Original Study Use and Effectiveness of Gonadotropin-Releasing Hormone Agonists for Prophylactic Menstrual Suppression in Postmenarchal Women Who Undergo Hematopoietic Cell Transplantation Philip D. Poorvu MD 1,*, Sara E. Barton MD 2, Christine N. Duncan MD 3, Wendy B. London PhD 4, Marc R. Laufer MD 5, Leslie E. Lehmann MD 3, Karen J. Marcus MD 6 1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts Heartland Center for Reproductive Medicine, Omaha, Nebraska Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 4 Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 5 Department of Obstetrics and Gynecology, Brigham and Women's Hospital; Division of Gynecology, Boston Children's Hospital, Boston, Massachusetts 6 Department of Radiation Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, and Brigham and Women's Hospital, Boston, Massachusetts 2 3
a b s t r a c t Study Objective: To describe the rates of use and effectiveness of gonadotropin-releasing hormone (GnRH) agonists and other forms of hormonal menstrual suppression in prevention of vaginal bleeding among young women who underwent hematopoietic stem cell transplantation (HCT). Design: Retrospective descriptive study. Setting: University-based pediatric HCT practice. Participants: Fifty-five postmenarchal women who underwent HCT between 2004 and 2011. Interventions: Administration of GnRH agonists or other forms of hormonal menstrual suppression. Main Outcome Measures: Rates of use of GnRH agonists and other forms of hormonal menstrual suppression, and rates and descriptions of vaginal bleeding. Results: Forty-six of the 55 patients had experienced regular or irregular vaginal bleeding before HCT and were considered to be at risk for thrombocytopenia-associated menorrhagia. Forty of the 46 (87%) received hormonal menstrual suppression. Thirty-three patients were treated with a GnRH agonist, 4 with combined hormonal contraceptive pills, 1 with a combined hormonal contraceptive patch, 1 with depot medroxyprogesterone, and 1 with oral norethindrone. Twenty-nine of the 33 patients (88%) who received a GnRH agonist had complete amenorrhea during HCT and 4 of 33 (12%) experienced some degree of vaginal bleeding. Conclusion: GnRH agonists appear effective in prevention of vaginal bleeding complications in most postmenarchal women who underwent HCT. Some patients who might benefit do not receive a GnRH agonist and multiple barriers exist in identification and treatment of them. Key Words: Gonadotropin-releasing hormone, Menorrhagia, Hematopoietic stem cell transplantation
Introduction
Patients who undergo myeloablative hematopoietic stem cell transplantation (HCT) receive preparative conditioning that consists of high doses of chemotherapy with or without total body irradiation. For pubertal women, vaginal bleeding occurs commonly during HCT, and is exacerbated by thrombocytopenia or other coagulopathies associated with HCT.1 Menorrhagia, particularly before platelet engraftment, can be a significant problem. It often requires transfusion of red cells and/or platelets, which increases patient risk of alloimmunization and infection,2,3 or medical therapies such as estrogen, which can cause hepatic or other toxicities. Gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide acetate (Lupron; AbbVie Inc, North Chicago, IL), are commonly used in postmenarchal The authors indicate no conflicts of interest. * Address correspondence to: Philip D. Poorvu, MD, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02115-5450; Phone (617) 632-3779 E-mail address: [email protected] (P.D. Poorvu).
