Men and women of reproductive age can be categorized as fertile, subfertile, or infertile in regards to their physiologic capability to conceive. It is most common for healthy couples younger than 35 years of age to conceive within six female reproductive cycles, after cessation of all birth control methods and initiation of regular unprotected sex; nearly 80% of couples fall into this category and are considered fertile [1]. Subfertile couples, who comprise about 10% of the population, will typically conceive between the 6th and 12th reproductive cycle [1]. The remaining 10% or so will be unable to conceive following 12 months of regular, unprotected sex and are considered infertile; this percentage varies based on age and several other factors that will be discussed later in this course [2].

There are two subcategories of infertility. Primary infertility describes individuals or couples who have never been able to conceive, and secondary infertility describes those who have successfully conceived and/or carried to full term prior to the current diagnosis of infertility [2]. Infertility in couples can be either a solely male or solely female fertility issue, or in some cases, both partners may be subfertile or infertile.

As noted, infertility may be attributed to the male or female partner or to the couple. It is estimated that roughly one-third of couples' infertility is male-related, one-third is female-related, and the remaining one-third of cases are due to both partners being infertile [3].

Approximately 4.8% of married women who are living in households at or below the poverty level are infertile, while 5.3% of those in low-to-moderate income households are infertile. However, married women whose households earn four times the income of those living in poverty have the highest infertility rate (8.7%) [4].

The hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes, two of several endocrine processes, effectively form what is known colloquially as the reproductive axis, complete with hormone signaling, cross-regulation, and feedback loops. Normal human sexual development and reproductive capability relies heavily on a properly functioning reproductive axis from early in fetal life through puberty and into adulthood.

In addition to directly aiding reproductive processes, these hormones provide feedback to the previous structures of the axes, regulating their function. One example of hormone feedback is the FSH/estrogen loop, whereby FSH from the pituitary stimulates the maturation of follicles in the ovaries; the maturing follicles produce estrogen, which signals the pituitary to lower FSH production and increase LH [11]. This example illustrates the dual role of the ovary as an endocrine organ and a reproductive organ whose functions are closely linked.

As discussed, normal sexual development and reproductive function is heavily dependent on a properly functioning reproductive axis; pathology of the hypothalamus, pituitary, adrenals, or gonads can quickly lead to a hormone imbalance, malformation of the genitals, and/or infertility. Likewise, steroid hormone dysfunction in the regulatory feedback loops has great potential detriment to fertility; for example, male obesity can disrupt the HPG axis due to the high levels of aromatase in fat [12]. Aromatase in Sertoli cells normally converts testosterone to estradiol to regulate spermatogenesis. Increased aromatase activity converts too much testosterone into estrogen, and with reduced testosterone feedback to the adrenals, gonadotropin release is inhibited and sperm production suffers. (Female obesity is also associated with disruptions of the reproductive axis and infertility, as will be discussed later in this course [13].)

The first endocannabinoid to be discovered was anandamide in 1992, with 2-arachidonoylglycerol discovered soon after; these neurotransmitters are biosynthesized from arachidonic acid, a polyunsaturated omega-6 fatty acid [21]. It is suggested that a deficiency of arachidonic acid, ingestion of obesity drugs (e.g., rimonabant) that compete for cannabinoid-receptor binding, or use of other exogenous cannabinoids (e.g., cannabis, dronabinol) can interfere with the endocannabinoid system and cause infertility. The endocannabinoid system is thought to also modulate the HPA axis and reduce the negative effects of stress hormones, among other functions, including pain and inflammation reduction, autonomic function and immunity, neuroprotection, tumor apoptosis, and feeding and hunger [21]. Further research is necessary to better understand the endocannabinoid system's effect on human reproduction and to learn how to utilize the system to positively affect fertility status. More information on the endocannabinoid system will be given in relation to cannabis use and its effect on fertility later in this course.

