General infertility workup in times of high assisted reproductive technology efficacy
2022; Elsevier BV; Volume: 118; Issue: 1 Linguagem: Inglês
10.1016/j.fertnstert.2022.05.019
ISSN1556-5653
AutoresNikolaos P. Polyzos, Jean Marc Ayoubi, Paul Pirtea,
Tópico(s)Assisted Reproductive Technology and Twin Pregnancy
ResumoThe assessments of oocyte quality and quantity and endocrine profile have traditionally been the cornerstone of the general workup of couples with infertility. Over the years, several clinical, hormonal, and functional biomarkers have been adopted to assess ovarian function and identify endocrine disorders before assisted reproductive technology. Furthermore, the genetic workup of patients has drastically changed, introducing novel markers. This not only allowed the prediction of response to ovarian stimulation but also contributed toward the development of a safer and more efficient management of women undergoing assisted reproductive technology.The scope of this review is to provide an overview of the current and novel strategies adopted for the assessment of ovarian function and ovulatory and endocrine disorders in women planning to conceive. Furthermore, it aims to provide an insight in the role of novel genetic biomarkers and use of expanded carrier screening as part of preliminary workup of women with infertility. The assessments of oocyte quality and quantity and endocrine profile have traditionally been the cornerstone of the general workup of couples with infertility. Over the years, several clinical, hormonal, and functional biomarkers have been adopted to assess ovarian function and identify endocrine disorders before assisted reproductive technology. Furthermore, the genetic workup of patients has drastically changed, introducing novel markers. This not only allowed the prediction of response to ovarian stimulation but also contributed toward the development of a safer and more efficient management of women undergoing assisted reproductive technology. The scope of this review is to provide an overview of the current and novel strategies adopted for the assessment of ovarian function and ovulatory and endocrine disorders in women planning to conceive. Furthermore, it aims to provide an insight in the role of novel genetic biomarkers and use of expanded carrier screening as part of preliminary workup of women with infertility. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/35011 DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/35011 The improved efficacy of assisted reproductive technology (ART) and, particularly, that of cryopreservation accomplished over the last decade have drastically changed the way we conduct infertility workups. It is, thus, sound to pound how we design our strategy for working up couples with infertility in light of these far-reaching changes. This review addresses the general infertility workup conducted in women with infertility in time of high-efficacy ART. This covers 4 primary scopes: the assessment of oocyte quantity and quality, as needed for optimizing ovarian stimulation (OS) outcome and, in turn, ART results; assessment of ovulation, ovulatory disorders, and amenorrhea; assessment of other endocrine disorders, which may compound infertility; and genetic screening and expanded carrier screening (ECS). Nowadays, in the absence of relevant medical history or physical findings, a complete systematic infertility workup—to identify all potential female and male causes of infertility—should be advised after 12 months of conceptual failure in women aged 35 years, this interval is commonly shortened to 6 months and even less in women aged >40 years. The assessment of ovarian function for optimizing OS remains the cornerstone of modern ART since it may allow an individualized treatment strategy adjusted to each patient's characteristics and needs. The scope of this section is to present an overview of the most relevant biomarkers associated with ovarian reserve, ovarian response, and oocyte quality and their clinical applicability (Table 1)Table 1Summary of the most relevant biomarkers associated with ovarian reserve, ovarian response, and oocyte quality and their clinical applicability.Ovarian reserveOvarian responseOocyte qualityClinical applicabilityClinical biomarkersAge+++++++++BMI−+++++++++Hormonal biomarkersFSH++−++LH−+aMarker relevant only in patients triggered with a gonadotropin-releasing hormone agonist.