Fertility evaluation of infertile women: a committee opinion

Infertility is a disease, condition, or status characterized by any of the following: the inability to achieve a successful pregnancy on the basis of a patient’s medical, sexual, and reproductive history, age, physical findings, diagnostic testing, or any combination of those factors. In patients having regular, unprotected intercourse and without any known etiology for either partner suggestive of impaired reproductive ability, evaluation should be initiated at 12 months when the female partner is <35 years of age and at 6 months when the female partner is ≥35 years of age or older. Nothing in this definition shall be used to deny or delay treatment to any individual, regardless of relationship status or sexual orientation. In women >40 years of age, more immediate evaluation and treatment may be warranted (1). However, diagnostic testing for infertility should be initiated without delay on presentation with a condition known to cause infertility, or a targeted evaluation may be appropriate in situations where patients are pursuing Assisted Reproductive Technologies for other indications. Such situations include, but are not limited to (2–8):

• Irregular menstrual cycles, cycle length <25 or >35 days, intermenstrual bleeding, or amenorrhea
• Recurrent pregnancy loss
• Known or suspected uterine/tubal/ peritoneal disease or endometriosis
• Known or suspected male subfertility
• Sexual dysfunction
• Genetic or acquired conditions that predispose to diminished ovarian reserve (e.g., chemotherapy, radiation exposure, FMR1 premutation)
• Genetic carrier status of individual(s) where preimplantation genetic testing (for aneuploidy, monogenic disorders, and structural chromosomal rearrangements) is being pursued
• Fertility preservation
• Third-party reproduction

Patients who desire the use of donor gametes or third-party reproduction to achieve pregnancy warrant a targeted fertility evaluation. These include single women, women in a same-sex relationship, and women in a heterosexual relationship who may require donor sperm. These women should undergo a directed history and physical examination if indicated, as well as a laboratory evaluation, similar to any other infertile patient. Assessment of tubal status or uterine cavity should be tailored to medical history using shared decision-making. Same-sex female couples may also elect to pursue reciprocal in vitro fertilization, where the oocytes are removed from one partner and are used to create embryos, which are subsequently transferred to the other partner to carry the pregnancy. Both patients need to be evaluated with specific laboratory analyses, and, for patients who will serve as the gestational carrier, radiologic studies for tubal/uterine assessment should be ordered. Similarly, transgender men and nonbinary patients require a similar targeted evaluation tailored to their desired fertility treatment.

When a male partner is contributing to the pregnancy, evaluation of both partners should begin at the same time. When applicable, a male partner’s reproductive and medical history and at least one semen analysis should be obtained at the onset of an infertility evaluation, given the high prevalence of a contributing male factor, which is up to 40% of cases (9). Methods for the evaluation of the male partner are described in detail in a separate document (2, 3).

HISTORY AND PHYSICAL EXAMINATION

The initial infertility appointment should have sufficient time to obtain a comprehensive medical, reproductive, and family history (Table 1) (2, 3, 10–17). This is also an opportune time to counsel patients regarding prepregnancy care and screening for relevant genetic conditions. Further information on prepregnancy care can be found in the joint American College of Obstetricians and Gynecologists (ACOG) and American Society for Reproductive Medicine (ASRM) Committee Opinion (18).

A routine physical examination is not indicated as part of the initial infertility evaluation of women, unless the history or other findings prompt a targeted examination. Along with the history, physical examination findings should prompt appropriate laboratory testing to ensure the patient is optimized for pregnancy and to address, if applicable, smoking, obesity, intimate partner violence, and mental health, along with selective viral immunity status (Table 2) (19). Further information can be found in other ASRM documents (16, 20).

DIAGNOSTIC EVALUATION

Subsequent diagnostic evaluation should be conducted in a systematic, expeditious, and cost-effective manner to identify all relevant factors, with an initial emphasis on the least invasive methods for the detection of the most common causes of infertility. The pace and extent of evaluation should take into account the couple's preferences, patient age, the duration of infertility, and the unique features of the medical history and physical examination.

