Male factor Infertility:
Male factor infertility is one of the most common causes of infertility accounting for 25-40% of all cases. The doctors at CRGW have a special interest and expertise in this area. We are able to help couples who have problems conceiving due to male factor infertility.
Before the advent of assisted conception, treatment was limited in this area. However, the introduction of ART has resulted in exciting advances in male infertility. We now have a number of treatment options that can be offered to men even those with no sperm in their ejaculate.
At CRGW members of our team have extensive experience and expertise in this area.
To understand the factors that may account for male factor infertility this section will briefly cover the following areas.
- Anatomy & Physiology
- Production to Maturation of spermatozoa
- Hormonal Control of Sperm production
- Genetics of male factor infertility
- Other causes of male factor infertility
- Essential Investigations
- Semen analysis
- Medical treatments
- Surgical treatments
The primordial germ cells migrate to the genital ridge at six weeks. Next the presence of the SRY gene (usually in the Y chromosome) results in the differentiation of the gonad to the male testis. There are other genes which affect this differentiation and amongst them is the SOX-9 gene.
Anatomy & Physiology:
The testis is divided into 10-15 lobules in which are present seminiferous tubules. It is in these tubules sperm production occurs. These meet in the area called the rete testis which leads into the epididymis. This is part of testis where sperm matures in about 10 days. Put simply the seminiferous tubules can be seen as an area where sperm is made in little factories whilst the epididymis can be seen as a storage place.
Spermatogenesis or sperm production) occurs in cycles in the testis with each part being at a different phase in the cycle. This ensures that there is a constant production of sperm. The tubules account for around 85% of testicular volume.
Spermatogenesis is a complex process whereby sperm is produced from stem cells by processes of cell division and maturation.
The germ cells develop in groups through the process of spermatogenesis. Groups of germ cells tend to develop and pass through spermatogenesis together. This sequence of developing germ cells is called a generation. The cycle of sperm development takes 74 days.
It is important to note that the sperm production occurs without any exposure of the cells to the blood (blood-testis barrier). The reason this is important is that the spermatozoa are immunologically protected. If this barrier was broken e.g. in vasectomy cases) then the body’s immune system would attack the spermatozoa resulting in antibodies and diminished function of the spermatozoa resulting in decreased fertilising ability.
Production to Maturation:
As mentioned earlier sperm is produced in the seminiferous tubules. The sperm here is usually non-motile. Motility is usually acquired later in the epididymis. The seminiferous tubules terminate within the rete testis. This leads to the ductuli efferentes. From here the testicular fluid containing spermatozoa moves into the head of the epididymis.
The epididymis which is at the side of the testis is essentially a tube that is 5-6 metres long. It is divided into three parts, the head, body and tail. It is in the epididymis that the sperm acquires motility and ability to fertilise the oocyte (egg). The epididymis also acts as a storage place for the spermatozoa. Around 400-600 million spermatozoa can be found in the epididymis in a normal healthy male.
From the tail arises the Vas (Vas deferens). It is a muscular tube which is around 30 cm in length. The tubular fluid from the epididymis (containing sperm) has secretions added to it by the seminal vesicles (into the vas) and the prostate (into the urethra).
During ejaculation fluid from all three areas is helped towards the penis by contraction of the muscles surrounding this area. The first portion of the ejaculate contains a small volume of fluid from the vas deferens which is rich in sperm. The major volume of the seminal fluid comes from the seminal vesicles and secondarily the prostate.
When a male ejaculates the tubular fluid from the epididymis (about 0.5mls) containing sperm moves collecting fluid from the seminferous tubules which produce alkaline fluid. This is the gland that produces the most of the fluid present in the ejaculate (70-80%). The vas meets the vas from the other side in the urethra in the prostate.
The fluid from the seminal vesicles has the sugar fructose as well as prostaglandins and coagulating substrates. It is alkaline in nature to counter act the acidic vaginal environment. The prostatic secretion is however acidic in nature and has enzymes which helps liquefy the ejaculate in the vagina.
The total ejaculate varies from 1.5 to 5.5 mls. It can now therefore be seen that in conditions like mutations of CFTR gene there can be absence of seminal vesicles resulting in decreased seminal volume as well as it being acidic (this is seen on the semen analysis report).
Hormonal Control of Sperm production.
This is controlled by the hypothalamic–pituitary-testicular axis.
The Hypothlamus produces a hormone called gonadotropin releasing hormone (GnRH). GnRH is produced in a pulsatile manner and it’s effect is to release luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary. LH goes to the Leydig cells in the testis and this results in the production and release of Testosterone. FSH together with Testosterone help Sertoli cells in the process of spermatogenesis.
There is another hormone produced by the pituitary called prolactin. Excess production of this hormone (in a condition called hyperprolactinaemia) results in decreased production of LH and testosterone as well as lack of libido and sexual function in the male.
Genetics of male factor Infertility:
It is likely that over 50% of the male factor infertility is genetic in nature. Over the last 10 years there is more known in this area. Essentially there are various genetic areas that can be responsible for male factor infertility but the three largest are the following.
- Y micro deletions
- Chromosome abnormalities
- CTFR gene (CFTR=cystic fibrosis trans-membrane regulatory gene)
Y Micro deletions:
In the long arm of the Y chromosome there are three regions called AZFa, AZFb and AZFc. If these areas have been deleted than this results in male factor infertility. Over the years genetic testing has resulted in increasing amounts of knowledge in this field. This has resulted in more genes being identified that may result in azoospermia. The consequence of this is that the three areas have grown in size.
