Infertility is defined as an inability to conceive. However, some degree of failure is normal. When couples try to conceive:

• 16% will still be unsuccessful at the end of 1 year
• 8% after 2 years
• 7% at the end of 3 years

Subfertility may be due to problems with one or both partners.

• Natural female fertility seems to decline quite rapidly after the age of 35, but this is just an average and the actual point of decline for any individual may vary significantly.¹
• Increasing maternal age occurs with increased obstetric risks and risk of miscarriage. This should be noted by women who choose to delay their family.

Some of the causes of failure of ovulation are relative rather than absolute which is why the term subfertility may be preferable, and these include problems of lifestyle. Infrequent ovulation carries a poor prognosis for conception, but is not a total bar.

Causes of female infertility

Disorders of ovulation

They may occur at the level or pituitary of hypothalamus as well as at the level of the ovary. If there is amenorrhoea it should be investigated as such and oligomenorrhoea along similar lines.

• Pituitary tumours will displace or destroy normal tissue and the production of follicle-stimulating hormone (FSH) and luteinising hormone (LH) is often the first to be affected. Panhypopituitarism is also called Simmonds' disease.
• Sheehan's disease is pituitary infarction following postpartum haemorrhagic shock.
• Hyperprolactinaemia may present with galactorrhoea or amenorrhoea. The control of prolactin is unlike the other releasing factors in that it is controlled by an inhibiting rather than a releasing factor from the hypothalamus into the hypothalamic-pituitary portal circulation. It is also released in response to thyrotrophin-releasing factor, as is thyroid-stimulating hormone (TSH), and so it is elevated if thyroxine is low.
• The pituitary gland may be responsible for other disorders such as Cushing's syndrome.
• A number of chromosomal disorders result in inadequate ovaries and usually primary amenorrhoea.
  • These include Turner's syndrome in which the ovaries are just streaks.
  • The condition may be a mosaic.
  • In testicular feminisation there is primary amenorrhoea.
  • The karyotype is XY but there is androgen insensitivity.
  • XXY or Klinefelter's syndrome appears as a male.
  • The XXX karyotype is sometimes called super-female, but is anything but super.
• Premature ovarian failure or premature menopause causes secondary amenorrhoea. Premature ovarian failure occurs in about 1% of women and, in the majority of cases, no cause is found.²
• Polycystic ovarian syndrome is usually, but not always, associated with obesity. Sclerocystic ovaries fail to ovulate but they can be very sensitive to clomifene.

Problems of tubes, uterus or cervix

• The Fallopian tubes are delicate structures whose cilia waft the ovum, or even early embryo, to its destination for implantation - more correctly called nidation.
  • Damage to the tubes may occur as a result of infection:
    • A history of pelvic inflammatory disease (PID) is highly suggestive of damage to tubes.
    • Everyone who may be investigated for infertility should be tested for chlamydia before any instrumentation of the genital tract.
    • Severe pelvic infection following illegal abortion is rarely seen in this country but still occurs in places where termination of pregnancy is illegal or difficult to secure.
    • Even a medical or spontaneous abortion can lead to infection of retained products of conception.
    • Postpartum infection can also affect fertility.
  • Previous Caesarean section does not impair fertility.³
  • Infection with an intrauterine contraceptive device (IUCD) in situ is also less common nowadays.
    • They are rarely used in the nulliparous and modern devices are changed after 5 years, whereas the worst infections were often with plastic devices that had been in place for many years.
    • However, insertion of an IUCD is a high-risk time for introducing infection.
• Sexually transmitted diseases may cause infertility, largely through associated PID.
  • Chlamydia and gonorrhoea are the most important.
• Infection may be less direct, and spread from appendicitis is possible, even without overt peritonitis. Risk factors include:
  • Late diagnosis
  • Having the disease before puberty - as the peritoneum in a little girl is less extensive and does not wall off the infection so readily
• Female sterilisation operations involve disruption of the tube and results of attempted reversal are poor.
  • Laparoscopic proof of patency of the tubes is not evidence that they function normally.
• Infection can also damage the uterus.
  • Adhesions in the uterus and cervix are called Asherman's syndrome.⁴
• Deformity of the uterus, such as a septum or bicornuate uterus, may be more likely to cause recurrent abortion than failure to conceive.
  • Significant distortion of the uterine cavity by fibroids can prevent implantation and hence fertility, although the impact on fertility remains a subject for debate.^5,6
• The cervix may have been shorted and damaged by a cone biopsy.
• There may be problems of cervical mucus including hostility to sperm.
• Endometriosis may cause such inflammation, adhesion and distortion in the pelvis that it causes tubal infertility.
  • Even when it is much less severe than that, it is commonly associated with subfertility.⁷
  • Whether or not minor degrees of endometriosis contribute to subfertility is still debated.