females before HCT to induce amenorrhea as a means to prevent thrombocytopenia-associated menorrhagia. Published case series report rates of amenorrhea associated with GnRH agonist administration of 90% and higher with no reported adverse events.4,5 There is a paucity of data on the approach to menstrual suppression in young postmenarchal women who undergo HCT. Herein we describe approaches to menstrual suppression with a focus on the rate of GnRH agonist use and its efficacy in prevention of vaginal bleeding during the acute HCT period. Materials and Methods
We performed a retrospective descriptive study of female patients at Boston Children's Hospital and DanaFarber Cancer Institute who underwent HCT for any indication between January 1, 2004 and June 1, 2011. Our institutional database was queried for patients aged 8 years or older to capture all patients who could have experienced normal menstrual periods or irregular vaginal bleeding and
1083-3188/$ - see front matter Ó 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpag.2015.10.013
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P.D. Poorvu et al. / J Pediatr Adolesc Gynecol 29 (2016) 265e268
Female HCT patients age >8 years (n = 96)
Excluded: Premenarchal (n = 41) Study group (n = 55)
Patients not at risk for menorrhagia (n = 9) No menstrual history (n = 5) Treatment-related amenorrhea (n = 4) Patients at risk for menorrhagia (n = 46) Patients treated with other hormonal menstrual suppression (n = 7): Combined hormonal contraceptive pill (n = 4) Combined hormonal contraceptive patch (n = 1) Depot medroxyprogesterone (n = 1) Norethindrone pill (n = 1)
No menstrual suppression (n = 6)
Patients treated with GnRH agonist (n = 33) Fig. 1. Flowchart of study group inclusion and exclusion. GnRH, gonadotropin-releasing hormone; HCT, hematopoietic stem cell transplantation.Ă
to exclude all patients who could have experienced precocious puberty. Ninety-six patients were initially identified; 41 were premenarchal and were excluded from further analysis (Fig. 1). The median age of the 55 patients in the study group was 16 years (range, 9-33 years; Table 1). All patients received conditioning regimens that included alkylating chemotherapy with or without the addition of total body irradiation (13.2-14.0 Gy). All patients who received prophylactic GnRH agonist treatment for menstrual suppression were analyzed for the effectiveness of GnRH agonists in prevention of vaginal bleeding during transplantation. Patients who did not receive prophylactic menstrual suppression with a GnRH agonist but received a GnRH agonist for menorrhagia during HCT were not assessed. Any vaginal bleeding during HCT, whether or not it required treatment, was considered failure of menstrual suppression and details of the bleeding were recorded. All data were gathered from the electronic medical record system and no subjects were contacted for additional information. Study data were collected and managed using Research Electronic Data Capture tools hosted at Partners
Table 1 Patient, Disease, and Treatment Characteristics Characteristic
Value
Age at time of transplant Diagnosis Hematologic malignancy Solid tumor Nonmalignant disease Conditioning regimen Chemotherapy alone Chemotherapy and TBI Transplant type Autologous Unrelated donor Related donor Source PBSC Bone marrow Cord
16 (9-33)
TBI, total body irradiation; PBSC, peripheral blood stem cells Data are presented as n or median (range).
43 2 10 25 30 16 25 14 19 31 5
Healthcare.6 The use and effectiveness of GnRH agonists in prevention of vaginal bleeding complications were evaluated with descriptive statistics and the analysis of variance test. The study was reviewed and approved by the institutional review board of the Dana-Farber Cancer Institute. Results
Of the 55 patients, 46 had regular or irregular vaginal bleeding before HCT and were considered to be at risk for thrombocytopenia-associated menorrhagia and eligible for prophylactic hormonal menstrual suppression. Four patients had treatment-related amenorrhea and 5 patients had no recorded menstrual history. Of the 46 at-risk patients, 40 (87%) received hormonal menstrual suppression, 33 (72%) with a GnRH agonist. Thirty-two patients received leuprolide acetate intramuscular injection. Dosing information was available for 21 patients; 2 patients received 3.75 mg, 1 patient received 7.5 mg, 5 received 11.25 mg, and 13 received 22.5 mg. One patient received goserelin acetate (Zoladex; AstraZeneca Pharmaceuticals LP, London, United Kingdom; dose and route not available). Among the 31 patients for whom timing of GnRH agonist therapy was documented, it was initiated a median of 46 days before the start of conditioning (range, 9 to 183 days). It was administered within 14 days of HCT to 9 patients and after conditioning began in 1 patient. Of the patients who received a GnRH agonist, amenorrhea during the HCT admission was successfully induced in 29 of 33 (88%). Four of the 33 patients (12%) treated with a GnRH agonist, 2 of 7 (29%) treated with other hormonal prophylaxis, and 4 of 6 (67%) who did not receive menstrual suppression experienced vaginal bleeding (P ! .01; Fig. 2). Descriptions of bleeding events among each group are provided. Patients with Bleeding Who Had Prophylaxis with a GNRH Agonist
