The Evaluation of Unexplained Infertility

An infertility evaluation is usually initiated after one year of regular unprotected intercourse in women under age 35 and after six months of unprotected intercourse in women age 35 and older. However, the evaluation may be initiated sooner in women with irregular menstrual cycles or known risk factors for infertility, such as Endometriosis, Tubal Disease, Premature Ovarian Aging, Immunological Infertility, 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

Over the past decade, significant advances have occurred in the diagnosis and treatment of reproductive disorders. In this review, we discuss the routine testing performed to diagnose unexplained infertility. We also discuss additional testing, such as assessment of ovarian reserve, and the potential role of laparoscopy in the complete workup of unexplained infertility. Finally, we outline the available therapeutic options and discuss the efficacy and the cost-effectiveness of the existing treatment modalities. The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile, and cost considerations.

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.

Significant advances have occurred in the diagnosis and, more importantly, in the treatment of reproductive disorders over the past decade. The overall incidence of infertility has remained stable; however, the success rates have markedly improved with the widespread use of assisted reproductive technologies. Treatment options and success vary with the cause of infertility. Approximately 15% to 30% of couples will be diagnosed with unexplained infertility after their diagnostic workup.

Infertility is customarily defined as the inability to conceive after 1 year of regular unprotected intercourse. The infertility evaluation is typically initiated after 1 year of trying to conceive, but in couples with advanced female age (> 35 years), most practitioners initiate diagnostic evaluation after an inability to conceive for 6 months. The Practice Committee of the American Society for Reproductive

History and physical examination and Diagnostic tests - Findings on history and physical examination and Diagnostic tests may suggest the cause of infertility and thus help focus the diagnostic evaluation.

Important History points:

·         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 lacks of mobility are signs of a uterine anomaly, leiomyoma, endometriosis, or pelvic adhesive disease.

·         Pathogenesis, clinical features, and diagnosis of endometriosis

·         Clinical features and diagnosis of pelvic inflammatory disease

·         Clinical manifestations and diagnosis of congenital anomalies of the uterus

·         Clinical manifestations and diagnosis of hyperprolactinemia

·         Diagnosis of and screening for hypothyroidism in nonpregnant adults

·         Diagnosis of hyperthyroidism

·         Clinical manifestations of polycystic ovary syndrome in adults

·         Clinical manifestations and diagnosis of Turner syndrome (gonadal dysgenesis)

·         Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas (fibroids)

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.

Risk factors noted from the couple's history may indicate the need for additional testing after the initial infertility evaluation. When the results of a standard infertility evaluation are normal, practitioners assign a diagnosis of unexplained infertility. Although estimates vary, the likelihood that all such test results for an infertile couple are normal that the couple has unexplained infertility is approximately 15% to 30%.

A thorough but time-efficient investigation of the infertile couple is required prior to a diagnosis of unexplained infertility. Couples should undergo a semen analysis, ovulation testing, assessment of ovarian reserve, and imaging to assess for tubal and uterine factors before a diagnosis of unexplained infertility is made. This workup can be completed within 1 menstrual cycle. In the couples with unexplained infertility, various treatment modalities are available, including expectant management with lifestyle changes, operative laparoscopy, COH (clomiphene citrate or gonadotropins) with IUI, and IVF (with or without ICSI). The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile such as multiple pregnancy, and cost considerations.

·         Couples should undergo a semen analysis, ovulation testing, assessment of ovarian reserve, and imaging to assess for tubal and uterine factors before a diagnosis of unexplained infertility is made.

·         The principal treatments for unexplained infertility include expectant observation with timed intercourse and lifestyle changes, clomiphene citrate and intrauterine insemination (IUI), controlled ovarian hyper stimulation with IUI, and in vitro fertilization (IVF).

·         Although expectant management is associated with the lowest cost, it results in the lowest cycle fecundity rates. It may provide an option for a couple with unexplained infertility in whom the female partner is young and the problem of oocyte depletion is not an immediate concern.

·         The most expensive, but also most successful treatment of unexplained infertility consists of the spectrum of assisted reproductive technology including IVF, with or without intracytoplasmic sperm injection. IVF is the treatment of choice for unexplained infertility when the less costly, but also less successful treatment modalities have failed.

·         The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile such as multiple pregnancy, and cost considerations.