[1][4][13][10][11][12] Clinical studies have found that, on the basis of endometrial changes, E2-EN/DHPA appears, at the doses used, to be an estrogen-dominant combination.

[56][1][2] In another study, the duration of action of DHPA was reported to be more than 100 days after a single subcutaneous injection, although it was unspecified as to whether this was in humans or animals.

[13][2][3] DHPA, also known as 16α,17α-dihydroxyprogesterone acetophenide, as well as 16α,17α-dihydroxypregn-4-ene-3,20-dione cyclic acetal with acetophenone or as (R)-16α,17-[(1-phenylethylidene)dioxy]pregn-4-ene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone.

[61][35][62][27] Development was discontinued by Squibb in the United States in the late 1960s due to concerns of toxicological findings in animals, including mammary gland tumors in beagle dogs and pituitary hyperplasia in rats, as well as possible accumulation of estradiol enantate in the body with continued use.

[1][17][16] Subsequent research has shed doubt that these animal findings are applicable to humans and that the dosages required for contraception would pose any risks.

[17][1] Although the medication was not marketed in the United States, its development was continued elsewhere and it went on to be introduced and widely used in Latin America and Spain.

[23][24][25] EBB has a shorter duration than E2-EN of about 3 weeks and hence EBB/DHPA was developed because it was thought that it would be more suitable for use as a once-monthly combined injectable contraceptive than E2-EN/DHPA.