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Infertility may be defined as the failure of a couple to establish a pregnancy after 1 year of coitus without using contraception. The definition is based on expected monthly conception rates of 20-25% among healthy young couples. Female fertility decreases significantly after age 35. In the United States, approximately 15% of couples are infertile; in 15% of these couples, no etiology can be identified by usual clinical and laboratory techniques. Using a "normal'' cumulative fecundability curve, 95% of couples attempting pregnancy should conceive within

Fecundity refers to the potential for a couple to reproduce; the term fertility, which refers to actual conception rates, is the preferred medical term.

The rate of infertility has appeared to increase in the United States over the past 25 years in response to several factors: an increase in sexually transmissible infections (in part associated with the increased use of nonbarrier methods of contraception), deferral of age for childbearing, societal changes in which infertility is discussed more openly, and widespread publicity of new methods for achieving fertility among infertile couples. The evaluation of a couple that has been unable to conceive can be undertaken before a 12-month trial if a woman is anovulatory, if one of the partners has had a sterilization procedure, or if a woman is 35 years of age or 

Evaluation of an infertile couple requires a detailed medical, sexual, and reproductive history. Specific elements to evaluate include length of time the couple has attempted to conceive, prior reproductive performance of each partner, menstrual cyclicity, symptoms suggestive of pelvic inflammatory disease or endometriosis, coital technique (timing, frequency, and level of satisfaction), use of medications, previous abdominal or pelvic surgery of the female, and urologic disorders of the male. Women should be given a thorough physical and pelvic examination, including an assessment of cervical cytology and cervical cultures (Chlamydia, gonorrhea, Ureaplasma). Preconceptional evaluation should accompany the history, and counseling and

A thorough initial evaluation involves analysis of semen, cervical and coital factors (a postcoital test), ovulation (basal body temperature, late-luteal-phase endometrial biopsy or a luteal-phase serum progesterone determination or both, and home ovulation detection kit), uterine and tubal factors (hysterosalpingography, possibly hysteroscopy), and peritoneal factors (laparoscopy with tubal chromotubation). Abnormalities found in any of these studies require a more detailed investigation. The basic appraisal should identify targets for correction in approximately 85% of couples. When

Table 7. Potential Causes of Isolated Semen Abnormalities

Semen Abnormality

Potential Causes

Low sperm concentration


Endocrine dysfunction including androgen receptor defects Varicocele

Germinal epithelial dysfunction/failure

Low semen volume

Inappropriate collection


Ductal obstruction or atresia

Destruction or dysfunction of the seminal vesicles or


Retrograde ejaculation

Low sperm motility




Antisperm antibodies

Epididymal dysfunction

Medication, tobacco, or marijuana use

Environmental toxins

Endocrine dysfunction including androgen receptor defects

Infrequent ejaculation

Ultrastructural ciliary defects (Kartagener's syndrome)

Low normal sperm morphology



Endocrine dysfunction including androgen receptor defects


Laboratory Tests

The evaluation of the potentially infertile male initially involves screening with semen analyses, followed by further examination when warranted. However, normal semen results do not exclude male causes of the couple's infertility. If the complete evaluation of the female partner fails to establish a cause for the couple's infertility, further subsequent examination of the male partner with specialized testing of sperm function is indicated. Virtually all semen samples, no matter how abnormal, could be candidates for assisted fertilization.

Several semen analyses, obtained by masturbation after abstinence for the man's usual ejaculatory interval, are required to begin the male evaluation. These samples should be obtained over a 75- to 90-day interval to evaluate the inherent long-term variability in semen measures. Normal semen parameters include a sperm concentration greater than 20 million/mL with at least 2 mL of semen that liquefies normally; at least 50% of sperm with

Evaluation of Sperm Function

Additional studies may be selectively used to further evaluate sperm transport in the female reproductive tract, sperm capacitation and acrosome reaction, zona pellucida binding, sperm-egg fusion and penetration, and sperm decondensation within the oocyte cytoplasm. Sperm transport is initially assessed by the postcoital test, with additional in vitro tests of sperm-mucus interaction to further characterize the abnormality detected on the postcoital test. Sperm-mucus interaction can be assessed by examination of sperm penetration through a mucus interface under the microscope and

The first contact between sperm and oocyte involving specific surface receptors is at the zona pellucida, an important site not assessed by the sperm penetration assay. The hemizona assay is used to evaluate this sperm-zona pellucida interaction. Human oocytes are microbisected to obtain two matched, half (hemi) zona surfaces, and the ooplasm is discarded. One hemizona is exposed to the patient's capacitated sperm population, and the


