The term 'subfertility' may be preferable to infertility, as many of the bars to conception are relative rather than absolute and in at least 25% of cases no cause is found.
People who are concerned about their fertility should be informed that over 80% of couples in the general population will conceive within one year if:
- The woman is aged under 40 years; and
- They do not use contraception; and
- They have regular sexual intercourse.
Of those who do not conceive in the first year, about half will do so in the second year (cumulative pregnancy rate over 90%).
Infertility may be due to problems with one or both partners. In around half of cases, a male infertility-associated factor is found, along with abnormal semen test results.In many cases, disorders are found in both partners. Although it has been traditionally accepted that fertility is more related to the age of the female than that of the male partner, recent literature suggests trends that increased paternal age is also associated with lower fertility.
The main causes of infertility in the UK are:
- Unexplained infertility (no identified male or female cause) (25%).
- Ovulatory disorders (25%).
- Tubal damage (20%).
- Factors in the male causing infertility (30%).
- Uterine or peritoneal disorders (10%).
In about 40% of cases, disorders are found in both the man and the woman. These percentages are an approximate prevalence.
Even in the absence of systemic illness, poor general health will impair fertility.
- Obesity may impair fertility. Aim for an ideal body mass index (BMI). In those who are overweight (BMI 25-30) and obese (BMI >30), there is a relationship between the degree of excessive weight and poor quality and quantity of sperm.Men who have a BMI of >30 should be informed that they are likely to have reduced fertility.
- The adverse effects of smoking on male fertility are well documented.
- Tight-fitting underwear affects semen quality. Men should be informed that although there is an association between elevated scrotal temperature and reduced semen quality, it is still uncertain whether wearing loose-fitting underwear improves fertility.
- Excessive alcohol consumption is known to impair fertility. There is no evidence that drinking within recommended limits has an impact.
- Anabolic androgenic steroids, marijuana, opioid narcotics, cocaine and methamfetamines have an adverse impact on male fertility, and adverse effects have been reported on the hypothalamic-pituitary-testicular axis, sperm function and testicular structure.
Disorders of the testis and spermatogenesis
These may be structural or hormonal.
- Persistent azoospermia is incompatible with fertility. Whilst a low sperm count is a poor prognostic feature, and the lower the count the worse the prognosis, it is not totally incompatible with fertility.
- A number of genetic disorders may be associated with infertility. These include:
- Klinefelter's syndrome with karyotype XXY, which is associated with hypogonadism and disorders of spermatogenesis. This is the most common sex chromosome disorder associated with infertility.
- Kallman syndrome, which causes hypogonadotrophic hypogonadism.
- Testicular feminisation (or androgen insensitivity syndrome), which is a condition where there is resistance to the virilising effects of androgens, and a child with an XY karyotype appears as a girl. This can be much less complete and more limited resistance to androgens can lead to poor development of the testes.
- Cryptorchidism is often associated with testicular dysgenesis and is a risk factor for infertility. Early orchidopexy (6-12 months of age) is beneficial for testicular growth and may improve spermatogenesis in adulthood. The optimal time for surgery is still unclear.
- The presence of varicocele in some men is associated with progressive testicular damage from adolescence onwards and a consequent reduction in fertility. However, although the treatment of varicocele in adolescents may be effective, there is a significant risk of overtreatment. European guidelines advise that varicocele repair may be effective in men with subnormal semen analysis, a clinical varicocele and otherwise unexplained infertility over at least two years. Guidelines from the UK's National Institute for Health and Care Excellence (NICE), however, do not advocate surgery for varicocele as treatment for infertility.
- Testicular tumours are usually treated by orchidectomy, possibly followed by radiotherapy. Treatment of testicular cancer reduces fertility.
- Trauma can cause testicular damage.
- Pituitary causes include:
- 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.
- Hyperprolactinaemia must be severe - ≥735 mU/L (usually due to a pituitary tumour) - to have an effect on sexual function.It may impair sexual desire, testosterone production and erectile function.
- Panhypopituitarism (unrelated to pregnancy) is called Simmonds' disease.
- Cushing's disease.
Disorders of the genital tract
- Failure of adequate differentiation of the embryonic testis can cause failure of proper development of the spermatic ducts.
- In vasectomy the objective is to interrupt the vas deferens and it may be possible to reunite this in an attempt to reverse the procedure; however, the success rate as measured by successful pregnancy is poor.
