In the UK, demands on fertility services are likely to increase. Changing sexual lifestyles are leading to increasing incidence of sexually transmitted diseases, some of which contribute to subfertility. In addition, women are delaying childbearing. Since 1975, there has been a doubling in the proportion of births to women age 30 and over in England and Wales. We know that one in six couples require referral for investigation and/or treatment for subfertility. Recent guidelines published by the National Institute for Clinical Excellence (NICE) and further comments by the Secretary of State for Health have made couples more aware of what may be available, although this often leads to falsely high expectations both of fertility treatments and of service provision. Natural human fertility is low compared with most other species. Peak human fertility (the chance of pregnancy per cycle in the most fertile couples) is no higher than 33%. Because of this, it is quite unrealistic for couples to expect (1) a higher chance of pregnancy than this from any fertility treatment, and (2) considerable effort on the part of scientists and clinicians to try to do so.

Normal expectations from attempts at conception

After the onset of regular unprotected intercourse, 90% of fertile couples should become pregnant within the first year. After 2 years, this rises to 95%. Conversely, 5-10% of normal fertile couples take more than a year or two to conceive. Some couples therefore will present with a delay in conceiving purely by chance, as they have low normal fertility rather than subfertility. The usual criterion to define subfertility, and therefore the trigger to initiate investigations, is a delay of more than 1 year. Investigations should establish a diagnosis promptly and identify couples likely to need referral for specialist treatment.

Causes of subfertility

In Table The most likely causes of infertility and their relative frequency, noting that up to 15% of couples have more than one cause for their subfertility, the major causes of subfertility are listed. They include sperm dysfunction, ovulation disorder and fallopian tube damage.

Table: The most likely causes of infertility and their relative frequency, noting that up to 15% of couples have more than one cause for their subfertility

Cause Frequency
Sperm defects or dysfunction 30%
Ovulation failure (amenorrhoea or oligomenorrhoea) 25%
Tubal damage 20%
Unexplained infertility 25%
Endometriosis (causing damage) 5%
Coital failure or infrequency 5%
Cervical mucus defects or dysfunction 3%
Uterine abnormalities (e.g. fibroids or abnormalities of shape) <1%

Disorders of sperm function (abnormal motility, survival or mucus penetration) impair the chances of fertilization. A complete absence of sperm in the man’s ejaculate due to blockage or failure of production is most unusual (2% of cases referred to specialist fertility clinics).

Women who are not ovulating may have variable cycle lengths, oligomenorrhoea or amenorrhoea. Poly cystic ovary syndrome will be present in 90% of women with oligomenorrhoea and 30% of women with amenorrhoea.

Most fallopian tube blockage or damage is due to Chlamydia trachomatis (up to 80% in our clinic). Such damage and adhesions (due to previous surgery or endometriosis) involving the tubes or ovaries are found in about 20% of couples referred to fertility clinics.

Endometriosis and cervical mucus disorders are infrequent causes of subfertility. Minor endometriosis, without structural damage or adhesions, may not even cause subfertility.

About 15% of couples will have more than one cause for their subfertility. Because of this, it is important to carry out complete investigations from the outset rather than focussing treatment on an incorrectly presumed, isolated cause. In about 25% of couples, no definite cause will be found, even after complete investigation. These couples are said to have unexplained subfertility.

Other factors that affect fertility

As mentioned, fertility and the likelihood of successful treatment is reduced as the female partner in a couple gets older. This effect is seen even in younger women, when a depleted ovarian reserve will reduce natural fertility and can be predicted by a raised serum follicle stimulating hormone (follicle stimulating hormone) level. Older women also have a reduced chance of success if using their own eggs in assisted-conception therapy.

Other factors such as extremes of weight loss or obesity also reduce female fertility. Being overweight reduces the chances of conception and increases the risk of miscarriage.

Smoking, particularly by the woman, has been shown to reduce fertility. The longer a couple are trying to conceive, the greater the likelihood that they will not do so, particularly if trying for more than 3 years. A previous term pregnancy is associated with a better chance of conception, either naturally or following treatment.

History and examination

Couples should be seen together from the outset, and a full medical history taken from both partners. Measurement of body mass index; assessment for any signs of endocrine disorder, particularly polycystic ovarian syndrome; and a pelvic examination should be part of any examination for the woman. Examination of the man is not usually necessary unless indicated by his medical history or if his initial semen analysis result is abnormal. In most couples the initial history and examination will give little indication of the cause of their subfertility and full investigations will be needed.

Investigations of Infertility

These can be considered as general investigations (justifiable for any couple desiring a pregnancy) and specific investigations (to help establish a particular cause). Full initial investigations are advisable for all couples. Do not make assumptions about the diagnosis — 15% are likely to have more than one abnormality.

Initial investigations for ovulatory disorder need to be undertaken at specific stages of the woman’s cycle:

Progesterone: For women with regular cycles, their luteal phase progesterone may be measured 7 days before the expected date of menstruation (and we advise that the patient ring to confirm the date of onset to ensure validity of the sample). For women with irregular length cycles, their luteal phase progesterone may be best measured at 5-day intervals from 7 days before the earliest expected date of menstruation until the time they begin their next period.

follicle stimulating hormone and luteinizing hormone: Measurement of follicle stimulating hormone and luteinizing hormone (luteinizing hormone) should be undertaken between days 2-5 in women who have periods or, if cycles are very infrequent or absent, a random follicle stimulating hormone and luteinizing hormone measurement is acceptable.

TSH: Measurement of thyroid stimulating hormone (TSH) is important, although it is rarely abnormal, especially in women with regular cycles. However, frank or compensated hypothyroidism is readily treated and, if missed, is associated with an increased risk of miscarriage and possible long-term health consequences for any child.

