{"paper_id":"dfbdf39f-8778-4f29-86bd-69e6112b8a6f","body_text":"FEMALE INFERTILITY AND ASSISTED REPRODUCTIVE MEDICINE (Y ZHAO, SECTION EDITOR)\nFemale Fertility Assessment\nSouzana Choussein & Nikos F. Vlahos\nPublished online: 23 August 2012\n# Springer Science+Business Media, LLC 2012\nCurr Obstet Gynecol Rep (2012) 1:174 –181\nDOI 10.1007/s13669-012-0022-7\nAbstract A fastidious fertility evaluation designed to dis-\ncern all factors contributing to a couple ’s inability to con-\nceive is the quintessential approach to a well-justified, cost-\neffective treatment plan. The purpose of this review is to\noutline the steps of female infertility evaluation as well as all\nevidence-based methods in a reproductive endocrinologist ’s\narmamentarium to perform it. Evaluation should always\nstart with the least invasive approaches for detection of the\nmost common causes of infertility. The most common iden-\ntifiable causes of female infertility include ovulatory disor-\nders, tubal blockade or other reproductive tract pathology\n(irregular cervical mucus production, endometriosis, pelvic\nadhesions), and/or other medical condition interacting with\nthe above (hyperprolactinemia, thyroid disorder). Incessant\nadvancement of Assisted Reproductive Technology techni-\nques renders more and more infertility causes amenable to\ntreatment; a rational use of available approaches in terms of\nboth personalized feasibility and cost-effectiveness should\nbe applied.\nKeywords Female infertility . Assisted reproductive\ntechnology . Evaluation of ovulatory function .\nEvaluation of female reproductive tract . Tubal patency .\nHysterosalpingo-contrast sonography (HyCoSy) .\nEvaluation of ovarian reserve . Serum anti-müllerian\nhormone (AMH)\nIntroduction\nAccording to the Practice Committee of the American Soci-\nety for Reproductive Medicine definition of infertility, a\ndiagnostic workup for infertility is evidenced for females\nwho fail to achieve a successful pregnancy after 12 months\nor more of regular unprotected intercourse. Earlier evalua-\ntion and treatment is warranted after 6 months of fruitless\nattempts to conceive for women older than age 35 years and\nmay be justified based on medical history and physical\nfindings [ 1], including but not limited to history of oligo-\nor amenorrhea, known or suspected uterine/tubal/peritoneal\ndisease or stage III–IVendometriosis, and known or suspected\nmale subfertility [ 2–4]. This definition has been censured as\nvague due to the fact that treatment-independent pregnancy\nrates after 12 months of trying have been shown to be as high\nas 61 % among couples defined as “infertile” [5, 6]. Instead,\nthe term subfertility often is used to describe the failure to\nconceive unless the couple has been proven to be sterile.\nFecundability, the probability of achieving a pregnancy in a\ngiven menstrual cycle, also is utilized as a more accurate\ndescriptor because it recognizes varying degrees of infertility.\nA system of prognostic grading in conjunction with state-\nments regarding the couple ’s fertility history and diagnosis\nhas been proposed to diminish confusing terminology, yet has\nnot been widely accepted [7].\nBecause approximately 85 % of couples will conceive\nwithin 12 months of attempting pregnancy —with fecund-\nability progressively decreasing over time —evaluation may\nbe indicated for as many as 15 %. Diagnostic assessment for\nfemale infertility should be performed in a systematic, ex-\npeditious, and cost-effective mode to determine all relevant\nfactors, starting with the least invasive approaches for de-\ntection of the most common causes of infertility. Evaluation\nof both partners should be performed concurrently [ 8].\nRecognition, evaluation, and treatment of infertility can\nbe a stressful and emotionally taxing process for the woman\n[9]. Involved health care professionals have to bear in mind\nthat under no circumstances should the medicalization of\ninfertility bring about disregard for the woman ’s emotional\nS. Choussein : N. F. Vlahos ( *)\n2nd Department of Obstetrics and Gynecology,\nSchool of Medicine, University of Athens, Aretaieion Hospital,\n76 V as. Sofias Av.,\n11527 Athens, Greece\ne-mail: office2888@gmail.com\ne-mail: souzanachoussein@gmail.com\nS. Choussein\nDepartment of Obstetrics, Gynecology and Reproductive Biology,\nBrigham & Women ’s Hospital, Harvard Medical School,\n75 Francis Street, ASB1-3,\nBoston, MA 02115, USA\ne-mail: schoussein@partners.org\n\nstate, because psychological interventions have been found to\nimprove some patients’ chances of becoming pregnant [10].\nHistory and Physical Examination\nFindings on history and physical examination may imply the\ncause of infertility, narrowing the focus of the diagnostic\nevaluation. This is why primary counseling should include a\ncomprehensive medical, reproductive, and family history\nand performance of a meticulous physical examination.\nAppropriate history includes several points starting with\nduration of infertility —defined as the period of time during\nwhich unprotected intercourse has taken place —as well as\nthe results of any previous evaluation and therapy. Menstru-\nal history, including age of menarche, cycle length and\ncharacteristics, presence of molimina, and presence/severity\nof dysmenorrhea, should be queried. Complete obstetrical\nhistory outlining gravidity, parity, pregnancy outcomes, and\nrelated complications along with medical and surgical his-\ntory has to be requested. In addition, gynecological history,\nincluding pelvic inflammatory disease, sexually transmitted\ninfections, and treatment of any previous abnormal Pap\nsmears, as well as sexual history pertaining to coital\nfrequency and sexual dysfunction, should be obtained.