Infertility is defined as the inability to become pregnant after one year of regular unprotected sexual intercourse. Healthy structure and function of the female reproductive system is essential to fertility. The structures of the female reproductive system (Figure 1) are:

• Ovaries. There are two ovaries present in the female pelvis. Each ovary has an outer cortex, where follicles develop, and an inner medulla comprising connective tissue and blood vessels. Before a woman’s birth, germ cells with the potential to become oocytes (cells that can mature into eggs) reproduce rapidly, reaching a peak of roughly 6–7 million around gestational week 20; however, most of these germ cells degrade before birth. The remaining one million or so germ cells undergo the first stage of transformation into primary oocytes and constitute ovarian reserve. These oocytes exist in dormant follicles until activated by cyclical hormone signals after puberty.^10,11 The ovaries are also made up of theca and granulosa cells, responsible for secreting estrogen, progesterone, androgens (male hormones), and other factors that regulate follicular activation and maturation.¹⁰ Ovarian reserve declines gradually as follicles degrade with age. Environmental and genetic factors can also contribute to diminished ovarian reserve.¹⁰

During regular hormone cycles, several oocytes undergo further development, and a dominant follicle emerges. This dominant follicle contains a fluid-filled cavity called the antrum. The oocyte from this dominant follicle is released from the ovary in a process known as ovulation. The remaining follicle cells transform into a progesterone-secreting structure called the corpus luteum.¹¹

• Fallopian tubes. There are two fallopian (or uterine) tubes, which collect oocytes released by the ovaries and carry them to the uterus. The end of each fallopian tube closest to an ovary has finger-like projections called fimbria that help sweep oocytes into the inner tube. The other end of each fallopian tube is in the inner uterus.¹¹ The fallopian tubes are the site of fertilization, which generally occurs within three days of ovulation. During fertilization, a fully mature sperm binds to the outer protective shell (zona pellucida) of the oocyte. This triggers the final maturation of the oocyte to an ovum (egg) and the generation of an embryo. In addition to their role in transport, the fallopian tubes are responsible for producing substances that sustain sperm and provide nutrition to the developing embryo.¹⁰
• Uterus. The uterus is the site of implantation, embryonic maturation, and growth of the developing fetus. The uterine cavity is surrounded by walls consisting of three layers: the inner blood vessel-rich endometrium, which expands or thins in response to hormonal signals during the menstrual cycle; middle muscular myometrium, which provides structural support and can contract to induce menses or childbirth; and serosa, which is the outer fibrous layer. A tubular structure known as the uterine cervix acts as a channel between the uterus and the vagina.¹¹ Implantation can occur between seven and 10 days after ovulation when the uterine lining, under the influence of high levels of estrogen and progesterone, is receptive. Even in normal circumstances, only about half of fertilized ova will implant and result in successful pregnancy.¹⁰
• Vagina. The vagina is the passageway from outside of the body to the uterus.¹¹

Figure 1: The female reproductive system. Credit: Suwin, Shutterstock

Female Hormonal (Menstrual) Cycle

Female fertility is controlled by cyclic hormone signals from the hypothalamus and pituitary gland via the hypothalamic-pituitary-ovarian (HPO) axis.¹⁰

• The female hormone (menstrual) cycle (Figure 2) begins with the follicular phase, which normally lasts approximately 14 days.
  • Estrogen and progesterone levels are at their lowest, and the hypothalamus responds by increasing secretion of gonadotropin releasing hormone (GnRH), which triggers pituitary production of gonadotropins—follicle stimulating hormone (FSH) and luteinizing hormone (LH). Rising FSH levels stimulate maturation of several ovarian follicles and the emergence of a dominant follicle. Estrogen production by granulosa cells also increases, causing thickening of the uterine endometrium to support implantation should fertilization occur.
• A surge in LH around mid-cycle is followed by ovulation, and the second phase of the cycle, the luteal phase, begins. This phase usually lasts from about days 15 through 28.
  • The luteal phase is marked by increasing progesterone production by the corpus luteum, which exerts negative feedback signaling that inhibits GnRH, FSH, and LH release and promotes maturation of the endometrium. The developing endometrium produces substances that support implantation of a fertilized ovum, or embryo. If implantation occurs, cells associated with the embryo produce human chorionic gonadotropin (hCG), which maintains the corpus luteum and keeps progesterone levels high.
• In the absence of implantation, diminishing LH and FSH levels result in corpus luteum breakdown, decreased production of progesterone and estrogen, sloughing away of the endometrium through menstruation, and the start of a new cycle.¹¹

Figure 2: The female hormone cycle. Credit: Pikovit, Shutterstock

The causes of fertility problems in women can be categorized as ovulation dysfunction, tubal infertility, uterine and cervical issues, and diminished ovarian reserve. It is important to note that, even when female causes are identified, factors related to the male partner may still be contributing to infertility; in fact, it is estimated male factors play a role in roughly 50% of couples with infertility.^2,12

Ovulation Dysfunction

Ovulation disorders are caused by hormonal imbalance and account for approximately 25% of infertility cases,³ and may be caused by one or more of the following:

• Genetics. Certain genetic mutations, particularly those affecting the X chromosome, can be an underlying cause of premature ovarian insufficiency (also known as primary ovarian insufficiency), a condition in which menstrual cycles become irregular or cease and FSH levels are persistently high before the age of 40 years. In vitro fertilization using donor eggs is generally the only treatment option for women with X chromosome-related infertility. Other gene mutations can affect function of the HPO axis and contribute to hormone imbalance.¹⁰
• Polycystic ovary syndrome (PCOS), a condition characterized by excess androgen (male hormone) production, ovarian structural and functional abnormalities, and metabolic disturbance, is a common hormonal cause of infertility. It is estimated that 80–85% of women with anovulation (lack of ovulation) have PCOS.³
• Hypogonadotropic hypogonadism is a condition marked by levels of gonadotropins (LH and FSH) that are too low to support normal ovarian function. This results in low production of estrogen and progesterone and anovulation. Hypogonadotropic hypogonadism may be related to genetic mutations, medical conditions, eating disorders, or drugs that affect hypothalamic or pituitary function.¹⁰
• Hyperprolactinemia (high blood levels of the hormone prolactin) causes inhibition of gonadotropin release and can lead to anovulation. Pregnancy, breastfeeding, hypothyroidism, and some pituitary tumors raise prolactin levels and thereby reduce fertility. In addition, stress, excessive exercise (ie, more than one hour of high-intensity exercise daily), and some medications are possible causes of hyperprolactinemia.^10,13
• Hypothyroidism can be a cause of infertility and pregnancy complications. Thyroid hormone is needed for normal ovarian function and ovulatory menstrual cycles to occur. In addition, high levels of thyroid stimulating hormone (TSH), a pituitary hormone that activates the thyroid gland, have been noted to be correlated with high levels of prolactin. Untreated hypothyroidism, even when subclinical (normal free thyroxine [fT4] levels with high TSH levels), is associated with poor pregnancy outcomes.^14,15
• Extreme stress and eating disorders can disrupt hypothalamic signaling, leading to ovarian dysfunction and anovulation.^3,10,16
• Idiopathic chronic anovulation (anovulation without a known cause) accounts for about 7–8% of cases of anovulatory infertility.¹⁶

Endometriosis

Endometriosis is the presence of endometrial tissue outside of the uterine cavity in any region of the pelvis or abdomen.¹⁶ Approximately 10–15% of reproductive-aged women have endometriosis and an estimated 40–50% of these women will experience infertility. In its early stages, endometriosis can limit fertility through inflammatory signaling, which impairs both ovarian and fallopian tube function and can reduce normal follicle formation, fertilization, and implantation; as the condition progresses, scarring and endometrial masses may form and block the movement of oocytes and sperm.³

Tubal Infertility

Any type of fallopian tube abnormality can contribute to female infertility.²⁰ Scarring and adhesions affecting one or both fallopian tubes can block movement of oocytes and sperm, preventing fertilization. Adhesions surrounding the tubes can also impair their ability to retrieve oocytes after ovulation.¹⁶ Acute and chronic inflammatory conditions can damage the integrity of the fallopian tubes and obstruct the normal movement of fluid, causing fluid buildup in the tubes, known as hydrosalpinges. Hydrosalpinges not only prevents natural fertilization, but also appears to inhibit implantation after in vitro fertilization by creating a hostile environment in the uterine cavity.³

