Asherman's syndrome

Infertility -defined as the failure to conceive after 1 year of regular, unprotected sexual intercourse-is a serious concern for millions of Americans (Table 1). One out of every 10 couples in the U.S. is estimated to be infertile, translating to more than 6 million people annually struggling to conceive.1

Conception is a complex process that depends on a precise fusion of timing and physical and hormonal factors; one problem in the process and conception will not occur. It is not surprising, then, that the chance of conceiving in a single month of regular, unprotected intercourse is only 30%.2 In general, 80% of couples wanting to conceive will do so within a year. About 25% will conceive in the first month, 60% within 6 months, 75% by 9 months, and 90% by 18 months.2

Interestingly, infertility is equally attributable to male and female factors. In 40% of cases, the problem can be attributed to the woman (known as female factors), and in another 40%, it is a problem with the man (known as male factors). Ten percent of cases can be attributed to a combination of male and female factors. In the remaining 10%, no cause can be determined.1

The good news for couples wanting to conceive is that 85% to 90% of cases of infertility can be remedied by drugs, surgery, or assisted reproductive technologies.3 This article will explore the causes of infertility and the options couples have to increase their chances of conceiving.

Physical Exam

A physical examination of the couple may quickly reveal a possible cause of infertility and suggest a course of action. A pelvic exam will determine if the woman has:

a perforated hymen, necessary for penile penetration

pink, rugated vaginal mucosa, indicating an estrogen effect

vaginal infections, which further acidify the vaginal fluid and destroy or reduce the number of sperm entering the cervix4

tears, polyps, or infection in the cervix

a normal cervical os

a normal uterus (size, position, and mobility)

a normal clitoris (an enlarged clitoris may indicate androgen excess)

signs of endometriosis or tumors.

Similarly, the man should undergo a physical examination to evalute the following:

hypospadias, which can result in sperm being deposited outside of the vagina 3

undescended testicles or testicular atrophy (testes should be at least 4 cm in diameter)4

presence of varicocele (varicose eins in the testicle, which may raise testicular temperature and cause infertility)3

evidence of testicular tumors or cysts

size and consistency of the prostate

evidence of sexually transmitted disease or other infections

presence or absence of pubic hair (absence may indicate that the man is not producing enough testosterone).2

Questions to Ask

The physical exam may fail to uncover an obvious explanation for infertility. Reviewing the couple's personal and medical histories may provide the missing clues. Questions to ask the couple include the following:

How old is the couple? At birth, a female's ovaries contain between 200,000 and 400,000 follicles with the cellular materials needed to develop into mature ova. For each ovum released during ovulation, up to 1,000 immature ova are reabsorbed into the body.5 This clearly has implications for fertility. As the woman ages, she has fewer viable ova; those that remain are aging with her and becoming less capable of being fertilized by sperm.? The infertility rate for women rises with age, therefore, infertility evaluation and treatment should not be delayed in a woman over the age of 35 who has had regular, unprotected sexual intercourse for 6 months without conceiving.

Some men also experience age-related changes that could contribute to infertility, including smaller, softer testes; decline in sperm morphology and motility; a decrease in libido due to changes in testosterone levels; and difficulty achieving or maintaining an erection.5 These changes may be the result of illness or medication use associated with aging and not simply aging itself.5

What is the woman's weight? Is there a history of obesity or anorexia? Some body fat is essential to normal hormonal balance in a woman. Most of a woman's estrogen is secreted from the ovaries. However, androgens produced in a woman's fat cells are also converted to estrogen. Above-normal body fat may result in excessive estrogen production, altering the woman's menstrual cycle and causing infertility. Conversely, a woman who is too lean may not produce enough estrogen to sustain a normal menstrual cycle.3

Does the couple smoke, drink excessively, or take recreational drugs? Smoking can alter a woman's estrogen metabolism, increasing the risk of infertility, ectopic pregnancy, and miscarriage.

Furthermore, cigarette smokers experience an earlier onset of menopause when compared with nonsmokers. In a man, smoking can significantly lower the sperm count, increase the number of abnormally shaped sperm, and cause chromosome damage.6 Excessive alcohol intake can also be harmful; it can cause erectile dysfunction and abnormal semen parameters in a man.7 In women, chronic alcohol use can lead to irregular or nonexistent menstruation, interfere with ovulation, cause early menopause, and increase the risk of spontaneous abortions.8 Recreational drug use should be strongly discouraged as it can impair fertility and create hormonal imbalances. The number and motility of sperm are reduced and more abnormal sperm are produced in men smoking marijuana, for example.4 Men who take heroin, methodone, or barbiturates generally experience a decrease in libido.4 In addition, anabolic steroid abuse can result in reduced testosterone levels and sperm production.4