−+AMH++++++++++Serum androgens (testosterone)−−++bMarker relevant mainly in women with polycystic ovary syndrome.++bMarker relevant mainly in women with polycystic ovary syndrome.Vitamins25-Hydroxyvitamin D−−++Functional biomarkersAFC++++++−+++Genetic biomarkersFMR1++−−++Gonadotropins/gonadotropin receptors FSHR++−++ rs6166, rs6165, rs1394205 FSHB gene++−+ rs10835638 LHB gene−+−+ rs1800447, rs34349826 LHCGR−+−+ rs2293275Note:"−" indicates irrelevant; "+" indicates limited relevance; "++" indicates moderate relevance; "+++" indicates significant relevance. AFC = antral follicle count; AMH = antimüllerian hormone; BMI = body mass index; FMR1 = fragile X mental retardation 1; FSH = follicle-stimulating hormone; FSHB = follitropin subunit beta; FSHR = FSH receptor; LH = luteinizing hormone; LHB = luteinizing hormone subunit beta; LHCGR = luteinizing hormone/choriogonadotropin receptor.a Marker relevant only in patients triggered with a gonadotropin-releasing hormone agonist.b Marker relevant mainly in women with polycystic ovary syndrome. Open table in a new tab Note:"−" indicates irrelevant; "+" indicates limited relevance; "++" indicates moderate relevance; "+++" indicates significant relevance. AFC = antral follicle count; AMH = antimüllerian hormone; BMI = body mass index; FMR1 = fragile X mental retardation 1; FSH = follicle-stimulating hormone; FSHB = follitropin subunit beta; FSHR = FSH receptor; LH = luteinizing hormone; LHB = luteinizing hormone subunit beta; LHCGR = luteinizing hormone/choriogonadotropin receptor. Age has traditionally been a clinical biomarker associated with oocyte quantity and quality. Women are born with a given number of nongrowing follicles (NGFs), and this number is progressively declining with age (1Wallace W.H. Kelsey T.W. Human ovarian reserve from conception to the menopause.PLoS One. 2010; 5e8772Crossref Scopus (449) Google Scholar). However, the NGF decline rate may widely vary among individuals, and only 81% of the variance in the NGF populations is because of age alone (1Wallace W.H. Kelsey T.W. Human ovarian reserve from conception to the menopause.PLoS One. 2010; 5e8772Crossref Scopus (449) Google Scholar). Ovarian surgery, gonadotoxic therapy (e.g., chemotherapy or radiotherapy), and genetic or idiopathic causes may be associated with an accelerated decline in the number of NGFs, leading to primary ovarian insufficiency (POI) (2De Vos M. Devroey P. Fauser B.C. Primary ovarian insufficiency.Lancet. 2010; 376: 911-921Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). In this context, despite the clear association between age and the number of NGFs, its predictive ability for ovarian response to stimulation is limited (3Broer S.L. Dolleman M. van Disseldorp J. Broeze K.A. Opmeer B.C. Bossuyt P.M. et al.Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis.Fertil Steril. 2013; 100: 420-429.e7Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 4Broer S.L. van Disseldorp J. Broeze K.A. Dolleman M. Opmeer B.C. Bossuyt P. et al.Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach.Hum Reprod Update. 2013; 19: 26-36Crossref PubMed Scopus (284) Google Scholar). Still, age is by far the most reliable biomarker for the prediction of oocyte quality, given that the embryo euploidy rates show a consistent continuous decline with age starting from approximately the age of 36 years (5Franasiak J.M. Forman E.J. Hong K.H. Werner M.D. Upham K.M. Treff N.R. et al.The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening.Fertil Steril. 