The most common cause of tubal dysfunction is sexually transmitted infections. Other possible causes include endometriosis, abdominal or pelvic surgery, pelvic inflammatory disease, other abdominal or pelvic infections, and previous tubal pregnancy (a dangerous condition in which the fertilized oocyte is implanted into the wall of a fallopian tube).^16,21

Uterine and Cervical Issues

Problems affecting the uterine cavity can interfere with implantation, leading to infertility. They also increase the risk of poor pregnancy outcomes, such as miscarriage and pre-term birth. Examples include¹⁶:

• Endometrial uterine polyps
• Uterine fibroids (leiomyomata)
• Endometriosis
• Congenital uterine malformations
• Intrauterine scarring and adhesions (synechiae), also known as Asherman syndrome²²

Abnormalities of the cervix, whether congenital or acquired through surgery or dysplasia (a precancerous condition), as well as decreased cervical mucous, can disrupt sperm progression and prevent fertilization.¹⁶

Diminished Ovarian Reserve

The number and quality of oocytes and follicles present in the ovaries diminish throughout a woman’s life, resulting in declining fertility. In addition to aging, ovarian reserve may be decreased due to ovarian surgery, chemotherapy, radiation therapy, and certain genetic factors. Decreasing levels of anti-Müllerian hormone (AMH), which is released by small growing ovarian follicles, is a marker of diminishing ovarian reserve. An AMH level below 1.66 ng/mL suggests the ovarian reserve may be diminished.¹⁶

Many factors can increase a woman’s risk of infertility. Chronic health problems, genetic (inherited) traits, lifestyle choices, and age can all contribute to female infertility. Some specific factors include:

Age. Women’s fertility naturally declines with age, as both the quantity and quality of oocytes diminish. This is due partly to cumulative effects of oxidative stress, which can damage DNA and impair oocyte viability.^24,28 Age-related inhibition of cellular growth and function, a process known as senescence, is also believed to play a role.³² Women over 35 years old in particular have a higher risk of infertility, lower chance of benefiting from treatment, and greater likelihood of poor pregnancy outcomes.^26,33

Abnormal menstrual cycles. Menstrual cycles that are shorter than 21 days or longer than 35 days may indicate hormone imbalance and anovulation.¹⁶ In addition, heavy or painful menses, bleeding between periods, pelvic pain, and pain during intercourse may be signs of problems such as endometriosis or fibroids.^34,35

Obesity. Obesity, even in women without PCOS, contributes to female infertility by disrupting the HPO axis and decreasing oocyte quantity and quality. In addition, multiple studies report a link between obesity and diminished ovarian reserve.^36,37 It is thought to negatively impact reproductive function by increasing inflammation, insulin resistance, and oxidative stress.³⁶

Type 2 diabetes. Women with type 2 diabetes have been found to have higher risks of infertility and miscarriage, as well as lower chances of viable pregnancy and childbirth, compared with non-diabetic women, and not all these differences are explained by obesity or PCOS.³⁸

Underweight and low body fat percentage. Being underweight and having a low body fat percentage (<26%) limits the energy available to the body for normal functioning and can suppress hypothalamic GnRH release, resulting in loss of menstrual cycles and ovulation.^39,40 Extremely intense exercise, stress, and eating disorders are known to increase the risk of infertility due to this type of hypothalamic suppression.³⁹

Autoimmune disorders. Systemic autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjögren syndrome, and mixed connective tissue disease increase the risk of female infertility.⁴¹ In addition, celiac disease has been correlated with increased risk of infertility, and Hashimoto’s disease can cause hypothyroidism-related ovulation dysfunction.^15,42

Other chronic health problems. Chronic health problems can predispose women to infertility, and female infertility may be an indicator of underlying health issues.^16,43

Sexually transmitted infections and pelvic inflammatory disease. Pelvic inflammatory disease, an infection of the upper female reproductive tract, is frequently caused by sexually transmitted infections such as gonorrhea and chlamydia. In some cases, it can be caused by microorganisms residing in the vagina. These infections can result in long-term scarring of the fallopian tubes and inability to conceive, as well as ectopic (tubal) pregnancy. Adolescents and young adults, especially those with multiple sexual partners and those who do not routinely use condoms, have a higher risk of sexually transmitted infections and pelvic inflammatory disease, which increase their risk of future infertility.⁴⁴

Intrauterine procedures. Dilation and curettage (D&C) is a procedure in which the uterine cervix is dilated and the uterine lining is partially or completely removed. It can be performed diagnostically, such as in women with abnormal uterine bleeding, or to clear the uterine lining after a miscarriage or termination (abortion). Curettage is a potential cause of Asherman syndrome, a condition marked by endometrial or cervical scarring and adhesions that can contribute to recurrent miscarriages and infertility.⁴⁵

Bacterial vaginosis. A healthy vaginal microbiome is essential for reproductive health. Bacterial vaginosis, a dysbiotic condition in which relative amounts of Lactobacillus species and other beneficial bacteria are reduced, has been linked to increased risk of infertility, as well as pregnancy complications.⁴⁶

Excessive alcohol consumption. Drinking more than two alcoholic drinks per day has been associated with a 60% increase in infertility risk.⁴⁷ Even moderate alcohol use (3–6 drinks per week) during the luteal (post-ovulatory) phase of the menstrual cycle has been shown to reduce fertility, while heavy drinking (defined in the study as more than six drinks per week) around ovulation and throughout the luteal phase appeared to disrupt reproductive function.⁴⁸ Alcohol also appears to have a detrimental effect on assisted reproductive technique outcomes.⁴⁹

Smoking and substance abuse. Smoking has multiple negative impacts on female reproductive function and has been associated with decreased fertility. Marijuana use appears to increase ovulation dysfunction-related infertility. Preclinical research suggests cocaine, methamphetamine, and heroin can each impair fertility by disrupting reproductive ovarian function, hormone balance, and menstrual cycles.

Medications. A number of medications can raise prolactin levels and negatively affect ovarian function and fertility by this or other mechanisms.^50,51 Many commonly used medications can adversely impact female fertility by affecting the HPO axis or through direct actions on the ovaries or uterus. The following are some important examples of drugs that can impact fertility, but women planning to conceive should discuss any medication use with their doctor.

L-carnitine and Acetyl-L-carnitine

L-carnitine is an amino acid that plays a critical role in cellular and mitochondrial metabolism. It also occurs in the form acetyl-L-carnitine. L-carnitine and its derivatives may improve female reproductive health through effects such as protecting DNA from oxidative damage, reducing inflammatory cytokine levels, supporting healthy lipid and glucose metabolism, improving cellular energy production, and stabilizing cell membranes.^77-79

In a controlled trial in 170 women with PCOS-related infertility undergoing ovulation induction who failed to show a follicular response to clomiphene after three cycles, 3 grams of L-carnitine or placebo daily, in addition to 250 mg clomiphene on days 3–7 of the menstrual cycle, was found to improve ovulation rate (64.4% vs. 17.4%, respectively) and pregnancy rate (51.5% vs. 5.8%, respectively).⁵ Acetyl-L-carnitine, at a dose of 1,500 mg twice daily, was found to add to the benefits of anti-diabetes medications in women with PCOS in a randomized controlled trial that included 147 participants. Those who received acetyl-L-carnitine in addition to metformin plus pioglitazone (Actos) had greater improvement in menstrual regularity as well as reductions in insulin and LH levels, waist circumference, and psychological stress scores.⁸⁰ Another placebo-controlled trial in 274 PCOS patients being treated with metformin found the addition of L-carnitine to treatment improved menstrual regularity, responsiveness to ovulation induction, and pregnancy rate.⁸¹ These positive effects may be due in part to L-carnitine’s ability to improve metabolic disturbances.^82-84

L-carnitine and acetyl-L-carnitine have been proposed to improve function of the HPO axis.⁷⁸ An uncontrolled trial in 27 patients with stress-induced pituitary suppression and amenorrhea (lack of menstrual periods) found 12 weeks of treatment with 500 mg L-carnitine plus 250 mg acetyl-L-carnitine daily decreased levels of markers of stress (cortisol and amylase) and increased LH levels in those with low baseline LH levels.⁸⁵ Similar uncontrolled trials in women with stress-induced amenorrhea found 1,000–2,000 mg acetyl-L-carnitine daily for 16–24 weeks raised LH levels in women whose LH levels were suppressed.^86,87 A combined supplement regime that included 500 mg L-carnitine, 250 mg acetyl-L-carnitine, 500 mg L-arginine, 50 mg NAC, and vitamins C and E, taken daily for 12 weeks, was also reported to improve hypothalamic LH release and reduce levels of stress markers (cortisol and amylase) in a trial in 29 women with stress-related amenorrhea.⁸⁸