Despite significant recent advances in the treatment of female infertility, successful specific medical and surgical treatment can be offered in no more than 10% of male infertility cases. The treatment of any infertile male ultimately depends both on an accurate determination of the underlying pathophysiologic process leading to disordered sperm production, delivery, or function and a thorough evaluation of the female partner. Those conditions for which specific therapy with proven efficacy are available include surgical repair of varicocele and some cases of obstructive azoospermia, medical therapy for hypothalamic-pituitary dysfunction with resulting gonadotropin deficiency, and antibiotic therapy for reproductive tract infection (Table 8). Otherwise, empiric medical therapy (eg, clomiphene citrate for oligozoospermia) has been shown to be either of minimal value or completely ineffective in clinical studies. Consequently, for most couples with male-factor infertility for whom specific therapy is unavailable, assisted reproductive technologies (ART), including superovulation-intrauterine insemination, IVF, and assisted fertilization with ICSI, appear to offer the best opportunity for conception. These modalities do not treat male infertility, but rather bypass it. Many men with significant oligozoospermia or obstructive azoospermia can now father a child with these microfertilization techniques. Indeed, the availability of ICSI with sperm obtained by aspiration or

Empiric intrauterine insemination of washed spermatozoa, combined with controlled superovulation of the female partner, has been shown to be efficacious in several studies for treatment of male infertility in which sperm function appears normal. Different procedures to prepare sperm for

Recent modifications of ART have significantly improved the success of IVF and related procedures (ie, GIFT, zygote intrafallopian transfer [ZIFT]) for male-factor infertility. As the efficiency of IVF and related procedures has improved, fewer spermatozoa are required to obtain embryos for transfer back to the uterus or fallopian tubes. The latest advance in ART, which has also proven to be the most successful micromanipulation

A number of studies published since 1994 have confirmed the efficacy (in terms of fertilization success and pregnancy) of ICSI for treatment of patients with severe male-factor infertility. Indeed, it is now possible to achieve pregnancy when literally only several sperm are available per oocyte, a number that might be obtained during testicular or epididymal aspiration in men with obstructive azoospermia or hypospermatogenesis. In addition, data are now emerging showing that when very few sperm are obtained and then cryopreserved, such as at diagnostic testicular biopsy, vasectomy, or vasovasostomy, these frozen-thawed spermatozoa may subsequently prove sufficient for ICSI.

Table 8. Treatment Options for Male Infertility

Treatment Option


Clomiphene citrate, exogenous gonadotropins,

or pulsatile GnRH

Hypogonadotropic testicular failure

Kallmann's syndrome

Idiopathic oligozoospermia*



"-Sympathomimetics, anticholinergics

Ejaculatory failure including retrograde ejaculation

Emission failure


Genital tract infection

Antisperm antibodies*


Immunosuppressive agents (eg, steroids)

Antisperm antibodies




Vasovasostomy and related reanastamoses

Acquired obstruction of vas deferens

Congenital obstruction/aplasia of vas deferens

Vasectomy reversal



Assisted reproductive technologies such as:

Sperm washing

Intrauterine insemination


Retrograde ejaculation

Impaired sperm function

Significant oligozoospermia, especially with sperm

concentration <1 million/mL

Assisted fertilization by micromanipulation (eg, ICSI)



Investigation and Treatment of the Infertile Female

General Strategy of Management

When the infertility evaluation has been completed, recommended management will depend on the specific factor(s) identified as potential causes of infertility, whether more than one etiologic factor has been identified, and the age of the woman. In every instance, the emotional response of the couple to the realization that they are infertile and their reaction to the stress of the subsequent evaluation and treatment must be considered. Sensitivity of the team is necessary in guiding the couple through the problem. When diagnosed as infertile, women characteristically will experience the following

If the woman is anovulatory or oligoovulatory and a thyroid or adrenal disorder is recognized, specific treatment for the endocrinopathy will usually result in resumption of ovulatory cycles. Similarly, hyperprolactinemic patients should resume ovulation after treatment with appropriate medication or, in the case of prolactin-secreting macroadenomas, after specific medical or surgical treatment. The most frequent cause of anovulation is a defect in

Uterine Factors

A variety of uterine conditions have been implicated in infertility. These include chronic endometritis, leiomyomata, intrauterine synechiae, congenital malformations, and polyps. Foreign bodies can also affect implantation. Most of these abnormalities can also cause recurrent abortion. Tuberculous endometritis is clearly associated with infertility.

