Introduction

The intention of this chapter is to provide an overview of a spectrum of disorders of female reproduction, including infertility, which may present to gynaecologists in clinical practice. Observations on epidemiological issues of importance are made, leading to a discussion of the initial assessment of infertile couples in the setting of primary care. A critique of the place of secondary investigations is provided, under the broad headings of disorders of ovulation, tubal factor infertility, endometriosis and uterine factors, and unexplained infertility. Insights into the pathogenesis of infertility brought about by assisted conception techniques are also examined. The need for integration of services in enabling efficient and accurate assessment of the infertile is emphasized throughout.

Epidemiology

Time to conception

A common definition employed in describing infertility is the inability of a couple to conceive following 12–24 months of exposure to pregnancy. The length of exposure time considered is determined by the observation that in the general population, which would include a proportion of couples with infertility, one would expect the chance of conception in any individual cycle to be 20%. Thus, by 1 year of exposure, approximately 85% of couples would have achieved conception, and once 2 years has elapsed, some 92% would have conceived (Evers 2002). Others have evaluated conception rates in truly fertile couples and found that the expectation of pregnancy at 3, 6, 9 and 12 months was 42%, 75%, 88% and 98%, respectively (Gnoth et al 2003). In practical terms, the failure to achieve pregnancy causes enormous distress to those affected. For people with fertility problems, using a definition of 1 year to describe infertility is usual, and most will have sought medical advice or assistance by that time. Natural fertility rates decline in association with increasing female age, although in an ultimately fertile group of women, it is not certain that their monthly fecundability (percentage chance of conception) is any less than younger cohorts. It may be sensible to consider specialist referral of women over 35 years of age in advance of 1 year, although it is acknowledged that, in many instances, conception will occur naturally in these cases since it can be assumed that a proportion will not be infertile.

Estimates of the prevalence of infertility in the population will be influenced by the duration of infertility used in the definition and the population studied. The setting of prevalence studies, such as primary care (Snick et al 1997) or hospital clinics (Hull et al 1985), will influence the prevalence figures. Community-based data, which would give an accurate reflection of prevalence within the general population, are limited. It is not surprising, therefore, that existing studies suggest a range of lifetime prevalence of infertility extending from 6.6% to 32.6%. One population-based study in the North East of Scotland (Templeton et al 1990), which took account of conceptions resulting in miscarriage and ectopic pregnancy, found a prevalence of 14% using a 2-year definition.

A number of factors have been a matter of concern in recent years with respect to their potential impact on the prevalence of infertility, including the incidence of sexually transmitted infection such as Chlamydia trachomatis in the young (Macmillan and Templeton 1999). In addition, there have been suggestions that environmental factors may affect male fertility (Oliva et al 2001), and one should wonder about the possible effects on female fertility of delayed childbearing as determined by changes in lifestyle and working patterns. Despite these legitimate concerns, when the population-based study was repeated (Bhattacharya et al 2009), the observed prevalence of infertility had not increased in North East Scotland in the succeeding 20 years.

A lack of observed change in prevalence should not encourage complacency in respect of public health responsibilities. While opportunities to prevent infertility are limited, encouragement to the young to engage in safe sexual practices, limiting exposure to risk of sexually transmitted infection, is clearly important. For teenage girls, rubella immunization programmes should be in place and human papillomavirus vaccination programmes are now being established. Education of the public about the known decline in fertility which occurs with age, particularly in females over 35 years of age, is also important. In addition, the need for folic acid supplementation for women to reduce the risk of neural tube defects should be promoted, as well as the need to make certain lifestyle adjustments on issues such as the potential need to moderate levels of smoking and alcohol consumption, as well as achieving optimal weight. There is convincing evidence that smoking, active or passive, affects reproductive performance in women and men, as well as increasing the risk of small-for-gestational-age infants, stillbirth and infant mortality (National Collaborating Centre for Women’s and Children’s Health for the National Institute of Clinical Excellence 2004).

The requirement to take account of future reproductive needs in women is essential where abdominal or pelvic surgery is carried out, and careful technique should be employed to minimize the risk of pelvic adhesions. Where uterine instrumentation is considered, particularly in women under 25 years of age, the prevention of Chlamydia infection is receiving appropriate attention (Macmillan and Templeton 1999). Screening tests to detect the organism in first-void urine samples or cervical swabs using nucleic acid amplification techniques should be available routinely, and antibiotic treatment should be given for identified cases and potential contacts. Good lines of communication to sexual health and genitourinary medicine services will facilitate swift management.

