Management of Menorrhagia Associated With Chemotherapy-Induced Thrombocytopenia in Women With Hematologic Malignancy

Jill S. Bates, Pharm.D., M.S.; Larry W. Buie, Pharm.D.; C. Brock Woodis, Pharm.D.

Pharmacotherapy. 2011;31(11):1092-1110.

Recommendations for Treatment Options

Many women undergoing chemotherapy may not have effective or timely prophylaxis against menorrhagia for a variety of reasons and may experience heavy menstrual bleeding. For many years, the mainstay of therapy to control menstrual bleeding has been hormonal therapies, specifically high-dose oral contraceptive pills or progestins. However, the data for use of these agents are sparse. The most robust data available for the treatment of menorrhagia are for tranexamic acid. Most women receiving the treatment in randomized trials experienced meaningful reductions in menstrual bleeding, and this translated into improved quality of life. Although there is some concern of increased risk of thrombosis with use of tranexamic acid, the risk was not observed in clinical trials. Again, it should be pointed out that these trials were not conducted in patients with cancer or women who had abnormal uterine bleeding due to thrombocytopenia. However, the data are relevant because of the meaningful reductions in blood loss and very few adverse events associated with the therapy.

Table 6 provides a management strategy for the prophylaxis and treatment of menorrhagia in patients with hematologic malignancies. For women receiving hormonal therapy, the estrogen components can be escalated to high doses (ethinyl estradiol ≥ 50 μg/day). Likewise, extended courses of progestin therapy can be given until cessation of menses occurs, then maintenance therapy can be started. For those who are nonresponsive to higher doses of oral estrogen, progestin, or antifibrinolytic therapy, a short course of intravenous conjugated estrogens is indicated to stop bleeding. Once bleeding has stopped, another means for suppressing menses that should be started is a GnRH analog with progestin overlap. Intravaginal danazol, desmopressin, and rFVIIa should be reserved for patients who are refractory to more conventional therapies. Because of the risk of thrombosis, rFVIIa should not be used without careful consideration in patients at risk.

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Cite this: Management of Menorrhagia Associated With Chemotherapy-Induced Thrombocytopenia in Women With Hematologic Malignancy - Medscape - Nov 01, 2011.

Table 1. Abnormal Uterine Bleeding Terminology^{1, 8, 13}
Term	Definition
Amenorrhea	No bleeding for at least 6 mo in a nonmenopausal woman
Menorrhagia	Heavy regular menstrual cycles with > 80 ml of blood loss or duration > 7 days
Menometrorrhagia	Excessive menstrual bleeding at regular intervals
Metrorrhagia	Bleeding between periods or irregular bleeding
Oligomenorrhea	Intermenstrual bleeding at intervals > 35 days that may be attributed to a prolonged follicular phase
Polymenorrhea	Bleeding occurring at intervals < 21 days that may be attributed to a luteal-phase defect

Table 2. Menorrhagia Impact Questionnaire²⁰
Questionnaire Concept	Questionnaire Item	Response Scale
Perception of the amount of blood loss	During your most recent menstrual period, your blood loss was?	1 = light, 2 = moderate, 3 = heavy, 4 = very heavy
Limitations in work inside or outside the home	During your most recent menstrual period, how much did your bleeding limit you in your work outside or inside the home?	1 = not at all, 2 = slightly, 3 = moderately, 4 = quite a bit, 5 = extremely
Limitations in physical activity	During your most recent menstrual period, how much did your bleeding limit you in your physical activities?	1 = not at all, 2 = slightly, 3 = moderately, 4 = quite a bit, 5 = extremely
Limitations in social or leisure activities	During your most recent menstrual period, how much did your bleeding limit you in your social or leisure activities?	1 = not at all, 2 = slightly, 3 = moderately, 4 = quite a bit, 5 = extremely
Global assessment of change in blood loss	Compared with your previous menstrual period, would you say that your blood loss during this period was?	0 = about the same 1 = better: (1) almost the same, hardly better at all (2) a little better (3) somewhat better (4) an average amount better (5) a good deal better (6) a great deal better (7) a very great deal better 2 = worse: (1) almost the same, hardly (2) a little worse worse at all (3) somewhat worse (4) an average amount worse (5) a good deal worse (6) a great deal worse (7) a very great deal worse
Meaningfulness of perceived change in blood loss	Was this a meaningful or important change for you?	0 = no, 1 = yes

Table 3. Pharmacologic Therapies for Menorrhagia Prevention and Treatment^{1, 7, 8}
Agent	Reduction in Menstrual Blood Flow	Reported Adverse Events	Comments
Combined oral contraceptives	43%	Mild: nausea, vomiting, breast tenderness Serious: thrombosis, hypertension	Causes cycle regularity, useful in dysmenorrhea, provides contraception
Danazol	22–99%	Weight gain, fatigue, acne, muscle cramps, atrophic vaginitis, hot flashes, lipid level changes,hirsutism, decreased breast size	Inhibits ovulation by suppressing midcycle surge of FSH and LH, contains hypoestrogenic properties by inhibiting steroidogenesis in the corpeus luteum
Recombinant factor VIIa	> 90% (in case reports)	Venous thromboembolism, cerebral and myocardial ischemia	Optimal dosing strategies for patients who are platelet refractory are unknown, and data for use are limited
Gonadotropin-releasing hormone agonists (leuprolide)	>90%	Hot flashes, night sweats, bone mineral density loss with use > 6 mo	Creates hypoestrogenic state
Levonorgestrel-releasing intrauterine system	> 90%	Mechanical: cramping, irregular bleeding, dysmenorrhea Systemic: weight gain, bloating, intermenstrual bleeding (especially during first 3 cycles)	Provides contraception, insertion of device requires training
NSAIDs (mefenamic acid,naproxen, ibuprofen indomethacin)	20–50% (in 75%, of women)	Nausea, gastrointestinal bleeding, abdominal discomfort	Decreases production of prostaglandins, no significant differences in clinical efficacy between NSAIDs, should be used only during menses
Progestins (medroxyprogesterone acetate)	32–50%	Bloating, weight gain, acne, nausea, hirsutism	May be used during luteal phase or for days 5–26 of menstrual cycle
Tranexamic acid	47–54%	Thrombogenic events, nausea, vomiting, possible disturbances in color vision	Inhibits plasminogen activation and inhibits fibrinolysis within endometrium