Do they use a lubricant with spermicide? Many couples use lubricants that have spermicidal properties. Even those that are not spermicidal, such as K-Y Jelly and mineral oil, may affect sperm motility and should be avoided.3 Women also should not douche, especially immediately after coitus, as some studies have found a correlation between women who douche and the risk of ectopic pregnancy and pelvic inflammatory disease.9

How long has the couple been having regular, unprotected intercourse? Many couples are unable to conceive simply because they do not know how to determine the woman's most fertile time of the month (Table 2). They may erroneously believe that ovulation occurs 14 days after the start of the woman's menstrual cycle. This myth can be a major obstacle to conception. In reality, conception generally occurs from intercourse that takes place during the 6 days leading up to and ending on the day of ovulation.10 Educating the couple about how small the window for conception really is and how to properly time intercourse is crucial.

Is there a history of miscarriages or abortion? A previous elective abortion or spontaneous abortion (miscarriage) is not a cause of infertility per se. However, curettage following elective or spontaneous abortion, especially repeated procedures, can leave intrauterine adhesions or scars that partially or completely obliterate the endometrial cavity (Asherman's syndrome).3 A woman who has had two or more spontaneous abortions should be evaluated for Asherman's syndrome. Other causes may be uterine abnormalities that impair vascularization of the womb and distort the uterine cavity, limiting the space for the developing fetus;3 endocrine abnormalities, such as thyroid disorders or uncontrolled diabetes;3 myomas and endometrial polyps;2 and a predisposition to venous thrombosis.3

Is there a history of menstrual problems? The normal menstrual cycle is detailed in Table 3. Irregular menstruation (oligomenorrhea) or absent menstruation (amenorrhea) may indicate that the woman is not ovulating, the major problem in about 40% of cases of female infertility.3 Failure to ovulate (anovulation) or infrequent ovulation (oligoovulation) may be caused by something as simple as body weight, excessive exercise, or diet. Or it may be much more complex, such as polycystic ovary syndrome (PCOS).

In PCOS, multiple small cysts-only a few millimeters in size-are found on the surface of the ovaries. These cysts are partially developed ova that have not been released, thus interrupting ovulation. Approximately 75% of women with ovulation difficulties leading to infertility have PCOS.11 Symptoms of PCOS include irregular, infrequent, or absent menstrual cycles; acne; excessively oily skin or hirsutism due to excessive androgens; and weight gain.

Extremely painful menstrual cycles (dysmenorrhea) may be related to endometriosis, a condition in which the tissue that normally lines the uterus (endometrium) grows in the abdominal cavity, on abdominal organs, or on the outside of the uterus, ovaries, or fallopian tubes; over time, scarring and inflammation can occur. Adhesions on the ovaries and fallopian tubes may impede tubal mobility and make it difficult for the ovum to move into the tube for fertilization, resulting in infertility. It is unclear whether peritoneal endometriosis affects fertility.3

Does either partner have a history of sexually transmitted infections (STis)? Have both partners been tested for STIs? Among women, one of the most common and serious complications of STIs is pelvic inflammatory disease (PID), resulting in pelvic adhesive disease (PAD). This infection of the upper genital tract-usually caused by chlamydia or gonorrhea-can affect the uterus, ovaries, fallopian tubes, and pelvis; if left untreated, PID may cause scarring or abscesses that can lead to infertility. It can also increase the risk of ectopic pregancy. An STI may also impair fertility in men, although the specific effect on male fertility has not been established.3

What is the couple's history of disease or trauma?

A number of chronic diseases, infections, or trauma can affect fertility. Postpuberty mumps, for example, can cause problems with spermatogenesis in the man.2 The inability to ejaculate normally is not uncommon in men with diabetes and men who have had prostate surgery; they may experience retrograde ejaculation into the bladder.3 Genetic diseases such as cystic fibrosis or chromosomal abnormalities are relatively rare causes of male infertility. A history of testicular trauma or testicular torsion may affect fertility; an abnormal semen analysis can be found in up to 40% of men who have had testicular torsion.12 In both men and women, treatment for cancer can destroy the ability to reproduce. A ruptured appendix may cause pelvic infections that can interfere with fertility. Diabetes, kidney disease, and hypertension are also associated with impaired fertility in women, as well as ejaculatory dysfunction in men.

Thyroid disorders can lead to infertility in men and women. Primary hypothyroidism is the most common medical cause of hyperprolactinemia, a disorder in which the body produces too much prolactin (the hormone which is produced by the anterior pituitary gland in both men and women). In men, prolactin influences the production of testosterone and affects spermatogenesis.