Patient 1 had a history of severe menorrhagia more than 2 months earlier during her hospitalization for induction
P.D. Poorvu et al. / J Pediatr Adolesc Gynecol 29 (2016) 265e268
GnRH agonist (n = 33)
No bleeding (n = 29)
267
Other hormonal suppression (n = 7)
Bleeding (n = 4)
Bleeding (n = 2)
No bleeding (n = 5)
No menstrual suppression (n = 6)
No bleeding (n = 2)
Bleeding (n = 4)
P < .01 Fig. 2. Vaginal bleeding outcomes according to form of menstrual suppression. GnRH, gonadotropin-releasing hormone.Ă
chemotherapy and required transfusions of packed red blood cells, platelets, and fresh frozen plasma as well as aminocaproic acid (Amicar; Xanodyne Pharmaceutics, Inc, Newport, KY), antihemophilic factor/von Willebrand factor complex (human; Humate P; CSL Behring, King of Prussia, PA), combined hormonal contraceptive (CHC) pills, and leuprolide. A workup for coagulopathy and abnormal uterine anatomy was unremarkable and, after her bleeding stopped, she was transitioned from CHC pills to a norethindrone pill. She experienced light vaginal bleeding 10 days before starting conditioning, 8 days after her second leuprolide injection, and required no additional treatment. Patient 2 received her first leuprolide injection on the day conditioning began and developed vaginal bleeding on day 20 that responded to platelet transfusions alone. Patient 3 had light vaginal bleeding on day 13, 15 days after her third monthly leuprolide injection, and was treated with platelet transfusions alone. Patient 4 had moderate vaginal bleeding on day 2, 12 days after leuprolide administration, and was treated with platelet transfusions and a CHC pill taper, containing an estrogen and a progestin. Two patients (6.1%) had documented adverse events attributed to administration of leuprolide acetate; 1 had injection site soreness and the other had a mass at the injection site that was biopsied and determined to be a granulomatous reaction. Prophylaxis with Other Forms of Hormonal Menstrual Suppression
Of the 7 patients who received prophylactic hormonal menstrual suppression other than a GnRH agonist, 4 were treated with CHC pills, 1 with a CHC patch, 1 with depot medroxyprogesterone, and 1 with a norethindrone pill. Two of the 4 patients (50%) treated with CHC pills for menstrual suppression had vaginal bleeding during HCT; 1 was treated with leuprolide and the other required neither additional hormonal treatment nor additional platelet transfusions. None of the remaining 3 patients experienced vaginal bleeding during HCT. Patients Who Received No Menstrual Prophylaxis
Of the 6 patients who had regular menses or irregular vaginal bleeding before conditioning and did not have documented menstrual suppression, 2 had previously been treated with leuprolide, but the medical record did not
show that it had been continued; neither had vaginal bleeding during HCT. Menstrual suppression with a GnRH agonist had been recommended during a gynecology consultation for 1 patient but was delayed until the week before conditioning and at that point the decision was made to defer use of a GnRH agonist because of proximity to conditioning; the patient had vaginal bleeding during HCT that did not require intervention. One patient experienced menarche within 1 week of conditioning and experienced heavy vaginal bleeding during her transplant procedure and required platelet transfusions. Another patient was evaluated by gynecology 1 week before conditioning and it was decided not to suppress her menses with a GnRH agonist because the certainty of a withdrawal bleed was believed to outweigh the risk of her possibly having her normal menses; she had vaginal bleeding during her transplant procedure and was treated with CHC pills. One patient did not receive menstrual suppression without explanation in the medical record and had vaginal bleeding that required no intervention. Of the 4 patients who had treatment-related amenorrhea before HCT, 1 had vaginal bleeding 1 week before conditioning that did not require treatment and another had vaginal bleeding during her transplant course and was treated with a CHC patch; neither required additional platelet transfusions. Of the 5 patients who lacked documentation of menstrual history in the medical record before HCT, none had documented vaginal bleeding during HCT. Discussion
Menorrhagia is a potentially serious complication during HCT.3 Causes include prolonged thrombocytopenia that results from marrow ablation, poor response to platelet transfusions, and development of coagulopathies due to sepsis or liver dysfunction. Previous studies have shown that administration of GnRH agonists might affect the incidence of vaginal bleeding and associated complications,4,5 and might be more effective at prevention of significant bleeding than supportive care or the use of depomedroxyprogesterone acetate.7 CHC pills provide another approach to menstrual suppression in HCT. There are, however, associated toxicities including transaminitis and increased risk of thrombotic events. In addition, it is often difficult to consistently administer oral medications