At birth, there are approximately 2 million primordial follicles or primary oocytes in the ovaries, but by menarche that number has already declined to around 300,000 to 500,000 due to a natural exponential depletion process called atresia [22,23,24]. At 25 years of age there are probably around 60,000, and by 40 years of age there are only 6,000 or so remaining. From birth, primordial follicles enter the growing follicle pool, but unless they are stimulated by FSH, which begins to occur around puberty, the follicles degenerate in the ovaries. A common misconception is that there are a set number of follicles that coincide with the exact number of menstrual cycles a woman will have during the course of her reproductive years. In reality, younger women have hundreds of follicles in the growing pool each year, which can be stimulated simultaneously, but usually only a small cohort (about five to seven) will be recruited by FSH, and a single dominant follicle will become a mature oocyte (female gamete) during gametogenesis. Therefore, the biologic design allows a great many primary oocytes to be lost each year in the selection process, while only about 400 will ever become fully mature. Menopause results from an exhaustion of the primordial follicle pool or an inability for recruitment, and therefore a lack of hormone-producing, growing follicles in the ovaries.

Besides ovarian function, fallopian tube patency and function are particularly important to natural reproduction. There are two types of cells found in the epithelium of the fallopian tube: ciliated cells and peg cells. Ciliated cells are the most numerous, especially near the infundibulum at the distal end of the tube and the ampulla at the midsegment, and are responsible for egg transport to the uterus; the expression of cilia is increased by estrogen. The second type of cells, peg cells, produces fluid that aids the transport of sperm toward the oocyte at the fimbriated end and provides nutrients for the sperm, oocyte, and zygote. Peg cell secretions also aid in sperm capacitation. The negative side of this function is that infections can also be carried deep into the fallopian tube. Estrogen enhances the fluid secretion, and progesterone increases the number of peg cells.

The male counterpart of an oocyte (female gamete) is spermatozoa (male gamete) and is produced through an analogous process of gametogenesis, or more specifically, spermatogenesis. Unlike oogenesis, whereby oocytes are matured from a depleting store of primordial follicles created before birth, sperm are continually generated after the onset of puberty in healthy males under the influence of sex hormones. Spermatogenesis begins with germ cells containing 46 chromosomes, and through processes of meiosis and mitosis, taking place initially in the testes and finally in the epididymis, mature sperm with 23 chromosomes are created and stored until they are ejaculated. Spermatogenesis, from germ cell to spermatozoa, takes a total of 64 days [28].

Amenorrhea, or absence of menstrual periods, can either be ovulatory or anovulatory. Although both types cause female infertility, anovulation is the most common cause of infertility overall [33].

Risk factors for PID include multiple sex partners, having a sex partner that has more than one sex partner, young age, young age at first intercourse, the use of an IUD, vaginal douching, the presence of bacterial vaginosis, and a history of an STI [46,49]. Adolescents are especially susceptible to the development of PID; one out of eight sexually active girls will have PID before 20 years of age [46,50]. Unsafe sexual practices and biologic factors both contribute to the increased incidence in this population. For example, the female cervix is not fully mature in shape, size, and function until 25 years of age, leaving the upper genital tract of sexually active younger women more susceptible to bacterial infections, such as chlamydia and gonorrhea [46,47].

A varicocele is an abnormal dilation of any of the veins of the spermatic cord just above the testicle (usually on the left side), similar to a varicose vein. The condition is generally asymptomatic, but pain may occasionally exist. Varicocele leading to testicular atrophy is the most common cause of azoo- and oligospermia; the incidence of varicocele in men with primary and secondary infertility is approximately 25% and 75%, respectively [56]. Varicoceles in adolescents and young adults have been associated with significant loss of testicular volume and growth arrest of the testes, the risk of which increases with the size of the varicocele [57,58]. These individuals should be monitored with physical examination and semen analyses to detect changes in testicular function, as earlier treatment will increase the likelihood of recovering normal spermatogenetic function [59,60].

