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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 –  info@bournhall-clinic.ae