How to Manage Truly and Virtually Azoospermic Men for IVF-ICSI? Paul J. Turek M.D. Emeritus Professor and Endowed Chair Department of Urology, University of California San Francisco Director, The Turek Clinic, San Francisco, CA
17. I read in one of the papers that couples can get pregnant with sex. Is that true? A patient, 1998
Obstructive Non-obstructive The Problem of Azoospermia 5% of infertile men History Physical Exam Hormones Semen Analysis Repair ICSI ICSI
Case #2 There once was a couple who wanted children. Partner is 37 y.o. “ never” pregnant 38 y.o. with no prior paternity. FSH, T normal. Testes: 20mL Testis biopsy: normal Why am I doing this ? I hope he doesn’t find out…..
Case 2 35 yo healthy man with 2 years of unprotected sex. Partner 38 years old and no prior pregnancies. His exam reveals atrophic testes bilaterally. Has a grade III left varicocele FSH 20 (1-8 normal); Testosterone 330 (>300) Normal volume azoospermia; Pellet: no sperm. Testis biopsy: Sertoli cell only
Infertility M.D. Provider (Male or Female) Genetic Counseling PROGENI Medical Evaluation Y microdeletions Karyotype CFTR/5T Post-Test Counseling Treatment Plan
When to do Genetic Testing? Sperm <5 million/mL No sperm/testis failure Idiopathic Obstruction, absent vas deferens Other syndromes Scenario Y Delet. Karyotype Cyst. Fibr X Whatever fits! X X X X Case #1 40% Case #2 30%
Testis Sperm Retrieval: Evidence-Based Guidelines Donoso, Tournaye, Devroey. Hum Reprod Upd. 2007, 13: 539-549 Van Peperstraten et al. Cochrane Database Syst Rev. 2006, 3:CD 002807 Nicopoullos et al. Fert Steril. 2004, 82: 691-701 <ul><li>For obstructive vs. nonobstructive azoospermia: </li></ul><ul><li>There is insufficient evidence to recommend one sperm retrieval technique over another. </li></ul><ul><li>Sperm retrieval in cases of nonobstructive azoospermia can be very difficult due to “patchy” or “focal” nature of production. </li></ul><ul><li>In cases of nonobstructive azoospermia, there is no relationship between the sperm technique chosen and ICSI outcomes. </li></ul>
Obstructive Azoospermia Guideline: Least invasive, least damaging, best yield. Turek et al. Ass Reprod Rev. 1999, 9: 60-64,
The Mini-MESA <ul><li>Local +/- sedation </li></ul><ul><li>1-2 hours </li></ul><ul><li>6-10 million TMC </li></ul><ul><li>Freeze-all approach </li></ul><ul><li>Mean 2 pain pills </li></ul><ul><li>Recovery 1-2 days </li></ul><ul><li><1% complication </li></ul><ul><li>1% need repeating </li></ul>Nudell et al. Hum Reprod.1998, 13: 1260 a b E E
1% 5% 40% 1% 5% 40% MESA PESA Why MESA and not PESA? 40% 8%
Cryptorchidism 52-74% Variocele 63% Epididymitis 67% Mumps 67% Torsion >50% Post-chemotherapy 55-75% Genetic AZF a, b 0% Genetic AZF c 75% Idiopathic 50-60% Chance of Finding Sperm by NOA Diagnosis Shefi and Turek, submitted Raman and Schlegel. J Urol.170:1287, 2003 Hopps et al. Hum Reprod. 180:1660, 2003 Damani et al. JCO. 15: 930, 2002
Can we predict if sperm are present in NOA? History of ejaculated sperm FSH, inhibin level Testis biopsy histology Testicular size . Tournaye et al. Hum. Reprod. 12: 80, 1997. Seo JT and Ko W-J. Int J. Androl. 24: 306, 2001 Raman and Schlegel. J Urol.170:1287, 2003
Testis Biopsy: Results Normal Hypo Maturation Arrest Sertoli cell Only Only inform us of the biopsied area. How about elsewhere?
Why is sperm prediction important? 1. Can minimize emotional and financial cost of IVF cycles. 2. Can minimize trauma/damage to testis during sperm harvesting.
