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Management of menorrhagia during chemotherapy

Management of menorrhagia during chemotherapy
Literature review current through: Jan 2024.
This topic last updated: Mar 17, 2021.

INTRODUCTION — In premenopausal patients and female adolescents, chemotherapy-induced thrombocytopenia can lead to menorrhagia (ie, heavy and prolonged menses) or irregular bleeding [1] whereas postmenopausal patients rarely have bleeding as a complication of chemotherapy-induced thrombocytopenia. Premenopausal patients and adolescents treated with alkylating agents are also at risk for development of hypogonadotropic amenorrhea.

This topic will review management of menorrhagia related to chemotherapy in premenopausal patients and adolescents. Ovarian failure related to anticancer drugs is discussed separately. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

ETIOLOGY — There are three potential cancer-related causes of uterine bleeding:

Bleeding directly from a genitourinary neoplasm (eg, endometrial carcinoma, cervical cancer, gestational trophoblastic neoplasia)

Bleeding secondary to thrombocytopenia induced by chemotherapy, radiation therapy, and/or the malignancy itself (eg, acute promyelocytic leukemia, non-Hodgkin lymphoma)

Bleeding related to disseminated intravascular coagulation (eg, acute promyelocytic leukemia)

CLINICAL MANIFESTATIONS — The most common menstrual manifestation of bleeding diathesis is menorrhagia; bleeding between periods is less common. Menorrhagia refers to excessive or prolonged menstrual bleeding occurring at regular intervals. It is technically defined as blood loss greater than 80 mL per cycle and/or menstrual periods lasting longer than seven days. Indirect indicators of menorrhagia include passage of blood clots (which suggests that the naturally fibrinolytic properties of the uterus are overwhelmed by a heavy volume of bleeding), anemia, and signs or symptoms of volume depletion during the menstrual period.

DIAGNOSTIC EVALUATION — All patients with abnormal uterine bleeding should be evaluated to determine the cause; the clinician should not assume that the bleeding is a side effect of chemotherapy. The evaluation should include:

A careful examination of the lower genital tract to look for a potentially causative lesion.

Cervical cytology (which may not be possible if the patient is experiencing heavy bleeding).

An endometrial biopsy to rule out endometrial pathology; however, since many patients with chemotherapy-induced thrombocytopenia are also leukopenic, some clinicians avoid endometrial biopsy as the procedure may increase the risk of infection.

In addition, a pelvic imaging study, such as pelvic ultrasound, can be helpful in identifying gynecologic causes of uterine bleeding, such as fibroids or endometrial polyps. In patients with chemotherapy-induced thrombocytopenia and menorrhagia, a normal pelvic ultrasound strongly suggests that the bleeding is due to the bleeding diathesis.

The evaluation of patients (adolescent, premenopausal, and postmenopausal) with abnormal uterine bleeding unrelated to chemotherapy is described in detail separately.

(See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis".)

(See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis".)

(See "Approach to the patient with postmenopausal uterine bleeding".)

DIAGNOSIS — A diagnosis of menorrhagia chemotherapy-induced thrombocytopenia can be made in thrombocytopenic patients after other causes of abnormal uterine bleeding have been excluded. Most such patients have a platelet count less than 20,000/microL, which is the level of thrombocytopenia associated with an increased risk of spontaneous bleeding.

PRIMARY PREVENTION OF MENORRHAGIA — If there is a one-month interval before the expected time of chemotherapy-induced thrombocytopenia, we suggest administering a gonadotropin-releasing hormone (GnRH) agonist, such as leuprolide acetate, so that amenorrhea can be induced prior to the start of chemotherapy [2-6]. Breakthrough bleeding often occurs in the first two weeks of therapy and may require that the patient be supported with blood products.

One small study of patients undergoing bone marrow transplantation achieved a high rate of amenorrhea by administering leuprolide acetate 7.5 mg intramuscularly every 28 days, with the first injection given four to five weeks prior to bone marrow transplant [3]. In this series, patients using oral contraceptives at the time of their initial leuprolide injection stopped their tablets either on the day of this injection or 21 days later. To avoid intramuscular injection in one patient with a platelet count of less than 50,000/microL at the time of scheduled repeat leuprolide injection, a daily intravenous infusion of 1 mg of the subcutaneous formulation of leuprolide was successfully administered for two weeks, at which time the platelet count was higher.

