Male Infertility: A Brief Overview Of Pathologies

Introduction

Infertility is a growing issue, especially in developing countries, that affects over 186 million people due to many reasons, mainly being lifestyle choices (1). Within the UK, infertility affects approximately 3.5 million individuals. In other words, 1 in 7 couples experience difficulties in achieving pregnancy (2). WHO defines infertility as the inability of a sexually active couple to achieve pregnancy without the use of any contraception in a time span of one year (3).

Decades ago, infertility was incorrectly associated to females frequently and still is to some extent in certain cultures (4). However, it is becoming more apparent that males contribute to infertility to a much more significant extent than previously thought (1,4). Male infertility can be defined as the inability to cause a pregnancy with a fertile female partner (5). Male infertility rates vary widely across different regions but on a whole, men solely account for 20-30% of all infertility cases. However, it contributes to 50% of overall cases, in which both the male and female may be partly responsible for the cause of infertility (1).

The presentation of male infertility depends on the exact underlying pathology resulting in infertility. In most cases, other than the inability to achieve pregnancy, there aren’t any other signs or symptoms (6).

This essay will focus on male infertility, discussing 3 medical causes of male infertility, its aetiology, pathophysiology and the available treatments for each of the pathologies.

Background

In order to understand the exact nature of these pathologies and the role it plays in infertility, it is important to first understand some key concepts such as basic of male reproductive physiology and the Hypothalamus-Pituitary-Gonadal axis (HPG).

The journey of spermatocytes begins in the testis, where spermatogenesis and testosterone synthesis occur (7,8). The testes are held in the scrotum, hanging outside the body, which keeps the temperature of the testes slightly lower than the rest of the body (9). This prevents the damaging effect of high temperature on spermatocytes. The testis is made of many cell types, 2 of which are the Sertoli and Leydig cells (7-9). The Sertoli cells line the seminiferous tubules, this is the region where sperm is made. The Sertoli cells provide vital support needed for germ cell development into spermatocytes. On the other hand, Leydig cells are between the seminiferous tubules and these cells secrete androgens, in particular testosterone (9). Testosterone is an important hormone, playing various physiological roles such as spermatogenesis, sexual development, puberty, testicular volume and erectile function (7,8).

Once the sperm is produced by the testes, it moves into the rete testes, an anastomosing network of tubules into which the seminiferous tubules empties. After which, the sperm is temporarily stored in the epididymis, a structure that connects the testicles to the vas deferens. Then, the sperm travels through the vas deferens in the spermatic cord into the pelvic cavity, behind the bladder to the prostate. At this point, the vas deferens joins with the seminal vesicle to form the ejaculatory duct. This duct passes through the prostate to empty into the urethra (10). The seminal vesicle and prostate gland secrete fluids that ultimately becomes the semen. The seminal vesicle secretes a significant proportion of alkaline fluid which allows the spermatocytes to survive in the acidic environment of the vaginal tract. Whereas, the prostatic secretions are zinc-rich, which only account for a small proportion of the semen (9-10).

Next, it is important to understand process of ejaculation in order to understand retrograde ejaculation, a pathology described in this essay. The process of ejaculation is a multistep process which occurs during sexual arousal. The two main regulators of this process are the internal and external sphincter (12). During the resting phase, both the sphincters are closed, but open to allow the passage of urine. The process of ejaculation can be grouped into 3 steps. The first step, the seminal fluid is transported to the posterior portion of the urethra via contractions of the vas deferens. The next step involves the closure of the internal sphincter, located at the neck of the bladder. This generates pressures between the two closed sphincters. Lastly, the expulsion of semen occurs when the external sphincter open. This is further aided by rhythmical contraction of penile muscles which propel the semen out of the urethra. During this process the internal sphincter remains closed to prevent retrograde flow (12,13).

The human reproductive system is governed by the HPG axis (7,8). The preoptic region of the hypothalamus is responsible for the secretion of Gonadotrophin-releasing-hormone (GnRH) in a pulsatile manner into the hypophyseal portal vessels. As a result, Luteinising hormone (LH) and Follicle stimulating hormone (FSH) are released in a pulsatile manner by the anterior pituitary. Then, LH acts on the Leydig cells to stimulate testosterone production, which diffuses to the Sertoli cells and circulation. The testosterone in circulation is important to regulate negative feedback at the level of the pituitary and hypothalamus, controlling the secretion of LH and FSH. On the other hand, FSH acts on the Sertoli cells, which has numerous functions, one of which is providing nourishment to developing spermatocytes. Additionally, secretions from Sertoli cells, specifically inhibin and activin regulate FSH secretion (7,8).

