Online Medical Reference


Tommaso Falcone

Published: December 2013
Last Reviewed: February 2016


Infertility is the inability to conceive after a year of actively trying.1

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There has been long-term decline in birth rate over the 50 years in the US that has been attributed to social factors, such as better contraception and delay in childbearing. However, the actual 12-month infertility has been decreasing with time among reproductive-age women from 8.5 % in 1982 to 7.4 % in 2002.2 These data were derived from the National Survey of Family Growth, a probability sample of the household population of women in the US between the ages of 15 and 44 years. Nonetheless this represents over 7 million women seeking medical attention.3 One reason proposed for the decrease in infertility rate is better treatment of the underlying disorders contributing to infertility. Therefore, the primary care physician has a significant role to play in providing infertility services to women.

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The trend of delayed marriage and childbirth are the main social causes of infertility. Excessive weight (body mass index [BMI] >35) or underweight (BMI <19) and smoking are clearly associated with diminished fertility. Smoking accelerates the natural loss of oocytes and is associated with decreased pregnancy rates from all assisted reproductive technology (ART). Passive smoking has also been demonstrated to have an effect on fertility.

It seems that a low weekly alcohol intake in women (1 drink/day) is not associated with decreased fertility.4 Higher levels (>2 drinks/day) may be associated with infertility. However, alcohol consumption does affect fetal development and therefore it should be minimized during fertility treatment. Heavy alcohol intake is associated with reproductive abnormalities in men (such as testicular atrophy), but minimal to moderate alcohol intake does not seem to have an effect. Caffeine consumption may be associated with infertility or miscarriages and it is generally recommended to keep caffeine intake to less than 250 mg per day (an 8-oz cup of brewed coffee has 130 mg of caffeine).

Stress is an independent risk factor that is associated with poorer results from ART.5 This effect is seen even if there is no disruption of the menstrual cycle.

Heavy use of marijuana decreases fertility in men and women. The effect is clear and reproducible in women, whereas it is equivocal in men. Box 1 shows a partial list of other potential toxins associated with decreased fertility. Some studies have linked high caffeine intake with delayed conception.6 Saliva and most lubricants sold in pharmacies are spermicidal.

Coital practice such as remaining supine does not influence pregnancy rates.  Lubricants such as KY Jelly can decrease sperm motility but mineral oil or hydroxyethylcellulose (e.g., Pre-Seed- INGfertility, Valleyford, WA)  does not. Frequent coitus (daily or every other day after cessation of menses) is associated with higher pregnancy rates than abstinence of greater than 5 days.  The highest pregnancy rates are obtained with intercourse during the 6 days leading to and including ovulation. If the patient is using an ovulation predictor kit that detects the luteinizing hormone (LH) surge, ovulation occurs within 2 days after the test is positive. Therefore the peak fertility is the day of the surge and the next 2 days.

Box 1: Reproductive Toxins
Dry Cleaning
Medical and Dental Offices
Ethylene oxide
Nitrous oxide
Ethylene glycol
Printing, Painting, and Hairstyling
Solvents (e.g., toluene)

Fertility and Age

Increasing age in the woman is an independent risk factor for decreased fertility. Reproductive aging is attributed mostly to the ovaries.7 Recipients of donated oocytes have pregnancy and live birth rates close to those of the age group of the donor. After age 30 years, there is a substantial decline in fertility and an increase in spontaneous pregnancy loss.

Follicular loss is a progressive process that depletes the germ cell pool by menopause. This loss is independent of hormonal therapy, such as birth control pills, and accelerates in the last decade before menopause. Observational studies of U.S. populations that have high birth rates and that condemn the use of contraception demonstrate decreasing fertility with age. By the age of 35 years, a woman has one half the chance of becoming pregnant that a 25-year-old woman has. The age of the male partner does not affect the ability of the sperm to fertilize an oocyte until after age 50.

