9
Infertility
Introduction
Infertility is a condition that affects approximately one in six couples at some stage in their lives. The cause may be related to a problem with the man, woman or both. In view of the intimate nature of the problem, infertility is often associated with personal distress and embarrassment; effective treatment is available to help an increasing proportion of these couples.
Definitions
Infertility is defined by the World Health Organization (WHO) as the inability of the couple to achieve a clinical pregnancy within 12 months of beginning regular unprotected sexual intercourse. A couple can have primary infertility – no previous pregnancies within the relationship – or secondary infertility, where the couple has had at least one pregnancy.
Infertility is rarely absolute, and most couples have a degree of subfertility. Around 84% of the normal fertile population will conceive within 1 year, and 92% by the end of 2 years. Cumulative pregnancy rates and live birth rates are the terms used to express the chance of conception within a given time interval. Figure 9.1 illustrates the cumulative pregnancy rate for the normal fertile population.
Fecundability is the percentage of women exposed to the risk of a pregnancy for one menstrual cycle, who will subsequently produce a live-born infant (normal range – 15–28%). Fecundability usually diminishes slightly with each passing month of not conceiving.
Age and fertility
Normal fertility declines as the woman’s age increases. A woman is born with a finite number of oocytes; around 1 million. This falls to approximately 250 000 at puberty, and by the time the menopause is reached, the number of oocytes has fallen to below 1000. During her reproductive life, a woman will release only 500 mature oocytes – a form of pre-conceptual natural selection – while the remaining oocytes undergo atresia or apoptosis. The rate of oocyte loss is a dynamic process with the rate of follicular recruitment increasing from birth to age 14 and then progressively decreasing until the menopause. At the menopause, which occurs at an average age of 51, there are no functioning oocytes.
The decline in fertility is directly related to the declining oocyte population and the eggs’ inherent quality. There is a small, but noticeable, fall in monthly fecundity rates from the age of 31 years, a more pronounced decrease from the age of 36 years, and a very steep decline over the age of 40 years. In assisted conception procedures, this decline is also observed with a gradual decline in success rates from age 32. In addition, in both natural and assisted conception pregnancies, there is a substantial increase in spontaneous miscarriage rates with advancing maternal age. Although older men are less fertile, the effect of age on men’s fertility is less pronounced than in women.
Causes of infertility
The causes of infertility can be categorized in a simple manner but in reality, more than one problem can be identified in a couple. Causes include: ovulation disorders (25%); male factor (25%); unexplained (25%) and tubal factors (15%). Remaining causes include endometriosis related infertility.
Diagnosis
The diagnosis of infertility is a process of exclusion, identifying couples where the cause is clear, those in whom there is a possible cause and those in whom the cause is unexplained. The aim of investigation should be to reach a diagnosis as soon as possible, using only tests that are of proven value.
History and examination
Factors that provide clues to the aetiology are outlined in Tables 9.1 and 9.2. Other important factors to be noted are the woman’s age and the duration of infertility – generally, the older the woman is and the longer the period of infertility, the poorer the prognosis. The order in which the investigations are performed varies, depending on whether the couple has primary or secondary infertility, with an earlier assessment of tubal patency in the latter. Early assessment is also indicated if a specific abnormality is suspected from the history, and for an older patient.
Table 9.1
Examination of a woman
| Examination | Reason |
| Height and weight for body mass index (BMI) | High or low BMI associated with lower fertility |
| Body hair distribution | Hyperandrogenism |
| Galactorrhoea | Hyperprolactinaemia |
| Uterine structural abnormalities (most usefully determined by transvaginal ultrasound) | May be associated with infertility |
| Immobile and/or tender uterus | Endometriosis or pelvic inflammatory disease, associated with tubal damage |
Table 9.2
Examination of a man
| Examination | Reason |
| Scrotum | Varicocele |
| Size (volume) of the testes | Small testes associated with oligospermia |
| Position of the testes | Undescended testes |
| Prostate | Chronic infection |
Examination of the woman
Height and weight should be recorded and used to calculate the body mass index (BMI), using the formula: weight (kg)/height (m)2. The normal range is between 19 and 25. A change of weight of > 10% in the preceding year may cause a disturbance of the menstrual pattern and anovulation. A BMI at either extreme is detrimental to fertility (see later).
Increased body hair is associated with hyperandrogenism, most commonly because of polycystic ovary syndrome. Breast examination may demonstrate galactorrhoea, which is associated with hyperprolactinaemia. Pelvic examination is important, to look for signs of structural abnormalities, infection and pathological processes, such as endometriosis or pelvic inflammatory disease.
Examination of the man
Examination of the man is not essential in the absence of any relevant history. If, however, the semen analysis is abnormal, examination of the genitalia may be helpful, looking specifically at size (volume); consistency and position of the testes; the outline of the epididymis (for the presence of the vas deferens) and finally, the scrotum, for any evidence of swellings.
