Chapter 53. Infertility

• Both male and female evaluation are needed to reach diagnosis.
• Male partner:
  • History
  • Semen analysis
  • If semen analysis abnormal, referral to urology, endocrine evaluation, and karyotyping in severe cases
  • State-mandated infectious disease panel if treatment includes intrauterine insemination or in vitro fertilization
• Female partner:
  • History, confirm ovulation
  • Physical exam to assess cervix, uterus, and adnexa for pathology
  • Cycle day 3 blood work and ultrasound to assess ovarian reserve
  • Hysterosalpingogram to evaluate uterine cavity and fallopian tubes
  • Possible saline sonogram to evaluate uterine cavity
  • Laparoscopy to assess endometriosis when indicated
  • State-mandated infectious disease panel if undergoing in vitro fertilization

The number of infertility visits has increased over the past decades. In some cases, couples have voluntarily delayed childbearing in favor of establishing careers and may experience an age-related decline in fertility. There have been significant advances in assisted reproductive technologies (ART), from improved embryo culture media to intracytoplasmic sperm injection (ICSI) and preimplantation genetic diagnosis (PGD), which have resulted in remarkable increases in in vitro fertilization–embryo transfer (IVF-ET) pregnancy rates. These advances coupled with increasing public awareness and acceptance of ART have spurred women or couples with infertility to seek medical care.

Definition

Infertility is defined as the inability of a couple to conceive within 1 year. Sterility implies an intrinsic inability to achieve pregnancy, whereas infertility implies a decrease in the ability to conceive and is synonymous with subfertility. Primary infertility applies to those who have never conceived, whereas secondary infertility designates those who have conceived at some time in the past.

Fecundity is the probability of achieving a live birth in 1 menstrual cycle. Fecundability is expressed as the likelihood of conception per month of exposure. Fertility, as well as infertility, of a woman or couple is best perceived as fecundability, as few infertile patients are sterile. It also allows for a direct comparison of treatment options over a more functional time frame.

The prevalence of women diagnosed with infertility is approximately 13%, with a range from 7 to 28%, depending on the age of the woman. It has remained stable over the past 40 years; ethnicity or race appears to have little effect on prevalence. However, the incidence of primary infertility has increased, with a concurrent decrease in secondary infertility, most likely as a result of social changes such as delayed childbearing.

In normal fertile couples having frequent intercourse, the fecundability is estimated to be approximately 20–25%. Approximately 85–90% of couples with unprotected intercourse will conceive within 1 year. Sterility affects 1–2% of couples.

Infertility can be due to either partner or both. Overall, an etiology for infertility can be found in 80% of cases with an even distribution of male and female factors, including couples with multiple factors. A primary diagnosis of male factor is made in approximately 25% of cases. Ovulatory dysfunction and tubal/peritoneal factors comprise the majority of female factor infertility. In 15–20% of infertile couples, the etiology cannot be found, and a diagnosis of unexplained infertility is made.

Prevention of infertility is difficult to achieve and thus discuss, as a couple isn't really aware of the diagnosis until they try to achieve pregnancy. Although difficult to do, there are a few steps one can take to possibly decrease risk of infertility.

Although infertility is defined as the failure to achieve pregnancy after 12 months or more, earlier evaluation may be justified depending on one's history and is warranted for women over the age of 35. Because fertility is related to aging in women and perhaps in men after the age of 50, one should be aware of these risks when considering delaying childbearing. Therefore, it is the responsibility of the primary care provider or gynecologist to openly discuss fertility and aging during a well-woman visit. The new techniques of oocyte cryopreservations hold a great promise for women who would like to delay childbearing and should be addressed with women to increase awareness.

Weight extremes have also been associated with infertility in women, mainly due to anovulation. Thus a healthy lifestyle may improve fertility for women with ovulatory dysfunction. However, beyond what has been mentioned previously, there is little evidence that dietary variations enhance fertility. Women should also be advised to take folic acid supplement (at least 400 μg daily) when trying to conceive.

Smoking has a substantial adverse effect on female fertility demonstrated by a recent meta-analysis and also causes abnormalities in male semen parameters. Thus couples who smoke and are trying to conceive should be advised accordingly. Moderate alcohol and caffeine consumption has no adverse effect on fertility; however. higher levels of alcohol and recreational drugs should be discouraged for couples trying to conceive.

