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Female infertility
SpecialtyGynaecology Edit this on Wikidata

Female infertility refers to infertility in female humans. It affects an estimated 186 million women, or one in every four couples in developing countries (WHO), [1] with the highest prevalence of infertility affecting people in South Asia, Sub-Saharan Africa, North Africa/Middle East, and Central/Eastern Europe and Central Asia (Mascarenhas 2012). [2] Infertility is caused by many sources, including nutrition, diseases, and other malformations of the uterus. Infertility affects women from around the world, and the cultural and social stigma surrounding it varies.

Definition

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."[3] 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.[3]

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.

Acquired

According to the American Society for Reproductive Medicine (ASRM), Age, Smoking, Sexually Transmitted Infections, and Being Overweight or Underweight can all affect fertility.[4]

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.

Age
Main article: Age and female fertility

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,[5] 12.72 in Canada,[6] 12.9 in the UK[7]), 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.[8] 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
See also: Women and smoking § Unique gender differences and health effects for Females

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.[9] Some damage is irreversible, but stopping smoking can prevent further damage.[10][11] Smokers are 60% more likely to be infertile than non-smokers.[12] Smoking reduces the chances of IVF producing a live birth by 34% and increases the risk of an IVF pregnancy miscarrying by 30%.[12] Also, female smokers have an earlier onset of menopause by approximately 1–4 years.[13]

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.[10]

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,[14] 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.[10] Too little body fat causes insufficient production of estrogen and disruption of the menstrual cycle.[10] Both under and overweight women have irregular cycles in which ovulation does not occur or is inadequate.[10] Proper nutrition in early life is also a major factor for later fertility.[15]

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.[16]

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.[17]

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.[18] Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin.[18] 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.[18]

Female infertility by chemotherapy appears to be secondary to premature ovarian failure by loss of primordial follicles.[19] 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.[19] Antral follicle count decreases after three series of chemotherapy, whereas follicle stimulating hormone (FSH) reaches menopausal levels after four series.[20] Other hormonal changes in chemotherapy include decrease in inhibin B and anti-Müllerian hormone levels.[20]

Patients may choose between several methods of fertility preservation prior to chemotherapy, including cryopreservation of ovarian tissue, oocytes or embryos.[21]

Other factors that can cause acquired 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).[29] 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.

Chromosomal abnormalities causing female infertility include Turner syndrome.

Some of these gene or chromosome abnormalities cause intersexed conditions, such as androgen insensitivity syndrome

Genes wherein mutation causes female infertility[30]
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 Hypogonadism and pseudohermaphroditism
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.[32]
  • Luteal dysfunction[33]

Tubal (ectopic)/peritoneal factors

  • Endometriosis[34] 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.[35] 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[36] in such cases.
  • Tubal dysfunction
  • Previous ectopic pregnancy. A randomized study in 2013 came to the result that the rates of intrauterine pregnancy 2 years after treatment of ectopic pregnancy are approximately 64% with radical surgery, 67% with medication, and 70% with conservative surgery.[39] In comparison, the cumulative pregnancy rate of women under 40 years of age in the general population over 2 years is over 90%.[3]

Uterine factors

Previously, a bicornuate uterus was thought to be associated with infertility,[42] but recent studies have not confirmed such an association.[43]

Cervical factors

Vaginal factors

Diagnosis

Diagnosis of infertility begins with a medical history and physical exam. The healthcare provider may order tests, including the following:

  • 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

There are genetic testing techniques under development to detect any mutation in genes associated with female infertility.[30]

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.