OVULATORY FUNCTION

Ovulatory dysfunction is identified in approximately 40% of women with infertility (21). It commonly results in obvious menstrual disturbances (oligomenorrhea/amenorrhea), but may be more subtle, present in women with apparent eumenorrhea. Once pregnancy has been excluded, other underlying causes for ovulatory dysfunction should be sought because specific treatment may be indicated. Some conditions that cause ovulatory dysfunction may have other health implications that need to be addressed. The most common causes of ovulatory dysfunction include polyendocrine metabolic ovarian syndrome (PMOS) (formerly polycystic ovary syndrome [PCOS]), obesity, perimenopause, weight gain or loss, strenuous or excessive exercise (i.e., RED-S syndrome), thyroid dysfunction, and hyperprolactinemia (22). Methods for evaluating ovulatory function may include any of the following:

Menstrual history

In most ovulatory women, menstrual cycles are regular and predictable, generally occur at intervals of 25–35 days, exhibit consistent flow characteristics, and may be accompanied by a consistent pattern of moliminal symptoms (23). Some degree of variation is entirely normal; in a study of ≥1,000 cycles, variations in intermenstrual interval exceeding 5 days were observed in 56% of patients within 6 months and in 75% of those followed for 1 year (24). However, sporadic anovulatory cycles in regularly menstruating women are relatively rare at 1%–14% (25, 26). Sporadic anovulation causes minimal variation in fecundity in regularly menstruating women (27). The prevalence of ovulatory cycles on the basis of a normal menstrual history in nonhirsute women is as high as 99.5% (28). Alternatively, the prevalence of regular ovulation in eumenorrheic women with hirsutism decreases to 60%. (29). In these women, luteal progesterone levels should be considered to assess for occult ovulatory dysfunction.

A history of oligomenorrhea or amenorrhea is clinically sufficient to establish ovulatory dysfunction and warrants further investigation to identify the underlying etiology, without the need for further testing of ovulatory status. The additional tests discussed below are not required to confirm ovulation but may be used to augment fertility evaluation when the menstrual history is indeterminate.

Luteal progesterone

Serum progesterone determinations provide a reliable and objective measure of ovulation if they are obtained at the appropriate time in the cycle. Given the range of normal variation in ovulatory cycles, a serum progesterone measurement should generally be obtained approximately 1 week before the expected onset of the next menses, rather than on any one specific cycle day (e.g., day 21). A progesterone concentration >3 ng/mL provides presumptive and sufficient evidence of recent ovulation (30). Because luteal serum progesterone levels can fluctuate sevenfold over a few hours, a single progesterone value may be used to confirm ovulation, but not to assess the quality of the luteal phase (30).

Ovulation predictor kits

Urinary luteinizing hormone (LH) determinations using various commercial ‘‘ovulation predictor kits’’ can identify the midcycle LH surge that precedes ovulation within 1–2 days. Urinary LH detection provides indirect evidence of ovulation (31). Results generally correlate well with the peak in serum LH, particularly when the test is performed on midday or evening urine specimens (24). Patients with PMOS may have a tonic elevation in basal LH levels, leading to false-positive results with urinary LH levels. However, accuracy, ease of use, and reliability vary among products, and testing may yield false-positive and false-negative results (32).

Transvaginal ultrasonography

Transvaginal ultrasonography is a useful tool to assess ovarian reserve, adnexal and uterine pathology, the size and number of antral and developing follicles, and may provide presumptive evidence of ovulation and luteinization when obtained in the putative luteal phase. Because of the associated cost and logistical demands, this method generally should be reserved for women in whom simpler methods fail to provide the necessary information.

Daily basal body temperature (BBT) testing

BBT is an inexpensive, although often unreliable method of predicting ovulation. Ovulatory cycles are generally associated with biphasic BBT recordings, and anovulatory cycles typically result in monophasic patterns. However, some ovulatory women cannot document clearly biphasic BBT patterns (33). Grossly short luteal phases (<10 days of temperature elevation) may identify women with more subtle ovulatory dysfunction. Theoretically, the period of highest fertility spans the 7 days before the midcycle rise in BBT. Given the tedious nature of the testing, lack of accuracy, and inability to proactively time intercourse with ovulation, this test is not routinely recommended, especially when the menstrual history is consistent with ovulatory cycles.