Lastly, couples trying to conceive should be advised to avoid using vaginal lubricants as these can be toxic to sperm based on their effect demonstrated in vitro. If needed, it may be better to recommend mineral oil, canola oil, or hydroxyethylcellulose-based lubricants.

The armamentarium of diagnostic tests available for the evaluation of an infertile couple is large. Therefore, a clinician should be judicious in his/her use of tests. The history and physical exam shape the endocrinologic and radiologic testing algorithm specific to each patient. Other factors to consider include patient age, risks associated with the test, invasiveness, expense, and probabilities of significant findings (Table 53–1). The patient(s) should be included in the decision-making process.

New Patient Assessment

The initial aspect of the interview includes discussion of the factors (ie, ovulation, sperm concentration, ovarian reserve, etc.) that affect fertility so that the patient(s) is aware of the potential etiologies. In this light, the physician can present an algorithm for the diagnostic evaluation that the patient will understand. This will help the patient grasp the peculiarities of the specific tests, such as timing the hysterosalpingogram to the day of the menstrual cycle, and provide an opportunity for the patient(s) to ask fertility-related questions and to address any information learned from friends, family, or the Internet.

The initial clinical assessment should begin with a thorough history of both partners. Factors to consider while obtaining the medical history are outlined in Table 53–2 for the female and in Table 53–3 for the male. The history should guide the physical examination beyond the general evaluation; for example, a rectovaginal exam to detect uterosacral ligament nodularity associated with endometriosis is indicated if a woman presents with a history of severe dysmenorrhea. However, a thorough physical exam may divulge key information such as acanthosis nigricans and its association with insulin resistance.

The laboratory and radiologic tests assess 4 key aspects for fertility in a couple: the sperm (male factor), the oocyte (ovulatory factor and ovarian reserve), transport (pelvic factor including fallopian tubes), and implantation of ova (uterus). In many cases, the couple will be attempting to absorb significant amounts of information, some of which may be highly technical, at a time of heightened emotion. It is therefore helpful to offer literature or a written summary of the discussion. Frequently, the initial history will indicate a probable diagnosis or a contributing cause of infertility, but it is important to complete a basic evaluation of all of the major factors so a secondary diagnosis is not ignored.

Evaluation of Male Partner

Male factor is diagnosed in 25–40% of infertile couples. The majority of the diagnoses involve testicular pathology such as varicocele. Although validation is incomplete, there is a trend toward increasing use of molecular techniques to quantify the fertility potential of semen as our knowledge of fundamental molecular genetics expands. Experience and investigation have relegated several tests previously used to assess fertilization to historical interest. Beyond the history and physical exam, the initial evaluation of male factor is through semen analysis. If abnormal, the semen analysis should be repeated in 4 weeks or more to confirm findings. Normal semen analysis excludes any important male factor, whereas abnormal semen analysis suggests the need for further evaluation (endocrine, urological, or genetic).

Semen Analysis

The male partner should abstain from coitus for 2–5 days before collecting the sample, and the specimen should be received in the lab within 1 hour of collection. Table 53–4 lists normal sperm values. If fundamental parameters of count and motility are normal, the assessment of the morphology of the sperm becomes more critical. Specialized expertise in determining sperm morphology and strict application of criteria should be used before declaring the semen normal.

The semen parameters in normal fertile males may vary significantly over time, and the first response to any abnormal result should be to wait an interval of several weeks and repeat the test. A normal semen analysis will usually exclude significant male factor. Although low counts, decreased motility, and increased numbers of abnormal forms are most frequently associated with infertility, unfavorable semen parameters may still be found in 20% of males undergoing vasectomy after having completed their families. If the semen analysis reveals abnormal or borderline parameters, the history should be reviewed for any proximate cause of an abnormality, keeping in mind that the cycle of spermatogenesis takes approximately 74 days. A male with <5 million sperm per milliliter warrants an endocrinologic evaluation including follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone, or a karyotype in selected cases. The patient should be referred to a urologist with a special interest and expertise in infertility as indicated.