2014; 101: 656-663.e1Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar). Studies on the effect of body mass index (BMI) on oocyte quantity and quality have been controversial. Although obesity is very frequent among women with polycystic ovary syndrome (PCOS) (6Ollila M.M. Piltonen T. Puukka K. Ruokonen A. Jarvelin M.R. Tapanainen J.S. et al.Weight gain and dyslipidemia in early adulthood associate with polycystic ovary syndrome: prospective cohort study.J Clin Endocrinol Metab. 2016; 101: 739-747Crossref PubMed Scopus (75) Google Scholar) and menopausal patients (7Davis S.R. Castelo-Branco C. Chedraui P. Lumsden M.A. Nappi R.E. Shah D. et al.Understanding weight gain at menopause.Climacteric. 2012; 15: 419-429Crossref PubMed Scopus (312) Google Scholar), BMI is not independently associated with ovarian reserve. However, BMI does affect response to stimulation because it is inversely associated with the circulating follicle-stimulating hormone (FSH) level after exogenous administration (8Steinkampf M.P. Hammond K.R. Nichols J.E. Slayden S.H. Effect of obesity on recombinant follicle-stimulating hormone absorption: subcutaneous versus intramuscular administration.Fertil Steril. 2003; 80: 99-102Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Women with obesity are at increased risk of an inadequate response leading to ART cancellation (9Loh S. Wang J.X. Matthews C.D. The influence of body mass index, basal FSH and age on the response to gonadotrophin stimulation in non-polycystic ovarian syndrome patients.Hum Reprod. 2002; 17: 1207-1211Crossref PubMed Google Scholar) and often require dose adjustments (10Christensen M.W. Ingerslev H.J. Degn B. Kesmodel U.S. Effect of female body mass index on oocyte quantity in fertility treatments (IVF): treatment cycle number is a possible effect modifier. A register-based cohort study.PLoS One. 2016; 11e0163393Crossref Scopus (13) Google Scholar). Therefore, BMI should always be taken into consideration when tailoring treatment dose. Regarding oocyte quality, inflammation and oxidative stress may impair oocytes' meiotic and cytoplasmic maturation, resulting in a reduction of their developmental competence for fertilization and preimplantation embryo development (11Snider A.P. Wood J.R. Obesity induces ovarian inflammation and reduces oocyte quality.Reproduction. 2019; 158: R79-R90Crossref PubMed Scopus (71) Google Scholar). In a study analyzing the follicular fluid of patients undergoing OS, women with obesity had an altered follicular environment, with increased insulin, lactate, triglyceride, and C-reactive protein levels, which could be associated with worse reproductive outcomes (12Robker R.L. Akison L.K. Bennett B.D. Thrupp P.N. Chura L.R. Russell D.L. et al.Obese women exhibit differences in ovarian metabolites, hormones, and gene expression compared with moderate-weight women.J Clin Endocrinol Metab. 2009; 94: 1533-1540Crossref PubMed Scopus (256) Google Scholar). The potential mechanism for oocyte organelle damage in obesity appears to be lipotoxicity (13Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity's impact.Fertil Steril. 2017; 107: 840-847Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). The excess fatty acids obtained from the diet result in elevated levels of free fatty acids in the follicular fluid, and these levels are correlated with abnormal morphology of cumulus-oocyte complexes (14Jungheim E.S. Macones G.A. Odem R.R. Patterson B.W. Lanzendorf S.E. Ratts V.S. et al.Associations between free fatty acids, cumulus oocyte complex morphology and ovarian function during in vitro fertilization.Fertil Steril. 2011; 95: 1970-1974Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). Furthermore, obesity results in a twofold increased production of reactive oxygen species (15Igosheva N. Abramov A.Y. Poston L. Eckert J.J. Fleming T.P. Duchen M.R. et al.Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes.PLoS One. 2010; 5e10074Crossref PubMed Scopus (328) Google Scholar), the reason for which is considered to be a chronic low-grade inflammatory state. Obese women have lower circulating levels of the anti-inflammatory adipokine adiponectin (13Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity's impact.Fertil Steril. 