Subfertility may be defined as lack of a clinically recognized pregnancy after 1 year of unprotected intercourse, as approximately 90% of normally fertile couples conceive within a year of attempting conception. It is a very common problem: it is thought that between 10% and 20% of couples in the reproductive age group are involuntarily infertile and request specialist help for this at some time in their lives (). Subfertility is an extremely distressing condition; the pressures on many couples to have a child are very strong and failure to achieve a successful pregnancy can have profound psychosocial consequences. Appropriate and sensitive investigation will usually lead to an explanation for subfertility, a possible basis for treatment and also a realistic prognosis.

If possible the couple should attend together for at least the first consultation. A plan of investigation and management can then be outlined.

Aetiology

It is thought that a female factor is predominantly responsible for subfertility in more than a third of couples and a male factor in another third. In many couples there are both adverse female and male factors. Approximately 25% of couples seeking advice for either primary or secondary infertility are found to have so-called unexplained infertility (). In one study of 708 couples with infertility of at least one year’s duration, and an average of two and a half years’ duration, the main identifiable causes of subfertility were defective spermatogenesis (24%), defective ovulation (21%), tubal damage (14%), endometriosis (6%), cervical mucus problems (3%) and coital failure (6%). Infertility was unexplained in 28% of these couples ().

In order to assess the efficacy of treatment it is important to use appropriate statistical methods. Adequate randomized controlled trials of new treatments should be performed when possible. Life table analysis is a useful method of describing the results of treatment and allowing predictions of the probability of conception in different groups of patients to be made ().

It is very important to know when to stop investigation and treatment, and even to discuss positively the advantages that there may be in not having children, if there is no chance of a successful pregnancy.

Investigation

If the woman is menstruating regularly and no obvious cause for infertility is found, she should be asked to complete a basal body temperature chart (see below). A luteal plasma progesterone level can be measured; the blood sample must be timed to be taken 9 to 5 days before the onset of a period, when the plasma progesterone should be >30nmol/l (). Rubella immunity can be checked at the same time if this has not already been assessed.

The partner is asked to provide a semen sample for analysis () and an arrangement is made to perform a postcoital test (). If the results of these investigations are satisfactory a test of tubal patency should be performed after 12-18 months of regular unprotected intercourse ().

Basal body temperature (BBT) chart

The sustained rise in BBT of approximately 0.3°C or 0.5°F in the luteal phase of the cycle is due to progesterone production by a corpus luteum. A similar rise occurs with the exogenous administration of progesterone or a progestogen.

Although a BBT chart is said to detect whether a woman is ovulating or not, a biphasic chart indicates that a corpus luteum has been produced rather than that ovulation has actually occurred. It is possible for a corpus luteum to be formed without the egg being released from the follicle (luteinized unruptured follicle syndrome) but this is probably usually a sporadic event and relatively uncommon in practice (). A normal biphasic temperature chart with a luteal phase of 10-14 days is therefore usually indicative of ovulation.

There is a diurnal and activity related variation in BBT and the temperature should therefore be taken on waking and before rising in the morning. BBT charts can be very difficult to interpret in those doing night work.

Temperature charts seldom look like the examples given in fertility booklets and the woman should be told this and that it is difficult to be sure that ovulation has occurred, except in retrospect, as small fluctuations in temperature are common. The chart should not be used to time intercourse, as once the temperature has definitely risen it becomes increasingly unlikely that conception will occur. If the pattern is consistent each month the chart can be used to predict the probable day of ovulation in subsequent cycles to within 3 or 4 days. The best advice for timing intercourse is for the couple to have intercourse roughly every other night from days 8 to 16 of the cycle if the woman has a regular 28-day cycle or from 4 or 5 days before the predicted temperature rise until 3 days after it has risen. It is important, however, that the couple are not mesmerized by the temperature chart.

Another advantage of a temperature chart is that it will give an early indication that pregnancy has occurred: if the temperature continues to be elevated for more than 16-18 days and menstruation does not occur, it is likely that the woman is pregnant. Many women are not keen on doing temperature charts and if three cycles are normal they should be encouraged to stop if they want to.

If the BBT chart is not biphasic a plasma progesterone estimation should be arranged a week before a period is due, as in some women a clear-cut rise in temperature is not evident even when ovulation is occurring and luteal progesterone levels are normal.

Postcoital test

The timing of the postcoital test is very important as it is most likely to be positive when the cervical mucus is increased in volume and made receptive to sperms by increased oestrogen levels in the late follicular preovulatory phase of the cycle. In a regular 28-day cycle the test should be performed on day 12 or 13, otherwise it should be timed by previous temperature charts or by an ovulation prediction kit which detects the luteinizing hormone surge in the urine. It is very demoralizing for the woman, her partner and the doctor if the test is performed on an inappropriate day of the cycle with a consequent negative result.

