Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations. They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate. CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.
Side effects of CEEs include breast tenderness and enlargement, headache, fluid retention, and nausea among others. It may increase the risk of endometrial hyperplasia and endometrial cancer in women with an intact uterus if it is not taken together with a progestogen like progesterone. The medication may also increase the risk of blood clots, cardiovascular disease, and, when combined with most progestogens, breast cancer. CEEs are estrogens, or agonists of the estrogen receptor, the biological target of estrogens like estradiol. Compared to estradiol, certain estrogens in CEEs are more resistant to metabolism, and the medication shows relatively increased effects in certain parts of the body like the liver. This results in an increased risk of blood clots and cardiovascular problems with CEEs relative to estradiol.
Premarin, the major brand of CEEs in use, is manufactured by Pfizer and was first marketed in 1941 in Canada and in 1942 in the United States. It is the most commonly used form of estrogen in menopausal hormone therapy in the United States. However, it has begun to fall out of favor relative to bioidentical estradiol, which is the most widely used form of estrogen in Europe for menopausal hormone therapy. CEEs are available widely throughout the world. An estrogen preparation very similar to CEEs but differing in source and composition is esterified estrogens. In 2020, it was the 283rd most commonly prescribed medication in the United States, with more than 1million prescriptions.
Medical uses
CEEs are a form of hormone therapy used in women. It is used most commonly in postmenopausal women who have had a hysterectomy to treat hot flashes, and burning, itching, and dryness of the vagina and surrounding areas. It must be used in combination with a progestogen in women who have not had a hysterectomy. For women already taking the medication, it can be used to treat osteoporosis, although it is not recommended solely for this use. Some lesser known uses are as a means of high-dose estrogen therapy in the treatment of breast cancer in both women and men and in the treatment of prostate cancer in men. It has been used at a dosage of 2.5 mg three times per day (7.5 mg/day total) for prostate cancer.
CEEs are specifically approved in countries such as the United States and Canada for the treatment of moderate to severe vasomotor symptoms (hot flashes) and vulvovaginal atrophy (atrophic vaginitis, atrophic urethritis) associated with menopause, hypoestrogenism due to hypogonadism, ovariectomy, or primary ovarian failure, abnormal uterine bleeding, the palliative treatment of metastatic breast cancer in women, the palliative treatment of advanced androgen-dependent prostate cancer in men, and the prevention of postmenopausal osteoporosis. The intravenous formulation of CEEs is specifically used to rapidly limit bleeding in women with hemorrhage due to dysfunctional uterine bleeding.
Available forms
Natural CEEs, as Premarin, are available in the form of oral tablets (0.3 mg, 0.625 mg, 0.9 mg, 1.25 mg, or 2.5 mg), creams for topical or vaginal administration (0.625 mg/g), and vials for intravenous or intramuscular injection (25 mg/vial). Synthetic CEEs, such as Cenestin (Synthetic A), Enjuvia (Synthetic B), and generic formulations, are available in the form of oral tablets (0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, or 1.25 mg) and creams for topical or vaginal administration (0.625 mg/g).
Contraindications
Contraindications of CEEs include breast cancer and a history of venous thromboembolism, among others.