\nPresence of thyroid disease, galactorrhea, hirsutism, pel-\nvic or abdominal pain, and dyspareunia has to be deter-\nmined. Past use of contraceptive methods together with\ncurrent medications and alle rgies should be disclosed\nas well as any exposure to known environmental/occu-\npation-associated toxin, tobacco, alcohol or illicit/recre-\national drug, or chemotherapeutic agents. Determining\nany family history of birth defects, mental retardation,\nearly menopause, and reproductive failure/compromise is\nof equal importance [ 8].\nPhysical examination should evaluate for signs indicative\nof potential infertility causes. Because association between\nextreme values of body mass index (BMI) and ovulatory\ninfertility has been documented [ 11, 12], patient ’s weight\nand BMI should be noted, as well as blood pressure and\npulse. A thorough physical examination should identify\nthyroid enlargement, nodules, or tenderness suggestive of\nthyroid dysfunction, breast secretions due to hyperprolacti-\nnemia, and virilizing effects of androgen excess (hirsutism,\nacne, hair thinning, male pattern baldness), due to adrenal\ndisorder or polycystic ovary syndrome. Pelvic examination\nto assess vaginal/cervical anatomical abnormalities or dis-\ncharge, as well as masses or tenderness in the adnexa or\npouch of Douglas should evaluate for the presence of mül-\nlerian anomalies, infection, and pelvic inflammatory disease\nor endometriosis. Size, shape position, and mobility of\nuterus has to be documented to exclude leiomyomas, endo-\nmetriosis, or uterine adhesive disease [ 8].\nEvaluation of Ovulatory Function\nOvulatory disorders can be identified in 15 –25 % of couples\npresenting with infertility and makes up approximately\n40 % of female infertility [ 13, 14].\nIrregular or absent menstruation and molimina are com-\nmonly, but not always, revealing of the dysfunction. Poten-\ntial causes of ovulatory dysfunction include most commonly\npolycystic ovary syndrome and thyroid disorders, or accom-\npany primary hypothalamic-pituitary dysfunction (intense\nexercise, eating disorders, hyperprolactinemia, pituitary ad-\nenoma, Kallmann ’s syndrome). Often anovulatory dysfunc-\ntion may be related to decreased ovarian reserve (as will be\ndiscussed later) or congenital adrenal hyperplasia.\nWhen oligomenorrhea or amenorrhea is reported in\npatient’s menstrual history, diagnosis of anovulation is very\nlikely. A basic hormonal evaluation, including follicle-\nstimulating hormone (FSH), estradiol, thyroid-stimulating\nhormone (TSH), and prolactin, as well as a serum HCG, is\na cost-efficient approach to establish the underlying etiology\nin the majority of the cases. However, ovulatory function\nassessment in infertile women with normal menses (monthly\nepisodes of bleeding) necessitates an objective marker.\nBasal body temperature (BBT) recording throughout the\ncycle can be an undemanding ovulation index. Ovulatory\ncycles are principally inferred by a biphasic BBT pattern\nand anovulatory by a monophasic one; however, several\ncases of ovulatory women failing to document a biphasic\nBBT charting have been reported [ 15]. Because the BBT\nnadir is thought to precede ovulation, it has been proposed\nthat the low temperature could be a useful predictor of\novulation. BBT nadir timing has been shown to be scattered\nfrom day −\n4 to day +6 of actual ovulation, proving itself as\nan unreliable ovulation marker [ 16]. Some providers suggest\nthat the shift in BBT during a menstrual cycle is more\nreliable as a confirmatory marker of ovulation than the\nBBT nadir as a predictor of ovulation. The BBT test cannot\naccurately define ovulation and is no more deemed a pref-\nerable method for assessing ovulatory function for most\ninfertile women [ 8].\nOvulation can simply be confirmed by a mid-luteal\nprogesterone level measurement. In the light of the\nnormal range in cycle length, serum progesterone levels\nshould be obtained approximately 1 week before the\nexpected onset of the upcoming menstrual period [ 8].\nFor a typical 28-day cycle, this coincides with\nday cycle day 21. A progesterone level >3 ng/ml is a\nputative but credible marker of ovulation occurrence\n[17]. However, failure of ovulation in which, despite\nthe absence of follicular rupture and release of the\noocyte, the unruptured follicle undergoes luteinization\nunder the action of luteinizing hormone (LH) and nor-\nmal production of progesterone and duration of the\nCurr Obstet Gynecol Rep (2012) 1:174 –181 175\n\nluteal phase of the cycle are evidenced, has been widely\nreported and is defined as luteinized unruptured follicle\nsyndrome [ 18–20]. Urinary over-the-counter ovulation\nprediction kits, by determini ng LH can detect effectively\nthe LH surge, which is the prelude to ovulation. Thus,\nurinary LH surge determination provides indirect evi-\ndence of imminent ovulation and denotes the 3-day\ninterval (the day of LH surge and the following two\n[21]) during the course of which conception rates are\noptimal, serving to maximize the user ’s knowledge of\nthe fertile window and thus ti me intercourse or insem-\nination. However, additional confirmatory testing occa-\nsionally may be necessary, because a 7 % false-positive\nrate has been reported [ 22].