Male infertility

Question 1

Azoospermia incidence and causes

Answer 1

1% male population
10% of those with male infertility have azoospermia
36% obstructive azoospermia
60% non-obstructive azoospermia
3% hypogonadotrophic hypogonadism

Pretesticular - amenable to medication intervention

Question 2

Genetics of azoospermia

Answer 2

NOA - 73% unknown. TEX11 (meiotic germ cell arrest). AZF microdeletions. Karyotype anomalies - 47XXY, 46XX male syndrome
CBAVD - CFTR gene mutation, ADGRG2, 10% unknown
Hypogonadotrophic hypogonadism - 50% idiopathic 50% genetic - i.e. ANOS1, SOX10, SOX2, GNRHR gene defect.

Question 3

Investigations for OA

Answer 3

Targeted investigations
Diagnosis of obstructive azoospermia
Low volume and acidic semen pH suspicious for OA.

Question 4

Retrograde ejaculation

Answer 4

Diminished volume or complete lack of seminal emission.
Often first symptoms of diabetes mellitus.
Diagnosed by microscopic examination of postejaculation urine.
Pseudoephedrine (Sudafed) 120mg tds ~25% will achieve antegrade ejaculation.
Ejaculation with a full bladder is sometimes helpful.
Urine can be alkalinised and the sperm from the postejaculate urine retrieved, processed and used for IUI, IVF or ICSI

Question 5

CBAVD

Answer 5

1 in 1000 males
Assoc with seminal vesicle agenesis in 50% of cases, renal agenesis (unilateral) in 5-10%
Prevalence of CBAVD in azoospermic men - 5-15%. 25% of cases of OA.
CBAVD with SV agenesis = azoospermia, low semen volume and pH <7
F508 and 5t alleles highest risk of CBAVD

Question 6

ADGRG2

Answer 6

Adhesion G protein couples receptor G2, critical regulator of male fertility, maintains pH homeostasis.
Found of X chromosome (Xp22.13)
Found in 10-20% of CBAVD patients with negative CFTR gene mutations.
Should be assayed if renal USS is normal.
Genetic counselling recommended.
?PGT-A and transfer male patients only.

Question 7

Investigations for NOA

Answer 7

If normal volume azoospermia.
Step one is to centrifuge sample to identify if cryptozoospermia (virtually no sperm) - may be able to retrieve enough from this to freeze for ICSI

FSH and testicular volume can be effective at predicting diagnosis.
High FSH >7.6IU/L and low testicular volume <4.6cm= NOA 96% accuracy
Low FSH <7.6IU/L and normal testicular volume >4.6cm = OA 89% accuracy

Sperm concentration to ask for karyotype.
<5million/ml.
If KS suspected always ask for 100cells to be tested for mosaicism.

Question 8

Predictive factors of SR in micro-TESE

Answer 8

FSH level, T levels, Testicular volume are all POOR predictors - AUC 0.52-0.59
AZF microdeletions - A (Awful) no sperm. B (bad) 5% chance of sperm C (chance) 45% SRR.
Histology best predictor but not recommended as may disrupt one area of spermatogenesis.
-hypospermatogenesis - 75-100% SRR
- Sertoli only syndrome - 22-40% SRR
- Maturation arrest - 30-80% SRR
- Seminiferous tubule hyalinisation - 14-48% SRR

Question 9

TESE versus micro-TESE

Answer 9

Conventional TESE
- blind approach
- failure to retrieve sperm
- Devascular injury
- massive tissue loss
- decrease in testicular function

SR - MicroTESE 1.5 higher SRR than conventionalTESE (2015)

Question 10

Klinefelter syndrome - incidence and impact on fertility

Answer 10

47XXY
Most common genetic abnormality in men (1 in 650) 50% never diagnosed.
14% of patient with azoospermia have Klinefelters
10-15% will be mosaic klinefelters (more likely to find sperm)

Question 11

Phenotype of KS and causes of variable phenotypes in Klinefelters

Answer 11

Varying degrees of hypogonadism
CAG repeat polymorphisms (androgen receptor repeats)
Mosaicism
X chromosome inactivation
Origin of extra X chromosome
Pseudo-autosomal region gene activty
Epigenetics

Question 12

Mechanism of Testicular dysfunction in KS

Answer 12

Consequence of progressive germ cell degeneration
Extensive fibrosis and hyalinisation of semniiferous tubules
Hyperplasia of interstitum and Leydig cells

Likely all driven by increased apoptosis.

