Disclosures: Wendy Kuohung, MD Nothing to disclose. Mark D Hornstein, MD Consultant/Advisory Board: WINFertility [Infertility, endometriosis]. Robert L Barbieri, MD Nothing to disclose. Deborah Levine, MD Nothing to disclose. Kristen Eckler, MD, FACOG Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — An infertility evaluation is usually initiated after one year of regular unprotected intercourse in women under age 35 years and after six months of unprotected intercourse in women age 35 years and older. However, the evaluation may be initiated sooner in women with irregular menstrual cycles or known risk factors for infertility, such as endometriosis, a history of pelvic inflammatory disease, or reproductive tract malformations.
The basic evaluation can be performed by an interested and experienced primary care physician or an obstetrician-gynecologist. The primary care physician generally should refer the patient to a specialist for treatment of infertility. Many gynecologists initiate treatment prior to referral to a reproductive endocrinologist. This decision depends upon the results of infertility tests and clinician experience.
Multiple tests have been proposed for evaluation of female infertility. Some of these tests are supported by good evidence, while others are not. This topic will provide an evidence-based approach to the evaluation of female infertility. The etiology and treatment of female infertility, as well as the etiology, evaluation, and treatment of male infertility, are discussed separately.
●(See "Overview of infertility".)
●(See "Causes of female infertility".)
●(See "Causes of male infertility".)
●(See "Evaluation of male infertility".)
●(See "Treatment of male infertility".)
INITIAL APPROACH — Both partners of an infertile couple should be evaluated for factors that could be impairing fertility. The infertility specialist then uses this information to counsel the couple about the possible etiologies of their infertility and to offer a treatment plan targeted to their specific needs.
It is important to remember that the couple may have multiple factors contributing to their infertility; therefore, a complete initial diagnostic evaluation should be performed to detect the most common causes of infertility, if present. When applicable, evaluation of both partners is performed concurrently .
The recognition, evaluation, and treatment of infertility are stressful for most couples . The clinician should not ignore the couple's emotional state, which may include depression, anger, anxiety, and marital discord. Information should be supportive and informative. (See "Psychological stress and infertility".)
History and physical examination — Findings on history and physical examination may suggest the cause of infertility and thus help focus the diagnostic evaluation. Components of the infertility history are listed in the table (table 1).
History — The most important points in the history are:
●Duration of infertility and results of previous evaluation and therapy.
●Menstrual history (cycle length and characteristics), which helps in determining ovulatory status. For example, regular monthly cycles with molimina (breast tenderness, ovulatory pain, bloating) suggest the patient is ovulatory and characteristics such as severe dysmenorrhea suggest endometriosis.
●Medical, surgical, and gynecological history (including sexually transmitted infections, pelvic inflammatory disease, and treatment of abnormal Pap smears) to look for conditions, procedures, or medications potentially associated with infertility. At a minimum, the review of systems should determine whether the patient has symptoms of thyroid disease, galactorrhea, hirsutism, pelvic or abdominal pain, dysmenorrhea, or dyspareunia. Young women who have undergone unilateral oophorectomy generally do not have reduced fertility since young women have many primordial follicles per ovary; however, prior unilateral oophorectomy may impact fertility in older women as they may develop diminished ovarian reserve sooner than women with two ovaries .
●Obstetrical history to assess for events potentially associated with subsequent infertility or adverse outcome in a future pregnancy.
●Sexual history, including sexual dysfunction and frequency of coitus. Infrequent or ineffective coitus can be an explanation for infertility.
●Family history, including family members with infertility, birth defects, genetic mutations, or mental retardation. Women with fragile X premutation may develop premature ovarian failure, while males may have learning problems, developmental delay, or autistic features.
●Personal and lifestyle history including age, occupation, exercise, stress, dieting/changes in weight, smoking, and alcohol use, all of which can affect fertility.
Physical examination — The physical examination should assess for signs of potential causes of infertility. The patient's body mass index (BMI) should be calculated and fat distribution noted, as extremes of BMI are associated with reduced fertility and abdominal obesity is associated with insulin resistance.
Incomplete development of secondary sexual characteristics is a sign of hypogonadotropic hypogonadism. A body habitus that is short and stocky, with a squarely shaped chest, suggests Turner syndrome.
Abnormalities of the thyroid gland, galactorrhea, or signs of androgen excess (hirsutism, acne, male pattern baldness, virilization) suggest the presence of an endocrinopathy (eg, hyper- or hypothyroidism, hyperprolactinemia, polycystic ovary syndrome, adrenal disorder).
Tenderness or masses in the adnexae or posterior cul-de-sac (pouch of Douglas) are consistent with chronic pelvic inflammatory disease or endometriosis. Palpable tender nodules in the posterior cul-de-sac, uterosacral ligaments, or rectovaginal septum are additional signs of endometriosis.
Vaginal/cervical structural abnormalities or discharge suggest the presence of a müllerian anomaly, infection, or cervical factor.
Uterine enlargement, irregularity, or lack of mobility are signs of a uterine anomaly, leiomyoma, endometriosis, or pelvic adhesive disease.
These conditions are described in detail separately:
●(See "Diagnosis of hyperthyroidism".)
Diagnostic tests — In addition to the history and physical examination, the initial diagnostic evaluation consists of:
●Semen analysis to detect male factor infertility.
●Documentation of normal ovulatory function. Women with regular menses approximately every four weeks with moliminal symptoms are almost always ovulatory.
●A test to rule out tubal occlusion. We usually perform a hysterosalpingogram (HSG), but laparoscopy with chromotubation may be more appropriate in women suspected of having endometriosis. Indigo carmine can be used for the chromotubation dye. (See 'Role of laparoscopy' below.)
Risk factors noted from the couple's history may indicate the need for additional testing after the initial infertility evaluation.