History

• Coitus must be satisfactory and occurring on a frequent basis, preferably at least 3 times a week.
  • Perhaps her partner is away much of the time of there may be physical or emotional problems.
  • Is penetration adequate?
• Anatomical considerations:
  • Congenital abnormalities of the vagina will cause problems, as may dyspareunia from whatever cause.
  • In certain parts of the world, mainly the Horn of Africa, female genital mutilation is still performed and this can impair coitus and fertility.
• There may be psychosexual dysfunction presenting as infertility.
• Systemic disease may well impair fertility, probably by interference with the hypothalamic-pituitary axis:
  • This may include autoimmune disease such as rheumatoid disease or systemic lupus erythematosus (SLE), although the latter, like antiphospholipid syndrome may be associated with recurrent abortion. Antiphospholipid antibodies should not be part of routine testing for infertility.⁸
  • Chronic renal failure will impair fertility.
  • Poorly controlled diabetes mellitus needs correction not just to improve fertility but to take account of the demands of diabetes in pregnancy, which dictate that control should be immaculate from the outset.
  • Undiagnosed coeliac disease is a poorly recognised problem.⁹

Medication history

A thorough review of all medication is required with a view to both fertility and possible adverse effects on pregnancy including teratogenicity.

• Legal drugs taken for legitimate purposes may also cause problems.
  • Phenothiazines and the older typical antipsychotics as well as metoclopramide increase levels of prolactin.¹⁰
  • Non-steroidal anti-inflammatory drugs (NSAIDs) can impair the rupture of ovarian follicles to release an ovum.¹¹
• The patient may be taking drugs like immunosuppressants for autoimmune disease or after transplantation.

Past medical history

This may reveal a cause for infertility such as previous treatment for malignancy.¹² Chemotherapeutic agents, such as those used in childhood leukaemia, may result in subsequent sterility. Surgery and radiotherapy may be relevant if they involved the pelvic region.

General health

Even in the absence of systemic illness, poor general health will impair fertility.

• Being overzealous about fitness with an obsession to run many miles a week may also be counterproductive but this is probably quite rare.
  • Athletic amenorrhoea, related to excessive training and not being underweight is uncommon.
  • The most common reason for failing to start the London Marathon, is pregnancy.
• Aim for an ideal body mass index (BMI).
  • A BMI below 19 is often associated with amenorrhoea, as occurs with anorexia nervosa.
  • At the other end of the scale, a BMI below 25 should be the aim, but the National Institute for Health and Clinical Excellence (NICE) gives a BMI above 29 as cause for concern.^13,14
  • It may be associated with polycystic ovary disease.
• Smoking cigarettes impairs fertility¹⁵ and smoking in pregnancy increases the risk of miscarriage, obstetric complications, intrauterine growth retardation and even delayed reading ability at least to the age of 7.
• Excessive alcohol consumption also impairs fertility¹⁶ as well as risking fetal alcohol syndrome and fetal alcohol effects that occur at lower levels of consumption.
• Any association between excessive caffeine consumption and subfertility is controversial.¹⁷
• Illicit drugs should be avoided. Some have adverse effects on fertility or the fetus or both and for most the question of teratogenicity has not been adequately addressed.¹⁸ Cannabis can impair ovulation and cocaine can cause tubal infertility. There is also reason to be concerned about the effect these drugs may have in pregnancy.