Pathologies

There are many conditions that can lead to male infertility, both partial and complete. Several of these conditions aren’t accompanied by any other signs or symptoms, making them hard to diagnose (6). This section will discuss 3 conditions: varicocele, Klinefelter’s syndrome and retrograde ejaculation.

1. Varicocele

Varicocele is defined as the abnormal dilation and engorgement of the pampiniform plexus and internal spermatic veins that drain the blood from the testes (8). In most cases, this condition presents as a painless scrotal swelling. However, the dilatation of these veins can hinder normal testicular function and growth (7,8). Varicocele is a common condition that affects roughly 10% to 15% of all men. Of these affected men, approximately 20% will experience problems with their fertility (15).

Varicocele is commonly caused by elevated hydrostatic pressure in the renal veins and the presence of incompetent valves or the complete absence of valves in the draining veins (17). Approximately 90% of varicoceles affect the left testicle, whereas about 10% are bilateral. It is rare for varicocele to be isolated on the right side (18). This is due to the right-angle insertion of the left internal spermatic vein into the left renal vein, whereas the right internal spermatic vein, inserts in an oblique angle into the inferior vena cava. Moreover, the left-sided veins are longer than its right-sided counterpart, making it more susceptible to elevated hydrostatic pressure. Incompetent valves or congenitally absent valves in the internal spermatic veins can lead to its dilatation and engorgement. Furthermore, the left pampiniform plexus is more prone to elevated hydrostatic pressure because of the way this vessel inserts into the left renal vein (18). In rare instances, varicoceles can be caused by compressive masses in the retroperitoneum or abdominal cavity (19).

The pathophysiology of varicocele is thought to mainly revolves around thermal regulation of the testes (9). As mentioned above, the scrotum containing the testis hangs outside the body, which ensures that the intrascrotal temperature is 1°C to 2°C lower than normal body temperature. This is important because the lower temperature allows normal spermatogenesis to occur (9). As with varicoceles, there are two main theories put forward that explain its role in infertility. Firstly, the dilation and engorgement of the veins draining the testicles hinders the normal cooling mechanism of the testicles and increases the intra-scrotal temperatures. It is thought that this rise in temperature is responsible for decreased spermatogenesis. The other theory suggests the possible role of reactive oxygen species (ROS). Recent studies have suggested that a varicocele leads to inadequate elimination of ROS due to improper arterial blood supply and impaired venous drainage. As a result, the testes are subject to hypoxia and thus damage (18,20).

Varicoceles are known to have a detrimental impact on testicular growth and development in adolescent males and fertility in adult males (7,8). Varicoceles, especially in teenage boys, can lead to loss of testicular volume and reduced sperm count. Furthermore, varicoceles can lead to various abnormal semen parameters, such as oligozoospermia (low sperm count), asthenozoospermia (decreased sperm motility) and teratozoospermia (abnormal sperm morphology). All of these abnormal semen parameters can negatively affect male fertility (18).

Nowadays, there are multiple treatment options available for varicocele and are curative in 90% of the cases. All of which involve outpatient surgical correction. The indications of treatment differ depending on the age group of the patient. In adolescents, treatment is indicated if the affected testicle is 2ml smaller than the unaffected testicle. However, for adult males, surgical repair is suggested if there are semen abnormalities or fertility issues. The available treatment options include open surgery, percutaneous embolization and laparoscopic surgery. As with open surgery or laparoscopic repair, the most common surgical approach is through a sub-inguinal or inguinal incision. On the other hand, percutaneous embolization is a minimally invasive procedure using an image-guided catheter through the femoral vein to treat the impedance to blood flow (21).

2. Klinefelter’s Syndrome

Klinefelter’s syndrome is a genetic disorder affecting only males, characterised by the presence of 2 or more X chromosomes (7,8). The karyotype of these individuals represented as 47XXY compared to the normal 46XY in males. The primary feature of this syndrome is infertility and small testicles (7,8). In some cases, individuals with this syndrome can present with muscle weakness, poor coordination, breast growth and so on. In rare cases, there could be the presence of more than 2 X chromosomes. In this case, the symptoms are much more severe (22).

This condition is one of the most common chromosomal abnormalities seen in males. Globally, it affects around 1 in 500 men and accounts for 3% of all infertile males across all ethnic groups (23).