Diagnostic categories

The management of people with infertility problems is largely dictated by the major diagnostic category in which they fit. Typical figures are shown in Table 20.1.

Table 20.1 Diagnostic categories and distribution of couples with primary and secondary infertility

Diagnostic category	Infertility
	Primary (%)	Secondary (%)
Male factor	25	20
Disorders of ovulation	20	15
Tubal factor	15	40
Endometriosis	10	5
Unexplained	30	20

Diagnostic categories in most studies include male factors, disorders of ovulation, tubal factors, endometriosis and unexplained infertility. The distribution of causes, when analysed, will be affected by whether the female has been pregnant in the past (i.e. secondary infertility). This has an association with an increased risk of tubal factor infertility compared with those couples with primary infertility (i.e. where there has not been a pregnancy in the past) (see Chapter 21, Disorders of male reproduction, for more information). The possibility that male factors may contribute to a couple’s infertility should not be ignored, even where the man has fathered a pregnancy in the past. It should be borne in mind that more than one factor may contribute to a couple’s infertility, and each may require simultaneous management; for example, ovulation induction for a woman who is not ovulating, in combination with donor insemination. Decisions to initiate active treatment will be influenced by the age of the female, the duration of infertility, and whether or not there has been a pregnancy in the past. Initiating intrusive and potentially harmful treatment should take account of natural expectations of pregnancy. In many instances, expectant management will be appropriate.

Initial Assessment

When to refer

The point at which any couple might seek assistance will be influenced by a number of factors, not least the degree of anxiety which couples feel in confronting seemingly relentless monthly disappointments. It should be borne in mind that libido and, consequently, coital frequency may be influenced by the experience of infertility and thus affect prognosis. While there is some evidence that sperm parameters may be adversely affected by very frequent ejaculation, the evidence suggests that fertility potential is unaffected. Bearing in mind that sperm can be expected to survive for up to 7 days within the female reproductive tract, couples should be advised to have intercourse every 2–3 days to optimize the chance of conception. The use of temperature charts or ovulation [luteinizing hormone (LH)] prediction kits to time intercourse should be discouraged.

It may be apparent to individuals that they may be at risk of a fertility problem, and advice may be sought at an early stage. For example, the male may have had a vasectomy, or undergone testicular surgery in childhood, e.g. orchidopexy; either partner may be a survivor of childhood cancer and have undergone chemotherapy; or the female may be aware of an association of absent or irregular periods with infertility. For some couples, a concern through the high profile which infertility now attracts in the media may have eroded their self-assurance about their fecundity.

In any circumstance, all people seeking advice about fertility should have prompt access to an integrated multidisciplinary service that provides efficient and accurate assessment of their clinical situation. This should lead to individualized care founded on evidence-based principles of management. Care should be reinforced by access to adequate information and appropriate counselling services. At all times, the infertile should be treated with respect and supported in making informed choices about their clinical management.

Integrated care

Integrated care, by definition, must include the general practitioner (GP), whose role is of fundamental importance (Hamilton 1992). Infertility is a deeply personal problem and many individuals will prefer to discuss intimate matters with someone they know and trust. The counselling support that the GP can provide as preliminary assessment is made and investigations initiated is an excellent foundation for provision of care. Not infrequently, the male and female may be registered with different GPs. This can present difficulties. One should always consider that infertility is a problem affecting both parties, and each may contribute to the pathogenesis. Once referral is made to a specialist clinic, increasing the demands on couples’ time, the intrusive nature of some of the investigations may add to the stress of the situation. Infertility, its investigation and treatment, can threaten domestic stability and it is often the GP, through longstanding knowledge of the couple and their families, who may be in the best position to provide support for those struggling to come to terms with continued disappointment.

All patients should be seen as couples in appropriate surroundings, and the facilities in the surgery should permit examination of both partners. Sufficient time, ideally 30 min, should be made available to permit adequate overall assessment of the problem.