DNA Assays

Several tests, including sperm chromatin structure assay (SCSA), comet, and terminal deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL), have been developed to quantify the damage to DNA or chromatin (packaged DNA). There is some evidence associating increased DNA damage as determined by these tests with poor fertility outcome. The SCSA determines the percent of chromatin that is fragmented by exposing sperm DNA to acid denaturation (fragmented DNA is more vulnerable). Clinical experience has not matched initial expectations, although the test may be useful for couples with unexplained infertility with repeated in vitro fertilization (IVF) failures. The comet assay consists of placing the sperm DNA on gel electrophoresis; DNA with increased strand breaks will be smaller and therefore travel further on the slide. The TUNEL assay identifies DNA strand breaks by their incorporation of labeled dUTP. The comet and TUNEL assay are not in wide clinical use.

Other Tests

More detailed assessment of sperm function may include postcoital test, antibody studies, a sperm penetration assay (hamster egg penetration assay). Such assessments are designed to investigate more subtle problems or abnormalities of function not revealed by the assessment of sperm number and motility. Although helpful in some cases, the sensitivity of these assays in detecting fertility is still uncertain and varies with the particular laboratory where the test is performed. Because no universal methodology has yet been accepted, the interpretation of these tests requires close communication with the laboratory selected.

Cervical mucus is a heterogeneous secretion containing more than 90% water. It has intrinsic properties including consistency, spinnbarkeit (stretchability), and ferning. When mucus is obtained from the cervical canal in the preovulatory phase, it normally exhibits a response to the high estrogen environment. The mucus is thin, watery, and acellular; it dries in a crystalline pattern (ferning), and acts as a facilitative reservoir for the sperm.

The functional sperm must interact normally with the egg and surrounding cells in the uterine tube. The normal migration of sperm is affected by attrition and filtering, and it is estimated that fewer than 1000 sperm will be found in the environment of the oocyte. The initial interaction of sperm and female genital tract can be determined by postcoital examination of the cervical mucus (Sims-Huhner test).

The purpose of the postcoital test is to determine the number of active spermatozoa in the cervical mucus and the length of sperm survival (in hours) after coitus. The test should be performed as close to ovulation as possible, but not after. The test involves aspirating cervical mucus with a syringe 6–8 hours after coitus and checking under a microscope for the number and the motility of the sperm; fewer than 10 motile sperm per high-power field is considered abnormal. The postcoital test is controversial and has limited use in the infertility workup. Its value in assessing cervical hostility to sperm has never been proven.

Tests developed to predict the fertilizing ability of sperm include the zona-free hamster egg penetration test (the sperm penetration assay) and the hemizona test. These assays compare the ability of sperm to penetrate the zona-free hamster egg (a hamster egg in which the zona pellucida has been enzymatically digested) or to bind to human zona with sperm from a known fertile donor. The value of these tests remains controversial, and they are not in general clinical use.

Sperm possess antigens and semen may contain antibodies including sperm-agglutinating, sperm-immobilizing, or cytotoxic antibodies. The antibodies can be measured in semen or in serum. The immunobead test is the antibody assay used in most labs and is considered positive when only 20% or more of motile spermatozoa have immunobead binding. However, the test is considered to be clinically significant when 50% of sperm are coated with immunobeads.

Evaluation of Female Partner

Ovulatory Factor

An ovulatory dysfunction is responsible for approximately 20–25% of infertility cases (~40% of female factor infertility). The problem should be investigated first by review of historical factors, including the onset of menarche, present cycle length (intermenstrual interval), and presence or absence of premenstrual symptoms (molimina), such as breast tenderness, bloating, or dysmenorrhea. Signs and symptoms of systemic disease, particularly of hyperthyroidism or hypothyroidism, and physical signs of endocrine disease (ie, hirsutism, galactorrhea, and obesity) should be noted. The degree and intensity of exercise, a history of weight loss, and complaints of hot flushes all are clinical clues to possible endocrine or ovulatory dysfunction.

Follicular Pool

Early in gestation, the germ cells undergo mitosis to produce oogonia. The oogonia undergo meiosis in their transformation to oocytes but arrest at prophase of meiosis I until the time of ovulation. A layer of granulosa cells encircles the oocytes, creating the follicle. A female will have the highest number of germ cells, approximately 6 million, in her ovaries at 20 weeks' gestational age. Henceforth, atresia depletes the follicular pool at a brisk pace, with only 1–2 million oocytes remaining at the time of birth. The ovaries contain approximately 500,000 oocytes at the time of first ovulation. Menopause signals the complete depletion of germ cells, with a woman having ovulated approximately 500 oocytes during her reproductive years.

