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.

Prevalence

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 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.

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.

Presumptive signs of ovulation

Similarly, clinical signs, in addition to regular menstruation, which suggest rather than prove that ovulation is occurring include the presence of Mittelschmerz (mid-cycle abdominal discomfort) or mid-cycle spotting induced through a transient fall in oestradiol coincidental to the LH surge. The production of mid-cycle mucus is oestrogen dependent, and a change in consistency and stretchability (Spinnbarkeit) occurs under the influence of progesterone. This is used in natural family planning techniques as a contraceptive method, but conversely may occasionally have a place in timing intercourse or artificial insemination in promoting fertility. Under the influence of progesterone, basal body temperature (BBT) may rise by 0.5–1.0°C after ovulation. While for some, the finding of such a rise (through serial measurement taken each morning during the periovulatory phase of the cycle) is reassuring, the correlation with serum progesterone levels is poor; couples often find the confusion and uncertainty this brings to be stressful. For this reason, BBT monitoring is not recommended routinely in most clinics.

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.

Ultrasound follicle tracking

Ovarian ultrasound to track follicular development, rupture and corpus luteum formation may be useful in ovulation induction treatment cycles; however, it is time consuming and intrusive, and thus is rarely used in the routine investigation of ovulation. Observation of cysts within the ovary in the luteal phase may be indicative of luteinized unruptured follicles. On occasions, these may be associated with subnormal production of progesterone, so-called ‘luteal-phase deficiency’. It is uncertain whether or not these phenomena are important in the genesis of infertility, since luteal cysts and suboptimal progesterone profiles are not seen consistently in tracked cycles in individual patients. However, scanning in the early follicular phase is helpful in assessing ovarian morphology. A diagnosis of polycystic ovaries is made if there are at least 12 follicles of 2–9 mm diameter and/or the ovarian volume is greater than 10 cm³. Assessment of endometrial thickness within the uterus may be a useful indicator of the level of oestrogen exposure in women presenting with amenorrhoea, which can be of assistance in reaching a diagnosis.

Ovulation failure

The World Health Organization (WHO) classification of ovulatory dysfunction (Table 20.3) is a helpful system of categorizing disorders of ovulation based on the pathogenesis of the disorder.

WHO Type I ovulatory dysfunction may be due to a failure of the hypothalamus to produce gonadotrophin-releasing hormone (GnRH) which regulates the production of gonadotrophins by the pituitary gland. Typically, FSH and LH levels are low (<5 IU/l). Oestrogen levels are also low, and an ultrasound scan of the uterus will show a thin or absent endometrial stripe. The patient fails to menstruate after exposure to a short course of progestagen treatment.

A similar situation may arise in cases of hyperprolactinaemia, which may be associated with galactorrhoea as well as amenorrhoea. Normal pulsatile release of GnRH from the hypothalamus is compromised, and follicular growth ceases with resultant amenorrhoea. This may also occur in some instances of hypothyroidism, where high levels of thyrotrophin-releasing hormone can alter dopamine-mediated regulation of the anterior pituitary and cause hyperprolactinaemia. If hyperprolactinaemia is found, magnetic resonance imaging of the pituitary may identify a microadenoma or, occasionally, a larger pituitary tumour. Some drugs that block the effect of dopamine, such as phenothiazines, certain antipsychotics, metoclopramide and others, can cause hyperprolactinaemia.

Acquired GnRH deficiency may also arise in association with weight loss, as seen in anorexia nervosa and in individuals who undertake excessive exercise. Kallman’s syndrome presents as hypothalamic amenorrhoea associated with anosmia, and results from a congenital absence of GnRH-releasing neurones in the hypothalamus. The syndrome is characterized by a lack of gonadotrophin secretion from the anterior pituitary and consequent hypogonadism. Pituitary failure may arise due to necrosis or thrombosis secondary to tumour formation. Rarely, massive obstetric haemorrhage and prolonged hypotension can lead to pituitary infarction (Sheehan’s syndrome).