Several factors are thought to cause infertility by distorting the uterine cavity, which prevents implantation either mechanically or by affecting endometrial development. Most of these factors are detected by hysterosalpingography and confirmed by hysteroscopy. There is also increasing

Tubal and Peritoneal Factors

There are four basic types of tubal obstruction: 1) obstruction at the cornu, 2) obstruction in the isthmus, 3) fimbrial obstruction (see the box), and 4) peritubal adhesions. Cornual and isthmic obstructions usually can be determined by hysterosalpingography; fimbrial obstruction and peritubal adhesions usually can be observed by laparoscopy. Persistent pelvic adhesions may occur as a consequence of previous inflammatory conditions such as pelvic inflammatory disease, endometriosis, appendicitis with rupture, ruptured ovarian cysts such as dermoids, previous surgery, and foreign-body reaction.

Tubal Anastomosis

Approximately 1% of women who undergo tubal ligation regret their decisions and subsequently have a microsurgical tubal anastomosis procedure. Incorporation of the surgical microscope and fine nonreactive suture material into this procedure has dramatically improved the outcome. The success rate after tubal anastomosis depends on the type of anastomosis performed; isthmic-isthmic anastomosis yields the highest success rate, and


Endometriosis is defined as the presence of ectopic endometrial tissue, histologically confirmed by the presence of endometrial glands and stroma and often hemosider inladen macrophages. It typically is found on dependent surfaces in the pelvis and most often affects the posterior cul-de-sac and ovaries. However, it can affect other sites such as abdominal viscera, urinary tract, and lungs. Although histologically benign, it has a unique ability to invade and destroy tissues and cause severe inflammation and adhesion formation. The tree prevalence of endometriosis is unknown; it is 

Treatment. Individual treatment of endometriosis should be based on the extent of the disease, the severity of symptoms, the patient's desire for childbearing, the patient's age, and other coexisting medical and surgical factors. Three modalities of treatment are available: expectant, hormonal, and surgical. Although minimal and mild forms of endometriosis appear to be more prevalent in patients with infertility, a comprehensive understanding of pathogenesis is lacking. Women with minimal endometriosis have a 30-70% chance of conceiving within 6 months of discontinuation of contraceptive therapy

Ovulation Failure and Ovulation Disorders

Evaluation of Ovulatory Disorders

Patients with ovulatory disorders may complain of amenorrhea, oligomenorrhea, menorrhagia, or infertility. The hypothalamic-pituitary-ovarian axis is sensitive to stimuli at many sites and can be disrupted by hypothalamic dysfunction, intracranial tumors, anorexia, obesity, systemic disease, or

Ovulation Induction

Clomiphene Citrate. Euestrogenic anovulation associated with euprolactinemia and normal (or inappropriate) gonadotropin levels is the primary indication for the use of clomiphene citrate. Clomiphene citrate is a nonsteroidal ovulation-inducing estrogen receptor ligand with mixed agonistic and antagonistic properties. It binds to and interacts with hypothalamic nuclei to stimulate increased GnRH pulsatility, thereby stimulating pituitary FSH and LH secretion.

Therapy is initiated at a starting dose of 50 mg daily for 5 days, starting on day 2 or 5 after a spontaneous or proges-tin-induced withdrawal bleed. Dosage may be increased at 50-mg increments until normal ovulatory cycles are obtained. When ovulation occurs, the dosage of clomiphene is

Menotropins. The two major forms of menotropins available are human menopausal gonadotropin, a combination of equal amounts of FSH and LH, and urofollitropin, which consists almost entirely of FSH. Acting directly on the ovary to stimulate follicular development, both drugs are administered intramuscularly and require close monitoring of the patient. Contraindications to menotropin therapy include ovarian failure and untreated hyperprolactinemia; alternative treatment methods are more appropriate. Inability to monitor follicular response adequately as well as lack of expertise in administration are other contraindications. Patients should be thoroughly evaluated for additional causes of infertility before use of these drugs, and these factors should be corrected. Patients should also be counseled regarding realistic expectations and the cost and extent of the monitoring involved. Risks of therapy, including multiple gestation, ovarian hyperstimulation, and spontaneous abortion, must be discussed before human menopausal gonadotropin or urofollitropin therapy is started.

