HASHIMOTO Tomomi

HORIBE Yu

NAKABAYASHI Akira

TABATA Tsutomu

TOMA Chihiro

YANAGISAWA Keiko

Tokyo Women’s Medical University

Is Fertility Treatment Prior to EstablishingGlycemic Control Effective for Type 2 DiabeticPatients? A Case Study Comparing OutcomesBefore and After Glycemic Control IsEstablished著者名 HASHIMOTO Tomomi, NAKABAYASHI Akira,YANAGISAWA Keiko, TOMA Chihiro, HORIBE Yu,TABATA Tsutomujournal orpublication titleTokyo Women's Medical University Journalvolume 6page range 126-129year 2022-12-20URL http://hdl.handle.net/10470/00033371doi: 10.24488/twmuj.2021012―126―Case ReportTWMUJ 6: 126-129, 2022Is Fertility Treatment Prior to Establishing Glycemic Control Effective forType 2 Diabetic Patients? A Case Study Comparing OutcomesBefore and After Glycemic Control Is EstablishedTomomi Hashimoto,１Akira Nakabayashi,１Keiko Yanagisawa,２Chihiro Toma,１Yu Horibe,１ and Tsutomu Tabata１１Department of Obstetrics and Gynecology, Tokyo Women’s Medical University, Tokyo, Japan２Diabetes Center, Tokyo Women’s Medical University, Tokyo, Japan(Accepted November 4, 2021)(Advance Publication by J-STAGE January 15, 2022)Some patients with type 2 diabetes desire egg retrieval for future embryo transfer, and would prefer the procedure to be per-formed prior to exerting glycemic control, which is technically possible. We experienced a case of a 38-year-old woman suf-fering from type 2 diabetes mellitus, hypertension, and severe obesity (body mass index 43) desiring early oocyte retrievaldue to suspected endometrial atypia. Only 3 transferable embryos were obtained through two oocyte retrieval procedures be-fore glycemic control was applied, whilst 5 transferable embryos were obtained in one egg retrieval cycle post inpatient treat-ment for insulin adjustment. The transfer of an embryo post-treatment resulted in delivery of a healthy full term child.Keywords: hyperglycemia, insulin therapy, in vitro fertilization (IVF), type 2 diabetes mellitus, oocyte retrievalIntroductionIt is not uncommon for type 2 diabetic patients to seekfertility treatment in order to have a baby. Hyperglyce-mia during pregnancy increases the likelihood of compli-cations such as gestational hypertension, premature birth,stillbirth, and shoulder dystocia associated with deliveryof an oversized baby, and may also be a factor in con-genital malformations of the baby. Therefore, it is im-perative to improve blood glucose levels before preg-nancy is attempted. However, some patients desire tohave fertility treatment first, due to the length of time itmay take to achieve glycemic control, and the adverseconsequences of aging in the interim. In recent years, thetechnique of embryo cryopreservation has been estab-lished, making it possible to retrieve oocytes before gly-cemic control for future embryo transfer.In this case study with the subject suffering type 2 dia-betes and obesity, and with suspected endometrial atypia,at the patient’s insistence, oocyte retrieval was performedat a time when blood glucose levels were not yet undercontrol. However, pregnancy and delivery were ulti-mately achieved with an oocyte obtained after controlhad been established. For each of the three oocyte re-Corresponding Author : Akira Nakabayashi, Department of Obstetrics and Gynecology, Tokyo Women’s Medical University, 8-1Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. nakabayashi.akira@twmu.ac.jpdoi: 10.24488/twmuj.2021012CopyrightⒸ 2022 Society of Tokyo Women’s Medical University. This is an open access article distributed under the terms of CreativeCommons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided theoriginal source is properly credited.―127―Table　1.　Results of oocyte retrieval prior to and post inpatient treatment for insulin adjustment.Prior to treatment Post treatmentGonadotropin total dose (IU) 3,300 3,600 3,600Number of follicles aspirated 10 8 8Number of oocytes obtained 2 3 6Number of fertilized eggs 2 1 6Number of frozen embryos 1 1 5trieval procedures, we noted and compared the amount ofgonadotropin used, number of oocytes retrieved, the fer-tilization rate, and the number of resulting frozen em-bryos, along with the changes in blood glucose levels andbody weight.Case PresentationA 38-year-old married woman, diagnosed with type 2diabetes mellitus (HbA1c 9.0%) and hypertension at theage of 35, was prescribed oral hypoglycemic and antihy-pertensive medication for the condition. No diabetes-related complications such as retinopathy, nephropathy,or neuropathy were observed. When she visited her pre-vious doctor with complaints of irregular menstruationand desire to have a baby, transvaginal ultrasonographyshowed endometrial thickening, and she was referred toour hospital because atypical endometrial hyperplasiawas suspected after performing total endometrial curet-tage. According to the endometrial cytology performed atour hospital this case was categorized atypical en-dometrial cells of undetermined significance, and the en-dometrial histology showed no signs of malignancy. Thehistological specimen from the previous doctor was re-examined and our diagnosis was suspected endometrialhyperplasia without atypia. The results