#91534: A Review of Infertility

Infertility is inexorably tied to age, and although increasing age causes reproductive decline in both men and women, it is especially important in the latter, as women have a definitive reproductive window that tapers to a distinct inability to conceive. Men, on the other hand, may be able to sire children well into their senior years. According to data from the Centers for Disease Control and Prevention (CDC) 2015–2019 National Survey of Family Growth (NSFG), 19.4% of married women 15 to 49 years of age in the United States have primary infertility; the percentage increases with age, with 12.6% of women 15 to 29 years of age, 22.1% of those 30 to 39 years of age, and 26.8% of those 40 to 49 years of age reporting primary infertility [7]. Secondary infertility is far less common among married women of all age groups, at around 6.0% [7].

The majority of statistical information on infertility is regarding married women, but those who are married do not comprise a typical cross section of all women. Data on impaired fecundity from the 2015–2019 NSFG shows that 13.8% of women 15 to 49 years of age (of all marital statuses) and 16.3% of currently married women 15 to 49 years of age have impaired fecundity [7]. The percentage increases with increasing age, with impaired fecundity in 9.2% of women 15 to 29 years of age; 22.2% in women 30 to 39 years of age; and 33.4% in women 40 to 49 years of age [7]. Data from the most recent NSFG does not include a separate category for single women, but data from the 2010 version of the NSFG indicated that single women (7.9% impaired) were more fertile than their cohabiting (12.8% impaired) and married (12.1% impaired) counterparts [4]. In single women, the lower incidence of impaired fecundity may be because these women are using assisted reproduction, which bypasses some of the physiologic obstacles (e.g., fallopian tube obstruction, sperm problems) facing couples engaging in intercourse and who may be also dealing with psychological issues, which can exacerbate infertility. Single women undergoing insemination or assisted reproductive procedures also have likely undergone medical examinations prior to attempts at conception, which would uncover and address infertility risk factors.

There is a scarcity of infertility data on lesbian women, partially because it has been found that lesbian women tend to respond as "single" on surveys [8]. However, one study that specifically encouraged participants to accurately identify themselves according to their sexual identity found that lesbians tended to have an even lower incidence of impaired fecundity than heterosexual single women; it was theorized that this was mainly due to the fact that the lesbian women were statistically younger when insemination or other ART treatments occurred [8].

Among married women in the United States 15 to 44 years of age, there is a slight variation in fertility status when race is taken into account. The overall infertility rate is 7.2% for Black women, 6.1% for Hispanic/Latina women, 5.6% for Asian women, and 5.5% for White women [4].

Fertility also varies according to education level. Among married women with less than a high school education, the infertility rate is 5.7%; for those with a high school or partial college education, the rate is 6.4% and 4.5%, respectively; and for women with a Bachelor's degree, the rate is 7.9% [4]. The infertility rate for women with a Master's degree or higher is 6.0%.

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 order for the body to create the sex hormones most often associated with reproduction (estrogen, progesterone, and testosterone), several processes of the HPG/HPA axes are necessary. In regard to the HPG axis, neurons in the hypothalamus send out gonadotropin-releasing hormone (GnRH) that stimulates the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the adenohypophysis (the anterior portion of the pituitary gland), which in turn act on the gonads and the adrenal cortex. In regard to the HPA axis, adrenocorticotropin-releasing hormone (CRH) is also produced in the hypothalamus and stimulates the pituitary production of adrenocortical tropic hormone (ACTH), which acts on the adrenal gland. The adrenals and the gonads have thus been signaled to produce various amounts of corticosteroids (e.g., cortisol) and sex hormones (e.g., estrogen, progesterone, and testosterone), respectively, and to commence various processes (e.g., spermatogenesis, follicular maturation) dependent on certain factors, such as the physical/mental condition of the individual.

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].)

Thyroid Function

According to the American Society for Reproductive Medicine, currently available data support that it is reasonable to test thyroid-stimulating hormone in infertile women attempting pregnancy.

(https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/practice-guidelines/for-non-members/subclinical_hypothyroidism_in_the_infertile_female_population.pdf Last Accessed: June 16, 2023)

Level of Evidence: B (There is fair evidence to support the recommendation.)

The thyroid gland and the hypothalamic-pituitary-thyroid (HPT) axis play another major part in human reproduction, and the HPT axis is interconnected with the HPA and HPG axes. Iodine from foods is combined with the amino acid tyrosine and converted by the thyroid to the hormones triiodothyronine (T3) and thyroxine (T4), which are necessary for cellular metabolism throughout the body. Thyroid hormones act directly on the testes and ovaries and indirectly by influencing GnRH, prolactin, and sex hormone-binding globulin (SHBG) production. Hypothyroidism and hyperthyroidism both can have a profound effect on ovarian function, menstrual cycling, and spermatogenesis, as can autoimmune thyroid diseases, such as Graves disease or Hashimoto disease, which can cause thyroid hormone deficiencies. Thyroid diseases affect millions of Americans but are far more common in women than in men [14]. Iodine deficiency, one cause of thyroid disorders, is associated with female infertility and impaired fecundity.

Sex Hormone-Binding Globulin

SHBG is also a major factor in fertility, as testosterone and estrogen (estradiol) bind to SHBG and are transported through the bloodstream. The correct amount of SHBG, which is produced in large part by the liver, is necessary to maintain proper hormonal balance. Conditions that affect the liver, such as diabetes and obesity, can have a negative effect on SHBG levels, leading to excessive estrogen in men and increased androgens in women [15].

A growing body of evidence shows that the endocannabinoid system plays a significant role in human development and reproduction, including hormone regulation; oocyte production; sperm production, motility, and capacitation; sperm-oviduct interactions; acrosome reactions; embryo oviductal transport; blastocyst implantation; post-implantation embryonic growth; and placental development [16,17,18,19,20]. The endocannabinoid system is made up of endogenous ligands, ligand-metabolizing enzymes, and cannabinoid receptors, of which the receptor CB1 is the most abundant G protein-coupled receptor in the brain; the CB2 receptor is mostly found in the immune system [21]. It is now known that processes previously thought to be signaled and regulated only by steroid hormones and the reproductive axis are, at least in part, regulated by endogenous cannabinoid neurotransmitters and the endocannabinoid system.

