{"paper_id":"7ae10b3b-3f41-4100-906b-1003e5eb1379","body_text":"Huang et al. J Med Case Reports          (2021) 15:327  \nhttps://doi.org/10.1186/s13256-021-02938-8\nCASE REPORT\nSevere hemoperitoneum resulting \nfrom restart of letrozole after oocyte retrieval \nprocedure: a case report\nHaipeng Huang*, Yasushi Takai, Kouki Samejima, Yosuke Gomi, Tatsuya Narita, Shunichiro Ichinose, Yukiko Itaya, \nYosihisa Ono, Sigetaka Matsunaga, Masahiro Saitoh and Hiroyuki Seki \nAbstract \nBackground: In the field of oncofertility, patients with breast cancer are often administered letrozole as an adjuvant \ndrug before and after oocyte retrieval to prevent an increase in circulating estradiol.\nCase presentation: We report a case of abdominal hemorrhage due to an ovarian rupture in a 29-year-old Japanese \npatient who restarted letrozole 2 days after an oocyte retrieval procedure in which 14 mature oocytes were retrieved. \nThe patient had sought embryo cryopreservation as a fertility preservation option before undergoing treatment \nfor recurrent breast cancer. A day after restarting letrozole treatment, the patient unexpectedly developed severe \nabdominal pain. Laparoscopic hemostasis was performed to manage the ovarian swelling and hemorrhage.\nConclusions: The ovaries can be restimulated by restart letrozole after an oocyte retrieval procedure. Therefore, \nreproductive-medicine practitioners should understand the potential complications of letrozole administration in \nsuch cases and take steps to ensure that they are minimized.\nKeywords: Breast cancer, Fertility preservation, Hemoperitoneum, Laparoscopic surgery, Letrozole, Ovarian \nhemorrhage\n© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco \nmmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\nIncidence of breast cancer in adolescent and young adult \nwomen is on the rise both in Japan and worldwide [1, 2]. \nIt is also the most common disease for which patients \nseek assisted reproductive technology procedures for \nfertility preservation. In the case of hormone-dependent \ntumors, the use of the aromatase inhibitor, letrozole, as \nan adjuvant is recommended to prevent an increase in the \ncirculating concentration of estradiol (E2) [3]. Moreover, \nRodgers et  al. concluded that letrozole does not dimin -\nish total oocyte yield [4]. Current recommendations for \nfertility preservation in women with E2-responsive breast \ncancer advise a second course of letrozole after oocyte \nretrieval to keep serum E2 levels low [5]. This regimen is \nknown to significantly reduce the circulating concentra -\ntion of E2 after oocyte retrieval [6]. However, letrozole \nhas also been reported to have ovary-stimulating effects, \neven if administered in the luteal phase of the menstrual \ncycle [7]. Here, we report a case of abdominal hemor -\nrhage due to ovarian rupture in a patient who restarted \nletrozole after an oocyte retrieval procedure.\nCase presentation\nThe patient was a 29-year-old nulligravid Japanese \nwoman with no history of infertility, who was seeking fer-\ntility preservation in advance of chemotherapy for breast \ncancer that developed shortly after her marriage. Her \nbody mass index (BMI) was 19.4 (height 157 cm, weight \n48  kg). Although she had a history of asthma, she had \nOpen Access\n*Correspondence:  haipeng3@saitama-med.ac.jp\nDepartment of Obstetrics and Gynecology, Saitama Medical Center, \nSaitama Medical University, 1981 Kamoda, Kawagoe City, Saitama \n350-3550, Japan\n\nPage 2 of 5Huang et al. J Med Case Reports          (2021) 15:327 \nbeen incident-free for more than 2  years. She had been \ndiagnosed with breast cancer 3 years previously and was \ntreated by partial resection of the left mammary gland. \nThe excised mass had a positive margin and was identi -\nfied as ductal carcinoma in situ based on histopathologi -\ncal findings: Estrogen receptor (ER) (+), Progesterone \nreceptor (PR) (+), HER2 (1+), and Ki67 (10%). These \nfindings prompted the doctors to perform a left total \nmastectomy, which yielded an excised mass with a nega -\ntive margin. The patient tested negative for lymph-node \nmetastasis. She declined postoperative chemotherapy \nand radiation therapy because of a strong desire to bear \nchildren. Follow-up tests every 3  months revealed no \nevidence of disease until 31 months after the total mas -\ntectomy, when subcutaneous recurrence was discov -\nered in the left chest. The mass was surgically removed, \nand identified as an invasive ductal carcinoma based on \nhistopathological findings: Nottingham Grade (NG) 1, \nER (8) PR (8) HER2 (2+) fluorescence in situ hybridiza -\ntion (FISH) (2.54) Ki67 (10–20%). The patient was then \nscheduled for 6  months of chemotherapy consisting of \ncyclophosphamide and HER2-targeted therapy and tras -\ntuzumab starting roughly 2  months after tumor exci -\nsion. Chemotherapy was followed by hormone therapy \nfor a minimum of 3  years. The patient was referred to \nSaitama Medical Center after expressing the desire, dur -\ning counseling, to preserve her fertility prior to starting \nchemotherapy.\nThe patient’s family history of multiple breast cancer \nreported for both her mother and grandmother led us to \nsuspect hereditary breast and ovarian cancer syndrome, \nand therefore, she was referred to a genetic counselor \nbefore beginning any fertility treatment. Blastocyst cry -\nopreservation was selected as the treatment option for \nfertility preservation after the ovaries were verified to be \ncancer-free.\nHer blood tests showed normal levels of infertility-\nrelated biomarkers [anti-Müllerian hormone (AMH): \n2.90  ng/mL, Base E2: 42.7  pg/mL, follicle-stimulating \nhormone (FSH): 5.8  mU/mL, luteinizing hormone \n(LH): 4.1 mU/mL] and no signs of coagulation abnormal-\nities. Her menstrual cycle was 30  days. Her ultrasound \ndid not reveal any characteristics of polycystic ovary syn -\ndrome. Her Pap test result was negative for intraepithelial \nlesions or malignancy (NILM) according to the Bethesda \nclassification. The results of her husband’s semen analy -\nsis were normal (semen volume: 3.8  mL, sperm count: \n43 million, motility: 69%).\nThe woman commenced oral letrozole (5.0 mg/day) on \nday 5 of her cycle, and started self-injecting recombinant \nFSH (225 IU/day) the next day. As expected, her circulat-\ning hormone levels were slightly elevated 6 days after FSH \nadministration, [E2: 469  pg/mL, LH: 3.1  mIU/m, FSH: \n19.3  mU/mL, progesterone (P4): 0.54  ng/mL], and the \ndominant follicle had a diameter of 16 mm. Daily admin -\nistration of ganirelix (0.25  mg/day) was started on the \nsame day. After 11 days of FSH administration, the domi-\nnant follicle had increased in size to 22  mm, and hor -\nmone levels were further elevated (E2: 1550 pg/mL, LH: \n1.6 mIU/m, FSH: 16.4 mU/mL, P4: 2.23 ng/mL). At this \npoint, we decided to proceed with the oocyte retrieval, \nexpecting to harvest 16 eggs of suitable size (> 14 mm). \nFinal oocyte maturation was triggered by administering \ntwo 300  μg doses of a gonadotropin releasing hormone \n(GnRH) agonist 1  hour apart (buserelin nasal spray \n0.2 mg, Nasanyl; Pfizer, Tokyo, Japan). After 36 hours, 15 \noocytes were retrieved, including 14 mature metaphase II \n(MII) eggs and one immature germinal vesicle (GV). The \nMII oocytes were fertilized before cryopreservation [split \ninsemination: seven in vitro fertilization (IVF), seven \nintracytoplasmic sperm injection (ICSI)], preserving only \nthe good-quality embryos; the lone GV oocyte was cryo -\npreserved unfertilized.