The presence of multiple ovarian cysts, anovulation, and endometrial progesterone resistance in the neonate seems remarkably similar to ovarian and endometrial features of the polycystic ovary syndrome (PCOS) of adolescent and adult women. In fact, in the absence of cyclic menstruations after menarche, the neonatal progesterone resistance is likely to persist and adversely affect young women with PCOS at the time of pregnancy after induction of ovulation, because any persisting defect in progesterone response can interfere with the process of decidualization and trophoblast invasion. The primigravid woman with PCOS therefore is likely to be at risk of defective deep placentation as manifested by the increased risk of major obstetric syndromes. A recent, large epidemiologic study has demonstrated that the risk of preeclampsia and preterm delivery is elevated in the 13- to 15-year old group, although it does not persist in the 16- to 17-year old group. It is proposed therefore that induction of ovulation in the infertile nulligravid woman with PCOS should be preceded by a period of progesterone withdrawal bleedings to achieve full endometrial progesterone response by the time of pregnancy. The cyclic administration of clomiphene citrate for a period to be determined by vascular response may be an appropriate tool to reduce the risk of major obstetric syndromes by menstrual preconditioning. The presence of multiple ovarian cysts, anovulation, and endometrial progesterone resistance in the neonate seems remarkably similar to ovarian and endometrial features of the polycystic ovary syndrome (PCOS) of adolescent and adult women. In fact, in the absence of cyclic menstruations after menarche, the neonatal progesterone resistance is likely to persist and adversely affect young women with PCOS at the time of pregnancy after induction of ovulation, because any persisting defect in progesterone response can interfere with the process of decidualization and trophoblast invasion. The primigravid woman with PCOS therefore is likely to be at risk of defective deep placentation as manifested by the increased risk of major obstetric syndromes. A recent, large epidemiologic study has demonstrated that the risk of preeclampsia and preterm delivery is elevated in the 13- to 15-year old group, although it does not persist in the 16- to 17-year old group. It is proposed therefore that induction of ovulation in the infertile nulligravid woman with PCOS should be preceded by a period of progesterone withdrawal bleedings to achieve full endometrial progesterone response by the time of pregnancy. The cyclic administration of clomiphene citrate for a period to be determined by vascular response may be an appropriate tool to reduce the risk of major obstetric syndromes by menstrual preconditioning. The polycystic ovary syndrome (PCOS) is among the most common female endocrine disorders, which occurs in 4-18% of reproductive-age women worldwide.1Moran L.J. Hutchison S.K. Norman R.J. Teede H.J. Lifestyle changes in women with polycystic ovary syndrome.Cochrane Database Syst Rev. 2011; 2: CD007506PubMed Google Scholar The syndrome is a complex metabolic and endocrine disorder that is associated with the presence of hyperandrogenemia, insulin resistance, obesity, infertility, and obstetric complications. As a consequence, it may have significant implications for the long-term physical and reproductive health of affected women. In view of the heterogeneity of the syndrome and the lack of understanding of its pathogenesis and mechanisms of action, it is not surprising that, even after 3 consensus meetings, the criteria to diagnose PCOS remain unsettled. Currently, PCOS is diagnosed by the presence of ≥2 of the following features: chronic oligo- or anovulation, clinical or biochemical evidence of androgen excess, and the presence of polycystic ovaries on sonographic examination.2Carmina E. Azziz R. Diagnosis, phenotype, and prevalence of polycystic ovary syndrome.Fertil Steril. 2006; 86: S7-S8Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Generally, the belief is that, in most cases of PCOS, infertility results from the absence of ovulation; at the same time, it has also been recognized that anovulation may not be the only reason for the failure to conceive.3Legro R.S. Zaino R.J. Demers L.M. et al.The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome.Am J Obstet Gynecol. 