Endometrial biopsy

Endometrial biopsy was historically used to histologically evaluate for the presence of secretory endometrial development in the luteal phase, thus implying prior ovulation (34). However, careful studies have since demonstrated that histologic endometrial dating is not a valid diagnostic method for ovulatory function because it lacks both accuracy and precision (35) and cannot distinguish fertile from infertile women (36). Thus, an endometrial biopsy is no longer recommended for routine infertility evaluation, nor is there sufficient evidence that the biopsy will assist in the diagnosis and management of chronic endometritis and endometriosis. (Table 3) (37).

Hormonal testing

If the provider has confirmed that a woman has oligomenorrhea or anovulation, it is imperative to search for an underlying cause. Routine testing of serum TSH is not indicated in the absence of symptoms, such as oligo-ovulation/anovulation or signs of thyroid dysfunction (38). Prolactin is not recommended as part of the routine infertility evaluation, but is indicated in the setting of galactorrhea, oligomenorrhea, or amenorrhea. In women with amenorrhea, random serum follicle-stimulating hormone (FSH) and estradiol measurements can distinguish women with premature ovarian insufficiency (FSH > 25 IU/L) (39) who may be candidates for oocyte donation from those with hypothalamic amenorrhea (low or normal FSH, low estradiol), who require exogenous gonadotropin stimulation for ovulation induction. In women with normal FSH and estradiol levels in the setting of oligomenorrhea or anovulation, evaluation for PMOS is warranted, and in those with clinical signs of androgen excess, additional screening for 21-hydroxylase deficient nonclassic adrenal hyperplasia should be performed (40). Serum antim€ullerian hormone (AMH) may be used as part of the criteria for PMOS but, currently, there is no recommended universal cut-off value (41). More information on the diagnosis of amenorrhea can be found in the ASRM Committee Opinion on the Current evaluation of amenorrhea (40).

OVARIAN RESERVE

The concept of ‘‘ovarian reserve’’ describes reproductive potential as a function of the number of oocytes (42). Decreased or diminished ovarian reserve describes women of reproductive age having regular menses whose response to ovarian stimulation is reduced relative to those in women of comparable age. Female age is the single most important predictor of fecundity. Ovarian reserve tests should augment and not replace patient counseling on the basis of age and diagnosis. The goal of using ovarian reserve testing is to identify women who may be poor responders to gonadotropin stimulation in efforts to tailor treatment and discuss realistic expectations of response to treatment (43, 44). Ovarian reserve tests include both biochemical analysis and ultrasound imaging of the ovaries. Biochemical tests, which aim to depict the biology of the ovary, include basal FSH and estradiol measurements and AMH concentrations. Basal FSH and estradiol should be measured together in the early follicular phase between menstrual cycle days 2 to 4. AMH can be measured at any point in the menstrual cycle (42). Transvaginal ultrasound can be used to assess the follicular phase antral follicle count and ovarian volume (42). Inhibin B and the clomiphene challenge test do not add additional diagnostic accuracy to assess ovarian reserve and are not recommended.

All ovarian reserve tests should be interpreted in the context of the entire clinical picture, taking into consideration age, risk factors, prior treatment, and response of the individual patient. Ovarian reserve testing does not have proven benefits in fertile women or as a random biomarker of ovarian function (44). AMH has been shown to be superior to FSH and estradiol as an ovarian age marker, given AMH is relatively stable across and throughout menstrual cycles (44). In women with ovarian reserve testing indicating diminished ovarian reserve, studies are conflicting regarding the ability to predict natural pregnancy rates. One study found no association between low AMH levels (<0.7 ng/mL) and reduced fertility in 750 women aged 30 to 44 years without a history of infertility (45). In contrast, in a cohort of 3,150 women, low AMH levels (<1ng/mL) were significantly associated with a lower chance of pregnancy, compared with normal (1–5.5 ng/mL) and high (≥5.5 ng/mL) AMH levels (45).

