|Classification and external resources|
Female infertility refers to infertility in female humans.
There is no unanimous definition of female infertility, but NICE guidelines state that: "A woman of reproductive age who has not conceived after 1 year of unprotected vaginal sexual intercourse, in the absence of any known cause of infertility, should be offered further clinical assessment and investigation along with her partner." It is recommended that a consultation with a fertility specialist should be made earlier if the woman is aged 36 years or over, or there is a known clinical cause of infertility or a history of predisposing factors for infertility.
Causes and factors 
Causes or factors of female infertility can basically be classified regarding whether they are acquired or genetic, or strictly by location.
Acquired versus genetic 
Although causes (or factors) of female infertility can be classified as acquired versus 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, mentioned further below) does not necessarily cause infertility, and even if a woman is definitely infertile then the infertility cannot definitely be blamed on any single risk factor even if the risk factor is (or has been) present.
In broad sense, acquired factors practically 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.
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 twenties, after which it starts to decline, with this decline being accelerated after age 35. However, the exact estimates of the chances of a woman 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.
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. Also, cigarette smoking 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. 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%. Also, female smokers have an earlier onset of menopause by approximately 1–4 years.
Sexually transmitted disease 
Sexually transmitted diseases are a leading cause of infertility. They often display few, if any visible symptoms, with the risk of failing to seek proper treatment in time to prevent decreased 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 1000 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 were, respectively, 54 and 100% higher than their normal weight counterparts, for ovulatory women they were 44 and 70% higher, respectively.
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.
Other factors that can cause acquired infertility 
- 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 only 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.
- Diabetes mellitus. A review of type 1 diabetes came to the result that, despite modern treatment, women with diabetes are at increased risk of female infertility, such as reflected by delayed puberty and menarche, menstrual irregularities (especially oligomenorrhoea), mild hyperandrogenism, polycystic ovarian syndrome, fewer live born children and possibly earlier menopause. Animal models indicate that abnormalities on the molecular level caused by diabetes include defective leptin, insulin and kisspeptin signalling.
- Significant liver or kidney disease
- Cannabis smoking, such as of marijuana causes disturbances in the endocannabinoid system, potentially causing infertility
- Radiation. A dose of 8 Gy or more to the ovaries generally causes permanent female infertility.
Genetic factors 
There are many genes wherein mutation causes female infertility, as shown in table below. Also, there are additional conditions involving female infertility which are believed to be genetic but where no single gene has been found to be responsible, notably Mayer-Rokitansky-Küstner-Hauser Syndrome (MRKH). Finally, an unknown number of genetic mutations cause a state of subfertility, which in addition to other factors such as environmental ones may manifest as frank infertility.
|Gene||Encoded protein||Effect of deficiency|
|BMP15||Bone morphogenetic protein 15||Hypergonadotrophic ovarian failure (POF4)|
|BMPR1B||Bone morphogenetic protein receptor 1B||Ovarian dysfunction, hypergonadotrophic hypogonadism and acromesomelic chondrodysplasia|
|CBX2; M33||Chromobox protein homolog 2 ; Drosophila polycomb class||
Autosomal 46,XY, male-to-female sex reversal (phenotypically perfect females)
|CHD7||Chromodomain-helicase-DNA-binding protein 7||CHARGE syndrome and Kallmann syndrome (KAL5)|
|DIAPH2||Diaphanous homolog 2||Hypergonadotrophic, premature ovarian failure (POF2A)|
|FGF8||Fibroblast growth factor 8||Normosmic hypogonadotrophic hypogonadism and Kallmann syndrome (KAL6)|
|FGFR1||Fibroblast growth factor receptor 1||Kallmann syndrome (KAL2)|
|FSHR||FSH receptor||Hypergonadotrophic hypogonadism and ovarian hyperstimulation syndrome|
|FSHB||Follitropin subunit beta||Deficiency of follicle-stimulating hormone, primary amenorrhoea and infertility|
|FOXL2||Forkhead box L2||Isolated premature ovarian failure (POF3) associated with BPES type I; FOXL2
402C --> G mutations associated with human granulosa cell tumours
|FMR1||Fragile X mental retardation||Premature ovarian failure (POF1) associated with premutations|
|GNRH1||Gonadotropin releasing hormone||Normosmic hypogonadotrophic hypogonadism|
|GNRHR||GnRH receptor||Hypogonadotrophic hypogonadism|
|KAL1||Kallmann syndrome||Hypogonadotrophic hypogonadism and insomnia, X-linked Kallmann syndrome (KAL1)|
|KISS1R ; GPR54||KISS1 receptor||Hypogonadotrophic hypogonadism|
|LHB||Luteinizing hormone beta polypeptide|
|LHCGR||LH/choriogonadotrophin receptor||Hypergonadotrophic hypogonadism (luteinizing hormone resistance)|
|DAX1||Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1||X-linked congenital adrenal hypoplasia with hypogonadotrophic hypogonadism; dosage-sensitive male-to-female sex reversal|
|NR5A1; SF1||Steroidogenic factor 1||46,XY male-to-female sex reversal and streak gonads and congenital lipoid adrenal hyperplasia; 46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency|
|POF1B||Premature ovarian failure 1B||Hypergonadotrophic, primary amenorrhea (POF2B)|
|PROK2||Prokineticin||Normosmic hypogonadotrophic hypogonadism and Kallmann syndrome (KAL4)|
|PROKR2||Prokineticin receptor 2||Kallmann syndrome (KAL3)|
|RSPO1||R-spondin family, member 1||46,XX, female-to-male sex reversal (individuals contain testes)|
|SRY||Sex-determining region Y||Mutations lead to 46,XY females; translocations lead to 46,XX males|
|SOX9||SRY-related HMB-box gene 9||Autosomal 46,XY male-to-female sex reversal (campomelic dysplasia)|
|TAC3||Tachykinin 3||Normosmic hypogonadotrophic hypogonadism|
|TACR3||Tachykinin receptor 3||Normosmic hypogonadotrophic hypogonadism|
By anatomic location 
Hypothalamic-pituitary factors 
Ovarian factors 
- Anovulation. Female infertility caused by anovulation is called "anovulatory infertility", as opposed to "ovulatory infertility" in which ovulation is present.
