Dysfunctional Uterine Bleeding Medication

Estrogens, progestins, androgens, nonsteroidal anti-inflammatory drugs (NSAIDs), ergot derivatives, antifibrinolytics, and gonadotropin-releasing hormone (GnRH) agonists have been used to treat dysfunctional uterine bleeding (DUB). More recently, desmopressin has been used to control bleeding when associated with diagnosed bleeding disorders that do not respond entirely to traditional management.

Ergot derivatives are not recommended for treatment of DUB because they have been shown to be effective rarely in clinical studies and have many side effects.

At the onset of menses, secretory endometrium contains a high concentration of plasminogen activator. A reduction in menstrual blood loss has been demonstrated in some ovulatory patients taking ε -aminocaproic acid (EACA) or aminomethylcyclohexane-carboxylic acid (AMCHA) tranexamic acid, both potent antifibrinolytics. However, this therapeutic effect was no greater than that seen with oral contraceptive therapy. Antifibrinolytics are associated with significant side effects, such as severe nausea, diarrhea, headache, and allergic manifestations, and cannot be used in patients with renal failure. Because of the high side-effect profile and expense, these agents rarely are used today for this indication.

Class Summary

Very effective in controlling acute, profuse bleeding. Exerts a vasospastic action on capillary bleeding by affecting the level of fibrinogen, factor IV, and factor X in blood, as well as platelet aggregation and capillary permeability. Estrogen also induces formation of progesterone receptors, making subsequent treatment with progestins more effective.

Most DUB is secondary to anovulation. In these patients, endometrium continues to proliferate with asynchronous development. As blood supply is outgrown, irregular shedding occurs. Bleeding might be controlled acutely with high-dose estrogen for a short period of time. Several hours are required to induce mitotic activity, so most regimens require 48 h of therapy before continued bleeding is ruled a treatment failure.

Estrogen therapy only controls bleeding acutely and does not treat underlying cause. Appropriate long-term therapy can be administered once the acute episode has passed.

Conjugated equine estrogen (Premarin)

Women in perimenopause generally are estrogen deficient and might experience bouts of estrogen withdrawal bleeding. Many of these patients will recover regular menses and develop an improved sense of well-being with the initiation of hormonal replacement therapy, including estrogen and a progestin.

Class Summary

Occasional anovulatory bleeding that is not profuse or prolonged can be treated with progestins. Progestins inhibit estrogen receptor replenishment and activate 17-hydroxysteroid dehydrogenase in endometrial cells, converting estradiol to the less active estrone. Medroxyprogesterone acetate (Provera) is the most commonly used progestin in this country, but other types, including norethindrone acetate (Aygestin) and norethindrone (Micronor), are equally efficacious. In some patients in which systemic progestins are intolerable due to side effects, a progestin secreting IUD (Mirena) may be considered.

Synthetic progestins have an antimitotic effect, allowing the endometrium to become atrophic if administered continuously. These drugs are very effective in cases of endometrial hyperplasia. In patients with chronic eugonadal anovulation who do not desire pregnancy, treatment with a progestin for 10-12 d/mo will allow for controlled, predictable menses and will protect the patient against the development of endometrial hyperplasia.

Some perimenopausal patients will not respond well to progestin therapy because of an inherent estrogen deficiency. Also, patients with thin, denuded endometrium occurring after several days of chronic bleeding might require induction of new endometrial proliferation by estrogen therapy first.

Avoid synthetic progestins in early pregnancy. They induce an endometrial response that is different from normal preimplantation secretory endometrium. Also, several reports suggest an association between intrauterine exposure to synthetic progestins in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias, 5-8 per 1000 male births, might be doubled with early in-utero exposure to these drugs. Some synthetic progestins might cause virilization of female external genitalia in utero.

Patients at risk for conception can be treated safely with natural progesterone preparations. These preparations induce a normal secretory endometrium appropriate for implantation and subsequent growth of a developing conceptus.

Medroxyprogesterone acetate (Provera)

Short-acting synthetic progestin. Drug of choice for patients with anovulatory DUB. After acute bleeding episode is controlled, can be used alone in patients with adequate amounts of endogenous estrogen to cause endometrial growth. Progestin therapy in adolescents produces regular cyclic withdrawal bleeding until positive feedback system matures.

Stops endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. Typically does not stop acute bleeding episode but produces a normal bleeding episode following withdrawal.

Class Summary

Contraceptive pills containing estrogen and progestin have been advocated for nonsmoking patients with DUB who desire contraception. Therapy also used to treat acute hemorrhagic uterine bleeding but is not as effective as regimens previously mentioned. Apparently takes longer to induce endometrial proliferation when progestin is present. In long-term management of DUB, combination oral contraceptives are very effective.

Ethinyl estradiol and a progestin derivative (examples: Ovral, Lo-Ovral, Ortho-Novum, Ovcon, Genora, Orthocyclen, and others)

Reduces secretion of LH and FSH from pituitary by decreasing amount of GnRH.

Class Summary

Certain androgenic preparations have been used historically to treat mild to moderate bleeding, particularly in ovulatory patients with abnormal uterine bleeding. These regimens offer no real advantage over other regimens and might cause irreversible signs of masculinization in the patient. They seldom are used for this indication today.

Use of androgens might stimulate erythropoiesis and clotting efficiency. Androgens alter endometrial tissue so that it becomes inactive and atrophic.

Danazol (Danocrine)

Isoxazole derivative of 12 alpha-ethinyl testosterone.

Class Summary

Blocks formation of prostacyclin, an antagonist of thromboxane, which is a substance that accelerates platelet aggregation and initiates coagulation. Prostacyclin is produced in increased amounts in menorrhagic endometrium. Because NSAIDs inhibit blood prostacyclin formation, they might effectively decrease uterine blood flow. NSAIDs have been shown to treat menorrhagia in ovulatory cycles but generally are not effective for the management of DUB.

Naproxen (Anaprox, Naprelan, Naprosyn)

Used for relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.

Class Summary

Work by reducing concentration of GnRH receptors in the pituitary via receptor down regulation and induction of postreceptor effects, which suppress gonadotropin release. After an initial gonadotropin release associated with rising estradiol levels, gonadotropin levels fall to castrate levels, with resultant hypogonadism. This form of medical castration is very effective in inducing amenorrhea, thus breaking ongoing cycle of abnormal bleeding in many anovulatory patients. Because prolonged therapy with this form of medical castration is associated with osteoporosis and other postmenopausal side effects, its use is often limited in duration and add back therapy with a form of low-dose hormonal replacement is given. Because of the expense of these drugs, they usually are not used as a first line approach but can be used to achieve short-term relief from a bleeding problem, particularly in patients with renal failure or blood dyscrasia.

Depot leuprolide acetate (Lupron)

Suppresses ovarian steroidogenesis by decreasing LH and FSH levels.

Class Summary

Indicated in patients with thromboembolic disorders.

Desmopressin acetate (DDAVP)

Has been used to treat abnormal uterine bleeding in patients with coagulation defects. Transiently elevates factor VIII and von Willebrand factor.