history and investigation in male infertilty
TRANSCRIPT
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Male factor infertility: History and investigation
Mr Oliver Wiseman Consultant Urologist and Andrologist
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Myths
• A man with azoospermia cannot become a biological father – “donor sperm (if allowed) or adoption are the only
choices” • A man who has had chemotherapy before is sterile
and cannot father a child • “Your FSH is too high: we will never find sperm” • A man with OAT does not need to see a urologist /
andrologist – “his sperm can be used for IVF and ICSI”
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• Epidemiology • Definitions • Anatomy and physiology • History • Investigations • Case studies • Q and A
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• 20-25% conception per month • 75% at 6 months • 85% of couples conceive in 1 year
– 15% of couples fit definition
• Further 2 years – 23% will conceive • Another 2 years – 10% will conceive • 10% left childless after 5 years if no action
Infertility: epidemiology
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• 30% = entirely ♂ • 20% = ♂ + ♀ • 50% = entirely ♀
Aetiology
50%
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• Azoospermia - The patient produces semen
containing no sperm – Obstructive (blockage to flow) – Non-obstructive (deficient production)
• Oligoasthenoteratozoospermia (sometimes
referred toas OAT) - less than 15 million sperm pr ml with less than 40% total motility and more than 96% abnormally shaped.
Definitions
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Hormonal control of testicular function
Inhibin is a 32-kD glycoprotein hormone secreted primarily by Sertoli cell.
deKretser DM, Meinhardt A, Meehan T, et al: The roles of inhibin and related peptides in gonadal function. Mol Cell Endocrinol 2000;161:43–46.
Anterior pituitary
testosterone levels in the testis > 100X greater than in the peripheral circulation 8
Male Infertility – Urological Diagnosis
• Varicocele 42.2 • Idiopathic 22.7 • Obstruction 14.3 • NAD + female factor 7.9 • Cryptorchidism 3.4 • Immunological 2.6 • Ejaculatory dysf 1.3 • Testicular failure 1.3 • Drugs/irradiation 1.1
• Endocrine 1.1 • Infection 0.9 • Sexual dysfunction 0.3 • Systemic disease 0.3 • Sertoli cell only 0.2 • Ultrastructural defect 0.2 • Genetic 0.1 • Testis Cancer 0.1
Sigman, Lipshultz, Howards 1997
1430 male partners
9 Ralph BJUI 2012 10
Male factor Evaluation
• History • Physical Examination • Laboratory evaluation • Ultrasound
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Male factor: History
• Sexual History – Does your partner have regular cycles? – Does she know when she ovulates? – Do you have normal erections? – Do you ejaculate?
• Pregnancy History – Have you been responsible for or has your partner had any
previous pregnancies? • Past medical and surgical history • Drug therapy • Gonadotoxins
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Past Medical and Surgical History
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Drug History
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• Impaired spermatogenesis • Sulphasalazine, nitrofurantoin, methotrexate, colchicine,
chemotherapy • Pituitary Suppression • Testosterone, GnRH analogues • Anti-androgenic effects • cimetidine, spironolactone • Drugs of abuse • Anabolic steroids, cocaine, cannabis, heroin • Ejaculation failure • alpha blockers, antidepressants, phenothiazines • Erectile dysfunction • beta blockers, thiazide diuretics, metoclopramide
Gonadotoxic drugs
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Gonadotoxins
• Tobacco • Alcohol • Cannabis • Recreational drugs • Anabolic Steroids • Chemotherapy
– type and dose dependent • Radiotherapy • Work based chemicals (eg: solvents)
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Recovery Potential after chemo
Good Moderate Poor Adriamycin Vincristine Cyclophosph Methotrexate PEB Chlorambucil Prednisolone ABVD Procarbazine Cisplatin MOPP Doxorubicin Androgens Oestrogens
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……..think ahead: Preserve Fertility
• Important that all patients bank sperm prior to chemo or radiotherapy
• Patients should not try to conceive for 2 years following chemotherapy.
