Estrogens
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 AUB 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 24-48 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)
Progestins
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.
Multiple levonorgestrel-secreting intrauterine systems (IUS), also referred to as progestin IUDs, are available for both parous and non-parous patients. These offer the advantage of contraception, along with decreased systemic side effects and excellent compliance. Downsides include the need for placement in a medical office as well as the likelihood of irregular bleeding, although bleeding decreases with time and about 20% of patients will be amenorrheic at 1 year of use.
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 AUB. 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.
Combination oral contraceptives
Class Summary
Contraceptive pills containing estrogen and progestin have been advocated for nonsmoking patients with AUB 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 AUB, 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.
Androgens
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.
Nonsteroidal anti-inflammatory drugs
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 bleeding endometrium. Because NSAIDs inhibit blood prostacyclin formation, they might effectively decrease uterine blood flow. NSAIDs have been shown to decrease heavy bleeding in ovulatory cycles but generally are not effective for the management of AUB.
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.
GnRH agonists
Class Summary
Work by reducing concentration of GnRH receptors in the pituitary via receptor down regulation and induction of post-receptor 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.
Gonadotropin Releasing Hormone Antagonists
Class Summary
The overall effect is similar to that of GnRH agonists. A GnRH antagonist is a competitive inhibitor of the GnRH receptor, thus blocking binding of GnRH to decrease gonadotropin (FSH and LH) production and secretion. An oral agent (elagolix [Orilissa]) is currently available. Similar to agonists, this results in substantial hypoestrogenemia with vasomotor symptoms and bone loss. This induces amenorrhea but is not intended for long-term management of AUB.
Elagolix (Orilissa)
Arginine vasopressin derivatives
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.
Antifibrinolytic Agents
Tranexamic acid oral (Lysteda)
Tranexamic acid blocks lysine binding sites on plasminogen resulting in an antifibrinolytic effect, thus decreasing clot breakdown. This is a generalized reaction, not limited to the uterus, enabling use in many surgeries to decrease blood loss. Thus, it is applicable to many causes of AUB, as its action is not hormonal. Initially, there was concern that tranexamic acid, especially with contraceptive estrogen, would increase the risk of venous thrombosis resulting in a black box FDA warning. Thus far, this has not been observed, and the European regulatory agencies do not have a similar warning.
Tables
| Examination | Finding | Differential |
|---|---|---|
| Vital signs | Tachycardia | Anemia Hypovolemia |
| Weight | Obesity | PCOS, weight-related anovulation |
| Eyes | Exophthalmos Periorbital edema |
Graves disease Hypothyroidism |
| Neck | Thyromegaly | Hypothyroidism |
| Breasts | Galactorrhea | Hyperprolactinemia |
| Skin | Increased skin tags Acanthosis nigricans Hirsutism Ecchymosis, purpura |
PCOS Insulin resistance PCOS, CAH, Cushing syndrome, androgen-secreting tumor Bleeding disorder |
| Pelvic examination | Cervical polyp/cervicitis/cervical ectropion Globally enlarged uterus Irregular uterus Adnexal mass |
Adenomyosis Fibroids Ovarian cyst or mass |
| AUB = abnormal uterine bleeding; CAH = congenital adrenal hyperplasia; PCOS = polycystic ovary syndrome. | ||