The most common ovulation disturbances (WHO Type II) are associated with disordered hypothalamic–pituitary–ovarian function. These women will have oestrogen levels in the normal range and many are overweight, presenting with infrequent or absent periods. A common finding is the presence of polycystic ovaries on ultrasound, seen in up to 90% of such cases. In contrast to WHO Type I patients, these women will usually menstruate after exposure to a short course of progestagen treatment. Ultrasound scanning should be timed to coincide with either a natural or progestagen-induced menstrual period. Where there is clinical or biochemical evidence of hyperandrogenism, this, together with menstrual irregularity and ovarian morphology, should be taken into account in reaching a diagnosis of polycystic ovary syndrome (PCOS). A consensus view on standardized criteria for the diagnosis of PCOS has helped in establishing a uniform approach, and facilitated easier comparison of clinical and research experience in different centres (Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group 2004a, b). It was agreed that the presence of any two of the following triad are sufficient to make the diagnosis: (i) oligo-ovulation and/or anovulation; (ii) polycystic ovaries on ultrasound; and (iii) clinical and/or biochemical hyperandrogenism.

Approximately 10–20% of patients with PCOS have an associated elevation in prolactin, but this is usually mild and not of clinical consequence. On occasions, ovulatory failure may result from 21-hydroxylase deficiency in the adrenal gland leading to elevated serum levels of 17-OHP, an androgenic steroid precursor of cortisol. High androgens disturb normal follicular growth, and patients may present with irregular or absent periods associated with signs of androgen excess including hirsutism, acne and enlargement of the clitoris. Other causes of hyperandrogenism, such as adrenal tumours and Cushing’s syndrome, may need to be considered where adrenal androgen levels are found to be high.

Insulin resistance has been well described in women with PCOS, and it has been estimated that they have a three to seven times higher risk of developing type 2 diabetes in later life; regular screening may therefore be appropriate. Amenorrhoea in PCOS may also be associated with an increased lifetime risk of endometrial cancer. Progestagen-induced menstruation should thus be facilitated three to four times per year, particularly if increased endometrial thickness is seen on ultrasound.

Ovarian failure

In patients presenting with amenorrhoea and where initial biochemical screening and physical examination lead one to suspect ovarian failure (WHO Type III), the presence of a genetic disorder such as Turner’s syndrome (45XO) or Turner mosaic (45XO/46XX) should be considered and a karyotype performed. Occasionally, deletions in one of the X chromosomes or defects in the fragile X gene may lead to ovarian failure, but agenesis of the ovaries (associated with primary amenorrhoea) and premature ovarian failure (presenting as secondary amenorrhoea before 40 years of age) is sometimes found in the presence of a normal karyotype. Acquired ovarian failure may occur as a result of previous medical treatment such as chemotherapy or radiotherapy for cancer. Autoimmune ovarian failure should be considered, and screening for antiovarian antibodies may be useful in reaching a diagnosis. If positive, the need to screen for other autoimmune disorders including hypothyroidism, adrenal insufficiency (Addison’s disease), diabetes mellitus and pernicious anaemia should be considered (see Chapter 17, Ovulation induction, for more information).

X-ray hysterosalpingography

This is an outpatient examination and involves the instillation of either a water- or oil-soluble contrast medium through a cannula attached to the cervix. The fluid, being radio-opaque, can be visualized under X-ray screening conditions. An assessment is made of the normality of the uterine cavity. Passage of dye to the side of the uterus permits an assessment of tubal anatomy (Figure 20.1). The diameter of the tube should be small through its interstitial, isthmic and ampullary portions, but the diameter increases slightly as the infundibulum is reached. Unimpaired passage of dye throughout the length of the tube and dispersal into the peritoneal cavity is suggestive of normal anatomy. If there is impaired flow or localization of spill distally, one should be suspicious of peritubal adhesions. The finding of a hydrosalpinx will be indicative of severe tubal damage. Sometimes, unilateral or bilateral tubal spasm occurs and a mistaken diagnosis of proximal tubal obstruction is made. An intravenous injection of glucagon can help to relax this, but if the finding persists, a cornual block is a possibility. It is important, particularly in women under 25 years of age, to consider the need for antibiotic prophylaxis since Chlamydia infection could be reactivated in susceptible women. Azithromycin or doxycycline is usually used.

Figure 20.1 X-ray hysterosalpingography. This shows a normal uterine outline with passage of dye through tubes of normal calibre and spillage of dye into the pelvis.

HSG should not be carried out if the patient is menstruating. In addition, women should be advised to avoid conception in the cycle in which the procedure is carried out. If unprotected intercourse has occurred, the examination should be deferred.