The most common causes of infertility are listed in Box 2. Uterine causes of infertility are uncommon. Leiomyomas may be uncommonly associated with infertility such as when they occur submucosally. Endometrial polyps may be associated with infertility and should be removed.

Box 2: Common Causes of Infertility
Disorders of ovulation
Idiopathic infertility
Male factor infertility
Pelvic pathology (tubal disease and endometriosis)

Tubal Disease and Pelvic Adhesions

Tubal disease is still the most common cause of infertility in the United States. The most common cause of tubal disease is previous pelvic inflammatory disease (PID). Most cases of PID in the United States are caused by sexually transmitted disease. Weström demonstrated that subsequent tubal infertility developed in 12% of women after one episode of PID, in 23% of women after two episodes of PID, and in 54% of women after three episodes of PID.8


Endometriosis is another common cause of pelvic disease that is associated with significant pelvic pain and infertility. It is characterized by the presence of endometrial glands and stroma outside of the uterus. The disease process is associated with reflux of menstrual debris into the peritoneal cavity. However, because this reflux occurs in the majority of women, there must be an associated immunologic or genetic abnormality that allows the disease to develop. A variety of cellular and humoral abnormalities have been reported in these patients. The peritoneal cavity has an increased number of activated macrophages. These macrophages secrete a variety of cytokines that might be associated with the observed peritoneal inflammatory reaction. The peritoneal cavity might have a wide spectrum of lesions ranging from a few peritoneal implants to severe adhesive disease that involves all pelvic organs. The most important issue with infertility associated with endometriosis is the management of endometriosis cysts of the ovary. Removal can improve spontaneous fertility but can also compromise the number of eggs present in the ovary.9


The most common cause of anovulation in North America is polycystic ovary syndrome (PCOS). PCOS is a metabolic disorder with a primary reproductive manifestation. The term PCOS is a misnomer because there are no cysts in the classic gynecologic sense. Many subcapsular follicles of less than 10 mm with increased thecal and stromal tissue characterize the morphology of the PCOS ovary.10

Most women with PCOS have insulin resistance that is independent of weight.11 Fasting and postprandial hyperglycemia are uncommon at this stage of the disease process when patients present with infertility. However, these patients are at greater risk for developing type 2 diabetes. There usually is a strong family history of diabetes or abnormal glucose tolerance. PCOS patients who achieve pregnancy often have gestational diabetes. Obesity is an independent disorder with associated endocrine changes that influence the phenotypic expression of PCOS patients.

Hyperprolactinemia is another common cause of anovulation. The elevated serum prolactin is due to a primary pituitary abnormality such as hyperplasia or an adenoma of the prolactinsecreting cells. Uncommonly, serum prolactin levels are elevated secondary to hypothyroidism. These patients usually have a disruption of the menstrual cycle. The most common nonmenstrual symptoms are headaches and galactorrhea.

Other causes of anovulation are listed in Box 3.

Box 3: Common Causes of Anovulation
Competitive exercise
Eating disorders
Hypo- or hyperthyroidism
Polycystic ovary syndrome
Primary pituitary hyperprolactinemia
Stress and anxiety

Male Factor Infertility

A significant part of infertility is due to the male factor. Environmental toxins, drugs such as cimetidine, and heavy tobacco, marijuana, and alcohol use can be associated with decreased sperm parameters and reduced fertility. Chemotherapy and radiotherapy for the treatment of malignancies are associated with severely depressed sperm counts that are sometimes irreversible. Counseling these patients to cryopreserve sperm before initiating treatment is important. Excellent success rates have been reported with the use of this sperm.

Increased scrotal temperature as a result of a febrile illness can cause a temporary alteration of semen parameters that is only identified 2 to 3 months after the episode.12 This is the time required for a germ cell to develop into a mature spermatozoon. Radiant heat, such as that experienced by welders or foundry workers, can also affect semen quality. However, conditions that result in a minor increase in scrotal temperature only, such as tight underwear, have not been shown to alter sperm function.

A varicocele, a dilation of the veins that ascend from the testes, is associated with abnormal semen parameters.

