Infertility

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Chapter 32 Infertility

CHAPTER CONTENTS

Factors in infertility 251
Investigation of infertility 251

Seminal analysis 252
Investigating the woman 252
Unexplained infertility 254
Treatment of infertility 254

Infertility in men 254
Infertility in women 254
Assisted reproductive technologies 254
Success rate of treatment 255
Psychosocial problems associated with infertility 255

A couple who have had regular unprotected intercourse for a period of 12 months without a pregnancy occurring is considered to be infertile and may seek help from a medical practitioner. Infertility affects 10–15% of couples. It is important to understand that humans like other primates are relatively subfertile.

During the first cycle 30% of couples will achieve pregnancy. During the second cycle a further 30% of couples will be successful and 80% will conceive in the first year. In the first three cycles, 30% of the conceptions will end in miscarriage, and almost half these miscarriages occur so early they are undetected except by a positive β-hCG pregnancy test

FACTORS IN INFERTILITY

The factors that may be involved in the couple’s infertility vary depending on local conditions, the population investigated and the referral procedures. Analyses reported by several clinics of large numbers of patients in the past two decades are given in Table 32.1. In a quarter of cases, more than one of the factors is believed to be involved.

Table 32.1 Factors in infertility

Factor Percentage of Cases
Male
Defective sperm production, insemination difficulties 30–40
Female
Ovulation factors 5–25
Tubal or uterine factors 15–25
Cervical/immunological factors 5–10
Unexplained after investigations 10–25

INVESTIGATION OF INFERTILITY

Of the many investigations suggested over the years, most have been found to be of little value, and today there is relative agreement about what tests should be made to reach a diagnosis.

In most cases the woman makes the first contact with a health professional. During this visit, the doctor should obtain information about the history of past illnesses and operations; the woman’s menstrual history; and the couple’s sexual behaviour, including frequency of sexual intercourse. Some women are concerned that they do not have an orgasm and that semen runs out of the vagina. The doctor should reassure the woman that neither of these affects her fertility.

A general physical examination, including a pelvic examination, is made to exclude any current disease. The pelvic examination is performed to detect any gross abnormalities of the genital tract, such as uterine myomata, ovarian tumours and endometriosis (see later). If a cervical smear (Pap smear) has not been taken in the previous year this should be done. Also, laboratory tests should be ordered and should include a full blood examination, including tests for syphilis, rubella and HIV infection, and a urine analysis. If the woman has attended during the luteal phase of her menstrual cycle, blood may be taken to measure the progesterone level to establish whether she is ovulating.

Having completed these initial investigations the medical practitioner should outline the investigations that will be carried out, and their sequence. It is customary to start with a seminal analysis, as the man may have azoospermia or severe oligospermia. This finding would make further examinations of the woman unjustified initially.

Seminal analysis

Ideally, a man should accompany his partner at the first visit so that the investigation plan can be discussed with them both, a history can be obtained from the man, and the man can also be examined. However, it is unusual for a man to attend with his partner. Because of this, and intercourse, the first step is to arrange for a semen analysis, and only if this is abnormal need the man be seen.

The seminal specimen can be obtained in two ways. The man can either attend the laboratory and masturbate there and so provide a fresh seminal specimen, or he can masturbate at home (or have his partner masturbate him) and ejaculate into a clean, dry glass container. This is then taken to the laboratory within 1 hour, and the analysis made.

Standards for a normal seminal specimen have been developed by the World Health Organization (WHO) and are shown in Box 32.1. If the first seminal appraisal is abnormal, two further specimens should be evaluated before a prognosis is made. The most important predictors of male fertility are the percentage of motile sperm, the quality of the motility of the sperm, the motile sperm concentration, the total motile count and the sperm morphology. The absolute count is not a good predictor.

Box 32.1 Normal seminal analysis

Volume >2 mL
Sperm concentration >20 million per mL
Total sperm count 40 million
Motility 60 min after ejaculation >50% with normal progression
Morphology >30% with normal morphology

When the sperm count is less than 20 million per mL, abnormal morphology and motility is often found

The semen analysis is traditionally graded as:

• Normal
• Oligospermia (a count of less than 20 million sperm per mL)

• with normally motile sperm
• with asthenospermia

• Severe oligospermia (less than 5 million sperm in total specimen)
• Azoospermia
• Asthenospermia with normal sperm count.

