Number 817
Committee on Adolescent Health Care
This Committee Opinion was developed by the American College of Obstetricians and Gynecologists’ Committee on Adolescent Health Care in collaboration with committee members Dawn Palaszewski, MD and Margaret Abraham, MD, MSc.
ABSTRACT: Obstetrician–gynecologists frequently are consulted either before the initiation of cancer treatment to request menstrual suppression or during an episode of severe heavy bleeding to stop bleeding emergently. Adolescents presenting emergently with severe uterine bleeding usually require only medical management; surgical management rarely is required. Surgical management should be considered for patients who are not clinically stable, or for those whose conditions are not suitable for medical management or have failed to respond appropriately to medical management. When used continuously, combined hormonal contraceptives are effective for producing amenorrhea, although complete amenorrhea cannot be guaranteed. The risk of venous thromboembolism in patients with cancer is compounded by multiple factors, including presence of metastatic or fast-growing, biologically aggressive cancers; hematologic cancers; treatment-related factors such as surgery or central venous catheters; and the number and type of comorbid conditions. Although as a group, patients undergoing cancer treatment are at elevated risk of venous thromboembolism compared with the general population, this risk may be extremely elevated for certain patients and existing guidance on risk stratification should be consulted. The decision to use estrogen in patients with cancer should be tailored to the individual patient after collaborative consideration of the risk–benefit ratio with the patient and the health care team; the patient should be closely monitored for known adverse effects such as liver toxicity and venous thromboembolism.
Recommendations and Conclusions
The American College of Obstetricians and Gynecologists makes the following recommendations and conclusions:
Adolescents undergoing cancer treatment are at high risk of abnormal menstrual bleeding as a direct result of hematologic malignancies or as a secondary effect of chemotherapy, radiation therapy, or pretreatment regimens for stem cell or bone marrow transplantation.
Therapy for both menstrual suppression and management of acute bleeding episodes should be tailored to the patient, the cancer diagnosis and treatment plan, and the individual’s contraceptive needs. Because of the complex nature of cancer care, collaboration with the adolescent’s oncologist is highly recommended.
Considerations when choosing an appropriate treatment for acute bleeding include the patient’s current menstrual status, current hemoglobin and platelet count, expected nadirs, planned cancer treatments, risk of thromboembolism, and request for contraception.
Options for menstrual suppression include gonadotropin-releasing hormone (GnRH) agonists, progestin-only therapy, and combined hormonal contraception.
It is important to remember that oncology patients may still be engaging in sexual intercourse and could become pregnant.
Many of the methods for prophylactic or maintenance menstrual suppression also can provide contraception for this population; however, if a patient is treated with leuprolide acetate for menstrual suppression, this should not be considered a contraceptive method because ovulation may not be universally suppressed.
Options for progestin-only oral therapies are medroxyprogesterone acetate (10–20 mg/day), norethindrone acetate (5–15 mg/day), drospirenone (4 mg/day), and norethindrone (0.35 mg/day). Drospirenone (4 mg/day) and norethindrone (0.35 mg/day) also provide contraception but do not confer the same degree of amenorrhea as other oral progestins, and unscheduled bleeding is relatively common in users.
If an adolescent had a levonorgestrel-releasing intrauterine device (LNG-IUD) or the etonogestrel single-rod implant inserted before her cancer diagnosis and has infrequent bleeding or amenorrhea, it is reasonable to continue the method for menstrual suppression.
Medical management is the initial approach for patients who are experiencing an episode of acute heavy bleeding.
In adolescents, surgical procedures such as endometrial ablation and uterine artery embolization are invasive measures that can cause infertility and should only be considered with life-threatening hemorrhage.