Several genetic abnormalities are associated with male factor infertility. Congenital bilateral absence of the vasa deferentia is associated with mutations of the cystic fibrosis transmembrane regulator gene. Chromosomal abnormalities have been detected in about 10% to 15% of azoospermic men and about 5% of oligospermic men. Sex chromosome aneuploidies such as Klinefelter's syndrome are the most commonly reported.

Microdeletions of the long arm of the Y chromosome are also associated with severe oligospermia or azoospermia. The azoospermia factor (AZF) locus has three regions: AZFa, AZFb, AZFc. A deletion in any one of these regions can lead to complete absence of sperm. If sperm are found and pregnancy is achieved through ART, these deletions may be passed on to the male offspring. There is a high prevalence of altered integrity of the genetic material in the sperm in the infertile males. This is reflected by the degree of high levels of DNA fragmentation, which is associated with male infertility.

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Signs and Symptoms

A detailed history usually gives a general idea of the possible causes of infertility. Box 4 outlines the key questions on the history that might point to a particular cause. A discussion with the patient should include environmental factors that might affect fertility.

Box 4: Key Questions on the History
Duration of infertility
Previous pregnancies with the current partner
Ovulatory Disorders
Alcohol or cigarette consumption
Menstrual cycle abnormalities
Weight problems (overweight or underweight)
Tubal Disease
History of sexually transmitted disease, pelvic inflammatory disease
Previous pelvic or tubal surgery
Pelvic pain
Male Disorders
Family history of male infertility
Operative procedures related to the genital tract

Deep dyspareunia and dysmenorrhea are the most common symptoms reported in patients with endometriosis. Pelvic examination is best carried out during a menstrual period. During this time, specific areas of tenderness and modularity can be more easily identified.

PCOS should be suspected if there is a history of a menstrual disorder such as amenorrhea or oligomenorrhea associated with androgen excess. PCOS usually starts at puberty and is associated with irregular periods and some manifestation of hyperandrogenism. The androgen excess could be a clinical manifestation, such as acne or hirsutism, or a laboratory finding of an elevated androgen level (Box 5). Increasing weight influences the expression of the disease. A variety of medical problems are associated with PCOS (Box 6).

Box 5: Manifestations of Polycystic Ovary Syndrome
Acanthosis nigricans
Androgen excess
Menstrual disorder
Abnormal LH/FSH ratio
Abnormal lipoprotein profile (increased triglycerides, low-density lipoprotein cholesterol and total cholesterol and decreased high-density lipoprotein cholesterol)
Decreased sex hormone-binding globulin
Elevated serum androgens (testosterone, androstenedione, DHEAS)
Insulin resistance (abnormal fasting glucose-to-insulin ratio)
Mildly elevated prolactin
Imaging Studies
Ultrasound appearance of polycystic ovary syndrome

Note: Not all manifestations are present in all patients.

DHEAS, Dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; LH, luteinizing hormone.

© 2002 The Cleveland Clinic Foundation.

Box 6: Medical Problems Associated with Polycystic Ovary Syndrome
Cardiovascular disease
Diabetes mellitus
Abnormal uterine bleeding
Endometrial cancer
Hyperandrogenic states such as acne and hirsutism
Lipid disorders

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Although infertility is defined as the inability to conceive after 12 months or more of regular unprotected intercourse, it is also suggested that women over 35 initiate a consultation within 6 months of trying. If there are obvious impediments to fertility such as amenorrhea, consultation is suggested immediately. A semen analysis, a hysterosalpingogram (HSG), and assessment of ovulation should be included in the initial investigation of all infertile couples (Box 7). Although the assessment of cervical mucus was often used to assess a possible cervical factor contribution to infertility, there are no reliable tests of function. The use of the post-coital test to assess cervical function is no longer recommended.13

Box 7: Basic Infertility Investigation
Assessment of ovarian reserve
Confirmation of ovulation
Semen analysis

Male Partner

The initial screening evaluation for the male partner is a detailed history and two semen analyses taken at least 1 month apart. However, if the abnormal result is due to an acute insult such as a viral infection, it will take 2 to 3 months before sperm parameters change. Therefore, the test should be repeated after an appropriate period of time.