Prolactin: Hyperprolactinaemia is rare in the absence of amenorrhoea.

SHBG: Sex hormone binding globulin (SHBG) is not a routine investigation, but a low sex hormone binding globulin result supports the diagnosis of polycystic ovary syndrome.

Seminal analysis is the primary male investigation, although it is a poor predictor of sperm function. A poor seminal analysis result is insufficient for making a diagnosis of sperm disorder. If the first result shows a low sperm count or complete absence of sperm, it should be repeated preferably 2-3 months later because of the long development cycle for sperm, which can be influenced by various factors, even by a high fever.

The best initial screen for tubal disorder is Chlamydia trachomatis serology. If raised (>1:256), the chlamydia antibody titre is associated with a high likelihood of tubal infective damage. High levels of antibodies indicate current or previous tubal infection and both partners should be treated with an appropriate antibiotic, e.g. doxycycline, azithromycin or ofloxacin (see Chlamydia). Consideration should be given to lower genital tract infection screening in the presence of high levels of IgM antibody in the screen. We do not advocate contact tracing in the presence of abnormal antibody titre alone. Treatment does not correct tubal damage but prevents reactivation if laparoscopy or other pelvic surgery is carried out.

What treatment options are open to couples?

When positive chlamydia serology or hysterosalpingography (HSG) suggest fallopian tube damage, appropriate antibiotic therapy for chlamydia followed by early referral for specialist opinion is indicated. If either HSG or laparoscopy indicate damage, surgical intervention is effective.

Treatment for disorders of ovulation depends on the underlying cause. Polycystic ovary syndrome (PCOS) accounts for most cases of oligomenorrhoea, and about one-third of those with amenorrhoea. A recent consensus document has been published jointly by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine and this provides further details on the diagnostic categories required to fulfil the diagnosis of polycystic ovary syndrom. In primary care, more can be done for the treatment of ovulatory dysfunction than for other causes of subfertility. Simple treatments to induce ovulation include clomifene citrate and, for women with hyperprolactinaemia, dopamine agonists. Clomifene citrate (usually given from cycle days 2-6 inclusive) promotes the release of additional follicle stimulating hormone and luteinizing hormone to stimulate follicular development. The starting daily dose should not exceed 50 mg and probably should never exceed 100 mg daily in primary care except in very obese women. Mid-luteal serum progesterone measurements can be used to check for an ovulatory response. Follicle numbers could also be monitored by ultrasound, but there is no convincing evidence that this reduces the risk of multiple pregnancy (mainly twins) with clomifene, which is about 8%. Because of a possible association with later borderline ovarian tumours, clomifene should not be prescribed in nulliparous women for more than 12 months.

Dopamine agonists such as bromocriptine and cabergoline are safe and effective treatments for hyperprolactinaemia. However, the diagnosis and monitoring of women with presumed hyperprolactinaemia can be sufficiently complicated to warrant specialist referral. It is worth considering pharmacological causes for hyperprolactinaemia, such as dopamine antagonists, some antihypertensives and major tranquillizers, before referral. It is unlikely that dopamine agonist therapy will overcome an iatrogenic cause of raised prolactin levels.

In the treatment of women with polycystic ovary syndrome, there has been recent interest in the use of metformin. It has been shown to increase sex hormone binding globulin, presumed to be a secondary response of reducing hyperinsulinaemia, and thus reduce free testosterone levels in circulation. It also reduces luteinizing hormone concentrations and ovarian sensitivity to luteinizing hormone. Over 90% of women with oligomenorrhoea or amenorrhoea undergoing treatment with metformin have been reported to experience a return of normal cycles, with 20% conceiving within 6 months of treatment.

The starting dose of metformin is 500 mg daily. At this dose, we find that many women get more regular ovulatory cycles. If not, the dose may be increased to 500 mg twice daily for 3 months minimum. If cycles become regular, it is worth continuing for 6 months at this dose. If the woman’s cycle remains irregular, the dose can be increased to 500 mg three times daily or 850 mg twice daily. Serum progesterone measurements at 5-day intervals from day 21 will indicate whether normal ovulation is occurring. Ovulation can be expected in about 30-40% of women with metformin alone. For women who are still not having periods and/or ovulatory progesterone levels, additional clomifene may be used as described above. The combination of metformin and clomifene will induce ovulation in about 90% of women with polycystic ovary syndrome. Side effects of metformin include mild nausea, diarrhoea and abdominal bloating. These are minimized by the gradual increase in dosage and are almost always transient. No teratogenic effects have been reported from it being taken in early pregnancy (and some have advocated its use); metformin should be stopped when the woman has a positive pregnancy test.

Couples in which the man has sperm dysfunction need early referral for in vitro fertilization (IVF), usually with intracytoplasmic sperm injection (ICSI), the direct injection of a single sperm into each egg. Where access to IVF/ICSI is not possible, there is the option of donor insemination.

For infertile women with endometriosis, clomifene may help optimize fertility if the duration of subfertility is less than 3 years. In the remainder, in vitro fertilization is the most effective treatment to achieve a pregnancy, and early referral to a specialist clinic is advised.

Provision of in vitro fertilization and other assisted reproduction therapies will continue to be less than transparent and of variable availability in the UK for some time. All couples who are infertile can expect to have certain levels of service provision, through NICE, such as three cycles of in vitro fertilization or intracytoplasmic sperm injection treatment. This is likely to occur at different rates in different parts of the UK, while the full implication of the NICE guidelines is considered.

Summary

In this section, the causative and contributory factors for infertility and the management options are reviewed, with a particular emphasis on treatment in primary care rather than in the hospital setting.

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