Question 13

Fertility options for KS

Answer 13

1. Ejaculated sperm (8%)
2. Sperm banking
3. Micro-TESE (gold standard)
4. Donor sperm
5. Donor embryo
6. Adoption
7. stem cell therapy (experimental and in infancy)

Question 14

KS pre microTESE preparation and outcomes

Answer 14

3-6months of anastrazole is generally prescribed if azoospermia confirmed on SA before SSR attempted.
Need to be off T for 6-9months at least
repeat microTESE not recommended.

cTESE - 42%
MicroTESE - 57%
LBR 29-43%

in KS for some reason the sperm only have the haploid chromosome number - vast majority is X or Y only.

Question 15

ROSI

Answer 15

round spermatid injection (in men with azoospermia)
Very poor outcomes - 39% fertilised but only 4% live birth per embryo transferred

Question 16

Sperm DNA frag

Answer 16

Caused by oxidative stress and ROS causing breaks in DNA (single or double stranded).
Need a small amount of DNA frag to help with capacitation, fertilisation, embryo development.
However too much not good, if oxidative stress is too high compared to anti-oxidants.
Sperm vulnerable as minimal cytoplasm with low antioxidant load, high proportion of highly unsaturated fatty acids - causes release of free radicals,

May be associated with:
Poor embryo development – particularly from cleavage stage to blastocyst development
RPL
Unexplained infertility
Repeated IVF failures
RIF – conflicting (not recommended to test for this in RIF by ESHRE)

Question 17

Sperm DNA fragmentation tests

Answer 17

TUNEL (GS) and COMET - direct identification of damage through enzymatic reactions and fluoroscence miscroscopy. DNA frag index result.

SCSA and SCD Sperm chromatin dispersion) - indirect test, DNA susceptible to degeneration by acid (halo around is the normal result in SCD, green stain normal in SCSA)

All have problems with lack of standardised protocols, inter-observer variability and no RCTs done

Question 18

Measuring DNA frag and Clinical outcomes of MAR: A SR and MA

Answer 18

2016
Current test have limited capacity to predict the chance of pregnancy in the context of MAR. Furthermore, DNA frag tests have little or no difference in predictive value between IVF and ICSI

Question 19

MOXI trial (2020)

Answer 19

effect of antioxidants on MFI, RCT. Fert ster 2020. SS 147.

No improvement in semen parameters or DNA integrity among men with MFI. Limited by sample size, but suggests don’t improve in vivo pregnancy or live birth rates.

Question 20

Role of sperm DNA frag testing in predicting IUI outcome - a SR and MA

Answer 20

2019
DNA frag index can’t predict IUI outcome or in advising for or against IUI

Question 21

Indications for testing for sperm DNA frag

Answer 21

Question 22

Erectile dysfunction

Answer 22

Lifestyle modifications - exercise, diet, stop smoking, stop drugs, reduce ETOH
Control risk factors - obesity, hypertension, dyslipidaemia, diabetes
Psychosexual counselling - if psychological cause
Medications - phosphodiesterase-5-inhibitors (PDE-5 inhibitors)

Question 23

Phosphodiesterase 5 inhibitors for ED (PDE-5 inhibitors)

Answer 23

sildenafil (viagra) - 50mg tablet once off, one hour before, effective for 4 hours
Tadalafil (cialis) - 10mg - 30mins, works up to 36hours post dose

Question 24

Premature ejaculation

Answer 24

SSRI - dapoxetine (short half life, rapid onset and offset, minimal side effects, need to take 3 hours before intercourse) can be used with PDE5 inhibitor)
parozetine -need to take daily rather than on demand, improves latency after a few days, max effect achieved after 1-2weeks)