Hyperprolactinemia causes testosterone levels to drop and reduces or halts sperm production, resulting in infertility. In women, prolactin is responsible for inducing and maintaining lactation. Hyperprolactinemia can lead to irregular or absent ovulation and menstruation.3

What medications do both partners take? Some prescription and over-the-counter medications can impact fertility. For example, cimetidine, spironolactone, nitrofurazone, sulfasalazine, erythromycin, tetracyclines, anabolic steroids, and chemotherapeutic agents can depress sperm quantity and quality.3 Alpha blockers, phentolamine, methyldopa, guanethidine, and reserpine have been associated with neurologic ejaculatory dysfunction.3 Even ibuprofen and aspirin can affect fertility in women if they are taken midcycle.

Diagnostic Tests

Over the course of several months-and possibly even years-the couple may undergo numerous tests to pinpoint the cause of infertility. However, not all couples will undergo every test. Each patient's health care professional will make the decision about what is appropriate based on the personal and medical histories and other test results. The following is a discussion of some of the most commonly ordered tests.

Semen analysis. Male factor infertility may be caused by an abnormality in the semen analysis including oligospermia (too few sperm), poor sperm motility, an increased number of abnormal sperm, or the complete lack of sperm (azoospermia). If a couple has been unsuccessful in conceiving, a semen analysis should be the first step in evaluating the man's fertility. The semen sample should be collected in a clean container after 2 or 3 days of abstinence but no longer than a week. If abnormal the semen analysis should be repeated two or three times, with an interval of several weeks in between each collection, to reflect the normal fluctuations in spermatogenesis.2,3 The normal values recommended by the World Health Organization can be found in Table 4. 13 To make these numbers more predictive of fertility, a formula is used to give total mobile sperm count (total sperm in the ejaculate x percent motility) or motile sperm per milliliter (sperm per mL x percent motility).3 These formulas combine count and motility to give the concentration of active sperm. Tests of sperm function (such as the sperm penetration assay and the human zona binding assay) have limited clinical utility because each measures only one aspect of the functions performed by sperm.3 None has emerged as the standard.

Basal body temperature. Women who have a menstrual period every 22 to 35 days are presumed to be ovulating.4 However, 5% are anovular.3 Ovulation can be assessed indirectly by having the woman record her basal body temperature over the course of several months. She takes her temperature every morning on awakening, before any activity. The numbers are recorded on a chart, along with days when the couple has intercourse.

The temperature should peak 2 days after the luteinizing hormone (LH) surge and remain evelvated for 11 to 16 days, returning to normal at the start of menstruation.3 The rise in temperature coincides with an increase in progesterone; the ovum is probably released the day before the first temperature spike.3 Although this method does not predict ovulation, the temperature rise and sustained increase is a reassuring indication that ovulation did occur. In addition, the couple may estimate ovulation based on previous temperature charts. If the woman ovulated on day 13 in one cycle, she may estimate ovulation around day 13 in subsequent cycles. (See Table 2 for more on methods to time intercourse).

Hormone levels. Blood tests may be ordered for both the man and the woman to evaluate hormonal functioning. In the man, testing may look at levels of thyroid hormone (hypothyroidism is associated with infertility), gonadotropins and testosterone (low levels may be a signal of hypothalamicpituitary failure or testicular damage), and prolactin (an increase may indicate a pituitary tumor).2

In the woman, levels of follicle-stimulating hormone and estrogen (estradiol) will be drawn on cycle day 3. Elevated levels of one or both of these hormones probably indicate a lower likelihood of pregnancy.3 A progesterone level may be drawn approximately 1 week after ovulation to confirm adequate corpus luteum development, possibly as an alternative to the more invasive endometrial biopsy.3 If testing shows that the woman has suboptimal ovulation, prolactin and thyroidstimulating hormone levels may provide further information.3

