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Year 3- Repro > Male Infertility > Flashcards

Male Infertility Flashcards

1
Q

Define infertility

A

It is the inability of a couple to conceive after 12 months of continuous unprotected sexual intercourse. Affects around 15% of couples worldwide.

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2
Q

Why is 12 months only a clinical reference?

A

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.

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3
Q

Male Infertility

A

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

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4
Q

What is the first step in male infertility diganosis

A

Semen Analysis

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5
Q

Semen Analysis

A

Analysis of seminal fluid and sperm parameters as an indicator of male fertility potential.
Remains the gold standard.
WHO criteria for normal semen parameters.
There are two ways for conducting semen analysis:
Manual semen analysis
Computer-assisted semen analysis (CASA)

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6
Q

Why are there marginal changes between the WHO 2021 and WHO 2011 references?

A

The differences are due to the use of a much larger data set. Men in 2011 were mainly from europe and asia, 2021 men were from africa and south america too.

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7
Q

Define Normozoospermia (normal)

A

All sperm parameters within normal range

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8
Q

Define Azoospermia

A

No spermatozoa found in semen sample

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9
Q

Crytozoospermia

A

Virtually no spermatozoa present under microscope examination – only found after extensive search (centrifugation) and examination of pellet.

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10
Q

Oligozoospermia

A

Sperm count/conc. <15million/ml. (LESS)

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11
Q

Asthenozoospermia

A

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

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12
Q

Teratozoospermia

A

Normal morphology <4%. Reduced sperm morphology below 4%

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13
Q

Leucospermia

A

Leucocytes >1million/ml. Elevated presence of WBCs

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14
Q

Necrozoospermia

A

Proportion of dead spermatozoa outside normal range.

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15
Q

Oligoasthenoteratozoospermia

A

count, motility and morphology all below normal range.

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15
Q

Oligoasthenoteratozoospermia

A

count, motility and morphology all below normal range.

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16
Q

Oligoasthenoteratozoospermia

A

count, motility and morphology all below normal range.

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17
Q

Provide some causes of male infertility

A

Sperm production problems:
Chromosomal/genetic
HH
Cyrptorchisdism and varicocoele
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

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18
Q

Give examples of some sperm production problems- chromosomal/genetic

A

KLINEFELTER’S SYNDROME

JACOB’S SYNDROME

XX MALE SYNDROME

Y CHROMOSOME DELETIONS

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19
Q

KLINEFELTER’S SYNDROME (XXY) or variants

A

The presence of an additional X chromosome
Present with
Hypergonadotropic hypogonadism
FSH and LH levels are normal but due to the chromosomal abnormalities they have very small testes and reduced ability to synthesize testosterone when they receive the FSH and LH signal.
Azoospermia/severe oligospermia
Sexual dysfunction
Reduced presence of testosterone results in less pronounced male features: reduced chest hair, breast development, female pubic hair pattern, small testicular size, wider hips, poor beard growth.

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20
Q

JACOB’S SYNDROME (XXY or variants)

A

Presence of additional Y chromosome (more rare)
1 in 1000 males.
Most show normal sexual development.
Increased incidence of chromosomally abnormal spermatozoa.
Sperm ranging from normal to azoospermic.

21
Q

XX MALE SYNDROME (SRY TRANSLOCATION)

A

Genetically XX but phenotypically male
In meiosis the 44 autosomes undergo crossover, however if there is a complete cross over in the sex chromosomes it is problematic as each gamete will have a mixture of X and Y in each sex chromosome. Each sex chromosome contains pseudo autosomal regions at the edges (PAR). The PAR regions are what undergo crossing over on the sex chromosomes.
So in the autosomes you have full crossing over but in the sex chromosomes its just the PAR regions.
In the Y chromosome the SRY region (male determining factor) is located just outside the PAR region.
Sometimes there is a fault in crossing over and the SRY region is captured in the crossing over. This results in an X chromosome that now contains the SRY region.
If a sperm cell with an X chromosome bearing the SRY fertilises an egg, it will result in an XX male.
1 in 20,000 – 30,000 males (rare)
Testosterone deficiency, impaired spermatogenesis
Azoospermia
Variation in phenotype:
Some have normal male secondary sexual characteristics, have intact SRY
Some have ambiguous secondary sexual characteristics, have fragment of SRY

22
Q

Y CHROMOSOME DELETIONS

A

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

23
Q

How does Congential Hypogonadotrophic Hypogonadism effect sperm production?