Preconceptional laboratory screening may also be undertaken at this time so these results can be used for diagnostic and therapeutic counseling. Genetic screening should be offered in accordance with risk as defined by ethnicity. The components of preconception evaluation and counseling are discussed separately. (See "The preconception office visit", section on 'Laboratory assessment'.)
Semen analysis — The semen analysis is the cornerstone of the assessment of the male partner of an infertile couple. In addition to the standard analysis, specialized analyses can be performed in some laboratories. The semen sample should be collected after two to seven days of abstinence and should be submitted to the laboratory within one hour of collection .
It is difficult to predict the likelihood of pregnancy based upon the results of semen analysis alone, as there is extensive overlap between the semen parameters of fertile and infertile men. If the semen analysis is abnormal, the clinician should review details of specimen collection and transport with the patient, repeat the test due to the marked inherent variability of semen analyses, and consider referral to a urologist or other specialist in male reproduction.
The techniques for semen analysis and interpretation of results are discussed in detail separately. (See "Evaluation of male infertility", section on 'Standard semen analysis'.)
Assessment of ovulatory function — Assessment of ovulatory function is a key component of the evaluation of the female partner since ovulatory dysfunction is a common cause of infertility. The treatment of women with ovulatory dysfunction is aimed at improving or inducing ovulatory function; a variety of treatment strategies is available. (See "Overview of treatment of female infertility".)
In women who do not have grossly abnormal menstrual cycles indicative of ovulatory dysfunction, laboratory assessment of ovulation should be performed. Ovulation is most easily documented by a mid-luteal phase serum progesterone level, which should be obtained approximately one week before the expected menses. For a typical 28-day cycle, the test would be obtained on day 21. A progesterone level >3 ng/mL is evidence of recent ovulation .
An alternative is to have the patient use an over-the-counter urinary ovulation prediction kit. These kits detect luteinizing hormone (LH) and are highly effective for predicting the timing of the LH surge that reliably indicates ovulation. Home kits have a 5 to 10 percent false positive and false negative rate. Therefore, serum confirmation can be useful in patients who are unable to detect a urinary LH surge.
Other methods of determining ovulation, such as daily ultrasounds to follow the development and ultimately the disappearance of a follicle (the most accurate method of documenting ovulation ) and endometrial biopsy to document secretory changes in the endometrium are too expensive or invasive for routine diagnostic assessment of ovulation.
If the progesterone concentration is <3 ng/mL, the patient is evaluated for causes of anovulation. The minimal work-up includes serum prolactin, thyrotropin (TSH), follicle-stimulating hormone (FSH), and assessment for polycystic ovary syndrome (PCOS). The etiology and diagnostic evaluation of anovulation are reviewed separately. (See "Etiology, diagnosis, and treatment of secondary amenorrhea".)
Assessment of ovarian reserve — Diminished ovarian reserve can refer to diminished oocyte quality, oocyte quantity, or reproductive potential. The identification of diminished ovarian reserve is an increasingly important component of the initial infertility evaluation as patients are presenting for diagnostic evaluation later in their reproductive lifespan. Guidelines for testing from national organizations are available [7,8]. However, there is no ideal test for assessing ovarian reserve. A number of screening tests are utilized, but no single test is highly reliable for predicting pregnancy potential. Therefore, coordination of tests provides the best assessment. Many (most in Europe) have moved to using anti-müllerian hormone (AMH) level as their main test for ovarian reserve. Curiously the test is NOT US Food and Drug Administration-approved, but insurance tends to pay for the test .
For women over 35 years of age and younger women with risk factors for premature ovarian failure, we suggest testing ovarian reserve with a day 3 FSH level. Other tests such as the clomiphene citrate challenge test (CCCT), antral follicle count, and AMH level are utilized by some specialists and in special circumstances. These tests have good specificity for predicting a poor response in in vitro fertilization (IVF) cycles, but have more limited value for predicting IVF outcome.
Day 3 FSH and CCCT — Both the day 3 FSH level (where day 1 is the first day of full menstrual flow) and the CCCT, which is a provocative test for measurement of FSH, are widely used for screening ovarian reserve. The CCCT involves oral administration of 100 mg clomiphene citrate on cycle days 5 through 9 with measurement of day 3 and day 10 FSH levels and day 3 estradiol level.
The basis of these tests is that women with good ovarian reserve have sufficient production of ovarian hormones from small follicles early in the menstrual cycle to maintain FSH at a low level. In contrast, women with a reduced pool of follicles and oocytes have insufficient production of ovarian hormones to provide normal inhibition of pituitary secretion of FSH, so FSH rises early in the cycle .
Meta-analyses of nonrandomized studies concluded that basal cycle day 3 FSH and the CCCT testing perform similarly for predicting ability to achieve a clinical pregnancy in women undergoing infertility treatment [11,12]. With either test, a normal result is not useful in predicting fertility, but a highly abnormal result (we use FSH >20 mIU/mL) suggests that pregnancy will not occur with treatment involving the woman's own oocytes.
Based on these findings and the cost advantage and simplicity of the day 3 FSH, we obtain a day 3 FSH concentration and consider a value less than 10 mIU/mL suggestive of adequate ovarian reserve, and levels of 10 to 15 mIU/ml borderline. The upper threshold for a normal FSH concentration is laboratory dependent; cutoff values of 10 to 25 mIU/mL have been reported because of use of different FSH assay reference standards and assay methodologies.
We also check a cycle day 3 estradiol level, although there are conflicting data as to whether it is predictive of ovarian reserve and the response to ovarian stimulation (as in IVF) [13,14]. We consider a value <80 pg/mL suggestive of adequate ovarian reserve, but other cut-offs are also utilized. In one prospective study of women undergoing IVF, day 3 estradiol levels >80 pg/mL resulted in higher cycle cancellation rates and lower pregnancy rates, and estradiol levels >100 pg/mL were associated with a 0 percent pregnancy rate .
