Review of Intrauterine Insemination in Polycystic Ovarian Syndromes - Cases Review and Current Approach

Review of Intrauterine Insemination in Polycystic Ovarian Syndromes - Cases Review and Current Approach | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Review of Intrauterine Insemination in Polycystic Ovarian Syndromes - Cases Review and Current Approach Alfonsus Zeus Suryawan, Artha Falentin Putri Susilo, Fridya Wulandari Djuwantono This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5266206/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Intrauterine insemination (IUI) is procedure which we introduce sperm into the fundal cavity. It’s help a lot of infertile couple to reach clinical pregnancy and currently mainly first choice of unexplained fertility. Usage in other cause of infertility was also consider with individualized approach. However IUI is not without flaw, it’s success rate rely heavily on sperm count and motility. It’s usage in polycystic ovary syndrome (PCOS) still in debates, due to high insulin resistance condition in PCOS hinders implantation and increase risk of fetal loss associated with endometrial dysfunction. This serial case report shows want to review 4 cases of IUI with PCOS on Aster Fertility Clinic from September 2023 – July 2024 and current approach of this condition which relevant to nowadays practice and knowledge. Figures Figure 1 Take home messages Despite it lower success rate then IVF, IUI still deemed main choices for PCOS with IUI if the male counterpart has normal sperm count. Before starting with IUI, TI with Letrozole should be suggested to return the cycle to ovulatory state from anovulatory one. This also improve the outcome later in IUI if the patient still no conceive yet with TI. Introduction The concept of intrauterine examination (IUI) could be traced back to founding of microscope in 1678 by Antoni van Leeuwenhoek, and later on first IUI on animal was performed and succeed by Lazzaro Spallanzani in 1974. 1 Later on John Hunter in 1970 wrote the first report of artificial insemination and in 1962 Cohlen et al publish the first paper entitled IUI. 1 – 3 Fast-forward to nowadays era with improved technique of sperm selection and deeper understanding of ovarian stimulation (OS), IUI combination with OS become therapy of choice in patients with with unexplained infertility. 4 According to Himpunan Endokrinologi Reproduksi dan Fertilitas Indonesia (HIFERI) guideline about infertility in 2019, stated IUI with or without OS is the first line treatment for unexplained infertility. 5 However IUI is not without flaw, it’s success rate rely heavily on sperm count and motility. Extremely low sperm count & motility (below 5 million/ml) should be treat with in-vitro fertilization (IVF). 5 In this occasion we would like to review 4 cases of polycystic ovarian syndrome (PCOS) which undergoes IUI on Aster Fertility Clinic from September 2023 to July 2024 with one successful pregnancy and three cases which pregnancy didn’t occurs. Cases Review Case 1 A 35 years old P0A0 (7 years married) came to Aster Policlinic for pregnancy program and medication for her polycystic ovary syndrome (PCOS). She was given Metformin 3 x 500mg and Inlacin (extract of Lagerstroemia speciosa and Cinnamomum burman ) for 3 months in 2019. Afterward she advised to undergo diagnostic laparoscopy, but she declined. Her menstrual cycle was presumably normal (26–28 days with duration of 7 days). Her body mass index (BMI) is 23,2 kg/m 2 . On TVUS uterus was within normal limit, EL 3 mm, right ovarium had 13 follicles with 3,4 x 9,24 cm in size, and left ovarium had 15 follicles with 3,5 x 2,0 cm in size. She was diagnosed as PCOS and primary infertility then planned for diagnostic laparoscopy and examination of AMH and Luteinizing Hormone (LH). Her AMH at 2.75 ng/mL, and LH at 2,28 mIU/mL. She then undergoes hysteroscope and diagnostic laparoscopy. On hysteroscope found 0,5 x 0,5 x 0,5 cm polyp on fundus. Polypectomy was performed alongside aspiration curettage. Pelvic adhesion was found and laparoscopic tubal patency results both tubes are patent. Patient then diagnosed as endometrial polyp; polycystic ovarian syndrome; pelvic adhesion grade III; and bilateral patent tubal. Laparoscopic ovarian drilling (LOD) was not performed on this patient. Pathology anatomy analysis reveals endometrial polyp accompanied atypical hyperplasia. Patient then starts her IUI programs 5 months after operation. Sperm analysis reveals total motile sperm count 5.89 mill/ml. On her 3rd day of cycle on TVUS found 13 follicles on right ovary and 8 follicles on left ovary. She’s not undergoes any stimulation then planned for control at day 12 of her cycle. On 12th day ovulation was triggered with hCG 5.000 IU with IUI 48 hours after. On 14th day which is 48 days after ovulation tigger IUI was perform with processed sperm at 3,24 mill/ml. Unfortunately, the patient had period on next month. She didn’t control herself afterward. Case 2 A 33 years old P0A0 (2 years married) came to Aster Policlinic for with referral from District Hospital due to her infertility and PCOS. Her body mass index (BMI) is 31,61 kg/m 2 , currently weighing 81 kg. Patient has no prior treatment previously and haven’t consumed any medicine before. Her menstrual cycle was quiet aberrant ranging from 1–3 months range. On TVUS uterus was within normal limit, EL 2 mm, right ovarium had 17 follicles with 4.2 x 8.98 cm in size, and left ovarium had 10 follicles with 3.47 x 2.86 cm in size. Hysterosalpingography shows bilateral patent tube and normal uterus. Her husband sperm analysis was normal. She was diagnosed as PCOS and primary infertility then undergoes lifestyle modification and Metformin prescription at 3 x 500mg for 3 months. After 3 months, there’s significant body weight reduction from 81 kg to 75 kg (BMI 29.29 kg/m 2 ). Patient menstrual cycle also gradually improving with cycle length of 28 days in last month. Patient last menstrual period 2 days before, Patient then planned for ovulation induction with Letrozole 2 times a day and timely intercourse (TI). Patient then controlled herself on tenth day of her cycle and dominant follicle was found on TVUS. However after 2 months after TI, patient failed to