Management of infertility

I H Lok 駱紅, L P Cheung 張麗冰, C J Haines 韓英士

HK Pract 2003;25:249-261

Summary

Up to 15% of couples find it difficult to conceive. The most common causes of infertility are ovulatory disorders, tubal disease, endometriosis and semen factors. Infertility may be due to a single or multiple factors, but in up to 25% of cases, no cause is identifiable. Doctors in primary care play an important role in identifying the underlying causes and either initiating treatment or making early referrals. This article outlines the important steps involved in the initial evaluation of an infertile couple. It also aims to provide a brief review on current management options according to the underlying causes.

摘要

15%的夫婦有受孕困難。不孕症最常見的成因是排卵紊亂、輸卵管疾病、子宮內膜異位和精液問題。 不孕症可以由單一或多種因素引起，但25%的個案原因不明。基層醫生在確定成因、開始治療和及早轉介方面， 扮演著重要的角色。本文概述初步評估不孕夫婦的重要步驟，並簡單回顧現行因應不同成因，而採用的治療選擇。

Introduction

Whilst for some couples childlessness may be a deliberate choice, up to 15% of couples are under the stress of being unable to achieve a pregnancy spontaneously. Advancing age of the female partner has an adverse effect on fertility, and delayed childbearing is increasingly contributing to the problem of infertility. Infertility or subfertility is generally defined as the failure of a couple to achieve a pregnancy after 1 year of regular unprotected sexual intercourse. This definition is based on the epidemiological observation that 80-90% of couples in the general population will normally conceive by that time. Although some couples will conceive after this time, many may have specific problems that require medical intervention. Prompt diagnosis should be made, as the earlier the problem is identified, the better the chance for successful treatment. Doctors in primary care are usually the first medical professionals that these couples approach. Therefore, they play an extremely important role in providing general education regarding reproductive health, carrying out initial counselling/assessment and making a timely referral to the infertility specialist when indicated.

Initial evaluation

Infertility should always be regarded as a problem for both partners. While female factors account for about 40% of cases and male factors account for another 25%, male and female problems frequently co-exist and both partners should be assessed together. The initial evaluation aims to identify the underlying cause(s) and to prepare the couples for a pregnancy. The steps in the initial evaluation of infertile couples are summarised in Figure 1.

Figure 1: Algorithm of initial evaluation of infertile couples

1. Causes of infertility

The commonest causes are listed in Table 1,¹ with tubal-peritoneal factors being more common in secondary infertility. In about 25% of cases, history and examination followed by complete investigations may fail to elicit any obvious cause and this is called "unexplained infertility". Coital problems, cervical factors, immunological factors and uterine anomalies are other uncommon causes.

2. Other factors which may affect fertility

Special attention should also be paid to other factors which may affect fertility. Advancing female age and depleted ovarian reserve reduces a woman's fertility and the likelihood of successful treatment.² Extremes of weight loss or obesity may both lead to ovulatory disorders. Both the natural pregnancy rate and the pregnancy rate after treatment with ovulation induction are reduced in obese women.^3,4 Smoking has also been found to be negatively associated with female fecundity⁵ and it also adversely affects sperm concentration⁶ and semen quality.⁷ Excessive alcohol intake can lead to testicular atrophy and reduced spermatogenesis, either via hypoandrogenisation caused by liver damage or through a direct toxic action of alcohol on the testes.^8,9 A previous successful pregnancy is associated with a better chance of natural conception as well as a better prognosis after fertility treatment.^10,11 whilst a longer duration of infertility is inversely associated with fertility treatment outcome.^10,11

3. History, examination and investigations

The cornerstone of any infertility evaluation relies on the exclusion of (i) coital problems (ii) semen abnormalities (iii) ovulatory disorders and (iv) tubal-peritoneal factors. History and examination for both female and male partners is outlined in Table 2. Coital problems can mostly be revealed with a sensitive history taking. However, history and examination alone often will not reveal any obvious cause and baseline investigations should be carried out. These include confirmation of ovulation and semen analysis. More specific hormonal assays should be done when there is a suspicion of an ovulatory disorder or an underlying endocrine disease. When no obvious ovulatory or male factors can be elicited, tubal peritoneal assessment should be performed. Initial investigations also aim to prepare the patient for a healthy pregnancy and these include tests for rubella immunity, blood screening for thalassaemia and a cervical smear.

Specific tests in the context of major causes will be discussed in the following.