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Physical Examination
• General • Genitalia
– Meatus normal? – Size of testes, consistency, location – Any scars? – Can you feel vas deferens? – Is epidiymis full? – Does the patient have a varicocoele?
• DRE
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Lab evaluation
• Semen analysis – Centrifugation of sperm – Repeat analysis (need minimum of two
analyses) – Ensure whole ejaculate collected
• Bloods – FSH, testosterone – Appropriate genetic tests
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Semen analysis
• Ideally after between 2 and 5 days abstinence
• Ensure whole ejaculate collected • Need to do two samples, minimum
three months apart
New parameters
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Azoospermia
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Male reproductive anatomy: duct system
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Components of seminal fluid
70%
20%
10%
• Prostate – acidic • Seminal Vesicles – fructose
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Two possible patterns from SA
Low volume acidic ejaculate
Normal volume alkali ejaculate
Semen analysis
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Two possible patterns from SA
Low volume acidic ejaculate
Normal volume alkali ejaculate
Semen analysis
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Low volume, acidic azoospermia
• Volume < 1cc • Ph < 7.2 • Azoospermia
• Indicates no SV contribution
– Fructose assay not required
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Low volume, acidic azoospermia
EDO
CBAVD
• Normal sized testes • Normal FSH • Normal testicular consistency • Diagnosis: • Vasal palpation • TRUS
These patients have normal spermatogenesis
CFTR-‐related disorders • CFTR-‐related disorders include:
– Classic cys2c fibrosis (CF) – Non-‐classic CF – CBAVD
• Autosomal recessive inheritance • Incidence 1 in 3000, carriers 1 in 25 • CFTR on Chr 7q31.2 • 100s of muta2ons causing CF • ΔF508 = 60-‐75% , next 12 = 10-‐15% • CFTR 29 muta2on panel -‐ standard test,
85% of N. European muta2ons • >95% of males with CF are infer2le • Azoospermia caused by absent,
atrophic, or fibro2c Wolffian duct deriva2ves
• Body and tail of epididymis and seminal vesicles abnormally dilated or absent
CFTR-‐related disorders
• Diagnosis of CF: – ≥1 characteristic phenotypic feature:
» Chronic sinopulmonary disease » GI abnormalities » Obstructive azoospermia » Salt-loss syndrome
+ evidence of abnormal CFTR function based on one of following:
» 2 CFTR pathogenic mutations » 2 abnormal sweat tests » Nasal potential difference measurements characteristic of CF
• Diagnosis of CFTR-related CAVD: – Azoospermia – Low volume ejaculated semen – Absence of vas deferens (clinic or US exam, unilateral or bilateral) – At least 1 pathogenic CFTR mutation
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Obstructive Azoospermia: CBAVD
• No palpable vas • Epididymal remnant firm • Do not need scrotal
exploration to confirm diagnosis
• Do not need testis biopsy to confirm diagnosis or show spermatogenesis
• Need CF mutation analysis (partner too)
• Need SSR (PESA) • 20% of pts will have renal
agenesis (not related to CFTR)
Tubular ectasia
Abrupt tapering between head and body of
epididymis
• Why screen for gene? – Pt’s family – Pt’s medical history – Counsel couple as to chance
of offspring having CF
CFTR-‐related disorders :Gene2c tes2ng
Clinical uses • Confirm diagnosis (CF, CBAVD) • Ensure partner tested and counseling arranged • Cascade carrier tes2ng in at risk rela2ves
– Importance of a 3 genera2on pedigree – REFER TO CLINICAL GENETICS
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Two possible patterns from SA
Low volume acidic ejaculate
Normal volume alkali ejaculate
Semen analysis
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Normal Volume Azoospermia
• SVs are present • Ejaculatory ducts are open
• Differential diagnosis – NOA (spematogenic failure) – Blockage of vas or epididymis
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Normal Volume Azoospermia
• Examination of external genitalia • Bloods
– FSH – Testosterone
• Differential diagnosis – NOA (spematogenic failure) – Blockage of vas or epididymis
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Normal Volume Azoospermia: Examination
Testes Size and
consistency
Small in NOA
Normal in OA
Epididymes Normal or full
and firm
Normal in NOA
Full and firm in OA
Diagnosis
History
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FSH: what is normal?