conceive and planned for IUI with OS. At time of presentation patient BMI was 25,7 kg/m 2 , weighing 66 kg. Patient then start OS with recombinant FSH using step up regiment. FSH starts at 75 IU until 150 IU at her 13th day of her cycle. On the same day ovulation was triggered with hCG 5.000 IU with IUI 48 hours after. Unfortunately, the patient also had period on next month. She didn’t control herself yet afterward. Case 3 A 36 years old P0A0 (3 years married) came to Aster Policlinic for pregnancy program. She was undergoes curettage 2 months ago due to atypical endometrial hyperplasia. Patient has aberrant cycle ranging from 1–3 months since 1 years ago. Patient presented on 2nd day of her cycle. Her body mass index (BMI) is 32.44 kg/m 2 , currently weighing 73 kg. Clinical hirsutism also presented at patient. On TVUS uterus retroflexed with normal size and density, EL 5.46 mm, bilateral ovarium was normal with each measuring 2.56 x 1.73 cm and 2.6 x 1.62 cm. Patient was diagnosed with chronic anovulation due to PCOS and undergoes dietary changes and was given Cyproterone acetate 2 mg and Ethinylestradiol 35 mcg for 30 days. Patient was also given Metformin 3 x 500mg and Inlacin. After patient had period, she controlled herself on 2nd day of her cycle with results of early infertility investigations. Hysterosalpingography shows bilateral patent tube and normal uterus. Her husband sperm analysis was normal. Patient then start OS with recombinant FSH using step up regiment. FSH starts at 75 IU until 100 IU at her 12th day of her cycle. On 13th day of her cycle ovulation was triggered with hCG 5.000 IU with IUI 48 hours after was perform with processed sperm at 8.37 mill/ml. Unfortunately, the patient also had period on next month. She was planned for next cycle in 3 months with lifestyle modification. Case 4 A 30 years old P0A0 (5 years married) came to Aster Policlinic for pregnancy program. Patient has aberrant cycle ranging from 1–3 months since adolescent. Her body mass index (BMI) was normal at 21.3 kg/m 2 . On TVUS uterus was within normal limit, accompanied with polycystic ovarian morphology (PCOM). She was diagnosed as PCOS and primary infertility then planned for diagnostic laparoscopy and was given Letrozole 2,5 mg and lifestyle modification for 2 months. After 2 months, her cycle was 28 days with currently on 5th day of her cycle. Basic infertility assessment such as hysterosalpingography and sperm analysis showed normal result. Her AMH at 4.07 ng/mL, LH at 2,81 mIU/mL, FSH at 7.1 mIU/mL which are also normal. On TVUS right ovary had 5 follicles ranging from 4.3 mm – 7.8 mm and left one had 9 follicles ranging from 4.5–5.9 mm. Patient then planned for IUI with OS. Patient was given with recombinant FSH using step up regiment. FSH starts at 75 IU until 150 IU at her 15th day of cycle. On her 15th day TVUS reveals 4 follicle ranging from 17–19 mm at her right ovary. The next day ovulation was triggered with hCG 5.000 IU and patient undergoes IUI with processed sperm at 9.98 mill/ml. Patient then controlled herself next month with successful pregnancy at 4 weeks gestation age and later controlled herself at 9 weeks of gestation age. Discussion In this occasion the author would like to review the IUI program according to nowadays practice. Artificial insemination has been used for infertile couples for 100 years since its’s first report in 1970’s. 1 , 2 Before we delve deeper into nowadays methods, IUI is one of artificial insemination methods. Another one is depositing sperms into the cervical ostium, but IUI is now almost universally performed, due to several reasons. First one cervical insemination give no advantage over what can be achieved by intercourse. Second, whereas unprocessed sperm could react to the proteins, prostaglandins, and bacteria in vagina which limits the volume of untreated semen that can be delivered to the upper female genital tract which was our goals. 6 Improvement of IUI improved from better sperm preparation, monitoring for pre-ovulatory timing and induction of ovulation with hCG. 3 Involvement of ovarian stimulation also benefit the IUI hence the ovulation could be control and induce at will. 4 , 7 Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders of reproductive-age women, occurring 7–15% of population. 8 Diagnosis of PCOS with revised Rotterdam criteria with two of the following three criteria and exclusion of other etiology; ovarian volume > 10 mL 3 and/or > 20 follicles between 2 and 9 mm in either ovary; oligoanovulation; and clinical or biochemical signs of hyperandrogenism. 9 Teelde et al at 2023 release revised US criteria with following categories for PCOS; follicle number per ovary (FNPO) ≥ 20 in at least 1 ovary, ovarian volume ≥ 10 mL, or follicle number per section (FNPS) ≥ 10 in at least 1 ovary in adults should be considered the threshold for polycystic ovarian morphology (PCOM). 10 It’s pathogenesis, whereas ovaries stay in steady state which gonadotropin and sex steroid concentrations vary relatively cause nonovulatory cycles. 9 In the first case, which IUI had failed, sperm analysis reveals TMSC count is 5.89 mill/ml which is above threshold for IUI according to HIFERI and ASRM. Even the post washing on the day of IUI 3,24 mill it’s considerably near the threshold and TMSC ranging from 1–4 million has clinical pregnancy rate of 28%. 11 This sperm count proved sufficient for pregnancy even thought on borderline level, however failure in implantation could be caused by elevated insulin resistance in PCOS. Insulin resistance affect endometrium with oxidative stress induced endometrial mitochondrial dysfunction which indicated by decreased mRNA expression of genes involved in mitochondrial fusion (Mfn1, Mfn2, and Opa1), fission (Fis1) and biogenesis (PGC1a, Erra, and Nrf1). 12 Failure of mitochondrial function leads to unmanaged reactive oxygen species (ROS) level which is one of recognize cause of repeated pregnancy loss and spontaneous abortion. 12 , 13 As for nutritional status of the patient considering patient has normal body mass index (BMI) she didn’t consume Metformin routinely after operation. Metformin is a biguanide drug which inhibits gluconeogenesis in liver and increase cellular sensitivity to insulin. 