Specific investigations

There are 4 factors influencing aerobic training response:

1. Male factor

Male infertility can be caused by problems in sperm production, blockage of the sperm delivery system and antibodies against sperm. The sperm may also be functionally abnormal in that it cannot penetrate and fertilise the egg. There are many factors that may affect sperm quantity and quality including smoking, environmental toxins, hormonal disturbances, undescended testes, varicocele, previous infection and injury to the genital tract, surgery on the genital tract or hereditary factors such as chromosomal abnormalities and genetic damage.

1. Semen analysis

Semen analysis is the single most important test in the assessment of the male partner. Proper semen sample collection is important and includes 1) abstinence from sexual activity for 2-3 days before collection (although prolonged abstinence is undesirable); 2) collection by masturbation and use of condoms is not recommended as most of the commercially available ones are made of latex rubber that are spermatotoxic; 3) the collected sample should be transported in room temperature and analysed within 1 hour. The criteria for a normal semen analysis set by World Health Organisation (WHO) are listed in Table 3.¹² Patients with an abnormal semen analysis should have the test repeated 3 months later as this may avoid some transient adverse factors such as febrile or viral illness affecting spermatogenesis. When an abnormal semen analysis is confirmed, the couple should be referred to a specialist infertility centre for further management.



2. Post-coital test

The infertility guideline work group (RCOG) has deleted post-coital test from the basic infertility evaluation. This is because of its limited correlation to fertility, lack of standardised normal values and the tendency of abnormal tests to create further testing without an apparent significant effect on the pregnancy rate. In addition, controversies remain in follow up treatment and the increasing use of empiric superovulation and intrauterine insemination treatment in unexplained infertility makes the post-coital test superfluous.¹³ However, it may still play a role when underlying sexual dysfunction is suspected or when the male partner cannot provide a semen sample for analysis.¹³

2. Ovulation disorders

Women with irregular or absent menstrual periods usually have an underlying ovulatory disorder. On the other hand, women cycling regularly are not invariably ovulating. It has been shown that 9% women with regular menstrual cycles are anovulatory,¹⁴ so ovulation should always be confirmed.

1. Mid-luteal phase progesterone, basal body temperature chart (BBT)

Failure of ovulation can result from hormonal imbalances due to stress, excessive weight gain or weight loss, extreme physical exertion, and endocrine disorders such as polycystic ovarian syndrome (PCOS), hyperprolactinaemia or thyroid dysfunction. Follicular phase (day 2 to day 5 of menstrual cycle) FSH/LH/E2 is helpful in differentiating the types of ovulation disorders and an elevated FSH (>10 IU/l) also reflects poor ovarian reserve. In anovulatory patients with androgenic features, a high LH:FSH ratio (>2) and a high testosterone level helps to diagnose PCOS. Prolactin and TFT should not be taken routinely except in patients with ovulatory disorders.¹³

2. Follicle stimulating hormone (FSH)/Luteinising hormone (LH)/Estradiol (E2), prolactin, thyroid function test (TFT), testosterone

Failure of ovulation can result from hormonal imbalances due to stress, excessive weight gain or weight loss, extreme physical exertion, and endocrine disorders such as polycystic ovarian syndrome (PCOS), hyperprolactinaemia or thyroid dysfunction. Follicular phase (day 2 to day 5 of menstrual cycle) FSH/LH/E2 is helpful in differentiating the types of ovulation disorders and an elevated FSH (>10 IU/l) also reflects poor ovarian reserve. In anovulatory patients with androgenic features, a high LH:FSH ratio (>2) and a high testosterone level helps to diagnose PCOS. Prolactin and TFT should not be taken routinely except in patients with ovulatory disorders.¹³

3. Tubal-peritnoeal factors

Tubal damage and pelvic adhesions may result from previous pelvic infection, or they may be due to endometriosis, previous ectopic pregnancy or pelvic surgery. While the presence of pelvic inflammatory disease or endometriosis may be suggested by history and examination, many patients may be asymptomatic. The gold standard in the diagnosis of both tubal-peritoneal factors and endometriosis remains to be laparoscopy with chromotubation. The reported prevalence of endometriosis found at laparoscopy in infertile women is as high as 25% while it is only 3-10% in a general population.¹⁵ It has been shown that even minimal to mild endometriosis is associated with infertility especially if the ovaries are involved. Unlike in moderate to severe endometriosis where obvious structural damage can be identified, the causal relationship between minimal/mild endometriosis and infertility is still unclear. Impairment in gamete transport, disturbance in ovulation, toxic immunological and peritoneal factors have been suggested.¹⁶

