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Infertility

Infertility is defined as the failure of a couple to es­tablish a pregnancy after 1 year of coitus without using contraception. The expected monthly conception rates among healthy young couples is about 20-25%. Female fertility decreases significantly after age 35. 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 13 months. Fecundity refers to the potential for a couple to reproduce; the term fertility refers to

    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 older.

    Establishment of pregnancy depends on the presence of several key factors:

  •     Release of an ovum from the ovary (ovulation), preferably on a regular cyclic basis 

•  Production of an ejaculate containing an ample number of morphologically normal, motile spermatozoa

 •  Deposition of spermatozoa in the female reproduc­tive tract at or near the cervical os

 •     Survival of spermatozoa within the female repro­ductive tract

 •     Arrival of the ovulated ovum in the fallopian tube

 •     Patency and normal physiologic function of the fallopian tube

 •     A normal intrauterine environment that enables migration of spermatozoa from cervix to tubal ostia and fosters embryonic implantation

 •     Fusion of gametes within the tubal lumen

 •     Transfer of the embryo into the uterine cavity

     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 appropriate studies should be a part of the management plan.

    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 causes of infertility are ana­lyzed, they can generally be attributed to the male in 40-50% of couples, to tubal and peritoneal factors in 25­30%, to ovulatory defects in 20-25%, and to cervical and uterine factors in 10%. Frequently, more than one factor contributes to a couple's infertility. The basic evaluation of an infertile couple can be expeditiously completed in 2-3 months. When the evaluation is complete, the couple must be provided with detailed options and statistics for outcome associated with each approach to correction.

INVESTIGATION AN D TREATMENT OF THE INFERTILE MALE

Male infertility is the cause of approximately 40% of all couples' inability to conceive. Thus, the obstetrician-gynecologist should be familiar with the available diagnos­tic and treatment approaches to the infertile male. 

History and Physical Examination

The history and physical examination are used to discover evidence of possible pre-testicular, testicular, or post-testicular disorders that may result in male infertility by one of several mechanisms: 1) abnormalities of sperm produc­tion, 2) disordered maturation within the male reproduc­tive tract, 3) abnormal sperm function, or 4) 

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.

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 crossed-hostility tests with donor mucus. The zona-free hamster oocyte

Treatment

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

Cervical Factors

The role of cervical factors in infertility remains a contro­versial one. However, most practitioners believe that cervi­cal mucus abnormalities, in combination with other factors, may contribute to subfertility and should be evaluated.

    There are two types of cervical problems: structural ab­normalities of the cervix and inadequate or abnormal mu­cus production. Structural problems are often iatrogenic and result from surgical procedures, such as conization. In such cases, destruction of the endocervical epithelium or stenosis leads to inadequate mucus production and sperm transport and, thus, disturbance of the function of cervical crypts for sperm storage. Extensive cauterization or laser ablation may impair cervical function; however, there is no evidence that cryosurgery affects cervical factors in normal women. Although a decrease in the amount of mucus and size of the cervical

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 inter­est in the use of ultrasonography in combination with fluid distention of the uterus to evaluate uterine anomalies. Endometritis is identified by endometrial biopsy and culture.

    Acute endometritis, which is associated with instrumen­tation of the uterus, foreign bodies, or gonorrhea, may cause transient infertility but is usually self-limiting. Occasion­ally a retained intrauterine device or fetal tissue is detected. Chronic endometritis is likely to be a cause in longstanding infertility. Cultures for Mycoplasma species

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. Peritubal adhesions may result in infertility or may be associated with  

ENDOMETRIOSIS

Endometriosis is defined as the presence of ectopic endometrial tissue, histologically confirmed by the presence of endometrial glands and stroma and often hemosiderin laden 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 true prevalence of endometriosis is unknown; it is estimated to exist in approximately 7% of U.S. women of reproductive age. The etiologies of endometriosis include the transport theory (tubal regurgitation, lymphatic and hematogenous spread, and direct implantations) and the coelomic metaplasia theory. Endometriosis may cause symp­toms as a result

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 abnormalities in the ovaries, thyroid, or adrenal glands that affect circulating hormone levels. It is im­portant that the etiology of ovulatory disorders be determined before initiation of therapy to aid in selection of the appropriate treatment method and to rule out sig­nificant disease.

    Anovulation is presumed in women with a menstrual cycle length of 42 days or more and in women with amenorrhea, in the absence of intrauterine synechiae. Anovulation can be present even in women with seemingly regular menstrual cycles and can be documented by a monophasic basal body temperature graph or serum

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 progestin-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 maintained for the duration of treatment. Failure to ovulate at 150-200 mg daily for 5 days usually necessitates use of other induction agents. Upon reaching an

    Although wide variations in results have been reported, approximately 80% of patients taking clomiphene citrate will ovulate. The reported pregnancy rate, however, is only about 40%. The discrepancy may result from other causes of infertility as well as clomiphene citrate's potential ad­verse effects on the cervical mucus and endometrium. Preg­nancy will usually occur within four to six ovulatory cycles, and other regimens should be considered if clomiphene fails after this interval. Although clomiphene is generally well tolerated, side effects can

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

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

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

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

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 pulsatile GnRH in the presence of high prolactin