Elevated basal estradiol levels are due to advanced premature follicle recruitment that occurs in women with poor ovarian reserve. High estradiol levels can inhibit pituitary FSH production and thus mask one of the signs of decreased ovarian reserve in perimenopausal women. Thus, measurement of both FSH and estradiol levels helps to avoid false-negative FSH testing.
If CCCT is performed, we consider FSH less than 15 mIU/mL on both day 3 and day 10 suggestive of adequate ovarian reserve; an elevated FSH level on either day 3 or day 10 suggests decreased ovarian reserve. Estradiol can be measured on day 3, but a cycle day 10 estradiol is not part of the standard CCCT as it reflects the magnitude of the ovarian follicular response to clomiphene 100 mg daily for five days, not ovarian reserve.
If the day 3 FSH or CCCT is abnormal, the patient should be referred to a reproductive endocrinologist to discuss further diagnostic and treatment options. These options depend on the results of other diagnostic tests, the patient’s age , and other factors and may include aggressive ovulation induction, IVF, or use of donor oocytes. However, patients with markedly diminished ovarian reserve rarely conceive without the use of donor eggs.
Antral follicle count (AFC) — Ultrasound examination can be used to determine the number of antral follicles (defined as follicles measuring 2 to 10 mm in diameter). On transvaginal ultrasound, the ovaries are visualized in their transverse and longitudinal planes and the antral follicles are counted and measured; the size of the follicle is the mean of two perpendicular diameters, one of which should be the largest dimension of each follicle [17,18]. A low AFC ranging from 4 to 10 antral follicles between days two and four of a regular menstrual cycle suggests poor ovarian reserve. AFC thresholds will vary by center and should be prospectively tested within a center to be most useful as a predictive tool [19-22]. Most clinicians perform an AFC during the early follicular phase, although a retrospective cohort study showed no difference in the predictive value of AFC for poor ovarian response when measured at different phases of the menstrual cycle . Although AFC is a good predictor of ovarian reserve and response, it is less predictive of oocyte quality, the ability to conceive with IVF, and pregnancy outcome .
Anti-müllerian hormone (AMH) — Anti-müllerian hormone (AMH) is a member of the TGF-beta family and is expressed by the small (<8 mm) preantral and early antral follicles. The AMH level reflects the size of the primordial follicle pool, and may be the best biochemical marker of ovarian function across an array of clinical situations . In adult women, AMH levels gradually decline as the primordial follicle pool declines with age ; AMH is undetectable at menopause .
The AMH level appears to be an early, reliable, direct indicator of declining ovarian function. It may play an especially useful role in identifying reduced ovarian follicle pool in certain types of patients, such as cancer patients  and patients who have had significant ovarian injury from radiation or surgery. In patients planning IVF, AMH level correlates with the number of oocytes retrieved after stimulation, and is the best biomarker for predicting poor and excessive ovarian response [13,29-31]. However, its diagnostic accuracy for predicting live birth is poor so it should not be used to exclude couples from IVF/ICSI .
There is no consensus on the threshold value suggestive of reduced fertility potential [13,27,28,33-37]. Interpretation of AMH levels is laboratory assay-dependent [38-40], there is no international standard; therefore, clinicians should be guided by their own laboratory’s reference ranges. In general, a level well-above the laboratory’s lower threshold for normal suggests adequate ovarian reserve. As the level falls below the lower limit of normal, the probability of diminished ovarian reserve progressively increases, with very low levels suggesting pregnancy is less likely to occur and the patient will have a poor response to IVF [13,33]. One review suggested the following general guidelines :
●AMH <0.5 ng/mL predicts reduced ovarian reserve with less than three follicles in an IVF cycle
●AMH <1.0 ng/mL predicts baseline ovarian reserve with a likelihood of limited eggs at retrieval
●AMH >1.0 ng/mL but <3.5 ng/mL suggests a good response to stimulation
●AMH >3.5 ng/mL predicts a vigorous response to ovarian stimulation and caution should be exercised in order to avoid ovarian hyperstimulation syndrome
AMH can be measured anytime during the menstrual cycle and typically demonstrates minimal intercycle and intracycle variability since the growth of small preantral follicles that express it is continuous, not cyclical. Reliable AMH kits  are readily available from multiple vendors and AMH measurements can be obtained from large clinical reference laboratories [43,44]. AMH level is being used to manage patients in Europe .
Assessment of fallopian tube patency — We perform HSG as the first-line test for evaluation of tubal patency because of its therapeutic, as well as diagnostic, benefits . Non- or minimally invasive alternatives to HSG for investigation of tubal subfertility include chlamydia antibody testing and/or hysterosalpingo-contrast sonography (HyCoSy) .
When the diagnosis is in doubt, more invasive tests can be used to confirm the diagnosis, and provide an opportunity for concurrent therapeutic intervention. These tests include laparoscopy with chromotubation and fluoroscopic/hysteroscopic selective tubal cannulation.
Hysterosalpingogram — We obtain a HSG to look for tubal occlusion in all patients, unless laparoscopy is planned [48,49]. Either water or lipid soluble contrast media can be used. HSG also provides information about the uterine cavity. Women with abnormalities on HSG should be referred to a reproductive endocrinologist to discuss treatment options. (See "Hysterosalpingography".)
HSG is not useful for detecting peritubal adhesions or endometriosis . We perform diagnostic laparoscopy and chromotubation in women suspected of having endometriosis or pelvic adhesions related to a previous pelvic infection or surgery. Ablation of implants and lysis of adhesions, when indicated, can be performed at the same procedure (see 'Role of laparoscopy' below).
