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Subfertility
Introduction
Subfertility is a condition that affects approximately one in six couples. The cause may be related to a problem with the man, woman or both. In view of the intimate nature of the problem, subfertility is often associated with personal distress and embarrassment; effective treatment is available to help an increasing proportion of these couples.
Definitions
Subfertility is formally recognized as a disease by the World Health Organization (WHO) and is defined as the inability of a couple to achieve a clinical pregnancy within 12 months of beginning regular unprotected sexual intercourse. A couple can have primary subfertility – no previous pregnancies within the relationship – or secondary subfertility, in which the couple have achieved at least one pregnancy.
Subfertility is rarely absolute (infertility). Around 84% of the normal fertile population will conceive within 1 year and 92% by the end of 2 years. However, this is strongly age dependent and the older the couple are when they start trying to conceive, the lower the chance of pregnancy. Age factors into when, even in the absence of critical history or physical findings, investigations and treatment may be initiated; at 12 months in women under 35 years of age; at 6 months in women aged 35 or older; and in women over 40 years, more immediate evaluation and treatment may be warranted.
‘Cumulative pregnancy rates’ and ‘live birth rates’ are the terms used to express the chance of conception within a given time interval. Fig. 5.1 illustrates the relationship between female age at which couples start building a family and their chance of realizing a family with one child, with and without use of in vitro fertilization (IVF).
Fecundability is the percentage of women exposed to the chance of a pregnancy for one menstrual cycle who will subsequently produce a live-born infant (normal range 15% – 28%). Fecundability decreases with increasing age, and hence diminishes slightly with each passing month of not conceiving.
Age and Fertility
Fertility declines as the woman’s age increases, reflecting the decrease in oocyte quantity and quality. A woman is born with a finite number of oocytes; around 1 million. This falls to approximately 250,000 at puberty; by the time menopause is reached, the number of oocytes has fallen to below 1000. During her reproductive life, a woman will release around 500 mature oocytes – a form of pre-conceptual natural selection – while the remaining oocytes undergo atresia or apoptosis. At menopause, which occurs at an average age of 51 years, there are in effect no functioning oocytes.
The decline in fertility is directly related to the declining oocyte population and the eggs’ inherent quality. There is a small fall in monthly pregnancy rates from the age of 31 years, a more pronounced decrease from the age of 36 years and a very steep decline from the age of 40 years. In assisted-conception procedures, this decline is also observed with a gradual decline in success rates from age 34 years. In addition, in both natural and assisted-conception pregnancies, there is a substantial increase in rates of miscarriage with advancing maternal age. Although older men become less fertile, the effect of age on men’s fertility is much less pronounced than for women.
Causes of Subfertility
The causes of subfertility can be categorized in a simple manner. In reality, however, more than one problem is often identified in a couple. Causes include ovulation disorders (25%), male factor (30%), unexplained (25%) and tubal factors (10%). Remaining causes include uterine or peritoneal disorders, such as endometriosis-related subfertility.
Diagnosis
The diagnosis of subfertility is a process of exclusion, identifying couples in whom 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 5.1 and 5.2 . Other important factors to be noted are the woman’s age and the duration of subfertility – generally, the older the woman is and the longer the period of subfertility, the poorer the prognosis. The order in which the investigations are performed varies depending on whether the couple has primary or secondary subfertility, 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 5.1
Examination of a Woman
| Examination | Reason |
|---|---|
| Height and weight to calculate 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 subfertility |
| Immobile and/or tender uterus | Endometriosis or pelvic inflammatory disease |
Table 5.2
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). The normal BMI range is between 19 and 25 kg/m 2 . 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 discussion).
Increased body hair is associated with hyperandrogenism, most commonly due to polycystic ovary syndrome (PCOS). 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. More detailed information regarding structural abnormalities of the pelvic organs is obtained by augmenting clinical examination with transvaginal ultrasound.
Examination of the man
Examination of the man is frequently omitted in the absence of a relevant history. However, if 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 evidence of swellings.
Investigations and Their Interpretation
Investigations should be arranged in a logical manner with reference to the history, along with appropriate general health screening ( Box 5.1 ). Additional tests may be necessary depending on the circumstances ( Box 5.2 ).