A

Kallmann syndrome HH:
Mutation in the genes that coordinates the migration of GnRH neurons from the olfactory region, are anosmic:
KAL1, KAL2, PROK2/PROK2R, FGF8

Normosmic IHH
Spontaneous mutations occurring in the genes that are not associated with the migration:
GnRH1/GnRHR, KISS1/GPR54, TAC3/TAC3R

Prader-Willi syndrome:
Mutation in Chr 15

Isolated FSH or LH deficiency:
FSH/LH

Laurence-Moon-Bardet-Biedl Syndrome:
multiple BBS genes

24
Q

ANOSMIC?

A

Inability to smell

25
Q

How does acquired Hypogonadotrophic Hypogonadism effect sperm production?

A

Brain tumors – Pituitary adenomas, hypothalamic gliomas, craniopharyngiomas
Interfere with the hypothalamus and anterior pituitary to modulate the HPG axis via the production of GnRH, FSH and LH

26
Q

What is Cryptorchidism and how does it affect sperm production?

A

UNDESCENDED TESTES

Unilateral or bilateral
When testes are undescended: Higher testicular temperatures compromise sperm production/quality.
If left untreated = Azoospermia/severe oligospermia (untreated)

27
Q

What is varicocele and sperm production

A

enlargement of the veins within the loose bag of skin that holds the testicles (scrotum)

Either Unilateral or bilateral (Affecting one or both testes)
Caused by failure in the valves in the veins that take blood away from the testes.
Increased dilation, testes are continuously being perfused with blood.
Higher testicular temperatures compromise sperm production/quality.
10-15% of general population; 30-40% of male infertility cases.

28
Q

What is testicular torsion and how does is affect sperm production?

A

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, due to the loss of blood.
The spermatic cord twists within the scrotum, the spermatic cord holds the testes in place.

29
Q

What is orchitis and how does it affect sperm production?

A

Inflammation of one or both testes resulting from an infection (bacterial or viral).
Risk of damage to seminiferous tubules if untreated.
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.

30
Q

How does radiation affect sperm production?

A

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

31
Q

How do chemical agents affect sperm production?

A

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

Usually will be asked to freeze sperm before.

32
Q

What are some medications that affect sperm production and how do they do this?

A

Salazopyrin®: used to treat inflammatory bowel disease & rheumatoid arthritis. Causes short-term infertility, but reversible after 2-3 months of stopping treatment. Known to be cytotoxic to sperm production.
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

33
Q

What are some anabolic steroids that affect sperm production and how do they do this?

A

Drug formulations that contain natural androgens like testosterone or synthetic androgens that are similar in chemical structure, and are able to bind to the testosterone receptor.
Side effects: testicular shrinkage, sustained decline in sperm production via –ve feedback on the hypothalamus and anterior pituitary

34
Q

Examples of sperm transport problems

A

CAVD
&
OTHER OBSTRUCTIONS OF THE VAS DEFERENS, EPIDIDYMIS OR EJACULATORY DUCT

35
Q

what is CAVD

A

Congenital absence of the Vas deferens

Mutations in the cystic fibrosis transmembrane regulator gene (CFTR).
Or:
Abnormalities in the differentiation of the mesonephric duct.
The vas deferens is absent so there is a gap between the testes and the seminal vesicles.
Sperm is being produced and seminal vesicle fluid. But there is no sperm release through the vas deferens or mixing with the vesicular secretions. When an individual ejaculates, it is jus seminal fluid with no sperm.
Accounts for up to 5% of azoospermic men.

36
Q

Examples of other obstructions

A

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

37
Q

Erectile and ejaculatory problems may be….

A

RETROGRADE, PREMATURE or DELAYED

38
Q

Retrograde Ejaculation

A

Semen makes its way into the bladder.
Semen goes backwards
Prostate gland surgery most common cause.
Other causes: diabetes, multiple sclerosis, alpha blockers.
Neuropathy of the sphincter valves of the bladder in diabetes patients
In IVF treatment, give medication that will create an alkaline buffer, so that the sperm is not damaged by the acidic environment of the urine.