Meta-analysis of 11 studies (n = 4,388) found that AMH had poor predictive value for spontaneous pregnancy overall (AUC = 0.59), and this remained poor in both younger (<35) and older (≥35) subgroups (46). The use of different AMH cutoffs across studies, varying populations, and the inherent limitation that AMH reflects oocyte quantity but not quality limits the clinical predictive value of AMH for natural conception and the ability to guide patient counseling.

Across menstrual cycles, AMH levels demonstrate modest intraindividual variability of approximately 1.3 ng/ mL (47). Although AMH declines across the reproductive lifespan, significant short-term intraindividual variability has been reported, and current guidelines do not recommend routine serial AMH testing to track ovarian reserve trajectories. A single AMH measurement, interpreted in the clinical context of age, risk factors, and treatment history, remains the standard approach to ovarian reserve assessment (9).

CERVICAL FACTORS

Examination of the cervix may reveal cervical pathology, such as stenosis or evidence of chronic cervicitis that merits further evaluation. Intercourse on days with type 4 cervical mucus (wet, slippery, clear, egg-white consistency) is associated with the highest day-specific probability of conception—approximately 40%—compared with substantially lower probabilities (1%–6%) on days with lower cervical mucus scores. Changes in mucus quality across the fertile interval predict the probability of conception better than timing of intercourse relative to ovulation (48). Clinical history of previous cervical surgical procedures or abnormal discharge should be addressed and treated. Abnormalities of cervical mucus production or sperm-mucus interactions are rarely the sole or principal cause of infertility. The post-coital test, in which a specimen of cervical mucus obtained shortly before expected ovulation is examined microscopically for the presence of motile sperm within hours after intercourse, was the traditional method for diagnosing cervical-factor infertility. The postcoital test is no longer recommended for the evaluation of infertile women (Table 3) because it is subjective, has poor reproducibility, is inconvenient to the patient, rarely changes clinical management, and does not predict inability to conceive (49, 50).

UTERINE ABNORMALITIES

Uterine abnormalities occur in 16.2% of women presenting for infertility evaluation, most commonly polyps (13%), submucous fibroids (2.8%), and adhesions (0.3%) (51). In women with abnormal uterine bleeding, the prevalence of uterine abnormalities increases to 39.6%. Uterine imaging may be warranted in infertile women given the significant prevalence of abnormalities.

Ultrasonography is the best imaging modality available to assess uterine anatomy since one can assess the uterine myometrium, endometrial cavity, and the surrounding adnexa simultaneously. Transvaginal ultrasound allows for visualization of most uterine pathologies, such as leiomyomas, endometrial polyps, and adenomyosis, which may play a role in infertility. Other imaging modalities, such as three-dimensional ultrasound and pelvic magnetic resonance imaging, may be used to further evaluate the uterus, most often to further characterize findings of an initial study, such as a pelvic ultrasound or hysterosalpingography (HSG). These radiologic studies have the advantage of assessing for intramural fibroids and adnexal pathology that are undetectable on HSG or hysteroscopy.

Hysterosalpingography defines the size and shape of the uterine cavity and can reveal potential developmental anomalies or other acquired abnormalities (endometrial polyps, submucous myomas, synechiae) that may impact reproduction. However, HSG has relatively a low sensitivity (50%) and positive predictive value (PPV) (30%) for the diagnosis of endometrial polyps and submucous myomas in asymptomatic infertile women (52). Because HSG cannot reliably differentiate a septate from a bicornuate uterus, further evaluation with pelvic magnetic resonance imaging or three-dimensional-ultrasonography may be necessary.

Sonohysterography (SHG), involving transvaginal ultrasonography after the introduction of saline into the uterine cavity, better defines the size and shape of the uterine cavity and has a high (>90%) positive predictive value and >90% negative predictive value for the detection of intrauterine pathologies (endometrial polyps, submucous myomas, synechiae) (52–54).