Question 25

Retrograde ejaculations

Answer 25

Question 26

Anejaculation -options

Answer 26

Prostatic massage
Penile vibratory stimulation (PVS)
Electroejaculation (EEJ)
Surgical correction of complet ejaculatory duct obstruction
Surgical sperm retrieval

Question 27

Treatment options for high DNA frag

Answer 27

Good egg quality
Life style changes
Treatment of infections
Clinical varicocele repair
Frequent ejaculation
Antioxidants
Sperm preparation methods
Use of testicular sperm

Question 28

Varicoclele - what and incidence

Answer 28

Varicocele = dilatation of pampiniform plexus of the testis.
15-20% of all men and 40-50% of infertile men have a varicocele.
More common in left testicle – right testicular vein drains directly into IVC, left drains into left renal vein at an acute angle = increased chance of varicocoele.
History – may present with pain/discomfort.

Question 29

Varicoclele - what and incidence

Answer 29

Varicocele = dilatation of pampiniform plexus of the testis.
15-20% of all men and 40-50% of infertile men have a varicocele.
More common in left testicle – right testicular vein drains directly into IVC, left drains into left renal vein at an acute angle = increased chance of varicocoele.
History – may present with pain/discomfort.

Question 30

Grade of varicocele

Answer 30

Examination -Identified by examining patient supine then standing
* Grade 0 or subclinical: varicocele diagnosed only with imaging techniques and not palpable or visible on physical examination;
* Grade 1: varicocele palpable in the upright position with Valsalva maneuver;
* Grade 2: varicocele palpable in the upright position without the Valsalva maneuver;
* Grade 3: varicocele visible through the scrotal skin in the upright position.

Question 31

Grade of varicocele

Answer 31

Examination -Identified by examining patient supine then standing
* Grade 0 or subclinical: varicocele diagnosed only with imaging techniques and not palpable or visible on physical examination;
* Grade 1: varicocele palpable in the upright position with Valsalva maneuver;
* Grade 2: varicocele palpable in the upright position without the Valsalva maneuver;
* Grade 3: varicocele visible through the scrotal skin in the upright position.

Question 32

Grade of varicocele

Answer 32

Examination -Identified by examining patient supine then standing
* Grade 0 or subclinical: varicocele diagnosed only with imaging techniques and not palpable or visible on physical examination;
* Grade 1: varicocele palpable in the upright position with Valsalva maneuver;
* Grade 2: varicocele palpable in the upright position without the Valsalva maneuver;
* Grade 3: varicocele visible through the scrotal skin in the upright position.

Question 33

Impact of varicocele on fertility

Answer 33

Hypothesis for impact on fertility –
increased testicular temperature from varicocele,
increased pressure leading to oxygen deprivation
impaired clearance of metabolites

Controversy with fertility:
- Grading, diagnostic criteria, absolute and relative indication for treatment, treatment methods and efficacy all remain controversial.

Question 34

Indications for treatment

Answer 34

ASRM recommend treatment when following conditions are met:
- Palpable on physical examination of scrotum
- Couple has documented infertility
- Female partner has normal fertility or potentially reversible infertility
- Abnormal semen parameters

Additional indications:
- Reversing testicular atrophy in adolescent men
- Treating testicular pain from varicocele
- Improving hypogonadism in men with varicocele
- in azoospermic men prior to micro-TESE

Treatment considerations:
- Degree of discomfort
- Cost-effectiveness of repair versus fertility treatments and female reproductive potential
- Takes up to six months to improve (AMA or DOR may be inappropriate)

Question 35

Indications for treatment

Answer 35

ASRM recommend treatment when following conditions are met:
- Palpable on physical examination of scrotum
- Couple has documented infertility
- Female partner has normal fertility or potentially reversible infertility
- Abnormal semen parameters

Additional indications:
- Reversing testicular atrophy in adolescent men
- Treating testicular pain from varicocele
- Improving hypogonadism in men with varicocele
- in azoospermic men prior to micro-TESE

Treatment considerations:
- Degree of discomfort
- Cost-effectiveness of repair versus fertility treatments and female reproductive potential
- Takes up to six months to improve (AMA or DOR may be inappropriate)

