Male infertility Flashcards
How is infertility defined?
- Inability of a couple to conceive after 12 months of continuous unprotected sexual intercourse. Affects around 15% of couples worldwide.
- When there is no conception after 12 months, data suggests that there is a significant chance of an existing pathology (either from the woman or the man).
- However, it does not mean that a couple could not conceive naturally later on down the line. Half of the couples which do not conceive during the first year will do so during the second year.
- Better to undergo fertility investigations after a year instead of wasting more time while the womb is aging.
- Male infertility is diagnosed when reproductive problems have been found in the male, after testing both partners. Implicated in 50% of infertility cases.
- 30% of cases are male infertility plus an additional 20% which is both partners.
What is the first step in male fertility diagnostics?
- Semen Analysis
- Usually the first diagnostic step in male fertility investigations.
- Analysis of seminal fluid and sperm parameters as an indicator of male fertility potential.
- Remains the gold standard for male fertility diagnosis.
- WHO criteria for normal semen parameters (updated this year).
What are the potential methods by which semen analysis is conducted?
- Two methods of conducting semen analysis
1) Manual semen analysis
2) Computer-assisted semen analysis (CASA)
How have the WHO reference values changed since 2010?
WHO (2010)
1) Volume = 1.5 - 6 ml
2) Grey-opalescent appearance
3) Liquefaction = <30 mins
4) Sperm concentration = ≥15million/ml
5) Motility = ≥40%
6) Progressive motility = ≥32%
7) Morphology (normal forms) = ≥4%
8) Vitality (live) = ≥58%
9) pH = 7.2-8.0
10) Leucocytes = <1 million/ml
WHO (2021)
1) Volume = 1.4 - 6 ml
2) Grey-opalescent appearance
3) Liquefaction = <30 mins
4) Sperm concentration = ≥16million/ml
5) Motility = ≥42%
6) Progressive motility = ≥30%
7) Morphology (normal forms) = ≥4%
8) Vitality (live) = ≥54%
9) pH = 7.2-8.0
10) Leucocytes = <1 million/ml
- Much larger (and comprehensive) data set was used to derive 2021 values.
- It is important to note that even though there are marginal differences between the reference values in the 2010 manual and the 2021 manual, remember that the 2021 criteria is statistically compliant with the 2010 criteria. The marginal differences are seen because a much larger data set was used to derive the 2021 values. In 2010, a lot of the men who were sampled came mainly from Europe and Asia, but a much more comprehensive data set in the 2021 manual has been included (where they sampled more men from South America and South Africa, for example, and there are larger numbers). Therefore, the figures differ slightly but clinically and statistically, there is compliance between both.
What are 9 of the potential diagnoses that could result from a semen analysis?
1) Normozoospermia (Normal) – All sperm parameters within normal range (WHO criteria)
2) Azoospermia – No spermatozoa found in semen sample. Azoospermia is conclusively diagnosed by microscopic examination of the semen sample. Then, the sample is centrifuged; the pellet is taken and analysed as well. It is only after these two steps that they conclusively diagnose that this sample is azoospermic.
3) Cryptozoozpermia – Virtually no spermatozoa present on wet slide – only found after extensive search (centrifugation). Cryptozoozspermia is when there is no sperm present on the wet preparation (the initial microscope examination), but then found after extensive search (centrifuge and pellet examined).
4) Oligozoospermia – Sperm count/conc. <15million/ml. The 2021 manual says 16 million for oligozoospermia but, since they are statistically compliant, this is still acceptable. Most clinics are likely to stick to 15 million going forward.
5) Asthenozoospermia – Sperm motility <42% (or progressive <30%).
6) Teratozoospermia – Normal morphology <4%.
7) Leucospermia – Leucocytes >1million/ml (indicative of infection or illness).
8) Necrozoospermia – Proportion of dead spermatozoa outside normal range (above WHO threshold).
9) Oligoasthenoteratozoospermia = count, motility and morphology all below normal range.
What are 5 causes of male infertility?
1) Sperm production problems
- Chromosomal/genetic
- HH
- Cyrptorchisdism and varicocoele
- Torsion and orchitis
- Chemo and radiotherapy
- Medicine and anabolic steroids
2) Sperm transport problems (obstruction)
- CBAVD and other obstructions.
3) Erectile and ejaculatory problems
- Retrograde ejaculation and other conditions.
4) Sperm antibodies
5) Sperm DNA fragmentation
What are chromosomal/ genetic causes of sperm production defects and how do they occur?
- Parental nondisjunction at meiosis II resulting in an extra Y chromosome produces a 47,XYY karyotype in the affected offspring
1) Klinefelter’s syndrome XXY or variants
- Common cause is Klinefelter’s syndrome (presence of an extra X chromosome).