Prevention

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.[48] 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

Often, when women cannot conceive, the blame is put on them, even when approximately 50% of infertility issues come from the man (WHO bulletin). [1] In addition, many societies only tend to value a woman if she is able to produce at least one child, and a marriage can be considered a failure when the couple cannot conceive (WHO bulletin). [1] The act of conceiving a child can be linked to the couple’s consummation of marriage, and reflect the social role played in their society (Araoye 2003). [49] Wealth is sometimes measured by the number of children a woman has, as well as inheritance of property (Araoye 2003; Dyer 2012). [49][50] In many cases, a woman who cannot bear children is excluded from social and cultural events including traditional ceremonies. This is personally humiliating practice and is a product of devaluing infertile women (Gerrits 1997; Whiteford, 1995). [51][52] In the Macua tradition, pregnancy and birth are considered major life events for a woman, with the ceremonies of nthaa´ra and ntha´ara no mwana, which can only be attended by women who have been pregnant and have had a baby (Gerrits 1997). [51] The effect of infertility leads to social shaming, due to internal and social norms surrounding pregnancy, which affects women around the world (Whiteford 1995). [52] When pregnancy is considered such an important event in life, and considered a “socially unacceptable condition”, it leads to a search for treatment in the form of traditional healers and expensive Western treatments (Inhorn 2003). [53] The limited access to treatment in many areas leads to extreme and sometimes illegal acts in order to produce a child (Inhorn 2003; Araoye 2003). [53][49]

Marital role

Men in some countries may find another wife when their first cannot produce a child, hoping that by sleeping with more women he will be able to produce his own child (Araoye 2003; Inhorn 2003; Dyer 2012). [49][53] [50] This can be prevalent in some African societies where polygamy is more common and more socially acceptable. In some cultures, including Mozambique, Nigeria, Cameroon, and Pakistan, women can select a woman with whom she allows her husband to sleep with in hopes of conceiving a child (Araoye 2003; Dyer 2012). [49] [50] Women who are desperate for children may compromise with her husband to select a woman and accept duties of taking care of the children to feel accepted and useful in society (Mogobe 2005). [54] Women, desperate for a child, also sleep with other men in hopes of becoming pregnant (Gerrits 1997). [51] This can be done for many reasons including advice from a traditional healer, or finding if another man was more compatible. In many cases, the husband was not aware of the extra sexual relations and would not be informed if a woman became pregnant by another man (Gerrits 1997). [51] This is not culturally acceptable however, and contributes to the gendered suffering of women who have fewer options to become pregnant on their own as opposed to men (Inhorn 2003). [53] Men also turn to divorce in attempt to find a new partner with whom to bear a child. Infertility in many cultures is a reason for divorce, and a way for the man to increase his chances of producing an heir (Gerrits 1997; Araoye 2003; Inhorn 2003; Mogobe 2005). [51][49][53][54] When a woman is divorced, she loses her security that often comes with land, wealth, and a family (Mogobe 2005). [54] This ultimately ruins marriages and leads to distrust in the marriage. The increase of sexual partners ultimately results with the spread of disease including HIV/AIDS, and can actually contribute to future generations of infertility (Mogobe 2005). [54]

Domestic abuse

The emotional strain and stress that comes with infertility in the household can lead to the mistreatment and abuse of a woman. The devaluation of a wife due to her inability to conceive leads to domestic abuse and emotional trauma such as victim blaming. Women are often blamed as the cause of infertility, which leads to emotional abuse, anxiety, and shame (Arroye 2003). [49] In addition, much of the blame for not being able to conceive is put on the female, even when it is often the man who is sterile (WHO). [1] Women who are not able to conceive can be starved, beaten, and neglected financially by her husband as if she had no use to him (Dyer 2012). [50] The physical abuse related to infertility stems from this and the emotional stress that comes with it. In many countries, the emotional and physical abuses that come with infertility lead to assault, murder, and suicide (Omberlet 2012). [55]

Mental and psychological impact

Many of these women cope with immense stress and social stigma behind their condition, which leads to considerable mental distress (McQuillan 2003). [56] The long-term stress involved in attempting to conceive a child, and the social pressures behind giving birth lead to emotional distress that can manifest as mental disease (Reproductive Health Outlook 2002). [57] Women who suffer from infertility deal with psychological stressors such as denial, anger, grief, guilt, and depression (Matthews 1986). [58] There is considerable shaming that leads to intense feelings of sadness and frustration that lead to depression and suicide (Mogobe 2005). [54] The implications behind infertility bear huge consequences for the mental health of an infertile woman due to the social pressures and personal grief behind being unable to bear children.

See also

References

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