14 Metformin also consider safe and didn’t pose a risk for fetal anomalies in early pregnancy. 15 Metformin works on AMPK ( AMP-activated protein kinase ) to inhibits gluconeogenesis in liver through organic cation transporters-1 (OCT1) and interact directly with cells mitochondria as it’s main target. 16 Following the same founding by Chen et al usage of Metformin could avoid endometrial defect and defunction which leads to increase possibility of clinical pregnancy in PCOS. Other than PCOS, the first patient complicated with atypical hyperplasia. This also affect endometrial receptivity in conjunction of hyperandrogenism effect which alters HOXA gene, aVβ3 integrin, CDK signalling pathway, MECA-79, and MAGEA-11. 17 The atypical hyperplasia needed to be treated before induce any pregnancy program, as RCOG green-top guideline stated in 2016 regression of endometrial hyperplasia should be achieved as this is associated with higher implantation and clinical pregnancy rates. 18 In the second case patient and third case the condition rather quite same, with TMSC counts above 5 million which would ensure high success rate of IUI in normal condition. However both of the women has obesity which occurs together with PCOS. Obesity itself was a condition which allows more androgen in the system due to excess cholesterol in the body. In general compared to normally cycling women, those with PCOS exhibit high LH concentrations, low FSH levels, and increased LH to FSH ratios which resulted from abnormal LH secretory dynamics 8 , 9 The regiment of OS given was step up regiment or known as chronic low dose regimen. 5 This regiment was given to ensure ovarian hyperstimulation doesn’t occur which commonly occurs in PCOS. FSH was given in both cases due to TI and Letrozole administration which act as first line regiment in PCOS with infertility didn’t results in pregnancy (Fig. 1 ). 10 High androgenic activity and high insulin resistance resulting in high ROS formation and reduced endometrial receptibility. The last case which resulted in successful pregnancy could be contributed to younger age of the patient and high TMSC. Patient also didn’t had obesity which could be linked with less insulin resistance then the rest of the cases. Looking at 4 cases of IUI with PCOS in this last year, it could be concluded the successful of the first cycle in such scenario is 25%. Gao et al in 2022 in studies of 1.086 PCOS patients undergoes 1.868 cycles of IUI most pregnancies occurred in the first three cycles of IUI. 19 They strongly recommended three attempts of IUI for PCOS women before they switched to IVF. 19 However in studies that presented Aly et al gathered from 2002–2017 in Shady Grove Fertility (US nationwide private centre for IVF) in 5,638 cycles of anovulatory women with PCOS; 3,726 cycles in the IUI group and 1,912 cycles in the timely intercourse (TI) group shows no differences in clinical pregnancy rate with percentage 4.2% IUI vs 3.6% TI respectively. 20 These number was terrifically lower then the data we found, however due to the data scarcity it’s quite hard to produce analytically number acquired. The principle of fertility in PCOS is to make the cycle become predictable which is the marker of ovulatory cycles. This is where ovulation induction came in, by the usage of clomiphene citrate and letrozole came in (Fig. 1 ). 10 Women with PCOS and infertility due to anovulation alone with normal semen analysis could ovulation induction with timed intercourse or intrauterine insemination after ovulation detected. 10 Since subfertility in women with PCOS is mainly due to anovulation, ovulation induction is the main treatment for women with PCOS not the ovarian stimulation. 21 On all of the cases, mild ovarian stimulation considering the risk of ovarian hyperstimulation syndrome (OHSS). 5 According to HIFERI and ESHRE, GnRH antagonist protocol is recommended for PCOS women with regards to improved safety and equal efficacy. 5 , 22 Referring to our national guideline the procedure could be given with step up or step down regiment. 5 Step up regiment starts from 50/75 IU until 150 IU with gradual raise of 37.5 IU, this was increased until follicle reach 18 mm in size, step down regiment however starts with 150IU with gradual decrease of 37,5 IU if follicle development was visible. 5 Laparoscopic ovarian drilling (LOD) could be consider in cases of resistance to clomiphene citrate and notably high LH (above 10 mIU/mL). 21 LOD mechanism in restoring normal menstrual cycle mainly mediated by it’s thermal effect. 23 The changes cause by it’s thermal effects are formation of artificial holes in thick cortical wall which also loosen of the dense cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, and destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response. 23 All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; and hard start hypothalamus–pituitary–ovary (HPO) axis for spontaneous ovulation. 23 , 24 Conclusion Intrauterine insemination in PCOS still recommend with maximum of 3 cycles before IVF. Individual approach to each patient is mandatory for cases of infertility of any causes, and IUI with or without OS still greatly consider due to it’s lower cost and easier procedure than IVF. Declarations Acknowledgement Not applicable Competing interest The authors declare that they have no competing interests. Source of funding The study did not receive external funding Ethical Approval This study is exempted from an ethical approval as determined by the institutional and department review board Consent for Publication Written informed consent was obtained from the patient for publication of this cases review. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Availability of data and materials Not applicable Author Contributions All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Registration of research studies : Registration of research is not applicable in our case References Ombelet W, Robays J. Artificial insemination history: hurdles and milestones. Facts, views & vision in ObGyn. 2015;7:137 – 43. Cohen MR. Intrauterine insemination. Int J Fertil. 1962;7:235–40. Intrauterine insemination. Hum Reprod Update. 2009;15(3):265–77. Evidence-based treatments for couples with unexplained infertility: a guideline. Fertil Steril. 