Box 5.1
Initial investigations
Female
-
Early follicular phase: luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, anti-Müllerian hormone (AMH)
-
Rubella (offer vaccination if not immune)
-
Luteal phase: serum progesterone (to determine whether ovulation has occurred)
-
Test of tubal patency (laparoscopic hydrotubation, hysterosalpingo-contrast sonography [HyCoSy], or hysterosalpingography [HSG])
Male
-
Semen analysis × 2
Box 5.2
Additional investigations to be performed selectively
FSH, Follicle-stimulating hormone; LH, luteinizing hormone.
Female
-
Pelvic ultrasound scan for ovarian morphology and uterine abnormalities
-
Laparoscopy for diagnosis of endometriosis – may be combined with tubal patency test
-
Hysteroscopy for intrauterine anomalies
-
Prolactin and thyroid function tests
-
Testosterone, androstenedione, 17-hydroxyprogesterone and sex hormone-binding globulin (SHBG; in order to calculate the Free Androgen Index – when raised, is an indicator of hyperandrogenism)
Male
-
Sperm function tests (see text), if initial test is consistently abnormal
-
Mixed agglutination reaction 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
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Male factors
Classification
Male factor subfertility can be a problem of sperm production, sperm function or sperm delivery. Sperm production may be completely absent (azoospermia) in testicular failure, for example. More commonly, there is a reduced count of sperm of normal appearance (oligospermia). Additionally, a high proportion of the sperm may demonstrate poor motility, 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 impair 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
Semen analysis is the cornerstone of the laboratory evaluation of the subfertile man and helps to define the severity of the male factor. Patients should receive standardised instructions for semen collection, including a defined pre-test abstinence interval of 2 to 5 days. Semen can be collected by means of masturbation into a specimen cup or by intercourse with the use of special semen collection condoms that do not contain substances toxic to sperm. Ideally, the specimen should be collected at the laboratory. If collected at home, the specimen should be kept at room or body temperature during transport and examined in the laboratory within 1 hour of collection.
Clinical reference ranges have been established for sperm concentration, motility and morphology to help classify men as fertile or subfertile. 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 5.3 ). The values, 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 5.3
WHO Criteria for Semen Analysis (2010)
| Parameter | Lower Limit of Reference Range |
|---|---|
| Volume | 1.5 mL |
| Concentration | 15 × 10 6 /mL |
| Total motility | 40% |
| Progressive motility | 32% |
| Normal forms | 4% |
| Vitality | 58% |
From World Health Organization. WHO Laboratory Manual for Examination and Processing of Human Semen . 5th ed. Geneva, Switzerland: WHO; 2010.
When the initial screening evaluation reveals an abnormal male reproductive history or demonstrates abnormal semen parameters, a thorough evaluation by a urologist or other specialist in male reproduction is indicated. Additional tests and procedures may be recommended, including serial semen analyses (>3 months apart), endocrine evaluation, post-ejaculatory urinalysis, ultrasonography, specialized tests on semen and sperm and genetic screening.
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 a subfertility clinic. The cause may be genetic, for example, 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 gonadotoxic chemotherapy. There will also be a proportion of women in whom no reason can be identified, termed ‘idiopathic premature ovarian insufficiency’ (POI).
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-hour 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 muscle bulk and decreasing body fat, have the same effect. Thus, 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 estrone, 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 and increases the risk of miscarriage, as well as substantially increasing the risk of obstetric complications during pregnancy and at birth. 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 reflects visceral fat distribution, is a more reliable guide to the impact of fat on fertility, than the BMI.
Polycystic Ovary Syndrome
Of the women presenting with anovulatory subfertility, 50% will have PCOS (see Chapter 4).
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’. 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% to 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 has occured. However, there are a number of investigations that imply that ovulation has taken place:
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History – over 90% of women with regular menstrual cycles will ovulate spontaneously. This is the basis for using tracking calendar apps.
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Urinary LH kit – this identifies the mid-cycle surge of LH that starts the cascade reaction leading to ovulation.
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Mid-luteal phase progesterone – a luteal-phase progesterone value of >28 nmol/L is found in conception cycles; 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 first day of the next menstrual period. This can only be determined with some knowledge of the length of the woman’s usual menstrual cycle; the information is inevitably retrospective.
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