Background
Adolescents undergoing cancer treatment are at high risk of abnormal menstrual bleeding as a direct result of hematologic malignancies or as a secondary effect of chemotherapy, radiation therapy, or pretreatment regimens for stem cell or bone marrow transplantation, all of which may induce myelosuppression leading to thrombocytopenia. Additional considerations include the potential for disruption of the hypothalamic–pituitary–gonadal axis during cancer treatment leading to anovulatory bleeding. Also, even normal menstrual blood loss may pose a threat to adolescents who already are anemic, thrombocytopenic, or both, from hematologic malignancies or cancer treatments. Thus, obstetrician–gynecologists frequently are consulted either before the initiation of cancer treatment to request menstrual suppression or during an episode of severe heavy bleeding to stop bleeding emergently 1. Therapy for both menstrual suppression and management of acute bleeding episodes should be tailored to the patient, the cancer diagnosis and treatment plan, and the individual’s contraceptive needs. Because of the complex nature of cancer care, collaboration with the adolescent’s oncologist is highly recommended.
Options for menstrual suppression include GnRH agonists, progestin-only therapy, and combined hormonal contraception 2. Adolescents presenting emergently with severe uterine bleeding usually require only medical management; surgical management rarely is required. Considerations when choosing an appropriate treatment for acute bleeding include the patient’s current menstrual status, current hemoglobin and platelet count, expected nadirs, planned cancer treatments, risk of thromboembolism, and request for contraception. If a patient is treated with leuprolide acetate for menstrual suppression, this should not be considered a contraceptive method because ovulation may not be universally suppressed 3 4.
This Committee Opinion has been updated to make treatment recommendations based on more recent studies, to address specific concerns about the use of combined hormonal contraception (CHC) in cancer patients, and to update nonmedical management to include the intrauterine Foley balloon.
General Considerations for Oncology Patients
The additional risks associated with estrogen or CHC use in cancer patients, specifically venous thromboembolic events (VTE), should be discussed with the patient and the oncology team 5 6 7 8 9. The risk of VTE in patients with cancer is compounded by multiple factors, including presence of metastatic or fast-growing, biologically aggressive cancers; hematologic cancers; treatment-related factors such as surgery or central venous catheters; and the number and type of comorbid conditions 8 9. However, the risk of bleeding requiring transfusion, the risk of unintended pregnancy, or both may outweigh the potential harms of VTE and shared decision making in these clinical situations is essential 8 9 10.
Nausea and vomiting are two of the most bothersome adverse effects associated with radiation therapy and chemotherapy. The addition of hormonal medication to control vaginal bleeding in cancer patients may compound this problem. High-dose combined oral contraceptive (OC) tapers are particularly emetogenic; in contrast, high-dose oral progestins and intramuscular depot medroxyprogesterone acetate (DMPA) are generally well tolerated. In a study of 24 adolescents with heavy vaginal bleeding prescribed a high-dose progestin taper starting at 60–120 mg of medroxyprogesterone daily, none reported bothersome nausea or vomiting 11. When adding hormonal medication, particularly high-dose combined OCs, obstetrician–gynecologists need to be mindful of consequent nausea and vomiting and should optimize antiemetic regimens accordingly. In addition to nausea and vomiting, oral agents also may be poorly tolerated or absorbed because of mucositis or diarrhea caused by radiation enterocolitis or chemotherapy. Similarly, use of other CHCs such as a vaginal ring or the contraceptive patch may be limited by mucositis or skin reactions during cancer treatment 12; switching to another hormonal method may be necessary.
It is important to remember that oncology patients may still be engaging in sexual intercourse and could become pregnant. Many of the methods for prophylactic or maintenance menstrual suppression also can provide contraception for this population. The U.S. Medical Eligibility Criteria for Contraceptive Use only mentions breast, ovarian, cervical, and endometrial cancers, and categorizes use of all hormonal contraceptive methods in these patients as Category 1 or 2 (no risk or the advantages of using the medication generally outweigh the risks) 13. There are two exceptions: 1) the use of hormonal contraception in patients with hormonally active breast cancer, and 2) IUD initiation in cervical and endometrial cancer patients because of concern for seeding with insertion.