2017; 107: 840-847Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar), and the C-reactive protein levels are elevated in the follicular fluid (12Robker R.L. Akison L.K. Bennett B.D. Thrupp P.N. Chura L.R. Russell D.L. et al.Obese women exhibit differences in ovarian metabolites, hormones, and gene expression compared with moderate-weight women.J Clin Endocrinol Metab. 2009; 94: 1533-1540Crossref PubMed Scopus (256) Google Scholar). Finally, the elevated leptin levels observed in women with obesity may also affect oocyte and embryo quality (16Catteau A. Caillon H. Barriere P. Denis M.G. Masson D. Freour T. Leptin and its potential interest in assisted reproduction cycles.Hum Reprod Update. 2016; 22: 320-341Crossref PubMed Scopus (34) Google Scholar) and granulosa cell function (17Lin X.H. Wang H. Wu D.D. Ullah K. Yu T.T. Ur Rahman T. et al.High leptin level attenuates embryo development in overweight/obese infertile women by inhibiting proliferation and promotes apoptosis in granule cell.Horm Metab Res. 2017; 49: 534-541Crossref PubMed Scopus (0) Google Scholar). As far as the endometrium is concerned, although there are studies suggesting that obesity negatively affects endometrial receptivity, data are conflicting (13Broughton D.E. Moley K.H. Obesity and female infertility: potential mediators of obesity's impact.Fertil Steril. 2017; 107: 840-847Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). All of the aforementioned may actually explain the evidence supporting a detrimental effect of high BMI on live birth rates (LBRs) (18Sermondade N. Huberlant S. Bourhis-Lefebvre V. Arbo E. Gallot V. Colombani M. et al.Female obesity is negatively associated with live birth rate following IVF: a systematic review and meta-analysis.Hum Reprod Update. 2019; 25: 439-451Crossref PubMed Scopus (102) Google Scholar) and cumulative live birth rates (CLBRs) (19Ding W. Zhang F.L. Liu X.C. Hu L.L. Dai S.J. Li G. et al.Impact of female obesity on cumulative live birth rates in the first complete ovarian stimulation cycle.Front Endocrinol (Lausanne). 2019; 10: 516Crossref PubMed Google Scholar) among patients with infertility undergoing in vitro fertilization (IVF) and justify proper counseling of women with obesity and infertility to lose weight before initiating treatment. Basal FSH has been one of the first biomarkers for the pretreatment assessment of ovarian function. However, although the basal FSH levels are elevated on menstrual days 2–4 in women with diminished ovarian reserve (DOR), its sensitivity and specificity across the whole field of ovarian response is rather limited (3Broer S.L. Dolleman M. van Disseldorp J. Broeze K.A. Opmeer B.C. Bossuyt P.M. et al.Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis.Fertil Steril. 2013; 100: 420-429.e7Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 4Broer S.L. van Disseldorp J. Broeze K.A. Dolleman M. Opmeer B.C. Bossuyt P. et al.Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach.Hum Reprod Update. 2013; 19: 26-36Crossref PubMed Scopus (284) Google Scholar). Furthermore, FSH is not a biomarker of oocyte quality (20Thum M.Y. Kalu E. Abdalla H. Elevated basal FSH and embryo quality: lessons from extended culture embryos: raised FSH and blastocyst quality.J Assist Reprod Genet. 2009; 26: 313-318Crossref PubMed Scopus (0) Google Scholar). Basal estradiol (E2) alone should not be used as a marker of ovarian reserve. However, it is essential for the correct interpretation of a normal basal serum FSH value. In this context, an elevated serum E2 level (which can occur in advanced-age patients) can lower an otherwise elevated basal FSH level into the normal range, thereby causing a misinterpretation of the test (21Practice Committee of the American Society for Reproductive MedicineTesting and interpreting measures of ovarian reserve: a committee opinion.Fertil Steril. 