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.

Controlled by the endocrine system, proper menstrual cycling requires a careful balance of hormones, primarily FSH, LH, progesterone, and estrogen [25]. The menstrual cycle involves concurrent processes of the uterus (endometrial shedding and growth), fallopian tubes (growth of cilia and peg cell fluid secretion), and ovaries (follicular maturation), which are signaled and regulated by varying levels of these sex hormones. The first phase of the ovulatory cycle, known as the follicular phase, corresponds with the onset of menses and the menstrual proliferative phase (growing uterine lining) and lasts for approximately 14 days. The second phase, ovulation, typically occurs on day 14. Finally, the luteal phase corresponds with the secretory phase, from days 14 to 28.

FSH stimulation of a cohort of follicles begins early in the follicular phase. The follicles begin to release estrogen, which steadily rises until just before ovulation, when estradiol peaks. Estrogen causes the endometrium to grow and become enriched with blood and glands. As discussed earlier, the estrogen feedback causes lowered FSH and increased LH. Just before the second stage (ovulation), the LH surge causes weakening of the follicle wall in the ovary, readying it for release, and then ovulation at LH peak. During the luteal phase, the corpus luteum produces a significant amount of progesterone, enabling the endometrium to become more receptive to the blastocyst in the event of fertilization, increasing basal body temperature, and preventing uterine contractions and the development of new follicles [26]. If fertilization of the oocyte does not take place, the rise in progesterone signals the inhibition of GnRH, which limits the production of additional progesterone. Following this, the corpus luteum degenerates, the uterine lining begins to die, and uterine cramps ensue.

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].

During the ejaculatory process, sperm is mixed first with seminal fluid (to gain an energy source and alkalinity, which aid survival in the acidic vaginal environment) and then with prostatic fluid (to aid sperm propulsion) to finally become semen [27]. Problems with spermatogenesis and/or seminal or prostatic fluid composition can lead to male infertility.

Two important cell types in the testes are Sertoli cells, located on the inner walls of the seminiferous tubes, and Leydig cells, found adjacent to the seminiferous tubes. Leydig cells release androgens (most notably testosterone) under the influence of LH; prolactin modulates the expression of Leydig cell LH receptors. Sertoli cells, or "nurse cells," are responsible for the nourishment and growth of immature germ cells (spermatogonium) into spermatids and for the transport of spermatids to the epididymis for the final stage of spermatogenesis, where they will become motile and mature. Sertoli cells are stimulated by FSH and also have a secretory role. Inhibin and activins (to regulate FSH), testosterone-binding globulin (to accumulate testosterone for sperm development), estradiol (to regulate spermatogenesis), and anti-Müllerian hormone (to prevent Müllerian duct development), among others, are secreted by Sertoli cells.

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].

Although rare, ovulation without menses is usually caused by obstructive disorders that can either be congenital, a result of arrested development of the Müllerian ducts, or acquired later in life, such as from surgery or infection (Table 1). Approximately 1 in 4,000 women are born with congenital vaginal agenesis (no vagina) and other variations of deformity to the vagina and uterus (e.g., Müllerian agenesis), though many of these women have fully functioning ovaries and secondary sexual features [34].

Anovulation, or a complete lack of ovulation, is typically caused by disorders of the HPA or hypothalamic-pituitary-ovarian axes. Extreme stress, exercise-induced stress, anorexia, obesity, malnutrition, diabetes, drug or alcohol use, and polycystic ovary syndrome (PCOS) are general risk factors for anovulatory amenorrhea and will be discussed later in this course. Table 2 lists several examples of conditions or causal factors that commonly lead to anovulation and amenorrhea according to which endocrine structure is affected.

About 1 in 100 women experience primary ovarian insufficiency between 30 and 39 years of age [23]. Women 15 to 29 years of age experience the condition at rates of about 1 in 1,000. The terms "early/premature menopause" are sometimes used colloquially; however, these are misnomers. Normal biologic menopause occurs at around 51 years of age, on average, and is caused by hormonal changes relating to the natural exponential depletion of follicles that typically follows 35 years of menstrual cycling. Primary ovarian insufficiency is instead an ovarian follicular disorder with two basic variations: premature follicular depletion and follicular dysfunction. Primary ovarian insufficiency is sometimes referred to as premature ovarian aging or failure.

Follicular depletion describes an unusually hasty loss of the finite number of follicles contained in the ovaries and can be caused by exposure to environmental toxins (e.g., heavy metals, industrial chemicals, pesticides, welding fumes), cancer treatments (e.g., chemotherapy, radiation therapy), certain viruses, or chromosomal defects/genetic factors (e.g., Turner syndrome, fragile X syndrome). There is also a 10% chance of developing primary ovarian insufficiency if a family member has the condition [11,36].

Follicular dysfunction describes conditions in which follicles in the ovaries are failing to reach maturity. Primary ovarian insufficiency most often occurs due to autoimmune diseases, such as antiphospholipid syndrome, but occasionally can also be due to inadequate gonadotropin signaling, eating disorders, or thyroid dysfunction [2,11,23]. Most women with primary ovarian insufficiency have sufficient levels of FSH; therefore, the ovaries do not respond to FSH supplementation.

The HPG axis (specifically, the FSH/estrogen feedback loop) becomes seriously disrupted in women with primary ovarian insufficiency because the follicles, which would normally produce estrogen, are non-functioning. Individuals with primary ovarian insufficiency will have a lack of estrogen and an excess of FSH that can be confirmed in laboratory tests. Most women with primary ovarian insufficiency are infertile, and their ovaries do not respond to fertility treatments [11]. Hormone replacement strategies have helped a small number of women with primary ovarian insufficiency to become pregnant [23].

PCOS is a common cause of female infertility, and it is estimated that between 1 in 10 and 1 in 20 women of childbearing age (or approximately 5 million American women) are affected by varying degrees of PCOS [37]. The name is derived from the characteristic appearance of the ovaries in most women with this condition; many roughly pea-sized cysts develop and remain embedded on the ovary, usually along the outer edge. In a normal ovulatory cycle, an egg develops within a follicle and the follicle ruptures and releases the egg during ovulation. When a fully mature egg fails to develop due to PCOS, the follicle remains unruptured in the ovaries, which become more enlarged with each successive cycle.