L- carnitine and its derivatives have also been shown to improve oocyte quality in animal studies and have the potential to be beneficial in women undergoing assisted reproductive therapies.⁷⁹ In an uncontrolled trial, 214 women who had experienced an unsuccessful in vitro fertilization attempt were treated with 1,000 mg L-carnitine daily for an average of 82 days. Oocyte quality was improved, and 21 women (10%) delivered healthy newborns conceived through in vitro fertilization following L-carnitine treatment.⁸⁹

Vitamin E

Vitamin E, a family of compounds that includes tocopherols and tocotrienols, is an essential fat-soluble antioxidant nutrient. Higher levels of vitamin E in the follicular fluid of women undergoing assisted reproductive techniques were associated with better outcomes in one study.⁹⁰

A randomized placebo-controlled trial in 105 women with PCOS-related infertility undergoing in vitro fertilization with intracytoplasmic sperm injection found 400 mg vitamin E per day, along with 50,000 IU (1,250 mcg) vitamin D every second week, for eight weeks increased pregnancy rates compared with placebo.⁹¹

Vitamin E may exert its beneficial effects in part by promoting endometrial health. A controlled trial in 103 women with unexplained infertility undergoing ovulation induction via assisted reproductive methods found 400 IU (268 mg) of vitamin E per day, beginning between three and five days into a menstrual cycle until the day of ovarian stimulation, resulted in increased endometrial thickness.⁶ A retrospective cohort trial in 321 women with PCOS and infertility undergoing ovulation induction found the addition of vitamin E, at 100 mg per day for either one luteal phase or one full menstrual cycle, to the ovulation induction protocol reduced the amount of medication needed and increased endometrial thickness, although it did not alter likelihood of pregnancy.⁹² In an observational study, 200 mg vitamin E three times daily for a full menstrual cycle increased endometrial thickness in 13 of 25 women with a thin endometrium, a condition that may be caused by low uterine blood flow and can contribute to infertility.⁹³ Another report described 19 cases of endometrial thinning that were unresponsive to hormone therapies. After supplementing with 1,000 IU (670 mg) vitamin E per day for an average of 8.1 months, endometrial thickness improved in 14 cases (approx. 74%) and pregnancy occurred in eight (42%).⁹⁴

Inositol

Inositol is a family of isomers (compounds with the same composition but structured differently) found in cells of plants and animals. Myo-inositol is the most abundant inositol isomer occurring in nature and the body, followed by D-chiro-inositol as the second most abundant.⁹⁵ Myo-inositol and D-chiro-inositol are present in high concentrations in the ovaries and, although their functions are different, are important for ovarian hormone production as well as oocyte maturation, fertilization, implantation, and embryo development. They also play a role in insulin signaling.⁹⁶

Inositol has been found in numerous clinical trials to have beneficial effects on hormonal, metabolic, and reproductive health in women with PCOS. Supplementing with myo-inositol, or a combination of myo-inositol plus D-chiro-inositol at a ratio of 40:1, has been found in multiple clinical trials to improve menstrual cycles and ovulation rates in women with PCOS.^96,97 Despite concerns that higher doses of D-chiro-inositol may have undesirable effects on hormone balance, one randomized controlled trial that included 60 women with PCOS undergoing intracytoplasmic sperm injection found a less than 4:1 ratio of myo-inositol to D-chiro-inositol (550 mg myo-inositol plus 150 mg D-chiro-inositol ) twice daily for 12 weeks prior to oocyte retrieval led to higher pregnancy and live birth rates than a 40:1 ratio (550 mg myo-inositol plus 13.8 mg D-chiro-inositol) twice daily. In addition, women given the higher dose of D-chiro-inositol were less likely to experience ovarian hyperstimulation, a dangerous side effect of ovulation-inducing medications.⁹⁸

A growing body of research suggests myo-inositol may be beneficial in women with infertility undergoing assisted reproductive therapies, particularly those with PCOS.⁹⁹ A meta-analysis of seven randomized controlled trials that included a total of 935 participants found myo-inositol supplementation increased pregnancy rate and decreased miscarriage rate in women with PCOS undergoing in vitro fertilization.¹⁰⁰ In one randomized controlled trial, 60 women with PCOS-related infertility received a combination of 500 mg metformin plus 600 mg myo-inositol three times daily for three months prior to ovulation induction for intrauterine insemination, and 60 similar women received 500 mg metformin three times daily alone; those given myo-inositol had a live birth rate of 55% versus 26.67% in those not given myo-inositol.¹⁰¹

Myo-inositol therapy does not appear to be as beneficial in women without PCOS. A controlled trial in 112 women with infertility preparing for intracytoplasmic sperm injection found 4,000 mg myo-inositol plus 400 mcg folic acid (680 mcg DFE) daily for one month prior to ovulation induction led to improved fertilization rate and embryo quality, but did not significantly impact implantation or pregnancy rate compared with folic acid alone.¹⁰² In a randomized controlled trial in 23 women with infertility and obesity preparing for in vitro fertilization, those given 2,000 mg myo-inositol plus 800 mg alpha-lipoic acid and 400 mcg folic acid (680 mcg DFE) daily for two months before stimulated ovulation induction had a higher pregnancy rate than those given folic acid alone, with their pregnancy rate being similar to that of normal-weight women with infertility.¹⁰³

Melatonin

Melatonin, a hormone produced mainly by the pineal gland in the brain, is needed to regulate the body’s circadian rhythms. It can also be produced by the ovaries and is found in high concentrations inside oocytes prior to ovulation where it acts as a free radical scavenger and is needed for oocyte growth and maturation, fertilization, and embryo development.^104,105 Some evidence suggests supplemental melatonin may reduce loss of ovarian reserve in women undergoing chemotherapy.¹⁰⁶

Fertility is strongly influenced by circadian rhythms, which are synchronized with changing levels of melatonin and cortisol. Disruption of circadian regulation due to stress or poor sleep has been implicated as a factor in infertility, increasing the risks of anovulation, loss of menstrual cycles, failed embryo implantation, and miscarriage.^107,108 Supplementing with melatonin may help restore circadian cycles and has been found to reduce oxidative stress within ovarian follicles, preserve ovarian reserve, and increase oocyte quality, which may lead to improved in vitro fertilization outcomes.^105,109,110 A meta-analysis of data from 10 randomized controlled trials with a total of 1,203 participants undergoing assisted reproductive techniques found treatment with melatonin, most commonly used at a dose of 3 mg per day, increased the number and quality of oocytes retrieved, number of good-quality embryos, and chance of pregnancy, but had no impact on miscarriage rate or the odds of live birth.⁷ Another meta-analysis of findings from seven randomized controlled trials found melatonin improved oocyte quality in women undergoing in vitro fertilization. Melatonin use was also found to increase the likelihood of pregnancy, but this effect was not statistically significant.¹¹¹

Disturbances in melatonin production and circadian rhythms also may contribute to infertility in women with PCOS.^112,113 A report from a pilot study that included data from 40 women with PCOS suggests melatonin supplementation may improve ovarian function, resulting in lower androgen levels and improved menstrual regularity.¹¹⁴ In a randomized controlled trial in 526 women with infertility related to PCOS, the addition of 3 mg melatonin per day to treatment with myo-inositol and folic acid led to improvement in quality of eggs before and after in vitro fertilization.¹¹⁵

Coenzyme Q10

Coenzyme Q10 (CoQ10) is a lipid-soluble compound involved in mitochondrial energy production. CoQ10 also quenches free radicals and lowers oxidative stress.⁸ Preclinical research indicates CoQ10 supplementation may reduce age-related and oxidative stress-induced loss of ovarian reserve.^116,117 One meta-analysis included findings from five randomized controlled trials with a combined total of 449 women being treated for infertility due to poor ovarian response or PCOS. Dosages of 600–1,200 mg CoQ10 per day for 8–12 weeks were used in trials in women with poor ovarian response, while a dose of 60 mg CoQ10 three times daily from the first day of a menstrual cycle until oocyte retrieval was used in trials in women with PCOS. The analysis found assisted reproductive procedures resulted in a higher pregnancy rate in those given CoQ10 (28.8%) than placebo or no treatment (14.1%).⁸