The contrast medium used in HSG may contain iodine, and the possibility of allergic reactions should be borne in mind. Significant extravasation of oil-soluble contrast media within the pelvis may lead to lipogranuloma formation. There is some evidence that the use of an oil-soluble contrast medium (lipiodol) may enhance the chance of pregnancy in unexplained infertility (Johnson et al 2004), although it has not gained widespread popularity as a therapeutic choice.

Laparoscopy and dye hydrotubation

It is generally accepted that laparoscopy and dye hydrotubation is the gold standard of tubal assessment. In this procedure, which, like HSG, should avoid the time of menstruation and any chance of pregnancy, a coloured dye is injected through the cervix while carrying out a laparoscopic inspection of the pelvis (Figure 20.2). Failure of dye to pass through the tube is indicative of blockage (Figure 20.3).

Figure 20.2 The technique of laparoscopy. (A) Instrumentation. This shows the uterine body with the right fallopian tube and the ovary. (Bi) Normal pelvis with spillage of dye from the fimbrial end of tube (Bii).

Figure 20.3 A blocked fallopian tube with hydrosalpinx formation. The distal end of the tube has been exposed, revealing terminal clubbing.

Direct visualization of the pelvis permits identification of adhesions, fibroids, endometriosis, ovarian cysts and other pathology which may be relevant to infertility and would be missed at HSG. The likelihood of finding tubal disease is increased if the patient has a positive Chlamydia screening test (Coppus et al 2007). Immediate treatment of pathology is also possible at laparoscopy, which may be particularly relevant where endometriosis is found, provided that appropriate consent has been obtained.

The procedure should be carried out in a systematic fashion and a written record, together with photographs if possible, should be made of the findings. At least two ports are required to allow manipulation of pelvic structures to ensure thorough assessment. The bowel can sometimes obscure the view, and a probe to move this out of the way will often be helpful. Sometimes, a third port may be required if the surgeon wishes to treat minor adhesions or endometriosis, in order to allow the introduction of scissors or diathermy/laser instruments and suction/irrigation apparatus.

The use of a diagram, such as that produced by the American Society for Reproductive Medicine (ASRM), to record findings is often helpful in explaining to patients what has been seen and done, as well as providing a formal record of the findings, particularly if endometriosis is found (Figure 20.4).

Figure 20.4 The revised American Society for Reproductive Medicine scoring system for endometriosis.

Revised classification of Endometriosis, American Society for Reproductive Medicine, Vol.47, No.8, May 1997.

General anaesthesia carries a small risk of reaction to the drugs used. In addition, the introduction of laparoscopic instruments presents a risk of injury to intra-abdominal structures such as the bowel, bladder and blood vessels. Patients who have undergone previous abdominal surgery, in particular those with a mid-line incision, are particularly at risk. The technique used in the introduction of instruments may need to be adapted to take account of this increased hazard. Alternatively, HSG may be preferred.

Hysterosalpingo contrast sonography

In the last two decades, HyCoSy has attracted some interest as an additional method for assessing tubal patency (Hamilton et al 1998). Carried out as an outpatient or office procedure, a small balloon catheter is inserted into the uterine cavity through the cervix (Figure 20.5). A vaginal scan is performed while a suspension of an ultrasound contrast agent (Echovist) is injected through the catheter. Usually, only 2–5 ml of fluid will be required. The medium contains galactose granules, and if flow is seen through the length of the tube, it is likely to be patent. Hydrosalpinges can also be identified. Saline alone can be used if inspection of the uterine cavity alone is required, and good imaging of endometrial polyps can be obtained. The technique requires considerable ultrasound skill, and some patients find the instillation of the fluid uncomfortable. There is no evidence of therapeutic benefit through flushing with the medium used in HyCoSy (Lindborg et al 2009).

Figure 20.5 Equipment set-up for hysterosalpingo contrast sonography.

Copyright © Bayer Healthcare Pharmaceuticals.

Hysteroscopy

Hysteroscopic examination of the uterine cavity may be carried out as an outpatient procedure, although if a laparoscopic assessment is being carried out, it is a simple affair to combine the two procedures. Either carbon dioxide or saline/glycine may be used to distend the cavity to permit adequate inspection. Uterine malformations, fibroids, endometrial polyps, adhesions and other conditions may be identified and treated using this technique, although it is controversial whether or not some of these findings contribute to infertility to any great degree.