Although the exact cause of PCOS is not yet fully understood, there are several factors that are thought to contribute to its development, including [38,39]:

Symptoms of PCOS include hirsutism, hyperandrogenism, male-pattern baldness, adult acne or severe adolescent acne, irregular periods, anovulation, infertility, and lipid abnormalities, but there are few or no obvious symptoms in some patients [38,39,40]. Obese individuals are more likely to have PCOS; however, one study found that the likelihood of obese adolescents developing hyperandrogenemia and PCOS was not exclusively linked to body mass index (BMI) but instead more closely followed hyperinsulinemia and hormone imbalance trends [41]. Most research supports the theory that body type/shape and fat distribution (i.e., waist-to-hip ratio) are more relevant to reproductive health than mere BMI score, although having a high BMI is generally considered a risk factor for PCOS [39].

Patients' symptoms vary greatly upon presentation, and because the symptoms are similar to many other conditions, diagnosis can be difficult. Information that can aid a diagnosis includes [39]:

Salpingitis is infection and inflammation of the fallopian tubes, fimbriae, and/or ovaries due to various bacterial infections (e.g., streptococcus, staphylococcus, gonococcus, Escherichia coli, tuberculosis, actinomycosis, schistosomiasis, Chlamydia trachomatis, Neisseria gonorrhoeae) ascended from the vagina, cervix, or uterus, such as those possibly caused by sexually transmitted infections (STIs), surgical abortion, childbirth, intrauterine device (IUD) insertion or removal, upper genital diagnostic procedures, surgery, and other procedures [43]. Ascent of the infection may be attributed to several factors, including sexual intercourse (e.g., bacteria "rides" sexual fluids into the uterus—especially during female orgasm with rhythmic uterine contraction, or sex during ovulation, when the cervical os is enlarged), other "silent" rhythmic uterine contractions, menstruation or retrograde menses, vaginal douching, young age (i.e., immature cervix), and the use of antibiotics, which can cause a disruption of normal vaginal flora. Salpingitis also causes lesions and scarring that may interfere with normal fallopian functioning and is a typical precursor to PID.

Tubal infection usually leads to an increase in peg cell secretions. These secretions normally reabsorb; however, the accumulation of excessive fluid can cause a hydrosalpinx—a collection of fluid that seals the fimbrial end of the tube. Despite the proximal end of the fallopian tube remaining open after an infection resolves, the hydrosalpinx does not drain and can eventually cause tubal distension and distortion of the reproductive tract [43]. A hydrosalpinx can form without noticeable infection or symptoms and may only be discovered upon investigation of infertility. Hysterosalpingography may be used to detect the condition because the proximal portion of the tube remains patent. Because hysterosalpingography involves filling the fallopian tubes with dye or medium, it may also be useful in improving the chances of conception, possibly by "flushing" the tubes of potential or partial blockages. A meta-analysis of 13 trials found a slightly increased chance of pregnancy and live birth after the procedure when an oil-based medium was used compared with no intervention at all [44].

PID is an inflammatory reaction of the upper reproductive tract or pelvic/peritoneal area to one of a variety of invasive organisms but is typically caused by bacterial infection with, in order of prevalence, C. trachomatis, N. gonorrhoeae, multibacterial infection, and mycoplasmas. It usually affects the distal portion of the fallopian tube [42]. The pathophysiology of PID usually involves salpingitis. Salpingitis and the resulting inflammation can cause scar tissue to build up on the previously healthy epithelial lining of the fallopian tube, creating a partial or total occlusion and inhibiting the fertilization of an oocyte by sperm cells. However, any invasive procedure of the upper genitalia (e.g., dilation and curettage, biopsy) has the potential to cause PID. Other infections or disorders of the pelvic or abdominal area also have the potential to cause PID. The anaerobe Bacteroides fragilis is especially destructive to the fallopian tubes, and many women with PID are found to have bacterial vaginosis [45].

Scarring or lesions can also inhibit the normal function of the fallopian tubes' cilia and, therefore, the passage of the zygote, greatly increasing the risk of ectopic pregnancy in the event of fertilization. PID is responsible for a large proportion of ectopic pregnancies occurring every year [36,46,47].

Up to one out of every five women with PID from any cause, including bacterial STIs, will become infertile [48]. It is estimated that there are nearly 1 million cases of PID every year in the United States [46]. These two statistics combined indicate that up to 200,000 women may become infertile each year due to PID and the associated tubal damage [36,46,48]. Infertility is found at higher rates with each successive episode of PID, with rates of 12%, 23%, and 54%, from the first, second, and third episodes, respectively, noted in a literature review of studies of women with a history of pelvic disease [47].

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].

It is critical to teach patients that vaginal douching is harmful, and even more so for those younger than 25 years of age, because it can force existing (even mild) bacterial vaginal infections into the upper reproductive tract, causing endometrial infection and acute salpingitis. One study found that women 18 to 24 years of age who douched had a 50% chance of reduced monthly fertility compared with women who did not douche. The risk of douching-related reduced monthly fertility was 29% in women 25 to 29 years of age and 6% among women 30 to 39 years of age [51].

Endometriosis is a chronic disease that causes abnormal growth of endometrial tissue outside of the uterus, on the bladder, or on the bowels. It is estimated that endometriosis affects nearly 5% of women in the United States and causes infertility in up to 50% of those women [52,53]. Approximately 25% to 50% of women with infertility are found to have endometriosis. Adhesions, inflammation, and distortion of the pelvic anatomy, in advanced cases of endometriosis, are responsible for mechanical infertility, but there are also thought to be endocrine factors at work in early cases (e.g., luteinized unruptured follicle syndrome, luteal phase defect, abnormal follicular growth, premature and multiple LH surges). A study published in 2010 found that monocyte chemotactic protein (MCP)-1 and peritoneal leptin play important roles in the pathogenesis of early-stage endometriosis-related infertility [42]. However, the causes of endometriosis-related infertility in the early stages of the disorder are still poorly understood, as are the causes of endometriosis itself [53].