A history of testicular injury, viral infection, or surgery in a man with an abnormal semen analysis requires a urologic evaluation. The World Health Organization's recommended normal values are given in Box 814. If any of the results are out of the normal range, the test is considered abnormal.

Box 8: WHO Standards for Semen Characteristics14
Semen volume: 1.5 mL
Total sperm in the ejaculate: 39 million
Sperm/mL: 15 million/mL
Vitality: 58% live
Progressive motility: 32%
Total motility: 40%
Morphologically normal: 4%

Most semen parameters reported on a routine semen analysis have a large coefficient of variation (CV). For example, a recent proficiency testing report by the American Association of Bioanalysts (Brownsville, Tex) reported a CV of 20% for sperm count and 39% for morphology. Kruger Strict Criteria rather than the WHO standard are sometimes used to evaluate the morphology of the sperm. Normal is considered to be any result greater than 14%. If the semen analysis is abnormal, the male partner should be referred for evaluation to a specialist in male reproduction.

Endocrine evaluation is indicated for patients with low sperm counts or a history of sexual dysfunction. The initial screening tests are a serum follicle-stimulating hormone (FSH) and testosterone. Antisperm antibody testing is considered by some infertility specialists to be part of the standard semen analysis. Others assess the presence of these antibodies only if the semen analysis results demonstrate an isolated decrease in motility or increased agglutination. A history of testicular trauma, surgery of the testes or vas deferens (such as a vasectomy reversal), or infection requires assessment of these antibodies. Antisperm antibodies that are clinically significant are those that occur on the surface of the sperm. Cystic fibrosis genetic screening, karyotyping, and microdeletion analysis of the Y chromosome should be offered in appropriate cases of male factor infertility. The extent of sperm DNA fragmentation can be determined by a variety of sperm chromatin structure assays.

Female Partner

Ovarian Reserve

Many reproductive endocrinologists think that an assessment of ovarian reserve should be performed in all infertile patients older than 34 years. Younger patients should be assessed if there is a history of ovarian surgery, a poor response to previous infertility treatment, or a family history of early menopause. Patients who have received gonadotoxic drugs and with idiopathic infertility should also have this assessment. All patients should be screened before beginning intensive infertility treatment such as in vitro fertilization (IVF).

There are several different tests used to measure ovarian reserve. The oldest tests measured serum FSH levels. If the levels are increased above a specified level, the probability of achieving pregnancy is reduced with fertility treatment. Many laboratories report a level above 10 mIU/mL in the early follicular phase as abnormal. The prognostic significance of this test depends on the assay used by the laboratory. Therefore, it is important to validate that the laboratory meets published criteria. Increased FSH levels appear to be related to decreasing production of inhibin by the granulosa cells.

A serum FSH and estradiol is obtained on the third day of the menstrual cycle. In practice, the test is equally valid when performed on day 2, 3, or 4 of the cycle. Numerous studies have shown that an abnormal test result, an elevated level of FSH, is associated with a high probability of failure to conceive with IVF, although this observation is more valid with increasing patient age. Upper limits used range from 11 to 14 IU/L. The test has been validated in patients who will be undergoing superovulation for IVF or insemination and in a general infertile population.15 The prevalence of an abnormal test depends on age. An abnormal test result is associated with a poor pregnancy rate irrespective of age. Estradiol levels are not considered a marker of ovarian reserve but serve only to interpret a serum FSH level. An elevated day 3 estradiol (>80 pg/mL) with a normal or elevated serum FSH can predict a poor response to infertility treatment.

The abnormally high serum levels in FSH seen with these tests have been attributed to a decreased production of inhibin B. Serum inhibin is a peptide heterodimer secreted by granulosa cells. However it is not routinely recommended as a test for ovarian reserve.

