Abstract
Male infertility is becoming a worldwide epidemic. Data suggest that there has been a constant decline in semen parameters throughout the decades of the 20th century with the mean sperm count ranging around 60 million sperm per ml in the late 1930s and dropping down to around 40 million sperm per ml in the late 1970s [1]. More recent data from the Human Fertilisation and Embryology Authority suggests that male factor infertility is the sole cause of couple infertility in around 30% of cases and in a further 10% of cases there is a combination of male and female factors. This means that in just under one half of couples seen in a typical infertility clinic setting there will be a male factor and hence the importance of thorough investigation and management of the male partner. The exact cause for this decline in male infertility is largely unknown but may be due to various environmental factors or lifestyle changes such as smoking and obesity [2].
1 Introduction -The Male Infertility Epidemic
Male infertility is becoming a worldwide epidemic. Data suggest that there has been a constant decline in semen parameters throughout the decades of the 20th century with the mean sperm count ranging around 60 million sperm per ml in the late 1930s and dropping down to around 40 million sperm per ml in the late 1970s [1]. More recent data from the Human Fertilisation and Embryology Authority suggests that male factor infertility is the sole cause of couple infertility in around 30% of cases and in a further 10% of cases there is a combination of male and female factors. This means that in just under one half of couples seen in a typical infertility clinic setting there will be a male factor and hence the importance of thorough investigation and management of the male partner. The exact cause for this decline in male infertility is largely unknown but may be due to various environmental factors or lifestyle changes such as smoking and obesity [2].
This chapter will examine the underlying causes of male factor infertility with a brief description of the background theory underlying sperm production. It will also aim to provide a clinical approach to the management of male factor infertility appropriate for both secondary and tertiary care clinicians.
2 Clinical Approach to Management of Male Infertility
Male fertility problems can be classified based on the semen analysis into two main categories. The first is when no sperm is seen in the ejaculate (azoospermia) and the second category is when sperm are present but of suboptimal quality. This may be due to a low sperm count (oligozoospermia), low sperm motility (teratozoospermia), poor sperm morphology (asthenozoospermia) or a combination of two or more of these problems. Azoospermia should be differentiated from aspermia, which is the absence of semen during ejaculation, which is either due to retrograde ejaculation into the urinary bladder or due to obstruction of the outflow tract. We will approach these two problems separately.
2.1 Azoospermia
Azoospermia is defined as the absence of sperm in the ejaculate. A second sample is always necessary to confirm the diagnosis. The diagnosis of the cause starts with a firm understanding of the different compartments responsible for sperm production. The first of these compartments is the hypothalamus and pituitary gland. The second is the testicle containing Leydig and Sertoli cells. The third compartment is the outflow tract (ejaculatory ducts) with contributions from the prostate gland and seminal vesicles.
2.1.1 Compartment 1: Hypothalamus and Pituitary (Hypogonadotrophic Hypogonadism)
This is the top compartment involved in spermatogenesis. The hypothalamus and pituitary gland affect spermatogenesis through producing FSH and LH, influencing the Sertoli and Leydig cells. Consequently the hypothalamic-pituitary compartment is assessed through measurement of the following hormones: FSH, LH, testosterone and sex hormone binding globulin (SHBG) in addition to prolactin and imaging in certain cases where a pituitary tumour is suspected. Clinical conditions that can affect this compartment include the following:
(i) Congenital conditions such as Kallman syndrome; this is due to a congenital defect in the arcuate nucleus where the GnRH producing neurones failed to migrate from olfactory bulb. The olfactory bulb is also affected leading to anosmia.
(ii) Suppression of gonadotrophin production through exogenous sources (anabolic steroids and exogenous testosterone therapy) or endogenous sources such as in cases of congenital adrenal hyperplasia [3].
(iii) Traumatic conditions such as surgical removal of the pituitary gland.
(iv) Neoplastic conditions leading to destruction of the pituitary gland such as pituitary macroadenomas or extra pituitary tumours compressing the pituitary gland, or microadenomas producing prolactin (prolactinomas).
(v) The use of anabolic steroids and testosterone supplements. This is becoming a growing problem with increased use of so-called exercise-enhancing supplements and bodybuilding products many of which can be purchased over the internet. The use of these products can lead to suppression of the hypothalamus and pituitary gland with suppression of sperm and testosterone production.