Tubal infertility as a result of bacterial infections that are caused, translocated, or reactivated by medical procedures involving the female upper reproductive tract, such as surgical abortions, IUD insertion and removal, natural and cesarean childbirth, laparoscopy, hysteroscopy, and tubal operations, is not uncommon. Medical procedures and infections of the pelvic area in general also increase infertility risk. One study found that adhesions form in approximately 75% of women undergoing pelvic surgery [36].

Appendicitis with rupture causes an almost five-fold increase in the chance of tubal infertility, but emergency removal of the appendix without rupture is not associated with greatly increased risk of infertility [36,54]. Inflammatory bowel disease is also associated with infertility, as is tuberculosis infection of the fallopian tubes [36].

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].

The causes of atrophy and lowered sperm count due to this condition are mainly theoretical—all have evidence for and against—and include increased pressure and temperature, disruption of the HPG axis, reflux of renal and adrenal metabolites down the spermatic vein, hypoxia, and oxidative damage [61]. High scrotal temperatures and oxidative damage are the leading theories. Smoking, a source of oxidative damage, greatly increases the risk of impaired spermatogenesis in men with this condition. Varicoceles are also associated with a decline in Leydig cell function and poor sperm quality [61]. Additionally, lowered testosterone levels are found in men older than 30 years of age with varicocele [62].

Another leading cause of infertility is dysfunction or failure of Leydig cells [63]. Although the role of Leydig cell dysfunction in male infertility has not been clearly elucidated, some studies have indicated that Leydig cell function is impaired in severely oligospermic men [64,65]. Leydig cell dysfunction is characterized by lower levels of serum testosterone, circulating free testosterone, and testosterone/LH ratios and higher levels of serum LH, estradiol, and estradiol/testosterone ratios. In one study conducted in Denmark in 2004, researchers compared the levels of these hormones in fertile men to those in men with infertility of unknown origin [65]. The study indicated that the men with infertility showed significant signs of Leydig cell impairment, the extent of which correlated with decreased spermatogenesis. However, it is important to note that the relationship in this case may not be causal; there may be a common cause of both Leydig cell dysfunction and decreased spermatogenesis, possibly testicular dysgenesis in utero [65].

Sertoli cell-only syndrome (SCOS) is a condition whereby Leydig cells are not present along the seminiferous tubes, causing a severe reduction of spermatogenesis. Patients are typically 20 to 40 years of age and normal on physical examination, with the condition presenting with infertility without sexual abnormality. Diagnosis usually is made based on findings of testicular biopsy. An estimated 5% to 10% of men with infertility may have SCOS [66]. On occasion, pockets of sperm are found; however, the individual is almost always azoospermic. There is no treatment for SCOS, and the cause of the condition is yet unknown.

A very high percentage of men with Klinefelter syndrome have SCOS. Klinefelter syndrome is the most common chromosomal defect in men, affecting approximately 250,000 men in the United States [26]. It is characterized by hypogonadism (i.e., small penis and testes, low testosterone, oligo- or azoospermia), feminine distribution of fat and pubic hair, gynecomastia, and lack of facial and body hair.

Congenital disorders of the tubal structure connecting the testicles to the prostate can result in effective sterility [67]. One example is the congenital abnormality of the Wolffian (mesonephric) duct, whereby it fails to properly develop into the vas deferens and/or seminal vesicle due to fetal testosterone deficiency, preventing the addition of semen and passage of sperm. The testicles, spermatogenesis, and endocrine function are usually normal, but sperm morphology may be affected. Often the epididymis is swollen with sperm. Remedies are intracytoplasmic sperm injection (ICSI) or reconstruction of the tubes.

Seminal fluid that has low fructose content cannot provide sperm with the necessary energy required to gain proximity to the oocyte [68]. Low seminal fructose levels are more common in older men than younger men and are primarily caused by androgen deficiency or inflammation of the seminal vesicles [69]. Treatment with chorionic gonadotropin is recommended.

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]:

Oxygen ions, peroxides, and free radicals can damage gametes and cause infertility in one of two ways. DNA can be damaged, causing defective DNA to be passed along and increasing the risk of miscarriage. Alternatively, gametes can suffer mechanical injury [70]. For example, acrosome damage can impair the ability of sperm to fuse with the oocyte and damage to the tail can cause reduced sperm motility.

Prolonged exposure to high temperatures, as found in hot tubs, hot baths, or saunas, is a factor for decreased fertility in men [72]. This type of infertility may be reversible. Occupational exposure to prolonged elevated temperatures can have similar negative effects [73].

Bacterial infection with C. trachomatis is normally confined to the lower genital tract, where the cervix serves as a barrier that protects the uterus, fallopian tubes, and ovaries. However, prolonged untreated infections can spread to the upper reproductive tract, and certain practices, such as douching, can cause the infection to ascend and may lead to PID. It is estimated that 10% to 15% of chlamydial infections in women of all age groups will lead to PID [47,126]. Due to sexual practices, such as failure to use condoms, and biologic factors, such as the cervix not yet being fully mature, adolescent girls have a 10 times greater chance of developing PID after acquiring chlamydia than women 25 years of age or older [47]. An additional risk factor for chlamydia infection and PID is having multiple sex partners [47].

Reinfection with chlamydia, due to the male partner(s) not being properly treated or not knowing which male partner is infected, is a serious concern that greatly elevates the chance of developing chlamydia-related PID and infertility [47,126]. Chlamydia, like most other STIs, has far greater potential for reproductive harm in women compared with men [47]. It is uncertain whether chlamydial infection is strongly associated with male infertility; however, when seminal chlamydial antibodies were found in men, a significant number of their partners were found to have tubal infertility and/or undiagnosed PID [127].

The odds ratio for tubal infertility in women who have had gonorrhea is 2.4 compared with women without any prior STIs. Infection with the trichomoniasis parasite is also associated with tubal infertility (odds ratio: 1.9) [128]. Human papillomavirus (HPV) is not directly responsible for ovulatory infertility or obstructive disorders, but treatments for and complications of the virus can damage the cervix (e.g., reduced cervical mucus, cervical scarring, cervical stenosis after cone biopsy, cervical cancer), causing infertility. Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) is known to increase the severity of pelvic disease [47].