Investigations and their interpretation
The investigations should be arranged in a logical manner with reference to the history, along with appropriate general health screening (Box 9.1). Additional tests may be necessary, depending on the clinical circumstances (Box 9.2).
Box 9.1
Initial investigations
early follicular phase LH, FSH, oestradiol
rubella (offer vaccination if not immune)
luteal phase serum progesterone (to assess ovulation)
test of tubal patency (laparoscopy, HyCoSy or hysterosalpingogram)
semen analysis × 2
Box 9.2
Additional investigations to be performed selectively
pelvic ultrasound scan for ovarian morphology and uterine abnormalities
salpingoscopy or falloposcopy for intraluminal tubal adhesions
hysteroscopy for intrauterine anomalies
prolactin and thyroid function tests
testosterone and sex hormone binding globulin (SHBG).
sperm function tests (see text), if initial test is consistently abnormal
mixed agglutination reaction (MAR) test or immunobead test for antisperm antibodies
FSH, LH, testosterone if low sperm count (oligospermia) (raised FSH if testicular failure, low if central nervous system cause)
transrectal ultrasound for suspected abnormalities of the seminal vesicles and prostate
Male factors
Classification
Male factor infertility can be a problem of sperm production, sperm function or sperm delivery. Sperm production may be completely absent (azoospermia) in, for example, testicular failure. More commonly, a patient may present with a reduced count of sperm of normal appearance (oligospermia). Additionally, a high proportion of the sperm may be poorly motile, lacking the normal forward progressive movement (asthenospermia) or may appear morphologically defective (teratospermia) with abnormalities of the head, midpiece or tail.
Normal sperm function – the ability of the sperm to reach, bind and fertilize the oocyte – is more difficult to demonstrate. At present, there are no reliable methods of measuring sperm function, other than monitoring the proportion of sperm moving and assessing the speed of their progress. Antisperm antibodies can affect sperm motility.
Problems with sperm delivery may be caused by absence or blockage of the vas deferens or epididymis. It may also be related to impotence, premature ejaculation or a physical inability to have normal sexual intercourse.
Semen analysis
This provides information about spermatogenesis and an aspect of sperm delivery, but gives little information about sperm function. The WHO has produced a normal range of values for semen, based upon semen analyses performed upon samples obtained from men with a time to pregnancy interval of up to 12 months (Table 9.3). The values, however, are empirical and do not reflect a cut-off point below which pregnancy will not occur. Rather, there is an increase in probability of conception with increasing numbers of sperm and motility up to 40 million/mL and 40%, respectively with a relative plateau thereafter.
Table 9.3
WHO criteria for semen analysis (2010) (2.5–97.5 centiles)
| Volume | 1.2–7.6 mL |
| Concentration | 9–259 × 106/mL |
| Total motility | 34–81% |
| Progressive motility | 28–75% |
| Normal forms | 3–48% |
| Vitality | 53–92% |
Reproduced with permission from WHO.
A man’s sperm count varies considerably, and in the presence of one abnormal result, a second count should be arranged. As spermatogenesis takes approximately 3 months to complete, the samples ought to be produced at least 3 months apart. Samples should be produced by masturbation or after intercourse into a non-lubricated condom after a period of abstinence of between 3 and 5 days. The sample should be analysed in an accredited laboratory and according to WHO guidelines.
Tests of sperm function
Sperm function tests are no longer used in routine clinical practice, with more emphasis now placed on the identification of the number of abnormal/normal sperm as part of the routine analysis. Some sperm function tests, such as the ability of sperm to swim through culture medium, are employed in specialized reproductive medicine units, where more complicated treatment may be contemplated.
The post-coital test involves asking the couple to have sexual intercourse timed to the woman’s mid-cycle. Then, 6–12 h later, a sample of endocervical mucus is taken, looking for the presence or absence of sperm. Some studies have shown a positive correlation between the finding of motile sperm in the mucus and the chance of subsequent pregnancy. The use of this test, however, is controversial, as other studies have shown that the finding of a positive or negative result does not alter the chance or timing of a pregnancy. As a result, most centres have abandoned this procedure.
Antibodies can develop against sperm in response to injury or infection of the testis and epididymis. Men who have had a vasectomy and attempted reversal are the commonest group in whom antisperm antibodies are identified. The antibodies can be serum (IgG) or bound (IgA), and attach principally to the tail, midpiece or head of the sperm. Tests used to detect antisperm antibodies include the mixed agglutination reaction (MAR) test, and the immunobead test. Levels between 17% and 49% are likely to be associated with a fall in fertility, and levels greater than 50% are thought to significantly affect fertility.
Female factors
Ovulation
Ovulation is an ‘all or nothing’ phenomenon, with usually one oocyte released per ovulatory cycle.