Ovarian Reserve

An inverse relationship exists between fecundity and the age of the woman. The decline in fecundity is a result of progressive follicular atresia through apoptosis, which accelerates in the early thirties and progresses rapidly in the late thirties and early forties. Concomitantly, there is a decrease in follicular quality as a result of an increase in oocytes with chromosomal anomalies and progressive deletions in mitochondrial DNA. The concept of ovarian reserve represents the remaining follicular pool of the ovaries. As ovarian reserve decreases, the ovaries' responsiveness to gonadotropins decreases, necessitating higher amounts of FSH to achieve follicular growth and maturation.

Ovarian reserve should be evaluated in women older than 35 years of age who are seeking fertility. Evaluation of the level of FSH and estradiol in the early follicular phase (cycle days 2–4) may provide helpful guidance in terms of the likelihood of achieving success, as mild elevations in either FSH or estradiol may precede overt ovulatory dysfunction but still indicate a poor prognosis for successful pregnancy. Use of the clomiphene challenge test has gone out of favor, whereas newer tests such as inhibin-B and anti-müllerian hormone (AMH) remain to be validated in large studies. The specific cause of oligo-ovulation or anovulation is determined by the history, the physical examination, and appropriate laboratory studies.

Confirmation of Ovulation

If the patient reports a history of mittelschmerz and/or regular menses with molimina (headaches, bloating, cramping, and emotional lability) and mild dysmenorrhea occurring at intervals of 28–32 days, the likelihood of the patient having regular ovulatory cycles is very high. Otherwise, ovulation can be confirmed with a serum progesterone assay performed in the mid-luteal phase or the third week of the cycle. Progesterone levels of 3 ng/mL or greater are consistent with ovulation.

Pelvic ultrasonography can provide evidence for ovulation. In the follicular phase, the developing follicle can be monitored to maturation and subsequent rupture. The disappearance of, or change in, the follicle and free fluid in the cul-de-sac can document ovulation.

To detect the LH surge, the patient can use commercially available urinary LH kits or serum LH assay. Ovulation occurs 24–36 hours after the onset of the LH surge and 10–12 hours after the peak of the LH surge. The kits can be used to time intercourse or intrauterine insemination.

The basal body temperature (BBT) is the temperature obtained in the resting state and should be taken shortly after awakening in the morning after at least 6 hours of sleep and before ambulating. Progesterone has a central thermogenic effect; it elevates the BBT by an average of 0.8 °F during the luteal phase. The luteal phase is thus characterized by a temperature elevation lasting about 10 days. When a biphasic monthly temperature pattern is recorded, it is confirmatory evidence of luteinization, but the absence of a biphasic pattern may be seen in ovulatory cycles.

The finding of secretory endometrium confirms ovulation. The use of an endometrial biopsy (EMB) near the end of the luteal phase can provide reassurance of an adequate maturational effect on the endometrial lining. Within 48 hours of ovulation, the cervical mucus changes under the influence of progesterone to become thick, tacky, and cellular, with loss of the crystalline fernlike pattern on drying.

The only absolute documentation of release of an oocyte is pregnancy. In the case of oligomenorrhea, amenorrhea, short or very irregular menstrual cycles, or when ovulation is not confirmed, evaluation of the hypothalamic–pituitary–ovarian axis is warranted. A usual initial assessment includes the serum concentrations of FSH, estradiol, prolactin, and thyroid-stimulating hormone.

Luteal Phase Defect

The subject of the inadequate luteal phase remains an area of controversy. There is disagreement on how to make the diagnosis, when the diagnosis is significant, and how best to treat the problem if diagnosed. Luteal phase defect is a histologic diagnosis made when the endometrium lags 3 days or more behind the expected pattern at the time of EMB. EMB to assess luteal phase defect is rarely performed nowadays due to high levels of variability in histologic diagnosis.

The Pelvic Factor

The pelvic factor includes abnormalities of the uterus, fallopian tubes, ovaries, and adjacent pelvic structures. Factors in the history that are suggestive of a pelvic factor include any history of pelvic infection, such as pelvic inflammatory disease or appendicitis, use of intrauterine devices, endometritis, and septic abortion. Endometriosis is included as a pelvic factor in infertility and may be suggested by worsening dysmenorrhea, dyspareunia, or previous surgical reports. Any history of ectopic pregnancy, adnexal surgery, leiomyomas, or exposure to diethylstilbestrol (DES) in utero should be noted as possibly contributory to the diagnosis of a pelvic factor. A pelvic examination can be informative, yielding information such as a fixed uterus suggestive of adhesions, leiomyomas, or adnexal masses.

