Female infertility refers to infertility in women, which is the inability to conceive after sexual intercourse. In 2021, it affected an estimated 110 million women globally. This represents an increase of 84.44% in prevalence since 1990, and is expected to continue to rise. Increases reflect structural aging in populations and the impact of risk factors such as delayed childbearing age, occupational stress, and environmental pollution.
Female infertility varies widely by region, with elevated risks in areas of high-medium sociodemographic index (SDI). It affects one in seven couples in developed countries and one in four in developing countries. Regions such as North Africa and the Middle East display high rates of primary infertility but low rates of secondary infertility while Central and Eastern Europe and Central Asia show lower incidence of primary infertility and higher prevalence of secondary infertility.
Fertility is affected by a variety of factors, including malformations of the uterus, hormones, disease, nutritional status, and pollution. Infertility affects women from around the world, and the social stigmas affecting infertile women may vary from region to region.
Cause Causes or factors of female infertility can be classified based on whether they are acquired or genetic, and by location.
Although factors of female infertility can be classified as either acquired or genetic, female infertility is usually more or less a combination of nature and nurture. Also, the presence of any single risk factor of female infertility (such as smoking) does not necessarily cause infertility, and even if a woman is definitely infertile, the infertility cannot definitely be blamed on any single risk factor even if that risk factor is (or has been) present.
Hormonal dysfunction Ovulatory hormonal disorders are the greatest single contributing factor to female infertility. Anovulation, or the failure to ovulate, is primarily caused by insufficient hormone levels, including low estrogen levels, insufficient GnRH secretion, as well as insufficient levels of other hormones secreted by the hypothalamus and pituitary glands. However, women with normal estrogen levels can also suffer from low fertility, such as in the case of women with PCOS.
It is not understood why women with PCOS and normal estrogen levels can still be infertile. However, it is believed that imbalanced secretion of GnRH can explain why such women fail to conceive, highlighting the need for hormonal balance in women with PCOS.
Acquired According to the American Society for Reproductive Medicine (ASRM), age, smoking, sexually transmitted infections, and being overweight or underweight can all affect fertility.http://www.fertilityfaq.org/_pdf/magazine1_v4.pdf
In a broad sense, acquired factors include any factor that is not based on a genetic mutation, including any intrauterine exposure to toxins during fetal development, which may present as infertility many years later as an adult.
Age
A woman's fertility is affected by her age. The average age of a girl's first period (menarche) is 12–13 (12.5 years in the United States, 12.72 in Canada, 12.9 in the UK), but, in postmenarchal girls, about 80% of the cycles are anovulatory in the first year after menarche, 50% in the third and 10% in the sixth year. A woman's fertility peaks in the early and mid 20s, after which it starts to decline, with this decline being accelerated after age 35. However, the exact estimates of a woman's chances to conceive after a certain age are not clear, with research giving differing results. The chances of a couple to successfully conceive at an advanced age depend on many factors, including the general health of a woman and the fertility of the male partner.
Menopause typically occurs between 44 and 58 years of age. DNA testing is rarely carried out to confirm claims of maternity at advanced ages, but in one large study, among 12,549 African and Middle Eastern immigrant mothers, confirmed by DNA testing, only two mothers were found to be older than fifty, the oldest mother being 52.1 years at conception (and the youngest mother 10.7 years old).Forster P, Hohoff C, Dunkelmann B, Schürenkamp M, Pfeiffer H, Neuhuber F, Brinkmann B. (2015) "Elevated germline mutation rate in teenage fathers". Proc Biol Sci 282:20142898
Tobacco smoking
Tobacco smoking is harmful to the ovaries, and the degree of damage is dependent upon the amount and length of time a woman smokes or is exposed to a smoke-filled environment. Nicotine and other harmful chemicals in cigarettes interfere with the body's ability to create estrogen, a hormone that regulates folliculogenesis and ovulation. Cigarette smoking also interferes with folliculogenesis, embryo transport, endometrial receptivity, endometrial angiogenesis, uterine blood flow and the uterine myometrium. Some damage is irreversible, but stopping smoking can prevent further damage.FERTILITY FACT > Female Risks By the American Society for Reproductive Medicine (ASRM). Retrieved on Jan 4, 2009 Smokers are 60% more likely to be infertile than non-smokers. Smoking reduces the chances of IVF producing a live birth by 34% and increases the risk of an IVF pregnancy miscarrying by 30%.Regulated fertility services: a commissioning aid - June 2009 , from the Department of Health UK Also, female smokers have an earlier onset of menopause by approximately 1–4 years.
Pollutants
Exposure to environmental pollutants in indoor and outdoor air can affect fertility, fetal development, health of offspring in later life, and the genetics of future generations. Common sources of pollutants include tobacco and marijuana smoke and e-cigarettes.; burning of fossil fuels through vehicle use, heating and cooking; cleaning and personal care products; and microplastics. Steps can be taken to minimize exposures such as avoiding smoking, minimizing dust, using glass instead of plastics, carefully selecting cleaning products and cosmetics, and avoiding vehicle exhaust fumes and heavy traffic areas.
