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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.

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.

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.

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.

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.

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.

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.


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.

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.

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.

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.

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.