Human menopausal gonadotropin is primarily indicated for treatment of hypogonadotropic hypogonadism, in which both LH and FSH are deficient; it is also used for assisted reproductive techniques and to treat unexplained infertility. Although human menopausal gonadotropin has been used to treat women who fail to ovulate or to conceive within six cycles of clomiphene citrate, urofollitropin has been suggested to improve results through normalization of the ratio of LH to FSH. High LH levels are associated with abnormal ovulation and increased risk of spontaneous abortion, and it appears that urofollitropin results in decreased spontaneous abortion rates compared with human menopausal gonadotropin. Administration of urofollitropin, however, has not significantly improved the pregnancy rote or the risk of hyperstimulation in these patients.

Treatment cycles with human menopausal gonadotropin and urofollitropin must be carefully monitored with serum estrogen measurements and ultrasonographic evaluation of follicular growth. Transvaginal ultrasonography adds information on follicle number and size. Treatment with human menopausal gonadotropin or urofollitropin is usually started on cycle day 3 after baseline ultrasonogra-phy and an estradiol level has been determined, with an initial dosage of 75-150 U intramuscularly daily for 3 days. The subsequent regimen is determined by the patient's response. Transvaginal ultrasonography is begun when the serum estradiol approaches 300 pg/mL and ultrasonography is done every 1-3 days until ovulation is imminent. Human chorionic gonadotropin (5,000-10,000 IU) is administered to simulate the LH surge when the lead follicle achieves a mean diameter of 18 mm in association with an estradiol level of 250-300 pg/mL per mature follicle. Most centers withhold hCG if the estradiol level is 2,000 pg/mL or greater or when there are four or more dominant follicles, thus reducing the risk of hyperstimulation.

Most pregnancies occur within four to six cycles of therapy. Ovulation rates of 90% are usually observed in hypothalamic amenorrheic patients and in approximately 80% of patients with PCOS. The success of ovulation induction with menotropin varies with the etiology of anovulation. Women with hypothalamic amenorrhea have a cumulative pregnancy rate of 91%, whereas women with hypothalamic-pituitary dysfunction (PCOS, normoestrogenic anovulation) who fail to conceive with clomiphene citrate have pregnancy rates ranging from 40% to 60%. Spontaneous abortion rates are reported to be 25-30%. Complications include multiple gestation (20%) and ovarian hyperstimulation. Whereas mild or moderate ovarian hyperstimulation is relatively common, severe hyper-stimulation, which can be life threatening, is fortunately uncommon (<1%).

Gonadotropin-Releasing Hormone. Although primary hypothalamic amenorrhea is the only approved indication for pulsatile GnRH administration, it has also been used successfully to induce ovulation and pregnancy in women with other forms of anovulation. Ovulation has been induced with

Bromocriptine. In patients with elevated prolactin levels, treatment with bromocriptine leads to the return of cyclic menses and ovulation in 2-3 months. Ovulation is restored in approximately 90% of patients with idiopathic hyperprolactinemia and in about 80% of women with evidence of

Confirmation of Ovulation and Evaluation of Corpus Luteum Function

Assessment of ovulation is an important step in the infertility investigation. The primary methods use either detection of the LH surge or progesterone secretion by the corpus luteum. Luteinizing hormone surge kits predict ovulation 12-24 hours before follicle collapse in approximately 90% of women, but they provide little qualitative information. Serial ultrasound examinations detect follicle rupture on the day of ovulation and exclude the diagnosis of

Immunologic Aspects of Infertility

The ability of spermatozoa coated with antibody to penetrate and survive within cervical mucus is often impaired. The extent of this impairment depends on 1) the proportion of spermatozoa in the ejaculate coated with immuno-globulin, 2) the amount of antibody coating the sperm surface, and 3) the immunoglobulin class (IgG versus IgA). Hence, postcoital testing timed to detection of the preovulatory urinary LH surge and basal body temperature charts remains the best initial method available to screen for antisperm antibodies. The presence of fewer than five motile sperm per

Antibody Testing

Antibody studies performed in humans have generally focused on circulating antisperm antibodies in serum that show immobilizing or agglutinating activities against the spermatozoa. However, the presence of sperm antibodies in the reproductive tract, in semen, or cervical mucus appears to be of greater clinical importance.

In men, the amount of immunoglobulin bound to the sperm surface at the time of ejaculation depends on 1) the transudation of antisperm antibodies from serum into epididymal, prostatic, and seminal vesicle secretions and their mixing with sperm at ejaculation; 2) the local production of IgA