A transvaginal ultrasound examination can be an efficient means of supplementing information gained from the standard bimanual examination. Hydrosalpinges, leiomyoma, and ovarian cysts, including endometriomas, can often be observed, and the appropriate focused evaluations initiated.

A hysterosalpingogram (HSG) is a fluoroscopic study performed by instilling radiopaque dye into the uterine cavity through a catheter to determine the contour of the endometrial cavity and patency of the fallopian tubes. Sensitivity and specificity of an HSG are approximately 65% and 85%, respectively. Abnormal findings include congenital malformations of the uterus, submucous leiomyomas, intrauterine synechiae (Asherman's syndrome), intrauterine polyps, salpingitis isthmica nodosa, and proximal or distal tubal occlusion. The hysterosalpingogram can be obtained in an outpatient setting with minimal analgesia consisting of premedication with a nonsteroidal anti-inflammatory drug. The test is usually scheduled for the interval after menstrual bleeding and before ovulation. Either water- or oil-based dye may be selected; Table 53–5 summarizes the advantages and disadvantages of each. There is evidence for a fertility-enhancing effect of HSG using the oil-based dye.

Peritonitis is a risk of the procedure observed in up to 1–3% of patients; many clinicians use a short-course doxycycline during the immediate period before and after the procedure to minimize risk. An HSG is contraindicated in the presence of an adnexal mass or an allergy to iodine or radiocontrast dye.

A sonohysterogram, a transvaginal ultrasound of the uterus with instillation of saline into the uterine cavity, is a sensitive and specific test for the detection of intrauterine lesions, specifically space-occupying lesions. Hysterosalpingo contrast sonography, transcervical injection of sonopaque material during ultrasonography, is used to determine tubal patency as well as detect intrauterine defects; more commonly used in Europe, the procedure's sensitivity is comparable to that of HSG.

Laparoscopy with chromotubation (dye instillation) is the gold standard for the evaluation of tubal factor, and when performed in conjunction with hysteroscopy, information on uterine contour can be obtained simultaneously. Tubal abnormalities such as agglutinated fimbria or adhesions (which restrict motion of the tubes) or peritubal cysts may suggest tubal disease that would not necessarily be detected on hysterosalpingogram. The diagnosis of endometriosis is usually based on laparoscopic findings.

The necessity of laparoscopy in an infertility workup is controversial. There is significant evidence that pelvic pathology may exist in almost one-third of patients with normal HSG and ultrasound; consequently, some believe that with laparoscopy one can treat the pathology (such as adhesions) found at the time of procedure or can spare a patient needless cycles of ovulation induction that are unlikely to succeed by providing knowledge of severe pelvic disease. Others believe that although pelvic disease may be present, a stepwise empiric approach is more cost-effective.

The Cervical Factor

A cervical factor may be indicated by a history of abnormal Papanicolaou (Pap) smears, postcoital bleeding, cryotherapy, conization, or DES exposure in utero. The major evaluation of the cervical factor is by speculum examination, which may reveal evidence of cervicitis that may require further evaluation and treatment, or cervical stenosis, especially in a patient with prior history of cervical conization. If none of these findings are present, it is unlikely that cervical mucous presents a major obstacle. The postcoital test has been part of the assessment of cervical factor for many years in the past; however, the current consensus is that it is no longer required due to high variability in its methodology and interpretation. Moreover, treatment for otherwise unexplained infertility generally is a combination of ovarian stimulation and intrauterine insemination (IUI), which therefore bypasses the cervical factor. Therefore, postcoital test may only be reserved for patients in whom results will actually influence the treatment strategy.

Combined Factors & Unexplained Infertility

After the completion of the diagnostic workup, the findings should be reviewed with the patients and a treatment plan finalized based on guidance from the physician and input from the patient(s). In approximately 20% of couples, a combination of factors found may be suboptimal, and multiple therapies may need to be instigated, either sequentially or simultaneously.