Hysteroscopy is the definitive method for the diagnosis and treatment of intrauterine pathologies. Depending on the operative setup, it may also be a more costly and invasive method for evaluating the uterus when compared with less invasive methods, such as HSG and SHG (55). Use of small caliber office hysteroscopes may be a reasonable approach for evaluating the uterine cavity with minimal discomfort, lower cost, and sometimes the ability to surgically remove a lesion.

TUBAL PATENCY

Tubal disease is an important cause of infertility and should be specifically excluded. Accurate diagnosis and effective treatment of tubal obstruction often require more than one of the following techniques (56).

An HSG can document proximal or distal tubal occlusion, demonstrate salpingitis isthmica nodosa, reveal tubal architectural detail of potential prognostic value, and may suggest the presence of fimbrial phimosis or peritubal adhesions when the escape of contrast is delayed or becomes loculated, respectively. A widely reported meta-analysis demonstrated that HSG has a sensitivity of 65% and a specificity of 83% for detecting tubal patency compared with laparoscopy with chromopertubation (57). Another meta-analysis, where a subset of nine studies examined both hysterosalpingosonography (sono-HSG) and HSG directly compared with laparoscopy with chromopertubation, reported diagnostic accuracy for HSG was sensitivity 94% and specificity 92% (58). When HSG shows unilateral proximal occlusion, there is a >40% chance the tube is actually patent on subsequent laparoscopy or repeat testing. (59). The specificity of HSG in the diagnosis of pelvic inflammatory disease (PID)-related tubal occlusion achieves 90% (9). Findings suggesting bilateral proximal tubal obstruction require further evaluation to exclude the possibility of an artifact affecting the results because of transient tubal/myometrial contractions or relating to catheter position.

Sonohysterography can also be used to demonstrate tubal patency. Although tubal patency can be observed by the appearance of fluid in the cul-de-sac with the saline infusion, the test does not differentiate between unilateral or bilateral patency. Hysterosalpingo-contrast sonography (HyCoSy), an adjunct to SHG, determines tubal patency with the use of contrast through a transcervical catheter. The technique can use agents, such as air bubbles or other solutions, to aid in the identification of the medium as it passes through the tubes. The accuracy of hysterosalpingo-contrast sonography may be more dependent on operator experience than HSG. The sensitivity of hysterosalpingo-contrast sonography for the determination of tubal patency ranges from 76% to 96%, although the specificity ranges from 67% to 100% (56). Hysteroscopic assessment of tubal patency is an emerging approach that is performed through the direct observation of fluid or air bubble flow into the tubal ostia. A meta-analysis of six published trials demonstrated that the utilization of hysteroscopy to predict tubal patency had a sensitivity of 88% and specificity of 85% (60).

Laparoscopy is not recommended as a routine method for assessing tubal patency. However, if laparoscopy is already being performed, then chromopertubation with a dilute solution of methylene blue or indigo carmine introduced via the cervix may demonstrate tubal patency or document proximal or distal tubal obstruction. The procedure can also identify and be used to correct tubal factors, such as fimbrial phimosis or peritubal adhesions, which may not be identified with less invasive methods like HSG or SHG. Fluoroscopic/hysteroscopic selective tubal cannulation will confirm or exclude any proximal tubal occlusion suggested by HSG or laparoscopy with chromopertubation and provides the means for possible correction via recanalization using specialized catheter systems (61).

Although not commonly used in the United States, some clinicians use the chlamydia antibody test (CAT) as a first-line assessment of tubal patency. The detection of antibodies to Chlamydia trachomatis has been associated with tubal pathology but lacks the clinical utility to predict tubal patency. Compared with laparoscopy, CAT has a more modest sensitivity (40%–50%) and PPV (60%), but a higher negative predictive value (80%–90%) for detecting distal tubal disease (62, 63). Therefore, a negative CAT may suggest the absence of tubal disease; however, a positive CAT requires further evaluation to determine tubal patency.

PERITONEAL FACTORS

Peritoneal factors, such as endometriosis and pelvic or adnexal adhesions, may cause or contribute to infertility. History and/or physical examination findings may raise suspicion but are rarely sufficient for diagnosis. Peritoneal factors should also be considered in women with otherwise unexplained infertility.