When the body's protective antioxidant defenses become depleted or reactive oxygen species are in excess, cellular damage can occur due to oxidation. Oxidative stress upon sperm is a pathology seen in roughly 50% of men with infertility [70]. Similarly, oxidation can damage oocytes during folliculogenesis. Though reactive oxygen species are byproducts of normal metabolism, several factors can lead to high levels of reactive oxygen species in semen and in the reproductive organs, including [70,71]:

Much attention has been focused on the evidence that obesity is a contributing factor in many disease conditions, including diabetes, cardiovascular disease, cancer, and arthritis, but what is less widely known is that obesity contributes significantly to infertility in both men and women [83,84,85,86,87]. Obesity in women can cause menstrual irregularities and pelvic organ prolapse and increases the risk of endometrial polyps, symptomatic fibroids, PCOS, and anovulation [83,88,89,90,91]. PCOS accounts for a majority of ovulation disorders, and a significant number of women with PCOS are obese. Additionally, fetal morbidity and mortality are increased with obesity [90,92]. ART treatments are also far less successful in patients with a BMI greater than 30 [88,90].

A 2010 study of 56 obese women around 30 years of age (with an average BMI of 37.7) found that the 40 anovulatory women in the research group had larger waist circumferences and significantly more abdominal and trunk fat than the ovulatory women [89]. Conditions that affect fertility, such as PCOS, diabetes, and hypertension, are particularly common among women with a central distribution of body fat (i.e., "apple shaped") compared with those that are "pear shaped" [39]. Another study of obese but regularly ovulating women found that for every BMI point greater than 29.0, there is a 4% to 5% drop in spontaneous pregnancy rate. Essentially, women with a BMI of 35 had a 26% decreased chance of becoming pregnant compared with women with BMIs between 21 and 29 [91].

Male obesity can lead to erectile dysfunction and cause increased scrotal temperatures, low semen quality, and changes in sperm proteomes, which are all factors that affect male fertility [84,85]. One study found that as BMI increases, ejaculate volume and sperm motility decrease [93]. Abnormal reproductive hormone levels, including elevated estrogen levels and reduced androgen, inhibin B, and SHBG levels, are thought to ultimately be responsible for decreased total sperm count, concentration, and motility as well as possibly leading to sperm DNA damage [85,93,94].

Men with diabetes typically have decreased sperm counts, increased DNA mutation and fragmentation of sperm, and a higher degree of oxidative stress on sperm than the general population [103]. The advancement of the disease to other conditions, the duration of the disease, and/or poor glycemic control are associated with higher infertility rates among men with diabetes [103]. As with women, tight glycemic control is required to maintain near normal fertility in adult male patients with type 1 and type 2 diabetes and to improve reproductive development in adolescence.

In addition to a poor overall diet, there are certain foods that should likely be avoided when trying to conceive. Soy products (a source of genistein, a phytoestrogen) are thought to affect endocrine function, and while further research is needed in this area, in the interim period, it may be wise for individuals to avoid soy while trying to conceive [114]. Various studies have found that very high intakes of genistein are associated with adverse effects on female reproductive physiology and pregnancy outcomes [113]. High intake of non- or low-fat dairy products may cause anovulatory infertility; it is proposed that changes in milk composition, such as the addition of whey proteins during the fat extraction process, are responsible for increased androgenic effects in women [115]. This finding is from one study alone and warrants further research, as low-fat dairy products are ubiquitous. A 2008 study implicates high intake of animal protein as a factor for ovulatory infertility and suggests replacing meat sources with vegetable protein sources; replacing as little of 5% resulted in a 50% increase in fertility in the high-meat-intake group [116]. When assessing patients for infertility, healthcare professionals should keep in mind that a varied, balanced, and calorie-appropriate diet is especially important to overall health.

There is increasing evidence that psychological stress has a negative effect upon fertility. Both follicle growth and sperm production can be compromised due to the body's adaptive stress response, which negatively influences the reproductive axis of both sexes and can lead to hyperprolactinemia, insulin resistance, and decreased antioxidant cofactors over time [117,118,119,120].