268
P.D. Poorvu et al. / J Pediatr Adolesc Gynecol 29 (2016) 265e268
because of nausea, vomiting, and mucositis. A survey of practices published in 2012 reported that GnRH agonists were used more often than CHC pills for menstrual suppression.8 Another survey of HCT physicians found that more than a third of respondents used leuprolide to suppress menses; among the subgroup of pediatric providers it was the favored option in more than 50%.9 Results of our study further support the efficacy and safety of GnRH agonists in the HCT setting and our study, to our knowledge, is the first to document the actual rates of GnRH agonist use among postmenarchal women who undergo HCT in a pediatric center. In our cohort of consecutive pubertal women who underwent HCT, 46 patients had either regular menses or irregular vaginal bleeding and were thus at risk for bleeding during the period of thrombocytopenia. The most common choice for prophylactic menstrual suppression, used in 33 patients, was the use of a GnRH agonist before HCT. Seven received other hormonal therapies and 6 lacked documentation regarding suppression. Our data suggest that the approach chosen to induce menstrual suppression affects the incidence of bleeding during HCT. Among the 33 patients who received a GnRH agonist, most (88%) achieved amenorrhea during the HCT course. Only 4 patients experienced vaginal bleeding; no episodes were life-threatening and only 2 required platelet transfusions to control bleeding. GnRH agonist therapy was not associated with any serious adverse events and appeared safe when used in this setting. Two of the 4 patients treated with CHC pills, the next most commonly used form of suppression, experienced vaginal bleeding and 4 of 6 postmenarchal patients who did not receive any prophylactic suppression experienced vaginal bleeding during HCT. In addition, 2 of 4 pubertal patients thought to not be at risk because of prolonged pre-HCT amenorrhea from previous chemotherapy actually experienced vaginal bleeding. This suggests that these patients remain at risk for menorrhagia during prolonged periods of thrombocytopenia despite previous periods of amenorrhea and suppression should thus be considered. Despite the efficacy and low toxicity associated with GnRH agonists relative to other forms of menstrual suppression, more than 20% of patients at risk for menorrhagia did not receive this therapy. Potential reasons include the multiple barriers that prevented successful identification and treatment of those who would benefit from menstrual suppression with a GnRH agonist. HCT most often occurs at tertiary care centers and patients might receive care at a local institution before HCT, which causes uncertainty as to which provider is responsible for initiating menstrual suppression. Because of the frequency and risk of withdrawal bleeding, GnRH agonists are most effective when administered at least 2 weeks before the expected menstrual period.2 For patients who arrive at the HCT center within 2 weeks of expected menstruation, the effectiveness of treatment is uncertain and the fear of prolonged withdrawal bleeding during HCT makes providers hesitant to administer this therapy in close proximity to the start of the transplant conditioning. Intramuscular injection of a GnRH
agonist might be contraindicated in patients with coexisting thrombocytopenia. Providers might also be uncomfortable in administration of GnRH agonists if they are not familiar with their efficacy and safety in the adolescent population. The risk-benefit ratio for patients with therapyassociated amenorrhea or infrequent vaginal bleeding might not be clear; however, our experience showed that some of these patients can experience thrombocytopeniaassociated menorrhagia during HCT. Before transplantation, a detailed menstrual history should be obtained because it is essential to ensure that atrisk patients can be identified and a thoughtful decision regarding suppression therapy can occur. In addition the need for hormonal replacement therapy after HCT can be evaluated to best prevent long-term medical issues including coronary artery disease10 and osteoporosis.11 The menstrual history must be included in the routine review of systems and its absence creates a significant barrier to ideal management of these issues. Lack of established practice guidelines and variability between providers also contribute to inconsistent use of menstrual suppression. Institutions should consider implementation of guidelines to identify all at-risk women including those with a history of treatment-related amenorrhea. This would allow treatment algorithms to be created that address the use of GnRH agonists and identification of situations in which alternative therapies might be warranted. Routine collaboration with pediatric gynecologists as part of pretransplant care would improve care and allow standardization of the approach to menstrual suppression, in addition to fertility preservation and treatment of premature loss of ovarian function in this vulnerable population.
