Male Infertility and Sperm

Sperm is made in the testis within very small tubes known as seminiferous tubules. Seminiferous tubules lead to larger tubes that deliver sperm to the vas deferens and ultimately, to the tube that runs through the penis known as the urethra. Secretions from the prostate gland and seminal vesicles empty into the urethra where they mix with sperm, collectively forming the semen that is released from the penis at ejaculation.

Sperm production in testis is stimulated by Follicle Stimulating Hormone (FSH). FSH is produced by the pituitary gland, which is located at the base of the brain. Another pituitary hormone, Luteinising Hormone (LH), leads to the production of the male hormone, testosterone, from a special type of cell in the testes known as Leydig cells. Testosterone is important for masculinity, sex drive, muscle development and male pattern hair growth and is also needed for sperm production. The production of both FSH and LH are stimulated by another hormone, gonadotrophin-releasing hormone (GnRH), produced by the hypothalamus in the brain.

One of the crucial differences between males and females pertains to how their reproductive cells, sperm and eggs, are produced.

Males retain precursor sperm cells (known as germline stem cells) within their testis that enable them to produce new sperm via a process known as spermatogenesis throughout their lifetime. The entire process of spermatogenesis lasts around 74-120 days and around 100 million viable sperm are produced every single day!

In stark contrast, females are born with a fixed quota of around 1-2 million eggs. Since no new eggs are produced after birth, the eggs and their surrounding follicles endowed at birth are the sole source of a woman’s eggs as well as the hormones, oestrogen and progesterone, which are produced by follicular cells. Being born with a fixed number of eggs has two important consequences: firstly, eggs undergo ageing which diminishes their quality and, secondly, egg numbers decline with age until they eventually run out resulting in the menopause.

A man’s sperm is tested using a test called a semen analysis. Sperm tests are used to try to predict the ability of the sperm to fertilise the egg.

To do this test, a man needs to ejaculate into a sterile plastic pot and take the sample to an accredited andrology laboratory which will determine a number of different features of the sperm. Semen analyses evaluate sperm features in the sample against stringent criteria set by the World Health Organisation (WHO 2010).

For reliable results, it is critical that semen production is performed properly:

1. The male should abstain from ejaculation for 2-7 days prior to the test
2. All the sample should be collected into a wide-mouth sterile plastic container
3. The sample must be delivered to the lab within 45-60 minutes of production

A number of parameters are analysed in the semen sample. The three key ones are:

1. Sperm concentration which should be greater than 15 million sperm/millilitre
2. Progressive sperm motility (or the proportion swimming fast in a straight line) which should be 32% or more
3. The proportion of normally shaped sperm (or normal morphology) which should be 4% or more

The main participants involved in producing sperm in the ejaculate include hormones (FSH, LH and testosterone), the testicular spermatogenic machinery and the ducts leading from the testes to the penis.

Sperm abnormalities can therefore result from problems with:

• Sperm production (or spermatogenesis) in the testes
• The transport of sperm from the testis to the penis

In the most severe cases, there is a complete absence of sperm in the ejaculate, a condition referred to as azoospermia.

Environmental and lifestyle factors:
In 65-80% of cases of sperm abnormalities there is no obvious cause. In these instances, there is an inherent problem in testicular spermatogenesis. It is believed that environmental factors (e.g. pesticides, “endocrine disruptors” etc.) and/or lifestyle factors may be important contributors.

In the Western world, these factors are having a major impact on sperm quality. Obesity, cigarette smoking and excessive alcohol intake have all been linked with poor sperm quality. A large study that analysed sperm tests from almost 43,000 men found that sperm counts had declined by a staggering 50-60% over the past 40 years in North America, Europe and Australia & New Zealand.

Klinefelter’s syndrome:
Reduced testicular spermatogenesis may be the result of chromosomal problems. The most common chromosomal disorder in men is Klinefelter’s syndrome, affecting 1 out of every 650 men. Human cells normally have a total of 46 chromosomes, made up of 22 pairs of autosomal chromosomes and 2 sex chromosomes; in males, the sex chromosomes are an X and a Y chromosome.

In Klinefelter’s syndrome, there is an extra X chromosome resulting in an XXY make-up rather than the typical XY pattern.

Men with Klinefelter’s syndrome often have small testicles and reduced levels of testosterone resulting in reduced body hair and muscle mass. It may also result in breast development, learning difficulties and behavioural problems.

Y chromosome microdeletions and genetic causes:
Reduced sperm production can also be the result of the loss of small segments from the Y-chromosome (known as microdeletions) before birth. Microdeletions in the Azoospermia Factor (AZF) region of the Y chromosome are well known to affect sperm production.

Alterations in genes such as SOX5, DAZL, TEX11, DPY19L2 and AURKC are also linked to sperm abnormalities.

Obstructive problems:
In around 5% of cases, sperm is being made in the testes but there is none in the ejaculate because of a blockage of one or more of the tubes leading from the testes to the penis. A frequently seen cause of blockage is a previous vasectomy. Blockages can also occur due to scarring brought about by infection.