Probiotics

Lactobacillus species are common in both the lower and upper female reproductive tract and play an important role in protecting against bacterial vaginosis and urogenital infections that frequently contribute to infertility.^74,118,119 The reproductive microbiome has been found to be altered in many women with infertility, with different patterns of disturbance seen in those with infertility due to an unknown versus known cause.¹²⁰ Treatment with various probiotic supplements have been shown to promote positive changes in the vaginal microbiome and may potentially improve fertility.¹²¹

One probiotic strain that has been clinically shown to be effective for improving the vaginal microbiome by increasing lactobacillus levels is Lactobacillus plantarum P17630, also known as ROSELLA.^122,123 When taken orally at a daily dose of 5 billion colony forming units (CFUs) for three cycles of 15 days followed by a 15-day washout (a study duration of 90 days), the probiotic was shown to improve vaginal Lactobacillus scores as well as vaginal tissue redness and swelling in women with recurrent vulvovaginal candidiasis.¹²³ Probiotics also have the potential to improve microbiome composition in women with infertility. In a preliminary study, women with infertility treated with a probiotic containing four Lactobacillus strains (L. crispatus LBV88, L. rhamnosus LBV96, L. gasseri LBV150N, and L. jensenii LBV116) experienced positive changes in their vaginal microbiome.¹²⁴ Findings from another preliminary study suggest a treatment regimen of antibiotics followed by a vaginal probiotic (as an inoculated tampon or suppository) containing two to three Lactobacillus strains (L. rhamnosus LN113, L. gasseri LN40, L. fermentum LN99) and oral lactoferrin at 300 mg daily may induce healthy Lactobacillus dominance in the endometrial microbiomes (as assessed by endometrial fluid sampling) of women with infertility and abnormal endometrial microbiomes.¹²⁵

One clinical trial included 44 women, 21 of whom had experienced three or more miscarriages and 23 of whom had unexplained infertility and had not conceived after at least two cycles of in vitro fertilization. The participants received a daily probiotic supplement providing 1 billion CFUs of freeze-dried L. salivarius CECT5713 for six months or until the 15th week of pregnancy. At the end of six months, 29 pregnancies occurred out of 44 participants (66%), including 25 that resulted in successful pregnancies with full-term deliveries. Interestingly, women who had successful pregnancies had more improvement in vaginal health parameters after using the probiotic than women who did not become pregnant.¹²⁶ A meta-analysis of nine randomized controlled trials in 587 women found probiotic and synbiotic (probiotic plus prebiotic) supplements improved hormonal, endocrine, and inflammatory disturbances in women with PCOS, a condition closely associated with infertility.¹²⁷

Vitex

Vitex (Vitex agnus-castus, also known as chaste tree or chaste berry) has been used historically as an herbal medicine for improving menstrual regularity and treating disorders related to hormonal imbalance.¹²⁸ Two clinical trials have examined the effect of a combination supplement containing vitex, along with L-arginine, green tea, folate, and other vitamins and minerals, on women’s fertility. In one placebo-controlled trial that included 30 women who had tried unsuccessfully to conceive for 6–36 months, taking the vitex-containing supplement for three months resulted in basal body temperature patterns suggestive of longer luteal phases; after five months, 33% of those in the supplement group and none in the placebo group had conceived.¹²⁹ The same research group conducted a similar placebo-controlled trial with 93 participants. Not only did the vitex combination supplement increase the number of days with an elevated basal body temperature, but it also raised progesterone levels in those with low baseline progesterone levels. After three months, 26% of supplemented women and 10% of women given placebo were pregnant; after six months, three additional women in the treatment group conceived.¹³⁰ An uncontrolled clinical trial investigated the effect of a combination of vitex plus maca (Lepidium meyenii) extracts and folate in 189 women with menstrual disorders trying to conceive. After six months of treatment, the percentage of women experiencing ovulatory cycles increased from 10% to 42.9%, and 37% of women had achieved pregnancy.¹³¹

L-arginine

L-arginine is an amino acid that acts as a precursor to nitric acid in the body. In addition to helping regulate blood vessel tone and function, L-arginine plays a role in adrenal and pituitary hormone activity.¹³² Some research suggests supplementing with L-arginine, in combination with other nutrients, may improve female sexual function.¹³³ One controlled trial included 34 women with infertility attempting assisted reproductive techniques who had not responded to prior ovulation induction therapies. Those given 16 grams of L-arginine daily along with an ovulation induction protocol were more likely to have successful oocyte retrieval, had a greater number of oocytes collected, and had a higher chance of pregnancy than those who did not take arginine.¹³⁴ In another controlled trial in 120 women preparing for in vitro fertilization, L-arginine, taken at doses of 1,000 or 2,000 mg per day for three months, improved pregnancy rates.¹³⁵ Evidence from an uncontrolled trial suggests L-arginine, at 1,500 mg four times daily from the beginning of a menstrual cycle until ovulation induction, can increase endometrial thickness in women with a thin endometrium, a condition associated with low pregnancy rates that may be due to poor uterine blood flow.⁹³

N-acetylcysteine

N-acetylcysteine (NAC), a form of the sulfur-containing amino acid cysteine, is a nutrient needed to produce glutathione, one of the body's most important antioxidants and detoxifiers. While cysteine is found in high-protein foods, NAC is not.¹³⁶

Some clinical trials have found NAC, at doses of 1,200–1,800 mg per day, can improve fertility parameters such as menstrual cycle regularity and oocyte quality in women with PCOS being treated with the ovulation inducing medications clomiphene citrate (Serophene) and letrozole (Femara).^137-140

Vitamin C

Vitamin C is needed to regulate oxidative stress, synthesize hormones, and produce collagen.¹⁴¹ Lower vitamin C levels have been noted in follicular fluid from women with, compared to those without, infertility.¹⁴² In one study that included data from 437 women with unexplained infertility, taking vitamin C supplements was associated with shorter time to pregnancy in those women who were not overweight and who were under 35 years old.¹⁴³ In a controlled trial in 150 women with luteal phase deficiency marked by low peak progesterone levels, those who received 750 mg vitamin C per day for three menstrual cycles were more likely to have increased progesterone levels. In addition, pregnancy occurred in 25% of vitamin C-treated participants versus 11% of controls.¹⁴¹ Vitamin C, at 1,000 mg per day, along with vitamin E, at 800 IU per day, reduced oxidative stress and pain symptoms after eight weeks in a placebo-controlled trial in 60 women with endometriosis.¹⁴⁴ In contrast, in a controlled trial in 245 patients with endometriosis undergoing in vitro fertilization, 1,000 mg vitamin C daily did not lower oxidative stress marker levels or affect any treatment outcomes after two months.¹⁴⁵

Selenium

Selenium is a trace mineral nutrient needed for proper function of the glutathione system, which regulates reduction-oxidation balance in the body. Selenium is also needed for normal thyroid hormone production and may have a role in supporting heavy metal detoxification.^146,147 Selenium deficiency impairs placental function and fetal development, and is associated with increased risk of miscarriage and preterm birth.¹⁴⁷

Low selenium status has been associated with unexplained female infertility.¹⁴⁶ In one study, women being treated for infertility were found to have lower selenium and higher mercury levels than a group of women not seeking fertility treatment.¹⁴⁸ Another observational study that included data from 1,060 pregnant women found lower selenium levels were correlated with a longer time to pregnancy and a 46% higher risk of having been unable to conceive for more than one year.¹⁴⁹

In a placebo-controlled trial in 70 women with unexplained early menopause, those who received 200 mcg selenium plus 400 IU vitamin E daily for 90 days had signs of improved ovarian function, including increased AMH levels, antral follicle counts, and ovarian volume, compared with placebo.¹⁵⁰

Vitamin D

Vitamin D deficiency and insufficiency are common—especially during winter months and in people with darkly pigmented skin—and may be a factor in female infertility. One study that examined the vitamin D status of 500 women pursuing assisted reproductive techniques found only 16% of women had sufficient vitamin D levels.¹⁵¹

Findings from several observational studies suggest healthy vitamin D status may be correlated with better female reproductive function and fertility outcomes.^152-155 However, a meta-analysis of observational data from 36 studies that included 7,882 participants found no overall association between vitamin D levels and indicators of ovarian reserve.¹⁵⁶ It has also been reported that certain genetic patterns related to vitamin D receptor expression were correlated with risk of infertility, suggesting vitamin D receptors may play a role in modulating female reproductive function.¹⁵⁷