- 1:500 males
- Individuals with this condition usually present with hypergonadotrophic hypogonadism; this means that the hypothalamus and pituitary are functioning normally, but the chromosomal abnormalities cause small testes and reduced ability to synthesise testosterone (hypogonadism) when they received the LH and FSH signal. Usually have elevated FSH/LH, meaning the problem is in the testicles/ovaries.
- In terms of sperm production and sperm quality, it can range from anywhere between severe oligospermia to azoospermia. - May also present with some sexual dysfunction as well. The reduced presence of testosterone results in less pronounced male features, such as reduced growth of chest hair, breast development, female type pubic hair pattern, small testicular size, wider hips and poor beard growth.
2) Jacob’s syndrome XYY or variants
- Similar condition (in the sense it is caused by the presence of an extra Y chromosome). Rarer condition.
- 1 in 1000 males.
- Most show normal sexual development.
- Characterized by increased incidence of chromosomally abnormal spermatozoa.
- Sperm ranging from normal to azoospermic (depends on how it manifests in the phenotype).
3) XX male syndrome (SRY translocation)
- 1 in 20,000 to 30,000 males. This is a much rarer form of male infertility pathology.
- This is the XX male syndrome, where the individual is genetically XX but phenotypically presents as male.
- In meiosis and mitosis, the 44 autosomes usually undergo full crossover. This would be problematic in the sex chromosomes, because each gamete would have a mixture of X and Y in each sex chromosomes. Instead, each sex chromosome contains pseudoautosomal regions at the edges; these are the regions that undergo crossing over in the sex chromosomes. In the Y chromosome, the SRY-coding region is located just outside of the pseudoautosomal region. This SRY-coding region is the male-determining factor in the Y chromosome; it is the gene sequence that determines the male gender. If there is a fault with the crossing over, the SRY-coding region can be captured in the crossing over, resulting in the formation of an X chromosome with the SRY region. If a sperm cell with this X chromosome bearing the SRY goes on to fertilise an egg, it would result in an XX male.
- Associated with testosterone deficiency, impaired spermatogenesis and ultimately, azoospermia
- There is variation in the expression of the phenotype; some individuals have normal male secondary sexual characteristics, even though they are azoospermic. With such individuals, they tend to have a demonstrable SRY region (when gene sequencing is carried out, their SRY region is in tact), while some individuals have ambiguous sexual characteristics, e.g. hypospadia, micropenis. Such individuals have been found to just have fragments of the SRY region (only took along a fragment of SRY in the crossing over).
4) Y chromosome deletions
- Deletions of genetic material in regions of the Y chromosome called azoospermia factor (AZF) A, B, or C
- Deletions in the azoospermia factor regions of the Y chromosome (azoospermia factor a, b and c) make up to 5-10% of azoospermia or severe oligospermia cases.
What are the two types of hypogonadotrophic hypogonadism and potential causes?
- Hypogonadotrophic hypogonadism can be divided into two categories = congenital and acquired.
1) Hypogonadotrophic hypogonadism (congenital)
- Kallmann syndrome HH = caused by a mutation in the genes that coordinate the migration of GnRH neurons from the olfactory region, e.g. KAL1, KAL2, PROK2/ PROK2R, FGF8. These are the most popular genes that are implicated (there are a lot more associated genes). Individuals with Kallmann syndrome present with anosmia as one of the symptoms.
- Normosmic IHH (idiopathic hypogonadotrophic hypogonadism) = GnRH1/ GnRHR, KISS1/GPR54, TAC3/TAC3R. There is also normosmic hypogonadotrophic hypogonadism, where there are spontaneous mutations that occur in the genes that are not associated with the migration. Therefore, they have the ability to smell (normosmia), but they have hypogonadotrophic hypogonadism as well. This is usually due to a mutation in GnRH and its receptor, kisspeptin and its receptor and TAC3 and its receptor (as well as other genes too).
- Prader-Willi syndrome = Chr 15. There are much rarer conditions, such as mutations in chromosome 15 that causes Prader-Willi syndrome. This also comes with hypogonadotrophic hypogonadism.
- Isolated FSH or LH deficiency = FSH/LR
- Laurence-Moon-Bardet-Biedl Syndrome = multiple BBS genes. Multiple genes are implicated. When there is a mutation in one or more of these genes, individuals present with hypogonadotrophic hypogonadism.
2) Hypogonadotrophic hypogonadism (acquired)
- Usually due to brain tumours = Pituitary adenomas, hypothalamic gliomas, craniopharyngiomas. This ultimately interferes with the ability of the hypothalamus and the anterior pituitary to modulate the HPG axis via production of GnRH, FSH and LH.
How may cryptorchidism/ varicocele affect fertility?