The couple should have intercourse as usual the night before the test. Sperms usually remain active in normal mucus for at least 18 hours and the woman can be examined in a morning or afternoon clinic. She must avoid douching or bathing.

A bivalve speculum, lubricated with water soluble jelly, is inserted into the vagina, and the external os of the cervix, which should be gaping, is exposed. Cervical mucus is aspirated, from the endocervical canal, with a syringe and a plastic quill, or a capillary tube, and is examined immediately under a microscope. The mucus should be abundant (>0.3 ml), clear and stretchable (>10cm) and there should be more than 5-10 sperms moving purposefully, with forward progression, per high power field. If the test is negative it should be repeated. A normal result was found to be a good prognostic indicator of future conception in one study () but not in another ().

Sperm mucus invasion test

A sample of the woman’s preovulatory cervical mucus is placed on a slide and stretched along the lines of its strands; an aliquot of the partner’s semen is then put at one end of the mucus. The rate of invasion of the sperms into the mucus and the activity of the sperms are observed under a microscope. If there is immobilization of the sperms, a crossed hostility test should be performed.

Crossed hostility test

The woman’s preovulatory cervical mucus is placed on a slide and stretched along the line of its strands; normal ‘donor’ sperms are then put at one end of the stretched mucus. The partner’s sperms are placed on another slide at the end of stretched ‘donor’ preovulatory mucus. The rates of invasion of the sperms into the mucus and the activity of the sperms are observed under a microscope.

In these tests it is important not to let the mucus dry out; an alternative method is to aspirate the mucus into a tube, the end of which is immersed in the semen to be tested. Alternatively a penetration meter can be used ().

Tubal patency tests

These are invasive and are not usually undertaken until the couple have been trying for a baby for at least a year and it has been demonstrated that ovulation and spermatogenesis are occurring.

Tubal insufflation with carbon dioxide

This is the simplest technique but it is seldom used nowadays. Carbon dioxide is delivered, using a specially designed apparatus, via a cannula placed in the cervix. The pressure is recorded on a graph and any obstruction to the passage of gas can be demonstrated. This may, however, be due either to tubal spasm or a pathological block of both tubes. If the gas flows freely the patient will often complain of shoulder-tip pain due to irritation of the diaphragm by carbon dioxide. A ‘normal’ result does not, however, exclude adhesions or unilateral tubal blockage. Tubal insufflation is therefore of limited value but it is sometimes used as an outpatient screening test.

Hysterosalpingography

This is usually performed as an outpatient procedure in the early follicular phase of the cycle (to ensure that the woman is not pregnant). It has recently been suggested, in addition, that the woman should not attempt to achieve a pregnancy in that cycle or the subsequent one because the ovum may be sensitive to radiation for at least 7 weeks before ovulation. Radio-opaque contrast medium is slowly introduced into the uterine cavity via a cannula placed in the cervix, having ensured that there are no air bubbles in the cannula or syringe. Screening is performed and appropriate X-rays are taken ().

Hysterosalpingography can be a valuable technique for demonstrating intrauter-ine (Figure 10.3) and intratubal pathology, and a useful alternative to laparoscopy when this is contraindicated. Many women find the procedure uncomfortable and it is very important that they should be told what to expect. General anaesthesia is seldom required but mefenamic acid (500 mg) can be given orally beforehand if necessary.

Laparoscopy

The advantage of laparoscopy is that the pelvic organs can be visualized; peritubal and periovarian adhesions and endometriosis are commonly found. Tubal patency is checked by instillation of dilute methylene blue via the cervix. As laparoscopy is an invasive and potentially dangerous procedure (), it should not be undertaken until the couple have been adequately investigated for other causes of infertility and have had an appropriate length of time to achieve a pregnancy.

Hysteroscopy

This can usefully be performed at the time of laparoscopy to exclude the presence of intrauterine pathology ().

Treatment of female causes of subfertility

Anovulation

The management of women with amenorrhoea and oligomenorrhoea is discussed in Chapters 6, 7 and 15. The management of appropriately investigated anovulation is summarized in Table Summary of treatment of anovulation, following appropriate investigation:

Hypothalamic amenorrhoea (LH, follicle stimulating hormone and prolactin normal):

  • Achieve normal body mass index, if abnormal
  • Clomiphene
  • Clomiphene + hCG
  • Gonadotrophin therapy or luteinizing hormone releasing hormone infusion

Polycystic ovary syndrome:

  • Clomiphene
  • Clomiphene + hCG
  • Ovarian diathermy

Hyperprolactinaemia (thyroid function normal):

Infrequent ovulation

Some women have ovulatory cycles with a long follicular phase. If the cycle length is 35-42 days, ovulation occurs only nine or ten times a year. Administration of clomiphene 50 mg/day from the third day of the cycle for 3 days will often shorten the follicular phase to a normal length and cause ovulation to occur more frequently and predictably.