2007; 196: 402.e1-402.e11Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Indeed, there is evidence that infertility in women with PCOS cannot be attributed to anovulation only but also to endometrial dysfunction. A recent endometrial biopsy study by Lopes et al4Lopes I.M.R.S. Maganhin C.C. Oliveira-Filho R.M. et al.Histomorphometric analysis and markers of endometrial receptivity embryonic implantation in women with polycystic ovary syndrome during the treatment with progesterone.Reprod Sci. 2014; 21: 930-938Crossref PubMed Scopus (23) Google Scholar showed that conventional doses of progesterone may not be enough to correct PCOS-associated changes in the endometrial histomorphologic condition and the receptivity markers. It is a fact that, despite the ability to correct ovulatory disorders in PCOS, pregnancy rates remain paradoxically low, and spontaneous pregnancy loss rates are high.5Sagle M. Bishop K. Ridley N. et al.Recurrent early miscarriage and polycystic ovaries.BMJ. 1988; 297: 1027-1028Crossref PubMed Scopus (242) Google Scholar Once a woman with PCOS has conceived, her problems are not over because she will be at a higher risk of miscarriage, both after spontaneous or assisted conception (ART).6Jakubowicz D.J. Iuorno M.J. Jakubowicz S. Roberts K.A. Nestler J.E. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome.J Clin Endocrinol Metab. 2002; 87: 524-529Crossref PubMed Scopus (388) Google Scholar A recent Cochrane-based data review7Tso L.O. Costello M.F. Albuquerque L.E. Andriolo R.B. Macedo C.R. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.Cochrane Database Syst Rev. 2014; 11: CD006105PubMed Google Scholar on the use of metformin (an oral antidiabetic drug used to reduce insulin resistance) evidenced that (1) there is no conclusive evidence that metformin treatment before or during ART cycles improves the live birth rates in women with PCOS who undergo ovulation induction or in vitro fertilization and (2) its use increases clinical pregnancy rates and decreases the risk of ovarian hyperstimulation syndromes. In this clinical opinion, we focus on a new theory of the pathogenesis of major obstetric complications that have been associated with PCOS to improve our understanding and potentially the management of these obstetric complications in women who are affected by PCOS. The literature was searched via Scopus and PubMed for the following key words: polycystic ovary syndrome, progesterone resistance, and metformin in combination with endometrium, menstrual preconditioning, pregnancy, trophoblast, preeclampsia, or preterm delivery. In addition, the references were examined in published papers on related topics. Several studies have documented an association between PCOS and major obstetric complications, particularly preeclampsia and preterm birth. A metaanalysis of pregnancy outcomes in women with PCOS demonstrated a significantly higher risk of the development of gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, and preterm birth (Table 1).8Boomsma C.M. Fauser B.C.J.M. Macklon N.S. Pregnancy complications in women with polycystic ovary syndrome.Semin Reprod Med. 2008; 26: 72-84Crossref PubMed Scopus (139) Google Scholar An exhaustive review of the literature that assessed pregnancy outcomes and the effect of metformin treatment among women with PCOS by Ghazeeri et al9Ghazeeri G.S. Nassar A.H. Younes Z. Awwad J.T. Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome: an overview.Acta Obstet Gynecol Scand. 2012; 91: 658-678Crossref PubMed Scopus (48) Google Scholar concluded that the weight of available evidence suggests that pregnant women with PCOS are at increased risk of the development of preterm birth and hypertensive disorders of pregnancy, with a prevalence of 6-15% for preterm birth, 10-30% for gestational hypertension, and 8-15% for preeclampsia. The authors concluded that metformin has proved to be effective in improving ovulation and pregnancy rates among patients who receive fertility-enhancing agents and supports its use among anovulatory women with PCOS. However, the continuation of metformin throughout pregnancy remains controversial.Table 1Major obstetric syndrome in women with polycystic ovary syndromeSyndromeOdds ratio95% confidence intervalPregnancy-induced