Estimates of the prevalence of infertility in different parts of the world give remarkably similar results, with a 12-month prevalence rate ranging from 3.5–16.7% in more developed nations and from 6.9–9.3% in less-developed nations, with an estimated overall median prevalence of 9%. Only half of all infertile couples seek medical help, with the proportion being similar in developed and less-developed nations. Based on these estimates and on the current world population, 72.4 million women are currently infertile and of these, 40.5 million are currently seeking infertility medical care. Although firm evidence is hard to find, it seems that the prevalence of infertility in the Western world is increasing due to a number of factors, including the increase in number of young people with sexually transmitted diseases, increase in obesity and increasing numbers of women deferring plans for childbearing until later in life.
At the end of this chapter you should be able to:
Knowledge criteria
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Describe the common causes of male and female infertility
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Describe the indications for and interpretation of investigations used in the assessment of the infertile couple
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Discuss the principles, indications for and complications of the common methods of treatment of infertility
Clinical competencies
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Take a history from a couple presenting with infertility
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Plan appropriate initial investigation of an infertile couple
Professional skills and attitudes
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Reflect on the impact of infertility on a couple
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Reflect on the social and ethical issues relevant to the management of infertility
Primary infertility is defined as infertility without a previous pregnancy or live birth and secondary infertility as failure to conceive after one or more pregnancies, whether successful or ending in miscarriage, ectopic pregnancy or voluntary termination. Improved methods for investigation of infertility frequently reveal a problem in both partners, leading to the concept of relative subfertility . A highly fertile female partner will often compensate for a male with poor sperm quality and conceive without difficulty, and vice versa.
If conception does not occur after 12 months of regular sexual intercourse then the couple should be considered to be potentially infertile, as 80% of couples normally conceive within 1 year. It is therefore reasonable to proceed with investigations at this time. However this definition should be tempered by common sense. For example, a woman who has lost both Fallopian tubes because of ectopic pregnancies or a man who is known to have had testicular torsion in his youth should not be denied early investigation and treatment.
Both partners should be seen and investigated together, as infertility may result from male or female factors and is often associated with a combination of both. At the completion of all investigations, about one quarter will be given a diagnosis of ‘unexplained infertility’. Long-term follow-up studies of couples with unexplained infertility have shown that 30–40% will conceive over a 7-year period after investigation. Many ‘unexplained’ cases involve women over age 35 years who may later be shown to have a poor response to ovarian stimulation and oocyte abnormalities if in vitro fertilization (IVF) is performed. Age, particularly female age, undoubtedly affects fertility. IVF success rates fall sharply for women age 35 or older ( Table 17.1 ), and natural fertility appears to decline slowly but irrevocably from the late 20s onwards. The effect of age on the male is less pronounced, but older men exhibit more sperm abnormalities and DNA fragmentation.
| Under 35 | 35–37 | 38–39 | 40–42 | 43–44 | Over 44 | |
|---|---|---|---|---|---|---|
| 2007 | 32.3% | 27.7% | 19.2% | 11.9% | 3.4% | 3.1% |
| 2008 | 33.1% | 27.2% | 19.3% | 12.5% | 4.9% | 2.5% |
The relative incidence of causative factors will vary according to country and whether the problem is primary or secondary. Furthermore, in many couples there are multiple reasons for the infertility. Table 17.2 shows the pattern of causative factors of primary infertility in a Western population.
| Diagnosis * | Primary infertile group ( n = 167) N (%) | Secondary infertile group ( n = 151) N (%) | P -value |
|---|---|---|---|
| Ovulation problems | 54 (32.3) | 35 (23.2) | 0.069 |
| Sperm quality problems | 49 (29.3) | 36 (23.8) | 0.268 |
| Blocked Fallopian tubes | 20 (12) | 21 (13.9) | 0.607 |
| Unexplained infertility | 49 (29.3) | 45 (29.8) | 0.928 |
| Endometriosis | 19 (10.7) | 15 (10) | 0.677 |
| Others | 23 (13.8) | 32 (21.2) | 0.081 |
History and examination
The initial consultation should involve both partners. Many clinics use a pro forma questionnaire to elicit basic information, allowing better use to be made of the time available in the consultation. Basic investigations, including baseline blood tests for both partners, and semen analysis, can be organized through the General Practice with results available at the initial meeting.
The history should include the following:
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Age, occupation and educational background of both partners.
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Number of years that conception has been attempted and the previous history of contraception.
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Previous conceptions of either partner in this or previous relationships.
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Details of any complications associated with previous pregnancies, deliveries and postpartum.
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Full gynaecological history including regularity, frequency and nature of menses, cervical smears, intermenstrual bleeding and vaginal discharge.
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Coital history, including frequency of intercourse, dyspareunia, post-coital bleeding, erectile or ejaculatory dysfunction
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History of sexually transmitted diseases and their treatment.
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A general medical history to include concurrent or previous serious illness or surgery, particularly in relation to appendicitis in the female or herniorrhaphy in the male; a history of undescended testes or of orchidopexy.
Female infertility
General factors such as age, serious systemic illness, inadequate nutrition, excessive exercise and emotional stress may all contribute to female infertility. The majority of cases of female infertility follow from disorders of tubal or uterine anatomy or function, or ovarian dysfunction leading to anovulation. Less frequently observed disorders include cervical mucus ‘hostility’, endometriosis and dyspareunia.
Disorders of ovulation
Disorders of ovulation are divided into four categories, defined by the World Health Organization (WHO):
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Type I – hypogonadal hypogonadism resulting from failure of pulsatile gonadotrophin secretion from the pituitary. This relatively rare condition can be congenital (as in Kallman’s syndrome) or acquired, for example, after surgery or radiotherapy for a pituitary tumour. Serum concentrations of luteinizng hormone (LH) and follicle-stimulating hormone (FSH) and oestradiol are abnormally low/ undetectable and menses will be absent or very infrequent.
