Sexual and reproductive dysfunction is a frequent complication of hematopoietic stem cell transplantation (HSCT), occurring in 50% of men and 80% of women.

Although it can have a strong negative impact on quality of life, it is unfortunately often overlooked by clinicians.

HSCT conditioning regimens cause severe pancytopenia, which can lead to profound uterine bleeding in women of reproductive age. Hormonal agents for menstrual suppression can be an important tool in the prevention of menorrhagia and severe hemorrhage, limiting the need for transfusions and preventing physical and emotional distress. In addition, they can address the need for contraception during transplant and possibly preserve fertility.

The choice of agent depends on the time to transplant, patient preference and medical history, and the drug’s overall safety and side effects. The pretransplant evaluation, which is frequently conducted by the transplant physician and an advanced practice provider, should include a focused menstrual and gynecologic history that assesses the date of menarche, the length and intensity of menstrual cycle, current hormone and contraceptive use, and contraindications to hormonal therapy. In consultation with a gynecologist, this history can be used to suppress menstruation in a way that is tailored to the patient’s needs and transplant plan. Although most myeloablative conditioning (MAC) regimens lead to infertility, contraception is required during transplant and for 2 years afterward, given the potentially teratogenic medications used and the risk of relapse. Thus, a menstrual suppression/contraception plan is preferred.

Gonadotropin-Releasing Hormone Agonist Injections

Options for menstrual suppression include continuous use of estrogen and progestin or progestin alone and single-dose intramuscular injections of gonadotropin releasing hormone (GnRH) agonist. Although not contraceptives, GnRH agonists achieve high rates of therapeutic amenorrhea in transplant recipients with minimal side effects and thus are the suppressive agent of choice among transplant physicians.

 In addition, GnRH agonists can preserve ovarian function and fertility in patients receiving chemotherapy; however, more data is needed about patients with hematologic malignancies.

There is some risk of withdrawal bleeding after initiation of GnRH agonists owing to a burst of gonadotropins and estrogen followed by downregulation of the hypothalamic-pituitary-ovarian axis. Thus, patients should ideally receive GnRH agonists at least 2 weeks before the start of transplant chemotherapy conditioning.

If switching to GnRH agonists from the pill, patch, or ring, the risk of withdrawal bleeding may be lessened by continuing the short-acting method for a week or more after injection. Given that amenorrhea is needed through engraftment (which typically occurs within 90 days), the recommended dose of GnRH agonist is 11.25 mg intramuscular once every 3 months.

 Side effects of GnRH agonists include hot flashes, vaginal dryness, headaches, mood changes, and other menopausal symptoms. Therapy should be limited to 6 months in the HSCT population because of the long-term risks associated with hypoestrogenism, such as the bone loss and lipid abnormalities that result from GnRH agonist and myeloablative conditioning chemotherapy. It is recommended that patients receive add-back hormonal therapy in the long-term transplant setting to mitigate these risks and improve potentially distressing menopausal symptoms.

Women already using long-acting reversible contraceptives (LARCs), like progestin-only implants, injections, and intrauterine devices (IUDs), may continue to use them during transplant, as they often suppress menses as well as prevent pregnancy. LARCs should not be initiated before transplant because they frequently cause irregular bleeding patterns and because IUDs can pose an infection risk if inserted too soon before expected pancytopenia. It is generally recommended that copper IUDs be removed before transplant given that they offer no menstrual suppression and can cause infection.

Short-acting hormonal methods, like the pill, and the patch may be considered, but are often not preferred. Although depot medroxyprogesterone acetate (DMPA) is both cost-effective and long-acting, it poses an increased risk of breakthrough bleeding. In a study evaluating suppressive agents in 101 women receiving myelosuppressive chemotherapy, 0% of GnRH agonist users experienced moderate to severe bleeding compared with 21.4% of DMPA users and 40% of untreated patients.9 Combined hormonal therapies carry an increased thrombotic risk and should be avoided in women with a history of coronary artery disease, thromboembolism, and liver disease and in those receiving MAC. Progestin-only oral contraceptives can induce amenorrhea and may be preferred when estrogen is contraindicated. However, various transplant-associated complications—nausea, vomiting, mucositis, gastrointestinal infections, and graft-versus-host disease—may limit their uninterrupted use. Because of concerns over skin reactions and infections, vaginal rings and transdermal patches should be avoided.

A common complication of HSCT in premenopausal women, menorrhagia is associated with morbidity and physical and psychological distress. Discussing menstrual suppression early in the pretransplant period and creating a plan, with the help of a gynecologist, can improve not only outcomes, but also patient satisfaction and quality of life. Advanced practice providers are well suited to initiating these conversations, thus ensuring this important issue ceases to be an afterthought.

Wong FL, Francisco L, Togawa K, et al. Longitudinal trajectory of sexual functioning after hematopoietic cell transplantation: impact of chronic graft-versus-host disease and total body irradiation. Blood. 2013; 122(24):3973-3981. doi:10.1182/blood-2013-05-499806

Syrjala KL, Kurland BF, Abrams JR, Sanders JE, Heiman JR. Sexual function changes during the 5 years after high-dose treatment and hematopoietic cell transplantation for malignancy, with case-matched controls at 5 years. Blood. 2008; 111(3):989-996. doi:10.1182/blood-2007-06-096594

Chang K, Merideth MA, Stratton P. Hormone use for therapeutic amenorrhea and contraception during hematopoietic cell transplantation. Obstet Gynecol. 2015;126(4):779-784. doi:10.1097/AOG.0000000000001031

Ghalie R, Porter C, Radwanska E, Fitzsimmons W, Richman C, Kaizer H. Prevention of hypermenorrhea with leuprolide in premenopausal women undergoing bone marrow transplantation. Am. J Hematol. 1993;42(4):350-353. doi:10.1002/ajh.2830420404

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(9):537-541.

. 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(8):821-823. doi:10.1038/sj.bmt.1701187

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(5):1033-1041. doi:10.3109/10428190109097723

Meirow D, Rabinovici J, Katz D, Or R, Ben-Yehuda D. Prevention of severe menorrhagia in oncology patients with treatment-induced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxyprogesterone acetate. Cancer. 2006;107(7):1634-1641. doi:10.1002/cncr.22199

Arecco L, Ruelle T, Martelli V, et al. How to protect ovarian function before and during chemotherapy? J Clin Med. 2021;10(18):4192. doi:10.3390/jcm10184192

Blumenfeld Z, Patel B, Leiba R, Zuckerman T. Gonadotropin-releasing hormone agonist may minimize premature ovarian failure in young women undergoing autologous stem cell transplantation. Fertil Steril. 2012;98(5):1266-70.e1. doi:10.1016/j.fertnstert.2012.07.1144

Articles

Menstrual suppression can improve outcomes and quality of life in premenopausal women undergoing hematopoietic stem cell transplant. 

Annie Austin, MSN, AGACNP, AOCNP

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Menstrual Suppression Is a Valuable Component of HSCT Care for Premenopausal Women