A meta-analysis of 20 studies involving 4179 patients compared HSG and laparoscopy with chromotubation (the gold standard); the calculated sensitivity and specificity for diagnosis of tubal patency were only 65 and 83 percent, respectively . However, when subgroups of women undergoing HSG were analyzed, HSG appeared to have very high specificity and sensitivity for diagnosing distal tubal occlusion or major distal tubal adhesions, but much lower specificity for diagnosing proximal tubal occlusion.
Proximal tubal occlusion on HSG often represents testing artifact due to tubal spasm or poor catheter positioning leading to unilateral tubal perfusion. Given these deficiencies, findings of proximal tubal occlusion on HSG could be confirmed by a secondary test such as a repeat HSG, fluoroscopic or hysteroscopic selective tubal perfusion, or laparoscopic chromotubation if definitive diagnosis will influence further management.
Diagnostic HSG also appears to have therapeutic effects. A systematic review of 12 randomized trials found that pregnancy rates were significantly higher in subfertile women who underwent tubal flushing with oil soluble media than in those who did not undergo HSG (OR 3.30, 95% CI 2.00-5.43), and that pregnancy rates were similar whether oil or water soluble media were used (OR 1.21, 95%CI 0.95-1.54) .
Chlamydia antibodies — Chlamydia trachomatis IgG antibody testing is a simple, inexpensive, noninvasive test with some evidence supporting its use as a method for predicting the presence of tubal disease. Studies suggest that antibodies to chlamydia are more predictive of infertility than an abnormal HSG or a history of previous use of a copper IUD [50-55]. Multiple tests are available , but not widely utilized given only limited data supporting their use. A cost-effective approach might be to screen women at low risk of tubal disease with chlamydia antibodies. A negative test is associated with <15 percent likelihood of tubal pathology and thus does not require further assessment . False positives are due to cross reactivity withC. pneumoniae, do not distinguish between remote and persistent infection, and do not indicate whether infection resulted in tubal damage ; therefore, an HSG is performed if the test results are positive . Women at high risk of tubal disease would be screened by HSG primarily.
In a study correlating results of five chlamydia antibody tests to laparoscopy findings in 315 subfertile women, the diagnostic performance of micro-immunofluorescence testing was superior to ELISA testing . However, there was significant cross-reactivity with C. pneumoniae antibodies for all tests except the pELISA Medac. Thus, positive test results from other modalities should be confirmed with this ELISA. In this study, a positive pELISA Medac had sensitivity and specificity of 55 and 87 percent, respectively, for tubal pathology at laparoscopy.
Chlamydia antibody testing can be used to screen women with an allergy to shellfish or iodinated contrast agents who cannot undergo an HSG. In women without risk factors for tubal disease, a negative test does not require further tubal assessment. If the test is positive, a sonohysterogram may be performed; presence of fluid in the cul-de-sac after intrauterine infusion of saline indicates patency of at least one tube.
Hysterosalpingo-contrast sonography — Hysterosalpingo-contrast sonography (HyCoSy) uses ultrasound to view the uterus, tubes, and adnexa before and after transcervical injection of echogenic contrast media. It is a safe, well tolerated, quick and easy method for obtaining information on tubal status, the uterine cavity, the ovaries, and the myometrium using conventional ultrasound . In a 2014 systematic review of studies that compared HyCoSy with HSG for diagnosis of tubal occlusion in subfertile women, both tests had high diagnostic accuracy compared with laparoscopy (reference standard), with no significant difference between them. For HyCoSy, sensitivity was 0.92 (95% CI 0.82-0.96) and specificity was 0.95 (95% CI 0.90-0.97) per tube for diagnosing tubal occlusion. Tubal spasm and tubal fistula, as well as operator error could account for misdiagnoses.
Assessment of the uterine cavity — In addition to assessment of tubal patency, HSG may identify developmental or acquired abnormalities of the uterine cavity with potential effects on fertility, such as submucous fibroids, a T-shaped cavity (associated with DES exposure), polyps, synechiae, and congenital müllerian anomalies. An experienced ultrasonographer can usually distinguish between a uterine septum and a bicornuate uterus. Abnormalities found on HSG generally require further evaluation by other imaging modalities (ultrasonography or magnetic resonance imaging), hysteroscopy, or laparoscopy and referral to a reproductive endocrinologist.
Ultrasonography is a useful test for evaluation of suspected leiomyomata, while saline infusion sonohysterography is the best imaging modality for detection of submucosal leiomyomas and is much better than routine ultrasonography for diagnosis of intrauterine adhesions, polyps, and congenital uterine anomalies . As discussed above, HyCoSy is a simple, time-efficient, and effective method for evaluation of tubal patency, the uterine cavity, and the myometrium .
Hysteroscopy is the definitive method for evaluation of abnormalities of the endometrial cavity, and also offers the opportunity for treatment at time of diagnosis. In patients undergoing laparoscopy, performing hysteroscopy at the same time and omitting HSG is efficient.
Evaluation of uterine anomalies depends on the anomaly.
●(See "Overview of hysteroscopy".)
●(See "Hysteroscopic myomectomy".)
●(See "Intrauterine adhesions".)
ROLE OF LAPAROSCOPY — The role of laparoscopy in the evaluation of infertility is controversial. Laparoscopy is invasive and expensive. Findings at laparoscopy usually do not alter the initial treatment of the infertile couple when the initial infertility evaluation is normal or when it shows severe male factor infertility. Couples with a normal infertility evaluation (ie, unexplained infertility) typically undergo a trial of ovarian stimulation with or without intrauterine insemination and many will conceive without further intervention. Couples with tubal or male factor infertility are typically offered IVF as one of their treatment options. (See "Unexplained infertility" and "In vitro fertilization".)