1. Hysterosalpingogram (HSG) and laparoscopy

When preliminary tests suggest that the woman is ovulating and the semen analysis is normal, pelvic assessment should be undertaken. Hysterosalpingogram (HSG) and diagnostic laparoscopy with chromotubation are the two most commonly performed and accepted tests. It remains debatable which of these two tests should be carried out.^15,17 HSG provides information about the uterine cavity and tubal patency. It is cheaper and can be performed as an outpatient procedure. However, it has a lower sensitivity in detecting peritubal adhesions and it is unable to detect pelvic endometriosis. HSG can be used as a screening test in patients at low risk for tubal-peritoneal factors while laparoscopy is of value in following up HSG abnormalities and for the evaluation of problems that cannot be detected by HSG.¹³ Laparoscopy is the investigation of choice for patients with high suspicion index including those with prolonged unexplained infertility and those who fail to conceive despite correction of the obvious underlying factors (e.g. after successful ovulation induction with clomiphene treatment). Laparoscopy is often the final diagnostic procedure in infertility evaluation and should be performed in an infertility centre where therapeutic surgery can be performed at the same time by experienced reproductive surgeons.

2. Pelvic ultrasound and hysteroscopy

Pelvic ultrasound should be performed when there is a suspicion of underlying pathology, e.g. endometrioma or PCOS. Routine hysteroscopy is not recommended unless there is a suspected endometrial abnormality such as submucosal fibroids, intrauterine synechiae or a congenital uterine abnormality.

1. General advice

Management of infertility in primary care should start with preventive measures. Education on practice of safe sex, prevention of sexually transmitted disease, early detection and thorough treatment of pelvic inflammatory disease, contact tracing with treatment of partners, screening of chlamydial infection in high risk groups are all important measures in preventing tubal damage.

General advice to stop smoking and reduce alcohol intake should be given for reasons aforementioned. Although there is no strong evidence linking alcohol and female infertility, excessive alcohol consumption can have a detrimental effect on foetal development. For obese women with a body mass index (BMI) 30kg/m², weight reduction should be advised. Women should also be advised to have a rubella vaccination if they are not immune. The couples should also be counselled about the increased risk of foetal chromosomal abnormalities and obstetric complications associated with advanced maternal age.

In addition, the infertile couple could suffer from a high level of psychological stress and anxiety. Infertility itself encompasses a series of significant losses, including loss of a "complete" family, feminine identity, manhood and self-esteem. These multisided losses are often entangled with and complicated by the physical and psychological traumas associated with treatment and treatment failures. It is of particular importance for family doctors to be aware of these psychological stresses and to provide sensitive counselling and support.

2. When to refer

It is important to note that after initial assessment, some couples should be referred to the specialist centre earlier so as to facilitate final assessment and timely treatment (Figure 1). Couples where the female partner is 35 years of age or older, where the infertility has lasted for more than 3 years or where there is an obvious history of tubal-peritoneal disease or male factor infertility, should be referred early. Specific treatments targeting at the underlying causes will be mentioned in the following section. Table 4 outlines the common fertility treatments including commonly performed assisted reproductive technology (ART) procedures and their indications.

Specific treatments

1. Male factor

If the male partner has an abnormal semen analysis, the couple should be managed in a specialist centre. Less than 10% of male infertility is amenable to conventional medical or surgical treatments. Most male infertility is idiopathic and many empirical medications such as gonadotropins or gonadotropin releasing hormones, androgens, anti-oestrogens, antioxidants or alpha blockers have not been proven to be useful.¹ For males with a borderline male factor (sperm concentration 10-20 million/ml; motility 20-50%, normal form 20-30%), sperm preparation and intrauterine insemination (IUI) with or without controlled ovarian hyperstimulation (COH) is the treatment of choice, though the latter using gonadotropins may improve the conception rate further. For males with a severe semen abnormality (count <10million/ml; motility <20% and normal form <20%) or for those where IUI has failed, in vitro fertilisation (IVF), usually with intracyto-plasmic sperm injection (ICSI) is the recommended treatment option.¹⁸

Patients with azoospermia (<2% of male infertility) should be referred to a urologist/andrologist and the underlying cause must be determined. Microsurgical epididymal sperm aspiration (MESA) in cases of obstructive azoospermia or testicular sperm extraction (TESE) in cases of non-obstructive azoospermia can be performed to provide sperm for ICSI. As increasing evidence has suggested a genetic linkage with reproductive failure in 10-30% of patients with severe male factor infertility, genetic counselling should be provided.¹⁹ In addition, as ICSI may bypass the fertility error associated with the possible chromosomal abnormalities and sex chromosome aberrations (e.g. Klinefelter syndrome or 47XXY, reciprocal X or Y chromosomal translocation, Y-chromosome microdeletions), counselling regarding the possible transmission to male offspring should be provided.

