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In Vitro Fertilization for Polycystic Ovarian Syndrome

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In Vitro Fertilization for Polycystic Ovarian Syndrome CLINICAL OBSTETRICS AND GYNECOLOGY Volume 64, Number 1, 39–47 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. In Vitro Fertilization for Polycystic Ovarian Syndrome JESSICA R. ZOLTON, DO,* and SAIOA TORREALDAY, MD† *Program in Reproductive Endocrinology and Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; and †Walter Reed National Military Medical Center, Bethesda, Maryland Abstract: In vitro fertilization is indicated for infertile treatment for infertility. Guidelines indi- women with polycystic ovarian syndrome (PCOS) after cate that IVF should be offered after failed unsuccessful treatment with ovulation induction agents or in women deemed high-risk of multiple gestations ovulation induction with oral agents or 1 who are ideal candidates for single embryo transfers. gonadotropin treatment. However, due to PCOS patients are at increased risk of ovarian hyper- the risk of twins and higher order multi- stimulation syndrome; therefore, attention should be ples, which is more commonly seen when made in the choice of in vitro fertilization treatment gonadotropin medications are utilized, protocol, dose of gonadotropin utilized, and regimen to achieve final oocyte maturation. Adopting these strat- IVF may be considered after failed ovula- egies in addition to close monitoring may significantly tion induction with clomiphene citrate or reduce the ovarian hyperstimulation syndrome risk. letrozole.2 In addition, PCOS patients are Future developments may improve pregnancy out- ideal candidates for consideration of elec- comes and decrease complications in PCOS women tive single embryo transfer to mitigate the undergoing fertility treatment. Key words: infertility, in vitro fertilization, polycystic risk of multiple pregnancies while under- ovarian syndrome, ovarian hyperstimulation syn- going IVF. drome, in vitro maturation PCOS patients undergoing IVF, without additional infertility confounders, are gen- In vitro fertilization (IVF) for the treat- erally good prognosis patients to achieve a ment of anovulatory polycystic ovarian live birth. During IVF stimulation, the large syndrome (PCOS) is considered third-line number of antral follicles seen within this population commonly results in a high Correspondence: Jessica R. Zolton, DO, Program in number of oocytes retrieved, the develop- Reproductive Endocrinology and Gynecology, Eunice ment of supernumerary embryos, and Kennedy Shriver National Institute of Child Health and consequently, excess embryos for cryopre- Human Development, National Institutes of Health; 10 Center Drive, Building 10, Room 8N248B, MSC 1840, servation. IVF cycles undertaken in the Bethesda, MD. E-mail: [email protected] PCOS population are characterized by The authors declare that they have nothing to disclose. slightly longer stimulation (1.2 d longer), CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 64 / NUMBER 1 / MARCH 2021 www.clinicalobgyn.com | 39 Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved. 40 Zolton and Torrealday higher number of developing of follicles, intractable nausea and vomiting, hypovo- higher estradiol levels, and retrieval of a lemia, and hypercoagulability. Electrolyte higher number of cumulus-oocyte com- disturbances resulting in hyperkalemia, hy- plexes (COC) [2.9 more COC; 95% con- ponatremia, and abnormal hepatic function fidence interval (CI) = 2.2, 3.6)] than in are also commonly present.7 Although women without PCOS.3 PCOS patients severe cases of OHSS are rare, maternal may require relatively high doses of gona- deaths have been reported.8 Therefore, it is dotropins at the start of stimulation due to important that infertility specialists identify their underlying hyperandrogenism, which women who are at risk of OHSS before the contributes to altered steroidogenesis and initiation of treatment and adopt strategies impaired follicular development.4 Increas- to prevent OHSS. ing gonadotropin dosage should be cau- tioned and closely monitored as these patients are also prone to overrespond to IVF Protocols stimulation, increasing the risk of develop- Treatment strategies employed during IVF ing ovarian hyperstimulation syndrome aim to achieve “controlled” growth and (OHSS). OHSS is an iatrogenic complica- development of a cohort of ovarian fol- tion that results from the stimulation of licles that is available and responsive to multiple corpus lutei following exogenous exogenous gonadotropin stimulus, while human chorionic gonadotropin (hCG) ad- concomitantly suppressing the hypothala- ministration. OHSS occurs in up to 3% to mic-pituitary-ovarian axis. In the absence 6%5 of all IVF cycles and results due to of a