An open trial in 30 women with low vitamin D levels and infertility found 1,250 mcg (50,000 IU) vitamin D weekly for three months increased levels of AMH, an indicator of ovarian reserve.¹⁵⁸ Nevertheless, clinical trials have not yet been able to demonstrate a clear benefit from vitamin D supplementation on likelihood of pregnancy and live birth. In one placebo-controlled trial in 630 women with infertility, a single dose of 15,000 mcg (600,000 IU) vitamin D 2–12 weeks prior to undergoing in vitro fertilization had no impact on outcomes.¹⁵⁹ In another placebo-controlled trial in 95 women with vitamin D deficiency undergoing in vitro fertilization, those given 0.5 mcg calcitriol (the active form of vitamin D3) daily for four weeks had a higher implantation rate but were no more likely than the placebo group to sustain pregnancy.¹⁶⁰

Resveratrol

Resveratrol is a free radical-scavenging flavonoid found in grape skin, red wine, cocoa, and peanuts. Preclinical research suggests resveratrol can reduce oxidative stress, prevent oxidative damage, and enhance mitochondrial activity in ovarian cells that support oocyte growth and development.^161,162 Furthermore, resveratrol appears to have anti-aging effects, such as promoting telomere repair and inhibiting AGE formation.²³ Research in animals showed resveratrol may protect ovaries from chemotherapy-induced damage.¹⁶³

Resveratrol may be beneficial in women with endometriosis: in a placebo-controlled trial in 34 women with endometriosis and infertility, 400 mg resveratrol daily for 12–14 weeks in addition to routine treatment was found to improve endometrial health.¹⁶⁴ In a randomized controlled trial in 101 women undergoing intracytoplasmic sperm injection cycles, the number and quality of oocytes retrieved were higher in those treated for three months with a resveratrol-based multi-nutrient supplement (including 150 mg resveratrol, 400 mcg folic acid [680 mcg DFE], 25 mcg vitamin D, 2.5 mcg vitamin B12, and 1.4 mg vitamin B6). Resveratrol-treated women also had higher fertilization rates and numbers of viable embryos, but there were no significant differences in pregnancy, miscarriage, or live birth rates.¹⁶⁵ A placebo-controlled trial in 62 women with PCOS and infertility undergoing intracytoplasmic sperm injection found resveratrol, at 800 mg daily for 40 days, increased the number of high-quality oocytes retrieved after ovulation induction but did not significantly influence pregnancy rate or outcomes.¹⁶⁶

Folate

Folate, one of the B-complex vitamins, is needed for critical methylation reactions. Folic acid is a stable and well-absorbed form of folate commonly used in supplements. Folate deficiency during pregnancy has long been recognized as a cause of birth defects known as neural tube defects, and various guidelines recommend reproductive-aged women supplement with 400–800 mcg folic acid (680–1,360 mcg DFE) daily to reduce the risk of neural tube defects. A growing body of evidence further suggests folic acid supplementation may increase the likelihood of conception and healthy birth. Observational evidence indicates women who regularly take multivitamins with folic acid may have a shorter time to pregnancy and lower risk of infertility related to ovulation dysfunction, and supplementing with doses higher than those needed to prevent neural tube defects has been correlated with reduced risk of miscarriage.^167,168

Folate, along with vitamins B12 (cobalamin) and B6 (pyridoxine), is needed for the metabolism of the amino acid compound homocysteine. High homocysteine levels are associated with a wide array of health problems, can trigger inflammation and oxidative stress in blood vessels, and have been correlated in some studies with increased risks of anovulation and recurrent miscarriages.¹⁶⁹ One study in 269 women seeking in vitro fertilization reported 31% had high homocysteine levels (>15 µmol/L), 56% had low B12 status, and 88% had intracellular folate levels lower than those believed to be optimal for preventing neural tube defects.¹⁷⁰ In an observational study in 100 women undergoing assisted reproductive treatment, those with higher blood levels of folate and B12 had higher pregnancy and live birth rates than those with lower levels.¹⁷¹

Certain mutations of the methylenetetrahydrofolate reductase (MTHFR) gene are known to cause abnormal homocysteine metabolism, resulting in high homocysteine levels, and some studies have found these mutations may be more common in women with infertility. Supplementing with 5-methyltetrahydrofolate (5-MTHF), an activated form of folate, and in some cases vitamin B12 may help women with these mutations, also known as single nucleotide polymorphisms or SNPs (pronounced “snips”), maintain lower homocysteine levels.¹⁷² In one study that included 92 women and 46 men undergoing assisted reproductive treatment and 161 controls, MTHFR mutations were correlated with poor in vitro fertilization outcomes and embryonic chromosomal abnormalities.¹⁷³ However, it is important to note at least two studies have found no relationship between folate intake, blood folate levels, MTHFR mutations, and assisted reproductive outcomes.^174,175

High homocysteine levels are also more common in women with than without PCOS. An open trial that included 32 women with PCOS found a multi-nutrient supplement providing 400 mcg (680 mcg DFE) 5-MTHF daily for three months decreased homocysteine levels compared with no treatment. In addition, in a subgroup of women with normal baseline homocysteine levels who received the supplement, AMH levels increased, suggesting improved ovarian function.¹⁷⁶ The possible impact of folate or folic acid supplementation in women with PCOS still requires further study.

Omega-3 Fatty Acids

Omega-3 fatty acids from fish oil may improve fertility through their important role in steroid hormone production and anti-inflammatory effects.¹⁶⁹ Some evidence suggests omega-3 fatty acids may lower the risk of anovulation, increase ovarian reserve, and improve oocyte quality and embryo development.^169,177,178 In a preliminary trial in 17 healthy reproductive-aged women, taking 4,000 mg of an omega-3 fatty acid supplement (providing 1,860 mg eicosapentaenoic acid [EPA] and 1,500 mg docosahexaenoic acid [DHA]) daily for one month led to reductions in levels of FSH, a hormonal marker of diminished ovarian reserve and early menopause, in normal weight, but not obese, participants.¹⁷⁹

Higher frequency of sexual intercourse and shorter time to pregnancy have been noted among couples in which either the male or female, and especially both partners, regularly consume seafood.¹⁸⁰ In an observational study that included 1,290 North American women, higher intake of omega-3 fatty acids from fish was correlated with shorter time to pregnancy, while higher intake of trans fatty acids was linked to lower pregnancy rates¹⁸¹; however, another study that included data from 5,126 North American women did not find a relationship between omega-3 fatty acid intake and pregnancy rates, although higher intake of fried shellfish (a source of trans fatty acids) was associated with lower likelihood of pregnancy.¹⁸² Studies that examined blood levels of fatty acids have noted omega-6 and omega-3 fatty acid levels and omega-6:omega-3 ratios were unrelated to pregnancy or miscarriage rates.^183,184

Observational studies examining the relationship between omega-3 fatty acids and assisted reproductive therapy outcomes have resulted in conflicting and inconclusive findings.^185,186 On the other hand, trans fatty acid intake has consistently been associated with poorer assisted reproductive outcomes.¹⁸⁷

Dehydroepiandrosterone (DHEA)

Dehydroepiandrosterone (DHEA) is a hormone produced mainly in the adrenal cortex, with smaller amounts produced in the testes, ovaries, and brain. Most DHEA is sulfated before being released into the bloodstream and circulates as DHEA-sulfate (DHEA-S).²⁵² DHEA and DHEA-S have androgenic (male hormone) properties and are also used to synthesize estrogens (estradiol and estrone) and other androgens (androstenedione, testosterone, dihydrotestosterone) in the adrenal glands and other tissues.²⁵³ Although the role of DHEA in female reproductive function is still not fully understood,²⁵² it appears to support fertility by increasing the growth, persistence, and mitochondrial function of ovarian follicles.²⁵⁴ Some evidence further suggests DHEA may increase AMH levels and improve oocyte and embryo quality, potentially increasing the odds of successful pregnancy.²⁵⁵

In an observational study, 277 women with infertility due to low ovarian reserve were treated with 75 mg DHEA daily and were followed for two years. After six months of treatment, 13.2% of the women experienced spontaneous pregnancy. The pregnancy rate increased to 21.3% after one year and 38.8% after two years.²⁵⁶