References 1. Amsterdam A, Jakubowki A, Castro-Malaspina H, et al: Treatment of menorrhagia in women undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2004; 34:363 2. 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 3. Quaas AM, Ginsburg ES: Prevention and treatment of uterine bleeding in hematologic malignancy. Eur J Obstet Gynecol Reprod Biol 2007; 134:3 4. 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 5. 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 6. Harris PA, Taylor R, Thielke R, et al: Research electronic data capture (REDCap) a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42:377 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. Adegite EA, Goyal RK, Murray PJ, et al: The management of menstrual suppression and uterine bleeding: a survey of current practices in the Pediatric Blood and Marrow Transplant Consortium. Pediatr Blood Cancer 2012; 59:553 9. Lee SJ, Astigarraga CC, Eapen M, et al: Variation in supportive practices in hematopoietic cell transplantation. Biol Blood Marrow Transplant 2008; 14: 1231 10. Colditz GA, Willett WC, Stampfer MJ, et al: Menopause and the risk of coronary heart disease in women. N Engl J Med 1987; 316:1105 11. Davies MC, Hall ML, Jacobs HS: Bone mineral loss in young women with amenorrhea. BMJ 1990; 301:790
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts Heartland Center for Reproductive Medicine, Omaha, Nebraska Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 4 Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 5 Department of Obstetrics and Gynecology, Brigham and Women's Hospital; Division of Gynecology, Boston Children's Hospital, Boston, Massachusetts 6 Department of Radiation Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, and Brigham and Women's Hospital, Boston, Massachusetts 2 3
a b s t r a c t Study Objective: To describe the rates of use and effectiveness of gonadotropin-releasing hormone (GnRH) agonists and other forms of hormonal menstrual suppression in prevention of vaginal bleeding among young women who underwent hematopoietic stem cell transplantation (HCT). Design: Retrospective descriptive study. Setting: University-based pediatric HCT practice. Participants: Fifty-five postmenarchal women who underwent HCT between 2004 and 2011. Interventions: Administration of GnRH agonists or other forms of hormonal menstrual suppression. Main Outcome Measures: Rates of use of GnRH agonists and other forms of hormonal menstrual suppression, and rates and descriptions of vaginal bleeding. Results: Forty-six of the 55 patients had experienced regular or irregular vaginal bleeding before HCT and were considered to be at risk for thrombocytopenia-associated menorrhagia. Forty of the 46 (87%) received hormonal menstrual suppression. Thirty-three patients were treated with a GnRH agonist, 4 with combined hormonal contraceptive pills, 1 with a combined hormonal contraceptive patch, 1 with depot medroxyprogesterone, and 1 with oral norethindrone. Twenty-nine of the 33 patients (88%) who received a GnRH agonist had complete amenorrhea during HCT and 4 of 33 (12%) experienced some degree of vaginal bleeding. Conclusion: GnRH agonists appear effective in prevention of vaginal bleeding complications in most postmenarchal women who underwent HCT. Some patients who might benefit do not receive a GnRH agonist and multiple barriers exist in identification and treatment of them. Key Words: Gonadotropin-releasing hormone, Menorrhagia, Hematopoietic stem cell transplantation
Introduction
Patients who undergo myeloablative hematopoietic stem cell transplantation (HCT) receive preparative conditioning that consists of high doses of chemotherapy with or without total body irradiation. For pubertal women, vaginal bleeding occurs commonly during HCT, and is exacerbated by thrombocytopenia or other coagulopathies associated with HCT.1 Menorrhagia, particularly before platelet engraftment, can be a significant problem. It often requires transfusion of red cells and/or platelets, which increases patient risk of alloimmunization and infection,2,3 or medical therapies such as estrogen, which can cause hepatic or other toxicities. Gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide acetate (Lupron; AbbVie Inc, North Chicago, IL), are commonly used in postmenarchal The authors indicate no conflicts of interest. * Address correspondence to: Philip D. Poorvu, MD, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02115-5450; Phone (617) 632-3779 E-mail address: [email protected] (P.D. Poorvu).
females before HCT to induce amenorrhea as a means to prevent thrombocytopenia-associated menorrhagia. Published case series report rates of amenorrhea associated with GnRH agonist administration of 90% and higher with no reported adverse events.4,5 There is a paucity of data on the approach to menstrual suppression in young postmenarchal women who undergo HCT. Herein we describe approaches to menstrual suppression with a focus on the rate of GnRH agonist use and its efficacy in prevention of vaginal bleeding during the acute HCT period. Materials and Methods
We performed a retrospective descriptive study of female patients at Boston Children's Hospital and DanaFarber Cancer Institute who underwent HCT for any indication between January 1, 2004 and June 1, 2011. Our institutional database was queried for patients aged 8 years or older to capture all patients who could have experienced normal menstrual periods or irregular vaginal bleeding and