\nEndometrial biopsy (EMB) and subsequent histological\nevaluation can confirm the secretory uterine lining, which is\nentailed and maintained by progesterone, implying ovula-\ntion. Histological dating of timed endometrial biopsy tissue\naccording to the criteria of Noyes et al. [ 23], has long been\nestablished as the “gold standard ” for assessing the func-\ntional integrity of the corpus luteum and diagnosing luteal\nphase deficiency (LPD) [ 8]. However, results from a large,\nprospective, multicenter study demonstrated that histologi-\ncal dating of the endometrium fails to discriminate between\nwomen of fertile and infertile couples [ 24]; this along with\nproven lack of both accuracy and precision [ 25] renders the\ntest an unsound, expensive, painful method to guide the\nclinical management of women with reproductive failure\n[26]. In view of these, endometrial biopsy is no longer\nrecommended as a diagnostic tool for ovulatory or lu-\nteal function evaluation in infertile women and should\nonly be applicable for women in whom specific endo-\nmetrial pathology (e.g., neoplasia, chronic endometritis)\nis highly suspected [ 8, 27].\nSerial sonographic examinations can track the sizes of\novarian follicles throughout the preovulatory phase of the\nmenstrual cycle, detect the collapse of the dominant follicle\nat ovulation, and identify that the collapsed cyst has reac-\ncumulated with fluid to become the progesterone producing\ncorpus luteum cyst (following ovulation) [ 28]. This can be\nburdensome for the patient, and given the relevant cost, this\nmethod is only recommended for women in whom other\nmethods proved inefficient to elucidate any ovulation-\nassociated disorder and those undergoing drug-induced\novarian stimulation [ 8].\nThyroid-stimulating hormone and prolactin levels also\nshould be measured in anovulatory women to identify thy-\nroid dysfunction and/or hyperprolactinemia. In women pre-\nsenting with amenorrhea, serum FSH and estradiol levels\nhave to be determined so that differentiation between ovar-\nian failure (high FSH, low es tradiol) and hypothalamic\namenorrhea (low FSH, low estradiol) is feasible and appro-\npriate management approach/counseling is applied.\nHaving confirmed tubal patency and normality of semen\nanalysis (discussed below), if infertile, anovulatory women,\nwho have successfully undergone three to six cycles of\novulation induction, still fail to conceive, additional diag-\nnostic evaluation should be performed or, if evaluation is\nover, other treatment options should be considered [ 8].\nSemen Analysis\nAppropriate semen laboratory testing is an integral compo-\nnent of the proper evaluation of the couple presenting with\ninfertility. The assessment of male fertility is based on\nexamination of a freshly produced ejaculate submitted to\nthe laboratory within 1 hour of collection, which takes place\nafter 2 to 7 days of abstinence have elapsed [ 29]. A semen\nvolume of 1.5 ml and a sperm count (or sperm concentra-\ntion) of more than 15 million sperm per milliliter is consid-\nered normal, according to the World Health Organization.\nAccording to WHO, lower reference limit for total sperm\ncount (or total sperm number) defined as the total number of\nspermatozoa in the entire ejaculate is 39 million per ejacu-\nlate. With regard to total spermatozoa motility and vitality,\nWHO sets a value of 40 % and 58 % live, respectively. A\npercentage of morphologically normal forms as high as 4 %\nrenders the sample normal [ 30].\nEvaluation of Female Reproductive Tract\nCervical Factors\nIrregular cervical mucus production or sperm-mucous inter-\naction are hardly ever demonstrated as the leading cause of\ninfertility [8]. The postcoital test (PCT) is scheduled close\nto ovulation and involves examination of active sperm pres-\nence in cervical mucus obtained from the female partner\nwithin hours after sexual intercourse. Despite its long-\nstanding use in the female infertility evaluation, PCT has\nbeen proved to lack validity as a diagnostic tool for infertil-\nity [ 31, 32]. Due to its poor to fair reproducibility among\ntrained observers [ 33], burden presented to patients and its\ninsufficiency to predict conception achievement [ 34], it\nrarely affects clinical management and its incorporation in\nthe routine workup for infertility evaluation is no longer\nrecommended [ 8].\nUterine Cavity\nUterine anatomy is a fairly unusual infertility cause that has\nto be ruled out [ 8]. Hysterosalpingography (HSG) is\nregarded as an effective screening assessment of the internal\nuterine cavity architecture and tubal patency but provides no\ninformation regarding ovarian morphology.\n176 Curr Obstet Gynecol Rep (2012) 1:174 –181\n\nHSG entails the injection of a radio-opaque material into\nthe cervical canal, usually under fluoroscopy; it is used to\ninvestigate shape and size of the uterine cavity and deter-\nmine the presence of any uterine filling defects (endometrial\npolyps, adhesions, submucous myomas) or congenital mül-\nlerian anomalies (unicornuate, septate, bicornuate uterus),\nwhich can adversely affect fertility.\nHSG is reported to have a sensitivity as low as 50 % and\na positive predictive value of 28.6 % for polypoid lesions\n[35]. Although the HSG is regarded to be safe, the proce-\ndure exposes patients to ionizing radiation and potentially\nallergenic contrast media [ 36].\nTransvaginal sonography (TVS) is considered a sim-\nple and innocuous examination with quite good accura-\ncy for the evaluation of the uterine cavity [ 37–39].\nWhen conventional TVS is not able to ensure uterine\ncavity normality or detects an abnormality but is proved\ninsufficient to define its nature, saline infusion sonohys-\nterography (SIS) can be utilized [ 40, 41].