Antimullerian hormone (AMH) is rapidly becoming one of the principal tests for assessing ovarian reserve. AMH is a peptide secreted by the granulosa cells of growing follicles, specifically of prenatal and small antral follicles. Antral follicles are follicles 2 to 6 mm in diameter. The advantage of this test is that it can be performed at any day of the menstrual cycle. It also requires no medication or multiple blood tests used with the CCT.

Another test that can predict ovarian reserve is the antral follicle count. A transvaginal ultrasound performed in the follicular phase can determine a total number of these follicles. A lower number (<4) is associated with a poorer outcome from ART.

National practice guidelines can be found at the official website for the American Society for Reproductive Medicine. Essentially all the recommendations have been covered in this chapter.16

Tubal Patency

HSG assesses tubal morphology and patency. It is usually performed in the follicular phase after the end of the menses. If a history suggests PID, an erythrocyte sedimentation rate (ESR) should be obtained, and the HSG should be postponed if the ESR is elevated. If the ESR is normal, give doxycycline 100 mg twice a day for 5 days starting 2 days before the procedure. Patients with dilated tubes on HSG are at significant risk for developing acute PID after the procedure. If dilated tubes are found on HSG, doxycycline 100 mg twice a day for 5 days should be given. Evidence of tubal disease requires referral for laparoscopy. Patients with a documented history of PID should be referred for laparoscopy.  Although ultrasonography with saline contrast has been used to assess tubal patency (sonohysterosalpingography) it has so far not replaced the HSG for assessment of tubal architecture. Anti-chlamydial antibodies have been used to determine exposure to previous STI, although it generally does not change management.


There are several methods to evaluate ovulation. Women with regular monthly periods are unlikely to be anovulatory. Basal body temperature charts are inexpensive and sometimes useful, but they are cumbersome and time consuming. They should not be overinterpreted. If there is a biphasic pattern, the patient is most likely ovulating.

We prefer to measure a single serum progesterone level in the luteal phase. This could be timed on the basis of a home urinary LH test kit. The onset of the LH surge occurs 34 to 36 hours before ovulation. Most LH kits detect this surge. Urine is collected between 10 AM and 8 PM. It should not be the first urine after waking. In an ideal 28-day cycle, testing is started on the 10th day of the cycle. A serum progesterone level is drawn approximately 5 to 7 days later. Levels greater than 3 ng/mL indicate the luteal phase. The value is not used to determine the “quality” of the luteal phase. There are no tests available to assess luteal function. Endometrial biopsies to assess normal ovulation are no longer recommended.

Anovulation or a history of irregular menstrual periods should be investigated with serum thyroid-stimulating hormone (TSH), FSH, and prolactin levels. If the patient presents with amenorrhea, serum estradiol levels should also be assessed.

If the signs and symptoms suggest PCOS, then serum levels of androgens and 17-hydroxyprogesterone should be obtained as well. The serum androgens are usually in the upper range of normal or higher. Serum levels for TSH, prolactin, FSH, and LH should also be obtained. Other disorders that can cause a similar phenotype are 21-hydroxylase deficiency, Cushing's syndrome, and an androgen-secreting adrenal or ovarian tumor. A consensus group from the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine has determined that to make a diagnosis of PCOS, the patient must have two out of three indicators: oligo- or anovulation, clinical or biochemical signs (or both) of hyperandrogenism, and polycystic ovaries seen on ultrasound (Figure 1).

Ultrasonography and endometrial biopsy are not considered parts of the basic infertility investigation. No blood tests or imaging studies can correctly diagnose endometriosis. Although ultrasound might identify an ovarian cyst that includes an endometrioma in the differential diagnosis, it is not conclusive. All serum markers are nonspecific. Laparoscopy is still required to make a definitive diagnosis.

Although traditionally evaluation of sperm and mucus interaction has been performed with a postcoital test, it is no longer considered a part of routine testing. Intrauterine inseminations (IUIs) are used so frequently with many infertility treatments that we are treating any subtle cervical abnormality.