1083-3188/$ - see front matter Ó 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpag.2015.10.013
266
P.D. Poorvu et al. / J Pediatr Adolesc Gynecol 29 (2016) 265e268
Female HCT patients age >8 years (n = 96)
Excluded: Premenarchal (n = 41) Study group (n = 55)
Patients not at risk for menorrhagia (n = 9) No menstrual history (n = 5) Treatment-related amenorrhea (n = 4) Patients at risk for menorrhagia (n = 46) Patients treated with other hormonal menstrual suppression (n = 7): Combined hormonal contraceptive pill (n = 4) Combined hormonal contraceptive patch (n = 1) Depot medroxyprogesterone (n = 1) Norethindrone pill (n = 1)
No menstrual suppression (n = 6)
Patients treated with GnRH agonist (n = 33) Fig. 1. Flowchart of study group inclusion and exclusion. GnRH, gonadotropin-releasing hormone; HCT, hematopoietic stem cell transplantation.Ă
to exclude all patients who could have experienced precocious puberty. Ninety-six patients were initially identified; 41 were premenarchal and were excluded from further analysis (Fig. 1). The median age of the 55 patients in the study group was 16 years (range, 9-33 years; Table 1). All patients received conditioning regimens that included alkylating chemotherapy with or without the addition of total body irradiation (13.2-14.0 Gy). All patients who received prophylactic GnRH agonist treatment for menstrual suppression were analyzed for the effectiveness of GnRH agonists in prevention of vaginal bleeding during transplantation. Patients who did not receive prophylactic menstrual suppression with a GnRH agonist but received a GnRH agonist for menorrhagia during HCT were not assessed. Any vaginal bleeding during HCT, whether or not it required treatment, was considered failure of menstrual suppression and details of the bleeding were recorded. All data were gathered from the electronic medical record system and no subjects were contacted for additional information. Study data were collected and managed using Research Electronic Data Capture tools hosted at Partners
Table 1 Patient, Disease, and Treatment Characteristics Characteristic
Value
Age at time of transplant Diagnosis Hematologic malignancy Solid tumor Nonmalignant disease Conditioning regimen Chemotherapy alone Chemotherapy and TBI Transplant type Autologous Unrelated donor Related donor Source PBSC Bone marrow Cord
16 (9-33)
TBI, total body irradiation; PBSC, peripheral blood stem cells Data are presented as n or median (range).
43 2 10 25 30 16 25 14 19 31 5
Healthcare.6 The use and effectiveness of GnRH agonists in prevention of vaginal bleeding complications were evaluated with descriptive statistics and the analysis of variance test. The study was reviewed and approved by the institutional review board of the Dana-Farber Cancer Institute. Results
Of the 55 patients, 46 had regular or irregular vaginal bleeding before HCT and were considered to be at risk for thrombocytopenia-associated menorrhagia and eligible for prophylactic hormonal menstrual suppression. Four patients had treatment-related amenorrhea and 5 patients had no recorded menstrual history. Of the 46 at-risk patients, 40 (87%) received hormonal menstrual suppression, 33 (72%) with a GnRH agonist. Thirty-two patients received leuprolide acetate intramuscular injection. Dosing information was available for 21 patients; 2 patients received 3.75 mg, 1 patient received 7.5 mg, 5 received 11.25 mg, and 13 received 22.5 mg. One patient received goserelin acetate (Zoladex; AstraZeneca Pharmaceuticals LP, London, United Kingdom; dose and route not available). Among the 31 patients for whom timing of GnRH agonist therapy was documented, it was initiated a median of 46 days before the start of conditioning (range, 9 to 183 days). It was administered within 14 days of HCT to 9 patients and after conditioning began in 1 patient. Of the patients who received a GnRH agonist, amenorrhea during the HCT admission was successfully induced in 29 of 33 (88%). Four of the 33 patients (12%) treated with a GnRH agonist, 2 of 7 (29%) treated with other hormonal prophylaxis, and 4 of 6 (67%) who did not receive menstrual suppression experienced vaginal bleeding (P ! .01; Fig. 2). Descriptions of bleeding events among each group are provided. Patients with Bleeding Who Had Prophylaxis with a GNRH Agonist
Patient 1 had a history of severe menorrhagia more than 2 months earlier during her hospitalization for induction
P.D. Poorvu et al. / J Pediatr Adolesc Gynecol 29 (2016) 265e268
GnRH agonist (n = 33)
No bleeding (n = 29)
267
Other hormonal suppression (n = 7)
Bleeding (n = 4)
Bleeding (n = 2)
No bleeding (n = 5)
No menstrual suppression (n = 6)
No bleeding (n = 2)
Bleeding (n = 4)
P < .01 Fig. 2. Vaginal bleeding outcomes according to form of menstrual suppression. GnRH, gonadotropin-releasing hormone.Ă