- Affects sperm production
1) Cryptorchidism (undescended testes)
- More common condition.
- There are different manifestations; can either be unilateral (one testis) or bilateral (both testes). Normal presentation of the testes is located in the scrotum, a few degrees lower than normal body temperature (optimal for sperm production). Undescended testes are exposed to higher temperatures, which ultimately compromise sperm production and quality. If this condition is left untreated (condition can be corrected via surgery = orchidopexy), it can result in azoospermia/severe oligospermia.
2) Varicocele
- Another very common condition
10-15% of general population; 30-40% of male infertility cases.
- Can also be unilateral or bilateral (can occur in one or both testes).
- Higher testicular temperatures compromise sperm production/quality.
- The testicular blood vessels originate in the abdomen and course down through the inguinal canal as part of the spermatic cord on their way to the testis. The inguinal canal is the tube down which the testes pass during their descent into the scrotum during foetal life. The blood, lymph and nervous supply pass through with it and form part of the spermatic chord. Upward flow of blood in the veins from the testis is ensured by small one-way valves that prevent backflow down into the testis, therefore any defect in the valves, or compression of the vein by a nearby structure, can cause of the veins near the testis dilatation, leading to the formation of a varicocele
- It is caused by failure of the valves in the veins that take blood away from the testes. This failure of the valves causes increased dilation. The testes are continuously perfused with blood and, ultimately, there is increased exposure to higher temperatures. The pronounced dilation can be seen in the diagram. When a clinical examination is performed, varicocele feels like a bag of worms. It is still possible for men with varicoceles to be fertile and have children.
How does torsion/ orchitis affect fertility?
- Affects sperm production
1) Testicular Torsion
- Much rarer condition is testicular torsion (twisting of the testis inside the scrotum, cutting off blood supply to the testes).
- Most common in teenagers and young men.
- Extremely painful; medical emergency.
- Spermatic cord, which holds the testis in place, twists within the scrotum and the testis follow suit. There is a condition that increases susceptibility to testicular torsion; it is not a harmful condition, but the tunica of the testes is not secured properly inside of the scrotum and, as a result, the testes are free to twist or rotate.
- Due to the loss of blood that occurs with this torsion, it is important that surgical intervention (orchidopexy) is performed within the first 6 hours of occurring for the best chances of preventing permanent testicular damage.
- Can be a very painful situation; symptoms include nausea, vomiting, very sharp pain in testes and abdomen and sometimes even blood in the urine as well = medical emergency. Also, sudden, severepainon one side of the scrotum, redness and swelling of the scrotum, one testicle suddenly sits higher than the other, abdominal pains, fever, needing to pee often, dizziness, lumps in the scrotum, blood in the semen.
2) Orchitis
- Inflammation of one or both testes resulting from an infection (bacterial or viral).
- Risk of damage to seminiferous tubules if left untreated.
- 1 in 10 males experience drop in sperm count (semen quantity) but rarely large enough to cause infertility.
- Mumps orchitis used to be the most common cause of orchitis but now less common due to vaccination. Mumps orchitis is the form of orchitis caused by the mumps virus. Used to be the most common cause until the MMR vaccine was developed. There used to be a lot of concern for individuals who were undergoing puberty and then having mumps orchitis; there was that fear about it compromising fertility potential, but this is now a lot less common due to vaccination.
- Mumps, STI or spread of an infection from other parts of the body.
How does radiation/chemical agents affect fertility?
- Affects sperm production
- Clinically, when individuals are going for either radiotherapy or chemo, it is often recommended to freeze sperm in case there is permanent damage.
1) Radiotherapy - Uses high energy X-rays to kill cancer cells in a specific area (localized regions) while limiting damage to normal cells.
- Testicular cancers = Potential damage to the testis, problems with spermatogenesis. Usually try to protect other unaffected areas from these x-rays but applying radiotherapy in the case of testicular cancers risks damage to the testes and subsequent problems with spermatogenesis.
- Brain/rest of the body = Could affect glands that produce reproductive hormones, e.g. anterior pituitary
2) Chemotherapy - The chemical agents used are known to attack cells in the seminiferous epithelium, temporarily or permanently damaging sperm/germ cells.
- Cyclophosphamide can cause infertility in both men and women. It is a commonly used drug in chemotherapy, despite causing gonadotoxicity.
- Return to normal fertility depends on type and duration of chemo.
- Whether the damage is temporary or permanent can depend on how long the patient is on chemotherapy.
How may medicines and anabolic steroids affect fertility?
1) Medicines
- Salazopyrin = used to treat inflammatory bowel disease & rheumatoid arthritis. Causes short-term infertility, but reversible after 2-3 months of stopping treatment. Salazopyrin is known to be cytotoxic to sperm maturation (compromises completion of maturation).