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Standard textbooks of reproductive medicine define infertility as the inability to conceive after 1 year of unprotected intercourse. This does not mean that we would not treat a patient with an obvious problem of anovulation or obstructed fallopian tubes if she has attempted to achieve pregnancy for less than 1 year. In patients older than 35 years, earlier investigation may be considered.


Once the diagnosis of PCOS is made, treatment should focus on modifying insulin resistance. Decreasing insulin levels with metformin will decrease androgen levels and result in ovulatory cycles. Diet and exercise will have the same effect. The primary approach is diet, weight loss, and exercise. In one study, 60 of 67 anovulatory patients with a BMI of 30 kg/m2 or more resumed spontaneous ovulation after losing 10 kg. Of these patients, 77% achieved pregnancy spontaneously (35%) or with the help of medication. The miscarriage rate was significantly reduced.17

If diet and exercise are not successful, then a trial of metformin should be offered. However, it is generally accepted that metformin or other drugs that modify insulin resistance are inferior to clomiphene therapy for induction of ovulation.18,19 Clomiphene citrate, an antiestrogen drug, is the only FDA-approved drug for inducing ovulation. This drug is started at 50 mg/day from cycle days 5 through 9. The drug can be used for 5 days starting on day 3, 4, or 5. If ovulation is not detected, the dose is increased in increments of 50 mg to a maximum dose of 200 mg. If maximum doses of clomiphene do not induce ovulation, additional medication can be given. Although not FDA approved letrozole, an aromatase inhibitor, has been shown to be more effective than clomiphene citrate for induction of ovulation in women with anovulation associated with PCOS.20

Metformin 1,500 mg/day in divided doses has been shown to be effective in cases of clomiphene citrate failure. It can be added to the clomiphene protocol. Typically, metformin is given for several months and clomiphene is added. Side effects are primarily gastrointestinal. Low-dose corticosteroids with clomiphene might help if the adrenal androgens are elevated.

If ovulation is still not induced, the patient should be referred for ovulation induction with gonadotropins. These patients have a high rate of ovarian hyperstimulation syndrome. Aromatase inhibitors such as letrozole can be tried in patients who fail clomiphene and metformin before attempting injectable medication. Letrozole is not FDA approved for this indication but has been shown in case series to be an effective ovulation-induction drug.

Tubal Disease

Mild cases of tubal disease can be treated with laparoscopic surgery. In moderate and severe cases of tubal disease, IVF is associated with better pregnancy rates with a smaller incidence of ectopic pregnancy. The most recent data for IVF success rates (2011) are available through the Centers for Disease Control and Prevention.21 The live birth rates per 100 cycles initiated are 40% for women younger than 35 years, 31.9% for women between 35 and 37 years, 21.5% for women between 38 and 40 years, 12.1% for women 41 and 42 years, 5.3% for women 43 and 44 years, and 1.1% for women older than 44 years. Severely damaged tubes (hydrosalpinx) are associated with decreased IVF pregnancy rates and should be removed before starting an IVF cycle.

The main complications associated with IVF are the potential for ovarian hyperstimulation syndrome and multiple births. Multiple births are associated with a higher incidence of prematurity and low birth weight. There do not appear to be any developmental problems with the offspring. There may be a slight increase in sex chromosome abnormalities and congenital malformations.


Treatment of endometriosis can be surgical or medical. Hormone treatments with drugs that suppress the menstrual cycle, such as gonadotropin-releasing hormone agonists, danazol, or progestins, have clearly been shown not to improve fertility. Although there is some controversy as to the success of surgical treatment of early disease, there are clear data to show that surgery is quite effective in treating advanced endometriosis.

Surgical treatment of endometriosis can usually be accomplished by laparoscopy, especially at early stages of the disease. Advanced endometriosis with severe adhesive disease can also be managed laparoscopically, but many gynecologists prefer to approach the disease by laparotomy. These cases often have rectal involvement and require extensive pelvic dissection. Pregnancy rates are similar with either approach. None of the different energy forms, such as lasers, has been shown to be associated with a higher pregnancy rate than conventional laparoscopic techniques.