No randomized trials have assessed the cost effectiveness and timing of diagnostic laparoscopy prior to ovulation induction in couples with unexplained infertility. Laparoscopy is indicated in women in whom endometriosis or pelvic adhesions/tubal disease is suspected based on physical examination, HSG, or history (eg, current dysmenorrhea, pelvic pain, or deep dyspareunia; previous complicated appendicitis, pelvic infection, pelvic surgery, or ectopic pregnancy) [62-64]. When we perform laparoscopy, we also perform chromotubation to assess tubal patency and hysteroscopy to evaluate the uterine cavity. For this reason, if laparoscopy is planned, then HSG can be omitted .
The advantage of performing laparoscopy early in the evaluation of women suspected of having endometriosis or pelvic adhesions is that surgical therapy can be initiated, while avoiding potentially ineffective or unnecessary empiric medical treatment for ovulation induction. Endometriosis, if identified, can be excised/ablated at the time of the diagnostic procedure and pelvic adhesions can be lysed. (See "Pathogenesis and treatment of infertility in women with endometriosis".)
The use of laparoscopy to treat infertility is covered in detail separately. (See "Reproductive surgery for female infertility".)
TESTS OF LIMITED CLINICAL UTILITY
Postcoital test — In agreement with other experts [1,66], we do not recommend postcoital testing.
The postcoital test has poor diagnostic potential and predictive value [67,68] that is due, in part, to the lack of consensus on a normal versus abnormal test result and to low inter- and intraobserver reproducibility . In addition, interventions designed to improve cervical factor infertility have not been effective, while widely used infertility therapies, such as intrauterine insemination and IVF bypass the cervix so improving cervical factors becomes irrelevant. Importantly, a randomized trial that compared the outcome of infertility investigations with and without the postcoital test showed no difference in pregnancy rates at 24 months . Thus, incorporation of the postcoital test in standard infertility evaluations increases the number of tests and treatments, but has no effect on the pregnancy rate.
Endometrial biopsy — Endometrial biopsy has been performed for two reasons: (1) to document a secretory endometrium, which is indirect evidence that ovulation has occurred, and (2) to evaluate whether the maturity of the secretory endometrium is in phase (ie, consistent with menstrual cycle date) or out of phase (ie, luteal phase defect). It is not a good test for either indication because it is invasive, expensive, uncomfortable, unnecessary for evaluation of ovulation, and ineffective for assessment of endometrial receptivity (ie, the ability of the endometrium to allow the blastocyst to attach, invade, and implant).
As discussed above, ovulation is optimally assessed using serum progesterone level >3 ng/mL obtained in the late luteal phase (see 'Assessment of ovulatory function' above).
Although endometrial receptivity during the implantation window is crucial for achieving pregnancy, histological assessment of endometrial response has a poor correlation with fertility [71-75]. For example, when repeated endometrial biopsies are performed in normal fertile women, half will have a single out-of-phase biopsy (using two-day or greater lag criteria) and over one-quarter will have sequential out-of-phase biopsies [76,77]. Moreover, in one study of 619 women with regular menstrual cycles, a biopsy that was out-of-phase by greater than two days was actually more common in fertile women than in infertile women (at day 21 to 22: 49 versus 43 percent; at day 26 to 27: 35 versus 23 percent).
Thus, it appears that histological dating does not discriminate fertile from infertile couples [76,77]. As the treatment of luteal phase defect does not improve pregnancy outcome in infertile women, luteal phase evaluation by histological dating of the endometrium is not worthwhile.
The American Society of Reproductive Medicine (ASRM) affirmed the lack of benefit of the endometrial biopsy in the evaluation of the infertile female and does not recommend use of this test .
Endometrial biopsy is appropriate when endometrial pathology is strongly suspected.
Basal body temperature records — Basal body temperature charts are the least expensive method for detecting ovulation, but interpretation of the charts can be difficult and subject to wide interobserver variation [78,79]. We prefer serum testing for assessment of ovulatory status in women with irregular cycles (see 'Assessment of ovulatory function' above).
Progesterone released from the corpus luteum at the time of ovulation has potent effects on the hypothalamus, one of which is to increase body temperature. As a result, daily temperature monitoring can be used to document progesterone production and, therefore, ovulation. The woman takes her temperature by putting the thermometer under her tongue every morning while she is still in the basal state (ie, before she gets out of bed, uses the bathroom, or has anything to eat or drink) and records the temperature on a chart. Although there is an expected amount of daily variability, an approximately 0.5ºF rise in body temperature can be detected in the luteal phase of the menstrual cycle compared with the follicular phase. In a normal cycle, the temperature rise begins one or two days after the LH surge and persists for at least 10 days. Thus, temperature changes are sufficient to retrospectively identify ovulation, but they occur too late to be useful for timing intercourse.
Zona-free hamster oocyte penetration test — This test is also known as the sperm penetration assay. Conflicting literature exists on whether the hamster oocyte test predicts human oocyte fertilization [80,81]. The utility of test results depends, in part, on the experience of the laboratory performing the assay. We do not order this test since the results would not influence our clinical management. (See "Evaluation of male infertility", section on 'Zona-free hamster oocyte penetration test'.)
Mycoplasma cultures — We do not suggest obtaining routine Ureaplasma urealyticum and Mycoplasma hominis cultures given that there is minimal evidence for a role of these organisms in female infertility .
Testing for antibodies — Routine testing for antiphospholipid, antisperm, antinuclear, and antithyroid antibodies is not supported by existing data . Although an association between antiphospholipid antibodies and recurrent pregnancy loss has been established, the other autoimmune factors remain under investigation as markers of fertility treatment failure. (See "Pregnancy in women with antiphospholipid syndrome".)