Postcoital test. This purpose of this test, albeit controversial, is to assess the receptivity of the cervical mucus to sperm. Just prior to ovulation, the couple will return to the health care professional's office 2 to 12 hours after intercourse (some practitioners may prefer a longer or shorter interval). Many programs perform this test the day after the LH surge is detected in the urine. Cervical mucus is withdrawn and evaluated for stretchability (spinnbarkeit) and consistency. Around the time of ovulation, the mucus should stretch up to 10 cm; it should be watery, thin, clear, acellular, and abundant; and under a microscope, it should appear to dry in a fern pattern.3 If the mucus is thick, the timing could be wrong; the test should be repeated with the next menstrual cycle, closer to expected ovulation. However, if the mucus continues to be thick at midcycle with repeated well-timed tests, it may prove to be a barrier to sperm penetration.3 The postcoital test is not a substitute for semen analysis. e Endometrial biopsy. Although no longer commonly performed in the infertility evaluation, a mid- or late-luteal phase endometerial biopsy may provide information about the normalcy of endometrial development after ovulation. A portion of endometrial tissue is removed via a small cannula inserted through the cervix and into the uterus. The tissue sample is then sent to the pathology lab for dating and for evaluation of its response to progesterone production. If this tissue is not exhibiting changes normally seen in an adequate luteal phase, it is considered "out of phase" and showing an abnormal response to progesterone.4

The reliability of this procedure is uncertain due to the difficulty in accurately dating the biopsy In addition, some research has found outof-phase biopsies in 20% to 30% of normal cycles, suggesting that abnormalities may occur by chance in both infertile and fertile women.3

Hysterosalpingography. This procedure can be used to assess the uterine cavity and fallopian tubes for abnormalities.2,4 It is generally peformed 2 to 5 days after menstruation ends for two reasons: to avoid inadvertently forcing menstrual tissue into the pelvis and to avoid the time of ovulation and the risk of interrupting a pregnancy.

In this procedure, a cannula is inserted into the cervix and 3 to 6 mL of a radiopaque dye is instilled.2,3 Image intensification fluoroscopy is used to view the area. Injecting the dye slowly should allow the health care professional to detect any abnormalities of the uterine cavity. If the fallopian tubes are patent, the dye will be seen flowing into one or both tubes, with droplets falling from the fimbriated end of the tube. The patient may be given a prostaglandin synthesis inhibitor (such as ibuprofen) about 30 minutes beforehand to reduce any cramping that may occur.3

Hysterosalpingography should not be performed if the woman has any question of having a sexually transmitted disease because of the risk of reinfection. If PID is suspected, a sedimentation rate can be drawn. If it is elevated, the woman should receive antibiotics and the procedure should be delayed for 1 month. If the sedementation rate is normal after treatment, the procedure can be done. The health care professional may want to administer prophylactic antibiotics to prevent infection.3

Some research indicates that hysterosalpingography may exert a therapeutic effect that promotes pregnancy. The dye used in the procedure may clear the tubes of mucus plugs or straighten them, breaking down adhesions. It may stimulate cilia in the tube, improving transport of the ovum and sperm. It may even eliminate tubal infections due to its bacteriostatic effect. These effects are more commonly seen with the use of oil-based dyes.3,4

Laparoscopy. Laparoscopy can be considered if either no cause for infertility can be found (unexplained infertility) or if a surgically correctable abnormality has been found. The exception would be in an older woman (over age 35) who does not have time to wait. In addition, laparoscopy is preferred over hysterosalpingography in women with PID.2,3

Laparoscopy is generally performed early in the menstrual cycle. An endoscope is passed through a small incision in the anterior abdominal wall; carbon dioxide elevates the abdominal wall and cold fiberoptic light sources are used to allow visualization of the pelvic structures.4 In about 'two-thirds of cases, the hysterosalpingography and laparoscopy findings agree. In most other cases, the health care provider detects pelvic adhesions or endometriosis that are not generally found with hysterosalpingography.3 Polycystic ovaries may also be seen.4

Treatment Options

Initial treatment for infertility will focus on the identified cause. Treatment can be divided into drug therapy, surgical repair, and assisted reproductive technologies.

Drug therapy

Low sperm density (referred to as oligospermia) or low motility (referred to as asthenospermia) related to hypothalamic-pituitary failure can be treated with injections of human menopausal gonadotropins (hMGs).2 Both men and women with hyperprolactinema may receive the dopamine agonist bromocriptine or cabergoline to normalize prolactin levels. Cervical infections should be treated with appropriate antibiotics.2

If an ovulatory abnormality is detected, generally the first line of medical treatment is clomiphene citrate (Serophene, Clomid). The initial starting dose is 50 mg a day, and it is given for 5 days starting between the second and the fifth day of the menstrual cycle (although it can be started a day or two earlier).3 The dosage is increased in 50-mg increments each month until normal ovulation is achieved, to a maximum of 200 to 250 mg for 5 days.3 The couple is advised to have intercourse every other day for 1 week starting after the fifth day of medication. A drawback to clomiphene is a higher rate of multiple births, almost all twins.14 Women who fail to conceive with clomiphene citrate within six ovulatory cycles should be referred to a reproductive endrocrinologist; she may need further evaluation and more advanced treatment (such as injectable gonadotropins).