A retrospective study described the outcome of oncology patients with regular menstrual cycles who received either depo-medroxyprogesterone acetate (DMPA; n = 42), or a GnRH agonist (n = 39) or no treatment (n = 20) before the administration of myelosuppressive chemotherapy [7]. Only patients who later developed severe thrombocytopenia (<25,000 platelets/microL) were included in the study. Severe or moderate menorrhagia occurred in none of the patients who received a GnRH agonist, in 21 percent of patients who received DMPA, and in 40 percent of untreated patients. Treatment with a GnRH agonist was significantly more effective than no treatment and appeared to be more effective than DMPA.

MANAGEMENT OF MENORRHAGIA — In general, we suggest supporting patients with moderate to severe menorrhagia with blood products, administering hormonal therapy, and inducing amenorrhea in those at risk of future chemotherapy-induced thrombocytopenia. There are no large randomized trials providing data on which to base recommendations for managing these patients. Our approach is based upon small observational studies, case reports, and personal experience.

It is important to set clear expectations about how well bleeding can be controlled. Often, patients with severe disease and low platelets do not achieve complete cessation of bleeding but have occasional or daily spotting/light bleeding. It is important to reassure these patients that changing one to two pads daily is not dangerous.

Initial therapy — We support patients with signs or symptoms of volume depletion during the menstrual period with blood products and start them on either estrogen, an estrogen-progestin preparation, or high-dose progestin [8,9]. A gonadotropin-releasing hormone agonist can be initiated subsequently to prevent recurrent menorrhagia. (See 'Prevention of recurrent menorrhagia' below.)

If a patient has been bleeding for a long time, it may be prudent to start oral estrogen to re-epithelialize the endometrium and thus stop the bleeding before initiating an estrogen-progestin preparation. Continuous use of estrogen alone is generally undesirable since unopposed estrogen can lead to endometrial cancer. If estrogens are contraindicated, but progestins are not, then progestins may be administered.

High-dose estrogen — Patients who have been bleeding heavily for a prolonged period of time (≥2 weeks) have an atrophic, denuded endometrial lining. These patients need to have their endometrium stabilized with oral, transdermal, or intravenous estrogen or high-dose estrogen-progestin pills. Estrogen promotes rapid regrowth of endometrium over the denuded epithelial surface, stabilizes lysosomal membranes, and stimulates proliferation of endometrial ground substance. However, a problem with this approach is that nausea and vomiting are common with high-dose estrogen therapy and also a side effect of chemotherapy. An antiemetic is often required (eg, promethazine 12.5 to 25 mg per rectum, as needed).

Options for estrogen therapy include:

Conjugated estrogen (eg, Premarin) 1.25 mg orally two or three times per day or

Estradiol 2 mg orally two or three times per day or

Conjugated estrogen 25 mg intravenously every six hours for 24 hours

The dose and duration of estrogen should be the minimum needed to control bleeding because thromboembolic events are a potential complication of high-dose estrogen therapy. In particular, intravenous therapy should not be continued for more than 24 hours. Other contraindications to high-dose estrogen therapy are listed below. (See 'Contraindications to estrogen' below.)

Typically, the transition from one of these high-dose estrogen regimens to standard estrogen-progestin contraceptive pills can begin within a few days and certainly by the time that hematologic indices have begun to return to normal. (See 'Estrogen-progestin' below.)

High-dose estrogen-progestin — Oral contraceptive pills (OC) at high doses (eg, an OC containing 35 mcg ethinyl estradiol taken two to four times per day (table 1 and table 2)) supplemented with an antiemetic medication (eg, promethazine 12.5 to 25 mg per rectum, as needed) will often cause acute moderate to severe bleeding to subside within 48 hours. This regimen may not be as effective as estrogen alone because progestins inhibit the synthesis of estrogen receptors and increase estradiol dehydrogenase, thereby impeding the rapid proliferation of endometrium induced by estrogen. However, some patients find this approach more convenient than beginning with estrogen alone. Contraindications to high-dose estrogen-progestin therapy are listed below. (See 'Contraindications to estrogen' below.)

A transdermal estrogen-progestin patch (eg, Xulane) may be used instead of OC pills; the patch has the advantage of avoiding oral administration in patients with nausea and vomiting or severe diarrhea. Two patches can be placed; however, this results in high estrogen levels (similar to two 100 mcg estrogen OC pills), which are possibly associated with an increased risk of thrombosis [10]. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects'.)

After the bleeding stops, the patient can be transitioned to once-a-day therapy. (See 'Estrogen-progestin' below.)