Karyotype — There is a general consensus to counsel and offer to karyotype the male partner if there is severe oligospermia, as these men are at higher risk of karyotypic abnormalities. Separate testing for Y chromosome microdeletions may also be offered. We suggest karyotyping women with very early premature menopause (prior to age 40) and both partners if there have been recurrent pregnancy losses. In most other circumstances, karyotyping is not indicated as part of the initial evaluation because of the low incidence of abnormalities in women with unexplained infertility, endometriosis, or tubal factor infertility . Karyotype may be useful in patients with these conditions who have failed initial treatment approaches and plan to undergo IVF, although the cost-effectiveness of universal karyotype screening prior to IVF has not been established .
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
SUMMARY AND RECOMMENDATIONS
●We suggest that an infertility evaluation be offered to couples who have not been able to conceive after 12 months of unprotected and frequent intercourse (Grade 2C). Earlier evaluation (eg, after six months) is indicated in some couples, such as those in whom the female partner is over 35 years of age or has a history of oligo/amenorrhea, known or suspected tubal disease or endometriosis, a history of chemotherapy or radiation therapy, and those in whom the male partner is known to be subfertile. (See 'Initial approach' above.)
●The history and physical examination are directed at identifying signs and symptoms suggestive of the etiology of the infertility. (See 'History and physical examination' above.)
●The basic infertility evaluation of all couples consists of:
•Semen analysis. (See 'Semen analysis' above.)
•Assessment of ovulatory status by history or laboratory testing. (See 'Assessment of ovulatory function' above.)
•Determination of tubal patency and presence or absence of abnormalities of the uterine cavity, usually by hysterosalpingogram. (See 'Assessment of fallopian tube patency' above and 'Assessment of the uterine cavity' above.)
●Ovarian reserve is assessed with day 3 follicle-stimulating hormone (FSH) and estradiol levels in women over 35 years of age and younger women with risk factors for premature ovarian failure. Other tests such as the clomiphene citrate challenge test (CCCT), antral follicle count, and anti-müllerian hormone (AMH) level are utilized in special circumstances. (See 'Assessment of ovarian reserve' above.)
●Diagnostic laparoscopy is indicated for women with suspected endometriosis or pelvic adhesions. When we perform laparoscopy, we also perform chromotubation to assess tubal patency and hysteroscopy to evaluate the uterine cavity. (See 'Role of laparoscopy' above.)
- Practice Committee of American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril 2012; 98:302.
- Cousineau TM, Domar AD. Psychological impact of infertility. Best Pract Res Clin Obstet Gynaecol 2007; 21:293.
- Lass A. The fertility potential of women with a single ovary. Hum Reprod Update 1999; 5:546.
- World Health Organization, WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th edition. Cambridge University Press, Cambridge, UK, 1999.
- Wathen NC, Perry L, Lilford RJ, Chard T. Interpretation of single progesterone measurement in diagnosis of anovulation and defective luteal phase: observations on analysis of the normal range. Br Med J (Clin Res Ed) 1984; 288:7.
- Ecochard R, Boehringer H, Rabilloud M, Marret H. Chronological aspects of ultrasonic, hormonal, and other indirect indices of ovulation. BJOG 2001; 108:822.
- Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril 2012; 98:1407.
- Committee opinion no. 618: ovarian reserve testing. Obstet Gynecol 2015; 125:268.
- Broer SL, Broekmans FJ, Laven JS, Fauser BC. Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications. Hum Reprod Update 2014; 20:688.
- Abdalla H, Thum MY. An elevated basal FSH reflects a quantitative rather than qualitative decline of the ovarian reserve. Hum Reprod 2004; 19:893.
- Jain T, Soules MR, Collins JA. Comparison of basal follicle-stimulating hormone versus the clomiphene citrate challenge test for ovarian reserve screening. Fertil Steril 2004; 82:180.
- Hendriks DJ, Mol BW, Bancsi LF, et al. The clomiphene citrate challenge test for the prediction of poor ovarian response and nonpregnancy in patients undergoing in vitro fertilization: a systematic review. Fertil Steril 2006; 86:807.
- Broekmans FJ, Kwee J, Hendriks DJ, et al. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006; 12:685.
- Licciardi FL, Liu HC, Rosenwaks Z. Day 3 estradiol serum concentrations as prognosticators of ovarian stimulation response and pregnancy outcome in patients undergoing in vitro fertilization. Fertil Steril 1995; 64:991.
- Smotrich DB, Widra EA, Gindoff PR, et al. Prognostic value of day 3 estradiol on in vitro fertilization outcome. Fertil Steril 1995; 64:1136.
- Souter I, Dimitriadis I, Baltagi LM, et al. Elevated day 3 follicle-stimulating hormone in younger women: is gonadotropin stimulation/intrauterine insemination a good option? Am J Obstet Gynecol 2014; 211:62.e1.
- Haadsma ML, Bukman A, Groen H, et al. The number of small antral follicles (2-6 mm) determines the outcome of endocrine ovarian reserve tests in a subfertile population. Hum Reprod 2007; 22:1925.
- Deb S, Campbell BK, Clewes JS, Raine-Fenning NJ. Quantitative analysis of antral follicle number and size: a comparison of two-dimensional and automated three-dimensional ultrasound techniques. Ultrasound Obstet Gynecol 2010; 35:354.
- Tomas C, Nuojua-Huttunen S, Martikainen H. Pretreatment transvaginal ultrasound examination predicts ovarian responsiveness to gonadotrophins in in-vitro fertilization. Hum Reprod 1997; 12:220.
- Chang MY, Chiang CH, Hsieh TT, et al. Use of the antral follicle count to predict the outcome of assisted reproductive technologies. Fertil Steril 1998; 69:505.