5 FSH Normal Range
This is where patients with normal sperm production lie
Most patients with inadequate sperm production lie here
FSH: -High in NOA -Normal in OA
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Redefining “normal” FSH
• 610 male infertility patients from a single clinic • AS FSH increases, semen quality decreases • Cut off should be 4.5 iu/l….
Gordetesky et al. BJUI. 2012
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Testosterone
Anterior pituitary
testosterone levels in the testis > 100X greater than in the peripheral circulation
• High intra-testicular levels key for spermatogenesis
• Endogenous only • Often lower end of ref
range • Consider attempt to
boost – Role of clomid
• Key to document prior to any treatment
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Normal Volume Azoospermia
Testes Size and
consistency
Epididymes Normal or full
and firm
FSH Normal or “high”
Diagnosis
History
NOA
OA
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To make a diagnosis in normal volume azoospermia…
• You do not need a testis biopsy • You do not need a vasogram
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FSH and testicular size predict OA and NOA
89% 96%
Schoor R et al. J Urol 2002 Jan;167(1):197-200
Testicular biopsy not required
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Maturation arrest
• Possible to have normal FSH with no azoopermia
• Maturation arrest beyond the spermatocyte stage
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Making a diagnosis in normal volume azoospermia
• Directs treatment and further investigations – In NOA
• Karyotype • Y chromosome microdeletion • Then SSR (mTESE / TESE)
– In OA • Reconstruction and / or sperm aspiration
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Genetic tests in suspected NOA Klinefelter syndrome (47,XXY)
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Klinefelter’s syndrome
• Myths – “Your testosterone is too high to be a pt with KS” – “You are too well virilised to have KS” – “You are a gynecologist / urologist. You cannot have
KS” • May present with infertility • Not necessarily hypogonadal • Not necessarily eunichoid • SSR can be successful
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Klinefelter’s syndrome
• Genotype – 47, XXY (pure) – 46, XY / 47, XXY (mosaic)
• Incidence – 1/500 live male births – 5-10% of azoospermics
• Spermatogenic axis failure – Severe oligospermia, azoospermia
• Androgenic axis failure – Failure of virilisation at puberty – Lower testosterone in adulthood
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• Cornell experience – 68% retrieval – 42% or retrievals clinical preg – All children born were 46 XX or 46 XY – Sperm retrieval no different from other
NOA
Klinefelter’s syndrome
Ramasamy et al. J Urol 2009 50
Region Frequency % No sperm on TESE
AZFa 5% 100%
AZFb 35% 100%
AZFc 60% 30-50%
Yp
Yq
1 2
3
4
5
6
SRY
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AZF a
AZF b
AZF c
Infertile
• 0.7 % oligospermic ( < 5 mil / cc) • 10% in severe oligospermic (< 1 mil / cc) • 15 % in azoospermia
Y chromosome microdeletion
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Y chromosome microdeletion
• Fluctuation in sperm density is seen over time
• There is no evidence to suggest that sperm production decreases over time
• No other known health consequences – Men somatically healthy – Adequate virilisation – Normal penile anatomy
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Summary of genetic basis of NOA
• Y chromosome microdeletions – 13%
• Klinefelter’s syndrome – 5-10%
• Translocations – 1-3%
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Summary of how to make a diagnosis
• Semen volume and pH are the key – Low volume, acidic pH
• CBAVD, EDO – Normal volume alkaline
• NOA, blockage of vas or epididymis
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Summary of treatment options in low volume acidic ejaculate
• EDO – Resection of ejac duct transurethrally – SSR: aspiration of SV, PESA or TESE
• CBAVD – PESA or TESE
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Summary of treatment options in normal volume azoospermia
– In NOA • SSR (mTESE / TESE)
– In OA • Reconstruction and / or sperm aspiration
PESA
TESE MicroTeSE
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Varicocoele
• Dilated & tortuous veins of pampiniform plexus
• 15% men, 40% infertile men
– grade I palpable only with Valsalva
– grade II are palpable with the patient in the standing position
– grade III are visible through the scrotal skin and are palpable when the patient is supine
– USS only detected no effect on fertility
• Causes OAT (dec no., motility, morphology)
• Left most common
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Guidelines
• ASRM / AUA – Infertile couples with no proven female factor, if
male has abnormal semen parameters repair of varicocoele should be considered if clinically palpable.