- Congenital urogenital abnormalities such as hypospadias can cause problems. It tends to deposit the semen in the acid environment of the vagina rather than near the friendlier environment of the cervix.
- Obstruction in the epididymis, or ejaculatory or seminal ducts may be congenital or acquired (for example, as a consequence of infection, trauma or surgery) and may cause azoospermia. A functional obstruction can occur secondary to medication such as selective serotonin reuptake inhibitors (SSRIs).
Other causes include:
- Disorders of ejaculation (eg, anejaculation, retrograde ejaculation).
- Erectile dysfunction.
- Idiopathic. The cause is unknown in around 44% of infertile men.
Investigation for the cause of infertility or subfertility should be systematic and led by clinical features, not a blind screening process for everything, so history is important to narrow the field of potential tests.
- Ask about smoking and alcohol.
- Establish the length of time the couple has been trying to conceive and about contraception used prior to this.
- Ask about prior fertility.
- Note family history, particularly of genetic disorders.
- Take a sexual history. Ask about coitus, which must be satisfactory and occurring on a frequent basis, preferably two to three times a week. Consider absences, physical or emotional problems and erectile dysfunction. Ascertain if there are ejaculatory problems - particular attention must be paid to the characteristics of micturition and ejaculation:
- Presence of nocturnal emission.
- Ejaculatory ability in given circumstances.
- Primary or acquired disorder.
- Consider psychosexual aspects (eg, features of affective relationship, pre-existent psychological trauma, previous psychological therapy).
- Direct questioning. Ask about haematospermia, urinary irritability, obstructive urinary symptoms, painful ejaculation, and hot flushes.
- Note previous medical and surgical history. Particularly ask about a past history of mumps (which may cause orchitis), urinary conditions (prostatitis, urethritis) and previous surgery around the genital area (hernia repair, orchidopexy, vasectomy etc). Establish if there is a history of torsion of the testis, which may be relevant, as failure to reduce it swiftly can compromise blood supply and cause lasting damage. Ask about history of sexually transmitted infections (STIs).
- Note previous treatment for malignancy:
- Chemotherapeutic agents, such as those used in childhood leukaemia, may result in subsequent sterility.
- Surgery and radiotherapy may be relevant if they involved the region.
- In men about to receive chemotherapy, the question of sperm banking needs to be considered. Retention of fertility for prepubertal boys with malignancy is a growing field.
- Drug and medication history. Ask about any recreational drug use and about prescribed medication. As well as recreational drugs (as discussed under 'General health', above), prescribed medication may adversely affect fertility:
- Phenothiazines and the older typical antipsychotics as well as metoclopramide increase levels of prolactin.
- Oral and rectal sulfasalazine impair spermatogenesis. This is reversible when the drug is withdrawn or switched to mesalazine.
- Immunosuppressants - eg, for autoimmune disease or after transplantation.
- Antidepressants - may interfere with erectile function as well as seminal tube function.
- It is prudent to record the patient's blood pressure, weight and height (to calculate their BMI).
- A comprehensive andrological examination is indicated if semen analysis shows abnormalities compared with reference values.
- The patient should be examined for age-appropriate development of male secondary sex characteristics, gynaecomastia or hirsutism.
- Testicular site, consistency and volume should be noted. Note cryptorchidism where present (unusual now in adults, as screening done as part of neonatal checks).
- Examine for the presence of a varicocele, epididymal thickening or scrotal swelling.
- Examine for inguinal lymphadenopathy in those with symptoms to suggest an STI or in those with risk factors for an STI.
In the male, semen analysis is the initial investigation. The specimen should be produced by masturbation (and not into a condom, as they contain spermatocides) and after three days of abstinence from sexual activity. The specimen should be kept warm and sent to the laboratory for examination, ideally within an hour from production, although in practice this is difficult to achieve. Prior arrangement with the laboratory may be necessary to ensure that they are able to deal with the specimen on the same day as collection.
Normal results based on World Health Organization (WHO) criteria are given below. Figures shown are lowest acceptable result (5th percentile) and 95% confidence limits in brackets:
- Semen volume (mL): 1.5 (1.4-1.7).
- Total sperm number (106 per ejaculation): 39 (33-46).
- Sperm concentration (106 per mL): 15 (12-16).