2.1.2 Compartment 2: The Testicle
Two types of cells in the testicle are of interest to sperm production; the first is the Sertoli cell which lines the seminiferous tubules and is important for the process of spermatogenesis. Circulating FSH influences Sertoli cells while the second type of cells, Leydig cells, located within the interstitial tissue of the testicles are influenced by LH and are responsible for the production of testosterone. The testicular compartment produces both testosterone and sperm. Production of both is important in the assessment of this compartment and they do not necessarily go hand in hand. Damage to the testicular compartment may be either primary as a result of testicular failure (hypergonadotrophic hypogonadism) or secondary as a result of a defect in the hypothalamic-pituitary compartment (hypogonadotrophic hypogonadism). Hence to fully assess this compartment, the products of both the testicles (testosterone and sperm) and the hypothalamus/ pituitary (LH and FSH) need to be assessed together. Additional tests such as genetic testing are necessary depending on the suspected aetiology.
A number of conditions can affect the testicle:
(i) Congenital conditions such as testicular dysgenesis or chromosomal anomalies such as Klinefelter syndrome (47 XXY).
(ii) Traumatic conditions such as direct trauma, torsion or surgical removal of the testicle as a result of testicular cancer.
(iii) Inflammatory conditions such as mumps epididymo-orchitis.
(iv) Sertoli cell–only syndrome is a condition where the tubules are lined with only Sertoli cells with absence of spermatogenic cells. Since Leydig cells are normal, LH and testosterone levels will be normal. Despite normal Sertoli cells, inhibin production is decreased, leading to increased FSH levels. Most cases of Sertoli-only syndrome are idiopathic and characterised by complete absence of germ cells due to failure of migration of the germ cells from the primitive yolk sac [4].
2.1.3 Compartment 3: The Outflow Tract
The outflow tract includes the vas deferens and contributing secretions from the seminal vesicles and prostate. Problems associated with this compartment will lead to obstructive azoospermia characterised by a normal hormonal profile (normogonadotrophic hypogonadism). Assessment of the outflow tract is conducted through thorough examination of the semen analysis (e.g., absence of fructose and acidic pH in cases of the seminal vesicles obstruction) and imaging techniques such as MRI, vasography and rectal ultrasound. Factors affecting this compartment include the following:
(i) Congenital conditions such as congenital absence of the vas, commonly associated with mutations of the cystic fibrosis gene.
(ii) Traumatic conditions such as surgical trauma during hernia operations and other types of scrotal surgery and most commonly as a result of previous vasectomy.
(iii) Inflammatory conditions such as mumps epididymitis or chlamydia.
2.1.4 Clinical Workup for Azoospermia
Clinical evaluation should be conducted in a comprehensive and systematic way starting with the history and examination. In fact, a provisional diagnosis is often reached on the basis of history and examination alone. History should include a thorough enquiry regarding history of trauma, hernia operations, and torsion of the testicle, testicular tumours, undescended testicle, mumps, smoking and the use of exercise-enhancing products, steroids or other medical treatments (chemotherapy/radiotherapy). Examination of the testicle should include the size and consistency. Often an orchidometer (Figure 6.1) is used to objectively evaluate the size of the testicle. A normal testicle should be around 15 mls in size with firm consistency. Testicular size correlates with sperm production and in many cases testicular failure can be diagnosed at this stage through finding a small soft testicle. Examination should also include the spermatic cord, the epididymis and the vas. Per rectal examination usually conducted by the urologist can reveal cystic distension of the seminal vesicles in cases of seminal vesicle obstruction and can also reveal problems with the prostate. Semen analysis can also be very helpful in establishing a diagnosis, apart from focussing on sperm count, morphology and motility, other aspects may be equally important including the presence of a low volume in cases with ejaculatory duct obstruction, low fructose and acidic pH may also be associated with seminal vesicle obstruction [5].
History, examination and gonadotrophin levels will then allow classification into one of the three categories of hypogonadism and can then direct further testing.