39
Q

Other erectile/ejaculatory problems that cause sperm problems

A

Erectile dysfunction

Premature ejaculation

Delayed ejaculation

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

40
Q

How do antibodies affect sperm production?

A

Anti-sperm antibodies are usually formed when there is a breach in the blood-testis barrier and exposure of immunogenic sperm antigens to the immune system.
Sperm are known to contain antigenic sites that can be recognized by the immune system. Therefore it is essential that the blood/testes barrier is in place, to protect the immune system from attacking the germ cells.
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.

41
Q

What do anti-sperm antibodies lead to?

(colour reference to diagram)

A

Impaired motility/cervical mucus penetration (when bound to tail)
Impaired oocyte interaction (when head bound)
Anti sperm antibodies can result in immunologic infertility

(Green = antigenic sites of the sperm. When there is a breach in the blood testes barrier, the antibodies bind to the antigenic sites)

42
Q

How do we test for anti-sperm antibodies?

A

IMMUNOBEAD TEST (DIAGNOSTICS/ SpermMar test

Performed by mixing sample with latex particles (beads) that have been coated with human IgA/G (same as ASA).
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
The antibody that is added will bind to both the sperm and the latex particle, as a result it will make the beads visible.
You have latex particles that have been coated with IgA and IgG. Sperm naturally have IgA and IgG.
If an antibody to the IgA ad IgG is added, in normal sperm you will not see anything. BUT if there are anti sperm antibodies already bound, when the monospecific antihuman IgA/G antiserum is added, it will bind to both the latex bead as well as the anti sperm antibody.

SO… If there is NO ASA, there will be no latex beads bound to the sperm.
You will see bead clusters. So When the secondary antibody is added, it binds to both the latex beads and the ASA on the sperm

43
Q

When may sperm DNA damage occur?

A

Sperm DNA damage usually occurs during spermatogenesis, chromosomal complement is in place, but the nuclear material packaged in the sperm can undergo damage or breaks in the sequence:

44
Q

Why does sperm DNA damage occur?

A

Sperm is transcriptionally inactive due to certain changes that occur during spermatogenesis. During the spermiogenesis phase there is a replacement of histones with protamines for the packaging of the nuclear material. This tight packaging and remodelling of the nuclear material results in transcriptional inactivity.
In other cells that undergo damage they normally can self repair. BUT as sperm are transcriptionally inactive this is not possible.

45
Q

Major cause of sperm DNA fragmentation?

A

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.
Happens in all men to different extents.
Variable incidence data as testing is not performed routinely.
Expensive to test for

↑sperm DNA fragmentation leads to higher miscarriage rates (ESHRE Recurrent Pregnancy Loss Guideline, 2017).

46
Q

Risk factors of sperm DNA fragmentation

A

(most associated with increased testicular temperature):

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

47
Q

How do we test for sperm DNA fragmentation?

A
  1. SPERM CHROMATIN STRUCTURE ASSAY (used in clinics)
  2. TUNEL ASSAY (used in research)
  3. COMET ASSAY (clinical use)
48
Q

Sperm Chromatin structure assay

A

Sperm cells stained with acridine orange
Red = DNA fragmentation
Green = Normal sperm (no fragmentation)
Analysis with fluorescent microscopy or flow cytometry
DNA Fragmentation Index DFI % = red/(red + green)
Normal → 0-15%

49
Q

TUNEL ASSAY

A

Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)
Cells treated with TDT and fluorescent–labelled dNTP
Spots breaks in the DNA and fills gaps with dNTPs
Detection via flow cytometry or fluorescence microscopy

dNTP=Deoxynucleotide triphosphate
TDT = Terminal deoxynucleotidyl transferase (form of DNA polymerase)

50
Q

COMET ASSAY

A

Comet assay = single cell gel electrophoresis assay
Cells are embedded on agarose-coated slides and lysed - to expose genetic material
↓
Electrophoresis and fluorescent labelling carried out
↓
Microscopy

There is a comet like appearance of genetic material. During electrophoresis, as DNA is negatively charged, they move towards the positive end, BUT if there are any breaks/damage in the sequence, they will move towards the positive end at a faster rate. So you can see tails, as they move faster. Normal cells will have no tail

51
Q

brief summary

A

Summary
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.

Year 3- Repro (34 decks)

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