Question 36

surgical approach to varicocele repair

Answer 36

Microsurgical varicocelectomy
- gold standard treatment
- subinguinal or inguinal microsurgical varicocelectomy is the most recommended treatment
- 3-4cm transverse incision is made in either inguinal or subinguinal regions in the groin to allow access to the spermatic cord.
- operating microscope, vas deferens and its vessels, testicular artery and lymphatic vessels are preserved.
- Dilated veins including internal spermatic and cremasteric veins are ligated and resected. Intraoperative micro-doppler maybe required to aid in identification of internal spermatic arteries.
- Complications rare = arterial injury leading to testicular atrophy, hydrocele, persistence and recurrence of varicocele

Percutaneous embolization
- Minimally invasive treatment option
- Quicker recovery
- Venous access is routinely made at the femoral vein to perform venogram to identify varicoceles which are then occluded with coils or liquid embolic agents.
- Complications include – coil or balloon migration, exposure to radiation, higher reported rates of persistence and recurrence compared to varicolectomy.

Question 37

Evidence for repair

Answer 37

Cochrane 2021 - remains uncertain whether any treatment (surgical or radiological) compared to no treatment in subfertile men may be of benefit on live birth rates; however, treatment may improve the chances for pregnancy. The evidence was also insufficient to determine whether surgical treatment was superior to radiological treatment.

• Varicocelectomy probably improves spontaneous pregnancy rates ?? LBR
• May improve outcomes after ART
• Probably beneficial to do for NOA as likely improves rates of SSR.

Question 38

Indications for vasectomy reversal

Answer 38

Two potential procedures:
- Vasovasostomy
- Vasoepididymostomy

Indication:
- Fertility desired (3-6% of men who undergo vasectomy request reversal)
- Post vasectomy pain syndrome
- Very occasionally primary genital tract obstruction (epidydimal trauma, infection, congenital hypoplasia) may benefit from vasoepididymostomy.
- May be more cost effect that IVF and allows ability to conceive naturally more than once.

Question 39

Factors impacting success of vasectomy reversal

Answer 39

Preoperative factors:
- Obstructive interval - >10 years lower chance of success and higher risk of needing VE
- Age of female partner
- Age of male

Intra-operative findings/factors:
- Surgical skill and frequency procedure performed by surgeon (>10/year recommended)
- If VV able to be performed over VE
- Microsurgical technique rather than macrosurgical
- Finding clear vasal fluid
- Finding motile spermatozoa
- Length of post-vasectomy testicular vas (longer is more likely to have sperm)

Question 40

Surgical considerations and steps

Answer 40

Surgical considerations:
- Consent
o Consented for both VV and VE
o Consented for collection and freezing of sperm sample
o Risks – infection, bleeding, damage to surrounding structures, pain, failure, loss of testis (very rare)
o Aim to repair both sides
- Cost – often not covered by health insurance, not performed publicly.

Surgical steps:

• Scrotal incision over prior vasectomy site
• Vas deferens mobilised
• Mobilisation of vas both testicular and abdominal – need adequate length for tension-free repair.
• Incised above and below the prior vasectomy site – dilated and irrigated to verify patency
• Fluid collected from the testicular vas – colour and microscopic identification of spermatozoa done.
• Indication for VE –
  o Thick, creamy and pasty vasal fluid with absent sperm
  o Epididymal blow out injury noted
  o Surgical sperm collection always recommended with VE due to high failure rate
• Key is tension free repair, water-tight, mucosa to mucosa approximation
• Abdominal vas often much smaller diameter to testicular vas so needs gentle dilatation.

Post-operative
- Day case procedure
- Simple analgesia
- No heavy lifting
- Post operative semen analysis 6/52, if azoospermic at 6/12 then need referral to fertility clinic and IVF consideration
- Success rates
o Bilateral VV with OI <10 years = 90% chance of spontaneous return of sperm in ejaculate
o Lower success for unilateral repair, OI >10 years, VE performed

Question 41

Ejaculatory duct obstruction

Answer 41

Either:
- TUI of EDO = transrectal ultrasound guided transurethral incision of ejaculatory duct obstruction
- TURED = Transrectal ultrasound guided transurethral resection of ejaculatory duct

TRUS guidance
Visualis EDO
Resectoscope with electrocautery loop used
Indigo carmine can be injected into vas deferens or seminal vesicle to ensure adequate incision/resection made
Complication: Injury to external urinary sphincter, bladder neck, rectum, infection, bleeding.