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Type II – normogonadotropic anovulation, most commonly caused by polycystic ovary syndrome (PCOS; see Chapter 16 ). Serum concentrations of FSH will be normal and LH normal or raised. Serum anti-Müllerian hormone (AMH) will be elevated and there may also be elevation of serum testosterone or free androgen index.
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Type III – hypergonadotropic hypogonadism, frequently described as ‘premature ovarian failure’ describes cessation of ovulation due to depletion of the ovarian follicle pool before age 40 years. Serum gonadotrophin concentrations will be greatly raised and AMH low/undetectable, with postmenopausal (low) concentrations of oestradiol.
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Type IV – hyperprolactinaemia, with elevated serum prolactin and low/normal serum FH and LH. Frequently due to a pituitary microadenoma although it is important to rule out a space occupying macroadenoma using pituitary MRI or CT.
Tubal factors
The Fallopian tube must first collect the ovum from its site of ovulation from the ruptured Graafian follicle and then transport the ovum to the ampullary segment, where fertilization occurs. The fertilized ovum must then be transported to the uterine cavity to arrive at the correct point in the menstrual cycle at which the endometrium becomes receptive to implantation (the ‘implantation window’). Tubal factors account for about 10–30% of cases of infertility: this figure varies considerably according to the population involved. Occasionally, congenital anomalies occur but the commonest cause of tubal damage is infection. Infection may cause occlusion of the fimbrial end of the tube, with the collection of fluid (hydrosalpinx) or pus (pyosalpinx) within the tubal lumen ( Fig. 17.1 ).
The commonest cause of acute salpingitis in UK is infection with Chlamydia trachomatis , but it may also result from infection with other organisms such as Neisseria gonorrhoeae, Escherichia coli , anaerobic and haemolytic streptococci, staphylococci and Clostridium welchii . The incidence of tubal damage is approximately 8% after the first episode of pelvic infection, 16% after two and 40% after three episodes. Tubal or uterine tuberculosis has begun to be seen more frequently in the UK in the immigrant population or their relatives.
Disorders such as appendicitis associated with peritonitis or inflammatory conditions including Crohn’s disease or ulcerative colitis can result in peritubal and peri-ovarian adhesions, leaving the internal structure of the Fallopian tube relatively unaffected.
Even in the presence of a patent tube, damage to the internal structure with depletion of cilia and impairment of tubal peristalsis may result in loss of tubal function.
Uterine factors
Implantation is less likely to occur if there is distortion of the uterine cavity due to submucous fibroids or congenital abnormalities such as an intrauterine septum. These disorders are often amenable to surgical correction. Subserous or entirely intramural fibroids do not appear to affect implantation. The effect of adenomyosis on implantation is unclear, although the disorder has been linked to recurrent implantation failure and miscarriage. Intrauterine adhesions or synechiae following over-vigorous curettage or infection (Asherman’s syndrome) result in inadequate endometrial development, absent or light periods and recurrent implantation failure.
Endometriosis
Endometriosis is an enigmatic condition with numerous theories related to aetiology and poorly defined links to infertility. Severe disease with large ovarian cysts and extensive adhesions distorting tubal anatomy and potentially interfering with approximation of the fimbriae to the mature follicle is likely to lead to subfertility due to impairment of ovulation and entrapment of the oocyte by the Fallopian tube. However, milder forms of the disorder have also been linked to problems of subfertility and surgical treatment of grade I and II endometriosis led to a significant improvement in spontaneous pregnancy and live birth rates in a large randomized trial.
Cervical factors
At the time of ovulation, endocervical cells secrete copious, clear, watery mucus, with high water content and elongated glycoprotein molecules containing channels that facilitate passage of spermatozoa into the uterine cavity. Sperm penetration occurs within 2–3 minutes of deposition. Between 100 000 and 200 000 sperm colonize the cervical mucus and remain at this level for approximately 24 hours after coitus. Approximately 200 sperm eventually reach the Fallopian tube. After ovulation, mucus produced by the cervix under the influence of progesterone is hostile to sperm penetration. Cervical infection or antisperm antibodies in cervical mucus or seminal plasma, can inhibit sperm penetration and result in subfertility.
Investigation of infertility
Investigation of the female partner
All women presenting with infertility should have their rubella immunity checked and, if seronegative, be offered vaccination before undertaking further treatment for their infertility. They should also be advised to take folic acid supplementation from the outset of investigation and treatment of their fertility problem, to reduce chances of spina bifida in their child.
Detection of ovulation
The assessment of ovulation depends on the menstrual history. In the presence of a regular menstrual cycle ovulatory status can be investigated by changes in basal body temperature, cervical mucus or hormone levels, by endometrial biopsy or by ultrasound. However, measurement of basal body temperature (BBT) is difficult for many women to achieve and requires daily charting, increasing stress with a daily reminder of failure to conceive. Hence measurement of BBT is no longer recommended. Similarly, many women find assessment of cervical mucus changes difficult and challenging and this method is also not recommended. Ovulation can be inferred by detection of the LH surge in blood or urine, with a peak that occurs approximately 24 hours before ovulation. Modern commercially available LH surge detection kits can provide reassurance and allow timing of intercourse. Formation of the corpus luteum can be demonstrated by measurement of serum progesterone in the luteal phase of the cycle. A mid-luteal concentration above 25 nmol/L is usually accepted as evidence of ovulation, although values vary from laboratory to laboratory.
There is no need to measure thyroid function or prolactin levels in women with regular menstrual cycles unless they have symptoms of galactorrhoea or thyroid disease.
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