of blood tests per-formed on the 19 th day of the menstrual cycle, thisshowed luteinizing hormone(LH) 6.9 mIU/mL, folliclestimulating hormone 7.1 mIU/mL, estradiol 41.4 pg/mL,and progesterone <0.2 ng/mL, indicating irregular men-struation associated with an ovulation disorder. As forher diabetes, her HbA1c, which had been around 7%, hadrisen to the 8% range after being prescribed metforminhydrochloride and selective dipeptidyl peptidase-4 in-hibitors. The patient was referred to the Diabetes Centerat our hospital because her HbA1c was not under controldespite the change to multiple daily injection. A physicalexamination was performed at the patient’s first visit tothe Diabetes Center, and the following metrics were re-corded; height of 167 cm, weight of 120 kg, body massindex(BMI) of 43.0, and an HbA1c of 8.9%.The patient, who had been diagnosed with suspectedendometrial hyperplasia without atypia in our hospital,wanted to achieve an early pregnancy, and strongly de-sired oocyte retrieval as soon as possible, and prior toglycemic control being established. The patient’s anti-mullerian hormone reading was 2.16 ng/mL. For the firstoocyte retrieval performed before her admission for dia-betes management, ovarian stimulation with clomiphencitrate and human menopausal gonadotropin(hMG) wasperformed and a total of 3,300 IU of hMG was adminis-tered. Ten follicles were aspirated, two oocytes obtained,and one viable embryos was achieved and subsequentlyfrozen (Table 1). Since the patient requested more oo-cyte retrievals, a second oocyte retrieval procedure wasperformed after confirming that there were no residualfollicles during menstruation. Her blood glucose leveland body weight were similar to that when the first oo-cyte retrieval was conducted. This time, the antagonistmethod of ovarian stimulation was used, and a total of3,600 IU of hMG was administered. On this occasion,eight follicles were aspirated, three oocytes acquired, andone viable embryo frozen (Table 1).The patient was then admitted to the Diabetes Center,where she was placed on a 1,200 kcal/day diet, and herinsulin dose adjusted. Her fasting blood glucose level,which had been over 140 mg/dL, decreased to less than100 mg/dL, and her 2-hour postprandial level, which hadbeen around 200 mg/dL, decreased to less than 140 mg/dL. During the 11 days of hospitalization, HbA1c de-creased to 7.0% by the following month (Figure 1A) .However, weight loss was deemed unsatisfactory, reduc-ing from 120 to 117 kg. That is, BMI only decreasedfrom 43.0 to 42.0 (Figure 1B). Nevertheless a third oo-cyte retrieval procedure was performed after discharge.This time flare protocol was used for ovarian stimulation,and a total of 3,600 IU of hMG was administered. Eightfollicles were aspirated, six oocytes acquired, and five vi-able embryos frozen (Table 1). After the patient’s weightwas reduced to 107 kg, a frozen embryo (10 cells, +fewfragments ) obtained from the second oocyte retrieval―128―Figure　1.　(A) HbA1c Trends.(B) BMI Trends.The month of the first visit to the Diabetes Center at our hospital was set as month 0.OR, oocyte retrieval; fET, frozen-thawed embryo transfer.A Bprocedure was thawed and transferred during the hor-mone replacement therapy cycle, but did not result inpregnancy. The pregnancy was subsequently achieved bytransferring an embryo (early blastocyst) obtained fromthe third oocyte retrieval procedure. Blood glucose wasstabilized through hospitalization for 10 days at 16 weeksof gestation, and self-monitoring of blood glucose levelafter discharge from hospital. To control blood pressure,one more antihypertensive drug was added at 24 weeksof gestation, but because this got elevated, the patientwas again hospitalized at 35 weeks of gestation. Laborwas induced at 38 weeks and 2 days of gestation, and a3,144 g baby boy with an Apgar score of 8/9 was born bycesarean section after normal delivery was unsuccessful.The patient gained 18 kg during pregnancy, however, nomaternal complications and no congenital abnormalitiesresulted.DiscussionIn this case, it was difficult for the patient to achieve gly-cemic control through her efforts alone, so she was ad-mitted to hospital, where she was placed on a strict dietof 20 kcal /kg of her ideal weight. This triggered herweight loss and she eventually lost 13 kg at the time ofembryo transfer. Weight loss alone was not sufficient tolower her blood glucose level, and hence insulin dosagewas adjusted to achieve a satisfactory level after 11 daysof hospitalization. Comparing the two oocyte retrievalprocedures performed before hospitalization and the oneafter, there was no change in the total gonadotropin dos-age in each case, which was because the weight loss wasonly 3 kg (about 3%), and hence there was relatively lit-tle change in body size. As for the fertilization rate, al-though it was low in the second oocyte retrieval proce-dure, overall it was satisfactory, and it was judged not tohave changed significantly from before and after hospi-talization. However, the number of viable embryos ap-peared higher after hospitalization. From studies on mice,there are reports that maternal diabetes affects oocytematuration, development, and granulosa cell apoptosis,１and that hyperglycemia decreases LH-luteinizing hor-mone / choriogonadotropin receptor expression,２suggest-ing that improving blood glucose levels may have posi-tively impacted oocyte retrieval and fertilization in thiscase. In humans, elevated fasting blood glucose has beenreported to be associated with prolonged time to preg-nancy.