DHEA has been found in multiple clinical trials and meta-analyses to increase the success of assisted reproductive therapies. A meta-analysis of 18 clinical trials involving 1,883 women with poor ovarian response undergoing IVF or intracytoplasmic sperm injection found supplementing with 75 mg DHEA daily for two to four months reduced the risk of miscarriage by 50%, increased the pregnancy rate by 53%, and increased successful births by 87%.²⁵⁷ Another meta-analysis of five clinical studies with a total of 910 infertile women with low ovarian reserve undergoing IVF also found 25 mg DHEA three times daily increased the likelihood of pregnancy and decreased the risk of miscarriage.²⁵⁸ In a meta-analysis of randomized controlled trials investigating various interventions in women with poor ovarian response undergoing IVF, the pooled findings from two trials using DHEA therapy, at 25 mg three times daily, showed it increased the odds of pregnancy nearly 2.5-fold.²⁵⁹

Importantly, DHEA may be contraindicated in women with PCOS, who generally have elevated levels of androgens, including DHEA-S.²⁶⁰ Studies in animal models of PCOS suggest DHEA treatment may contribute to poor ovarian health and function in the context of this condition.²⁶¹ Women with infertility and PCOS should therefore have their DHEA-S level checked before considering DHEA therapy.

For more information about DHEA, please see Life Extension’s DHEA Restoration Therapy protocol.

While some causes of female infertility are not preventable, mitigating the risks of other common contributors to infertility through lifestyle and dietary measures may improve the chance of conceiving.

Lifestyle

One of the most important ways to support fertility naturally is to avoid behaviors that can cause reproductive harm. This includes:

• Not smoking. As described in the “Risk Factors” section, smoking impairs fertility and leads to worse outcomes with assisted reproductive techniques.
• Limiting alcohol use. As even moderate drinking may impair fertility,⁴⁸ women (and men) with fertility concerns should limit their alcohol use to amounts well within the moderate drinking levels defined by the 2020-2025 Dietary Guidelines for Americans. These levels are ≤ 1 drink daily for women and ≤ 2 drinks daily for men.
• Avoiding heavy caffeine use. High caffeine intake (more than 500 mg or about five cups of coffee per day) reduces the chance of pregnancy by an estimated 45%.⁴⁷
• Getting tested and treated for sexually transmitted infections. Sexually active women can protect reproductive health by using condoms when not trying to conceive and through regular visits with a healthcare professional who can assist with prevention, provide screening, and initiate prompt treatment of sexually transmitted infections.¹⁸⁸
• Maintaining a healthy body weight. Healthy weight maintenance is important for reproductive health and fertility. Being either overweight or underweight has significant negative effects on the ability to conceive.^36,189,190 In overweight or obese women with polycystic ovary syndrome, weight loss of 5% or more restored regular ovulatory menstrual cycling within six months in the majority of women.^3,191
• Maintaining healthy sleep habits. A growing body of research connects poor sleep with impaired reproductive function and infertility in women. Menstrual irregularity, PCOS, premature ovarian insufficiency, difficulty conceiving and infertility, and pregnancy loss have been linked to sleep disturbances and disorders. Getting quality sleep that is adequate in duration, synchronous with circadian rhythms, and not interrupted or fragmented may help support conception and pregnancy.¹⁹²

Sleep apnea, a condition in which breathing stops and restarts intermittently throughout sleep, has been associated with infertility in both men and women.^246-248 In women, obstructive sleep apnea is associated with poor pregnancy outcomes, including gestational diabetes, preeclampsia, and fetal growth restriction.²⁴⁹ Some data also suggest sleep apnea is linked to higher rates of miscarriage.²⁵⁰ Additionally, sleep apnea is closely correlated with obesity and is more common in women with PCOS, both of which are associated with increased risk of female infertility.²⁵¹

In addition to reducing harmful exposures, women’s fertility may be supported through positive measures such as getting regular exercise and stress reduction.^13,193 Unfortunately, a diagnosis of infertility along with interventions to achieve pregnancy are frequently a source of stress and can deteriorate quality of life.¹⁹³

Timing of Intercourse

For a couple trying to conceive, the timing of sexual intercourse is critical. Taking into account the three- to five-day lifespan of sperm and the 12–24 hours of receptiveness of an oocyte released at ovulation, the chance that intercourse will lead to conception is greatest from five days before until one day after ovulation. This is sometimes referred to as the fertile window.¹⁹⁴ Thus, couples hoping for pregnancy may benefit from tracking menstrual cycles and predicting ovulation, although results from studies have been mixed.¹⁹⁵

While tracking menstrual cycles to predict ovulation may potentially improve the likelihood of conception, it can also be stressful, triggering or aggravating sexual dysfunction and relationship difficulties.^196,197 It is important to note that couples who have used timed intercourse unsuccessfully for five consecutive cycles are unlikely to become pregnant without other interventions.¹⁹⁴

Diet

Diet has a substantial impact on fertility. Observational data suggest higher fruit intake and lower intake of fast food and sugar-sweetened beverages are linked to shorter time to pregnancy (a marker of fertility).¹⁹⁸ In one study that included 113 women with infertility, adequate maternal vegetable intake was associated with increased likelihood of embryo implantation after in vitro fertilization with intracytoplasmic sperm injection.¹⁹⁹

Maternal seafood consumption has also been correlated with higher fertility, with eight or more servings per menstrual cycle corresponding with a 60% shorter time to pregnancy than women who consumed ≤1 serving.¹⁸⁰ Fish consumption has also been linked to increased live birth rate after assisted reproductive procedures.²⁰⁰ Of note, however, is that certain fish species may contain higher levels of harmful compounds like mercury and should be avoided, especially by women who are pregnant or seeking to become pregnant. These include king mackerel, marlin, orange roughy, shark, swordfish, tilefish from the Gulf of Mexico, and bigeye tuna.²⁰¹

Higher intake of soy foods has also been correlated with improved assisted reproductive technology outcomes.^202,203 In a study that included 239 women undergoing in vitro fertilization, increasing urinary levels of BPA correlated with diminished live birth rates in women who did not consume soy. However, the correlation between urinary BPA levels and lower birth rates was not apparent among women who regularly consumed soy foods. These findings suggest soy may mitigate the negative effect of BPA on fertility.²⁰³

Dietary patterns that emphasize fruits, vegetables, whole grains, fish, poultry, and healthy fats have been generally associated with better fertility.³¹ A study that looked at dietary patterns in 357 women undergoing assisted reproductive interventions found adherence to a pro-fertility diet, characterized by high intake of low-pesticide fruits and vegetables, seafood, soy foods, dairy, and whole grains; low intake of high-pesticide fruits and vegetables; and supplemental folic acid, vitamin B12, and vitamin D, was more closely related to live birth rate than other dietary patterns. In the study, foods and beverages with low pesticide residue included¹⁶⁷:

Investigations into infertility causes are typically undertaken after one year of unsuccessful attempts to become pregnant, or after six months in women over age 35.³ However, if a couple has concerns about their fertility, a screening history and physical exam can be undertaken at any time. A thorough history can help ascertain whether a woman is likely to be ovulating regularly and identify possible contributors to reduced fertility such as genetics, stress, sexually transmitted infections, vaginal dysbiosis, endometriosis, smoking, high alcohol or caffeine intake, and other lifestyle factors. Counseling around proper timing of intercourse may be useful. A physical exam can help with preliminary screening for pelvic abnormalities or infections, androgen excess, obesity, thyroid disease, and other overt medical issues.^3,33

Tests for Male Infertility

Once infertility has been diagnosed based on time trying to conceive, a more thorough investigation is appropriate. Since roughly half of infertility is due at least in part to male factors, a semen analysis is recommended early in the evaluation process.^2,3,12 In addition, a postcoital test, in which a cervical mucus sample is collected 4–8 hours after intercourse, may be recommended to assess sperm survival.²⁰⁴

Imaging Tests

Transvaginal ultrasound is used to screen for problems with the uterus, fallopian tubes, or ovaries. It can also be used to count antral follicles, also known as resting follicles, in the ovaries.^3,33 Antral follicles are those that have reached a stage at which they can be stimulated to release an oocyte in a future ovulatory cycle, and the antral follicle count is an accurate indicator of ovarian reserve and predictor of responsiveness to ovulation induction methods. In some cases, daily ultrasound may be used to track ovulation.³