2.1.4.1 Hypergonadotrophic Hypogonadism (Primary Testicular Failure): FSH and LH Will Be Elevated along with Normal/Low Testosterone Levels
Further tests should be directed towards genetic testing including screening for aneuploidies (e.g., Klinefelter syndrome, 47 XXY), translocations and Y chromosome microdeletions. Y chromosome microdeletions are present in about 10% of cases of non-obstructive azoospermia and are of particular interest from a prognostic point of view. Three main types of microdeletions can affect the azoospermia factor (AZF) regions present on the long arm of the human Y chromosome AZFa, AZFb and AZFc [6]. The chances of surgical sperm recovery are negligible in patients with AZFa and AZFb complete microdeletions whilst those with AZFc usually will have a successful surgical sperm recovery [7].
2.1.4.2 Normogonadotrophic Hypogonadism (Obstructive Azoospermia): FSH, LH and Testosterone Levels Are Normal
Further testing should include cystic fibrosis screening, particularly in men with congenital bilateral absence of the vas. The commonest CF mutation associated with abnormal sperm production abnormality is the Δ-F508 mutation. The finding of a CF mutation in the male partner indicates testing the female partner. If both carry a CF mutation then in vitro fertilisation / intracytoplasmic sperm injection (IVF/ICSI) with preimplantation genetic diagnosis can be offered. Radiological investigations are necessary before surgical intervention to correct an obstruction and include vasography, MRI scan and transrectal ultrasound.
2.1.4.3 Hypogonadotrophic Hypogonadism (Hypothalamic-Pituitary Disorders, Secondary Testicular Failure): FSH and LH Will Be Inappropriately Normal or Low with Low Testosterone Levels
Further investigations should be directed towards any abnormalities in the hypothalamic-pituitary axis. This includes estimation of prolactin levels along with checking other anterior pituitary hormones and appropriate pituitary imaging. Endocrinology referral may be appropriate.
2.1.5 Treatment of Azoospermia
2.1.5.1 Hypergonadotrophic Hypogonadism (Primary Testicular Failure)
Treatment will depend on whether sperm is present or absent in the testicular tissue and/or the epididymis. Therefore the first step is to offer surgical sperm recovery. If sperm is detected, then the couple can proceed with IVF/ICSI treatment, if no sperm is found then the couple will need to be counselled regarding alternative treatments such as treatment with donor sperm or adoption.
Techniques of Surgical Sperm Recovery
Surgical sperm recovery can be achieved from either the epididymis (PESA, percutaneous epididymal sperm aspiration) or from the testicle. In men with non-obstructive azoospermia, sperm are usually retrieved from the testicular biopsy. There are different methods for obtaining sperm from the testicle, the least invasive is known as TESA (testicular sperm aspiration). This involves the insertion of a fine needle into the testes to aspirate a small amount of tissue, different areas in the testicle can be sampled and provided tubules are seen in the specimen, sperm can usually be extracted. In order to increase the yield of tissue retrieved from the testicle, an open testicular biopsy can be used (TESE, testicular sperm extraction). Both these procedures can be performed under a local anaesthetic and are minimally invasive. Several techniques have been used to improve sperm yield using these procedures, including perivascular nerve stimulation and testicular aspiration under ultrasound guidance. Unfortunately none of these techniques are, as yet, supported by good quality evidence [8].
In a further attempt to improve sperm yield, a technique known as Micro TESE may be used which involves surgical sperm extraction from the testicle using the surgical microscope. The use of optimal magnification can allow the surgeon to explore and sample areas where sperm are likely to be found after dissecting the seminiferous tubules. The technique also allows minimal testicular trauma and maximises exposure. Micro TESE can offer higher success rates than conventional TESE [9]. Furthermore, Micro TESE has been reported to successfully result in sperm extraction in over 60% of men with Klinefelter syndrome [10].
Predictors of Success of Surgical Sperm Recovery
Several indices have been used to predict the success of surgical sperm recovery. Perhaps one of the most important, as previously discussed, is testing for the type of AZF microdeletion if present. Other biochemical indicators include FSH, AMH and inhibin. Testicular volume has also been suggested to correlate with the success of surgical sperm recovery. Unfortunately none of these tests has been shown to be a good predictor. In one study, men with FSH levels of 31–45 still had around a 60% chance of having surgical sperm recovery [11]. A further study comparing AMH, inhibin and testicular volume showed no significant advantage for any of these over the other in predicting success of surgical sperm recovery. All of them had a poor sensitivity and specificity [12].
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