FSH = follicle-stimulating hormone; LH = luteinizing hormone; NSAID = nonsteroidal antiinflammatory drug.

Table 4. Summary of Clinical Studies Evaluating Gonadotropin-releasing Hormone Analogs for the Prevention of Menorrhagia Associated with Thrombocytopenia Caused by Myelosuppressive Chemotherapy
Study Design	Patient Population	Study Treatment	Comments
Prospective cohort³¹	Premenopausal women with acute myeloid leukemia (n=16)	Gestodene 0.075 mg–ethinyl estradiol 0.03 mg/day (n=8) or leuprolide acetate 3.75 mg s.c. every 28 days (n=8)	Liver toxicity was observed in both groups, but grade III–IV toxicity was demonstrated only in the gestodene–ethinyl estradiol cohort; use of L-asparaginase may have confounded the toxicity profile
Prospective, open-label,noncomparative³²	Premenopausal women aged 16–50 yrs with hematologic malignancy (n=21)	Nomegestrol acetate 5 mg/day on days 1–35 + leuprolide acetate 3.75 mg s.c. every 28 days, except for the second injection, which was administered 21 days after the first injection	The authors concluded that a second leuprolide injection on day 21 could not be recommended based on these data; an increased osteoporosis risk was observed if leuprolide use was > 6 mo; they recommended reducing the platelet threshold to 50 × 103/mm3 to lessen the risk
Open-label, noncomparative³³	Premenopausal women undergoing stem cell transplantation:Autologous transplantation (n=21) Allogeneic transplantation (n=9)	Leuprolide acetate 3.75 mg s.c. at least 30 days before transplantation, with second injection administered 28 days later	The authors noted that the adverse effects of the GnRH agonist analog were primarily related to the long and profound estrogen suppression; use of leuprolide completely prevented vaginal bleeding during periods of thrombocytopenia except in one patient who had hemorrhagic complications
Open-label, noncomparative³⁴	Premenopausal women undergoing either autologous or allogeneic transplantation (n=10)	Leuprolide acetate 7.5 mg i.m. every 28 days	All patients had successful induction of amenorrhea except for one patient who had documented uterine fibroids
Retrospective cohort³⁵	Premenopausal women with CML, MDS, acute leukemia, lymphoma, breast cancer,or Ewing sarcoma: Stem cell transplant (n=93) Induction chemotherapy (n=8)	No treatment (control), depo-medroxyprogesterone 150 mg i.m. every 3 mo, or D-tryptophan–6-luteinizing hormone–releasing hormone 3.75 mg i.m. once/mo	Both treatment groups had decreased occurrence of menorrhagia; vaginal bleeding rate in the control cohort was 65%
Retrospective, observational³⁶	Premenopausal women undergoing bone marrow transplantation: Autologous (n=17) Allogeneic (n=17)	Leuprolide acetate 1 mg/day i.v. or 7.5 mg i.m. once/mo	The authors noted that the best predictor of therapeutic success was the timing of initiation of leuprolide therapy relative to the onset of thrombocytopenia, with success favoring an earlier start

GnRH = gonadotropin-releasing hormone; CML = chronic myelogenous leukemia; MDS = myelodysplastic syndrome.

Table 5. Successful Hormonal Strategies for Menorrhagia Not Responding to Initial Therapy in Seven Patients Undergoing Stem Cell Transplantation²⁹
Patient	Sequence of Therapy
1	i.v. conjugated estrogens → high-dose OCPs → transdermal estrogens → high-dose OCPs
2	i.v. conjugated estrogens → transdermal estrogens → high-dose OCPs
3	i.v. conjugated estrogens → high-dose OCPs
4	Transdermal estrogens-progestin → high-dose OCPs
5	Transdermal estrogens-progestin → i.v. conjugated estrogens → transdermal estrogens → high-dose OCPs
6	Transdermal estrogens-progestin → standard-dose OCPs
7	High-dose OCPs → transdermal estrogens-progestin → high-dose OCPs

OCP = oral contraceptive pill.

Table 6. Management of Menorrhagia in Patients with Hematologic Malignancies
Type of Therapy	Drug
Prophylaxis	Gonadotropin-releasing hormone analog + 35 days of medroxyprogesterone
Treatment
Level 1	Tranexamic acid during 5 days of menses
Level 2	Medroxyprogesterone or oral contraceptive
Level 3	i.v. estrogen
Level 4 (refractory)	Danazol, rFVIIa, + desmopressin

rFVIIa = recombinant factor VIIa.

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