Numerous studies have concluded that tobacco smoking is a risk factor for infertility in men and women and that nicotine and/or smoking affects reproduction in a dose-dependent manner [70,71,129,137,138,141,142,143,144,145]. In-vitro models have shown that nicotine displays an oxidizing effect on the sperm plasma membrane and sperm DNA, resulting in nonviability [141]. In-vivo research shows that smoking increases seminal reactive oxygen species by more than 100% and, compounding the potential for spermatic damage, decreases seminal plasma concentrations of the antioxidants vitamin E and vitamin C and antioxidant cofactors (e.g., zinc) [70,146,147,148]. It is known that tobacco smoke contains many reactive oxygen species and stable and unstable free radicals, including the highly toxic superoxide anion and hydroxyl radicals. This is in addition to the many carcinogenic, mutagenic, and other toxic chemicals contained in the particulate and gas phase of cigarette smoke [148].

Women who smoke put their reproductive system under increased oxidative stress and suffer the same depletion of antioxidants and unnatural aging as men. On average, menopause begins 1.5 years earlier in women who smoke [71]. It has also been suggested that the effect of smoking on female fertility is similar to a 10-year increase in age [129]. One meta-analysis of 12 studies found that the odds ratio of infertility in female smokers is 1.6 versus nonsmokers, and another meta-analysis of 9 IVF treatment studies found that the odds ratio for becoming pregnant is 0.66 versus nonsmokers [142]. A 2009 meta-analysis of 17 studies on the effects of active smoking during any ART treatment found that, compared with nonsmokers, the odds ratio for becoming pregnant was 0.56; spontaneous miscarriage, 2.65; and ectopic pregnancy, 15.69 [149]. These risks can be reversed by cessation of smoking [129]. Nicotine alone has been found to disrupt follicular growth, but not vascularization, in human ovarian follicles [145]. Granulosa cell apoptosis increases relative to the dosage of nicotine [145].

While some investigations have focused on nicotine (and/or cotinine, a nicotine metabolite) as the prime component of tobacco products leading to reproductive damage, others have examined the effects of heavy metals, such as cadmium, and other compounds isolated from tobacco smoke. Cadmium, found in soils of tobacco growing regions, is taken up by tobacco plants and highly accumulates in the leaves [150]. One study concluded that cadmium exhibited the potential to negatively affect intrafollicular processes (e.g., oocyte-cumulus expansion) with increasing dosages, as a result of decreased progesterone synthesis and suppression of FSH [143]. A 2010 literature review specifically cites cadmium and polycyclic aromatic hydrocarbons, among the thousands of other components, as responsible for damage to every stage of female reproductive function [151]. High levels of cadmium were found in the semen of male smokers with asthenozoospermia [152]. The synergistic effect of smoking and other environmental toxins, such as asbestos, plasticizers (e.g., phthalates, bisphenol A [BPA]), and diesel and coal particulates, on reproduction has also been noted [143; 144; 148; 151; 153].

Results of studies to determine whether or not caffeine use can lead to infertility are mixed and inconsistent, but as with moderate alcohol use, individuals with infertility are generally advised to limit caffeine intake (especially from coffee) to 100 mg/day. For reference, the caffeine levels of products Americans are most likely to consume are [154]:

A multinational European study published in 1997 concluded that 500 mg/day or more of caffeine significantly increased the odds of subfecundity for women who had never conceived; the odds ratio was even higher for concurrent smokers [155]. This study also showed an 11% increase in time to first pregnancy among those who consumed caffeine [155]. A Danish study published one year later found that, compared with women consuming 300 mg of caffeine per day or less, those consuming 300–700 mg of caffeine per day had a fecundability odds ratio of 0.88 per cycle; for those consuming in excess of 700 mg of caffeine per day the ratio further declined to 0.63. Similar numbers were seen in men as well [156].

Female coffee drinkers have been found to have more infertility problems compared with those who consumed other sources of caffeine (e.g., tea, chocolate, colas) [156]. The conclusion that the caffeine in coffee has the greatest impact on fertility in women is supported by at least one other study; incidentally, the same study also found that men who drink tea heavily are more likely to be infertile [157]. The mechanism of how caffeine affects fertility is not clear, but it is thought that the alkaloid may alter hormone levels. In fact, a Japanese study found that caffeine elevates SHBG and estradiol levels in women [112,158]. Elevated estradiol levels (70% greater) were also found during the early follicular phase in women consuming 500 mg/day compared with a 100 mg/day intake group [159].

On the other hand, some research has shown that caffeine intake is not a significant factor for infertility in women [160,161,162,163]. A 2009 study concluded that while high soft drink intake is a risk factor for ovulatory disorder infertility, caffeinated sodas were no more likely to cause ovulation irregularities than noncaffeinated types [160]. A separate study found that although menstrual cycles tend to be shorter, women who are heavy caffeine consumers are no more likely to have an anovulatory episode, short luteal phase, long follicular phase, or long cycle. The shorter total cycle duration was due to short menses, attributable to vasoconstriction [161]. Another group of researchers found that there was no increase in length of time to conception between women with caffeine intake levels of 500 mg and 7,000 mg per month [162]. Yet another study found that caffeine only negatively affected the probability of conception when used concurrently with alcohol [163].

It has been suggested that research regarding caffeine and fertility may be biased due to self-reporting of use and the retrospective collection of data on consumption, in some cases as much as six years later [112]. One well-designed study, in particular, addressed this concern by interviewing participants at three-month intervals and concluded that women who drank 1 cup or less of coffee per day were twice as likely to become pregnant than those who drank more and that increased intake inversely correlated with conception rates [164]. However, another well-designed study, in which women reported their intakes monthly, found that no source or amount of caffeine influenced fertility outcomes except tea; one-half cup or more of tea per day doubled the chances of conception each cycle [165].

In spite of these mixed results, it is generally recommended that women who wish to become pregnant begin to reduce caffeine intake, as the substance crosses the placenta and has been shown to affect fetal development and gestation (e.g., birth defects, premature labor, preterm delivery, low-birth weight offspring) in animals [166]. Although human studies have been inconclusive, it should be noted that caffeine causes increased blood pressure, dehydration, and changes in fetal sleep pattern and that the fetus is not adept at metabolizing the stimulant.