2020;113(2):305–22. Hendy Hendarto BW, Budi Santoso, Achmad Kemal Harzif. Konsensus Penanganan Infertilitas. Jakarta: HIFERI; 2019. Hugh S. Taylor MAF, Lubna Pal, Emre Seli. Section IV: Infertility. Speroff's Clinical Gynecologic Endocrinology and Infertility. Philadelphia: Wolters Kluwer; 2020. Use of exogenous gonadotropins for ovulation induction in anovulatory women: a committee opinion. Fertil Steril. 2020;113(1):66–70. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33(6):981–1030. Hugh S. Taylor MAF, Lubna Pal, Emre Seli. Section II: Clinical Endocrinology. Speroff's Clinical Gynecologic Endocrinology and Infertility. Philadelphia: Wolters Kluwer; 2020. Teede HJ, Tay CT, Laven JJE, Dokras A, Moran LJ, Piltonen TT, et al. Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2023;108(10):2447–69. Gubert PG, Pudwell J, Van Vugt D, Reid RL, Velez MP. Number of motile spermatozoa inseminated and pregnancy outcomes in intrauterine insemination. Fertility Research and Practice. 2019;5(1):10. Chen M, Li J, Zhang B, Zeng X, Zeng X, Cai S, et al. Uterine Insulin Sensitivity Defects Induced Embryo Implantation Loss Associated with Mitochondrial Dysfunction-Triggered Oxidative Stress. Oxid Med Cell Longev. 2021;2021:6655685. Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10:49. Nanovskaya TN, Nekhayeva IA, Patrikeeva SL, Hankins GD, Ahmed MS. Transfer of metformin across the dually perfused human placental lobule. Am J Obstet Gynecol. 2006;195(4):1081–5. Cassina M, Donà M, Di Gianantonio E, Litta P, Clementi M. First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis. 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Consensus on infertility treatment related to polycystic ovary syndrome. Human Reproduction. 2008;23(3):462–77. Ovarian Stimulation T, Bosch E, Broer S, Griesinger G, Grynberg M, Humaidan P, et al. ESHRE guideline: ovarian stimulation for IVF/ICSI(†). Hum Reprod Open. 2020;2020(2):hoaa009. Seow K-M, Chang Y-W, Chen K-H, Juan C-C, Huang C-Y, Lin L-T, et al. Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome. International Journal of Molecular Sciences. 2020;21(21):8147. Sinha P, Chitra T, Papa D, Nandeesha H. Laparoscopic Ovarian Drilling Reduces Testosterone and Luteinizing Hormone/Follicle-Stimulating Hormone Ratio and Improves Clinical Outcome in Women with Polycystic Ovary Syndrome. J Hum Reprod Sci. 2019;12(3):224–8. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5266206","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":366817415,"identity":"ca941954-62b1-4f2d-ace8-d843d5c19920","order_by":0,"name":"Alfonsus Zeus Suryawan","email":"data:image/png;base64,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","orcid":"","institution":"Universitas Padjadjaran","correspondingAuthor":true,"prefix":"","firstName":"Alfonsus","middleName":"Zeus","lastName":"Suryawan","suffix":""},{"id":366817417,"identity":"6770b119-5ed7-42e1-8351-9d23b3b7fbc4","order_by":1,"name":"Artha Falentin Putri Susilo","email":"","orcid":"","institution":"Universitas Padjadjaran","correspondingAuthor":false,"prefix":"","firstName":"Artha","middleName":"Falentin Putri","lastName":"Susilo","suffix":""},{"id":366817419,"identity":"3c872475-8f4e-4f7f-b2c2-b2300983adca","order_by":2,"name":"Fridya Wulandari Djuwantono","email":"","orcid":"","institution":"Universitas Padjadjaran","correspondingAuthor":false,"prefix":"","firstName":"Fridya","middleName":"Wulandari","lastName":"Djuwantono","suffix":""}],"badges":[],"createdAt":"2024-10-15 06:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5266206/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5266206/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67285951,"identity":"56321574-0e38-47d9-b020-cf4a665b74be","added_by":"auto","created_at":"2024-10-23 09:30:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":772504,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eApproach of infertility treatment in PCOS patient.\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e","description":"","filename":"Fig1.PCOSPathway.png","url":"https://assets-eu.researchsquare.com/files/rs-5266206/v1/645b666c658cb5a628e05fa0.png"},{"id":67288112,"identity":"5a31875a-686d-4495-8379-6a0b4699b3d2","added_by":"auto","created_at":"2024-10-23 09:46:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":986407,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5266206/v1/38b790ef-6af8-4e06-9384-c6ab6eb77de7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Review of Intrauterine Insemination in Polycystic Ovarian Syndromes - Cases Review and Current Approach","fulltext":[{"header":"Take home messages","content":"\u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDespite it lower success rate then IVF, IUI still deemed main choices for PCOS with IUI if the male counterpart has normal sperm count.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eBefore starting with IUI, TI with Letrozole should be suggested to return the cycle to ovulatory state from anovulatory one. This also improve the outcome later in IUI if the patient still no conceive yet with TI.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eThe concept of intrauterine examination (IUI) could be traced back to founding of microscope in 1678 by Antoni van Leeuwenhoek, and later on first IUI on animal was performed and succeed by Lazzaro Spallanzani in 1974.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Later on John Hunter in 1970 wrote the first report of artificial insemination and in 1962 Cohlen \u003cem\u003eet al\u003c/em\u003e publish the first paper entitled IUI.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Fast-forward to nowadays era with improved technique of sperm selection and deeper understanding of ovarian stimulation (OS), IUI combination with OS become therapy of choice in patients with with unexplained infertility.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e According to \u003cem\u003eHimpunan Endokrinologi Reproduksi dan Fertilitas Indonesia\u003c/em\u003e (HIFERI) guideline about infertility in 2019, stated IUI with or without OS is the first line treatment for unexplained infertility.