chemotherapy and required transfusions of packed red blood cells, platelets, and fresh frozen plasma as well as aminocaproic acid (Amicar; Xanodyne Pharmaceutics, Inc, Newport, KY), antihemophilic factor/von Willebrand factor complex (human; Humate P; CSL Behring, King of Prussia, PA), combined hormonal contraceptive (CHC) pills, and leuprolide. A workup for coagulopathy and abnormal uterine anatomy was unremarkable and, after her bleeding stopped, she was transitioned from CHC pills to a norethindrone pill. She experienced light vaginal bleeding 10 days before starting conditioning, 8 days after her second leuprolide injection, and required no additional treatment. Patient 2 received her first leuprolide injection on the day conditioning began and developed vaginal bleeding on day 20 that responded to platelet transfusions alone. Patient 3 had light vaginal bleeding on day 13, 15 days after her third monthly leuprolide injection, and was treated with platelet transfusions alone. Patient 4 had moderate vaginal bleeding on day 2, 12 days after leuprolide administration, and was treated with platelet transfusions and a CHC pill taper, containing an estrogen and a progestin. Two patients (6.1%) had documented adverse events attributed to administration of leuprolide acetate; 1 had injection site soreness and the other had a mass at the injection site that was biopsied and determined to be a granulomatous reaction. Prophylaxis with Other Forms of Hormonal Menstrual Suppression
Of the 7 patients who received prophylactic hormonal menstrual suppression other than a GnRH agonist, 4 were treated with CHC pills, 1 with a CHC patch, 1 with depot medroxyprogesterone, and 1 with a norethindrone pill. Two of the 4 patients (50%) treated with CHC pills for menstrual suppression had vaginal bleeding during HCT; 1 was treated with leuprolide and the other required neither additional hormonal treatment nor additional platelet transfusions. None of the remaining 3 patients experienced vaginal bleeding during HCT. Patients Who Received No Menstrual Prophylaxis
Of the 6 patients who had regular menses or irregular vaginal bleeding before conditioning and did not have documented menstrual suppression, 2 had previously been treated with leuprolide, but the medical record did not
show that it had been continued; neither had vaginal bleeding during HCT. Menstrual suppression with a GnRH agonist had been recommended during a gynecology consultation for 1 patient but was delayed until the week before conditioning and at that point the decision was made to defer use of a GnRH agonist because of proximity to conditioning; the patient had vaginal bleeding during HCT that did not require intervention. One patient experienced menarche within 1 week of conditioning and experienced heavy vaginal bleeding during her transplant procedure and required platelet transfusions. Another patient was evaluated by gynecology 1 week before conditioning and it was decided not to suppress her menses with a GnRH agonist because the certainty of a withdrawal bleed was believed to outweigh the risk of her possibly having her normal menses; she had vaginal bleeding during her transplant procedure and was treated with CHC pills. One patient did not receive menstrual suppression without explanation in the medical record and had vaginal bleeding that required no intervention. Of the 4 patients who had treatment-related amenorrhea before HCT, 1 had vaginal bleeding 1 week before conditioning that did not require treatment and another had vaginal bleeding during her transplant course and was treated with a CHC patch; neither required additional platelet transfusions. Of the 5 patients who lacked documentation of menstrual history in the medical record before HCT, none had documented vaginal bleeding during HCT. Discussion
Menorrhagia is a potentially serious complication during HCT.3 Causes include prolonged thrombocytopenia that results from marrow ablation, poor response to platelet transfusions, and development of coagulopathies due to sepsis or liver dysfunction. Previous studies have shown that administration of GnRH agonists might affect the incidence of vaginal bleeding and associated complications,4,5 and might be more effective at prevention of significant bleeding than supportive care or the use of depomedroxyprogesterone acetate.7 CHC pills provide another approach to menstrual suppression in HCT. There are, however, associated toxicities including transaminitis and increased risk of thrombotic events. In addition, it is often difficult to consistently administer oral medications
268
P.D. Poorvu et al. / J Pediatr Adolesc Gynecol 29 (2016) 265e268
because of nausea, vomiting, and mucositis. A survey of practices published in 2012 reported that GnRH agonists were used more often than CHC pills for menstrual suppression.8 Another survey of HCT physicians found that more than a third of respondents used leuprolide to suppress menses; among the subgroup of pediatric providers it was the favored option in more than 50%.9 Results of our study further support the efficacy and safety of GnRH agonists in the HCT setting and our study, to our knowledge, is the first to document the actual rates of GnRH agonist use among postmenarchal women who undergo HCT in a pediatric center. In our cohort of consecutive pubertal women who underwent HCT, 46 patients had either regular menses or irregular vaginal bleeding and were thus at risk for bleeding during the period of thrombocytopenia. The most common choice for prophylactic menstrual suppression, used in 33 patients, was the use of a GnRH agonist before HCT. Seven received