Question 42

Medical management of Hypo hypog

Answer 42

GnRH replacement - most physiological approach, not widely available, expensive, subcut pump 24h/day pulses every 90-120minutes, inconvinient, requires intact pituitary and normal functioning GnRH receptors.

Gonadotrophin therapy (most common)
1. Restore intratesticular testosterone
- hCG (LH) - 1500IU twice weekly subcut, 4-6months, monitor T and testis volume
- titrated up to get T levels in range
- if post pubertal HH may be all that is required fro spermatogenesis.
2. Re-evaluate semen analysis 4-6 months after hcg monotherapy - if <10million/mL and no conception
- add FSH 75-150 IU three times weekly subcut
- can take 2-3 years to work.
- increase dose if sperm conc remain <20million/mL and no conception
3. In no sperm still - micro-TESE and ICSI
4. If advancing maternal age/no natural conception IVF +/- ICSI depending on semen parameters

Prepubertal HH onset - 70-90% achieve spermatogenesis
Postpubertal HH onset - 95% achieve spermatogenesis
No reported adverse effects with FSH, hcg safe and generally well tolerated (acne and gynaecomastia are rare).

Poor prognostic markers - small testicular volume (<4mls, prepubertal onset, cryptorchidism, poor medication compliance), Previous T does not appear to affect results.

Question 43

Role of FSH in idiopathic infertility (evidence)

Answer 43

SR and meta-analysis (2015)
Idiopathic male infertility: FSH versus placebo or no treatment. (not all RCTs)
15 studies.
spontaneous PR higher (4.5) and PR after ART higher (1.6)
Issues: Heterogenous, high risk of bias, lack of precis criteria to guide FSH, future studies needed, FSH in tx of male infertility should be cautious.

Meta-analysis SR (2020)
RCTs only.
P = Normogonadotrophic idiopathic oligozoospermia.
I = FSH
C = placebo or no treatment.
O =4.5million/ml higher sperm concentration, dose dependent response. Also improved progressice motlity. No change to morphology.

FSH may be helpful in idiopathic male infertility with normal gonadotrophins, most promising empiric therapy, data inconclusive and further RCTs are needed.

Guidelines all say can consider treatment with FSH in idiopathic infertility (OAT) with the aim of improving sperm conc, preg rate and live birth rate. (low/verylow quality evidence)

Question 44

Anti-oestrogens in idiopathic male infertility

Answer 44

Data conflicting
Poor quality data
No clear evidence of benefit

Question 45

Aromastase inhibitors in idiopathic male infertility

Answer 45

Rational in men with low serum T and high E2 (obesity)
Associated with imrpved hormonal profile and semsn paramters
No evidence to suport role in tx of male infertiltty
Concerns re side effects, especially bone effects.

Question 46

Anti-oxidants/multivitamin

Answer 46

Widely avialable, inexpensive related to other treatments, certain subgroups may particularly benefit.
Negatives = cost, inconvinience, uncertain evidence, side effects.
~$30/month for Menevit
Others: Coenzyme Q10, vitamin C, vitamin E, folate, zinc, selenium, carnitine, carotenoids

Cochrane RCT 2022
12 RCTs looked at LB
Live birth: antioxidants may lead to increased live birth rates (odds ratio (OR) 1.43, 95% confidence interval (CI) 1.07 to 1.91, P = 0.02, 12 RCTs, 1283 men, I2 = 44%, very low‐certainty evidence).

Question 47

Phenotypic appearance of Klinefelter syndrome

Answer 47

47XXY (1 in 500 - 1000)
Physical - smaller than average testicles and penis, taller than average, osteoporosis, decreased muscle mass, gynaecomastia (30%), low energy levels, decreased sex drive, poor beard growth
Psychological - poor social skills/bahvioural problems, mild IQ impairment,