Hyperprolactinemia is a known cause of hypogonadism and anovulatory amenorrhea; one study found that 20 out of 70 women with infertility in a research group had excessive levels of prolactin [120]. Another study, published in 2010, postulates that catecholamines released in response to stress can slow blood flow enough to delay egg implantation in the uterus [121]. The same study found that reduced conception rates coincide with increasing levels of alpha-amylase, but not cortisol, in the female body. These studies add to the abundance of anecdotal evidence that suggests stress contributes to or causes ovulatory infertility.

Psychological factors, such as stress, anxiety, and depression, existing before or as a result of not being able to conceive, are thought to heavily influence the outcome of infertility treatments. Stress and anxiety cause an increased immune response (e.g., high levels of activated T-cells in the peripheral blood), resulting in reduced implantation rates in women undergoing embryo transfer IVF [122]. It has been found that women experience a significant amount of distress during the second and third years of attempts at conception, either naturally or though IVF or other ART treatments [123]. One study of couples undergoing IVF treatment in Turkey found that when detailed explanation of the IVF process, psychological support, and counseling were provided, the success rates more than doubled [33]. However, stress levels can be difficult to accurately quantify; therefore, most studies—as in the Turkish study—use women or couples attending counseling interventions or support groups as an experiment group to compare with those receiving standard care as a control. Because questions about how stressed one felt during the last cycle are subjective and stress is thought to have a similar effect on physiology in both individuals trying to conceive naturally and those undergoing infertility treatment, the results of infertility treatment/stress studies are usually extrapolated to determine that stress is a factor for infertility in the general population.

For men with abnormal semen parameters, the physical exam should include an evaluation of the prostate and the scrotal contents, which would assess testicular size and consistency, epididymis, vas deferens, and varicocele [205,206]. Other considerations are body mass, hair distribution, and penile abnormalities. If the initial semen analysis is normal, this indicates that the infertility is most likely due to a female infertility factor [205,206]. Even in these cases, another semen analysis should be completed if pregnancy has not occurred after four months and again after five months. If the semen analysis returns with abnormal findings, additional testing is necessary. The first consideration should be of exposure to gonadotoxins, including [207]:

Weight loss and exercise has been proven to greatly improve fertility in anovulatory overweight and obese women [45,83,87,209]. One study demonstrated that in as few as six months, 12 out of 13 anovulatory women on an exercise/calorie-restriction program (with an average weight loss of 14 pounds) resumed normal ovulation and 11 became pregnant. None of the women in the comparison group (who did not complete the six-month program) showed any positive changes in fertility indicators or pregnancy status [83]. Other research has shown improvements in regular ovulation and reduced biochemical abnormalities after a total weight loss of 5% [87]. Morbidly obese women should be warned of the pregnancy risks associated with extreme obesity and encouraged to lose a substantial amount of weight before attempting to conceive [209].

Likewise, BMI reduction in men is crucial to the restoration of normal hormone levels, spermatogenesis, and semen parameters [84]. Natural weight loss is attainable for many individuals who are overweight and slightly obese, but for individuals who are obese and morbidly obese, breaking the hypogonadal-obesity cycle can be extremely challenging without medical interventions (e.g., bariatric surgery, testosterone replacement therapy).

Based on guidelines set by the CDC, patients suspected to have obesity-related infertility should try to achieve at least 150 minutes of moderate-intensity aerobic exercise per week and muscle-strengthening exercise that works every major muscle group at least two times per week [210]. A reduced-calorie diet is also paramount for those wishing to reduce their BMI. Individuals should limit their total daily calories, based on their height and a normal BMI. Replacing fat and sugar calories with vegetables, whole grains, and other sources of fiber is also recommended.

As previously discussed, non- or low-fat dairy products may aggravate infertility in women with high BMIs and should not be recommended to replace full- or condensed-fat dairy products. For the time being, animal protein sources should not be replaced with soy proteins but should instead be replaced with other vegetable proteins. Additionally, a weight-loss support or counseling program should be recommended. Lifestyle modification is extremely important in this group of patients because even IVF and ART treatments have little chance of success in anovulatory women with a BMI greater than 29 [88,90,91].