2020; 114: 1151-1157Abstract Full Text Full Text PDF PubMed Google Scholar). Therefore, careful interpretation is needed when a basal FSH level is normal but the E2 level is elevated (>60 to 80 pg/mL) because this suggests ovarian dysfunction attributable to DOR (22Evers J.L. Slaats P. Land J.A. Dumoulin J.C. Dunselman G.A. Elevated levels of basal estradiol-17beta predict poor response in patients with normal basal levels of follicle-stimulating hormone undergoing in vitro fertilization.Fertil Steril. 1998; 69: 1010-1014Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). On the other hand, the role of basal luteinizing hormone (LH) as part of fertility workup is not very clear. The basal LH levels are not associated with ovarian reserve and oocyte quality (23Kassab A. Sabatini L. Lieberman G. Tozer A. Zosmer A. Davis C. et al.Does measuring early basal serum follicular luteinising [correction of lutinising] hormone assist in predicting in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcome?.Reprod Biol Endocrinol. 2007; 5: 32Crossref PubMed Scopus (0) Google Scholar). However, in the modern era of gonadotropin-releasing hormone (GnRH) agonist triggering and freeze-all (24Devroey P. Polyzos N.P. Blockeel C. An OHSS-free clinic by segmentation of IVF treatment.Hum Reprod. 2011; 26: 2593-2597Crossref PubMed Scopus (319) Google Scholar, 25Humaidan P. Polyzos N.P. Human chorionic gonadotropin vs. gonadotropin-releasing hormone agonist trigger in assisted reproductive technology-"the king is dead, long live the king.Fertil Steril. 2014; 102: 339-341Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), a large retrospective study has shown that low basal LH levels are associated with a suboptimal oocyte yield after trigger with a GnRH agonist, and thus, it may be considered when a freeze-all strategy is planned (26Popovic-Todorovic B. Santos-Ribeiro S. Drakopoulos P. De Vos M. Racca A. Mackens S. et al.Predicting suboptimal oocyte yield following GnRH agonist trigger by measuring serum LH at the start of ovarian stimulation.Hum Reprod. 2019; 34: 2027-2035Crossref PubMed Scopus (13) Google Scholar). Antimüllerian hormone (AMH) has undeniably been one of the pretreatment biomarkers that revolutionized the general workup of patients with infertility and has been rapidly adopted in everyday clinical practice. Being produced by the granulosa cells of large preantral and antral follicles, AMH has proven to be an excellent biomarker of ovarian reserve (27La Marca A. Broekmans F.J. Volpe A. Fauser B.C. Macklon N.S. ESHRE Special Interest Group for Reproductive Endocrinology--AMH Round Table. Anti-Mullerian hormone (AMH): what do we still need to know?.Hum Reprod. 2009; 24: 2264-2275Crossref PubMed Scopus (0) Google Scholar) with an excellent ability to predict the extremes of ovarian response (3Broer S.L. Dolleman M. van Disseldorp J. Broeze K.A. Opmeer B.C. Bossuyt P.M. et al.Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis.Fertil Steril. 2013; 100: 420-429.e7Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 4Broer S.L. van Disseldorp J. Broeze K.A. Dolleman M. Opmeer B.C. Bossuyt P. et al.Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach.Hum Reprod Update. 2013; 19: 26-36Crossref PubMed Scopus (284) Google Scholar). A clear advantage vis-a-vis other biomarkers is its remarkably low variability, either between different treatment cycles (low intercycle variability) (28van Disseldorp J. Lambalk C.B. Kwee J. Looman C.W. Eijkemans M.J. Fauser B.C. et al.Comparison of inter- and intra-cycle variability of anti-Mullerian hormone and antral follicle counts.Hum Reprod. 2010; 25: 221-227Crossref PubMed Scopus (260) Google Scholar) or during the same menstrual cycle (low intracycle variability) (28van Disseldorp J. Lambalk C.B. Kwee J. Looman C.W. Eijkemans M.J. Fauser B.C. et al.Comparison of inter- and intra-cycle variability of anti-Mullerian hormone and antral follicle counts.Hum Reprod. 