other hormonal therapies and 6 lacked documentation regarding suppression. Our data suggest that the approach chosen to induce menstrual suppression affects the incidence of bleeding during HCT. Among the 33 patients who received a GnRH agonist, most (88%) achieved amenorrhea during the HCT course. Only 4 patients experienced vaginal bleeding; no episodes were life-threatening and only 2 required platelet transfusions to control bleeding. GnRH agonist therapy was not associated with any serious adverse events and appeared safe when used in this setting. Two of the 4 patients treated with CHC pills, the next most commonly used form of suppression, experienced vaginal bleeding and 4 of 6 postmenarchal patients who did not receive any prophylactic suppression experienced vaginal bleeding during HCT. In addition, 2 of 4 pubertal patients thought to not be at risk because of prolonged pre-HCT amenorrhea from previous chemotherapy actually experienced vaginal bleeding. This suggests that these patients remain at risk for menorrhagia during prolonged periods of thrombocytopenia despite previous periods of amenorrhea and suppression should thus be considered. Despite the efficacy and low toxicity associated with GnRH agonists relative to other forms of menstrual suppression, more than 20% of patients at risk for menorrhagia did not receive this therapy. Potential reasons include the multiple barriers that prevented successful identification and treatment of those who would benefit from menstrual suppression with a GnRH agonist. HCT most often occurs at tertiary care centers and patients might receive care at a local institution before HCT, which causes uncertainty as to which provider is responsible for initiating menstrual suppression. Because of the frequency and risk of withdrawal bleeding, GnRH agonists are most effective when administered at least 2 weeks before the expected menstrual period.2 For patients who arrive at the HCT center within 2 weeks of expected menstruation, the effectiveness of treatment is uncertain and the fear of prolonged withdrawal bleeding during HCT makes providers hesitant to administer this therapy in close proximity to the start of the transplant conditioning. Intramuscular injection of a GnRH
agonist might be contraindicated in patients with coexisting thrombocytopenia. Providers might also be uncomfortable in administration of GnRH agonists if they are not familiar with their efficacy and safety in the adolescent population. The risk-benefit ratio for patients with therapyassociated amenorrhea or infrequent vaginal bleeding might not be clear; however, our experience showed that some of these patients can experience thrombocytopeniaassociated menorrhagia during HCT. Before transplantation, a detailed menstrual history should be obtained because it is essential to ensure that atrisk patients can be identified and a thoughtful decision regarding suppression therapy can occur. In addition the need for hormonal replacement therapy after HCT can be evaluated to best prevent long-term medical issues including coronary artery disease10 and osteoporosis.11 The menstrual history must be included in the routine review of systems and its absence creates a significant barrier to ideal management of these issues. Lack of established practice guidelines and variability between providers also contribute to inconsistent use of menstrual suppression. Institutions should consider implementation of guidelines to identify all at-risk women including those with a history of treatment-related amenorrhea. This would allow treatment algorithms to be created that address the use of GnRH agonists and identification of situations in which alternative therapies might be warranted. Routine collaboration with pediatric gynecologists as part of pretransplant care would improve care and allow standardization of the approach to menstrual suppression, in addition to fertility preservation and treatment of premature loss of ovarian function in this vulnerable population.
References 1. Amsterdam A, Jakubowki A, Castro-Malaspina H, et al: Treatment of menorrhagia in women undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2004; 34:363 2. 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 3. Quaas AM, Ginsburg ES: Prevention and treatment of uterine bleeding in hematologic malignancy. Eur J Obstet Gynecol Reprod Biol 2007; 134:3 4. 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 5. 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 6. Harris PA, Taylor R, Thielke R, et al: Research electronic data capture (REDCap) a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42:377 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. Adegite EA, Goyal RK, Murray PJ, et al: The management of menstrual suppression and uterine bleeding: a survey of current practices in the Pediatric Blood and Marrow Transplant Consortium. Pediatr Blood Cancer 2012; 59:553 9. Lee SJ, Astigarraga CC, Eapen M, et al: Variation in supportive practices in hematopoietic cell transplantation. Biol Blood Marrow Transplant 2008; 14: 1231 10. Colditz GA, Willett WC, Stampfer MJ, et al: Menopause and the risk of coronary heart disease in women. N Engl J Med 1987; 316:1105 11. Davies MC, Hall ML, Jacobs HS: Bone mineral loss in young women with amenorrhea. BMJ 1990; 301:790