Naturally restoring normal ovulation and menstrual periods for women with low body fat stores can be particularly difficult to accomplish unless the patient is willing to address the source of the problem. Women with eating disorders or exercise-induced amenorrhea are almost certainly aware of the irregularity or lack of menstruation. However, these patients may be seeking a medical approach to fertility or, rarely, may not have made the connection between amenorrhea and infertility. As discussed, it is particularly important not to inadvertently help this group of women become more fertile without first attempting to treat their low BMI (i.e., less than 19) due to self-health and gestational risks [45,110].

Many female athletes and women who engage in extreme levels of exercise are goal oriented. For these women, emphasizing achieving the goals of temporarily gaining weight, becoming pregnant, and delivering a healthy child may be met with more acceptance than in eating disordered women. Furthermore, athletes are often cognizant of their physical condition and may be less resistant to weight gain. For other women, the initial patient interaction may be the best chance for meaningful discourse relating to low-BMI-related infertility. Remember that the eating disorder may have been in place since adolescence or earlier and the desire to become pregnant may not be as strong as the desire to stay thin; avoid giving in-depth lectures on etiology [211]. Refrain from making referrals initially, and instead set a goal of gaining a few pounds in one month to assess ovulatory function. Explain that weight gain and resumption of normal menstruation is the overall safest method of conception and that low BMI extends risks to the fetus, such as low birth weight and premature delivery.

Recommend a temporary eating plan that involves three meals a day without calorie counting, and explain that soy and non- or low-fat dairy products may contribute to infertility; switching to whole milk products is advisable in this case [114,115]. For extreme exercisers, stress the importance of cutting back on workout frequency, duration, and intensity. Coffee is often consumed by those who exercise excessively; recommend switching to tea or quitting altogether [165]. Again, emphasize the goal of resuming normal menstruation and the idea that even medical approaches to infertility rely on overall health, including proper nutrient levels from foods.

Nutritional factors preventing optimum fertility usually accompany other diseases and conditions, including alcoholism, smoking, drug use, obesity, diabetes, and eating disorders. Identifying and addressing these primary risk factors is obviously paramount; however, recommendations of proper diet to infertility patients should be included in all courses of treatment. Specifically, diets rich in food sources of vitamins, minerals, and other antioxidants should be recommended, along with the addition of a multivitamin. This can help the body and reproductive tissues to repair and protect against oxidative damage and reactive oxygen species. As always, a rundown of foods to avoid while attempting to conceive should be given. A proper meal plan should be discussed, and patient education should focus on eating a variety of different foods (especially vegetables) while cutting back on simple sugars, carbohydrates, and fats.

If a patient is a current smoker, he or she should be advised to quit. Reproductive damage caused by smoking has been shown to be mostly reversible upon cessation in both men and women, but the time to pregnancy is increased [129]. It is estimated that the effects of smoking upon sperm production and other male reproductive factors can be reversed within one year of cessation, and based on results from women undergoing IVF treatments, the same approximate time frame is expected for recovery of the female reproductive system [129,144]. After approximately one year of not smoking, the odds ratios for spontaneous miscarriage and ectopic pregnancy also return to near normal [129,149].

The results of one study showed a "very fast and drastic improvement" in semen characteristics following alcohol withdrawal in chronic heavy users [135]. Male research participants were followed over a six-year period of continued alcohol abuse, during which their condition steadily worsened from teratozoospermia to azoospermia. Upon cessation of alcohol use, semen parameters returned to normal within three months [135]. This study illustrates one of the fundamental lifestyle changes that can be implemented to improve outcomes of male factor infertility, and while alcoholics are an obvious extreme, most research suggests that low-to-moderate users with infertility will also benefit from abstaining from alcohol use. Additionally, there are far fewer congenital defects in infants whose fathers abstain from alcohol at least two months before and during conception as spermatogenesis takes approximately 60 days [135]. Because drinking alcohol during pregnancy is strongly discouraged in general, women who are trying to conceive should also be advised to stop drinking for a similar time frame to allow hormone levels to normalize and oxidative damage upon oocytes to cease.