Short luteal phase or inadequate progesterone level

The inadequate luteal phase is an ill-defined and poorly understood condition which has been recently reviewed by Soules () and McNeely and Soules (). Various definitions have been proposed, such as a short luteal phase, detected with a BBT chart, decreased luteal progesterone levels and persistently out of phase endometrial biopsies, but none are satisfactory. The temperature chart may appear normal even when plasma progesterone levels appear suboptimal and the endometrium is out of phase; progesterone is secreted in a pulsatile fashion and a single estimation may not be representative of overall production; there is considerable variation in the interpretation of endometrial biopsies (), and it is unreasonable to undertake this investigation repeatedly. In addition a defective luteal phase may occur as a sporadic event from time to time in an otherwise normally fertile woman.

However, in practice a short luteal phase is usually diagnosed from a temperature chart, and an inadequate progesterone level from persistently low midluteal progesterone levels, measured 9 to 5 days before the next period. Endocrine disorders such as hyperprolactinaemia and abnormalities of thyroid function should be excluded.

An inadequate luteal phase is often associated with an inadequate follicular phase and treatment with clomiphene 50 mg/day for 3-5 days from the third day of the cycle will often be effective; alternatively progesterone supplementation of the luteal phase may be tried (), or gonadotrophin therapy may by instituted. If there is no response to these forms of treatment and no endocrine abnormality is found, ultrasound evaluation of ovarian function during the cycle should be undertaken and, if indicated, endometrial biopsy should be performed in the luteal phase.

Treatment of abnormal cervical mucus

If the mucus is very cellular and there is evidence of infection this should be treated. Inadequate mucus may sometimes be improved by the administration of small doses of oestrogen in the late follicular phase, or occasionally gonadotrophin therapy may be indicated to increase endogenous oestrogen levels.

Variable results have been reported following intrauterine () or pouch of Douglas () insemination of prepared sperms to bypass the cervix. Alternatively, other assisted conception procedures, such as gamete intrafallopian tube transfer or in vitro fertilization, may be performed ().

Uterine causes of infertility

Asherman’s syndrome of traumatic intrauterine adhesions is uncommon (). Women with this condition may present with amenorrhoea and/or infertility, usually dating from a manual removal of the placenta or uterine curettage related to pregnancy.

Fibroids are very common but are seldom a cause of infertility. Many women with fibroids become pregnant and have straightforward pregnancies. Fibroids are usually best left untreated in women who are trying to become pregnant unless they are symptomatic, or there is a strong likelihood that they are the cause of infertility, as myomectomy can be followed by the development of adhesions which themselves cause infertility. Fibroid polyps and fibroids blocking the intramural portions of both tubes clearly can cause infertility and should be treated. Fibroid polyps should be removed surgically either vaginally or abdominally; those blocking the tubes can be treated using an luteinizing hormone releasing hormone analogue () and/or surgically. Submucous fibroids may also cause infertility.

Uterine anomalies are an uncommon cause of subfertility. Many women with uterine anomalies have successful pregnancies. Surgery can lead to infertility and to problems if a pregnancy does occur.

Tubal problems

These are a major cause of subfertility and are often very difficult to overcome other than by assisted conception.

Tubal surgery for damaged tubes has a low success rate because even if tubal patency can be restored the epithelium is often severely damaged and normal transport of the gametes and fertilized ova is impaired. The overall success rate is about 10-20%, in terms of intrauterine conception, but will depend on the extent of damage in a particular case. Success will be most likely when there are peritubal adhesions but the tubes themselves are normal, and least likely when the tubes are damaged and distorted.

Infertility surgery such as adhesiolysis, salpingostomy and ovarian diathermy can be undertaken using the laparoscope and may be performed at the time of the initial diagnostic laparoscopy ().

Reversal of sterilization has a high success rate when the tubes are otherwise normal and only a small segment of the tube has been damaged by surgery. The success rate of reversal of clip sterilization, when the tubes are otherwise normal, is greater than 80% but the chance of successful reversal following diathermy sterilization is much less, and is virtually nil when multiple diathermy burns have been performed (). Before undertaking reversal of sterilization, the type of sterilization that was performed must be ascertained, the couple must be interviewed together and a BBT and semen analysis must be performed. The woman’s rubella status should be determined. A laparoscopy and possibly a hysterosalpingogram may be indicated to check the state of the tubes before it can be decided whether surgery offers a reasonable chance of success.

A woman undergoing any form of tubal surgery must be warned about the increased incidence of ectopic pregnancy that follows tubal surgery.

Endometriosis

The significance and management of this condition is discussed in Chapter 9.

Sexual problems

Appropriate advice should be given and if necessary the couple should be referred for psychosexual counselling.

 

Selections from the book: “Introduction to Clinical Reproductive Endocrinology”. Edited by Gillian C. L. Lachelin, 1991.

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