Abnormal results indicate that the man should be examined and a history taken. The history may show that he is exposed to high heat, certain chemicals, or is taking anticancer drugs. The examination of the man’s genitals is important. The size of his testicles is evaluated and his scrotum is palpated, with the man standing, to detect if he has a varicocele. Treatment of the varicocele has been shown to be beneficial only if the man is oligospermic, as this will double the chance of pregnancy. If azoospermia or severe oligospermia is diagnosed, blood is drawn to measure the level of follicle-stimulating hormone (FSH). A raised level (three times the normal upper limit) indicates testicular failure. If severe oligospermia is diagnosed and the testicular volume and FSH levels are normal, a testicular biopsy is sometimes taken.

Absolute infertility is diagnosed if azoospermia and raised FSH levels are found. Severe infertility is diagnosed if severe oligospermia is found. Relative infertility is diagnosed if the sperm count is between 5 000 000 and 20 000 000/mL. Treatment may be offered to men with relative infertility, although it has to be said that none has proved more effective than placebo.

Investigating the woman

Factors that may delay or prevent fertility in women are:

• Anovulation or infrequent ovulation
• Tubal damage which prevents the passage of the sperm
• Uterine factors, such as intra-uterine adhesions (Asherman’s syndrome)
• Cervical mucus ‘hostility’, which in most cases is an immunological defect.

These factors require to be investigated in the work-up of infertility.

Ovulation

The most effective way to determine whether the woman is ovulating is to measure the serum progesterone level in the midluteal phase of the menstrual cycle. The older methods of daily temperature charting and diagnostic curettage to determine whether endometrial luteinization had occurred are obsolete.

Anovulation is obvious if the woman is amenorrhoeic, and may occur in women who have normal menstrual periods. The investigation of anovulation is discussed in Chapter 28.

Time of ovulation

Knowledge of the time of ovulation is increasingly important in the treatment of some causes of infertility, because conception is most likely to occur on this day or on one of the 5 preceding days. The time of ovulation can be detected by measuring the plasma level of luteinizing hormone (LH) daily over this period. The peak of LH release coincides with ovulation.

Defective luteal phase

A number of infertility specialists believe that some cases of infertility are due to the poor development of the luteal phase endometrium, with the result that the fertilized egg is unable to implant. Other specialists deny that the condition exists. Many treatments have been tried to treat the condition, but none has been evaluated scientifically or proved to be of value.

Tubal factors

The patency of the Fallopian tubes can be evaluated in three ways:

• The first, hysterosalpingography, is performed by inserting a cannula, attached to a syringe, into the cervix and injecting a radio-opaque substance into the uterus under direct imaging. The passage of the dye is observed as it fills the uterine cavity and passes along the Fallopian tubes to spill into the peritoneal cavity. The advantages of hysterosalpingography are that it is a minor operation (the patient need not be admitted as a day-case) and that it will detect any intra-uterine abnormalities (Fig. 32.1).
• A more recent innovation is to use hysterosalpingo-contrast sonography. Under transvaginal ultrasound scanning, a galactose solution is injected into the uterus and passes along the Fallopian tubes, which delineates them more accurately than hysterosalpingography using a radio-opaque substance.
• The third method is to perform a laparoscopy and then to inject a water-soluble dye into the uterine cavity which is observed as it spills through the fimbrial ends of the Fallopian tubes. The advantage of laparoscopy is that, as well as ascertaining that the Fallopian tubes are patent, any peritubal adhesions and endometrial deposits can be detected. Endometriosis is the only abnormality found in about 10% of infertile women, and 40% of women who have endometriosis are involuntarily infertile, but the relationship between the two conditions is unclear. The topic is discussed further in Chapter 35.
image

Fig. 32.1 Hysterosalpingogram showing a normal uterus and tubes.

Currently, the use of colour Doppler ultrasonography is being investigated, as is the use of tuboscopy.