Cannabis is by far the most commonly used recreational drug in the United States, with an estimated 31.6 million regular (past month) users 12 years of age or older in 2019. Its use increased from 22.2 million users in 2015, and its popularity is rising [139,167]. Knowledge of how the drug affects fertility is also increasing.

The action of cannabis's primary active components, delta-9-tetrahydrocannabinol (THC), cannabidiol, and cannabinol, upon fertility and reproduction was unknown before the discovery of cannabinoid receptors in 1988 and the unraveling of the mammalian endocannabinoid system in the 1990s. It is now thought that cannabinoids influence many reproductive processes, including hormone regulation; oocyte production; sperm production, motility, and capacitation; sperm-oviduct interactions; acrosome reactions; embryo oviductal transport; blastocyst implantation; post-implantation embryonic growth; and placental development [16,17,18,20,168]. Any variation in these processes can lead to infertility. Animal research has identified several structures previously thought to be regulated only by hormones that are at least partially regulated or signaled by the endocannabinoid system [19,20].

The perception that cannabis has no deleterious effects is perpetuated in popular culture. With a number of U.S. states allowing its sale for medicinal and recreational use and growing knowledge of cannabinoid therapy, a belief in cannabis as a cure-all flourishes in some circles. While the drug and its synthetic derivatives do undoubtedly offer promise as therapeutic agents for certain conditions, reproductive detriment can befall those who abuse cannabis (or partake moderately) or even those who may be taking a cannabinoid obesity drug.

Results of studies regarding the outcome of recreational cannabis use upon human reproduction show primarily ill effects. For example, many of the same negative reproductive effects of tobacco smoking, such as oxidative damage and a decrease in antioxidant levels, are caused by smoking cannabis as well. Cannabis smoke contains many of the same harmful and/or carcinogenic compounds as cigarette smoke (e.g., polycyclic aromatic hydrocarbons, ammonia, hydrogen cyanide, nitrogen oxides), and some are found in much higher levels than in cigarette smoke. Ammonia is present in both mainstream and sidestream cannabis smoke in concentrations 20 times greater than in tobacco smoke [169]. Certain studies have also linked cannabis use with testicular germ cell tumors [170].

In addition to cellular damage caused by oxidation and toxins, several studies have linked cannabis use with increased odds of ovulatory factor infertility, early loss of pregnancy, and decreased semen parameters [19,171,172,173,174]. Researchers found that the risk ratio for abnormal ovulation in women who had used cannabis within the same year of trying to conceive was 2.1, and for those who had stopped using the drug more than one year prior to attempting pregnancy, the risk factor was 1.7 [171]. Occasional cannabis users (defined as using less than three times in three months) have been found to have a follicular phase 3.5 days longer on average than non-users; interestingly, heavy users (more than three times in three months) had only a two-day increase [174]. Long follicular phase, causing ovulatory delay or inhibition, is associated with infertility and miscarriage.

One longitudinal study found no impact of cannabis use on sperm concentrations [175]. However, sperm motility may be impacted by cannabis use, as are straight-line velocity, average path velocity, and acrosome reactions [173,176]. These impaired sperm are likely unable to fertilize an egg, and if one happens to achieve success, the embryo is at great risk of being nonviable. One study posits that sperm propulsion is affected by cannabis use because THC mimics anandamide, an endocannabinoid responsible for opening Hv1 channels in sperm flagella; excessive cannabinoid causes the channels to open prematurely and the sperm to "burn out" before reaching the ovum [177]. A 2013 study found that seminal plasma levels of anandamide are significantly reduced in men with asthenospermia and oligoasthenoteratospermia (i.e., oligospermia, asthenospermia, and teratospermia combined) [168]. Thus, it appears that anandamide and other cannabinoid levels must not be too high or too low for optimal reproductive potential.

In light of the relatively new discovery of the endocannabinoid system, research suggests that a carefully balanced endogenous cannabinoid system, which is involved in regulation and signaling of reproductive processes, plays an important role in reproduction [168]. A disruption of this delicate balance by exocannabinoids, or even a lack of certain endocannabinoids, can greatly decrease the likelihood of conception, as cannabinoid receptor expression has been identified in reproductive tissues in the testes, uterus, and endometrium and in sperm and ova [19,20,168]. Though the endocannabinoid system is still poorly understood, it appears that tailored exocannabinoid therapy may be a new frontier in fertility treatment and/or contraception [19,168,176].

Use of cocaine is known to cause low sperm concentration and motility [178]. One study showed that men who used cocaine within the previous two years had a high risk for low sperm count. Chronic users (more than five years) had an increased risk for low sperm count and motility and malformed sperm.

Cocaine use is also strongly associated with tubal infertility. Fallopian tube abnormities are 11 times more likely in women who have used this drug [171]. Although no studies have assessed the impact of cocaine on human ovulatory function, heavy cocaine use has been shown to inhibit the release of LH in animal studies. This, in theory, could cause anovulation; however, one study found that cocaine use is not significantly associated with ovulatory infertility [171].

In one small scale study, 93% of heroin addicts had abnormal semen parameters [179]. Among these men, problems with motility were the most common finding (78%), followed by mutated sperm (28%) and low sperm concentration (16%). Heroin abuse can lead to lowered levels of hormones necessary for proper male gonad function, including LH and testosterone [180]. Lower than normal LH, FSH, and progesterone have been found to be responsible for ovulatory factor infertility in women addicted to heroin [181]. Additionally, heroin has been shown to affect the HPA axis in humans [180,182]. It should be noted that these effects are expected with the use of other opioids as well, including the prescription drugs oxycodone, fentanyl, and morphine.

There are very few studies that have examined the effects of methamphetamine use on human reproduction and specifically on fertility status. It is certain that methamphetamine places the reproductive organs under extreme oxidative stress and causes metabolic distress [183]. Regular methamphetamine users often become severely malnourished and typically consume a large portion of their calories from sugar and carbohydrates. The same prognosis for infertility as those with poor diet, eating disorders, and possibly insulin resistance is to be expected in these individuals.

Available data from animal studies shows a high level of sperm DNA fragmentation and a diminished ability to contribute to conception in men who are heavy methamphetamine users [184]. Another animal study conducted in 2002 found a dose-dependent increase in terminal deoxyuridine triphosphate nick-end labeling-positive cells in the seminiferous tubules of the testes, indicating apoptosis [185].