Certain illicit drugs leave a lasting effect on the reproductive organs that no lifestyle change will mitigate. Heavy and prolonged cocaine use in women, for example, severely damages the fallopian tubes, from which there may be no reversal. Male reproductive damage from chronic, heavy cocaine use is also permanent in most cases. The best initial course of treatment would be for ex-addicts to eliminate all other sources of oxidative damage from their lives and to switch to a diet rich in vitamins, minerals, and antioxidants, but referral to an assisted reproductive specialist is probably in order. Occasional users (of all illegal narcotics) should be advised to quit several months before trying to conceive to lessen the chances of miscarriage and congenital defects.

To a certain extent, timing is crucial. Ideal timing for sex is just one or two days before ovulation; however, variations in cycles, due to stress, nutrition, and other causes, can make predicting ovulation difficult. Techniques to monitor ovulation include recording menstrual cycles on a calendar; checking cervical mucus, position, and/or firmness; tracking basal body temperature; and using ovulation predictor kits [200]. Basal body temperature monitoring is useful for tracking patterns of temperature increase that indicate ovulation and estimating future ovulation dates, but it often indicates ovulation too late and can be too subtle to be effective in one-cycle conception assistance. Cervical mucus consistency is a very good indicator of impending ovulation, but reading can be subjective, as can other methods of cervical monitoring. These techniques can be taught to patients and will lead to some increased success. However, the best advice is often to recommend having sex every day (or every other day) starting just after the last day of menstruation [200]. There is no evidence that any sex positions are better for conception or that retaining ejaculate inside the vagina after intercourse increases pregnancy odds.

The primary pharmacotherapy for anovulation is the oral antiestrogen clomiphene citrate [45]. For women resistant to clomiphene, second-line therapies include clomiphene plus metformin or gonadotropins. Risks of these endocrine therapies are multiple pregnancies and becoming pregnant; therefore, other health concerns should be evaluated and addressed before beginning treatment. Dopamine agonists (e.g., bromocriptine) can be prescribed for women with hyperprolactinemia-related ovulatory disorders [45].

To date, there are no medications approved by the U.S. Food and Drug Administration for the treatment of PCOS; however, several medications are used off label. Clomiphene, an oral antiestrogen medication, has been a mainstay for ovulation induction in women with PCOS; unfortunately, up to 15% of cases do not respond to clomiphene therapy and about 50% of those responding do not lead to increased pregnancy rates [218]. Many studies have tried to prove that combination therapy with the diabetes drug metformin can improve the efficacy of clomiphene, especially in women with BMIs less than 25 who do not have diabetes. However, the results of these studies have been mixed. Nonetheless, metformin is currently recommended for the treatment of hyperinsulinemia, type 2 diabetes, and hyperandrogenism in patients with PCOS and may improve pregnancy rates but not necessarily live births [217]. Treatment guidelines have continually indicated combination clomiphene/metformin as primary therapy for these women [45,217]. A 2015 meta-analysis comparing the use of letrozole (an aromatase inhibitor) to clomiphene for ovulation induction found a significant increase in pregnancy and live birth rates with letrozole; some are predicting that letrozole will replace clomiphene as the first-line ovulation induction therapy for women with PCOS [219,220,221]. Combination clomiphene/metformin therapy remains preferred for certain patient subgroups.

Endocrine disorders in men can be treated with exogenous gonadotropins directly or with oral antiestrogen medications (e.g., clomiphene) that stimulate the release of endogenous gonadotropins to boost testosterone levels. As with women, men with hyperprolactinemia may be prescribed bromocriptine. For obesity-related infertility, testosterone replacement therapy and aromatase inhibitors may be prescribed; maintenance and regulation of adipose-derived hormones (particularly leptin) should be a priority [84].