- Total motility (%): 40 (38-42).
- Progressive motility (%): 32 (31-34).
- Vitality (live spermatozoa, %): 58 (55-63).
- Sperm morphology (normal forms, %): 4 (3.0-4.0).
If the first test is normal, a second test is not required. Repeat confirmatory tests should ideally be undertaken three months after the initial analysis, to allow time for the cycle of spermatozoa formation to be completed. However, if a gross spermatozoal deficiency (azoospermia or severe oligozoospermia) has been detected, the repeat test should be undertaken as soon as possible.
The following terms are used:
- Oligozoospermia: <15 million spermatozoa/mL.
- Asthenozoospermia: <32% motile spermatozoa.
- Teratozoospermia: <4% normal forms.
Further andrological investigation is indicated if two tests are abnormal.
Depending on findings from history, examination and semen analysis, further investigations may be indicated, such as:
- Hormone analysis. After a second unsatisfactory semen analysis result, an FSH level and testosterone should be taken. Impaired spermatogenesis is often associated with elevated FSH concentration. Further hormonal investigations which may be indicated include LH, prolactin and free testosterone.
- Genetic testing.
- Ultrasound. This may be required where there have been urinary symptoms or abnormal findings on examination.
- Testicular biopsy is the best procedure to define the histological diagnosis and the possibility of finding sperm. Spermatozoa are found in about 60% of patients with non-obstructive azoospermia (NOA). These may be simultaneously extracted and used in treatment.
- Viral screening. People undergoing IVF treatment should be offered testing for HIV, hepatitis B and hepatitis C. Those people found to test positive for one or more of HIV, hepatitis B, or hepatitis C should be offered specialist advice and counselling and appropriate clinical management.
- General. Men with ejaculatory disorders should have their fasting glucose performed to exclude diabetes mellitus.
See separate Infertility Treatments article.
Further reading and references
Guidelines on Male Hypogonadism; European Association of Urology (2015)
Fertility Problems; NICE Quality Standards, October 2014
Esteves SC, Miyaoka R, Agarwal A; An update on the clinical assessment of the infertile male. [corrected]. Clinics (Sao Paulo). 201166(4):691-700.
Fertility - Assessment and treatment for people with fertility problems; NICE Guidance (February 2013, updated Aug 2016)
Guidelines on Male Infertility; European Association of Urology (2015)
Balasch J, Gratacos E; Delayed childbearing: effects on fertility and the outcome of pregnancy. Curr Opin Obstet Gynecol. 2012 Jun24(3):187-93. doi: 10.1097/GCO.0b013e3283517908.
Hinz S, Rais-Bahrami S, Kempkensteffen C, et al; Effect of obesity on sex hormone levels, antisperm antibodies, and fertility after vasectomy reversal. Urology. 2010 Oct76(4):851-6.
Santos EP, Lopez-Costa S, Chenlo P, et al; Impact of spontaneous smoking cessation on sperm quality: case report. Andrologia. 2011 Dec43(6):431-5. doi: 10.1111/j.1439-0272.2010.01089.x. Epub
Braga DP, Halpern G, Figueira Rde C, et al; Food intake and social habits in male patients and its relationship to intracytoplasmic sperm injection outcomes. Fertil Steril. 2012 Jan97(1):53-9. Epub 2011 Nov 10.
Fronczak CM, Kim ED, Barqawi AB; The Insults of Recreational Drug Abuse on Male Fertility. J Androl. 2011 Jul 28.
Haugnes HS, Bosl GJ, Boer H, et al; Long-term and late effects of germ cell testicular cancer treatment and implications for follow-up. J Clin Oncol. 2012 Oct 2030(30):3752-63. doi: 10.1200/JCO.2012.43.4431. Epub 2012 Sep 24.
Maggi M, Buvat J, Corona G, et al; Hormonal causes of male sexual dysfunctions and their management (hyperprolactinemia, thyroid disorders, GH disorders, and DHEA). J Sex Med. 2012 Apr 23. doi: 10.1111/j.1743-6109.2012.02735.x.
Wyns C; Fertility preservation: current prospects and future challenges. Gynecol Endocrinol. 2013 Jan 25.
Bostwick JR, Guthrie SK, Ellingrod VL; Antipsychotic-induced hyperprolactinemia. Pharmacotherapy. 2009 Jan29(1):64-73.
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