Diagnosis of unexplained infertility, on the other hand, generally implies normal uterine cavity, bilateral patent tubes, normal semen analysis, and evidence of ovulation. Postcoital tests and endometrial biopsy are no longer necessary in order to diagnose unexplained infertility. For the couple with unexplained infertility, an empiric stepwise approach is an excellent option. However, depending on the history, workup, and individual situation, additional test(s) including surgery to rule out endometriosis should be discussed.

Male Factor Infertility

Treatment options progress from least to most invasive or use of donor sperm. Mild to moderate disease can be treated with intrauterine insemination (IUI). Before the insemination, the semen is prepared to select for highly motile sperm, concentrate sperm, and remove seminal fluid (with prostaglandins). The prepared sperm is transcervically injected into the uterus.

ICSI is used in conjunction with IVF for treatment of severe disease (<2 million motile sperm or <4% normal sperm). In this procedure, a sperm is individually injected into each oocyte. The sperm can be retrieved from the testes by microsurgical epididymal sperm aspiration (MESA) or testicular sperm aspiration (TESA); a minimum number of sperm is necessary.

Indications for ICSI include poor semen analysis parameters (low number of motile sperm, poor morphology), fertilization failure with standard IVF, and spermatozoal defects leading to poor fertilization. A decade of experience with the procedure has proven its overall safety. However, offspring conceived using ICSI may be at increased risk of imprinting disorders (eg, Angelman's syndrome), and male children are at risk for inheriting the genetic disorder (eg, Y chromosome microdeletions) that rendered their father infertile.

The initial evaluation of FSH, LH, testosterone, and prolactin helps to differentiate between obstructive defects, primary hypogonadism (testicular defect), and secondary hypogonadism (hypothalamic or pituitary). Obstructive defects may be addressed through surgical reanastomosis or through retrieval of sperm via MESA or TESA for use with ICSI. Retrograde ejaculation can be treated with alpha sympathomimetics or urine can be centrifuged to collect sperm for IUI. Patients with primary hypogonadism should have a karyotype, as Klinefelter's syndrome (47,XXY) is the most common etiology.

Secondary hypogonadism, or hypogonadotropic hypogonadism, may be a result of a pituitary lesion such as prolactinoma or a hypothalamic etiology such as Kallmann's syndrome. Most prolactinomas respond to medical management. Pulsatile gonadotropin-releasing hormone (GnRH) administration with a pump or FSH replacement restores testosterone and sperm production in disorders leading to hypogonadotropic hypogonadism.

A varicocele is a dilatation of scrotal veins in the pampiniform plexus and is postulated to impair fertility through elevation of scrotal temperature. A clinical varicocele is one that is detected by examination and is present in 15% of men. Subclinical varicoceles can be detected by ultrasound or venography. There is contradicting evidence regarding whether ligation of clinical varicoceles leads to improved pregnancy rates; infertility is a questionable indication for the correction of subclinical varicoceles.

When male infertility is not amenable to therapy, donor sperm for insemination or IVF offers an opportunity for pregnancy. The use of donor sperm is common in clinical practice, and experience has lessened some of the medical, emotional, ethical, and legal issues. The American Society for Reproductive Medicine (ASRM) advocates use of frozen semen to reduce risk of transmission of infectious disease.

Female Factor Infertility

The Ovulatory Factor

The treatment and success of specific ovulatory disorders is determined by the age of the patient and the etiology of the anovulation. A stepwise approach, from least to most invasive (and expensive), usually starts with clomiphene citrate and progresses to ovulation induction with gonadotropins and, ultimately, IVF. The risk to the patient, cost of therapy, and fecundability increase with each step closer to IVF. If premature ovarian failure or early menopause is the etiology, the options include oocyte or embryo donation.

Induction of ovulation can be accomplished in 90–95% of patients with chronic anovulation, normal ovarian reserve, and absence of other endocrine abnormalities (eg, hyperprolactinemia or hypothyroidism). Clomiphene citrate is the agent of choice for women younger than 36 years of age with oligomenorrhea or amenorrhea and normal FSH, including women with polycystic ovary syndrome (PCOS). Clomiphene citrate blocks the feedback inhibition of estradiol on the hypothalamus and pituitary, leading to an increase in endogenous FSH. It is administered orally for 5 days starting on day 3–5 of the cycle; approximately half of the patients will ovulate at 50 mg/d and another 25% at 100 mg/d. Ultrasonographic and hormonal monitoring of follicular development is an option, which provides more information and allows greater control of the cycle. After a regimen has achieved ovulation, 3 cycles with either timed intercourse or IUI should be attempted. Side effects with clomiphene are common, including hot flushes, emotional lability or depression, bloating, and visual changes; most are mild and all disappear with discontinuation of the drug. The incidence of twin gestation is 8% and triplets or higher-order multiple pregnancy is <1%.