Menstrual Suppression
Gonadotropin-Releasing Hormone Agonists
Gonadotropin-releasing hormone agonists are highly effective at inducing menstrual suppression when initiated before cancer treatment 2. A survey of the principal investigators in the Pediatric Blood and Marrow Transplant Consortium found that for menstrual suppression, GnRH agonists were preferentially chosen by 41% of health care professionals, compared with combined OCs (29%), progesterone-only oral medication (21%), DMPA (6%), and ethinyl estradiol-norelgestromin patch (3%) 14. Although there are no studies directly comparing GnRH agonists with combined OCs, advantages of treatment with GnRH agonists include no prothrombotic risk combined with high rates (up to 96%) of amenorrhea 15 16. The primary role of GnRH agonists is for menstrual suppression. Though they appear to have a protective effect on the ovary during chemotherapy in terms of resumption of menstruation and treatment-related premature ovarian failure, there is no conclusive evidence demonstrating efficacy of GnRH agonists in fertility preservation 17 18 19.
Most of the data on GnRH agonists focuses on the use of leuprolide acetate, a synthetic GnRH agonist that acts as a potent inhibitor of gonadotropin release when given in therapeutic doses. Studies, including a systematic review of women undergoing cancer treatment, report high rates of amenorrhea with leuprolide acetate (ranging from 73% to 96%) 20 21. In a retrospective review of 101 females of reproductive age (12–51 years) undergoing myelosuppressive chemotherapy that compared pretreatment with leuprolide acetate (3.75 mg intramuscularly per month) to DMPA (150 mg intramuscularly every 3 months) or placebo, none of the females who received leuprolide acetate experienced moderate to severe bleeding, compared with 21.4% of females who used DMPA and 40% of untreated females 15.
After an initial flare response that causes a transient increase in circulating gonadotropins and sex steroids, leuprolide acetate reliably causes a hypoestrogenic state in 2 weeks 22. Therefore, bleeding may occur for 2–3 weeks after the first injection until hormone levels decrease and endometrial proliferation ceases 20 23. When initiating treatment with leuprolide, adding norethindrone acetate 5 mg daily will help mitigate breakthrough bleeding and other adverse effects of leuprolide 24. If patients experience heavy bleeding during a flare, it can be managed according to the below guidance for heavy bleeding. Different dosing regimens for leuprolide acetate are reported in the literature. It may be given in doses of 3.75 mg intramuscularly monthly or 11.5 mg intramuscularly every 12 weeks 25 26. The 12-week formulation decreases the risk of more frequent monthly injections that may be due at a time of treatment-induced thrombocytopenia. If intramuscular injections are contraindicated, subcutaneous formulations are available.
Disadvantages of leuprolide acetate include the expected adverse effects related to a low-estrogen state, such as vasomotor symptoms and bone density loss. When leuprolide acetate is used to treat endometriosis in adolescents, add-back therapy with a progestin (such as norethindrone acetate 5 mg once daily), has been shown to preserve bone mass and substantially reduce vasomotor symptoms without increasing the rate of bleeding 27 28. Given the safety of progestins in women with complex disease, its use is a reasonable strategy to mitigate the adverse effects of leuprolide acetate without reducing its efficacy 26. Data support that combination norethindrone acetate (5 mg/day) and conjugated equine estrogen (0.625 mg/day) add-back is more effective for increasing bone mineral density when compared with norethindrone acetate alone 29 30. Treatment should be individualized; certain cancer patients, depending on potential risks and benefits, may be candidates for combined add-back therapy.
Elagolix, a GnRH antagonist approved by the U.S. Food and Drug Administration in 2018 for the management of pain associated with endometriosis, has amenorrhea rates similar to leuprolide acetate with the convenience of daily oral dosing. However, currently there is no guidance for its use to suppress menses in patients with cancer.
Progestin-Only Therapy
Progestin-Only Pills
Daily administration of oral progestins allows for decreased endometrial proliferation and prevention of menses. Options for progestin-only oral therapies are medroxyprogesterone acetate (10–20 mg/day), norethindrone acetate (5–15 mg/day), drospirenone (4 mg/day), and norethindrone (0.35 mg/day) 11 31. Drospirenone (4 mg/day) and norethindrone (0.35 mg/day) also provide contraception but do not confer the same degree of amenorrhea as other oral progestins, and unscheduled bleeding is relatively common in users 32 33.