More advanced imaging of the uterus (saline infusion sonogram or hysteroscopy) and fallopian tubes (hysterosalpingogram or laparoscopy) may be recommended to rule out uterine problems, endometriosis, adhesions, or other blockages, especially in women with normal antral follicle counts and AMH levels.^3,33

Lab Tests

Certain lab tests are often helpful in the diagnostic process, including³:

• Anti-Müllerian hormone (AMH). AMH is produced by growing follicles and is used as a measure of ovarian function. Very low levels may predict decreased responsiveness to ovulation induction medications.
• Progesterone. A low progesterone level approximately one week before the onset of menses suggests anovulation.
• Follicle stimulating hormone (FSH). A high FSH level on day three of the menstrual cycle may indicate low ovarian reserve, with less follicular hormone production leading to a lack of suppression of FSH release by the pituitary gland.
• Estradiol. High levels of estradiol, the predominant type of estrogen produced by the ovaries, early in the menstrual cycle can be an indicator of HPO axis dysfunction.
• Testosterone. A high testosterone level may be due to PCOS and can impair ovarian function and fertility.
• Prolactin. High prolactin levels inhibit gonadotropin release and can cause anovulation.
• Thyroid stimulating hormone (TSH). Abnormal TSH levels suggest a thyroid disorder may be an underlying factor.
• Urinary luteinizing hormone (LH). This test can be performed using an over-the-counter at-home testing kit and is used to confirm a mid-cycle surge in LH release, which suggests the occurrence of ovulatory cycles. Some women use urinary LH to time intercourse.

Female infertility treatment is based on the cause. Some causes of infertility, such as certain genetic conditions, severe uterine disease, and substantial loss of ovarian reserve, are unfortunately not treatable.

Ovulation Induction

Women with infertility who have few or no ovulatory cycles may benefit from the use of medications that induce ovulation. Ovulation-inducing drugs can be used prior to timed intercourse, but are more likely to be effective when combined with intrauterine insemination.^3,16,205 The combination of intrauterine insemination with ovulation-inducing drugs also may be used in the setting of male infertility due to low sperm counts. It is important to note ovulation-inducing drugs are associated with an increased likelihood of pregnancy with twins, triplets, and higher-order births due to the release of more than one oocyte. These pregnancies are associated with higher risk of complications and poorer outcomes.^206,207 Medical ovulation induction, especially using gonadotropin hormone therapy, can also cause ovarian hyperstimulation syndrome, in which multiple follicles mature simultaneously, causing the ovaries to swell and become painful. In rare instances, ovarian hyperstimulation syndrome can lead to life-threatening outcomes.^16,207-209

Clomiphene citrate, an oral antiestrogen medication and first-line infertility treatment for anovulatory female infertility, binds to estrogen receptors and reduces estrogenic activity. Through a negative feedback mechanism, this stimulates FSH and LH secretion by the pituitary gland, leading to follicular maturation and ovulation.¹⁶

Clomiphene citrate can be effective in women with normal estrogen levels and normal or suppressed FSH levels during the follicular phase (first half) of the menstrual cycle, women with luteal phase deficiency, PCOS, and unexplained infertility; however, it is not beneficial in women with low estrogen levels due to impaired ovarian function, such as those with premature menopause or problems with the HPO axis.^3,210 Women treated with clomiphene citrate have been shown to have a 30–50% chance of becoming pregnant within six ovulatory cycles.²¹¹

Adverse side effects of clomiphene citrate include mood swings, hot flashes, breast tenderness, abdominal cramps, and nausea.²⁰⁷ In addition, clomiphene citrate is associated with a 5–7% increased risk of a multiple pregnancy, usually with twins.²¹¹

Letrozole, an oral antiestrogen medication used to treat breast cancer, has also been found to promote ovulation. Letrozole works by inhibiting aromatase, the enzyme needed for conversion of androgens to estrogens. Decreased estrogen signaling triggers increased FSH release from the pituitary gland, and increased FSH signaling increases the chance of ovulation.^3,210

Multiple randomized controlled trials and meta-analyses have shown letrozole has a similar safety profile and is more effective than clomiphene citrate in women with PCOS.^211-214 Although letrozole is not FDA approved for the treatment of infertility, it appears to be the most effective treatment available and is frequently recommended as a first-line therapy, particularly in PCOS patients.^3,211

Known side effects of letrozole include digestive upset, low energy, hot flashes, headache, and back pain.²⁰⁷

Gonadotropin therapy is a second-line intensive infertility treatment approach that may be recommended to women who do not respond to multiple cycles of oral antiestrogen therapy, or women with anovulation due to premature menopause or dysregulation of the HPO axis.³ In this approach, synthetic or urine-derived FSH, sometimes with small amounts of LH, is injected to stimulate follicular maturation and increase the likelihood of ovulation.²¹⁰

Gonadotropin therapy has been found to increase the odds of successful birth by 13–28% in women with PCOS who did not become pregnant using clomiphene citrate.²¹⁵ Examples of gonadotropin medications are follitropin alfa (Gonal-f), follitropin beta (Follistim), urofollitropin (Bravelle, Fertinex), and menotropins (Menopur).²¹⁵ These medications cause the ovaries to enlarge, which can lead to abdominal discomfort and in some cases nausea and vomiting. They also may be more likely than antiestrogens to cause multiple pregnancies, such as with twins, and ovarian hyperstimulation syndrome.²⁰⁹

Luteal phase support has been shown to be important for enhancing outcomes in women treated with gonadotropin therapy followed by intrauterine insemination or in vitro fertilization.^17,216 Progesterone, as subcutaneous injections, vaginal formulations, and oral forms, are widely used for this purpose. Triptorelin (Decapeptyl), a drug that activates GnRH receptors, has also been shown to effectively provide luteal phase support, increasing rates of implantation, pregnancy, and live births. Human chorionic gonadotropin (HCG), a hormone that stimulates progesterone production during pregnancy, is sometimes used for luteal phase support but is used with caution since it is more likely than other methods to induce ovarian hyperstimulation syndrome.²¹⁷

Laparoscopic ovarian drilling is a minor surgical procedure used to induce ovulation in women with infertility related to PCOS who have not responded to first-line measures.²¹⁸ The procedure involves producing small holes in the ovary surface using a laser or heat. Although the exact mechanism by which this stimulates ovulation is not known, it is thought the reduction in ovary size and removal of some follicles results in reduced androgen production, enhanced ovarian blood flow, increased FSH secretion, and restored HPO signaling.^210,218 Ovarian drilling can be highly effective, with reported pregnancy rates as high as 88% after one year; however, a potential side effect of the procedure is worsened infertility due to scarring or ovarian failure.²¹⁸

Surgery

Women with infertility related to uterine or fallopian tube abnormalities or scarring may benefit from targeted surgical procedures. For example, surgical removal of uterine polyps, certain fibroid tumors, and uterine adhesions can increase pregnancy rates. In women with mild tubal disease affecting the portion of the tube closest to the ovary, surgery to open the tube can improve fertility, although it also increases the risk of ectopic (tubal) pregnancy. On the other hand, surgical removal of the fallopian tubes followed by assisted reproductive measures may be recommended to women with severe tubal disease affecting both tubes.³

Assisted Reproductive Techniques

Assisted reproductive techniques (also called assisted reproductive technology) are recommended to couples for whom other treatments are not indicated or are unsuccessful. Oocyte retrieval is an essential part of all assisted reproductive techniques. To harvest oocytes, an ultrasound-guided needle aspiration of the ovary is generally performed through the vaginal wall after ovulation stimulation, usually with an injection of gonadotropins.³

When considering whether to pursue assisted reproductive techniques, it is worth bearing in mind that these procedures come with known and theoretical risks. For example, assisted reproductive techniques are known to increase the chance of multiple pregnancies (such as with twins or triplets) and related pregnancy complications due to the use of ovulation-inducing medications. Although only 1.7% of all live births in the United States are attributable to assisted reproductive techniques, it is estimated 40% of twins and 77% of triplets and higher multiples are the result of assisted reproductive techniques. Importantly, multiple pregnancies are associated with much higher risks of pregnancy complications, preterm birth, and low birth weight.²¹⁹ In addition, ovulation-inducing drugs can cause side effects, including potentially life-threatening ovarian hyperstimulation syndrome.²²⁰ Theoretical risks include health problems in offspring related to genetic and epigenetic effects of oxidative stress, which may occur as a result of the procedure or may be inherited.²²¹ Observational studies have found a higher incidence of birth defects in babies conceived via assisted reproductive techniques, especially those conceived using intracytoplasmic sperm injection.^222-224 In addition, assisted reproductive technique-conceived babies have been found to be more likely to experience perinatal problems (eg, low birth weight and preterm birth) compared with those conceived naturally, and some evidence suggests they may potentially be at higher risk of cardiovascular problems later in life.²²⁴

Another important consideration is the psychological toll to both partners of pursuing expensive, invasive procedures without a guarantee of success. Stress, anxiety, and depression are common in men and women being treated for infertility, and psychological support has been shown to improve couples’ mental health and well-being.²²⁵ While some research suggests psychosocial interventions may increase pregnancy rates in infertile couples, it is perhaps more important that psychosocial support improves acceptance of outcomes.^225,226 This may help couples to adapt to a child-free life or begin exploring the possibility of adoption.