Microsurgical varicocelectomy is the treatment of choice for repairing varicocele and restoring normal blood flow and spermatogenesis due to the low risk of damage and high success rate compared with percutaneous varicocelectomy or laparoscopic repair [61]. The pregnancy rate after one year is 43% and after two years is 69%, compared with a rate of 16% in men with varicocele who elect to undergo insemination or hormone treatment. The procedure involves delivery of the testicle through an incision in the lower abdomen in order to accurately identify and preserve the testicular artery or arteries, cremasteric artery or arteries, lymphatic channels, and all internal spermatic veins and gubernacular veins. All defects may be repaired using this technique [61].

Laparoscopic ovarian drilling procedures are a second-line treatment for women with PCOS when treatment with clomiphene/metformin or letrozole fails to induce ovulation. The procedure involves puncturing the ovary 5 to 10 times with an electrosurgical needle or laser fiber to reduce androgens. Patients with PCOS and high BMI (greater than 35), severe hyperandrogenism, and/or three or more years of infertility will generally respond positively to laparoscopic ovarian drilling. High LH levels are a good indicator of successful pregnancy after laparoscopic ovarian drilling [233]. Repetition of laparoscopic ovarian drilling treatments further improves PCOS symptoms, including infertility and hyperandrogenemia, in women sensitive to previous laparoscopic ovarian drilling [234]. Women who did not previously respond to medication treatments may be more responsive after laparoscopic ovarian drilling [234]. A multicenter observational study conducted between 2004 and 2013 examined the long-term pregnancy rate in 289 women with PCOS treated with ovarian drilling [235]. The average follow-up time was 28.4 months. One hundred thirty-seven (47.4%) women became pregnant following ovarian drilling; 71 (51.8%) of these pregnancies were spontaneous. Forty-eight (16.6%) women achieved at least two pregnancies following drilling, and 27 (56.3%) of these were spontaneous. Factors that predicted success were a normal BMI, an infertility period of less than three years, and an age younger than 35 years. Of the 33 women who underwent a second ovarian drilling, 19 (57.6%) achieved at least one pregnancy, and 10 (52.6%) of these were spontaneous [235].

Intravaginal insemination (IVI) is typically used for healthy women wishing to become pregnant with donor semen, or less often, the semen of a partner with an ejaculatory problem (e.g., delayed or premature ejaculation). With IVI, a partner's or donor's semen is placed into a syringe and the semen is deposited near the cervix. IVI can take place at home or in an outpatient setting, and success rates are similar to natural conception rates.

The first successful human conceived through IVF was born in 1978 in the United Kingdom. Her mother had been trying to conceive naturally for many years, and upon examination was found to have occluded fallopian tubes. This case is typical in that tubal infertility was once a distinct obstacle to pregnancy but has been greatly addressed by the development of IVF. Now more than 81,000 infants are born each year in the United States as a result of IVF [10].

The initial steps of IVF involve pharmacologic ovarian stimulation (to bring several oocytes to maturity simultaneously), oocyte retrieval, and sperm collection. Drugs typically given for ovarian stimulation include clomiphene, letrozole, FSH, LH, and hMG. Usually, these medications cause the ovaries to become very enlarged due to the development of an unusual number of follicles [237]. To help with oocyte maturation, human chorionic gonadotropin is administered, and GnRH agonists and antagonists are used to influence the timing of ovulation. The most common retrieval method involves an ultrasonically guided aspiration needle with a transvaginal approach. If a transvaginal method is not feasible, laparoscopic retrieval is used. During the brief procedure, several ovarian follicles are punctured to remove the mature oocytes. Studies indicate that the optimum number of oocytes to retrieve per cycle is 10 to 15 [238].