- Testosterone (tablets/ injections) = used to treat androgen deficiency. When testosterone is prescribed, e.g. in cases of testosterone or androgen deficiency, it could result in a sustained decline in sperm production as a result of the negative feedback that it will have on the hypothalamus and anterior pituitary. It is usually a balancing act when it comes to the dosing and how long the drugs are taken for; on one hand, testosterone deficiency is being supplemented but, in the long-term, the HPG axis is being compromised.
2) Anabolic steroids - Drug formulations that contain natural androgens like testosterone or synthetic androgens that are similar in chemical structure. Anabolic steroids can contain synthetic androgens that are able to bind to the androgen receptor. There are also other formulations that the metabolism will break down into testosterone. The mode of action is via negative feedback where serum levels of testosterone are extremely high. This feeds back negatively on the HPG axis and then reduces endogenous production of testosterone as a result.
- Side effects = testicular shrinkage, sustained decline in sperm production via –ve feedback on the hypothalamus and anterior pituitary.
What defects in sperm transport may affect fertility?
1) Congenital absence of the Vas deferens (CAVD)
- Most common cause is CAVD (a relatively common cause in terms of affecting sperm transport).
- Mutations in the cystic fibrosis transmembrane regulator gene (CFTR) or
Abnormalities in the differentiation of the mesonephric duct.
- Some individuals that have cystic fibrosis also present with congenital absence of the vas deferens. It is considered an obstruction because sperm and seminal vesicle fluid is produced and, in a normal male individual, sperm would be released through the vas deferens to mix with vesicular secretions, but there is no such connection in this case (sperm stays where it is, so ejaculation contains seminal fluid with no sperm).
- Up to 5% of azoospermic men.
2) Other obstructions
- There are other treatable causes of obstruction.
- Obstruction of the vas deferens, epididymis or ejaculatory duct.
- Caused by infections, hernias or scarring from corrective surgeries around the male reproductive tract, e.g. vasectomy reversal.
What erectile and ejaculatory problems affect fertility?
1) Retrograde ejaculation = means the semen goes backwards (into the bladder) instead of coming out of the penis.
- Prostate gland surgery most common cause.
- Other causes: diabetes (neuropathy of the bladder in diabetes patients), multiple sclerosis, alpha blockers (often used to treat high blood pressure). Neuropathy of the sphincter valves that are just outside of the bladder is the main cause. These conditions can result in that neuropathy and it can be a side effect of prostate gland surgery as well.
- Normally, during ejaculation, the sphincter valve that guards the entrance of the bladder is usually shut, but a neuropathy in this area means it is either half open or always open. Due to the pressure differential (difference in pressure) when the valve is open, the semen goes backwards into the bladder. The semen then comes out with urine. Normally, the sphincter guarding the bladder would be shut and the other would be open. When such individuals come in for IVF treatment, they are given certain medication that will create an alkaline buffer so that the sperm isn’t damaged by the acidic environment of the urine. Once they urinate, the sample is centrifuged, the pellet (containing sperm) is withdrawn and transferred into culture immediately. This must be done very quickly to salvage the sperm from the urine. These individuals will have intercourse and the sensation of an orgasm, but there will be no ejaculation and the semen will come out when they urinate next. Therefore, it can sometimes take a while to pick up on this.
2) Erectile dysfunction
3) Premature ejaculation
4) Delayed ejaculation
5) Physical and psychological causes = There are also psychosexual and psychological causes (shown by studies). There are other underlying conditions that can lead to neuropathies that contribute to these conditions.
- Physical = diabetes, spinal cord injuries, multiple sclerosis, prostate/bladder surgery, thyroid (overactive or underactive), anti-depressants, beta-blockers, antipsychotics, muscle relaxants, recreational drugs.
- Psychological = depression, stress
How do anti-sperm antibodies form?
- Formed when there is a breach in the blood-testis barrier and exposure of immunogenic sperm antigens to the immune system. Mammalian sperm are known to contain antigenic sites that can be recognised by the immune system. Therefore, it is essential that the blood-testis barrier is in place to prevent the immune system from attacking the germ cells. The immune system can encounter the sperm when there is a breach in the barrier, triggering an immune response and the generation of anti-sperm antibodies.
- Immune response, resulting in an inflammatory reaction and ASA formation.
- Rare cases = ASA present in female reproductive tract resulting from an allergic reaction.
- Variable incidence data as testing is not performed routinely. It is only after semen analysis is carried out and certain other things are unclear. 5-30% incidence in male infertility patients according to numerous studies
- Risk factors = Genital trauma, testicular torsion, biopsy, e.g. prostate, vasectomy, cryptorchidism. These risk factors could all result in exposure of the germ cells to the immune system.