The use of androgenic anabolic steroids (testosterone derivatives) among amateur and professional athletes and bodybuilders is known to contribute to or cause infertility by interfering with the body's endogenous production of hormones and causing hypogonadotrophic hypogonadism [186]. Gonadotropin secretion is suppressed in users, who are typically male, due to the artificial negative feedback induced by testosterone analogues (10 to 40 times higher than normal levels). Low gonadotropin causes low FSH and LH and consequently a drastic reduction in spermatogenesis. Testosterone preparations similar to certain androgenic anabolic steroids have been studied as possible male contraceptives due this same effect.

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.

For recovering heroin users, methadone treatment will not restore normal ovulation in all women, though it may help for some [212]. Before attempting to conceive, it is best to be opiate-free (including methadone) for several months, for the sake of the fetus and to allow the body to normalize. It appears that cessation of use is also the only way to restore some degree of fertility for men, but heroin has been shown to cause permanent male reproductive damage [33]. Semen parameters of a methadone treatment group were measured against heroin-user and non-user controls in one study; testosterone levels and sperm motility were actually lower in methadone users than in both of the controls [213]. Ex-heroin users experiencing infertility should be referred to specialists.

Cannabis use is not associated with lasting damage to the reproductive organs, so cessation of use will typically restore ovulation and normal semen parameters. A restoration time frame similar to tobacco smoking cessation is likely in these patients.

Based on testing of steroidal male contraceptives, the impact on spermatogenesis can usually be reversed after about one year of cessation of steroid use. However, anabolic steroids used for muscle development are typically taken in dosages 40 times higher than therapeutic contraceptive dosages, so the recovery time may be lengthened [214]. Nonetheless, men have successfully fathered children within two years of quitting steroids [186]. Of course, in chronic heavy users, fertility may be permanently impaired.

As discussed, there are several prescription medications that can interfere with fertility and hormone homeostasis. Identification of the drug(s) affecting fertility and cessation of use will usually restore fertility. Of course, not all medications can be discontinued, and the benefits and risks of eliminating any medication should be discussed with the patient and the healthcare team. If necessary, some medications may be tapered down slowly.

Studies have shown that stress reduction has the potential to markedly improve fertility outcomes due to the associated reduction of biochemical anomalies [117,118,119,121,123,124]. The American Medical Association has suggested the following approaches for patients to cope with stress [215]:

Infertility patients also seem to benefit from psychological interventions, such as support groups and cognitive-behavioral therapy, though the latter has effected superior improvements in fertility status [123,124]. It is recommended that this information be shared with patients and referrals be made to cognitive-behavioral specialists if patients seem especially frustrated or distressed.

Along with proper nutrition, the most important lifestyle change that most Americans would benefit from is the initiation of regular exercise. In addition to providing cardiovascular benefits and protection from other infertility cofactors, such as diabetes, obesity, psychological stress, depression, and hypertension, moderate exercise directly improves sexual and reproductive health [112]. In women with PCOS, the foremost recommendation for restoring regular ovulation and achieving pregnancy is weight loss and regular exercise along with other lifestyle modifications (e.g., improved diet) [209].

As noted, the CDC recommends 150 minutes of medium-intensity aerobic exercise per week and muscle strengthening exercise at least two times per week for moderate health benefits. For greater health benefits, 150 minutes per week of high-intensity exercise or 300 minutes per week of medium-intensity aerobic exercise is recommended, in addition to strength training [210].

Unexplained infertility may be due to one (or more) of thousands of toxic exposures, which may or may not be avoidable or practical to avoid as a result of where the patient lives or is employed. When there are no easily identifiable risk factors for infertility, inquiry should be made about the individual's occupation. Because many reproductive toxins are endocrine disruptors, symptoms of an endocrine disorder may be present and hormone testing will often reveal abnormalities. Suspicion of endocrine disruption in the absence of other risk factors (e.g., obesity, underweight, cannabis use) warrants referral to a reproductive endocrinologist.

For most couples, having unprotected sex two to three times per week will lead to pregnancy. Because good quality sperm survives in healthy fallopian tubes for up to seven days, under these circumstances, chances are good that the timing of ovulation will occur when there is live sperm available for fertilization.

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.

If and when normal sexual intercourse fails to produce pregnancy, other interventions are available to treat infertility. However, along with these interventions come side effects, increased health risks (to the parents, fetus, and child), and often a high financial burden [216]. Therefore, whenever feasible, lifestyle interventions should be the first treatment choice, as they usually improve the patients' overall health, energy level, and ability to produce healthy offspring.

Communication with couples regarding lifestyle changes is a vital step in improving the chances of natural conception. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter should be utilized. Frequently, this may be easier said than done, as there may be institutional and/or patient barriers.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. When providing care for patients for whom English is a second language, the consideration of the use of an interpreter and/or patient education materials in their native language may improve patient understanding and outcomes.

Ovulatory Disorders

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].

Endometriosis

Initial therapies for endometriosis include oral contraceptives (progestins and combined estrogen-progestin therapy), GnRH agonists/antagonists, aromatase inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). Medications used for this condition inhibit ovulation and therefore cannot be considered direct fertility treatments; there is also no solid evidence that medical treatment of endometriosis improves fertility [53]. Only surgical approaches to treatment are completely effective in regaining fertility.

A three-month course of a GnRH agonist is recommended if the condition is unresponsive to the previous treatments; however, it has been found that if medication therapy is stopped, the condition will become worse [217]. Danazol may be prescribed for endometriosis (with good reduction of symptoms and morbidity), but serious negative side effects appear in up to 80% of those taking the drug, causing many to abandon this therapy. Additionally, it can cause harm to a fetus, so administration to those trying to conceive is not recommended.

PCOS

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.