\nTo prevent any delays in her cancer treatment due to \novarian hyperstimulation syndrome (OHSS), the patient \nstarted taking oral cabergoline (0.5  mg) after oocyte \nretrieval. Only mild ovarian swelling (right: 57  × 50 mm, \nleft: 58  ×  46  mm) and mild ascites were observed on a \nfollow-up visit 2 days later, after 52 hours of the oocyte \nretrieval procedure (Figs.  1, 2). She did not complain of \ntenderness during the pelvic examination. As the patient \nexperienced only minor abdominal pain after oocyte \nretrieval, analgesic use was considered unnecessary. On \nthe same day, she was restarted on letrozole (5.0 mg/day) \nto prevent the increase of circulating E2, since her tumor \nwas E2 receptor-positive. The next day, 76 hours after the \noocyte retrieval procedure, she unexpectedly developed \nsevere abdominal pain and was urgently admitted to our \nhospital.\nFig. 1 Ultrasonography showing mild ascites 2 days after oocyte \nretrieval\n\nPage 3 of 5\nHuang et al. J Med Case Reports          (2021) 15:327 \n \nOn admission, the patient complained of abdomi -\nnal distension and lower abdominal and lower back \npain. Her blood biochemistry profile was as follows: \nwhite blood cell (WBC): 8200/μL, hemoglobin (Hb): \n14.2  g/dL, hematocrit (Hct): 40.1%, C-reactive protein \n(CRP): 0.02  mg/dL, total protein (TP): 7.2  g/dL, albu -\nmin (Alb): 4.5 g/dL, Creatinine (Cre): 0.53 mg/dL, Uric \nAcid (UA): 4.8 mg/dL,  activated partial thromboplas -\ntin time (APTT): 31.7 seconds, prothrombin time (PT): \n12.0  seconds, PT%: 107, D-dimer: 0.78  μg/mL. Ultra -\nsonography revealed bilateral exacerbation of ovarian \nswelling (right: 105  × 49 mm, left: 70  × 60 mm;) and \nincreased (moderate) ascitic volume (Fig.  3). Ovarian \ntorsion was suspected based on tenderness and swell -\ning noted in the left ovary.\nAn emergency laparoscopic surgery was performed \nto confirm the diagnosis. The left ovary was enlarged \nand had ruptured at what was apparently an aspiration \nsite from oocyte retrieval. Hemoperitoneum, caused by \ncontinued abnormal bleeding from the same site, was \nalso observed (Fig.  4). Laparoscopic hemostasis was \nperformed. A day later, her blood biochemistry profile \nshowed normal findings with a slight reduction in hemo -\nglobin (WBC: 9400/μL, Hb: 12.7  g/dL, Hct: 36.4%, TP: \nFig. 2 Ovarian ultrasonography showing mild ovarian swelling 2 days after oocyte retrieval\nFig. 3 Ovarian ultrasonography 3 days after oocyte retrieval (1 day after restarted letrozole). The ultrasonograph shows bilateral exacerbation of \novarian swelling and increased ascitic volume\n\nPage 4 of 5Huang et al. J Med Case Reports          (2021) 15:327 \n6.3 g/dL, Alb: 3.9 g/dL, Cre: 0.48 mg/dL, APTT: 30.7 sec -\nonds, PT: 12.9  seconds, PT%: 93). The patient’s general \ncondition after the intervention was good. She was dis -\ncharged from the hospital 4 days later (that is, 7 days after \noocyte retrieval) after bilateral shrinkage of the ovar -\nian swelling was confirmed by ultrasonography (right: \n46 × 44 mm, left: 42 × 42 mm; Fig. 5), and no worsening \nof OHSS symptoms in the past week of daily oral caber -\ngoline (0.5 mg) was noted.\nDiscussion and conclusions\nThe incidence of severe hemoperitoneum was 0.08% in \n2007, decreasing 0.29-fold by 2015 in Japan [8]. Severe \nhemoperitoneum symptoms usually appear within \n24 hours after oocyte retrieval procedures [9].\nLetrozole is an oral medication frequently used in the \nfield of oncofertility, and few reports of complications \nor side effects have been published. Despite showing no \nsigns of abnormality during a follow-up examination \n2  days, that is, 52  hours, after the oocyte retrieval pro -\ncedure, our patient unexpectedly experienced ovarian \nswelling after 76 hours of the oocyte retrieval procedure \nwithin 24 hours of restarting letrozole, which apparently \ncaused ovarian rupture and persistent ovarian hemor -\nrhage. Given the clinical findings and time line, the ovu -\nlation-stimulating effects of letrozole clearly contributed \nto the swelling observed [7]. However, as ovarian swell -\ning is also a hallmark symptom of OHSS, this syndrome \nmay also have played a role. We believe this case serves as \na timely warning that should encourage practitioners to \nexercise caution when considering letrozole administra -\ntion after oocyte retrieval.