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e However IUI is not without flaw, it\u0026rsquo;s success rate rely heavily on sperm count and motility. Extremely low sperm count \u0026amp; motility (below 5\u0026nbsp;million/ml) should be treat with in-vitro fertilization (IVF).\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e In this occasion we would like to review 4 cases of polycystic ovarian syndrome (PCOS) which undergoes IUI on Aster Fertility Clinic from September 2023 to July 2024 with one successful pregnancy and three cases which pregnancy didn\u0026rsquo;t occurs.\u003c/p\u003e"},{"header":"Cases Review","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCase 1\u003c/h2\u003e \u003cp\u003eA 35 years old P0A0 (7 years married) came to Aster Policlinic for pregnancy program and medication for her polycystic ovary syndrome (PCOS). She was given Metformin 3 x 500mg and Inlacin (extract of \u003cem\u003eLagerstroemia speciosa\u003c/em\u003e and \u003cem\u003eCinnamomum burman\u003c/em\u003e) for 3 months in 2019. Afterward she advised to undergo diagnostic laparoscopy, but she declined. Her menstrual cycle was presumably normal (26\u0026ndash;28 days with duration of 7 days). Her body mass index (BMI) is 23,2 kg/m\u003csup\u003e2\u003c/sup\u003e. On TVUS uterus was within normal limit, EL 3 mm, right ovarium had 13 follicles with 3,4 x 9,24 cm in size, and left ovarium had 15 follicles with 3,5 x 2,0 cm in size. She was diagnosed as PCOS and primary infertility then planned for diagnostic laparoscopy and examination of AMH and Luteinizing Hormone (LH). Her AMH at 2.75 ng/mL, and LH at 2,28 mIU/mL. She then undergoes hysteroscope and diagnostic laparoscopy. On hysteroscope found 0,5 x 0,5 x 0,5 cm polyp on fundus. Polypectomy was performed alongside aspiration curettage. Pelvic adhesion was found and laparoscopic tubal patency results both tubes are patent. Patient then diagnosed as endometrial polyp; polycystic ovarian syndrome; pelvic adhesion grade III; and bilateral patent tubal. Laparoscopic ovarian drilling (LOD) was not performed on this patient. Pathology anatomy analysis reveals endometrial polyp accompanied atypical hyperplasia.\u003c/p\u003e \u003cp\u003ePatient then starts her IUI programs 5 months after operation. Sperm analysis reveals total motile sperm count 5.89 mill/ml. On her 3rd day of cycle on TVUS found 13 follicles on right ovary and 8 follicles on left ovary. She\u0026rsquo;s not undergoes any stimulation then planned for control at day 12 of her cycle. On 12th day ovulation was triggered with hCG 5.000 IU with IUI 48 hours after. On 14th day which is 48 days after ovulation tigger IUI was perform with processed sperm at 3,24 mill/ml. Unfortunately, the patient had period on next month. She didn\u0026rsquo;t control herself afterward.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCase 2\u003c/h3\u003e\n\u003cp\u003eA 33 years old P0A0 (2 years married) came to Aster Policlinic for with referral from District Hospital due to her infertility and PCOS. Her body mass index (BMI) is 31,61 kg/m\u003csup\u003e2\u003c/sup\u003e, currently weighing 81 kg. Patient has no prior treatment previously and haven\u0026rsquo;t consumed any medicine before. Her menstrual cycle was quiet aberrant ranging from 1\u0026ndash;3 months range. On TVUS uterus was within normal limit, EL 2 mm, right ovarium had 17 follicles with 4.2 x 8.98 cm in size, and left ovarium had 10 follicles with 3.47 x 2.86 cm in size. Hysterosalpingography shows bilateral patent tube and normal uterus. Her husband sperm analysis was normal. She was diagnosed as PCOS and primary infertility then undergoes lifestyle modification and Metformin prescription at 3 x 500mg for 3 months.\u003c/p\u003e \u003cp\u003eAfter 3 months, there\u0026rsquo;s significant body weight reduction from 81 kg to 75 kg (BMI 29.29 kg/m\u003csup\u003e2\u003c/sup\u003e). Patient menstrual cycle also gradually improving with cycle length of 28 days in last month. Patient last menstrual period 2 days before, Patient then planned for ovulation induction with Letrozole 2 times a day and timely intercourse (TI). Patient then controlled herself on tenth day of her cycle and dominant follicle was found on TVUS. However after 2 months after TI, patient failed to conceive and planned for IUI with OS. At time of presentation patient BMI was 25,7 kg/m\u003csup\u003e2\u003c/sup\u003e, weighing 66 kg. Patient then start OS with recombinant FSH using step up regiment. FSH starts at 75 IU until 150 IU at her 13th day of her cycle. On the same day ovulation was triggered with hCG 5.000 IU with IUI 48 hours after. Unfortunately, the patient also had period on next month. She didn\u0026rsquo;t control herself yet afterward.\u003c/p\u003e\n\u003ch3\u003eCase 3\u003c/h3\u003e\n\u003cp\u003eA 36 years old P0A0 (3 years married) came to Aster Policlinic for pregnancy program. She was undergoes curettage 2 months ago due to atypical endometrial hyperplasia. Patient has aberrant cycle ranging from 1\u0026ndash;3 months since 1 years ago. Patient presented on 2nd day of her cycle. Her body mass index (BMI) is 32.44 kg/m\u003csup\u003e2\u003c/sup\u003e, currently weighing 73 kg. Clinical hirsutism also presented at patient. On TVUS uterus retroflexed with normal size and density, EL 5.46 mm, bilateral ovarium was normal with each measuring 2.56 x 1.73 cm and 2.6 x 1.62 cm. Patient was diagnosed with chronic anovulation due to PCOS and undergoes dietary changes and was given Cyproterone acetate 2 mg and Ethinylestradiol 35 mcg for 30 days. Patient was also given Metformin 3 x 500mg and Inlacin.\u003c/p\u003e \u003cp\u003eAfter patient had period, she controlled herself on 2nd day of her cycle with results of early infertility investigations. Hysterosalpingography shows bilateral patent tube and normal uterus. Her husband sperm analysis was normal. Patient then start OS with recombinant FSH using step up regiment. FSH starts at 75 IU until 100 IU at her 12th day of her cycle. On 13th day of her cycle ovulation was triggered with hCG 5.000 IU with IUI 48 hours after was perform with processed sperm at 8.37 mill/ml. Unfortunately, the patient also had period on next month. She was planned for next cycle in 3 months with lifestyle modification.