Gonadotropin therapy, such as with human menopausal gonadotropin (hMG) (a combination of LH and FSH isolated from the urine of postmenopausal women), is an option as an effective second-line approach to treating PCOS. However, use comes with an increased chance of serious side effects and multiple births. One particularly negative side effect of gonadotropin therapy is ovarian hyperstimulation syndrome, which causes excessive follicles to grow simultaneously, possibly leading to kidney failure, blood clots, fluid build-up in the abdomen or chest, or severe electrolyte imbalance if pregnancy is achieved. Cheng et al. have shown a pregnancy rate of 43.3% (compared with 20% in the placebo group) when metformin was combined with clomiphene and hMG in a study of women with PCOS [222]. In 2000, a systematic review of gonadotropin therapy in women with PCOS found that the data were limited and inconclusive to support its use [218]. The review was withdrawn in 2015 [223].

There is fairly strong evidence that the contraceptive medroxyprogesterone acetate is useful for restoring menstrual regularity and menses in women with PCOS [217]. Combination oral contraceptives are not recommended as a first line of therapy, due to their negative influence on insulin sensitivity, but they do offer some benefits, including prevention of endometrial hyperplasia, reduction of endometrial cancer risk, and possibly improved lipid levels [217,218]. However, because medroxyprogesterone acetate is a contraceptive, it cannot be considered an infertility treatment. Use should be identified, evaluated, and halted in women who wish to become pregnant, especially due to the length of time it takes for medroxyprogesterone (particularly parenterally administered doses) to leave the system.

STIs and PID

The two major STIs responsible for causing PID and infertility—chlamydia and gonorrhea—are treatable with antibiotics, as are other bacterial infections. However, the damage caused by these infections can be much more difficult or even impossible to reverse. Treatment of PID should include broad-spectrum antibiotics capable of killing both N. gonorrhoeae and C. trachomatis, as endocervical testing can return false negatives. Inpatient treatment may be required for some patients [224]. Hospital-based therapy is suggested when [224]:

Traditionally, there has been a standard practice for adolescent patients with PID to be hospitalized. This is not recommended and has not been found to improve outcomes unless any of the criteria for hospital-based care are present [224]. Despite antibiotic therapies, it is unclear if treatment can completely eradicate certain infections from the upper reproductive tract or if treatment can prevent long-term complications, such as ectopic pregnancy and tubal infertility. Another bacterium implicated in the pathogenesis of PID, and speculated to be a cause of endometriosis and tubal infertility, is M. genitalium. This is a relatively recently discovered mycoplasma (1983) and has been identified as a significant cause of urethritis [224]. The recommended treatment is azithromycin for at least five days.

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].

In cases of mild or moderate endometriosis, surgical treatment of adhesions or lesions has been shown to improve fertility and result in a small but significant increase in live birth rates [53]. One study found that ablation alone using a thermal coagulation device helped 10 out of 43 women with previous infertility to become pregnant, with no miscarriage or ectopic pregnancy reported [225]. Another study of fecundity outcomes of both resection and ablation concluded that about one-quarter of women with infertility would conceive within one year after surgical intervention [226]. However, another study using different measures found no improvement in pregnancy rates after either procedure compared with medication or no treatment [227]. In cases of mild-to-moderate endometriosis, the Practice Committee of the American Society for Reproductive Medicine states that there is insufficient evidence to recommend laparoscopy over expectant management [53].

In cases of severe endometriosis, conservative surgical interventions (including laparoscopy) have been found to significantly improve fertility and are recommended [53]. One study of 216 patients showed that pregnancy rates two years after laparoscopy or laparotomy were 45% and 63%, respectively [228]. Patients with ovarian endometriomas greater than 4 cm may benefit from laparoscopic cystectomy for improved fertility compared to cyst drainage and coagulation, which is associated with a high risk of cyst recurrence [229].

A 2010 retrospective study found that tubal microsurgery, including adhesiolysis, anastomosis, fimbrioplasty, salpingostomy, and refertilization after former sterilization, resulted in better pregnancy outcomes than one cycle of IVF treatment. Additionally, this approach results in fewer multiple births and related complications. Women can become pregnant many times after a single surgery versus having to potentially undergo multiple cycles of IVF treatments each time pregnancy is desired [230]. A 2006 Cochrane review found a significant increase in pregnancy rates attributable to microsurgery versus macrosurgery [231].

It should be noted that treating fallopian tube occlusion with manual pelvic physical therapy has been shown to restore patency in some women with confirmed bilateral occlusion [232]. A 2008 study used a 20-hour series of manual physical therapy treatments to improve soft tissue mobility and clear adhesions by indirectly manipulating the peritoneum, uterine/ovarian ligaments, and neighboring structures. Manual therapy restored unilateral or bilateral patency in 17 of the 28 patients, and 9 of those 17 patients reported a subsequent natural intrauterine pregnancy [232].

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].

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 Society of Obstetricians and Gynaecologists of Canada recommends that all men with unexplained obstructive azoospermia be offered genetic/clinical counseling and genetic testing for cystic fibrosis prior to in vitro fertilization with ICSI.

(https://www.jogc.com/action/showPdf?pii=S1701-2163%2815%2930685-X Last Accessed: June 12, 2020)

Level of Evidence: II-2A (There is good evidence from well-designed cohort or case-control studies to recommend the clinical preventive action.)

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].

Zygote intrafallopian transfer (ZIFT) and gamete intrafallopian transfer (GIFT) are two spinoff treatments similar in some aspects to IVF. Though not technically IVF, GIFT shares the first steps of the process (i.e., ovarian stimulation, oocyte retrieval, and sperm collection). However, because ova and sperm are laparoscopically deposited into the fallopian tubes, fertilization does not take place in vitro. Immediately following retrieval, oocytes are mixed with collected and washed sperm and inserted, via the fimbrial end of the fallopian tube, into the ampulla. Advantages to GIFT are that the natural selection and competition of sperm still occurs and procedure times are greatly reduced compared with IVF. Certain semen parameters must be relatively normal (e.g., morphology, low DNA fragmentation), but others (e.g., motility, seminal fructose level) are less of a factor. Some couples may prefer using GIFT for religious reasons because fertilization takes place in vivo.

ZIFT treatments involve fertilization in vitro but use laparoscopy to deposit the zygote into the fallopian tube. ZIFT offers the advantage of confirmation of fertilization, and like GIFT, some patients who do not have success with IVF respond better to this type of treatment. GIFT and ZIFT combined represent less than 1% of ART treatment cycles performed in the United States today [10].