2010; 25: 221-227Crossref PubMed Scopus (260) Google Scholar), making it a very reliable marker for assessing ovarian reserve. Still, careful consideration for other factors is essential when interpreting AMH in a clinical setting, given that lifestyle determinants, such as smoking and the use of combined contraceptives (29Kallio S. Puurunen J. Ruokonen A. Vaskivuo T. Piltonen T. Tapanainen J.S. Antimullerian hormone levels decrease in women using combined contraception independently of administration route.Fertil Steril. 2013; 99: 1305-1310Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 30Dolleman M. Verschuren W.M. Eijkemans M.J. Dolle M.E. Jansen E.H. Broekmans F.J. et al.Reproductive and lifestyle determinants of anti-Mullerian hormone in a large population-based study.J Clin Endocrinol Metab. 2013; 98: 2106-2115Crossref PubMed Scopus (125) Google Scholar), may suppress the serum AMH levels, an effect which seems reversible and confined to current use (30Dolleman M. Verschuren W.M. Eijkemans M.J. Dolle M.E. Jansen E.H. Broekmans F.J. et al.Reproductive and lifestyle determinants of anti-Mullerian hormone in a large population-based study.J Clin Endocrinol Metab. 2013; 98: 2106-2115Crossref PubMed Scopus (125) Google Scholar). In terms on ovarian response to stimulation, AMH demonstrates excellent ability to predict low and excessive response (3Broer S.L. Dolleman M. van Disseldorp J. Broeze K.A. Opmeer B.C. Bossuyt P.M. et al.Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis.Fertil Steril. 2013; 100: 420-429.e7Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 4Broer S.L. van Disseldorp J. Broeze K.A. Dolleman M. Opmeer B.C. Bossuyt P. et al.Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach.Hum Reprod Update. 2013; 19: 26-36Crossref PubMed Scopus (284) Google Scholar), with a predictive ability that remains high at least up to 12 months after AMH measurement (31Polyzos N.P. Nelson S.M. Stoop D. Nwoye M. Humaidan P. Anckaert E. et al.Does the time interval between antimullerian hormone serum sampling and initiation of ovarian stimulation affect its predictive ability in in vitro fertilization-intracytoplasmic sperm injection cycles with a gonadotropin-releasing hormone antagonist? A retrospective single-center study.Fertil Steril. 2013; 100: 438-444Abstract Full Text Full Text PDF PubMed Google Scholar). Nonetheless, there is only limited association between AMH and oocyte quality. Although early reports associated the serum AMH levels with oocyte quality (32Ebner T. Sommergruber M. Moser M. Shebl O. Schreier-Lechner E. Tews G. Basal level of anti-Mullerian hormone is associated with oocyte quality in stimulated cycles.Hum Reprod. 2006; 21: 2022-2026Crossref PubMed Scopus (225) Google Scholar), more recent studies were controversial, supporting the AMH has either modest or no ability to predict the LBR and CLBR (33Hamdine O. Eijkemans M.J.C. Lentjes E.G.W. Torrance H.L. Macklon N.S. Fauser B.C.J.M. et al.Antimullerian hormone: prediction of cumulative live birth in gonadotropin-releasing hormone antagonist treatment for in vitro fertilization.Fertil Steril. 2015; 104: 891-898.e2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 34Tal R. Seifer D.B. Wantman E. Baker V. Tal O. Antimullerian hormone as a predictor of live birth following assisted reproduction: an analysis of 85,062 fresh and thawed cycles from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database for 2012-2013.Fertil Steril. 2018; 109: 258-265Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). In this context, it is more likely that AMH is not a biomarker associated with oocyte quality, considering that low or high basal AMH levels are not associated with spontaneous conception rates (35Steiner A.Z. Pritchard D. Stanczyk F.Z. Kesner J.S. Meadows J.W. Herring A.H. et al.Association between biomarkers of ovarian reserve and infertility among older women of reproductive age.JAMA. 2017; 318: 1367-1376Crossref PubMed Scopus (176) Google Scholar). The role of serum androgens in patients' general workup appears to be limited and potentially useful only in certain patients' categories. Several studies demonstrated that the testosterone levels may be lower in women with DOR (36Gleicher N. Kim A. Weghofer A. Kushnir V.A. Shohat-Tal A. Lazzaroni E. et al.Hypoandrogenism in association with diminished functional ovarian reserve.Hum Reprod. 