Depot Medroxyprogesterone Acetate
Use of DMPA results in relatively high rates of amenorrhea over time, with rates at 12–24 months reaching approximately 50–70% in the general population 32 34 35. However, initial irregular bleeding with DMPA makes it a less reliable method for rapid therapeutic menstrual suppression, 15 20 and episodes of breakthrough bleeding can be challenging to manage, particularly in patients who are not candidates for adjuvant estrogen. It is classified as a Category 2 method (the advantages of using the method generally outweigh the theoretical or proven risks) among those with a history of VTE and active cancer according to the Centers for Disease Control and Prevention’s U.S. Medical Eligibility Criteria for Contraceptive Use 13. Data on the use of progestin-only methods by patients with cancer are limited. Depot medroxyprogesterone acetate typically is administered every 12 weeks, but the dosing interval can be shortened to achieve amenorrhea quickly 36. Its long dosing interval of up to 3 months minimizes concerns over adherence and is a good option for patients unable to swallow or tolerate pills. A subcutaneous formulation (dose of 104 mg) is available and is recommended for adolescents with thrombocytopenia who are at risk of developing an intramuscular hematoma with intramuscular administration.
Progestin-Only Long-Acting Reversible Contraceptive Methods
Although there are limited data regarding menstrual management with an LNG-IUD in patients undergoing cancer treatment, it is a reasonable option to manage heavy menstrual bleeding in a patient with benign or malignant disease 37. Furthermore, the World Health Organization and the Centers for Disease Control and Prevention state that IUDs can be used safely in women with immunosuppression because of cancer treatment 13 38. Amenorrhea rates after 3 months of use in women aged 18–45 years with heavy menstrual bleeding were 32% in one randomized comparative parallel group study (n=22) 39. Although initial irregular bleeding may limit its use, many studies in noncancer patients have demonstrated the superiority of the 52 micrograms LNG-IUD over oral medroxyprogesterone acetate, norethindrone acetate, DMPA, and CHC for long-term menstrual control 40 41 42.
The etonogestrel single-rod contraceptive implant has not been studied in this patient population. Although it is associated with an amenorrhea rate of 29.5% within the first 2 years of use, its most common side effect is irregular bleeding 43. The inability to predict bleeding patterns limits the usefulness of the implant for menstrual suppression in cancer patients.
If an adolescent had an LNG-IUD or the etonogestrel single-rod implant inserted before her cancer diagnosis and has infrequent bleeding or amenorrhea, it is reasonable to continue the method for menstrual suppression. However, if an adolescent had an implant inserted before her cancer diagnosis and experiences bothersome bleeding, the bleeding can be temporized with a norethindrone acetate or medroxyprogesterone taper and the implant continued.
Combined Hormonal Contraceptives
When used continuously, CHCs are effective for producing amenorrhea, 44 45 although complete amenorrhea cannot be guaranteed. The Centers for Disease Control and Prevention’s 2016 U.S. Medical Eligibility Criteria for Contraceptive Use notes that when oral contraceptives primarily are used as therapy, rather than to prevent pregnancy, even in women where contraceptive use might be cautioned against or contraindicated (such as in those with cancer), the benefits from therapeutic use might outweigh the risks 13. Although as a group, patients undergoing cancer treatment are at elevated risk of VTE compared with the general population, this risk may be extremely elevated for certain patients and existing guidance on risk stratification should be consulted 8 9. For example, in patients undergoing bone marrow transplant, combined OCs are not recommended when alternatives are available. Studies have observed increases in hyperbilirubinemia and hepatic veno-occlusive disease in patients treated with combined OCs during bone marrow or stem cell transplant 5 6 7 8 46. The decision to use estrogen in patients with cancer should be tailored to the individual patient after collaborative consideration of the risk–benefit ratio with the patient and the health care team; the patient should be closely monitored for known adverse effects such as liver toxicity and VTE.