Investigations

The search for the cause of infertility or subfertility should be systematic and led by clinical features, not a blind screening process for everything.
They are covered in more detail in the separate article Subfertility Investigations and Management.

Document references

1. Schwartz D, Mayaux MJ; Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS. N Engl J Med. 1982 Feb 18;306(7):404-6.
2. Goswami D, Conway GS; Premature ovarian failure. Hum Reprod Update. 2005 Jul-Aug;11(4):391-410. Epub 2005 May 26. [abstract]
3. Porter M, Bhattacharya S, van Teijlingen E, et al; Does Caesarean section cause infertility? Hum Reprod. 2003 Oct;18(10):1983-6. [abstract]
4. Magos A; Hysteroscopic treatment of Asherman's syndrome. Reprod Biomed Online. 2002;4 Suppl 3:46-51. [abstract]
5. Donnez J, Jadoul P; What are the implications of myomas on fertility? A need for a debate? Hum Reprod. 2002 Jun;17(6):1424-30. [abstract]
6. Farquhar C; Do uterine fibroids cause infertility and should they be removed to increase fertility? BMJ. 2009 Jan 16;338:b126. doi: 10.1136/bmj.b126.
7. Trinder J, Cahill DJ; Endometriosis and infertility: the debate continues. Hum Fertil (Camb). 2002 Feb;5(1 Suppl):S21-7. [abstract]
8. Backos M, Rai R, Regan L; Antiphospholipid antibodies and infertility. Hum Fertil (Camb). 2002 Feb;5(1):30-4. [abstract]
9. Hin H, Ford F; Coeliac disease and infertility: making the connection and achieving a successful pregnancy. J Fam Health Care. 2002;12(4):94-7. [abstract]
10. Smith S; Effects of antipsychotics on sexual and endocrine function in women: implications for clinical practice. J Clin Psychopharmacol. 2003 Jun;23(3 Suppl 1):S27-32. [abstract]
11. Stone S, Khamashta MA, Nelson-Piercy C; Nonsteroidal anti-inflammatory drugs and reversible female infertility: is there a link? Drug Saf. 2002;25(8):545-51. [abstract]
12. Lutchman Singh K, Davies M, Chatterjee R; Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing. Hum Reprod Update. 2005 Jan-Feb;11(1):69-89. Epub 2004 Nov 29. [abstract]
13. Fertility: assessment and treatment for people with fertility problems, NICE Clinical Guideline (2004)
14. Satpathy HK, Fleming A, Frey D, et al; Maternal obesity and pregnancy. Postgrad Med. 2008 Sep 15;120(3):E01-9. [abstract]
15. Augood C, Duckitt K, Templeton AA; Smoking and female infertility: a systematic review and meta-analysis. Hum Reprod. 1998 Jun;13(6):1532-9. [abstract]
16. Bradley KA, Badrinath S, Bush K, et al; Medical risks for women who drink alcohol. J Gen Intern Med. 1998 Sep;13(9):627-39. [abstract]
17. Golding J; Reproduction and caffeine consumption--a literature review. Early Hum Dev. 1995 Aug 30;43(1):1-14. [abstract]
18. Mueller BA, Daling JR, Weiss NS, et al; Recreational drug use and the risk of primary infertility. Epidemiology. 1990 May;1(3):195-200. [abstract]

Internet and further reading

• Infertility, Clinical Knowledge Summaries (2007)
• Cahill DJ, Wardle PG; Management of infertility. BMJ. 2002 Jul 6;325(7354):28-32.
• Thomson F, Shanbhag S, Templeton A, et al; Obstetric outcome in women with subfertility. BJOG. 2005 May;112(5):632-7. [abstract]

Acknowledgements