Azoospermia may also be due to an inborn absence of the tube known as the vas deferens, which is required for transporting sperm from the testes (see “How is sperm produced?” above); this condition is known as congenital bilateral absence of the vas deferens (CBAVD) and occurs in 1-2% of infertile men. It is estimated that around three-quarters of men with CBAVD carry an abnormality in the CFTR gene that causes cystic fibrosis.

Hormonal causes:
Problems leading to reduced production of the hormones GnRH, FSH and LH can impair spermatogenesis. Some of these may be present from birth whilst others may occur later in life, for instance, as a result of a brain tumour.

Undescended testes, varicoceles and hyperthermia:
Prior to birth, the testis travels (or descends) from a position within the abdominal cavity to the scrotal sac outside of the body via a canal in the groin area known as the inguinal canal. This position outside the body keeps the testes a couple degrees cooler than core body temperature and is crucial for proper spermatogenesis. In some cases, one or both testes become trapped in the abdomen resulting in undescended testis (also known as cryptorchidism). Persistent undescended testes occur in around 1 in 50 males. If the testes are not brought down into the scrotum, there will be poor sperm production due to the detrimental effects of the higher temperatures found within the abdominal cavity.

Other factors linked with increased testicular heat (hyperthermia) have also been implicated in poor sperm quality. These include varicoceles (dilatations of the spermatic veins), chronic sauna exposure, tight-fitting underwear and professions involving prolonged durations of sitting (e.g. truck driving).

Testicular trauma and torsion:
Trauma to the groin area, for instance, while playing sport, can cause sudden pain and swelling of the testes. In some cases, the testis can twist on its suspensory cord thereby cutting off its blood supply, a condition known as testicular torsion. Torsion is a medical emergency and if left untreated, causes permanent testicular damage.

Anabolic steroids, chemotherapy and other drugs:
Anabolic steroids are used by some athletes and bodybuilders. They shut down the body’s own production of FSH thereby stopping spermatogenesis (see “How is sperm produced?” above). Men who use anabolic steroids for extended periods of time develop severely suppressed pituitary FSH production and absent spermatogenesis. Sperm production can be very slow to recover after discontinuing steroids following extended periods of steroid usage.

Drugs used for cancer treatment (chemotherapy) are acutely toxic to rapidly dividing cells such as sperm-producing cells. Depending on the chemotherapeutic agents used and the duration of treatment, spermatogenesis can sometimes recover after chemotherapy is stopped, but, unfortunately, in many cases, the damage is permanent. Prior to undergoing chemotherapy, therefore, it is strongly advised that sperm be frozen for preserving fertility. For more information, see my section on Fertility Preservation.

Other drugs such as opioids, many psychotropic medications, cimetidine, spironolactone and ketoconazole can impair spermatogenesis.

Treatments for sperm problems are directed at the underlying causes.

General lifestyle advice and antioxidants:
In cases of sperm abnormalities, men should be advised that measures such as losing weight (if obese), avoiding long hot baths, loose-fitting underwear and eliminating smoking and alcohol may be beneficial for sperm parameters.

Many of these factors are thought to impair sperm production by increasing the level of damaging “oxidative stress” within the spermatogenic tubules. Consequently, there has been extensive interest in the use of antioxidants (e.g. Vitamins C and E and Zinc) for improving sperm quality, although the evidence that they make any marked improvement is inconclusive.

Hormonal treatment:
In cases in which hormones such as GnRH, FSH and LH are lacking, they can be replaced using hormonal medications.

Artificial insemination:
In cases of mild sperm defects, artificial insemination or IUI may be beneficial. For more details, see my section on Artificial Insemination.

IVF with ICSI:
In cases in which, sperm is present in the ejaculate but is of very low quality, IVF in combination with Intra Cytoplasmic Sperm Injection (ICSI) is the appropriate treatment. For more information of how to diagnose sperm quality problems see my section on Infertility: Causes, Tests and Treatments. For more information on IVF and ICSI, see my section on IVF/ICSI Treatment.

Surgical sperm retrieval:
In obstructive causes in which there is blockage or absence of tubes leading from the testes, sperm can be surgically retrieved using techniques such as PESA and TESA. When sperm is retrieved surgically in his manner, IVF with ICSI must then be used to fertilise the eggs since such sperm have not gone through the steps required for enabling them to fertilise eggs on their own. See my section on IVF/ICSI treatment for further information. Professor Homer wrote the chapter on how sperm undergo preparation for fertilisation in one of the world’s most popular textbooks of Gynaecology (Gynaecology 4th Edition; Chapter 19).

Donated sperm:
If spermatogenesis is severely disrupted such as after extensive chemotherapy or in some cases of Klinefelter’s syndrome, it may not be possible to obtain sperm, even with surgical techniques. In such cases, the only other available option is the use of third-party donated sperm. For more information, see my section on Donor Treatment.

Who can help diagnose and treat sperm problems:
An expert in infertility is required to interpret semen analyses and advise on the correct treatments. Prof Homer has extensive expertise in treating male factor infertility and has been accredited by the Australian & New Zealand Royal College in O&G as well as the British Royal College in O&G for performing advanced treatments for male infertility such as surgical interventions for retrieving sperm from the testes.