0 20% 40% 60% 80% 100% Sensitivity and Sampling Technique in NOA Testes Likelihood of finding sperm 1 biopsy 3 FNA MAP Weiss et al. Harefuah 132: 614, 1997 Kim et al. J. Urol, 157: 144, 1997 30% 36% 50%
Approaches to the NOA Patient a) Who has sperm? b) Where is it? 1. Simultaneous diagnostic and therapeutic biopsies with "Up front" cryopreservation of sperm. 2. Realtime Multi-biopsy or deep (Micro) biopsy TESE with/without diagnostic biopsy. 3. Diagnostic Systematic FNA "mapping" of testes with subsequent "directed" TESE. Van Peperstraten A. et al. Cochrane Database Syst Rev 2006; 3:CD002807.
FNA Mapping, Directed TESE How Can We Find Sperm? And Microdissection TESE
How Can We Find Sperm? Microdissection TESE in OR Sperm Found? IVF/ICSI Yes No Donor Sperm Adoption +/- Pregn Microdissection Office FNA Map Sperm Found? Yes No IVF/ICSI "Directed" TESE Donor Sperm Adoption FNA Mapping
The Microdissection TESE Concept: Testis seminiferous tubules containing sperm are “thicker” than those that don’t. Schlegel PN. Hum Reprod 14: 131, 1999 Points: Systematic examination of testis lobules under 25x microscopy, general anesthesia
The Microdissection TESE Amer M, et al. Hum Reprod 15: 653, 2000 Approach Success (%) Tissue TESE biopsy 30/100 (30%) 54 mg Microdissection 45/100 (45%) 4.6mg Concept: 100 men with “identical” bilateral histology. One side TESE, the other microdissection
Microdissection TESE Amer et al 2000 100 45% 30% Okada et al 2002 98 45% 17% Okubu et al 2002 17 48% 24% Tsujimura et al 2002 93 43% 35% Ramon et al 2003 321 62% 58% Study #Pts %MicroTESE %TESE Success Success 49% 33%
The Microdissection TESE Concerns: 1) Operating microscope needed 2) General anesthesia 3) Expertise with experience 4) Long term effects (especially if bilateral) 5) A repeatable procedure?
Prostate Biopsies 1 2 3 4 5 6 X X X X X X X X X Testis The Idea Testis FNA Mapping
Does “Mapping” Help in Redo NOA cases? TESA/TESE Attempts (n=51) (n=12) (n=3) % Patients Successful 90% 91% 100%
1. Where are sperm generally found? 2. Are there any "hot spots" or "sperm rich" areas? 3. Is there any side to side correlation? 4. Are certain histologies more likely to have sperm? What have we learned? Testis FNA Mapping
1 2 3 Sperm Frequency Maps Where are sperm found?
How “Patchy” or “Focal” is Sperm Production? Bx-FNA Discrepancy 27% FNA + Bx - Intratestis Variability - + 25% of testes Intertestis Variability - + 19% of testes Turek et al. J. Urol. 163: 1709, 2000
The FNA Map: An Archival Tool 1. What germ cells are present in the testis? 2. What other pathology is present? 3. Important for patient phenotyping. Meng MV et al. Hum Reprod. 16: 529, 2001 Nudell DM et al. Hum Reprod. 15, 1289, 2000 Fox M et al. Mol Reprod Dev. In press 4. Can it replace the standard biopsy? Meng et al. Am. J. Surg. Path. 25: 71, 2001
What’s Really New? MRI MRS Metabolic imaging of the testes with NMR
NMR Spectroscopy of the Testis Ex Vivo study of Testis Biopsies from Normal and Infertile Men Aronson, Kurhanewicz, Turek
MR Spectroscopy: Determining the Metabolic Fingerprint of the Normal and Abnormal Testis A non-invasive way to determine presence and location of spermatogenesis? Aaronson et al, 2007
“ Back up” in Cases with Low or No Ejaculated Sperm IVF Bank sperm FNA map Fresh TESA, TESE, MicrodissectionTESE 1-3 mos <ul><li>Have patient bank small numbers of motile sperm. </li></ul><ul><li>Diagnostic FNA map to streamline sperm retrieval. </li></ul><ul><li>Fresh sperm retrieval day of, or day before, egg retrieval. </li></ul><ul><li>Donor sperm. </li></ul><ul><li>Sperm first, if none, then cancel egg retrieval. </li></ul><ul><li>Freeze eggs. </li></ul>
A tough nut to crack No standard approach exists Be kind to your embryologists Be kind to your patients X X X X X X X X X How to Manage Truly and Virtually Azoospermic Men for IVF-ICSI?