Sperm is also collected, either through ejaculation or directly from the testicles (i.e., testicular sperm aspiration) or epididymis (i.e., microepididymal sperm aspiration) through needle aspiration. The sperm is then "washed" to remove seminal plasma and to form a concentrate. Sperm from men with HIV can also be washed to ensure the female partner will not be infected during conception.

The next stage of IVF is fertilization. Sperm and oocytes are incubated together in vitro or are combined by ICSI, whereby one sperm is injected directly into each oocyte; up to 70% of IVF cycles use ICSI [10]. Controversy has surrounded ICSI because the technician is responsible for choosing a healthy sperm and because somewhat higher rates of genetic defects are associated with the procedure due to overriding the natural competition/selection process. Hyaluronan binding assay (HBA) is now often used to assist sperm selection; however, so far studies have shown no significant benefit to fertilization/conception rates and the avoidance of congenital abnormalities with HBA prediction [239,240]. Fertilization rates with incubation or ICSI are about 40% to 75% if the sperm and oocytes are of sufficient quality, but neither technique guarantees fertilization [237].

One to six days after retrieval, while at various stages of development, the embryos or blastocysts are suspended in a transfer medium. Drawn into the transfer catheter and inserted past the cervix, the embryo-containing medium is deposited into the uterus. The number of embryos transferred depends on age, health, and other factors decided by the reproductive endocrinologist and agreed upon by the client(s). For women younger than 35 years of age, it is recommended that only two embryos are transferred to prevent tripleting. Because blastocyst-stage embryos (days 5 to 7) are more likely to implant than cleavage-stage (day 2 or 3) embryos, fewer blastocysts should be transferred [241].

Mood disorders are relatively common in women and men with infertility, particularly before the initiation of treatment. However, women tend to display more distress than men in couples with infertility. In a study of 545 couples attending an infertility clinic, 30.8% of the women and 10.2% of the men presented a psychiatric diagnosis; of these, by far the most common were mood disorders, comprising 85% and 90% of all diagnoses, respectively [242]. The most common mood disorder was major depression. In another study, women being treated for infertility scored significantly lower on mental health subscales than the normative values [243]. A nationwide study conducted in Finland found that childless women with infertility were more likely to report depression and anxiety disorders (odds ratio: 3.4 and 2.7, respectively) than women who had not experienced infertility [244]. The researchers also found that women with infertility but with a current child had an increased risk for panic disorder (odds ratio: 2.6). Overall, it appears that the most common psychological effects of infertility on women are major depression and anxiety [242,243,244]. As discussed, principal concerns appear to center around the impact of infertility on relationships and the prospect of remaining childless [125].

Although much of the literature on psychological effects of infertility has focused on women, male partners in couples with infertility are also at risk for negative repercussions. A European study of 121 couples with infertility analyzed the psychological health of male partners [245]. The researchers found that depression, erectile dysfunction, and sexual problems were prevalent among male partners of couples with infertility. Furthermore, depression and anxiety, even at subthreshold levels, are associated with lower quality-of-life scores in men with infertility [246].

The relationship between infertility and psychiatric disorders is complex, and many factors can interact to increase the risk for developing depression and anxiety. Recognizing patients that may be at increased risk can lead to earlier diagnosis and treatment of psychological conditions. Duration of infertility is one such risk factor. Scores on depression inventories are significantly higher among couples with infertility of one to three years' duration compared with those with infertility that has lasted one year or less [247]. Treatment failure is associated with increased levels of anxiety and depression during the treatment period and after the end of treatment [248]. On the other hand, women with infertility who do not seek medical advice have reported higher rates of depression and other mental health issues compared with women with infertility who do seek medical attention [249].

It has also been found that a diagnosis of infertility can precipitate depressive symptoms in women with certain personality types, coping styles, susceptibility to stress, and beliefs and values [250]. Researchers have identified women with lower levels of neuroticism and higher levels of extroversion and optimism to be at a lower risk for negative mental health consequences of an infertility diagnosis. Conversely, avoidance coping styles were associated with an increased risk for a more negative emotional response [250].