Cervical hostility

Although this term is usually used to indicate that the sperm fail to penetrate the cervical mucus at the time of ovulation, it is more likely that the failure is due to defective sperm function, probably immunological.

Many gynaecologists continue to believe in cervical hostility, and test it by means of the postcoital test. This has been in use for over 100 years and was originally carried out to detect sperm in the cervix. Today, the test is performed as follows:

• The couple have intercourse on one of the two days before ovulation, or on the day of ovulation.
• After the man has ejaculated the woman lies on her back for 20 minutes, and attends the doctor 8–12 hours later so that a sample of cervical mucus can be removed (using a plastic tube attached to a syringe).
• The specimen is smeared on a slide and is examined to determine the degree of penetration of the mucus by actively moving sperm, and their numbers per field.

A positive test (more than 20 actively moving sperm per field) indicates that there is unlikely to be an immunological problem; a negative test provides no useful information. Because of this, more specific sperm–mucus tests have been developed. A second test is the mixed agglutinin reaction (MAR). Human red cells are sensitized with IgG and mixed with sperm. If the spermatozoa are coated with antibody, the mixed agglutinates will be visible. However, the value of these tests is unclear and the predictive value poor.

Unexplained infertility

After adequate investigation, up to 25% of infertile couples will still not have had a cause for their infertility found. Unexplained infertility is frustrating for both the couple and the health professionals.

TREATMENT OF INFERTILITY

Infertility in men

Azoospermia is an absolute barrier to conception, and it is unusual for a pregnancy to occur in a couple if the man has severe oligospermia. For these couples, donor insemination (DI) is a choice. Using DI monthly for 12 months, if necessary, will enable over 65% of women to become pregnant. If sperm can be recovered from the epididymis, a single spermatozoon can be microinjected into the space under the zona pellucida or into the ovum. The delivery rate per treatment cycle is 30%.

Improvement in the sperm count of men with non-severe oligospermia has been attempted using an oral form of testosterone (mesterolone), bromocriptine and antioestrogens, clomifene and tamoxifen, but none have been shown in controlled trials to have a significant effect on pregnancy rates.

An attractive alternative is to concentrate a seminal sample and fertilize several ova using the in vitro fertilization (IVF) technique.

Infertility in women

Anovulation (usually associated with amenorrhoea)

The treatment is as discussed in the treatment of amenorrhoea on page 223. Inducing superovulation with drugs can assist conception when the man has a low sperm count or the woman is experiencing oligomenorrhoea.

Tubal damage

Two choices are available, depending on the severity of the tubal damage and the wishes of the patient. The first approach is to attempt to make the Fallopian tubes patent, using microsurgery. If only the fimbrial ends of the tubes are blocked, a salpingostomy or fimbriolysis is carried out. This results in a 40% chance of the woman conceiving in the 2 years following the operation. Greater tubal damage necessitates a tubal anastomosis, with a success rate of no more than 20%, whereas reversal of a tubal ligation is followed by a pregnancy rate of 60%.

Given these relatively poor results (except in the case of reversal of a tubal ligation), the alternative approach – IVF – is recommended. The procedure is less invasive, the risk of ectopic gestation is lower and the chance of giving birth to a healthy baby is greater.

Cervical hostility (immunological infertility)

The oldest method of treatment is for the man to use condoms for 6 months in the hope that the antisperm antibodies will be eliminated. Other treatments are for the man to take low-dose corticosteroids (prednisone 20 mg twice daily for the first 10 days of the woman’s menstrual cycle) for 3 months; to use washed sperm introduced into the uterine cavity; or to use IVF or gamete intrafallopian transfer (GIFT) techniques. None of these treatments has been properly evaluated, and it appears that as many pregnancies occur with treatment as when no treatment is given.

Unexplained infertility

Current opinion about the treatment of couples who have been diagnosed with unexplained infertility is confused. If no treatment beyond reassurance is given, over 40% of the women will become pregnant within 3 years. However, if the couple wish, or if the woman is over 35, IVF or GIFT may be used soon after diagnosis, rather than delaying for 3 years.

