History and investigation in male infertilty

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Male factor infertility, History and investigation

By: Mr Oliver Wiseman
Consultant Urologist and Andrologist

Read more on our website http://www.bournhall-clinic.ae

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History and investigation in male infertilty

  1. 1. 01/04/2014 1 1 Male factor infertility: History and investigation Mr Oliver Wiseman Consultant Urologist and Andrologist 2 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 3 •  Epidemiology •  Definitions •  Anatomy and physiology •  History •  Investigations •  Case studies •  Q and A 4 •  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 5 •  30% = entirely ♂ •  20% = ♂ + ♀ •  50% = entirely ♀ Aetiology 50% 6 •  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
  2. 2. 01/04/2014 2 7 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 9Ralph BJUI 2012 10 Male factor Evaluation •  History •  Physical Examination •  Laboratory evaluation •  Ultrasound 11 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 12 Past Medical and Surgical History
  3. 3. 01/04/2014 3 13 Drug History 14 •  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 15 Gonadotoxins •  Tobacco •  Alcohol •  Cannabis •  Recreational drugs •  Anabolic Steroids •  Chemotherapy – type and dose dependent •  Radiotherapy •  Work based chemicals (eg: solvents) 16 Recovery Potential after chemo Good Moderate Poor Adriamycin Vincristine Cyclophosph Methotrexate PEB Chlorambucil Prednisolone ABVD Procarbazine Cisplatin MOPP Doxorubicin Androgens Oestrogens 17 ……..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. 18 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
  4. 4. 01/04/2014 4 19 Lab evaluation •  Semen analysis – Centrifugation of sperm – Repeat analysis (need minimum of two analyses) – Ensure whole ejaculate collected •  Bloods – FSH, testosterone – Appropriate genetic tests 20 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 22 Azoospermia 23 Male reproductive anatomy: duct system 24 Components of seminal fluid 70% 20% 10% •  Prostate –  acidic •  Seminal Vesicles –  fructose
  5. 5. 01/04/2014 5 25 Two possible patterns from SA Low volume acidic ejaculate Normal volume alkali ejaculate Semen analysis 26 Two possible patterns from SA Low volume acidic ejaculate Normal volume alkali ejaculate Semen analysis 27 Low volume, acidic azoospermia •  Volume < 1cc •  Ph < 7.2 •  Azoospermia •  Indicates no SV contribution –  Fructose assay not required 28 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
  6. 6. 01/04/2014 6 31 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       33 Two possible patterns from SA Low volume acidic ejaculate Normal volume alkali ejaculate Semen analysis 34 Normal Volume Azoospermia •  SVs are present •  Ejaculatory ducts are open •  Differential diagnosis – NOA (spematogenic failure) – Blockage of vas or epididymis 35 Normal Volume Azoospermia •  Examination of external genitalia •  Bloods – FSH – Testosterone •  Differential diagnosis – NOA (spematogenic failure) – Blockage of vas or epididymis 36 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
  7. 7. 01/04/2014 7 37 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 38 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 39 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 40 Normal Volume Azoospermia Testes Size and consistency Epididymes Normal or full and firm FSH Normal or “high” Diagnosis History NOA OA 41 To make a diagnosis in normal volume azoospermia… •  You do not need a testis biopsy •  You do not need a vasogram 42 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
  8. 8. 01/04/2014 8 43 Maturation arrest •  Possible to have normal FSH with no azoopermia •  Maturation arrest beyond the spermatocyte stage 44 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 45 Genetic tests in suspected NOA Klinefelter syndrome (47,XXY) 47 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 48 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
  9. 9. 01/04/2014 9 49 •  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 7 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 51 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 52 Summary of genetic basis of NOA •  Y chromosome microdeletions – 13% •  Klinefelter s syndrome – 5-10% •  Translocations – 1-3% 53 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 54 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
  10. 10. 01/04/2014 10 55 56 57 Summary of treatment options in normal volume azoospermia – In NOA •  SSR (mTESE / TESE) – In OA •  Reconstruction and / or sperm aspiration PESA TESE MicroTeSE
  11. 11. 01/04/2014 11 61 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 62 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 63 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. 64 Pregnancy Outcome: ITT 65 Pregnancy Outcome: As-treated 66 Sperm Concentration
  12. 12. 01/04/2014 12 67 Sperm Motility 68 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 69 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 70 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 71 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.
  13. 13. 01/04/2014 13 73 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. 75 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 76 Contact • Copy of presentation –  http://bournhall-clinic.ae –  info@bournhall-clinic.ae

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