\nSonohysterography uses infusion of sterile saline through\na soft plastic catheter placed in the cervix in conjunction\nwith transvaginal ultrasound. Sonohysterography has been\nshown to have a diagnostic accuracy of 100 % compared\nwith hysteroscopy, defined as the “gold standard, ” for pol-\nypoid lesions (polyps or myomas) and 100 % specificity for\nuterine malformations. In diagnosis of intrauterine adhe-\nsions, SHG has limited accuracy, similar to that obtained\nby HSG, with a high false-positive diagnosis rate [ 35].\nHysterosalpingo-contrast sonography (HyCoSy) is an ul-\ntrasound procedure used to assess abnormalities of the uter-\nine cavity, myometrium, and adnexal architecture, as well as\npatency of the fallopian tubes before and after transcervical\ninjection of a noniodine contrast agent. This method has\nproven to be a time-efficient, safe, and well-tolerated alter-\nnative to HSG with comparable accuracy in the assessment\nof the uterine cavity and tubal patency [ 36, 42].\nHysteroscopy is the authoritative method for the diagnosis\nand treatment of intrauterine abnormalities. However, due to\nits high cost and invasiveness, it is advised to be reserved for\nsupplemental evaluation and treatment of pathology already\ndetermined by the other, less invasive methods [8].\nTubal Patency\nTubal pathology accounts for 25–35 % of female factor infer-\ntility, with more than half of the cases due to pelvic inflam-\nmatory disease (PID) [ 43]. A history of ectopic pregnancy,\npelvic PID, endometriosis, or prior pelvic surgery can be\nconsidered as risk factors for tubal factor fertility [ 44].\nHysterosalpingography (HSG) is the standard first-line\ntest to evaluate tubal patency and also may be of therapeutic\nbenefit with higher fecundity rates reported several months\nafter the procedure [ 8, 45]. If HSG indicates patent tubes,\ntubal blockage is very unlikely [ 46]. However, almost 60 %\nof patients in whom HSG showed proximal tubal blockage\nhad been proved to have patent tubes by a second HSG\nperformed 1 month later or on subsequent laparoscopy [ 46,\n47]. Thus, revelations indicative of proximal tubal blockade\nhave to be further assessed to rule out testing artifacts due to\ntransient tubal spasm or poor catheter positioning [ 8].\nSaline infusion sonography (SIS) also can be used for eval-\nuation of tubal patency. However, the test cannot define\nunilaterality or bilaterality of patency [ 8].\nAs discussed above, hysterosalpingo-contrast sonography\n(HyCoSy) has clinical applicability to tubal patency assess-\nment. A comprehensive meta-analysis involving 1,007 wom-\nen who underwent diagnostic im aging for tubal-related\nsubfertility has revealed a concordance of 83 % between\nHyCoSy and HSG when detecting tubal pathology. However,\na 10.3 % false occlusion rate and 6.7 % false patency rate were\ndetermined when HyCoSy was compared with laparoscopy\n[48]. Overall, increasing evidence supports HyCoSy as an\nacceptable screening method for the subfertile patient, com-\nbining comprehensive evaluation with methodological sim-\nplicity, cost-effectiveness, and time efficiency [36].\nLaparoscopy with chromotubation can determine tubal\npatency, detect proximal or distal tubal occlusion, and iden-\ntify and rectify tubal-associated pathology, such as fimbrial\nphimosis and peritubal adhesions, which can easily slip\nwhen less invasive methods, such as HSG, are used [ 8].\nHowever, randomized trials ev aluating cost-effectiveness\nand timing of diagnostic laparoscopy before ovarian stimu-\nlation in females with unexplained infertility are yet to be\nconducted. Fluoroscopic/hysteroscopic selective tubal can-\nnulation while verifying diagnosis based on HSG or lapa-\nroscopy with chromotubation can be used as the initial\nmethod to attempt treatment of tubal obstruction [ 49].\nSome evidence has been reported in support of chlamyd-\nia antibody testing (CA T) as a method to evaluate tubal\npathology presence. Some studies have suggested that chla-\nmydia trachomatis IgG antibodies determination is a method\nof equal or superior predictive value compared with HSG\nfor prediction of tubal factor infertility [ 50–52]. False-\npositive results can ensue due to cross-reactivity with C.\npneumoniae , whereas a positive CA T is indicative of a\nprevious infection but not of a persistent one and cannot\nclearly define causality between the infection and any tubal\ndamage [53]. ASRM practice committee classifies CA T as a\nmethod of limited clinical utility [ 8].\nPeritoneal Factors\nEndometriosis and pelvic or adnexal adhesions often may\ninterfere with fertility. Several revelations on history/physical\nexamination, such as dysmenorrhea, pelvic pain or cramping,\ndyspareunia, prior pelvic surgery or infection, or ectopic\nCurr Obstet Gynecol Rep (2012) 1:174 –181 177\n\npregnancy, can infer peritoneal pathology but cannot ade-\nquately justify diagnosis [8].\nTransvaginal ultrasound can be utilized as a display of\npelvic pathology; however, laparoscopy with direct visuali-\nzation of the pelvis is the “gold standard ” for accurate and\nspecific detection of peritoneal pathology. Per ASRM Prac-\ntice Committee report, laparoscopy is indicated for women\nwith symptoms or risk factors suggestive of pelvic patholo-\ngy or women with an abnormal HSG/ultrasound having no\nother indication for undergoing ART [ 8, 54, 55]. Diagnos-\ntic laparoscopy occasionally can be applicable for young\nwomen who have more than a 3-year period of infertility but\nno other pathology has been determined [ 8].\nEvaluation of Ovarian Reserve\nOvarian reserve alludes to the residual repertory of follicles\nleft in the ovary at any given time, with respect to number\nand quality, providing evidence of pacing along the contin-\nuum of reproductive senescence .