- Broekmans FJ, de Ziegler D, Howles CM, et al. The antral follicle count: practical recommendations for better standardization. Fertil Steril 2010; 94:1044.
- Jayaprakasan K, Chan Y, Islam R, et al. Prediction of in vitro fertilization outcome at different antral follicle count thresholds in a prospective cohort of 1,012 women. Fertil Steril 2012; 98:657.
- Rombauts L, Onwude JL, Chew HW, Vollenhoven BJ. The predictive value of antral follicle count remains unchanged across the menstrual cycle. Fertil Steril 2011; 96:1514.
- Hsu A, Arny M, Knee AB, et al. Antral follicle count in clinical practice: analyzing clinical relevance. Fertil Steril 2011; 95:474.
- Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update 2014; 20:370.
- Seifer DB, Baker VL, Leader B. Age-specific serum anti-Müllerian hormone values for 17,120 women presenting to fertility centers within the United States. Fertil Steril 2011; 95:747.
- de Vet A, Laven JS, de Jong FH, et al. Antimüllerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril 2002; 77:357.
- Lutchman Singh K, Muttukrishna S, Stein RC, et al. Predictors of ovarian reserve in young women with breast cancer. Br J Cancer 2007; 96:1808.
- Nardo LG, Gelbaya TA, Wilkinson H, et al. Circulating basal anti-Müllerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization. Fertil Steril 2009; 92:1586.
- Anckaert E, Smitz J, Schiettecatte J, et al. The value of anti-Mullerian hormone measurement in the long GnRH agonist protocol: association with ovarian response and gonadotrophin-dose adjustments. Hum Reprod 2012; 27:1829.
- Broer SL, Dólleman M, Opmeer BC, et al. AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis. Hum Reprod Update 2011; 17:46.
- Iliodromiti S, Kelsey TW, Wu O, et al. The predictive accuracy of anti-Müllerian hormone for live birth after assisted conception: a systematic review and meta-analysis of the literature. Hum Reprod Update 2014; 20:560.
- Gnoth C, Schuring AN, Friol K, et al. Relevance of anti-Mullerian hormone measurement in a routine IVF program. Hum Reprod 2008; 23:1359.
- van Rooij IA, Broekmans FJ, Scheffer GJ, et al. Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil Steril 2005; 83:979.
- Steiner AZ, Herring AH, Kesner JS, et al. Antimüllerian hormone as a predictor of natural fecundability in women aged 30-42 years. Obstet Gynecol 2011; 117:798.
- Almog B, Shehata F, Suissa S, et al. Age-related normograms of serum antimüllerian hormone levels in a population of infertile women: a multicenter study. Fertil Steril 2011; 95:2359.
- Weghofer A, Dietrich W, Barad DH, Gleicher N. Live birth chances in women with extremely low-serum anti-Mullerian hormone levels. Hum Reprod 2011; 26:1905.
- Nelson SM, Iliodromiti S, Fleming R, et al. Reference range for the antimüllerian hormone Generation II assay: a population study of 10,984 women, with comparison to the established Diagnostics Systems Laboratory nomogram. Fertil Steril 2014; 101:523.
- Rustamov O, Smith A, Roberts SA, et al. Anti-Mullerian hormone: poor assay reproducibility in a large cohort of subjects suggests sample instability. Hum Reprod 2012; 27:3085.
- Su HI, Sammel MD, Homer MV, et al. Comparability of antimüllerian hormone levels among commercially available immunoassays. Fertil Steril 2014; 101:1766.
- Toner JP, Seifer DB. Why we may abandon basal follicle-stimulating hormone testing: a sea change in determining ovarian reserve using antimüllerian hormone. Fertil Steril 2013; 99:1825.
- Dorgan JF, Spittle CS, Egleston BL, et al. Assay reproducibility and within-person variation of Müllerian inhibiting substance. Fertil Steril 2010; 94:301.
- Fleming, R, Deshpande, N, Traynor, I, Yates, RW. Dynamics of FSH-induced follicular growth in subfertile women. Hum Reprod 2006.
- Visser JA, de Jong FH, Laven JS, Themmen AP. Anti-Müllerian hormone: a new marker for ovarian function. Reproduction 2006; 131:1.
- Johnson NP, Bagrie EM, Coomarasamy A, et al. Ovarian reserve tests for predicting fertility outcomes for assisted reproductive technology: the International Systematic Collaboration of Ovarian Reserve Evaluation protocol for a systematic review of ovarian reserve test accuracy. BJOG 2006; 113:1472.
- Luttjeboer F, Harada T, Hughes E, et al. Tubal flushing for subfertility. Cochrane Database Syst Rev 2007; :CD003718.
- Lim CP, Hasafa Z, Bhattacharya S, Maheshwari A. Should a hysterosalpingogram be a first-line investigation to diagnose female tubal subfertility in the modern subfertility workup? Hum Reprod 2011; 26:967.
- Swart P, Mol BW, van der Veen F, et al. The accuracy of hysterosalpingography in the diagnosis of tubal pathology: a meta-analysis. Fertil Steril 1995; 64:486.
- Papaioannou S, Bourdrez P, Varma R, et al. Tubal evaluation in the investigation of subfertility: a structured comparison of tests. BJOG 2004; 111:1313.
- Thomas K, Coughlin L, Mannion PT, Haddad NG. The value of Chlamydia trachomatis antibody testing as part of routine infertility investigations. Hum Reprod 2000; 15:1079.
- Dabekausen YA, Evers JL, Land JA, Stals FS. Chlamydia trachomatis antibody testing is more accurate than hysterosalpingography in predicting tubal factor infertility. Fertil Steril 1994; 61:833.