Donor insemination can be considered in cases of severe male factors or under some specific circumstances like following vasectomy or failed vasovasostomy, patients with ejaculatory dysfunction, who had chemotherapy/radiotherapy or genetic disorders. In Hong Kong, the number of donors for sperm is limited and Family Planning Association (FPA) provides the only sperm bank locally. Donation should not be performed at a commercial base. All donors have to be tightly screened to have any possible transmitted disease ruled out and to be assessed for suitability according to the Code of Practice on Reproductive Technology and Embryo Research in Hong Kong.

2. Ovulation disorders

This is the area where general practitioners can take most part in the treatment. After excluding secondary medical or endocrine diseases, anovulatory problems may be managed as outlined below with reference to the World Health Organisation (WHO) classification. Hyperprolactinaemia will be mentioned in a separate category.

1. Normogonadotrophic anovulation (WHO Group II: Hypothalamic-Pituitary dysfunction)

This is the most common form of anovulatory infertility and PCOS accounts for a large proportion of cases. Patients usually have normal FSH and E2, but the LH and testosterone may be elevated in patients with PCOS.

Clomiphene citrate (CC) remains the most commonly used ovulation induction drug. It acts mainly by blocking oestrogen receptors in the hypothalamus and pituitary, which will in turn promote the release of additional endogenous FSH and LH to stimulate follicle development. It is usually given from day 2 to day 6 of the cycle and should start at a dose of 50mg daily. The treatment response should be monitored with either confirmation of ovulation using ultrasound monitoring, mid-luteal phase progesterone level or with BBT. The dose can be increased if no ovulation occurs after two cycles. Patients who do not ovulate after the dose is increased in steps up to 200mg or those who fail to conceive after successful ovulation should be referred for further treatment and evaluation. Despite the high ovulation rate with CC (50-90%), the pregnancy rate is much lower (20-40%). Such a discrepancy is believed to be due to the adverse peripheral anti-oestrogenic effect, particularly on cervical mucus and the endometrium. The risk of a twin pregnancy is 8%. A possible association of CC and ovarian cancer has been described, especially if CC is given for more than 12 months.²⁰ Therefore, CC should be prescribed at a minimal effective dose and for not longer than 12 months.

The alternatives for patients with clomiphene resistant polycystic ovarian disease are either medical induction of ovulation with pulsatile GnRH or gonadotrophins, or surgical treatment with laparoscopic ovarian drilling. Medical treatments provide a good cumulative pregnancy rate, but a higher risk of multiple pregnancies and ovarian hyperstimulation syndrome. Regarding laparoscopic drilling, a cumulative ovulation rate of 84% and a pregnancy rate of 55% have been described²¹ but the potential ovarian damage associated with the procedure has yet to be evaluated and postoperative adhesion formation remains a concern. The exact mechanism of how ovarian drilling induces ovulation is still unknown, but it is believed to be related to altering the hormonal milieu, especially the androgen profile, by damaging the theca and stroma.

Obesity is found in 35-50% of women with PCOS and this has a deleterious effect on glucose tolerance and insulin sensitivity. Weight loss in obese patients with PCOS has been found to result in a marked improvement in ovulatory function and hyperandrogenism, largely related to amelioration of obesity related hyperinsulinaemia.²² Weight reduction also results in improved pregnancy rates and better reproductive outcomes of fertility treatment in obese infertile women.

The recognition of an association between insulin resistance and PCOS has led to the introduction of insulin sensitising agents in the treatment of PCOS infertility. Metformin is the most commonly used agent. Emerging evidence has demonstrated that metformin is beneficial for ovulation induction in women with PCOS, especially the obese ones with proven insulin resistance.²³

2. Hypogonadotrophic hypogonadism anovulation (WHO Group I: Hypothalamic pituitary failure)

This is diagnosed by low follicular phase FSH, LH, low E2, normal prolactin and normal pituitary imaging in the absence of withdrawal bleeding after a progesterone challenge test. It usually represents a functional suppression of reproduction, often a psychobiologic response to life events. The underlying causes such as stress, extreme weight reduction or excessive exercise should be explored and corrected accordingly. Anti-oestrogens such as clomiphene citrate are usually not effective and ovulation induction with gonadotropins or pulsatile gonadotropin releasing hormones is likely to be required.²⁴

3. Hypergonadotrophic hypogonadism anovulation (WHO Group III: Ovarian failure)

This is a rare cause of anovulation. Patients with secondary amenorrhoea together with a high follicular phase FSH (>20IU/L) have ovarian resistance or ovarian failure (i.e. premature menopause for females younger than 40 years of age) which requires further investigation for the underlying causes, e.g. chromosomal abnormalities, autoimmune disease or history of chemotherapy/radiotherapy. Oocyte donation may be the only treatment option.

