male infertility

nability of a couple to conceive after 12 months of continuous unprotected sexual intercourse. Affects around 15% of couples worldwide. 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. Male infertility Diagnosed when after testing both partners, reproductive problems have been found in the male. Implicated in 50% of infertility cases.

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. WHO criteria for normal semen parameters. Can be manual semen analysis or computer assisted semen analysis

Volume 1.5 – 6.0 ml Appearance/Colour Grey-opalescent appearance Liquefaction <30 minutes Sperm concentration >15million/ml Motility >40% Progressive motility >32% Morphology (normal forms) >4% Vitality (live) >58% pH 7.2 - 8.0 Leucocytes <1 million/ml

Normozoospermia (Normal) – All sperm parameters within normal range. Azoospermia – No spermatozoa found in semen sample. Cryptozoozpermia – Virtually no spermatozoa present – only found after extensive search (centrifugation). Oligozoospermia – Sperm count/conc. <15million/ml. Asthenozoospermia – Sperm motility <40% (or progressive <32%). Teratozoospermia – Normal morphology <4%. Leucospermia – Leucocytes >1million/ml. Necrozoospermia – Proportion of dead spermatozoa outside normal range.

Sperm production problems Sperm transport problems (obstruction) Erectile and ejaculatory problems Sperm antibodies Sperm DNA fragmentation

Sperm production problems Chromosomal/genetic Hypogonadotrophic hypogonadism Cyrptorchisdism (a condition in which one or both of the testes fail to descend from the abdomen into the scrotum) and varicocoele (enlarged veins in scrotum) Torsion and orchitis Chemo and radiotherapy Medicined and anabolic steroids Sperm transport problems (obstruction) CABVD ( and other obstructions. Erectile and ejaculatory problems Retrograde ejaculation and other conditions. Sperm antibodies Sperm DNA fragmentation

KALLMANS SYNDROME- Hypergonadotrphic hypogonadism Azoospermia/severe oligospermia Sexual dysfunction 1 in 1000 males. Most show normal sexual development. JACOBS SYNDROME- Increased incidence of chromosomally abnormal spermatozoa. Sperm ranging from normal to azoospermic. Parental nondisjunction at meiosis II resulting in an extra Y chromosome produces a 47,XYY karyotype in the affected offspring XX MALE SYNDROME- Happens due to SRY transolcation 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.

Diseases causing congenital hypogonadotropic hypogonadism 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 Diseases causing acquired hypogonadotropic hypogonadism: Brain tumours – Pituitary adenomas, hypothalamic gliomas, craniopharyngiomas Prolatin-secreting pituitary adenoma = prolactinoma

Unilateral or bilateral Higher testicular temperatures compromise sperm production/quality. Azoospermia/severe oligospermia (untreated) 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 Varicocele: Unilateral or bilateral Higher testicular temperatures compromise sperm production/quality. 10-15% of general population; 30-40% of male infertility cases.

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.

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.

Medications: Salazopyrin®: used to treat inflammatory bowel disease & rheumatoid arthritis. Causes short-term 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

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

Congenital absence of the bas 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. Obstruction of the vas deferens, epididymis or ejaculatory duct. Caused by infections, hernias or scarring from corrective surgeries around the male reproductive tract.

Erectile dysfunction Premature ejaculation Delayed ejaculation Retrograde ejaculation: Semen makes its way into the bladder. Prostate gland surgery most common cause. Other causes: diabetes, multiple sclerosis, alpha blockers. Physical and psychological causes 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

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.

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

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

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 (ESHRE Recurrent Pregnancy Loss Guideline, 2017).

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

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 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