Assisted reproductive technologies

These technologies, that is, IVF and its variants (Table 32.2), have added a new dimension to the treatment of infertility. In the past decade considerable advances have been made in reducing the pain involved, the invasiveness of the procedure and the cost. The procedure is as follows:

1. The woman is given ovulatory drugs, FSH, gonadotrophin-releasing hormone agonists and human chorionic gonadotrophin, to produce superovulation.
2. The eggs are retrieved from the ovaries by the transvaginal route under ultrasonic guidance.
3. The eggs are prepared for fertilization and only good ova are selected.
4. Sperm are added to the selected eggs in vitro.
5. One or two (occasionally three) fertilized eggs are transferred into the uterus, or into the Fallopian tubes.

Table 32.2 Methods of assisted conception

image

The GIFT technique involves similar procedures except that fertilization does not taken place before transfer of the ova and sperm into the Fallopian tubes.

Intracytoplasmic sperm injection involves the direct injection of the sperm into the nucleus of the ova and is the treatment of choice for male infertility due to oligospermia.

The calculation of the success rates of IVF procedures is complex because couples who have not been successful early in treatment cycles may not return for further treatment. The ‘take-home baby’ rates stratified by age are shown in Table 32.3.

Table 32.3 Percentage cumulative live-birth rates after IVF according to maternal age

image

Success rate of treatment

Four couples in every 10 treated for infertility will have a ‘take-home baby’, in most cases thanks to treatment, but about 20% of cases cannot be attributed to the treatment. The success rate for the treatment of various infertility factors is shown in Table 32.4.

Table 32.4 Pregnancy rates in infertility*

  Proportion of All Cases of Infertility (%) Pregnancy Rate† (%)
Male:
Azoospermia 7 65 (using DI)
Oligospermia 25 30
Female:
Amenorrhoea 7 90
Other ovulatory 14 60
Tubal damage 16 20
Endometriosis (severe) 2 30
Uterine abnormalities 1 70
Male–female (immunological) 5 15
Unexplained 23 60

* Take-home baby’ rates are lower.

† Within 2 years of diagnosis with or without treatment.

PSYCHOSOCIAL PROBLEMS ASSOCIATED WITH INFERTILITY

The conception, and later the birth, of a healthy child is a significant life event. To most women, motherhood is the expression of their nurturing gender role and their femininity, and to most men the siring of a child is a visible demonstration of their masculinity and potency. For most couples, parenthood is an expression of their love for each other. However, society still regards infertility as an illness.

The psychological impact of infertility can be considerable and the necessary investigations psychologically disturbing, particularly to the woman, who has more tests performed than her partner. She may perceive these as invasive and intimate, involving a loss of control over her body.

If a bar to fertility is detected in either partner or, if after investigation and treatment a pregnancy does not occur, the couple may be subjected to considerable psychological strain and may develop psychosexual problems.

This possibility can be reduced in several ways, which involve the infertility specialist and the couple’s general practitioner, who should have a key role as he knows the couple better. This implies that there must be good communication between specialist and doctor.

• As early as possible in the infertility work-up the medical practitioner should provide the couple with a clear detail of the investigations proposed, the reasons for them, and the sequence in which they will be performed. As the couple may be so anxious that they may listen to but not hear what is being said, it is helpful to suggest that they read a book about infertility or are provided with pamphlets.
• The investigations should be kept to a minimum, and only those that produce reliable information should be made. Once information is obtained, the couple should be told the results and be given the opportunity to ask questions.
• The attitude and behaviour of the doctor should be supportive, communicative and empathetic.
• If an absolute or severe barrier to conception is found, appropriate counselling should be offered. Inability to have a child represents a real loss, and mourning is an appropriate response. In counselling, the approach is to consider all the findings together as causing the couple’s shared unhappiness, so that neither partner blames the other.

Couples who are in an IVF, GIFT or other assisted reproductive programme need special care, as in most cases these technologies are a ‘last resort’ in their attempt to have a child. The egg retrieval may be painful and the whole process psychologically traumatic, particularly if the woman perceives parenthood as a prerequisite for personal fulfilment. Most couples cope well, but one-third of women experience anxiety or depression and one in seven becomes severely distressed.

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