hypertension3.671.98–6.81Preeclampsia3.471.16–2.62Preterm birth1.751.16–2.62Gestational diabetes mellitus2.941.70–5.08Perinatal death3.071.03–9.21Boomsma et al.8Boomsma C.M. Fauser B.C.J.M. Macklon N.S. Pregnancy complications in women with polycystic ovary syndrome.Semin Reprod Med. 2008; 26: 72-84Crossref PubMed Scopus (139) Google ScholarBrosens. Menstrual preconditioning in polycystic ovary syndrome. Am J Obstet Gynecol 2015. Open table in a new tab Boomsma et al.8Boomsma C.M. Fauser B.C.J.M. Macklon N.S. Pregnancy complications in women with polycystic ovary syndrome.Semin Reprod Med. 2008; 26: 72-84Crossref PubMed Scopus (139) Google Scholar Brosens. Menstrual preconditioning in polycystic ovary syndrome. Am J Obstet Gynecol 2015. A population-based cohort study of the risk of adverse pregnancy outcomes in women with PCOS found that, in singleton births, PCOS was associated strongly with preeclampsia (adjusted odds ratio, 1.45; 95% confidence interval [CI], 1.24–1.69) and very preterm birth (adjusted odds ratio, 2.21; 95% CI, 1.69–2.90).10Roos N. Kieler H. Sahlin L. Ekman-Ordeberg G. Falconer H. Stephansson O. Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study.BMJ. 2011; 343: d6309Crossref PubMed Scopus (179) Google Scholar A systematic review that involved 2544 patients with at least 2 features of the 2003 Rotterdam criteria for PCOS11The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop groupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).Hum Reprod. 2004; 19: 41-47Crossref PubMed Scopus (4412) Google Scholar and 89,848 patients without PCOS confirmed that women with the syndrome had significantly higher rates of gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, preterm delivery, and small-for-gestational-age infants.12Kjerulff L.E. Sanchez-Ramos L. Duffy D. Pregnancy outcomes in women with polycystic ovary syndrome: a meta-analysis.Am J Obstet Gynecol. 2011; 204: 558.e1-558.e6Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar A 4-fold increase in the risk of pregnancy-induced hypertension linked to arterial wall stiffness has also been observed in these patients. The risk of preeclampsia, which is the most severe of all complications, is also 4 times higher in those who experience PCOS.13Katulski K. Czyzyk A. Podfigurna-Stopa A. Pregnancy complications in polycystic ovary syndrome PubMed Scopus Google Scholar A on by et The of metformin in pregnant women with polycystic ovary syndrome: a of clinical Endocrinol Google Scholar found that, in pregnant women with PCOS, the odds was CI, for early pregnancy CI, for gestational diabetes mellitus, CI, for preeclampsia, and CI, for preterm delivery. The authors concluded that metformin throughout pregnancy complications in pregnant women with PCOS with no An of 2 that women with PCOS who were old and who had singleton by et E. M. L. the of metformin to preterm delivery in women with polycystic ovary syndrome: an Obstet Gynecol Scand. 2012; 91: PubMed Scopus Google Scholar showed that the patients had the same time, there was no in the prevalence of gestational diabetes and preeclampsia between the metformin and the The authors that studies should be before can be The of that, in there is a of to et 196: PubMed Scopus Google Scholar In recent the has been particularly in women with et resistance in to failure to 2006; PubMed Scopus Google Scholar is evidence that an progesterone response can be found in the endometrium of women with PCOS. et et throughout the menstrual in and Clin Endocrinol Metab. 2002; 87: PubMed Scopus Google Scholar demonstrated that the of the which as for a of and is in the endometrium during the menstrual in women but is in the endometrium of women with PCOS. et D. of by in vitro and in the endometrium of patients with polycystic ovary syndrome.J Clin Endocrinol Metab. PubMed Scopus Google Scholar the of the that is for the receptivity to In vitro and endometrial biopsy that were from women with PCOS that decreases which to the that may to the of women with PCOS. A review of endometrial of the of in women with PCOS that on that endometrial receptivity seems to be the major for the of I.M.R.S. Maganhin C.C. Oliveira-Filho R.M. et al.Histomorphometric analysis and markers of endometrial receptivity embryonic implantation in women with polycystic ovary syndrome during the treatment with progesterone.Reprod Sci. 2014; 21: 930-938Crossref PubMed Scopus (23) Google Scholar et et resistance in PCOS a analysis in clomiphene and menstrual Clin Endocrinol Metab. 