Potential mechanisms of action of pollutants include oxidative stress, inflammation, changes in placental function, endocrine disruption and genetic alterations. Infertility risk has been observed to be higher with prolonged exposure to SO2, CO, particulate matter (PM2.5, PM10), nitrous oxides (NOx, NO, NO2), hydrocarbons and methane (CH4). Elevated levels of PM2.5 have been linked to alterations in serum markers of ovarian function such as anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and antral follicle count (AFC). Exposure to endocrine-disrupting chemicals is correlated with diminished ovarian reserve and peak estradiol (E2) levels, lower oocyte and embryo quality, and lower rates of fertilization and implantation. Environmental pollutants like bisphenols (BPs) and polycyclic aromatic hydrocarbons (PAHs) cause increased inflammation and cell death within the ovary, reducing the number of ovarian germ cells, impairing follicular development, and depleting the ovarian reserve. SO2 exposure is also linked to decreases in antral follicle count (AFC) and diminished ovarian reserves. Disruption of follicle development is implicated in ovarian disorders such as diminished ovarian reserve (DOR) and polycystic ovarian syndrome (PCOS).
Sexually transmitted infections Sexually transmitted infections are a leading cause of infertility. They often display few, if any visible symptoms, and failing to seek proper treatment in time can decrease fertility.
Body weight and eating disorders
Twelve percent of all infertility cases are a result of a woman either being underweight or overweight. Fat cells produce estrogen, in addition to the primary sex organs. Too much body fat causes production of too much estrogen and the body begins to react as if it is on birth control, limiting the odds of getting pregnant. Too little body fat causes insufficient production of estrogen and disruption of the menstrual cycle. Both under and overweight women have irregular cycles, in which ovulation does not occur or is inadequate. Proper nutrition in early life is also a major factor for later fertility.
A study in the US indicated that approximately 20% of infertile women had a past or current eating disorder, which is five times higher than the general lifetime prevalence rate.
A review from 2010 concluded that overweight and obese subfertile women have a reduced probability of successful fertility treatment, and their pregnancies are associated with more complications and higher costs. In hypothetical groups of 1,000 women undergoing fertility care, the study counted approximately 800 live births for normal weight and 690 live births for overweight and obese anovulatory women. For ovulatory women, the study counted approximately 700 live births for normal weight, 550 live births for overweight and 530 live births for obese women. The increase in cost per live birth in anovulatory overweight and obese women was, respectively, 54 and 100% higher than their normal weight counterparts; for ovulatory women they were 44 and 70% higher, respectively.
Radiation Exposure to radiation poses a high risk of infertility, depending on the frequency, power, and exposure duration. Radiotherapy is reported to cause infertility.How Cancer Treatments Can Affect Fertility in Women
Chemotherapy
Chemotherapy poses a high risk of infertility. Chemotherapies with high risk of infertility include procarbazine and other alkylating drugs such as cyclophosphamide, ifosfamide, busulfan, melphalan, chlorambucil and chlormethine. Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin. On the other hand, therapies with low risk of gonadotoxicity include plant derivatives such as vincristine and vinblastine, antibiotics such as bleomycin and dactinomycin and antimetabolites such as methotrexate, mercaptopurine and 5-fluorouracil.
Female infertility by chemotherapy appears to be secondary to premature ovarian failure by loss of primordial follicles. This loss is not necessarily a direct effect of the chemotherapeutic agents, but could be due to an increased rate of growth initiation to replace damaged developing follicles. Antral follicle count decreases after three series of chemotherapy, whereas follicle stimulating hormone (FSH) reaches menopausal levels after four series. Other hormonal changes in chemotherapy include decrease in inhibin B and anti-Müllerian hormone levels.
Women may choose between several methods of fertility preservation prior to chemotherapy, including cryopreservation of ovarian tissue, oocytes or embryos.
Immune infertility Antisperm antibodies (ASA) have been considered a cause of infertility in around 10–30% of infertile couples. ASAs are directed against surface antigens on sperm, which can interfere with sperm motility and transport through the female reproductive tract, inhibiting capacitation and acrosome reaction, impairing fertilization, influencing the implantation process, and impairing the growth and development of the embryo. Factors contributing to the formation of antisperm antibodies in women are disturbance of normal immunoregulatory mechanisms, infection, violation of the integrity of the mucous membranes, rape and unprotected oral or anal sex.
Other acquired factors Adhesions secondary to surgery in the peritoneal cavity is the leading cause of acquired infertility. A meta-analysis in 2012 came to the conclusion that there is little evidence for the surgical principle that using less invasive techniques, introducing less foreign bodies or causing less ischemia, reduces the extent and severity of adhesions.