If surgery fails or is not an option, then ART provides an excellent pregnancy outcome.

Male Factor Infertility

Mild male factor infertility can be treated with IUI. However, most moderate to severe male factor infertility requires IVF with intracytoplasmic sperm injection. This procedure consists of a direct injection of a single spermatozoon or spermatid into the oocyte. Success rates have been equivalent to those of IVF cycles with normal sperm. In our experience, the pregnancy rate per embryo transfer is 41%, a rate similar to that in patients with normal sperm.

The management of men with no sperm in the ejaculate, azoospermia, is complex. If there is no obstruction of the ejaculatory ducts, it is called non-obstructive azoospermia (NOA). NOA can be due to a primary hypothalamic or pituitary problem. In these cases, treatment is aimed at the cause, such as hyperprolactinemia. Most cases are due to a primary testicular disorder and are usually idiopathic or the result of some genetic disorder, as discussed earlier. Some of these patients have testicular sperm and therefore require a procedure to extract the sperm. The extracted sperm can then be used with IVF to achieve fertilization.

Other patients with azoospermia have an obstruction of the ejaculatory ducts, termed obstructive azoospermia. The most common duct obstructed is the vas. If the cause of the obstruction was a previous vasectomy, then a vasectomy reversal is possible. This procedure is associated with a high pregnancy rate. A congenital obstruction is usually bilateral. The treatment is microsurgical epididymal sperm extraction followed by IVF.

Intrauterine Insemination

In couples with idiopathic infertility, insemination may be considered. However IUI alone has not been proven to be effective. IUI is typically used with some form of ovulation induction drugs such as clomiphene citrate or injectable drugs. Clomiphene citrate is superior to an aromatase inhibitor for treatment of idiopathic (ovulatory) infertility.22 The cycle fecundity rate with clomid with IUI is about 8 % per cycle.23

The use of injectable drugs (goandotropins) with IUI does have a higher pregnancy rate, approximately 11 % per cycle). These cycles are associated with a high multiple birth rate. For this reason and the far superior pregnancy rate associated with IVF, many infertility specialists recommend proceeding directly to IVF after clomid failure.24

In Vitro Fertilization

IVF is the most commonly used ART procedure for infertility.25 Tens of thousands of babies have been born around the world with this procedure. Success rates have improved because of improvements in laboratory methods for handling gametes and early embryos.21 The general principles of IVF have not changed. The patients are given gonadotropins to stimulate the ovaries, and oocyte maturation is assessed by ultrasonography and blood levels of estradiol. The oocytes are retrieved by transvaginal aspiration under conscious sedation. After fertilization, the embryos are grown to either a cleaved stage of 6 or 7 cells (day 3 after fertilization) or a blastocyst stage (day 5 after fertilization). An embryo transfer is then performed. Extra embryos can be cryopreserved effectively and with a high pregnancy rate. Patients may consent to destroy or donate unwanted embryos.

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Infertility is a medical problem of the couple. There is a natural decrease in fertility with age, and therefore investigation and management are initiated earlier in some couples. There are many environmental and medical problems that might cause infertility in either partner. Some disorders that cause infertility have a long-term impact on the patient's health.

Most patients consult physicians for advice and investigation. Therefore, the primary care physician should be aware of the most common causes of infertility. A few basic investigations can be performed before referral to an infertility specialist. Basic treatment of anovulation is straightforward.

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  • Basic investigation of the infertile couple requires an assessment of the male partner with a semen analysis and documentation of ovulation and tubal patency in the female partner.
  • Polycystic ovary syndrome (PCOS) is the most common cause of anovulation, and sexually transmitted disease is the most common cause of tubal disease.
  • An aromatase inhibitor is the drug therapy of choice for patients with anovulation and PCOS.
  • Patients with normal ovulation and open tubes can be treated empirically with clomiphene citrate.
  • Clomiphene citrate is the drug therapy of choice for treating anovulation associated with infertility.
  • Severe male factor infertility is associated with genetic disorders such as mutations in the cystic fibrosis genes and is treated effectively only with in vitro fertilization.