Emergent Treatment of Acute Uterine Bleeding
Some adolescents may present with life-threatening bleeding in the setting of a new cancer diagnosis, whereas others who are undergoing myelosuppressive treatment may not have the time to benefit from prophylactic menstrual suppression and need more urgent therapy once bleeding occurs. Medical management is the initial approach for patients who are experiencing an episode of acute heavy bleeding. Surgical management should be considered for patients who are not clinically stable, or for those whose conditions are not suitable for medical management or have failed to respond appropriately to medical management 47. See Figure 1 for details on management. Some hormonal therapies that are used for menstrual suppression, such as leuprolide acetate, DMPA, LNG-IUD, and the etonogestrel implant, are not appropriate for the initial management of acute heavy bleeding because the onset of action is delayed, and, in some cases, the bleeding pattern is unpredictable. Instead, these therapies may be used in conjunction with therapy for acute bleeding to prevent future episodes of acute uterine bleeding. Ultrasonography can be useful to guide management. Endometrial thickness can guide whether the patient may benefit from progestin or estrogen.
In adolescents with contraindications to estrogen use, cessation of acute uterine bleeding can be achieved with oral progestins alone or in combination with DMPA. For rapid menstrual control, oral progestins are preferable to DMPA or LNG-IUD 48. In one series of 24 adolescents with acute uterine bleeding and anemia, oral medroxyprogesterone acetate at a dose of 60–120 mg (5 mg every 1–2 hours) for the first day followed by 20 mg daily for 10 days successfully controlled bleeding. Complete cessation of bleeding was noted in 25% of patients within 24 hours and in all patients by the fourth day of therapy 11. Similar regimens have proven efficacy in adult women 49 47. Another suggested regimen is high-dose medroxyprogesterone (60–80 mg) two times a day until bleeding stops; then begin a progestin taper such as medroxyprogesterone 10 mg every 4–6 hours, tapering as tolerated to maintain control of bleeding 33. Notably, a small proportion of norethindrone is metabolized to ethinyl estradiol, approximately equivalent to 4 micrograms of ethinyl estradiol per 5 mg of norethindrone 50. In a prospective study, DMPA 150 mg intramuscularly combined with 3 days of medroxyprogesterone acetate 20 mg every 8 hours stopped bleeding within 2.6 days in adults with heavy menstrual bleeding.51 Additional studies are needed in adolescents.
Estrogen therapy with combined OCs or intravenous estrogen has proven useful. As in the case of menstrual suppression, estrogen therapy for acute bleeding should be balanced against the elevated risk of VTE. For adolescents who have been given estrogen, therapy should continue with standard-dose combined OCs until platelet counts have recovered and withdrawal bleeding can occur. If there is a risk of recurrent bleeding because of the course of therapy, menstrual suppression with another agent such as a GnRH agonist should be strongly considered along with the treatment of acute bleeding.
Antifibrinolytics prevent fibrin degradation and decrease production of tissue plasminogen activator by endometrial cells or increase the rate of clearance. Oral and intravenous tranexamic acid is approved by the U.S. Food and Drug Administration for the treatment of cyclic heavy menstrual bleeding. It is contraindicated in patients with active thromboembolic disease, a history of thrombosis or thromboembolism, or an intrinsic risk of thrombosis or thromboembolism 52. Although the product labeling also lists using CHC as a contraindication, clinical experience does not indicate an increased risk of VTE with combined use 53. The vast majority of studies on the use of tranexamic acid in treating heavy menstrual bleeding have excluded oncology patients, making it difficult to assess the true risk of use in this population 37. More information is needed, but it may be reasonable to consider tranexamic acid as an option for an oncology patient with life-threatening bleeding.
Nonmedical Management
In adolescents, surgical procedures such as endometrial ablation and uterine artery embolization are invasive measures that can cause infertility and should only be considered with life-threatening hemorrhage 33 54. Fertility preservation should be a priority.
Nonmedical options that may spare fertility include an intrauterine Foley balloon and suction evacuation or suction curettage (machine or manual), rather than sharp curettage. If the obstetrician–gynecologist performs a uterine evacuation, concomitant placement of an LNG-IUD for long-term management should be considered. In these cases of heavy menstrual bleeding, patients should be counseled about the higher risk of expulsion. Once the acute bleeding episode has been controlled, continued menstrual suppression with any of the methods previously described is recommended.