Contraindications to estrogen — High-dose estrogen-progestin regimens or high-dose estrogen alone should be avoided in smokers because of the risk of venous thrombosis. (See 'High-dose estrogen' above.)

Other medical contraindications to use of estrogen and estrogen-progestin preparations include:

Previous thromboembolic event or stroke

Known inherited thrombophilia

History of an estrogen-dependent tumor

Ischemic heart disease

Active liver disease

Pregnancy

Known hyperlipidemias

Poorly controlled hypertension

Migraine headaches with aura

Diabetes mellitus with vascular disease

High-dose progestin — If estrogens are contraindicated, but progestins are not, then high-dose progestins may be administered. Progestin-only regimens are less successful than estrogen-progestin regimens and associated with more irregular bleeding. Progestin-only options include any one of the following for 5 to 10 days:

Medroxyprogesterone acetate (20 to 40 mg per day in divided doses) or

Megestrol acetate (40 to 120 mg per day in divided doses) or

Norethindrone acetate (5 to 10 mg per day)

Progestins, like estrogen, can be associated with an increased risk of thromboembolic disease [9,11,12], so we do not use high-dose progestins in most patients with contraindications to estrogen therapy. However, we use progestins in smokers, unless they have a history of thromboembolic disease.

After the bleeding stops, the patient can be transitioned to lower dose progestin therapy. (See 'Progestin only' below.)

Other medications that can be used for acute management of bleeding — The following drugs are nonhormonal alternatives for acute management of menorrhagia. Both are contraindicated in patients with a history of venous thrombosis or hypercoagulability.

Tranexamic acid 1300 mg orally three times daily for a maximum of five days; tranexamic acid should not be used with estrogen-containing medications as this increases the risk for thromboembolic events.

Aminocaproic acid 100 mg/kg (maximum dose 5 g) intravenously or orally.

Refractory cases

Endometrial ablation — In rare cases, endometrial ablation can be performed if all other methods of controlling bleeding have failed; however, this should be considered primarily in patients who have completed childbearing since fertility cannot be guaranteed after the procedure. Furthermore, pregnancy after ablation can be hazardous (increased risk of miscarriage, antepartum hemorrhage, preterm delivery, abnormal placental attachment). (See "Overview of endometrial ablation".)

We suggest administering antibiotic prophylaxis prior to and after the procedure since these patients are considered immunocompromised and at increased risk of infection. For example, cefazolin is a reasonable option in the non-leukopenic patient, and the combination of ampicillin, gentamicin, and clindamycin is a reasonable option in leukopenic patients.

We also suggest curettage after antibiotic prophylaxis and prior to ablation. This improves the success of the ablative procedure since a thin endometrium is more completely destroyed [13,14]. It also provides endometrial tissue for histopathologic evaluation to exclude malignancy.

More invasive procedures, such as uterine artery embolization, are contraindicated in thrombocytopenic patients. However, there are case reports of uterine artery embolization being used to treat life-threatening uterine hemorrhage in acute myeloid leukemia patients treated with chemotherapy [15].

Prevention of recurrent menorrhagia — After initial therapy, the patient should be placed on an ongoing hormonal regimen to induce endometrial atrophy and thereby prevent recurrent menorrhagia, as long as there are no contraindications to hormonal therapy.

Estrogen-progestin — Patients may be started or continued on estrogen-progestin preparations with 35 mcg ethinyl estradiol or equivalent after initial therapy of menorrhagia. These agents provide the dual benefits of reducing or suppressing menses and providing contraception. The maximum benefit can be achieved with continuous, rather than cyclic, administration. Either pills or a transdermal patch can be used; the latter has the advantage of being retained in patients with chemotherapy-induced nausea and vomiting. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Continuous or extended use'.)

Some breakthrough bleeding will occur in the first 6 to 12 months of hormonal therapy. In patients with thrombocytopenia, this is undesirable since a low platelet count can lead to uncontrolled bleeding. Therefore, these agents are most useful when continued in patients already taking them at the time of their cancer diagnosis. Those who will receive chemotherapy over several months can be supported with blood products, as needed, for breakthrough bleeds.

Progestin only — A progestin (eg, megestrol acetate 20 to 40 mg daily in divided doses or norethindrone acetate 5 to 10 mg per day) can be given to suppress menses. Patients can often be supported with this regimen for a considerable period of time.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Abnormal uterine bleeding".)