\nAdjuvant letrozole is effective in preventing OHSS [10, \n11]. In one randomized clinical trial [12] either aspirin \nFig. 4 Intraoperative findings. Left: ruptured ovary; right: blood pooling in the pelvic cavity\nFig. 5 Ovarian ultrasonography before discharge, showing bilateral shrinkage of the ovarian swelling to ~ 4.5 cm size\n\nPage 5 of 5\nHuang et al. J Med Case Reports          (2021) 15:327 \n \nor letrozole was taken orally for 5 consecutive days after \novulation was induced using an hCG trigger, and letro -\nzole resulted in a lower incidence of OHSS compared \nwith aspirin. However, 25% of the letrozole group experi -\nenced moderate or higher OHSS, and, just as concerning, \npatients treated with letrozole had higher serum vascular \nendothelial growth factor (VEGF) levels than those not \ntreated with it. Similar research has shown increased lev -\nels of VEGF and decreased levels of pigment epithelium-\nderived factor (a potent angiogenesis inhibitor) in the \nfollicular fluid of patients treated with letrozole [13]. Fac-\ntors such as these could have led to the abnormal ovar -\nian bleeding observed in our patient in the days following \noocyte retrieval.\nThe adjuvant use of letrozole after oocyte retrieval sup-\npresses circulating E2 and may reduce the likelihood of \nOHSS. Nonetheless, our experience here suggests that \nletrozole treatment can also lead to ovarian restimula -\ntion, causing ovarian rupture and persistent ovarian \nhemorrhage.\nIn conclusion, the use of letrozole has become essen -\ntial to oocyte retrieval protocols for E2-receptor-positive \nbreast-cancer patients seeking fertility preservation. This \ncase report highlights a potential complication associ -\nated with letrozole treatment in such patients. Therefore, \nwhen considering letrozole administration in anticipation \nof subsequent oncotherapy, reproductive medicine prac -\ntitioners should consider its potential complications and \ntake appropriate steps to ensure that they are minimized.\nAbbreviations\nE2: Estradiol; NILM: Negative for intraepithelial lesions or malignancy; MII: \nMetaphase II; GV: Germinal vesicle; OHSS: Ovarian hyperstimulation syndrome; \nVEGF: Vascular endothelial growth factor.\nAcknowledgements\nWe would like to thank Editage for English language editing.\nAuthors’ contributions\nHH was a major contributor in writing the manuscript. YT was involved in \ndrafting and revising the manuscript. KS, YG, TN, SI, YI, YO, SM, and MS were \ninvolved in revising the manuscript. HS contributed to the study concept and \ndesign. All the authors read and approved the final manuscript.\nFunding\nThis report received no specific grant from any funding agency in the public, \ncommercial, or not-for-profit sectors.\nAvailability of data and materials\nNot applicable.\nDeclarations\nEthics approval and consent to participate\nEthical approval was waived by the ethical committee of Saitama Medical \nUniversity, Saitama Medical Center.\nConsent for publication\nWritten informed consent was obtained from the patient to publish this case \nreport and any accompanying images. A copy of the written consent is avail-\nable for review from the Editor-in-Chief of this journal.\nCompeting interests\nHH, YT, KS, YG, TN, SI, YI, YO, SM, MS, and HS declare that they have no conflicts \nof interest.\nReceived: 26 March 2021   Accepted: 1 June 2021\nReferences\n 1. Johnson RH, Chien FL, Bleyer A. Incidence of breast cancer with distant \ninvolvement among women in the United States, 1976 to 2009. JAMA. \n2013;309:800–5.\n 2. 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Reprod Biol Endocrinol. \n2018;16:54.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}