Aromatase inhibitor letrozole is an alternative option for patients who do not respond to clomiphene citrate or instead of clomiphene citrate. It was first used to induce ovulation in 2001. Letrozole works by inhibiting estrogen biosynthesis, thus releasing the hypothalamus/pituitary from negative feedback and increasing endogenous FSH secretion by the pituitary. It is also administered orally for 5 days starting on day 3–5. The starting dose is 2.5 mg, but studies have revealed improved response and higher pregnancy rates with 5 mg. The dose can be increased to up to 7.5 mg daily. As in the case of clomiphene citrate, ultrasound and hormonal monitoring is an option and may provide more information on individual response and how to proceed with future cycles. Letrozole has fewer side effects than clomiphene, and studies reveal at least similar if not better success rates than clomiphene. Lastly, letrozole has less thinning effect on the endometrium than clomiphene.

A patient in whom there is no response to clomiphene or letrozole, response but no pregnancy, pituitary insufficiency, or hypothalamic insufficiency should undergo ovulation induction with gonadotropins, often used in conjunction with IUI. Human menopausal gonadotropin (hMG) consists of FSH and LH isolated from the urine of postmenopausal women to various levels of purification (and LH content); recombinant FSH (rFSH) contains purely FSH. Gonadotropins are administered by subcutaneous (rFSH) or intramuscular injection (hMG), and the overall evidence indicates that the 2 preparations have similar efficacy.

Because of an increased risk of side effects such as multiple gestation and ovarian hyperstimulation syndrome (OHSS), the use of gonadotropins requires close monitoring with ultrasonography and estradiol levels. Consequently, it is more time-consuming and expensive than clomiphene or letrozole. The monitoring reveals both the number of developing follicles and their level of maturity. Mimicking the effects of the LH surge, human chorionic gonadotropins (hCG) is used to trigger ovulation. With perseverance, cumulative pregnancy rates of 45–90% can be achieved over 3–4 cycles with gonadotropin treatment; but even with careful monitoring there is a 25% risk of a multiple gestation. OHSS is a rare complication that occurs in <2% of cycles.

If pregnancy is not achieved with ovulation induction, IVF/embryo transfer (ET) is the next modality in the treatment algorithm. Development of the follicular cohort is induced with higher doses of FSH (hMG or rFSH). Follicular growth is monitored by ultrasonography and estradiol levels. When the leading follicles are mature, ovulation is triggered with hCG. The oocytes are retrieved from the follicles before ovulation by ultrasound-guided transvaginal aspiration of the follicular fluid. The oocytes are incubated with sperm for fertilization. Alternatively, ICSI is performed if male factor is also a concern. On average, several (from 1 to >3) embryos are transferred into the uterine cavity on day 3–5 after retrieval of the oocytes. OHSS is minimized by withholding hCG if there is a high number of follicles or elevated estradiol levels. Another option to limit the extent of OHSS is to cryopreserve the embryos for transfer at a later time, as pregnancy can prolong the course of OHSS.

When modification of lifestyle or body habitus does not successfully restore ovulation in the patient diagnosed with hypothalamic insufficiency, pulsatile GnRH is another viable option with high likelihood of restoring normal ovulation. Normal fertility is then restored during cycles of treatment, and most pregnancies occur within 3–6 cycles.

Hypothyroidism and hyperprolactinemia can lead to ovulatory dysfunction. Primary hypothyroidism leads to elevated thyroid-stimulating hormone levels, which is a secretogogue of prolactin. Elevated prolactin levels inhibit GnRH secretion, causing oligomenorrhea or amenorrhea. If elevated prolactin levels are detected in a woman with normal thyroid function, a full workup including thorough history (to rule out drugs such as psychotropics), physical exam (galactorrhea), and imaging (magnetic resonance imaging to rule out a prolactinoma or other central nervous system tumors) is likely to reveal the etiology. The elevated prolactin can be medically managed with dopamine agonist, leading to normalization of the cycle.