\nTesting for diminished ovarian reserve (DOR) has be-\ncome an integral part of evaluation of women at increased\nrisk, such as those who 1) are older than 35 years, 2) have\nfamily history of early menopause, 3) have a solitary ovary\nor have undergone ovarian surgery, chemotherapy, or pelvic\nradiation therapy, 4) have unexplained infertility, 5) are poor\nresponders to gonadotropin stimulation, or 6) intend to\nundergo treatment with any assisted reproductive technolo-\ngy technique [ 8].\nBecause no benchmark for ovarian reserve status, in\nterms of quantity and quality, is applicable and proxy vari-\nables of true ovarian reserve (poor ovarian response to\nmaximal stimulation and nonpregnancy after IVF) are used\nfor evaluation of available tests, it should become clear that\novarian reserve tests are better considered as screening tests\nand not diagnostic ones; they do not establish diagnosis but\nonly provide an accurate estimate of ovarian response to\nstimulation with exogenous gonadotropins and, to a much\nlesser extent, of the likelihood of pregnancy occurrence with\nART [56]. Tests utilized for ovarian reserve assessment are\nbriefly discussed below.\nDay 3 FSH and Estradiol\nSubstantiation of day 3 FSH as a useful test for ovarian\nreserve lies upon the principle that women with good\novarian reserve can produce adequate amounts of Inhib-\nin B early in the menstrual cycle to maintain a low FSH\nlevel, contrary to women with DOR who fail to provide\nnormal feedback inhibition of pituitary secretion of FSH\nand demonstrate high FSH levels early in the cycle [ 57,\n58]. V alues less than 10-15 mIU/ml suggest adequate\novarian reserve. Exact cutoff depends on the particular\nlaboratory reference standards [ 59].\nBasal estradiol levels alone should not be considered as a\nscreening method for DOR, but should only be used as an\nadjunct to correctly interpret a “normal” basal serum FSH\nvalue [ 8], because abnormally high estradiol levels\ndue to advanced premature follicle recruitment in wom-\nen with DOR can inhibit FSH secretion and thus mask\nthis sign of DOR. When basal FSH is “normal” but estra-\ndiol is high (>60 –80 pg/ml) in the early follicular phase,\nsome evidence of associated poor ovarian response, higher\ncycle cancellation rates, and lower pregnancy rates has\nbeen reported [60–62].\nClomiphene Citrate Challenge Test\nClomiphene citrate challenge test (CCCT) involves FSH\nmeasurement before clomiphene citrate administration (50-\nmg tablets, 2 daily) on cycle days 5 through 9 and subse-\nquent FSH levels determination on day 10. Administration\nof clomiphene citrate stimulates follicular development and\nthus estradiol and inhibin B production, which in turn sup-\npresses pituitary FSH production. By day 10 of the CCCT,\nthe FSH levels should be suppressed down to the normal\nrange (<10 mIU/ml). Elevated FSH concentration after\nCCCT is therefore indicative of DOR. Cycle day 10 FSH\ndetermination seems to be more sensitive but less specific\ncompared with cycle day 3 FSH measurement [ 63]. It must\nbe stressed that a normal Clomid challenge test is not\nevidential of fertility and it does not prove that ovaries have\nnormal functioning; it simply fails to prove otherwise [ 64].\nStudies comparing basal FSH and CCCT showed that the\nCCCT has hardly any additional value [ 63, 64].\nAntral Follicle Count\nAntral follicle count (AFC) is the number of antral follicles in\nboth ovaries during the early follicular phase (cycle days 2 to 4\nof a regular menstrual cycle) determined with transvaginal\nultrasound. Antral follicles are defined as follicles 2-10 mm\nor 3-8 mm in mean diameter in the greatest two-dimensional\nplane [8, 65]. An AFC of 4-10 is suggestive of an acceptable\novarian reserve, whereas a low AFC (3-10 antral follicles)\nindicates poor ovarian reserve and serves as a good predictor\nof poor response to ovarian stimulation and, to a much lesser\nextent, of poor oocyte quality and nonpregnancy [ 66, 67].\nSerum Antimüllerian Hormone\nAntimüllerian hormone (AMH) has been acknowledged as\nan ovarian reserve marker of emerging clinical significance.\nAMH is a member of the large transforming growth factor β\n(TGFβ) family of growth and differentiation factors and is\n178 Curr Obstet Gynecol Rep (2012) 1:174 –181\n\nhighly expressed in granulosa cells of preantral and small\nantral follicles until they become sensitive to FSH [ 68].\nBeing independent of gonadotropin effect, along with being\nthe earliest marker to change with age and the least to vary\nwithin menstrual cycle, AMH is acclaimed as a useful and\nsensitive marker of ovarian follicular primordial pool and\nthus ovarian reserve [ 69, 70–74]. On the whole, AMH\nlevels <1 ng/ml have been correlated with poor oocyte\nnumber and quality as well as poor response to IVF in terms\nof embryo quality and pregnancy outcomes [ 8, 56, 75–78].\nConclusions\nA rational, cost-effective evaluation of the female partner in\nan infertile couple should include a thorough history and\nphysical examination combined with the selective use of\nspecific tests. These include a basic hormonal evaluation\nin the follicular phase of the cycle (FSH, estradiol, TSH, and\nprolactin) combined with information obtained from the\nHSG on the anatomy of the reproductive organs. This initial\nevaluation together with a semen analysis may identify the\nmajority of the reasons for infertility. Additional tests may\nbe required on an individual basis.\nDisclosures No potential conflicts of interest relevant to this article\nwere reported.\nReferences\nPapers of particular interest, published recently, have been\nhighlighted as:\n Of Importance\n Of Outstanding Importance\n1. Practice Committee of the American Society for Reproductive Med-\nicine. Definitions of infertility and recurrent pregnancy loss. Fertil\nSteri. 