３However, there have been no reports on the ef-fects of hyperglycemia and hyperinsulinemia on oocyteretrieval.With regard to obesity and pregnancy rate, it has beenreported that spontaneous pregnancy decreases linearly ininfertile women with ovulation when BMI exceeds 29.４In addition, a meta-analysis reported that women with aBMI of 30 or more had a lower production rate after invitro fertilization (IVF, RR 0.85) compared to women ofnormal weight.５However, a randomized study of obeseinfertile patients with a BMI of between 30 and 35 who―129―underwent intensive weight loss by caloric restriction be-fore IVF, reported an average weight loss of 9.44 kg butno improvement in reproduction rate.６Furthermore, bari-atric surgery prior to IVF has already been performed,but it was also reported that there was no significant ef-fect on reproductive rates.７However, Pregnancies com-plicated by obesity have increased incidence of issuessuch as gestational hypertension and thrombosis, as wellas perinatal problems such as increased necessity of ce-sarean section, and increased instance of blood loss dur-ing delivery. In addition, weight loss reduces insulin re-sistance, therefore weight management is just as criticalas glycemic control.Although it cannot be determined with any certaintyfrom a single case, it may indicate that in diabetic pa-tients, high blood glucose may affect oocyte retrieval re-sults. Hence, it may be desirable to perform oocyte re-trieval after blood glucose is under control, in order to in-crease the likelihood of achieving pregnancy. In this par-ticular case, the success of IVF may have been related toimprovement in blood glucose levels through educationon diabetes, including strict dietary treatment throughhospitalization, and appropriate insulin administration.ConclusionIn order to avoid an age-related decline in fertility, it istechnically possible to perform oocyte retrieval early andcryopreserve the fertilized eggs. However, in diabetic pa-tients, high blood glucose may affect the oocyte retrievalresults, so it is desirable to perform oocyte retrieval aftercontrolling blood glucose, in order to increase the likeli-hood of achieving pregnancy. In this case, the success ofIVF may have been related to improvement in blood glu-cose levels through education on diabetes, includingstrict dietary treatment through hospitalization, and ap-propriate insulin administration.Sources of Funding: Not Applicicable.Conflicts of Interest: The authors declare that they haveno conflict of interest regarding the publication of this casereport.Author Contributions : Tomomi Hashimoto and AkiraNakabayashi: involved in preparing and writing the manu-script. Keiko Yanagisawa, Chihiro Toma, Yu Horibe, andTsutomu Tabata: critically reviewed and approved the finalmanuscript version for submission.All authors: participated in the procedure and the manage-ment of the patient.Acknowledgments: We thank the patient for consenting tothe publication.Ethical Approval: Not Applicicable.References1．Chang AS, Dale AN, Moley KH. Maternal diabetes ad-versely affects preovulatory oocyte maturation, develop-ment, and granulosa cell apoptosis. Endocrinology.2005;146(5):2445―53.2．Lee J, Lee HC, Kim SY, et al. Poorly-controlled type 1diabetes mellitus impairs LH-LHCGR signaling in theovaries and decreases female fertility in mice. YonseiMed J. 2019;60(7):667―78.3．Zhao J, Hong X, Zhang H, et al. Pre-pregnancy maternalfasting plasma glucose levels in relation to time to preg-nancy among the couples attempting first pregnancy.Hum Reprod. 2019;34(7):1325―33.4．van der Steeg JW, Steures P, Eikemans MJ, et al. Obe-sity affects spontaneous pregnancy chances in subfertile,ovulatory women. Hum Reprod. 2008;23(2):324―8.5．Sermondade N, Huberlant S, Bourhis-Lefebvre V, et al.Female obesity is negatively associated with live birthrate following IVF : a systematic review and meta-analysis. Hum Reprod Update. 2019;25(4):439―51.6．Einarsson S, Bergh C, Friberg B, et al. Weight reductionintervention for obese infertile women prior to IVF: arandomized controlled trial. Hum Reprod. 2017;32(8):1621―30.7．Grzegorczyk-Martin V, Fréour T, De Bantel FA, et al.IVF outcomes in patients with a history of bariatric sur-gery: a multicenter retrospective cohort study. Hum Re-prod. 2020;35(12):2755―62.

Is Fertility Treatment Prior to Establishing Glycemic Control Effective for Type 2 Diabetic Patients? A Case Study Comparing Outcomes Before and After Glycemic Control Is Established

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Is Fertility Treatment Prior to Establishing Glycemic Control Effective for Type 2 Diabetic Patients? A Case Study Comparing Outcomes Before and After Glycemic Control Is Established

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