4. Hyperprolactinaemic anovulation

For patients with elevated serum prolactin levels, investigations to exclude a pituitary adenoma (magnetic resonance imaging of pituitary gland) and hypothyroidism (TFT) should be performed. A detailed drug history is also important as medications like major tranquillers can be associated with hyper-prolactinaemia. Dopamine agonists such as bromocriptine or cabergoline are safe and effective treatments. These drugs can be combined with anti-oestrogens if ovulation does not occur despite the prolactin level being normalised. For patients with abnormal thyroid function, antithyroid antibodies should be checked and the patient should be referred to an endocrinologist for further treatment.

3. Tubal-peritoneal factors

Patients with tubal-peritoneal infertility should be managed in a specialist infertility centre. The treatment options for this group of patients are surgery or IVF and the decision depends on the type and severity of tubal disease. In general, for patients with moderate to severe tubal damage or extensive pelvic adhesions, the treatment of choice should be IVF as surgery carries a low success rate and a relatively high ectopic pregnancy rate. For patients with mild pelvic adhesions, proximal tubal obstruction or mild distal tubal disease, the prognosis after reconstructive surgery is more promising. When compared with conventional microsurgery, laparoscopic tubal anastomosis for patients with previous tubal ligation provides similar success rates of more than 80% in experienced hands.²⁵ However, if a pregnancy has not occurred within 2 years of reconstructive surgery, IVF should be offered.

4. Endometriosis

Medical treatment (ovulation suppression using GnRH agonists) either alone or in combination with surgical treatment has not been shown to improve endometriosis-associated infertility. Rather, it may delay the proper fertility treatment. For patients with moderate to severe endometriosis, IVF should be considered. The optimal treatment for minimal to mild endometriosis remains debatable. When compared with expectant management, both laparoscopic ablation of endometriosis²⁶ and controlled ovarian stimulation together with IUI has been reported to enhance pregnancy rates in infertile couples with minimal to mild endometriosis.²⁷ However, there is no evidence to determine which option is better or whether laparoscopic ablation followed by OI/IUI offers greater promise.

5. Unexplained infertility

The prognosis and the management of unexplained infertility depends on the age of the female partner, the duration of infertility and history of a previous pregnancy.^2,11 For couples with a good prognosis, i.e. young (<30 years), short duration of infertility (<3 years) or a previous successful pregnancy, the chance of natural conception is realistic. Reassurance should be given and expectant management can be offered. On the contrary, for older women (>35 years) or long duration of infertility (3 years), the couple should be referred early for treatment in a specialist centre. Clomiphene citrate is not effective in this situation but ovulation induction using gonadotropins combined with intrauterine insemination (OI/IUI) offers a moderate success rate and should be the initial treatment of choice.²⁸ Upon repeated failure of OI/IUI (up to 6 cycles), IVF should be considered.

Conclusion

Most of the investigations in the initial evaluation of infertility can be performed in the primary care setting. The major causes of infertility include male factor, ovulation disorders, tubal-peritoneal factors and endometriosis. However, a considerable number of patients have no identifiable cause while others may have more than one cause. Early referral should be considered when the female partner is of advanced age, when there is a long duration of infertility or when there are obvious tubal-peritoneal factors or male factor infertility.

Key messages

1. Subfertility is a common problem affecting 15% of couples. Natural human fertility is low and patients should not have falsely high hopes for treatment outcome.
2. The most common causes of infertility are sperm problems, ovulation disorders, tubal damage and endometriosis. Unexplained infertility occurs in up to 25% of cases.
3. Basic investigations are simple and should include semen analysis and confirmation of ovulation. Couples with advanced female age, prolonged infertility and history of tubal damage should be investigated and referred early.
4. General advice on stopping smoking, reducing alcohol consumption and weight reduction in obese women is important.
5. Treatment for ovulation disorders is usually simple and can be initiated in primary care. However, those who fail to respond to simple treatment, have sperm problems, tubal damage or unexplained infertility should be referred for specialist management.