Causes of anovulation
Ovarian failure is found in about 50% of women with primary amenorrhoea, and 15% of those presenting with secondary amenorrhoea. Most women with primary amenorrhoea will have an established diagnosis before presenting to an infertility clinic. The cause may be genetic, e.g. Turner syndrome (45,XO) or autoimmune. In those presenting with secondary amenorrhoea and ovarian failure, there may be an obvious cause, such as previous ovarian surgery, abdominal radiotherapy or chemotherapy. There will also be a proportion of women in whom no reason can be identified – idiopathic premature menopause.
Weight-related anovulation
Weight plays an important part in the control of ovulation. A minimum degree of body fat (considered to be around 22% of body weight) is needed to maintain ovulatory cycles. Substantial weight loss leads to the disappearance of the normal 24-h secretory pattern of gonadotrophin-releasing hormone (GnRH), which reverts to the nocturnal pattern seen in pubescent girls. As a result, the ovaries develop a multifollicular appearance on ultrasound. Prolonged exercise can, by increasing the muscle bulk and decreasing the body fat, have the same effect, and it is not uncommon for women athletes or ballerinas to be amenorrhoeic. Excessive weight can also have an adverse effect on ovulation. This probably results from excess oestrone, generated in the adipose tissue by conversion from androgens, interfering with the normal feedback mechanism to the pituitary gland.
Excess weight has a profound effect on female fertility, with a significant reduction in the chance of a successful pregnancy: it reduces the chance of conception, increases the risk of miscarriage, as well as substantially increasing the risk of obstetric complications during the pregnancy and at delivery. The distribution of the fat is important, with central (visceral) fat having a bigger impact than peripheral fat distribution. The waist–hip ratio, which more reliably picks up visceral fat distribution, seems a more reliable guide to the impact of fat on fertility than the body mass index (BMI).
Polycystic ovary syndrome
Of the women presenting with anovulatory infertility, 50% will have polycystic ovary syndrome (PCOS) (see Chapter 8).
Luteinized unruptured follicle syndrome
In certain patients, the oocyte may be retained following the luteinizing hormone (LH) surge, the so-called ‘luteinized unruptured follicle syndrome’ (LUF). Repeated pelvic ultrasound scans fail to show the expected collapse of the follicle at ovulation, and the follicle persists into the luteal phase. As no longitudinal studies have shown this to be a persistent finding in the same woman, there is uncertainty regarding its relevance to fertility.
Hyperprolactinaemia
Hyperprolactinaemia is diagnosed in 10–15% of cases of secondary amenorrhoea. About one-third of these women will have galactorrhoea, and occasionally, there may be some evidence of visual impairment (bitemporal hemianopia) due to pressure on the optic chiasma from a pituitary adenoma.
Tests of ovulation
Only a pregnancy categorically confirms ovulation. However, there are a number of investigations that imply that ovulation has taken place:
history – over 90% of women with regular menstrual cycles will ovulate spontaneously
urinary LH kit – this picks up the mid-cycle surge of LH that starts the cascade reaction leading to ovulation. Biochemical measurement of the LH surge requires repeated blood tests and is restricted to specialist reproductive medicine units
mid-luteal phase progesterone – this is the most commonly used test of ovulation. A luteal phase progesterone value of > 28 nmol/L is found in conception cycles, and as a result, this value is generally regarded as evidence of satisfactory ovulation. However, it is important to time the blood sample carefully – between 7 and 10 days before the next menstrual period. This can only be determined with some knowledge of the length of the patient’s normal menstrual cycle.
Other tests
Less commonly employed tests include serial ultrasound scans to monitor the growth, and subsequent disappearance, of a Graafian follicle. A luteal phase endometrial biopsy looking for appropriately timed secretory changes is no longer considered of value. Basal body temperature was previously considered to be of value as there is a rise of 0.5°C if ovulation has occurred (due to the thermogenic effect of a rise in serum progesterone) but in practice, this is now rarely used.
Testing ovarian reserve
Ovarian reserve is defined as the number of viable oocytes in the ovary. This is particularly important in women contemplating more complex fertility treatment, and may provide a guide to their response to treatment. Determining the level of follicle-stimulating hormone (FSH) at the beginning of the menstrual cycle, is probably the most commonly employed test. A raised FSH taken between days 2 and 5 of the menstrual cycle indicates impaired ovarian reserve, and a likely poor response to ovarian stimulation. Other methods that appear to be more reliable include:
measuring the antral follicle count – the number of small developing follicles seen in the ovary on ultrasound
measuring the ovarian volume – this is an indication of ovarian activity, as ovaries decrease in size with advancing age and decline in oocyte numbers
measuring the concentration of anti-Müllerian hormone (AMH). AMH is produced in small developing follicles and, unlike FSH, can be measured reliably throughout the menstrual cycle.