More information about drugs commonly used to treat infertility can be found in Table 5.

Surgical repair

If the man has a varicocele and poor semen quality, surgical ligation of the vein may improve the quality of the semen by improving blood drainage from the testicle.2 Results are generally seen about 4 months after surgery. 12

Proximal fallopian tube obstructions may be cleared with tubal cannulation or balloon tuboplasty.3 Distal tubal obstructions require laparoscopic surgery. The success of these procedures depends on the extent of tubal damage as well as surgical skill. Laparoscopy can be used to cauterize or vaporize endometrial implants and lyse adhesions.4 Patients requiring laparoscopic surgery may have a better pregnancy success rate with in vitro fertilization, especially if the disease is severe.3

Assisted reproductive technologies

If the man has azoospermia, severe oligospermia, or asthenospermia that does not respond to treatment, therapeutic donor insemination (TDI), generally from an unrelated donor, may be an option. To minimize the risk of HIV transmission, donor sperm samples are quarantined for 6 months and the donor is rescreened. Only then is the sample released for insemination. In general, a single welltimed interuterine insemination is performed each cycle. The woman monitors her urine for the LH surge, with insemination scheduled for the day after the surge.

Another option for severe male factor infertility is in vitro fertilization. This procedures is also indicated for patients with unexplained infertility, endometriosis, immunologic causes of infertility, and severe or distal tubal obstruction.3 In addition, it is useful for women with premature ovarian failure or decreased ovarian function when a donor oocyte is available.

The success rate for in vitro fertilization depends on the infertility diagnosis and the woman's age. For this procedure, the woman is given medication to stimulate the growth of multiple oocytes. When mature, the oocytes are retrieved via a needle attached to a vaginal untrasound transducer. The transducer is placed into the vagina, then guided through the vaginal sidewall and into the ovary. A follicle is punctured and the oocytes are aspirated.3 This takes place about 35 hours after an injection of human chorionic gonadotropin (up to 39 hours if gonadotropin-releasing hormone and gonadotropin are used together).15 The oocytes are exposed to 50,000 to 100,000 sperm (depending on the quality of the sperm) about 4 to 6 hours after retrieval.16 They are examined for signs of fertilization (presence of two pronuclei) the next day. If fertilization has occurred, the embryos will be transferred 2 to 5 days after retrieval.3 In many cases, up to three embryos (depending on the quality, stage of development, and the patient's age) will be transferred to increase the chances for success. Unfortunately, this also increases the risk of multiple pregnancy. Progesterone may be prescribed to supplement the luteal phase. A pregnancy test is usually performed about 2 weeks after oocyte retrieval and, if positive, repeated 2 to 7 days later to confirm a normal rise in the human chorionic gonadotropin level.

In cases of severe male factor infertility, a technique called intracytoplasmic injection of single sperm (ICSI) may be used in an in vitro fertilization cycle to facilitate men with azoospermia or severe oligospermia fathering their own children.

Two other techniques that have been used in couples with unexplained infertility are gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT). In GIFT, oocytes retrieved by aspiration and sperm are placed together into one or both fallopian tubes. In ZIFT, the retrieved oocytes are fertilized in vitro by the sperm, then the resulting pronuclear-stage embryos are transferred to the fallopian tubes.3

Conclusion

Infertility is a problem faced by many couples, particularly those who choose to delay attempts at pregnancy into their 30s and even early 40s. In most cases, time is of the essence. Health care providers must be vigilant in assessing the couple, making the correct diagnosis of the cause of their problem, and prescribing an appropriate treatment plan. The concepts discussed in this article can be used to assist the health care provider in helping couples achieve their dream of conceiving.

References

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9. Zhang J, Thomas AG, Leybovich E. Vaginal douching and adverse health effects: A meta-analysis. Am J Public Health 1997;87:1207-11. 10. Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in re

lation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby. N Engl J Med 1995;333:1517-21. 11. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853-61. 12. Minnesota Men's Health Center. Male infertility.

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13. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction, 4th ed. New York, NY: Cambridge University Press; 1999.

14. Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997;3:359-65.

15. Gorlitsky GA, Kuse NG, Speroff L. Ovulation and pregnancy rates with clomiphene citrate. Obstet Gynecol 1978;51:265-9.

16. Downs KA, Gibson M. Clomiphene citrate therapy for luteal phase defect. Fertil Steril 1983;39:34-8.

Karen R. Hammond, MSN, CRNP, is OB/GYN Nurse Practitioner and Nurse Coordinator in the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, at the University of Alabama at Birmingham, Birmingham, AL.

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