\u003c/p\u003e\n\u003ch3\u003eCase 4\u003c/h3\u003e\n\u003cp\u003eA 30 years old P0A0 (5 years married) came to Aster Policlinic for pregnancy program. Patient has aberrant cycle ranging from 1\u0026ndash;3 months since adolescent. Her body mass index (BMI) was normal at 21.3 kg/m\u003csup\u003e2\u003c/sup\u003e. On TVUS uterus was within normal limit, accompanied with polycystic ovarian morphology (PCOM). She was diagnosed as PCOS and primary infertility then planned for diagnostic laparoscopy and was given Letrozole 2,5 mg and lifestyle modification for 2 months.\u003c/p\u003e \u003cp\u003eAfter 2 months, her cycle was 28 days with currently on 5th day of her cycle. Basic infertility assessment such as hysterosalpingography and sperm analysis showed normal result. Her AMH at 4.07 ng/mL, LH at 2,81 mIU/mL, FSH at 7.1 mIU/mL which are also normal. On TVUS right ovary had 5 follicles ranging from 4.3 mm \u0026ndash; 7.8 mm and left one had 9 follicles ranging from 4.5\u0026ndash;5.9 mm. Patient then planned for IUI with OS. Patient was given with recombinant FSH using step up regiment. FSH starts at 75 IU until 150 IU at her 15th day of cycle. On her 15th day TVUS reveals 4 follicle ranging from 17\u0026ndash;19 mm at her right ovary. The next day ovulation was triggered with hCG 5.000 IU and patient undergoes IUI with processed sperm at 9.98 mill/ml. Patient then controlled herself next month with successful pregnancy at 4 weeks gestation age and later controlled herself at 9 weeks of gestation age.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this occasion the author would like to review the IUI program according to nowadays practice. Artificial insemination has been used for infertile couples for 100 years since its\u0026rsquo;s first report in 1970\u0026rsquo;s.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Before we delve deeper into nowadays methods, IUI is one of artificial insemination methods. Another one is depositing sperms into the cervical ostium, but IUI is now almost universally performed, due to several reasons. First one cervical insemination give no advantage over what can be achieved by intercourse. Second, whereas unprocessed sperm could react to the proteins, prostaglandins, and bacteria in vagina which limits the volume of untreated semen that can be delivered to the upper female genital tract which was our goals.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Improvement of IUI improved from better sperm preparation, monitoring for pre-ovulatory timing and induction of ovulation with hCG.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Involvement of ovarian stimulation also benefit the IUI hence the ovulation could be control and induce at will.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePolycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders of reproductive-age women, occurring 7\u0026ndash;15% of population.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Diagnosis of PCOS with revised Rotterdam criteria with two of the following three criteria and exclusion of other etiology; ovarian volume\u0026thinsp;\u0026gt;\u0026thinsp;10 mL\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e and/or \u0026gt;\u0026thinsp;20 follicles between 2 and 9 mm in either ovary; oligoanovulation; and clinical or biochemical signs of hyperandrogenism.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Teelde \u003cem\u003eet al\u003c/em\u003e at 2023 release revised US criteria with following categories for PCOS; follicle number per ovary (FNPO)\u0026thinsp;\u0026ge;\u0026thinsp;20 in at least 1 ovary, ovarian volume\u0026thinsp;\u0026ge;\u0026thinsp;10 mL, or follicle number per section (FNPS)\u0026thinsp;\u0026ge;\u0026thinsp;10 in at least 1 ovary in adults should be considered the threshold for polycystic ovarian morphology (PCOM).\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e It\u0026rsquo;s pathogenesis, whereas ovaries stay in steady state which gonadotropin and sex steroid concentrations vary relatively cause nonovulatory cycles.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the first case, which IUI had failed, sperm analysis reveals TMSC count is 5.89 mill/ml which is above threshold for IUI according to HIFERI and ASRM. Even the post washing on the day of IUI 3,24 mill it\u0026rsquo;s considerably near the threshold and TMSC ranging from 1\u0026ndash;4\u0026nbsp;million has clinical pregnancy rate of 28%.\u003csup\u003e11\u003c/sup\u003e This sperm count proved sufficient for pregnancy even thought on borderline level, however failure in implantation could be caused by elevated insulin resistance in PCOS. Insulin resistance affect endometrium with oxidative stress induced endometrial mitochondrial dysfunction which indicated by decreased mRNA expression of genes involved in mitochondrial fusion (Mfn1, Mfn2, and Opa1), fission (Fis1) and biogenesis (PGC1a, Erra, and Nrf1).\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Failure of mitochondrial function leads to unmanaged reactive oxygen species (ROS) level which is one of recognize cause of repeated pregnancy loss and spontaneous abortion.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAs for nutritional status of the patient considering patient has normal body mass index (BMI) she didn\u0026rsquo;t consume Metformin routinely after operation. Metformin is a biguanide drug which inhibits gluconeogenesis in liver and increase cellular sensitivity to insulin.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Metformin also consider safe and didn\u0026rsquo;t pose a risk for fetal anomalies in early pregnancy.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Metformin works on AMPK (\u003cem\u003eAMP-activated protein kinase\u003c/em\u003e) to inhibits gluconeogenesis in liver through organic cation transporters-1 (OCT1) and interact directly with cells mitochondria as it\u0026rsquo;s main target.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Following the same founding by Chen \u003cem\u003eet al\u003c/em\u003e usage of Metformin could avoid endometrial defect and defunction which leads to increase possibility of clinical pregnancy in PCOS. Other than PCOS, the first patient complicated with atypical hyperplasia. This also affect endometrial receptivity in conjunction of hyperandrogenism effect which alters HOXA gene, aVβ3 integrin, CDK signalling pathway, MECA-79, and MAGEA-11.