SUMMARY AND RECOMMENDATIONS

Abnormal uterine bleeding in patients with cancer may be from chemotherapy-induced thrombocytopenia, hematologic changes caused by the tumor, or from a source unrelated to the tumor or its therapy. Therefore, all patients with abnormal uterine bleeding should be evaluated to determine the cause; the clinician should not assume that the bleeding is a side effect of chemotherapy. (See 'Etiology' above and 'Clinical manifestations' above.)

In premenopausal patients at risk of chemotherapy-induced thrombocytopenia, we suggest inducing amenorrhea with a gonadotropin-releasing hormone agonist (Grade 2C). (See 'Primary prevention of menorrhagia' above.)

For patients with moderate to severe menorrhagia due to thrombocytopenia, we suggest estrogen therapy (and blood products, as needed) for acute treatment rather than other hormonal therapies (Grade 2C). (See 'High-dose estrogen' above.)

After initial therapy of menorrhagia, we suggest continuous administration of an estrogen-progestin preparation with 35 mcg ethinyl estradiol or equivalent (Grade 2C). (See 'Estrogen-progestin' above.)

Tranexamic acid or aminocaproic acid are nonhormonal options for acute therapy of menorrhagia; both are contraindicated in patients with a history of venous thrombosis or hypercoagulability. (See 'Other medications that can be used for acute management of bleeding' above.)

  1. Committee opinion no. 606: Options for prevention and management of heavy menstrual bleeding in adolescent patients undergoing cancer treatment. Obstet Gynecol 2014; 124:397. Reaffirmed 2019.
  2. Lhommé C, Brault P, Bourhis JH, et al. Prevention of menstruation with leuprorelin (GnRH agonist) in women undergoing myelosuppressive chemotherapy or radiochemotherapy for hematological malignancies: a pilot study. Leuk Lymphoma 2001; 42:1033.
  3. Stabinsky SA, Einstein M, Breen JL. Modern treatments of menorrhagia attributable to dysfunctional uterine bleeding. Obstet Gynecol Surv 1999; 54:61.
  4. Laufer MR, Townsend NL, Parsons KE, et al. Inducing amenorrhea during bone marrow transplantation. A pilot study of leuprolide acetate. J Reprod Med 1997; 42:537.
  5. Ghalie R, Porter C, Radwanska E, et al. Prevention of hypermenorrhea with leuprolide in premenopausal women undergoing bone marrow transplantation. Am J Hematol 1993; 42:350.
  6. Chiusolo P, Salutari P, Sica S, et al. Luteinizing hormone-releasing hormone analogue: leuprorelin acetate for the prevention of menstrual bleeding in premenopausal women undergoing stem cell transplantation. Bone Marrow Transplant 1998; 21:821.
  7. Meirow D, Rabinovici J, Katz D, et al. Prevention of severe menorrhagia in oncology patients with treatment-induced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxyprogesterone acetate. Cancer 2006; 107:1634.
  8. Amsterdam A, Jakubowski A, Castro-Malaspina H, et al. Treatment of menorrhagia in women undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2004; 34:363.
  9. Kropsky B, Shi Y, Cherniack EP. Incidence of deep-venous thrombosis in nursing home residents using megestrol acetate. J Am Med Dir Assoc 2003; 4:255.
  10. van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein MC. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception 2005; 72:168.
  11. Thürlimann B, Castiglione M, Hsu-Schmitz SF, et al. Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK 20/90). Swiss Group for Clinical Cancer Research (SAKK). Eur J Cancer 1997; 33:1017.
  12. Hägglund H, Remberger M, Klaesson S, et al. Norethisterone treatment, a major risk-factor for veno-occlusive disease in the liver after allogeneic bone marrow transplantation. Blood 1998; 92:4568.
  13. Jack SA, Cooper KG, Seymour J, et al. A randomised controlled trial of microwave endometrial ablation without endometrial preparation in the outpatient setting: patient acceptability, treatment outcome and costs. BJOG 2005; 112:1109.
  14. Qian Y, Gan N, Zhou J, et al. Microwave endometrial ablation for menorrhagia in patients with systemic disorders. Int J Gynaecol Obstet 2005; 91:32.
  15. Phelan JT 2nd, Broder J, Kouides PA. Near-fatal uterine hemorrhage during induction chemotherapy for acute myeloid leukemia: a case report of bilateral uterine artery embolization. Am J Hematol 2004; 77:151.
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