- Luteal dysfunction
- Gonadal dysgenesis (Turner syndrome)
Tubal (ectopic)/peritoneal factors 
- Endometriosis Endometriosis can lead to anatomical distortions and adhesions (the fibrous bands that form between tissues and organs following recovery from an injury). However, the link between infertility and endometriosis remains enigmatic when the extent of endometriosis is limited. It has been suggested that endometriotic lesions release factors which are detrimental to gametes or embryos, or, alternatively, endometriosis may more likely develop in women who fail to conceive for other reasons and thus be a secondary phenomenon; for this reason it is preferable to speak of endometriosis-associated infertility in such cases.
- Pelvic adhesions
- Tubal dysfunction
Uterine factors 
- Uterine fibroids (leiomyoma)
Cervical factors 
Vaginal factors 
- Vaginal obstruction
- Lab tests
- hormone testing, to measure levels of female hormones at certain times during a menstrual cycle
- day 2 or 3 measure of FSH and estrogen, to assess ovarian reserve
- measurements of thyroid function (a thyroid stimulating hormone (TSH) level of between 1 and 2 is considered optimal for conception)
- measurement of progesterone in the second half of the cycle to help confirm ovulation
- Examination and imaging
- an endometrial biopsy, to verify ovulation and inspect the lining of the uterus
- laparoscopy, which allows the provider to inspect the pelvic organs
- fertiloscopy, a relatively new surgical technique used for early diagnosis (and immediate treatment)
- Pap smear, to check for signs of infection
- pelvic exam, to look for abnormalities or infection
- a postcoital test, which is done soon after intercourse to check for problems with sperm surviving in cervical mucous (not commonly used now because of test unreliability)
- special X-ray tests
Diagnosis and treatment of infertility should be made by physicians who are fellowship trained as reproductive endocrinologists. Reproductive Endocrinologists are usually Obstetrician-Gynecologists with advanced training in Reproductive Endocrinology & Infertility (in North America). These highly educated professionals and qualified physicians treat Reproductive Disorders affecting not only women but also men, children, and teens.
Prospective patients should note that reproductive endocrinology & infertility medical practices do not see women for general maternity care. The practice is primarily focused on helping their patients to conceive and to correct any issues related to recurring pregnancy loss.
Some cases of female infertility may be prevented through identified interventions:
- Maintaining a healthy lifestyle. Excessive exercise, consumption of caffeine and alcohol, and smoking are all associated with decreased fertility. Eating a well-balanced, nutritious diet, with plenty of fresh fruits and vegetables (plenty of folates), and maintaining a normal weight are associated with better fertility prospects.
- Treating or preventing existing diseases. Identifying and controlling chronic diseases such as diabetes and hypothyroidism increases fertility prospects. Lifelong practice of safer sex reduces the likelihood that sexually transmitted diseases will impair fertility; obtaining prompt treatment for sexually transmitted diseases reduces the likelihood that such infections will do significant damage. Regular physical examinations (including pap smears) help detect early signs of infections or abnormalities.
- Not delaying parenthood. Fertility does not ultimately cease before menopause, but it starts declining after age 27 and drops at a somewhat greater rate after age 35. Women whose biological mothers had unusual or abnormal issues related to conceiving may be at particular risk for some conditions, such as premature menopause, that can be mitigated by not delaying parenthood.
Society and culture 
Social stigma 
Ethnographic research into female infertility within “pronatalist developing societies” has shown that women who are infertile may be stigmatized, reflecting a deep-seated patriarchal belief system. In these societies, the vocation of motherhood is considered to be intrinsically linked to the notion of womanhood, so in effect, a woman’s infertility conflicts with normative concepts of gender identity. The woman’s inability to adopt this “mandatory status” and “gain entrance to the cult of motherhood” often leads to dysfunctional relationships with the in-laws, extended family and community members, culminating in feelings of “isolation, loneliness and despair”. Furthermore, this cultural milieu can impact negatively on “marital dynamics”, possibly leading to “divorce or polygamous remarriage”.
See also 
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