The Pelvic Factor

Adhesions resulting from endometriosis or tubal occlusion after salpingitis are 2 of the most common problems confronting infertile couples. With increasing pregnancy rates, IVF represents improved fecundability and lower risk over surgical repair except in unique circumstances. The role of surgical treatment is mostly limited to what can be accomplished at the time of diagnostic laparoscopy. There is some evidence to suggest that resection of mild endometriosis results in improved pregnancy rates. Laparoscopic resection or ablation of moderate or advanced endometriosis enhances fecundity in infertile women for the period immediately after surgery. Reversal of tubal sterilization is indicated in young women with adequate residual tubal length. Tubal interruption or resection increases IVF pregnancy rates in women with hydrosalpinx.

The role of fibroids in infertility is unclear, and most surgeons reserve myomectomy for treatment of recurrent abortion, repeated implantation failure, or with distortion of the endometrial cavity by a submucosal leiomyoma. The fibroids that distort the endometrial cavity are considered to be significant. These may be diagnosed by hysterosalpingogram, sonohysterogram, hysteroscopy, or magnetic resonance imaging.

The Cervical Factor

The absence of nurturing mucus at midcycle can be treated by bypassing the mucus with IUI. When the cervical mucus appears to be affected by cervicitis and inflammatory changes, some physicians advocate empiric treatment of patient and partner with doxycycline. When the cervix is altered by congenital malformation or past surgical treatment that has rendered endocervical glands absent or nonfunctional, IUI with washed sperm can be anticipated to result in pregnancy in 20–30% of patients per cycle in each of the first 3 cycles of treatment. Cervical factor patients who do not respond to these therapies can be offered IVF, gamete intrafallopian transfer (GIFT), or zygote intrafallopian transfer (ZIFT), although GIFT and ZIFT are now rarely used.

Unexplained Infertility

A diagnosis of unexplained infertility is assigned to couples with normal results of a standard infertility workup. The main treatment options include expectant observation with timed intercourse, ovarian stimulation with or without IUI, and IVF. Studies support the use of clomiphene with IUI for up to 4 cycles. The next step is usually hMG with intrauterine insemination for 3 cycles; if unsuccessful, IVF should be considered. The rationale for treatment with superovulation in women with documented ovulation is that by increasing the number of oocytes available, the likelihood of pregnancy is increased. In instances in which unexplained infertility may be the result of a fundamental defect in fertilization or in embryo transfer to the uterus, IVF may play a role in treatment. Donor oocytes or donor sperm may be considered in couples with continued difficulties in achieving pregnancy. For many, the hardest course to contemplate is no therapy at all.

The major complication associated with ovarian stimulation is OHSS. It has a broad spectrum of disease, ranging from mild to extremely severe cases. The pathophysiology of the disease is due to increased capillary permeability resulting in fluid shift from the intravascular to extravascular spaces. Risk factors for OHSS include young age, PCOS, higher doses of gonadotropins, and high serum estradiol levels. Severe cases of hyperstimulation warrant very careful monitoring and hospitalization, as it can lead to electrolyte abnormalities, abnormal liver function tests, respiratory distress, and hyponatremia. There are several methods used nowadays in order to prevent OHSS, including gentler stimulation protocols, coasting until lower estradiol levels are achieved, and most recently, GnRH agonist instead of hCG trigger.

There is also a concern about a possible association between ovulation induction agents, specifically >12 cycles of clomiphene citrate, and ovarian cancer. The possibility that ovulation induction increases the risk of ovarian cancer remains unproven. Primary infertility and endometriosis are independent risk factors for ovarian cancer. Although additional investigation is necessary, the low incidence of ovarian cancer makes it difficult to design an adequate study to detect an association of infertility drugs with ovarian cancer.

The success rates of treatment for infertility depends on a variety of factors, including cause of infertility, woman's age, duration of infertility, and treatment modality. Health insurance plans vary a great deal in the amount and type of infertility treatments that are covered. For those couples without infertility coverage, treatment choices are dictated by medical and financial considerations. Not uncommonly, infertility treatment does not actually make the difference between conceiving and not conceiving, but allows for conception in the more immediate future rather than at a delayed point of time (increasing fecundability).