The males with these deletions are healthy with no illnesses. Around 15% of patients with azoospermia will have one of these defects. This can also be found in around 8% of oligospermic patients. Thus it is important when ICSI treatment in carried out in these patients, they know this defect will be passed on to any male infant.
If the defect has resulted in deletion of AZFa or b regions then no sperm will be found in the testis.
We all have 46 chromosomes (44 autosomes and 2 sex chromosomes). Abnormalities in our chromosome make up can result in ill health as well as problems with sperm production. This abnormality can be extra chromosome material (duplication), loss of chromosome material, inversion or translocation of chromosome material.
For example presence of an extra chromosome X in Klinefelter’s syndrome (47XXY) can result in 40% of these men having no sperm… Overall chromosome abnormality accounts for 10-15% of azoospermia.
This gene is located on chromosome seven. Abnormality in this gene can lead to cystic fibrosis as well as male factor infertility. However there are a large number of mutations in this gene and frequency of each mutation depends on population studied.
The problem that occurs is Congenital Absence of the Vas Deferens (CAVD). This results in azoospermia. It is important that if this is found in the male patient then the female partner should be genetically screened for this as well. It is recommended that couples have genetic counselling prior to any treatment.
Other causes of male factor infertility:
- Ionising Radiation
- Chronic heat
- exposure to heavy metals and dyes
- industrial Toxins and pesticides
- Radiation treatment
- Erection and ejaculation problems
- Hypothalamic-Pituitary disorders e.g. Kallmann’s syndrome
- Drugs – there is a long list of these and many have not been tested for their effects on sperm. Another type of drugs which cause infertility are the anabolic steroids used by some body builders. They also use a variety of other drugs like Testosterone, hCG etc which have an effect on the testis as well as the hypothalamic-pituitary function.
The basic investigations will depend on examination and clinical findings as well as results of semen analysis. For patients with azoospermia the following are the basic investigation CRGW would recommend.
- FSH, LH and Testosterone
- Chromosome analysis
- Cystic Fibrosis Screening
In 2010 WHO set up a new criteria for semen analysis to be described as normal. They are as follows:
Volume 1.5 to 5.5 mls
Concentration >15 million per ml
Morphology >4% Normal
No agglutination, increased white cells or viscosity
However there are problems with the above criteria. The above figures were from a study looking at fertile couples. The figures are based on the fertile population’s 5th centile. If this criteria was used and patients having 4% morphology had IVF carried out then fertilisation rate would only be around 8-10%. If we compare this with IVF carried out in patients with morphology of >14% over 80% fertilisation will occur. Whilst those in between will have around 70% fertilisation.
This can be divided into either medical or surgical. Of course what we use will depend on what the abnormality is.
- Gonadotrophins: This is undertaken in patients with FSH & LH deficiency such as patients with Kallmann’s syndrome. The treatment is in the form of hCG 2500iu twice a week for 3-6 weeks, followed by FSH at a dose of 75 to 150IU twice a week. The hCG is continued with FSH. Sperm production can be seen to rise as well as testosterone production.
- Hyperprolactinaemia: In patients with this condition, after an MRI scan, simple treatment with drugs like Cabergoline will rectify the defect
- Anti-oxidant treatment: Excess Reactive Oxygen species (free oxygen radicals) can be found in patients who have poor sperm morphology. This leads to DNA damage in the sperm. This can be improved by the use of anti-oxidants like Vitamin C and E.
- Zinc, Folic acid and Selenium are also thought to help, but randomised clinical trials in infertility are lacking. Zinc and folic acid act as co-enzymes in DNA and RNA synthesis.
- Erectile and ejaculatory problems: Erectile problems can be treated by phosphodiesterase type 5 inhibitor like Sildenafil, Tadalafi etc.
Ejaculation problems can be treated by use of alpha-adrenergic stimulation using sympathomimetic agents like Sudafed. Alkalinization of the bladder urine with oral sodium bicarbonate and retrieval of sperm from the bladder after ejaculation can also be used.
These are mainly used for obstructive azospermia. Its indications include all those obstructive disorders that are not surgically remedial like cases of absent vas, infectious blockage, previous vasectomy failure etc. Post sperm recovery the best results are obtained after ICSI treatment.
The options we carry out at CRGW are as follows:
- Percutaneous Epididymal Sperm Aspiration (PESA)
- Microsurgical Epididymal Sperm Aspiration (MESA)
- Testicular sperm extraction (TESE)
We perform this procedure under Local anaesthesia and sedation. The testis is cleaned and the epididymis identified. A 21-gauge butterfly needle attached to a 2ml syringe is inserted into the epididymis. Epididymal fluid is aspirated and given to the scientific team to identify spermatozoa. In patients in whom no sperm is obtained after a number of attempts we perform a TESE procedure.
MESA is an alternative treatment method for obstructive azoospermia in order to obtain sperm from the epididymis with the use of an operating microscope. The patient is given a general anaesthetic and then the scrotum is opened. The epididymis is identified and the tubules exposed. Under the guidance of an operating microscope the tubules obtained and tubular fluid aspirated for spermatozoa.
Like PESA this technique we perform under Local anaesthesia and sedation. Here the scrotal skin is opened. Tunica of the testis opeded and testicular tissue obtained. This is given to the scientific team who try and identify spermatozoa.
In all these procedures spermatozoa obtained are cryopreserved and then the ICSI procedure carried out.
If you would like to know more about how we can help you please get in touch with us at CRGW.