2011; PubMed Scopus Google Scholar who between endometrial of and women with PCOS, concluded that in evidence of progesterone resistance in PCOS endometrium, of clomiphene citrate It can also that were observed in this of women in of and reproductive In an in vitro et H. et in endometrial resistance to Steril. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar the effect of on the of that are involved in resistance in endometrial that were from were with cyclic and progesterone in the presence or absence of at The authors concluded that a in the decidualization process at the time of implantation and trophoblast by resistance to in the endometrium of patients with PCOS, et L. A. L. M. of in the endometrium of polycystic ovary syndrome patients during the of 2012; PubMed Scopus (23) Google Scholar showed in that a in and and that a that the of as during the of that the in during the implantation in patients with PCOS may be of the of endometrial a recent review of endometrial progesterone resistance in women with PCOS concluded that of and in the are H. R. progesterone resistance and Sci. 2014; 21: PubMed Scopus Google Scholar pregnancy, the is to of and in the to higher in the because of the of the of the D. E. and in J Obstet Gynecol. Full Text PDF PubMed Scopus Google Scholar and on the endometrium and ovary in the Google Scholar neonatal ovaries and in a of and observed that, in ovaries are but to any of ovulation or In the in the response of the endometrium to the progesterone and this response as or in of or early response in and full or in only at birth most the criteria for the of PCOS by the presence of polycystic anovulation, and G. as of Reprod. PubMed Scopus Google Scholar It can be that the of progesterone resistance that is in the endometrium at birth is likely to persist the of to endometrial G. as of Reprod. PubMed Scopus Google E. G. of endometrial in the pathogenesis of Reprod. 2014; PubMed Scopus Google Scholar full progesterone response with has been linked to in and G. as of Reprod. PubMed Scopus Google E. G. of endometrial in the pathogenesis of Reprod. 2014; PubMed Scopus Google Scholar a persisting of progesterone resistance of the endometrium after can be linked to defective deep placentation and major obstetric disorders, which preeclampsia, and preterm G. The of placentation disorders in the young J Obstet Gynecol. Full Text Full Text PDF PubMed Scopus Google A. G. The of major reproductive disorders in the Full Text Full Text PDF PubMed Scopus Google Scholar The of progesterone and of that the may as a that the for deep placentation in response to by miscarriage, or A. R. 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Full Text Full Text PDF PubMed Scopus Google Scholar Menstrual preconditioning that progesterone withdrawal bleedings or menstruations in the because of the to decidualization in the absence of pregnancy and from the and that are associated with deep It is that, in most young progesterone resistance may persist and that full is only after the of cyclic et M. of endometrial progesterone 2012; PubMed Scopus Google Scholar that in the endometrium are likely to be and complex resistance, as manifested in as is not only a of progesterone by chronic but also is associated with of in the endometrium and In this it is that cyclic endometrial decidualization by menstrual is an of preconditioning that for the vascular that is associated with deep Indeed, deep placentation the of the in the placentation which the endometrial most the It is that the pathogenesis of preeclampsia in the primigravid woman is linked with defective deep which is by a of the of the in the The of the in the pathogenesis of Gynecol Google Scholar is as the process of endometrial in for pregnancy, which of the of and vascular A of the process the and biochemical of the endometrial process is on the of cyclic and progesterone that changes at both the and the of the and clinical Reprod Med. 2007; PubMed Scopus Google Scholar of and trophoblast to and and to et L. et of spontaneous the of of of conception in clinical a Reprod. 