suppressive strategy, escalating estra- excess production of vascular endothelial diol levels that arise with the development growth factor (VEGF) and cytokines which of ovarian follicles can initiate an endog- cause arteriolar vasodilation and increased enous luteinizing hormone (LH) surge capillary permeability.6 Womenwithan with subsequent ovulation. During the antral follicle count > 24 and an anti- early days of IVF, suppression of the Mullerian hormone ≥ 3.5 ng/mL have been hypothalamic-pituitary-ovarian axis was identified to be at increased risk of OHSS; extensively done utilizing gonadotropin- bothparametersarecommoninPCOS releasing hormone (GnRH) agonist in patients. During the IVF cycle, high estra- efforts to prevent the premature luteiniza- diol values > 3500 pg and ≥ 24 oocytes tion during controlled ovarian hyperstimu- retrieved are also associated with an in- lation. GnRH agonists bind to the creased risk of OHSS.7 Early-onset OHSS, pituitary GnRH receptors and stimulate which occurs within 10 days of oocyte the release of the endogenous gonadotro- retrieval, is due to exposure to hCG when pins, follicle-stimulating hormone (FSH) used as a trigger for oocyte maturation. and LH. This sudden increase in FSH and Late-onset OHSS ( ≥ 10 d from oocyte LH secretion following receptor binding is retrieval) is caused by the secretion of oftenreferredtoasthe“flare-effect.” After hCG by the developing embryo after em- continuous stimulation with a GnRH ago- bryo transfer. OHSS symptoms range from nist, desensitization and downregulation mild, with patients reporting abdominal of GnRH receptors occurs resulting in distention, mild dyspnea, and nausea and FSH and LH suppression. vomiting, to moderate, with laboratory There are 2 primary GnRH agonist evidence of hemoconcentration and ultra- protocols, the long luteal and the short sound evidence of ascites, to severe cases GnRH agonist protocols, that are com- requiring hospitalization. In severe cases, monly used in IVF cycles. In the long patients may require fluid resuscitation and luteal GnRH agonist protocol, the GnRH anticoagulation to treat oliguria/anuria, agonist is typically initiated in the luteal www.clinicalobgyn.com Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved. IVF for PCOS 41 phase of the preceding cycle and exoge- protocol). GnRH antagonist protocols nous gonadotropins are not started until permit the use of either hCG or GnRH after downregulation has occurred. In agonist trigger for final oocyte matura- contrast, in the short GnRH agonist prot- tion, whereas, in a GnRH agonist cycle ocol, GnRH agonist is administered at hCG trigger is the only option due to the the beginning of the menstruation cycle depletion of pituitary LH stores. The concomitantly with the start of exogenous disadvantage of exogenous hCG is that gonadotropins. The short GnRH agonist it has a longer half-life then LH (24 h vs. protocol is often reserved for poor res- 60 min) and the duration of the hCG ponders due to the advantage of having surge is also significantly longer than the endogenous gonadotropin “flare- LH (24 to 36 h vs. 6 d).12 As a result, effect” and to prevent the excessive pitui- hCG stimulates the corpus luteum for a tary suppression often seen in long GnRH prolonged period of time which promotes agonist cycles. Since GnRH agonist VEGF production and thus increases the cycles exhaust the pituitary of its gonado- risk of OHSS.6 tropin stores, the use of hCG as a surro- For patients that receive an hCG trigger gate LH surge is a necessity. hCG, which and are deemed high risk for OHSS, shares structural similarities to LH and recommendation to delay transfer and therefore can bind to the LH receptor, subsequently cryopreserve all embryos is induces luteinization of granulosa cells, encouraged. Therefore, adopting a GnRH achieves final oocyte maturation, and antagonist protocol with GnRH agonist allows for resumption of meiosis. trigger is more beneficial for PCOS pa- In PCOS patients who are generally tients. In a randomized controlled trial “good responders” to gonadotropins, the (RCT) of 220 patients with PCOS, GnRH use of the short GnRH agonist protocol antagonist protocols were associated with with subsequent “flare-effect” can result in a decreased risk in OHSS in comparison to an increased risk of OHSS. One study the GnRH agonist protocol (40% vs. 60%, reported that GnRH agonist protocols with difference −20%, 95% CI = −7.1 to hCG trigger for oocyte maturation were −31.9%, P < 0.01).13 hCG trigger was used associated with a 20% incidence of OHSS in in both groups which explains the high PCOS patients compared with a 7% inci- incidence of OHSS overall.13 In a meta- dence in non-PCOS groups (P = 0.53).9 analysis including 9 RCTs and 1294 With the introduction of GnRH ago- women,
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