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e The atypical hyperplasia needed to be treated before induce any pregnancy program, as RCOG green-top guideline stated in 2016 regression of endometrial hyperplasia should be achieved as this is associated with higher implantation and clinical pregnancy rates.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the second case patient and third case the condition rather quite same, with TMSC counts above 5\u0026nbsp;million which would ensure high success rate of IUI in normal condition. However both of the women has obesity which occurs together with PCOS. Obesity itself was a condition which allows more androgen in the system due to excess cholesterol in the body. In general compared to normally cycling women, those with PCOS exhibit high LH concentrations, low FSH levels, and increased LH to FSH ratios which resulted from abnormal LH secretory dynamics\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e The regiment of OS given was step up regiment or known as chronic low dose regimen.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This regiment was given to ensure ovarian hyperstimulation doesn\u0026rsquo;t occur which commonly occurs in PCOS. FSH was given in both cases due to TI and Letrozole administration which act as first line regiment in PCOS with infertility didn\u0026rsquo;t results in pregnancy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e High androgenic activity and high insulin resistance resulting in high ROS formation and reduced endometrial receptibility.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe last case which resulted in successful pregnancy could be contributed to younger age of the patient and high TMSC. Patient also didn\u0026rsquo;t had obesity which could be linked with less insulin resistance then the rest of the cases. Looking at 4 cases of IUI with PCOS in this last year, it could be concluded the successful of the first cycle in such scenario is 25%. Gao \u003cem\u003eet al\u003c/em\u003e in 2022 in studies of 1.086 PCOS patients undergoes 1.868 cycles of IUI most pregnancies occurred in the first three cycles of IUI.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e They strongly recommended three attempts of IUI for PCOS women before they switched to IVF.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever in studies that presented Aly \u003cem\u003eet al\u003c/em\u003e gathered from 2002\u0026ndash;2017 in Shady Grove Fertility (US nationwide private centre for IVF) in 5,638 cycles of anovulatory women with PCOS; 3,726 cycles in the IUI group and 1,912 cycles in the timely intercourse (TI) group shows no differences in clinical pregnancy rate with percentage 4.2% IUI vs 3.6% TI respectively.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e These number was terrifically lower then the data we found, however due to the data scarcity it\u0026rsquo;s quite hard to produce analytically number acquired.\u003c/p\u003e \u003cp\u003eThe principle of fertility in PCOS is to make the cycle become predictable which is the marker of ovulatory cycles. This is where ovulation induction came in, by the usage of clomiphene citrate and letrozole came in (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Women with PCOS and infertility due to anovulation alone with normal semen analysis could ovulation induction with timed intercourse or intrauterine insemination after ovulation detected.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Since subfertility in women with PCOS is mainly due to anovulation, ovulation induction is the main treatment for women with PCOS not the ovarian stimulation.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e On all of the cases, mild ovarian stimulation considering the risk of ovarian hyperstimulation syndrome (OHSS).\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e According to HIFERI and ESHRE, GnRH antagonist protocol is recommended for PCOS women with regards to improved safety and equal efficacy.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Referring to our national guideline the procedure could be given with step up or step down regiment.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Step up regiment starts from 50/75 IU until 150 IU with gradual raise of 37.5 IU, this was increased until follicle reach 18 mm in size, step down regiment however starts with 150IU with gradual decrease of 37,5 IU if follicle development was visible.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eLaparoscopic ovarian drilling (LOD) could be consider in cases of resistance to clomiphene citrate and notably high LH (above 10 mIU/mL).\u003csup\u003e21\u003c/sup\u003e LOD mechanism in restoring normal menstrual cycle mainly mediated by it\u0026rsquo;s thermal effect.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e The changes cause by it\u0026rsquo;s thermal effects are formation of artificial holes in thick cortical wall which also loosen of the dense cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, and destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; and hard start hypothalamus\u0026ndash;pituitary\u0026ndash;ovary (HPO) axis for spontaneous ovulation.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIntrauterine insemination in PCOS still recommend with maximum of 3 cycles before IVF. Individual approach to each patient is mandatory for cases of infertility of any causes, and IUI with or without OS still greatly consider due to it\u0026rsquo;s lower cost and easier procedure than IVF.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSource of funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study did not receive external funding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is exempted from an ethical approval as determined by the institutional and department review board\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this cases review. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegistration of research studies :\u0026nbsp;\u003c/strong\u003eRegistration of research is not applicable in our case\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOmbelet W, Robays J. Artificial insemination history: hurdles and milestones. Facts, views \u0026amp; vision in ObGyn. 