Male infertility

Question 1

What is male infertility? (5)

Answer 1

Diagnosed when after testing both partners, reproductive problems have been found in the male. Implicated in 50% of infertility cases.

• 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.
• WHO criteria for normal semen parameters.

Question 2

Normozoospermia (Normal)

Answer 2

All sperm parameters within normal range.

Question 3

Azoospermia

Answer 3

No spermatozoa found in semen sample.

Question 4

Cryptozoozpermia

Answer 4

Virtually no spermatozoa present – only found after extensive search (centrifugation).

Question 5

Oligozoospermia

Answer 5

Sperm count/conc. <15million/ml.

Question 6

Asthenozoospermia

Answer 6

Sperm motility <42% (or progressive <30%).

Question 7

Teratozoospermia

Answer 7

Normal morphology <4%.

Question 8

Leucospermia

Answer 8

Leucocytes >1million/ml.

Question 9

Necrozoospermia

Answer 9

Proportion of dead spermatozoa outside normal range.

Question 10

Male infertility - Causes (5)

Answer 10

1. Sperm production problems
   2.Sperm transport problems (obstruction)
   3.Erectile and ejaculatory problems
   4.Sperm antibodies
   5.Sperm DNA fragmentation

Question 11

Sperm production - chromosomal/genetic (4)

Answer 11

Klinefelter’s syndrome XXY or variants:
-Hypergonadotrphic hypogonadism
-Azoospermia/severe oligospermia
-Sexual dysfunction

Jacob’s syndrome XYY or variants:
-1 in 1000 males.
-Most show normal sexual development.
-Increased incidence of chromosomally abnormal spermatozoa.
-Sperm ranging from normal to azoospermic.

XX male syndrome (SRY translocation):
-1 in 20,000 – 30,000 males
-Testosterone deficiency, impaired spermatogenesis
-Azoospermia

Y chromosome deletions:
-Deletions of genetic material in regions of the Y chromosome called azoospermia factor (AZF) A, B, or C
-5-10% of azoospermia or severe oligospermia cases.

Question 12

Sperm production – Hypogonadotrophic Hypogonadism congenital vs acquired (2)

Answer 12

Hypogonadotrophic hypogonadism (congenital):
- Kallmann syndrome HH – KAL1, KAL2, PROK2/PROK2R, FGF8
- Normosmic IHH – GnRH1/GnRHR, KISS1/GPR54, TAC3/TAC3R
- Prader-Willi syndrome – Chr 15
- Isolated FSH or LH deficiency – FSH/LR
- Laurence-Moon-Bardet-Biedl Syndrome – multiple BBS genes

Hypogonadotrophic hypogonadism (acquired):
- Brain tumours – Pituitary adenomas, hypothalamic gliomas, craniopharyngiomas

Question 13

Sperm production – cryptorchidism | varicocoele (2)

Answer 13

Cryptorchidism (undescended testes):
- Unilateral or bilateral
- Higher testicular temperatures compromise sperm production/quality.
- Azoospermia/severe oligospermia (untreated)

Varicocele:
- Unilateral or bilateral
- Higher testicular temperatures compromise sperm production/quality.
_ 10-15% of general population; 30-40% of male infertility cases.

Question 14

Sperm production – torsion | orchitis (2)

Answer 14

Testicular Torsion:
- Rare condition - Twisting of the testis inside the scrotum. This cuts off blood supply to the testis.
- Most common in teenagers and young men.
- Torsion is a medical emergency and intervention (orchidopexy) within 6hrs
gives best chance of avoiding permanent damage.

Orchitis:
- Inflammation of one or both testes resulting from an infection (bacterial or viral).
- Risk of damage to seminiferous tubules.
- 1 in 10 males experience drop in sperm counts 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.

Question 15

Sperm production – radiation | chemical agents (2)

Answer 15

Radiotherapy:
- Uses high energy X-rays to kill cancer cells in a specific area while limiting damage to normal cells.
- Testicular cancers: Potential damage to the testis, problems with spermatogenesis.
- Brain/rest of the body: Could affect glands that produce reproductive hormones e.g. anterior pituitary

Chemotherapy:
- Attacks cells in the seminiferous epithelium, temporarily or permanently
damaging sperm/germ cells.
- Return to normal fertility depends on type and duration of chemo

Question 16

Sperm production – medicines | anabolic steroids (4)

Answer 16

Medicines
Salazopyrin®: used to treat IBS & rheumatoid arthritis. Causes ST infertility, but reversible after 2- 3 months of stopping treatment.