• EAU – “Issue is controversial”
• NICE – “men should not be offered surgery for
varicocoele as a form of fertility treatment because it does not improve pregnancy rates”
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Pregnancy outcome in oligospermic men
• Four RCTs, repair of clinical varicocoele in oligospermic men
• 380 couples • Suggestion of beneficial effect of repair, but
significant non-homogeneity of studies – Low recruitment, high drop out rate, loss to follow
up, very high treatment arm preg rate vs very low observation arm preg rate (considering short duration of infertility)
• “As treated analysis” found difference in favour of repair.
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Pregnancy Outcome: ITT
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Pregnancy Outcome: “As-treated”
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Sperm Concentration
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Sperm Motility
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Conclusions
• Varicocoele repair associated with – Signif improvement in sperm concentration and
sperm motility – Reduces seminal oxidative stress and sperm DNA
damage • There is insufficient evidence to demonstrate
a beneficial effect of repair on spont pregnancy rates
• All methods of repair are viable options, microsurgical repair is associated with better outcomes and lower complication rates
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Hormonal treatment for male factor infertility
• Hypogonadotrophic hypogonadism – Management by endocrinologist – HCG +/- FSH / HMG
• For NOA – Clomiphene citrate – Non steroidal oestrogen receptor modulator – Block oestrogen receptor preventing
oestrogenic inhibition of gonadotrophin secretion
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Action of Clomiphene
• Increases endogenous gonadotropin-releasing hormone secretion from the hypothalamus and gonadotropin hormone secretion directly from the pituitary
• Increases intra-testicular testosterone concentration
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Clomid
• Previous study showed use of clomiphene citrate therapy in NOA may result in sufficient sperm for ICSI, either – Through sperm being found to be present in the
ejaculate or – potentially through increasing the probability of
successful microsurgical (micro)-TESE. In that study, all patients with Sertoli-cell-only syndrome were excluded.
• 42 pts NOA: sperm returned in 64%. Sperm found in all remaining pts at SSR
Hussein A , Ozgok Y , Ross L , Niederberger C . Clomiphene administration for cases of nonobstructive azoospermia: a multicenter study . J Androl 2005 ; 26 : 787 – 91 72
Niederberger Group, BJUI 2013.
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Study protocol
• In all, 116 patients randomly chose to undergo micro-TESE without any medical treatment and formed the control group.
• The remaining 496 patients were administered oral clomiphene citrate at a starting dose of 50 mg every other day.
• After a minimum of 2 weeks, plasma testosterone was assayed. The dose of clomiphene citrate was increased in increments of 25 mg every other day until morning serum testosterone was 600 – 800 ng/dL, or until 3 months had passed.
• In cases where the serum testosterone was noted to be > 800 ng/dL, the dose of clomiphene citrate was decreased to 50 mg once every 3 days.
Niederberger Group, BJUI 2013. 74
Niederberger Group, BJUI 2013.
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Summary
• Male fertility problems require careful history, examination and appropriate tests to make a diagnosis
• Working diagnosis drives further genetic tests as well as method of and prognosis for sperm retrieval
• Consider adjuvant treatments to help maximise chances of sperm retrieval
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Contact
• Copy of presentation
– http://bournhall-clinic.ae – [email protected]