Evaluation of diagnostic tests of tubal factor infertility

With HSG, one is interested to know whether the test identifies normal and abnormal tubes correctly compared with the gold standard, laparoscopy. The value of a test for tubal blockage (test positive) can therefore be described using a number of statistical descriptors, as shown in Table 20.4.

A meta-analysis evaluating HSG assessment of tubal patency using laparoscopy as the gold standard showed 65% sensitivity and 83% specificity (Swart et al 1995, Mol et al 1996). One can deduce from this that although HSG is of limited value in detecting tubal blockage because of its low sensitivity, its high specificity makes it a better test for identification of tubal patency. The negative predictive value (94%) of the test as a predictor of tubal patency is also high, suggesting that the finding of normal tubes on HSG is likely to be correct. However, a low positive predictive value of 38% of the test suggests that HSG is not a reliable indicator of tubal occlusion, and in the circumstances of an abnormal HSG result, it would be wise to consider a laparoscopic assessment to confirm or refute the findings (National Collaborating Centre for Women’s and Children’s Health for the National Institute of Clinical Excellence 2004).

HyCoSy also performs fairly well in detecting normality and hydrosalpinx formation; however, similar to HSG, it is less reliable in identifying tubal blockage (Hamilton et al 1998).

Endoscopic assessment of the tubal lumen to study mucosal appearance has not proved to be helpful in routine work-up of infertility. Falloposcopy achieves access to the tube per vaginam (Rimbach et al 2001). Salpingoscopy can be performed at laparoscopy or laparotomy where the tube is cannulated through the fimbria (de Bruyne et al 1997). Initially thought to be of potential use in selecting patients with healthy tubal epithelium who might be suitable for tubal surgery, neither of the techniques has gained much popularity and they are rarely used.

Endometriosis

Endometriosis is a debilitating condition which has associations with infertility, particularly where there is anatomical distortion of the pelvis. Women who are susceptible to the condition may have genetic, immunological, hormonal or environmental factors contributing to the problem (Crosignani et al 2006). A family history of the condition should alert the gynaecologist to the possibility, particularly if the common symptoms of dysmenorrhoea and chronic pelvic pain are present. Pelvic examination may reveal a fixed, tender retroverted uterus, and on occasions, there may be endometriotic nodules presenting the vault of the vagina or the rectovaginal septum. A combined rectal and vaginal examination may be helpful if this is suspected. Laparoscopic visualization of endometriotic lesions is the cornerstone of diagnosis, although a histological confirmation of an excised lesion is strictly necessary to be absolutely certain. The accuracy of the diagnosis therefore depends on the degree of skill and vigilance of the surgeon. If endometriosis is found at laparoscopy, it is helpful to stage the disease by reference to the ASRM guidelines (American Society for Reproductive Medicine 1996). There is some evidence that women with mild endometriosis have reduced fertility (Akande et al 2004), and that treatment, such as with diathermy, may improve the natural chances of conception in minimal/mild disease (Marcoux et al 1997). A suspicion of endometriosis may be raised if vaginal ultrasound examination of the pelvis is painful, or if a cyst with a hazy ‘ground glass’ appearance is seen in the ovary, suggestive of an endometrioma. Magnetic resonance imaging of the uterus may be helpful if one suspects adenomyosis. Biochemical assay of CA125, if raised, may be suggestive of endometriosis, although this is non-specific. Women with Müllerian abnormalities promoting retrograde menstruation are at greater risk of developing endometriosis.

Fibroids

Fibroids are among the most common benign tumours in women, with a reported prevalence of 3–8% in unselected women of reproductive age (Borgfeldt and Andolf 2000), although they occur with higher frequency in older women and in certain ethnic populations. Fibroids are often asymptomatic but an association with infertility is possible (Somigliana et al 2007), particularly where the tumour impinges on the cavity of the uterus (Khalaf et al 2006, Klatsky et al 2007). Abdominal palpation and vaginal examination may reveal a mass arising from the pelvis. Ultrasound examination is usually performed to confirm the diagnosis, and this has high sensitivity and specificity as a test. If the relationship between the fibroid and the uterine cavity is unclear from an initial ultrasound assessment, HyCoSy or HSG may be useful to distinguish submucosal from intramural lesions. Hysteroscopic evaluation of the degree of myometrial penetration by the fibroid is essential if surgical excision is contemplated (Di Spiezio Sardo et al 2008). Discrimination between adenomyosis and fibroids may be facilitated with the use of ultrasound where the absence of a tumour capsule and lacunae within the lesion may be suggestive of the former. Magnetic resonance imaging can also be of help.