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Suggested Readings

  • Abma J, Chandra A, Mosher W, Peterson L, Piccinino L. Fertility, family planning, and women's health: new Data from the 1995 National Survey of Family Growth. National Center for Health Statistics. Vital Health Stat 1997; 23(19):65–66.
  • Loumaye E, Billion JM, Mine JM, Psalti I, Pensis M, Thomas K. Predication of individual response to controlled ovarian hyperstimulation by means of a clomiphene citrate challenge test. Fertil Steril 1990; 53:295–301.


  1. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 2013; 99:63.
  2. Stephen EH, Chandra A. Declining estimates of infertility in the United States: 1982–2002. Fertil Steril 2006; 86:516–523.
  3. Chandra A, Stephen EH. Infertility service use among U.S. women: 1995 and 2002 [published online ahead of print December 18, 2008]. Fertil Steril 2010; 93:725–736.
  4. Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Reproductive Endocrinology and Infertility. Optimizing natural fertility: a committee opinion. Fertil Steril 2013; 100:631–637.
  5. Manheimer E, Zhang G, Udoff L, et al. Effects of acupuncture on rates of pregnancy and live birth among women undergoing in vitro fertilisation: systematic review and meta analysis [published online ahead of print February 7, 2008]. BMJ 2008; 336:545–549.
  6. Hatch EE, Bracken MB. Association of delayed conception with caffeine consumption. Am J Epidemiol 1993; 138:1082–1092.
  7. Gallardo E, Simön C, Levy M, Guanes PP, Remohi J, Pellicer A. Effect of age on sperm fertility potential: oocyte donation as a model. Fertil Steril 1996; 66:260–264.
  8. Weström L, Joesoef R, Reynolds G, Hagdu A, Thompson SE. Pelvic inflammatory disease and fertility: a cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results. Sex Transm Dis 1992; 19:185–192.
  9. Falcone T, Lebovic DI. Clinical management of endometriosis. Obstet Gynecol 2011; 118:691–705.
  10. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81:19–25.
  11. Falcone T, Finegood DT, Fantus IG, Morris D. Androgen response to endogenous insulin secretion during the frequently sampled intravenous glucose tolerance test in normal and hyperandrogenic women. J Clin Endocrinol Metab 1990; 71:1653–1657.
  12. Wang C, McDonald V, Leung A, et al. Effect of increased scrotal temperature on sperm production in normal men. Fertil Steril 1997; 68:334–339.
  13. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion [published online ahead of print June 13, 2012]. Fertil Steril 2012; 98:302–307.
  14. Cooper TG, Noonan E, von Eckardstein S, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010; 16:231–245.
  15. Scott RT, Leonardi MR, Hofmann GE, Illions EH, Neal GS, Navot D. A prospective evaluation of clomiphene citrate challenge test screening of the general infertility population. Obstet Gynecol 1993; 82:539–544.
  16. Practice committee documents. American Society for Reproductive Medicine website. Accessed November 21, 2013.
  17. Clark AM, Thornley B, Tomlinson L, Galletley C, Norma RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 1998; 13:1502–1505.
  18. Palomba S, Orio F Jr, Falbo A, et al. Prospective parallel randomized, double-blind, double dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome [published online ahead of print April 19, 2005]. J Clin Endocrinol Metab 2005; 90:4068–4074.
  19. Legro RS, Barnhart HX, Schlaff WD, et al; for the Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356:551–566.
  20. Legro RS, Brzyski RG, Diamond MP, et al; ICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014; 371:119-129.
  21. Assisted Reproductive Therapy (ART) Success Rates. Centers for Disease Control and Prevention website. October 2015. Accessed February 16, 2016.
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