Testosterone (tablets/injections): used to treat androgen deficiency. Can result in a sustained decline in sperm production via –ve feedback on the hypothalamus and anterior pituitary

Anabolic steroids:
Drug formulations that contain natural androgens like testosterone or synthetic androgens that are similar in chemical structure.

Side effects: testicular shrinkage, sustained decline in sperm production via –ve feedback on the hypothalamus and anterior pituitary

Question 17

Sperm transport – CAVD | other obstructions (2)

Answer 17

Congenital absence of the Vas deferens:
- Mutations in the cystic fibrosis transmembrane regulator gene (CFTR).
or
- Abnormalities in the differentiation of the mesonephric duct.
- Up to 5% of azoospermic men.

Other obstructions:
- Obstruction of the vas deferens, epididymis or ejaculatory duct.
- Caused by infections, hernias or scarring from corrective surgeries around the male reproductive tract.

Question 18

Erectile and ejaculatory – retrograde | premature | delayed (2)

Answer 18

Retrograde ejaculation:
- Semen makes its way into the bladder.
- Prostate gland surgery most common cause.
- Other causes: diabetes, multiple sclerosis, alpha blockers

Other conditions:
- Erectile dysfunction
- Premature ejaculation
- Delayed ejaculation
- 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

Question 19

How do you get anti-sperm antibodies? (5)

Answer 19

• Breach in the blood-testis barrier and exposure of immunogenic sperm antigens to the immune system.
• 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.

Risk factors: Genital trauma, torsion, biopsy, vasectomy, cryptorchidism.

Question 20

Explain the effects of anti-sperm antibodies (3)

Answer 20

• Impaired motility/cervical mucus penetration (tail bound)
• Impaired oocyte interaction (head bound)
• Immunologic infertility

Question 21

How do you test for anti-sperm antibodies – Immunobead test? (3)

Answer 21

• Performed by mixing sample with latex particles that have been coated with human IgA/G.
• To this mixture, a monospecific antihuman IgA/G antiserum is added.
• The formation of agglutinates between particles and motile spermatozoa indicates the presence of IgA/G antibodies on the spermatozoa

Question 22

Sperm DNA fragmentation (4)

Answer 22

• Major cause = oxidative stress.
• Free radicals (ROS) attack the DNA molecule causing breaks in the sperm DNA strands.
• Can be present in men with both abnormal and normal semen parameters.
• Variable incidence data as testing is not performed routinely.

↑sperm DNA fragmentation leads to higher miscarriage rates

Question 23

Sperm DNA fragmentation – risk factors (10)

Answer 23

Varicocoele
Increased testicular temperature
Male reproductive tract infection
Infrequent ejaculation
Aging
Toxins and radiation
Cancer
Increased BMI and poor diet
Recreational drugs & medications
Smoking

Question 24

Sperm DNA fragmentation – Diagnostic tests (3)

Answer 24

Sperm chromatin structure assay: Cells stained with acridine orange
Red = DNA fragmentation
Green = Normal
DFI % = red/(red + green) Normal → 0-15%

TUNEL assay: Cells treated with TDT and fluorescent–labelled dNTP
normal vs fragmented
Detection via flow cytometry or fluorescence microscopy
dNTP=Deoxynucleotide triphosphate
TDT = Terminal deoxynucleotidyl transferase

Comet assay: Cells embedded on agarose-coated slides and lysed
↓
Electrophoresis and fluorescent labelling
↓
Microscopy

Question 25

Summary (3)

Answer 25

Male infertility is implicated in 50% of infertility cases and the first diagnostic step is a semen analysis test using the WHO (2021) criteria.

Male infertility could result from conditions that impair sperm production, sperm transport, as well as erectile and ejaculatory function.

Anti-sperm antibodies and sperm DNA fragmentation are known to impair sperm function and are also implicated in infertility.