2015;7:137\u0026thinsp;\u0026ndash;\u0026thinsp;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen MR. Intrauterine insemination. Int J Fertil. 1962;7:235\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIntrauterine insemination. Hum Reprod Update. 2009;15(3):265\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEvidence-based treatments for couples with unexplained infertility: a guideline. Fertil Steril. 2020;113(2):305\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHendy Hendarto BW, Budi Santoso, Achmad Kemal Harzif. Konsensus Penanganan Infertilitas. Jakarta: HIFERI; 2019.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHugh S. Taylor MAF, Lubna Pal, Emre Seli. Section IV: Infertility. Speroff's Clinical Gynecologic Endocrinology and Infertility. Philadelphia: Wolters Kluwer; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUse of exogenous gonadotropins for ovulation induction in anovulatory women: a committee opinion. Fertil Steril. 2020;113(1):66\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDiamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33(6):981\u0026ndash;1030.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHugh S. Taylor MAF, Lubna Pal, Emre Seli. Section II: Clinical Endocrinology. Speroff's Clinical Gynecologic Endocrinology and Infertility. Philadelphia: Wolters Kluwer; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTeede HJ, Tay CT, Laven JJE, Dokras A, Moran LJ, Piltonen TT, et al. Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2023;108(10):2447\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGubert PG, Pudwell J, Van Vugt D, Reid RL, Velez MP. Number of motile spermatozoa inseminated and pregnancy outcomes in intrauterine insemination. Fertility Research and Practice. 2019;5(1):10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen M, Li J, Zhang B, Zeng X, Zeng X, Cai S, et al. Uterine Insulin Sensitivity Defects Induced Embryo Implantation Loss Associated with Mitochondrial Dysfunction-Triggered Oxidative Stress. Oxid Med Cell Longev. 2021;2021:6655685.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10:49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNanovskaya TN, Nekhayeva IA, Patrikeeva SL, Hankins GD, Ahmed MS. Transfer of metformin across the dually perfused human placental lobule. Am J Obstet Gynecol. 2006;195(4):1081\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCassina M, Don\u0026agrave; M, Di Gianantonio E, Litta P, Clementi M. First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis. Hum Reprod Update. 2014;20(5):656\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eViollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBajpai K, Acharya N, Prasad R, Wanjari MB. Endometrial Receptivity During the Preimplantation Period: A Narrative Review. Cureus. 2023;15(4):e37753.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eManagement of Endometrial Hyperplasia. Green-top Guideline No 67. 2016(RCOG/BSGE Joint Guideline).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao Y, Jiang S, Chen L, Xi Q, Li W, Zhang S, et al. The pregnancy outcomes of infertile women with polycystic ovary syndrome undergoing intrauterine insemination with different attempts of previous ovulation induction. Front Endocrinol (Lausanne). 2022;13:922605.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAly J, Evans MB, Jahandideh S, Decherney A, Devine K, Hill M. THE UTILITY OF INTRA-UTERINE INSEMINATION IN THE TREATMENT OF POLYCYSTIC OVARIAN SYNDROME. Fertility and Sterility. 2020;113(4):e44-e5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGroup TTEA-SPCW. Consensus on infertility treatment related to polycystic ovary syndrome. Human Reproduction. 2008;23(3):462\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOvarian Stimulation T, Bosch E, Broer S, Griesinger G, Grynberg M, Humaidan P, et al. ESHRE guideline: ovarian stimulation for IVF/ICSI(\u0026dagger;). Hum Reprod Open. 2020;2020(2):hoaa009.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeow K-M, Chang Y-W, Chen K-H, Juan C-C, Huang C-Y, Lin L-T, et al. Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome. International Journal of Molecular Sciences. 2020;21(21):8147.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinha P, Chitra T, Papa D, Nandeesha H. Laparoscopic Ovarian Drilling Reduces Testosterone and Luteinizing Hormone/Follicle-Stimulating Hormone Ratio and Improves Clinical Outcome in Women with Polycystic Ovary Syndrome. J Hum Reprod Sci. 2019;12(3):224\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5266206/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5266206/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntrauterine insemination (IUI) is procedure which we introduce sperm into the fundal cavity. It’s help a lot of infertile couple to reach clinical pregnancy and currently mainly first choice of unexplained fertility. Usage in other cause of infertility was also consider with individualized approach. However IUI is not without flaw, it’s success rate rely heavily on sperm count and motility. It’s usage in polycystic ovary syndrome (PCOS) still in debates, due to high insulin resistance condition in PCOS hinders implantation and increase risk of fetal loss associated with endometrial dysfunction. This serial case report shows want to review 4 cases of IUI with PCOS on Aster Fertility Clinic from September 2023 – July 2024 and current approach of this condition which relevant to nowadays practice and knowledge.\u003c/p\u003e","manuscriptTitle":"Review of Intrauterine Insemination in Polycystic Ovarian Syndromes - Cases Review and Current Approach","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-23 09:30:12","doi":"10.21203/rs.3.rs-5266206/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e7bb1295-5c68-41e8-86be-5e8066a056f6","owner":[],"postedDate":"October 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-23T09:30:14+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-23 09:30:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5266206","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5266206","identity":"rs-5266206","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}