2007; PubMed Scopus Google Scholar that the of and complications that are associated with PCOS may be related to trophoblast in the In a et A. evidence for endometrial before and during early pregnancy in women who PubMed Scopus Google Scholar used a and found evidence for endometrial in early pregnancy in women who preeclampsia. et S. 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G. et trophoblast and placentation in women with PCOS 2014; Full Text Full Text PDF PubMed Scopus Google Scholar found that and weight were significantly in the PCOS and ovary the ovulatory and The of was only significantly between and the and The of was significantly among PCOS and was significantly higher in the and in the ovulatory and A major of these studies is that (1) are based on the of the which the between and trophoblast, as is a for deep and (2) biopsy from the of the may not be for deep because is not observed in the but in the R. L. R. The are associated with disorders of deep J Obstet Gynecol. 2011; 204: Full Text Full Text PDF PubMed Scopus Google Scholar As preeclampsia and preterm birth are major obstetric risks in women with PCOS and are by defective deep R. L. R. 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Am J Obstet Gynecol 2015. Several studies have demonstrated the of in with metformin for the induction of ovulation in oligo- or anovulatory women (Table on the results of a clinical et E. of citrate metformin and citrate on induction of ovulation in women with diagnosed polycystic ovary syndrome: clinical 2006; PubMed Scopus Google Scholar proposed to use as a for the induction of ovulation metformin or to metformin to et R. A. Norman R.J. of clomiphene or the combination of both for ovulation of pregnancy, and live birth in women with polycystic ovary syndrome: a Steril. 91: Full Text Full Text PDF PubMed Scopus Google Scholar confirmed in an study that is to metformin in ovulation in anovulatory women with of clomiphene citrate for the induction of ovulation in women with anovulatory polycystic ovary et S. A. A. citrate metformin as for the treatment of anovulation in infertile patients with polycystic ovary syndrome.J Clin Endocrinol Metab. 2007; PubMed Scopus Google et E. of citrate metformin and citrate on induction of ovulation in women with diagnosed polycystic ovary syndrome: clinical 2006; PubMed Scopus Google higher of with et R.S. Zaino R.J. Demers L.M. et al.The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome.Am J Obstet Gynecol. 2007; 196: 402.e1-402.e11Abstract Full Text Full Text PDF PubMed Scopus (84) Google to et R. A. Norman R.J. of clomiphene or the combination of both for ovulation of pregnancy, and live birth in women with polycystic ovary syndrome: a Steril. 91: Full Text Full Text PDF PubMed Scopus Google the treatment for induction of clomiphene Menstrual preconditioning in polycystic ovary syndrome. Am J Obstet Gynecol As for the induction of ovulation in women with anovulatory polycystic ovary syndrome. Open table in a new tab clomiphene Brosens. Menstrual preconditioning in polycystic ovary syndrome. Am J Obstet Gynecol 2015. on the to ovulatory cycles in young patients with PCOS, are in treatment with is although it has been its long-term use may the risk of ovarian et N.S. in a cohort of infertile J Med. PubMed Scopus Google Scholar who a cohort of women who had been for infertility over an found a risk of or ovarian of CI, In a found that the use of the drug during cycles was associated with an increased risk of ovarian among both women with ovarian and those without 95% CI, In for not to an increased large cohort study by et et risk associated with of Steril. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar observed a of CI, in of although in a with after it CI, a very recent study by et S.K. A. 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K.A. of by with pregnancy in Reprod Sci. 2014; PubMed Scopus Google Scholar The clinical studies that can be used during ovulatory cycles to the of progesterone response by the presence and of In the menstruations or cyclic progesterone withdrawal bleedings may a in the preconditioning or of the endometrial progesterone the has been that the woman with full anovulatory PCOS who a pregnancy in the absence of cyclic menstruations is likely to be to endometrial progesterone resistance with increased risk of miscarriage, preeclampsia, and preterm delivery.
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