- Hubacher D, Lara-Ricalde R, Taylor DJ, et al. Use of copper intrauterine devices and the risk of tubal infertility among nulligravid women. N Engl J Med 2001; 345:561.
- Veenemans LM, van der Linden PJ. The value of Chlamydia trachomatis antibody testing in predicting tubal factor infertility. Hum Reprod 2002; 17:695.
- Mol BW, Dijkman B, Wertheim P, et al. The accuracy of serum chlamydial antibodies in the diagnosis of tubal pathology: a meta-analysis. Fertil Steril 1997; 67:1031.
- Rodgers AK, Budrys NM, Gong S, et al. Genome-wide identification of Chlamydia trachomatis antigens associated with tubal factor infertility. Fertil Steril 2011; 96:715.
- Fiddelers AA, Land JA, Voss G, et al. Cost-effectiveness of Chlamydia antibody tests in subfertile women. Hum Reprod 2005; 20:425.
- den Hartog JE, Morré SA, Land JA. Chlamydia trachomatis-associated tubal factor subfertility: Immunogenetic aspects and serological screening. Hum Reprod Update 2006; 12:719.
- Mol BW, Collins JA, Van Der Veen F, Bossuyt PM. Cost-effectiveness of hysterosalpingography, laparoscopy, and Chlamydia antibody testing in subfertile couples. Fertil Steril 2001; 75:571.
- Land JA, Gijsen AP, Kessels AG, et al. Performance of five serological chlamydia antibody tests in subfertile women. Hum Reprod 2003; 18:2621.
- Saunders RD, Shwayder JM, Nakajima ST. Current methods of tubal patency assessment. Fertil Steril 2011; 95:2171.
- Soares SR, Barbosa dos Reis MM, Camargos AF. Diagnostic accuracy of sonohysterography, transvaginal sonography, and hysterosalpingography in patients with uterine cavity diseases. Fertil Steril 2000; 73:406.
- Balasch J. Investigation of the infertile couple: investigation of the infertile couple in the era of assisted reproductive technology: a time for reappraisal. Hum Reprod 2000; 15:2251.
- Smith S, Pfeifer SM, Collins JA. Diagnosis and management of female infertility. JAMA 2003; 290:1767.
- Luttjeboer FY, Verhoeve HR, van Dessel HJ, et al. The value of medical history taking as risk indicator for tuboperitoneal pathology: a systematic review. BJOG 2009; 116:612.
- Perquin DA, Dörr PJ, de Craen AJ, Helmerhorst FM. Routine use of hysterosalpingography prior to laparoscopy in the fertility workup: a multicentre randomized controlled trial. Hum Reprod 2006; 21:1227.
- Oei SG, Helmerhorst FM, Keirse MJ. When is the post-coital test normal? A critical appraisal. Hum Reprod 1995; 10:1711.
- Griffith CS, Grimes DA. The validity of the postcoital test. Am J Obstet Gynecol 1990; 162:615.
- Collins JA, So Y, Wilson EH, et al. The postcoital test as a predictor of pregnancy among 355 infertile couples. Fertil Steril 1984; 41:703.
- Glatstein IZ, Best CL, Palumbo A, et al. The reproducibility of the postcoital test: a prospective study. Obstet Gynecol 1995; 85:396.
- Oei SG, Helmerhorst FM, Bloemenkamp KW, et al. Effectiveness of the postcoital test: randomised controlled trial. BMJ 1998; 317:502.
- Balasch J, Fábregues F, Creus M, Vanrell JA. The usefulness of endometrial biopsy for luteal phase evaluation in infertility. Hum Reprod 1992; 7:973.
- Edwards RG. Physiological and molecular aspects of human implantation. Hum Reprod 1995; 10 Suppl 2:1.
- Creus M, Balasch J, Ordi J, et al. Integrin expression in normal and out-of-phase endometria. Hum Reprod 1998; 13:3460.
- Giudice LC. Potential biochemical markers of uterine receptivity. Hum Reprod 1999; 14 Suppl 2:3.
- Murray MJ, Meyer WR, Zaino RJ, et al. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril 2004; 81:1333.
- Davis OK, Berkeley AS, Naus GJ, et al. The incidence of luteal phase defect in normal, fertile women, determined by serial endometrial biopsies. Fertil Steril 1989; 51:582.
- Coutifaris C, Myers ER, Guzick DS, et al. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril 2004; 82:1264.
- Bauman JE. Basal body temperature: unreliable method of ovulation detection. Fertil Steril 1981; 36:729.
- Kambic R, Gray RH. Interobserver variation in estimation of day of conception intercourse using selected natural family planning charts. Fertil Steril 1989; 51:430.
- Shibahara H, Mitsuo M, Inoue M, et al. Relationship between human in-vitro fertilization and intracytoplasmic sperm injection and the zona-free hamster egg penetration test. Hum Reprod 1998; 13:1928.
- Zainul Rashid MR, Fishel SB, Thornton S, et al. The predictive value of the zona-free hamster egg penetration test in relation to in-vitro fertilization at various insemination concentrations. Hum Reprod 1998; 13:624.
- Gump DW, Gibson M, Ashikaga T. Lack of association between genital mycoplasmas and infertility. N Engl J Med 1984; 310:937.
- Kallen CB, Arici A. Immune testing in fertility practice: truth or deception? Curr Opin Obstet Gynecol 2003; 15:225.
- Papanikolaou EG, Vernaeve V, Kolibianakis E, et al. Is chromosome analysis mandatory in the initial investigation of normovulatory women seeking infertility treatment? Hum Reprod 2005; 20:2899.
- Riccaboni A, Lalatta F, Caliari I, et al. Genetic screening in 2,710 infertile candidate couples for assisted reproductive techniques: results of application of Italian guidelines for the appropriate use of genetic tests. Fertil Steril 2008; 89:800.