2013; 28: 1084-1091Crossref PubMed Scopus (71) Google Scholar, 37Drakopoulos P. Bardhi E. Scherer S. Blockeel C. Verheyen G. Anckaert E. et al.Androgens and anti-Mullerian hormone in infertile patients.Reprod Sci. 2021; 28: 2816-2821Crossref PubMed Scopus (0) Google Scholar, 38Lin L.T. Li C.J. Tsui K.H. Serum testosterone levels are positively associated with serum anti-mullerian hormone levels in infertile women.Sci Rep. 2021; 11: 6336Crossref PubMed Scopus (0) Google Scholar). However, this positive association between testosterone and ovarian reserve markers needs to be interpreted with great caution, given that ovarian androgens are produced by follicular theca cells and the key reason for decreased androgen levels in women with DOR is the reduction of the number of follicles, whereas others have shown that the serum androgen levels decline with age from the early reproductive years (39Davison S.L. Bell R. Donath S. Montalto J.G. Davis S.R. Androgen levels in adult females: changes with age, menopause, and oophorectomy.J Clin Endocrinol Metab. 2005; 90: 3847-3853Crossref PubMed Scopus (711) Google Scholar). Therefore, the clinical applicability of testosterone as a marker of reserve remains limited. On the other hand, serum androgens may be associated with oocyte quality in women with PCOS serum androgen determination is a part of pretreatment counseling for these patients. Early experimental studies of cultured mouse follicles have shown that exposure to testosterone may impair oocyte meiotic competence (40Romero S. Smitz J. Exposing cultured mouse ovarian follicles under increased gonadotropin tonus to aromatizable androgens influences the steroid balance and reduces oocyte meiotic capacity.Endocrine. 2010; 38: 243-253Crossref PubMed Scopus (15) Google Scholar) and that hyperandrogenism alters intrafollicular microenvironment, leading to abnormal folliculogenesis and premature arrest of immature developing oocytes (41Wood J.R. Dumesic D.A. Abbott D.H. Strauss III, J.F. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis.J Clin Endocrinol Metab. 2007; 92: 705-713Crossref PubMed Scopus (219) Google Scholar), and this may partially explain why hyperandrogenic PCOS phenotypes may have, according to certain, lower CLBR than their normoandrogenic counterparts (42De Vos M. Pareyn S. Drakopoulos P. Raimundo J.M. Anckaert E. Santos-Ribeiro S. et al.Cumulative live birth rates after IVF in patients with polycystic ovaries: phenotype matters.Reprod Biomed Online. 2018; 37: 163-171Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). However, this association does not at all suggest a cause-effect relationship between excess androgens and oocyte quality in PCOS. Hyperandrogenism in normal-weight women with PCOS is associated with preferential intraabdominal fat deposition and an increased population of small subcutaneous abdominal adipocytes that can promote metabolic dysfunction (43Dumesic D.A. Akopians A.L. Madrigal V.K. Ramirez E. Margolis D.J. Sarma M.K. et al.Hyperandrogenism accompanies increased intra-abdominal fat storage in normal weight polycystic ovary syndrome women.J Clin Endocrinol Metab. 2016; 101: 4178-4188Crossref PubMed Scopus (97) Google Scholar). The most common provocative factors of ovarian hyperandrogenism appear to be obesity and insulin resistance, which occur in 50% of the patients and have heritable components (44Rosenfield R.L. Ehrmann D.A. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited.Endocr Rev. 2016; 37: 467-520Crossref PubMed Scopus (458) Google Scholar). In this context, obesity up-regulates ovarian androgen production primarily via insulin-resistant hyperinsulinemia and, to some extent, via inflammatory cytokines (44Rosenfield R.L. Ehrmann D.A. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited.Endocr Rev. 2016; 37: 467-520Crossref PubMed Scopus (458) Google Scholar). Serum 25-hydroxyvitamin D has been a common biomarker in th
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