2008, 90(5 Suppl):S60. doi:10.1016/j.fertnstert.2008.08.065.\n2. Guttmacher AF. Factors affecting normal expectancy of concep-\ntion. J Am Med Assoc. 1956;161(9):855 –60.\n3. Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse\nin relation to ovulation. Effects on the probability of conception,\nsurvival of the pregnancy, and sex of the baby. N Engl J Med.\n1995;333(23):1517–21. doi: 10.1056/nejm199512073332301.\n4. Zinaman MJ, Clegg ED, Brown CC, O'Connor J, Selevan SG.\nEstimates of human fertility and pregnancy loss. Fertil Steril.\n1996;65(3):503–9.\n5. Collins JA, Wrixon W, Janes LB, Wilson EH. Treatment-\nindependent pregnancy among infertile couples. N Engl J Med.\n1983;309(20):1201–6. doi: 10.1056/nejm198311173092001.\n6. Zhao Y , Kolp L, Yates M, Zacur H. Clinical evaluation of\nfemale factor infertility. Reproductive endocrinology and in-\nfertility: integrating modern clin ical and laboratory practice.\nNew Y ork: Springer; 2010.\n7. Habbema JD, Collins J, Leridon H, Evers JL, Lunenfeld B, te\nV elde ER. Towards less confusing terminology in reproductive\nmedicine: a proposa l. Fertil Steril . 2004;82(1):36 –40.\ndoi:10.1016/j.fertnstert.2004.04.024.\n8.  Practice Committee of the American Society for Reproductive\nMedicine. Diagnostic evaluation of the infertile female: a committee\nopinion. Fertil Steril. 2012. doi: 10.1016/j.fertnstert.2012.05.032. A\nvery recently released report on appropriate female infertility evalu-\nation developed under the direction of the Practice Committee of the\nAmerican Society for Reproductive Medicine (ASRM); this can\nroughly be a useful guide for the practicing clinician.\n9. Cousineau TM, Domar AD. Psychological impact of infertility.\nBest Pract Res Clin Obstet Gynaecol. 2007;21(2):293 –308.\ndoi:10.1016/j.bpobgyn.2006.12.003.\n10. Hammerli K, Znoj H, Barth J. The efficacy of psychological\ninterventions for infertile patients: a meta-analysis examining men-\ntal health and pregnancy rate. Hum Reprod Update. 2009;15\n(3):279–95. doi:10.1093/humupd/dmp002.\n11. Grodstein F, Goldman MB, Cramer DW. Body mass index and\novulatory infertility. Epidemiology. 1994;5(2):247 –50.\n12. Rich-Edwards JW, Goldman MB, Willett WC, Hunter DJ, Stamp-\nfer MJ, Colditz GA, et al. Adolescent body mass index and\ninfertility caused by ovulatory disorder. Am J Obstet Gynecol.\n1994;171(1):171–7.\n13. WHO Technical Report Series. Recent advances in medically\nassisted conception number 820, 1992, pp 1-111.\n14. Mosher WD, Pratt WF. Fecundity and infertility in the United\nStates: incidence and trends. Fertil Steril. 1991;56(2):192 –3.\n15. Luciano AA, Peluso J, Koch EI, Maier D, Kuslis S, Davison E.\nTemporal relationship and reliability of the clinical, hormonal, and\nultrasonographic indices of ovulation in infertile women. Obstet\nGynecol. 1990;75(3 Pt 1):412 –6.\n16. Guermandi E, V egetti W, Bia nchi MM, Uglietti A, Ragni G,\nCrosignani P . Reliability of ovulation tests in infertile women.\nObstet Gynecol. 2001;97(1):92 –6.\n17. Wathen NC, Perry L, Lilford RJ, Chard T. Interpretation of single\nprogesterone measurement in diagnosis of anovulation and defec-\ntive luteal phase: observations on analysis of the normal range. Br\nMed J (Clin Res Ed). 1984;288(6410):7 –9.\n18. Marik J, Hulka J. Luteinized unruptured follicle syndrome: a subtle\ncause of infertility. Fertil Steril. 1978;29(3):270 –\n4.\n19. Kerin JF, Kirby C, Morris D, McEvoy M, Ward B, Cox LW.\nIncidence of the luteinized unruptured follicle phenomenon in\ncycling women. Fertil Steril. 1983;40(5):620 –6.\n20. LeMaire GS. The luteinized unruptured follicle syndrome: anov-\nulation in disguise. J Obstet Gynecol Neonatal Nurs. 1987;16\n(2):116–20.\n21. Practice Committee of American Society for Reproductive Medi-\ncine in collaboration with Society for Reproductive Endocrinology\nand Infertility. Optimizing natural fertility. Fertil Steril. 2008;90(5\nSuppl):S1-6. doi: 10.1016/j.fertnstert.2008.08.122.\n22. McGovern PG, Myers ER, Silva S, Coutifaris C, Carson SA,\nLegro RS, et al. Absence of secretory endometrium after false-\npositive home urine luteinizing hormone testing. Fertil Steril.\n2004;82(5):1273–7. doi: 10.1016/j.fertnstert.2004.03.070.\n23. Noyes RW, Hertig A T, Rock J. Dating the endometrial biopsy. Am\nJ Obstet Gynecol. 1975;122(2):262 –3.\n24. Coutifaris C, Myers ER, Guzick DS, Diamond MP , Carson SA,\nLegro RS, et al. Histological dating of timed endometrial biopsy\ntissue is not related to fertility status. Fertil Steril. 2004;82\n(5):1264–72. doi: 10.1016/j.fertnstert.2004.03.069.\n25. Murray MJ, Meyer WR, Zaino RJ, Lessey BA, Novotny DB,\nIreland K, et al. A critical analysis of the accuracy, reproducibility,\nand clinical utility of histologic endometrial dating in fertile wom-\nen. Fertil Steril. 2004;81(5):1333 – 43. doi: 10.1016/\nj.fertnstert.2003.11.030.\nCurr Obstet Gynecol Rep (2012) 1:174 –181 179\n\n26. Haney AF. Endometrial biopsy: a test whose time has come and\ngone. Fertil Steril. 2004;82(5):1295 –6. doi: 10.1016/j.\nfertnstert.2004.06.037. discussion 301-2.\n27. Kazer RR. Endometrial biopsy should be abandoned as a routine\ncomponent of the infertility eval uation. Fertil Steril. 2004;82\n(5):1297–8. doi:10.1016/j.fertnstert.2004.05.080. discussion 300-2.\n28. de Crespigny LC, O'Herlihy C, Robinson HP . Ultrasonic observa-\ntion of the mechanism of human ovulation. Am J Obstet Gynecol.\n1981;139(6):636–9.\n29. World Health Organization. WHO laboratory manual for the ex-\namination of human semen and sperm-cervical mucus interaction.\n4th ed. Cambridge: Cambridge University Press; 1999.\n30. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW,\nBehre HM, et al. World Health Organization reference values for\nhuman semen characteristics. Hum Reprod Update. 2010;16\n(3):231–45. doi: 10.1093/humupd/dmp048.\n31. Griffith CS, Grimes DA. The validity of the postcoital test. Am J\nObstet Gynecol. 1990;162(3):615 –20.\n32. Collins JA, So Y , Wilson EH, Wrixon W, Casper RF. The postco-\nital test as a predictor of pregnancy among 355 infertile couples.\nFertil Steril. 1984;41(5):703 –8.\n33. Glatstein IZ, Best CL, Palumbo A, Sleeper LA, Friedman AJ,\nHornstein MD. The reproducibility of the postcoital test: a pro-\nspective study. Obstet Gynecol. 1995;85(3):396–400. doi:10.1016/\n0029-7844(94)00390-y.\n34. Oei SG, Helmerhorst FM, Bloemenkamp KW, Hollants FA,\nMeerpoel DE, Keirse MJ. Effectiveness of the postcoital test:\nrandomised controlled trial. BMJ. 1998;317(7157):502 –5.\n35. Soares SR, Barbosa dos Reis MM, Camargos AF. Diagnostic\naccuracy of sonohysterography, transvaginal sonography, and hys-\nterosalpingography in patients with uterine cavity diseases. Fertil\nSteril. 2000;73(2):406 –11.\n36.  Saunders RD, Shwayder JM, Nakajima ST. Current methods of\ntubal patency assessment. Fertil Steril. 2011;95(7):2171 –9.\ndoi:10.1016/j.fertnstert.2011.02.054. A comprehensive, critical re-\nview of the existing literature on current methods of uterine cavity\nand tubal patency assessment as compared with the gold standard–\nlaparoscopy-. Special reference is made on the increasing evidence in\nsupport of hysterosalpingo-contrast sonography (HyCoSy) as a use-\nful, screening method for the subfertile patient.\n37. Emanuel MH, V erdel MJ, Wamsteker K, Lammes FB. A prospec-\ntive comparison of transvaginal ultrasonography and diagnostic\nhysteroscopy in the evaluation of patients with abnormal uterine\nbleeding: clinical implications. Am J Obstet Gynecol. 1995;172(2\nPt 1):547 –52.\n38. Fedele L, Bianchi S, Dorta M, Vignali M. Intrauterine adhesions:\ndetection with transvaginal US. Radiology. 1996;199(3):757 –9.\n39. Glatstein IZ, Harlow BL, Hornstein MD. Practice patterns among\nreproductive endocrinologists: further aspects of the infertility\nevaluation. Fertil Steril. 1998;70(2):263 –9.\n40. Cullinan JA, Fleischer AC, Kepple DM, Arnold AL. Sonohyster-\nography: a technique for endometrial evaluation. Radiographics.\n1995;15(3):501–14. discussion 15-6.\n41. Bingol B, Gunenc Z, Gedikbasi A, Guner H, Tasdemir S, Tiras B.\nComparison of diagnostic accuracy of saline infusion sonohyster-\nography, transvaginal sonography and hysteroscopy. J Obstet\nGynaecol. 2011;31(1):54–8. doi: 10.3109/01443615.2010.532246.\n42.\n Luciano DE, Exacoustos C, Johns DA, Luciano AA. Can\nhysterosalpingo-contrast sonography replace h ysterosalpingography\nin confirming tubal blockage after hysteroscopic sterilization and in\nthe evaluation of the uterus and tubes in infertile patients? Am J Obstet\nGynecol. 2011;204(1):79 e1–5. doi:10.1016/j.ajog.2010.08.065. This\nstudy provides evidence that hysterosalpingo-contrast sonography\n(HyCoSy) is a time-efficient, safe and well-tolerated alternative to\nHSG with comparable accuracy in the assessment of the uterine cavity\nand tubal patency.\n43. Honore GM, Holden AE, Schenken RS. Pathophysiology and man-\nagement of proximal tubal blockage. Fertil Steril. 1999;71(5):785–95.\n44. Practice Committee of the American Society for Reproductive\nMedicine. Committee opinion: role of tubal surgery in the era of\nassisted reproductive technology. Fertil Steril. 2012;97(3):539-45.\ndoi:10.1016/j.fertnstert.2011.12.031.\n45. Johnson N, V andekerckhove P , Watson A, Lilford R, Harada T,\nHughes E. Tubal flushing for subfertility. Cochrane Database Syst\nRev. 2005;18(2):CD003718. doi:10.1002/14651858.CD003718.pub2.\n46. Evers JL, Land JA, Mol BW. Evidence-based medicine for diag-\nnostic questions. Semin Reprod Med. 2003;21(1):9 –15.\ndoi:10.1055/s-2003-39990.\n47. Dessole S, Meloni GB, Capobianco G, Manzoni MA, Ambrosini\nG, Canalis GC. A second hysterosalpingography reduces the use of\nselective technique for treatment of a proximal tubal obstruction.\nFertil Steril. 2000;73(5):1037 –9.\n48. Holz K, Becker R, Schurmann R. Ultrasound in the investigation\nof tubal patency. A meta-analysis of three comparative studies of\nEchovist-200 including 1007 women. Zentralbl Gynakol.\n1997;119(8):366–73.\n49. V alle RF. Tubal cannulation. Obstet Gynecol Clin North Am.\n1995;22(3):519–40.\n50. Dabekausen Y A, Evers JL, Land JA, Stals FS. Chlamydia trachoma-\ntis antibody testing is more accurate than hysterosalpingography in\npredicting tubal factor infertility. Fertil Steril. 1994;61(5):833–7.\n51. V eenemans LM, van der Linden PJ. The value of Chlamydia\ntrachomatis antibody testing in predicting tubal factor infertility.\nHum Reprod. 2002;17(3):695 –8.\n52. Rodgers AK, Budrys NM, Gong S, Wang J, Holden A, Schenken\nRS, et al. Genome-wide identification of Chlamydia trachomatis\nantigens associated with tubal factor infertility. Fertil Steril.\n2011;96(3):715–21. doi: 10.1016/j.fertnstert.2011.06.021.\n53. den Hartog JE, Morre SA, Land JA. Chlamydia trachomatis-\nassociated tubal factor subfertility: Immunogenetic aspects and\nserological screening. Hum Reprod Update. 2006;12(6):719 –30.\ndoi:10.1093/humupd/dml030.\n54. Smith S, Pfeifer SM, Collins JA. Diagnosis and management of\nfemale infertility. JAMA. 2003;290(13):1767 –70. doi: 10.1001/\njama.290.13.1767.\n55. Luttjeboer FY , V erhoeve HR, van Dessel HJ, van der V een F, Mol\nBW, Coppus SF. The value of medical history taking as risk\nindicator for tuboperitoneal pathology: a systematic review. BJOG.\n2009;116(5):612–25. doi: 10.1111/j.1471-0528.2008.02070.x.\n56. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A\nsystematic review of tests predicting ovarian reserve and IVF out-\ncome. Hum Reprod Update. 2006;12(6):685 –718. doi: 10.1093/\nhumupd/dml034.\n57. Abdalla H, Thum MY . An elevated basal FSH reflects a quantita-\ntive rather than qualitative decline of the ovarian reserve. Hum\nReprod. 2004;19(4):893\n–8. doi: 10.1093/humrep/deh141.\n58. Klein NA, Illingworth PJ, Groome NP , McNeilly AS, Battaglia DE,\nSoules MR. Decreased inhibin B secretion is associated with the\nmonotropic FSH rise in older, ovulatory women: a study of serum\nand follicular fluid levels of dimeric inhibin A and B in spontaneous\nmenstrual cycles. J Clin Endocrinol Metab. 1996;81(7):2742–5.\n59. Hurt KJ, Guile MW, Bienstock JL, Fox HE, Wallach EE. The\nJohns Hopkins manual of gynecology and obstetrics. 4th ed. Phil-\nadelphia: Lippincott Williams & Wilkins; 2011.\n60. Evers JL, Slaats P , Land JA, Dumoulin JC, Dunselman GA.\nElevated levels of basal estradiol-17beta predict poor response in\npatients with normal basal levels of follicle-stimulating hormone\nundergoing in vitro fertilization. Fertil Steril. 1998;69(6):1010 –4.\n61. Licciardi FL, Liu HC, Rosenwaks Z. Day 3 estradiol serum con-\ncentrations as prognosticators of ovarian stimulation response and\npregnancy outcome in patients undergoing in vitro fertilization.\nFertil Steril. 1995;64(5):991 –4.\n180 Curr Obstet Gynecol Rep (2012) 1:174 –181\n\n62. Smotrich DB, Widra EA, Gindoff PR, Levy MJ, Hall JL, Stillman\nRJ. Prognostic value of day 3 estradiol on in vitro fertilization\noutcome. Fertil Steril. 1995;64(6):1136 –40.\n63. Hendriks DJ, Mol BW, Bancsi LF, te V elde ER, Broekmans FJ.\nThe clomiphene citrate challenge test for the prediction of poor\novarian response and nonpregnancy in patients undergoing in vitro\nfertilization: a systematic review. Fertil Steril. 2006;86(4):807 –18.\ndoi:10.1016/j.fertnstert.2006.03.033.\n64. Jain T, Soules MR, Collins JA. Comparison of basal follicle-\nstimulating hormone versus the clomiphene citrate challenge test\nfor ovarian reserve screening. Fertil Steril. 2004;82(1):180 –5.\ndoi:10.1016/j.fertnstert.2003.11.045.\n65. Broekmans FJ, de Ziegler D, Howles CM, Gougeon A, Trew G,\nOlivennes F. The antral follicle count: practical recommendations\nfor better standardization. Fe rtil Steril. 2010;94(3):1044 –51.\ndoi:10.1016/j.fertnstert.2009.04.040.\n66. Hendriks DJ, Mol BW, Bancsi LF, Te V elde ER, Broekmans FJ.\nAntral follicle count in the prediction of poor ovarian response and\npregnancy after in vitro fertilization: a meta-analysis and compar-\nison with basal follicle-stimulating hormone level. Fertil Steril.\n2005;83(2):291–301. doi:10.1016/j.fertnstert.2004.10.011.\n67. Hsu A, Arny M, Knee AB, Bell C, Cook E, Novak AL, et al. Antral\nfollicle count in clinical practice: analyzing clinical relevance. Fertil\nSteril. 2011;95(2):474–9. doi:10.1016/j.fertnstert.2010.03.023.\n68. Visser JA, de Jong FH, Laven JS, Themmen AP . Anti-Mullerian\nhormone: a new marker for ov arian function. Reproduction.\n2006;131(1):1–9. doi: 10.1530/rep. 1.00529 .\n69.  Seifer DB, Baker VL, Leader B. Age-specific serum anti-Mullerian\nhormone values for 17,120 women presenting to fertility centers\nwithin the United States. Fe rtil Steril. 2011;95(2):747 –50.\ndoi: 10.1016/j.fertnstert.2010.10.011 . A retrospective study of\n17,120 women of reproductive age ranging from 24 to 50 years\nold, reiterating the decreasing trend of AMH levels as age increases\nthus, reinforcing the value of AMH as an ovarian reserve marker.\n70. de V et A, Laven JS, de Jong FH, Themmen AP , Fauser BC.\nAntimullerian hormone serum levels: a putative marker for ovarian\naging. Fertil Steril. 2002;77(2):357 –62.\n71. van Rooij IA, Tonkelaar I, Broekmans FJ, Looman CW, Scheffer\nGJ, de Jong FH, et al. Anti-mullerian hormone is a promising\npredictor for the occurrence of the menopausal transition. Meno-\npause. 2004;11(6 Pt 1):601 –6.\n72. Seifer DB, Maclaughlin DT. Mullerian inhibiting substance is an\novarian growth factor of emerging clinical significance. Fertil\nSteril. 2007;88(3):539 –46. doi: 10.1016/j.fertnstert.2007.02.014.\n73. Fanchin R, Schonauer LM, Righini C, Guibourdenche J, Frydman R,\nTaieb J. Serum anti-Mullerian hormone is more strongly re-\nlated to ovarian follicular status than serum inhibin B, estra-\ndiol, FSH and LH on day 3. Hum Reprod. 2003;18(2):323 –7.\n74. Tsepelidis S, Devreker F, Demeestere I, Flahaut A, Gervy C, Englert\nY . Stable serum levels of anti-Mullerian hormone during the men-\nstrual cycle: a prospective study in normo-ovulatory women. Hum\nReprod. 2007;22(7):1837–40. doi:10.1093/humrep/dem101.\n75. Gnoth C, Schuring AN, Friol K, Tigges J, Mallmann P , Godehardt\nE. Relevance of anti-Mullerian hormone measurement in a routine\nIVF program. Hum Reprod. 2008;23(6):1359 –\n65. doi: 10.1093/\nhumrep/den108.\n76. Muttukrishna S, McGarrigle H, Wakim R, Khadum I, Ranieri DM,\nSerhal P . Antral follicle count, anti-mullerian hormone and inhibin\nB: predictors of ovarian response in assisted reproductive technol-\nogy? BJOG. 2005;112(10):1384 –90. doi: 10.1111/j.1471-\n0528.2005.00670.x.\n77. van Rooij IA, Broekmans FJ, te V elde ER, Fauser BC, Bancsi LF,\nde Jong FH, et al. Serum anti-Mullerian hormone levels: a novel\nmeasure of ovarian reserve. Hum Reprod. 2002;17(12):3065 –71.\n78. Ebner T, Sommergruber M, Moser M, Shebl O, Schreier-Lechner\nE, Tews G. Basal level of anti-Mullerian hormone is associated\nwith oocyte quality in stimulated cycles. Hum Reprod. 2006;21\n(8):2022–6. doi: 10.1093/humrep/del127.\nCurr Obstet Gynecol Rep (2012) 1:174 –181 181","source_license":"CC0","license_restricted":false}