Potential endometrial abnormalities

Undiagnosed uterine pathology as a cause of infertility, recurrent implantation failure (RIF) or recurrent miscarriage is an attractive concept. However, the evidence that disturbed endometrial receptivity is important in infertility is mixed. Endometrial assessment by timed sampling and histological dating is the most described method of assessing the normality of endometrial development. It is dependent on accurate timing of sampling endometrium relevant to the LH surge (Li et al 2002), and has been largely abandoned in routine practice, as has the concept of luteal-phase deficiency as a major cause of infertility. Ultrasound-measured endometrial thickness is a poor predictor of implantation potential in in-vitro fertilization (IVF) (Margalioth et al 2006), particularly where high-quality embryos are available. Disturbances in cytokine expression and action have been postulated as a cause of RIF, but analysis of these factors remains a research tool rather than a clinical tool. The role of immunological causes and thrombophilia in infertility is also uncertain. Some early studies suggested an association between antiphospholipid syndrome and RIF, but this has not been confirmed in larger prospective studies. The role of natural killer cells in RIF is disputed (Rai et al 2005). For the moment, there is no convincing evidence for an association. An association between hereditary thrombophilia and RIF has also been described in some, but not all, studies, and screening for these disorders is still controversial (see Chapter 23, Sporadic and recurrent miscarriage, for more information).

Postcoital testing

An area of considerable interest over many years has been the assessment of sperm–cervical mucus interaction through the postcoital test (PCT). As the time of ovulation nears, cervical mucus secretion, under the influence of oestradiol, changes in quantity. After intercourse, sperm should swim freely within the mucus and transportation of sperm to the upper genital tract can take place. Cervical mucus–sperm hostility as a cause of infertility continues to be debated due to the methodological issues of concern in its use. The test is intrusive in so far as the couple are asked to have intercourse at a prescribed time, and then the female attends the clinic for a sample of mucus to be obtained from the cervix. The investigator examines the specimen to determine if there are motile sperm visible under light microscopy. In theory, the test could give an indication that intercourse has taken place, that timing is correct, that the mucus is receptive, and that sperm numbers and motility are adequate. In critically evaluating the usefulness of the PCT in clinical practice, many would argue that it lacks predictive power in its ability to identify those who will conceive naturally from those who will not (Oei et al 1995). Furthermore, there is no standardization of the methodology of the test; for example, timing of intercourse in relation to ovulation, timing of examination of sampled mucus relative to intercourse, and ‘normal’ sperm numbers and motility levels within examined mucus (Evers 2002). One study (Glazener et al 2000) found the PCT to be useful in predicting spontaneous conception in couples with otherwise unexplained infertility of a short duration (<3 years). However, a study which examined whether or not intrauterine insemination improved the chance of conception, where a PCT was negative, only showed a marginal effect (Mol 2001).

Diagnostic category

Unexplained infertility presents a frustrating diagnosis for both clinician and patient. The range and accuracy of the tests which are used to investigate the infertile will influence the chance of a ‘diagnostic label’ being attached to the problem (Gleicher and Barad 2006). Whether such a label leads to help in forming a prognosis or formulating a treatment plan is debatable (Siristatidis and Bhattacharya 2007). In some instances, the finding of ‘abnormality’ occurs with similar frequency in both those who ultimately conceive naturally and those who remain infertile (Guzick et al 1994). In recent times, the age profile of patients attending fertility clinics has changed, with many women delaying childbearing for a variety of reasons. For many, age alone is a major factor in determining prognosis, and age may also influence the probability of a diagnosis of unexplained infertility being made. It has been estimated that the chance of reaching a diagnosis of unexplained infertility is doubled if the female is over 35 years of age compared with females under 30 years of age (Maheshwari et al 2008). As discussed below, diminished ovarian reserve may, in theory, be a missed cause of infertility in otherwise unexplained infertility. For most clinics, female age, together with parity and the duration of infertility, are the three factors with the greatest bearing on prognosis.