Transvaginal ultrasonography may reveal otherwise unrecognized pelvic pathology that may have reproductive implications, such as an endometrioma (64). The likelihood of pelvic endometriosis in an asymptomatic woman with a normal pelvic ultrasound and normal HSG is low but not negligible, estimated at 2% to 23% on the basis of the prevalence of endometriosis in asymptomatic women and the limitations of these imaging modalities (65). Laparoscopy with a direct visual examination of the pelvic reproductive anatomy is the only method available for the specific diagnosis of peritoneal factors that may impair fertility. However, the impact of minimal and mild endometriosis on fertility is relatively small (66), and most women with significant adnexal adhesions have historical risk factors (pelvic pain, moderate or severe endometriosis, previous pelvic infection, or surgery) or an abnormal HSG. Consequently, laparoscopy is not recommended for the routine evaluation of an infertile woman without a suspected pelvic pathology or another specific indication (i.e., severe dysmenorrhea) that requires surgical evaluation (Table 4).

SUMMARY

• Female fertility declines with increasing age, and female age is the single most important predictor of fecundity.
• A comprehensive medical, reproductive, and family history combined with a physical examination when medically indicated can reveal anatomic and physiologic causes of infertility.
  
  

CONCLUSIONS

• An infertility evaluation should be initiated, in heterosexual couples having regular unprotected intercourse without known factors for infertility, at 12 months in women <35 years of age and at 6 months in women aged ≥35 years. In women >40 years, a more immediate evaluation may be warranted.
• An infertility evaluation should be initiated immediately if there is a known medical history that is associated with infertility.
• The following patient populations warrant a targeted fertility evaluation before services are provided:
  • Diverse patient populations, including LGBTQ+ and nonbinary individuals
  • Individuals with known genetic carrier status
  • Individuals with a need for or who are planning preimplantation genetic testing
  • Individuals presenting for donor sperm treatment, recurrent pregnancy loss, or fertility preservation
• The infertility evaluation should include an evaluation of ovulatory status, the structure and patency of the female reproductive tract, and semen evaluation of the male partner.
• In nonhirsute women with regular menstrual cycles between 25 to 35 days, additional testing to confirm ovulation is not required.
• When applicable, parallel fertility evaluation of the male partner should occur.
• Ovarian reserve testing should not be used to exclude women from infertility treatment but should be used as an adjunct to the evaluation of infertile women.
• Hysterosalpingo-contrast sonography and HSG have comparable diagnostic accuracy for tubal patency assessment.
• Laparoscopy, advanced sperm function testing, postcoital testing, thrombophilia testing, immunologic testing, karyotype, endometrial biopsy, serum TSH, and prolactin are not recommended as part of the routine infertility evaluation without other clinical indications.
  
  

Acknowledgments

This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine (ASRM) as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. The Practice Committee and the Board of Directors of the American Society for Reproductive Medicine have approved this report. This document was reviewed by ASRM members, and their input was considered in the preparation of the final document. The following members of the ASRM Practice Committee participated in the development of this document: Clarisa Gracia, M.D., M.S.C.E.; Rebecca Flyckt, M.D.; Denny Sakkas, Ph.D.; Karl Hansen, M.D., Ph.D.; Tarun Jain, M.D.; Suleena Kalra, M.D., M.S.C.E.; Bruce Pier, M.D.; Belinda Yauger, M.D.; Torie C. Plowden, M.D., M.P.H.; Ryan Smith, M.D.; Mark Trolice, M.D., M.B.A.; Suneeta Senapati, M.D.; Robert Brannigan, M.D.; Amy Sparks, Ph.D., H.C.L.D; Jared Robins, M.D.; Chevis N Shannon, Dr.Ph., M.B.A., M.P.H.; Jessica Goldstein, R.N.; and Madeline Brooks, M.B.A., M.P.H. The Practice Committee also acknowledges the special contribution of Mark Trolice, M.D., M.B.A.; and Micah Hill, D.O., in the preparation of this document. All committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the Committee who were found to have conflicts of interest on the basis of the relationships disclosed did not participate in the discussion or development of this document.

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