Intrauterine insemination. Intrauterine insemination involves the separation of motile sperm from semen and their placement directly in the uterus shortly after natural or induced ovulation.^2,16 Medical ovulation induction prior to intrauterine insemination increases the likelihood of pregnancy when the cause of infertility is unknown or due to female factors.²²⁷ It also may be used if there is male infertility due to low sperm counts. The chance of pregnancy using intrauterine insemination is lower in women over 40 years old.² In addition, most studies suggest pregnancy is unlikely using intrauterine insemination if male infertility is severe (<5 million total sperm count) but may be helpful if sperm counts are higher (10 to 30 million).²²⁸ In general, the successful pregnancy rate with intrauterine insemination is about 12% per attempt but decreases with each successive attempt. Although this pregnancy rate is lower than with in vitro fertilization and intracytoplasmic sperm injection, intrauterine insemination is often recommended first when feasible due to its lower invasiveness and cost.²

In vitro fertilization (IVF). In vitro fertilization (IVF) (Figure 3), which involves the fertilization of a mature oocyte outside of the female body, is available to infertile couples for whom intrauterine insemination is infeasible or unsuccessful. Typically, about 12 eggs are harvested after ovulation induction and placed in a fertilization medium with 50,000 to 500,000 motile sperm. If the number of healthy sperm is too low, intracytoplasmic sperm injection can be used. Several days later, 2‒4 embryos (successfully fertilized and growing oocytes) are transferred into the uterus and the rest are frozen.^2,3 Genetic testing prior to embryo transfer may be recommended if one or both parents have known genetic mutations.³ IVF has been reported to be associated with a live birth rate of 3.1–47.6%, with greater success in younger women.²²⁰

Figure 3: Basic overview of the steps of in vitro fertilization. Credit: Inspiring, Shutterstock.

Intracytoplasmic sperm injection. Intracytoplasmic sperm injection, a form of IVF in which a single mature sperm is injected directly into the cytoplasm of a mature oocyte in the laboratory, is the most widely used assisted reproductive technique in the world. The use of intracytoplasmic sperm injection has led to better IVF outcomes in couples with male infertility; however, its use in cases without a male infertility factor are still controversial.^229,230 Intracytoplasmic sperm injection has been reported to result in successful pregnancy and birth in about 30% of cases overall.²³¹

Mesenchymal stem cells (MSCs) are cells that have the ability to give rise to many types of cells, given the appropriate conditions. Emerging research suggests MSCs may be able to restore fertility to women with ovarian dysfunction, possibly by supporting the growth of immature ovarian follicles or generating new follicles.^232-234 There are many sources of MSCs, including bone marrow, adipose (fat) tissue, amniotic fluid, umbilical cord tissue, placental tissue, and menstrual blood. Regardless of the source, MSCs have been shown in preclinical research to migrate and attach to injured ovarian tissue, where they then generate new ovarian cells in response to stimulation by growth factors and hormones.^232,234 MSC therapy to promote healthy endometrial tissue has also been proposed as a future treatment for endometrial problems related to infertility, such as Asherman syndrome (intrauterine adhesions) and possibly even endometriosis.^235,236

Early human clinical trials have yielded promising findings. In an uncontrolled trial, nine women with premature ovarian failure (also called premature menopause) had 5, 10, or 15 million MSCs derived from their own adipose tissue transplanted into their ovaries and were monitored for one year. Some participants experienced sporadic or short-term resumption of menstrual cycles and reduction in FSH levels, and the effects appeared to vary between individuals rather than number of MSCs used.²³⁷ In another clinical trial, 14 women with premature ovarian failure and 4‒5 years of infertility underwent injection of donor umbilical cord-derived MSCs into an ovary, resulting in increased ovarian volume, blood flow, and function in some women three months later. Two spontaneous pregnancies and one healthy birth occurred. The response to treatment appeared to be stronger in women who received MSCs loaded on a collagen scaffold, a fibrillary network that helps retain the stem cells in the ovary.²³⁸ Donor umbilical cord MSCs on a collagen scaffold were also found to improve endometrial health in a trial that included 26 women with recurrent uterine adhesions. In the trial, MSCs were transplanted into the uterus after adhesions were surgically separated. Endometrial thickening (a sign of endometrial health) and reduced adhesions were noted after three months, and after 30 months 10 women had become pregnant: eight pregnancies resulted in healthy childbirth, one pregnancy was ongoing, and one miscarriage had occurred.²³⁹

Findings from a small controlled trial further indicate MSC therapy may help women who have not responded to other treatments. In the trial, 15 women with poor ovarian response to ovulation-inducing therapies underwent transplantation of MSCs from their own menstrual blood into an ovary while 16 similar women underwent routine intracytoplasmic sperm injection (control). Four MSC-treated women and no control women became pregnant during the three months after treatment. Subsequent assisted reproductive techniques led to pregnancy in an additional three women in the MSC group and two in the control group. Ultimately, there were five live births (a rate of 33%) in the MSC group and one (a rate of 6.3%) in the control group.²⁴⁰

Infertility can be a devastating diagnosis that can trigger psychological, emotional, and social distress above and beyond the stress inherent in infertility testing and treatments. Many women experience feelings of grief and loss when they find themselves unable to conceive or following a miscarriage.²⁴¹ Stigmatization of childless women can take many forms, depending on cultural norms and expectations, and may contribute to shame and diminished self-esteem.²⁴² Infertility may also trigger sexual dysfunction and relationship tension.²⁴³ Individual psychotherapy and group support may help women cope with the trauma of infertility and begin making decisions to shape their families’ future.^241,244 Some evidence suggests psychological tasks such as acknowledgement, acceptance, instilling meaning, and pursuing new life goals are key to healthy adjustment.^244,245

After fully processing the grief of infertility and coming to a point of acceptance, some couples will find adoption is a fulfilling way to become parents and grow a family. If you are considering adoption, here are some resources that may be helpful:

• Creating a Family
• Adoptive Families
• National Council for Adoption
• Adoption Learning Partners

When should I see my doctor about female infertility?

Generally, women 35 years old or younger who have not conceived after 12 months of trying (having regular unprotected sex) should seek medical care, while women over 35 should seek care sooner. Women with symptoms such as menstrual irregularity, abnormal pain or bleeding, vaginal soreness or itching, unusual vaginal discharge, fever, and pain with intercourse should speak with their doctor as soon as possible.

What happens if a woman is infertile?

A woman who is infertile has many options available to her, depending on the cause of her infertility. These range from non-invasive lifestyle and nutritional interventions to highly invasive assisted reproductive techniques, as well as adoption.

What are the signs of infertility in women?

The main sign of infertility is an inability to become pregnant. Especially short (less than 21 days) or long (35 days or more) menstrual cycles, irregular cycles, or absence of periods may be symptoms of reduced fertility. Other signs and symptoms of infertility can exist, depending on the cause.

What are the reasons why a woman cannot get pregnant?

A woman may have difficulty getting pregnant if she does not ovulate regularly or at all; has problems affecting her fallopian tubes or uterus; has endometriosis; or does not have many eggs in her ovaries due to aging, toxic exposures, or health problems. She may also have trouble conceiving if her partner does not have healthy sperm in adequate numbers. In some cases, no reason is found.

How can I check my fertility?

Women can use cervical mucous and basal body temperature records to track their menstrual cycle and identify their most fertile time of the month. At-home ovulation test kits can also help women see when they are ovulating.