Female assessment: history

Points requiring particular attention in the history and examination of the female are shown in Table 20.2.

Table 20.2 The initial assessment of female infertility: history and examination

Appropriate Initial Investigations

Should couples present to the GP in advance of 1 year of infertility, it may be unnecessary to pursue vigorous investigation unless there is something obvious in either the history or examination. For the GP, it is advisable to ensure that the female is rubella immune and that she is taking folic acid supplementation (0.4 mg/day) to reduce the chance of the fetus developing a neural tube defect. If there is a past history of neural tube defect or the patient is taking antiepileptic medication, a higher dose (5 mg/day) is required.

Merely providing the couple with an outline of their excellent fertility potential over the next year may be all that is required to set their minds at rest. More urgency may be required where the female partner is over 35 years of age.

In the hospital setting, the infertile should have access to advice in a multidisciplinary fertility clinic. It may be helpful for the clinic to employ dedicated liaison staff to assist with the referral process.

The sequence of investigation will be the same regardless of whether the couple are seen for the first time in the GP surgery or the fertility clinic. An explanation of the steps in the process of investigation should be given to the couple at the outset. Three simple questions need to be answered:

• Are sperm available? (i.e. is there evidence of normal spermatogenesis and ejaculatory competence?)

• Are eggs available? (i.e. is the woman ovulating?)

• Can the gametes meet? (i.e. is there a pelvic problem in the female impairing normal gamete/embryo transport and is coital function adequate?)

The principles of investigation of the male will be discussed in detail in Chapter 21. Suffice it to say that semen analysis remains the cornerstone of assessment. In administrative terms, it is helpful if the analysis is done in a dedicated andrology laboratory which serves the fertility clinic, to which onward referral would be made if required.

Disorders of Ovulation

Disturbances in ovulation are the principal factor in approximately 20% of couples presenting to clinics with fertility difficulties. In women who have a regular monthly menstrual cycle (21–42 days), it is most likely that ovulation is occurring normally. The release of the egg from a mature follicle is dependent on the production of a surge of LH by the pituitary gland. This hormonal dynamic initiates the final steps in meiosis, required to allow the oocyte to reach maturity, thus permitting normal fertilization. LH causes the ovarian follicle to rupture and release the egg within; under its influence, the steroid biosynthetic capability of the ovary changes dramatically. Granulosa cells almost exclusively synthesize and release oestradiol in the follicular phase of the cycle, but produce both oestradiol and progesterone during the luteal phase of the cycle. The direct observation of follicular rupture to assess ovulation is not practical in a clinical sense, and thus the release of the oocyte is usually inferred through indirect methods, most often the measurement of progesterone in the putative luteal phase of the cycle.

Presumptive signs of ovulation

Measurement of serum progesterone

Serum progesterone levels in excess of 30 nmol/l 7 days after ovulation are usually taken as indicative of satisfactory ovulation, although lower levels are not incompatible with egg release and corpus luteum formation (Hull et al 1982, Wathen et al 1984). This is a retrospective measure of ovulation in so far as the peak level of progesterone is found after egg release. It is important to relate progesterone levels to the timing of subsequent menstruation. Samples will typically be checked on day 21 of a 28-day cycle. Serial checks will be required if the cycle is longer than this or is variable in length. Shorter cycle length will require an assessment earlier than day 21. Testing for LH is difficult in practice since the day of the LH surge cannot be predicted in advance with certainty. Urinary kits are available to detect LH and can be helpful in treatment cycles where the timing of artificial insemination is critical. Their use in detecting ovulation in routine investigation is not encouraged.

In the absence of any additional clues in history or examination to suggest an endocrine disturbance, assessment of ovulation through progesterone measurement will be sufficient on its own to confirm normal ovulatory function. However, if there is a history of irregular periods or amenorrhoea, especially if associated with galactorrhoea, hirsutism or obesity, additional endocrine investigations will be required. These include the measurement of follicle-stimulating hormone (FSH), LH, thyroid-stimulating hormone and prolactin, timing sampling to coincide with the early follicular phase of the cycle if the woman is having periods. If significant hirsutism or acne is present, the measurement of testosterone, sex-hormone-binding globulin and adrenal androgens, including androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulphate and 17-hydroxy progesterone (17-OHP), should be performed.