As mentioned, Klinefelter’s syndrome is caused by congenital aneuploidy of the X chromosome. This arises very early on in development, particularly in meiosis during gametogenesis. The extra X chromosome can be retained due to non-disjunction in meiosis 1 or meiosis 2 on either the paternal or maternal side (23). Non-disjunction is the abnormal separation of homologous chromosomes in meiosis 1 or sister chromatids in meiosis 2 or the failure of sister chromatids to split in mitosis (7,8). In this case, the X and Y or X and X chromosome fail to separate, leading to an extra X chromosome in one of the gametes. If an abnormal sperm with XY fertilises a normal egg, the offspring would have the Klinefelter’s syndrome karyotype of 47XXY. Fertilisation of a normal sperm with a XX egg yields the same result (7,8,23).

Klinefelter’s syndrome is a common cause for male primary hypogonadism, leading to testicular failure, variable degree of androgen deficiency and infertility. Affected individuals have smaller testicles (>4mls) compared to eugonadal men (15 to 25mls). Furthermore, they have very low circulating serum testosterone levels and high FSH and LH (23). The exact nature as to how the presence of an extra X chromosome results in testicular failure is yet to be discovered.

In Recent studies, testicular biopsies of affected individuals at different ages revealed reduced germ cell in infancy, hyalinising fibrosis of seminiferous tubule during puberty and ultimately small firm testis with azoospermia in adulthood. Moreover, a small number of cases also present with reduced sperm motility and morphology. All of these factors are responsible for infertility in this population (23).

As with most genetic disorder, there is no curative measure to change the chromosomal makeup. However, there are a number of treatments and therapies available to tackle the symptoms and improve quality of life. The most frequently prescribed treatment is testosterone replacement or substitute (7,23). This counters some of the symptoms caused by low serum testosterone such as low muscle mass, less facial and body hair. As for infertility, the use of in vitro fertilisation (IVF) has shown to be successful in these individuals (23).

3. Retrograde ejaculation

Normal ejaculation of semen is a vital aspect of human reproduction and the failure to do so leads to infertility. One of the disorders of ejaculation is called retrograde ejaculation. This disorder is defined as the backward flow of semen, resulting in an orgasm without semen (25). Although retrograde ejaculation doesn’t hinder with a male’s ability to achieve an erection or to have an orgasm, it can still cause infertility as the sperm isn’t introduced into the female’s reproductive tract.

There are several possible causes for retrograde ejaculation, all of which centre around neuromuscular damage of the internal sphincter (26). Damage to the internal sphincter can occur as a complication of surgeries such as prostatectomy, transurethral resection of prostate, pelvic surgery, surgery of the bladder and retroperitoneal lymph node dissection. These surgical procedures can accidently damage the autonomic nerves that controls the internal sphincter, the sphincter itself or both. Furthermore, nerve damage can be caused by medical illness such as multiple sclerosis and poorly controlled diabetes. Additionally, side-effects of certain medication can temporarily lead to this condition. For example, Tamsulosin, sertraline and risperidone (26).

Retrograde ejaculation results in the backward flow of semen into the bladder. This is due to the inability of the internal sphincter, located at the bladder neck, to close. Normally, the internal and external sphincter are shut to generate pressure for ejaculation. However, with retrograde ejaculation, the external sphincter is shut but the internal sphincter fails to close, resulting in the backward flow of semen (12,13). As mentioned, this leads to a dry organism and the urine of these males, post-orgasm, are often cloudy.

The treatment depends on the severity of damage, most men don’t need any specific treatment. If it causes infertility, treatment is recommended (26). Medications such as tricyclic antidepressants, antihistamines and decongestants tighten the bladder neck muscle and prevent the retrograde flow of semen into the bladder. However, these medications only work in a few cases (27). Surgical repair of the bladder neck is not often considered as the first option but is recommended if other measures fail (26-28). For infertility, there is intrauterine insemination and for more severe cases, IVF with intracytoplasmic sperm injection. All of these treatments aim to restore normal physiological ejaculation and hence fertility (28).

Summary

In conclusion, male infertility is a growing issue in developing nations, contributing to approximately half of all infertility cases (1). There are many possible aetiologies to male infertility, all of which aren’t necessarily medically related. Often, there is a psychological aspect that can impact fertility (29). In spite of all the available treatments and assisted reproductive therapies, there is still a need for an effective screening program to identify infertile males early on. Furthermore, it is important to raise awareness about the causes of male infertility, specifically regarding the negative lifestyle choice. In my opinion, male infertility is an important issue to be addressed because it can have a negative effect on both the male and female trying to conceive, not only physically but also mentally.

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