What makes a man infertile and how do we find him? › v3-app_crowdc › assets › 4 › 45 ›...
Transcript of What makes a man infertile and how do we find him? › v3-app_crowdc › assets › 4 › 45 ›...
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Craig Niederberger MD FACSClarence C. Saelhof Professor and Head, Department of Urology, UIC College of MedicineProfessor, Department of Bioengineering, UIC College of Engineering
What makes a man infertile and how do we find him?
July 19, 2016
29th Annual IN VITRO FERTILIZATION AND EMBRYO TRANSFER A Comprehensive Update
Disclosures
ASRM Journal Editor Medical Communications
AUA Journal Section Editor Medical Communications
Ferring Investigator Scientific Study
NexHand Co-Founder Medical Device Company
No relationship presents a conflict of interest with the material in this presentation.
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Disclosures
These drugs are off-label:
rFSHhMGClomipheneTamoxifenAnastrozoleTestolactone
Male Endocrine System
Consequences
Sperm
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Male Endocrine System
GnRH+
Clomiphene Tamoxifen
Anastrozole Testolactone
HCG rFSH hMG
LH+ FSH+
Activin+ Inhibin-
Testosterone
Estradiol-
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GnRH+
Testosterone
10,000 ng/dL
300 ng/dLLH+ FSH+
Activin+ Inhibin-
Testosterone
Estradiol-
GnRH+
Testosterone
Estradiol-
300 ng/dL
300 ng/dLLH+ FSH+
Activin+ Inhibin-
Testosterone
Estradiol-
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Khosla S, Melton LJ 3rd, Atkinson EJ, O'Fallon WM. J Clin Endocrinol Metab. 2001 Aug;86(8):3555-61.
Estradiol and Bone in Men
S. Bhasin. In: Kronenberg H. M., Melmed S., Polonsky K. S., and Reed Larsen P., eds. Williams Textbook of Endocrinology 11th ed., 2008; 647.
Albumin Bound Unbound SHBG Bound
2%
50-68%
30-45%Using 300 ng/dL,
156-210 ng/dL
“Bioavailable” Testosterone
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Vermeulen A, Verdonck L, Kaufman JM. J Clin Endocrinol Metab. 1999 Oct;84(10):3666-72.
How to Calculate
Commercial “free testosterone” assays are innacurateAlbumin, SHBG assays are reliablehttp://issam.ch/freetesto.htm
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Sussman EM, Chudnovsky A, Niederberger CS. Urol Clin North Am. 2008 May;35(2):147-55, vii.
Testosterone and InfertilityIn
ciden
ce T
esto
ster
one
< 30
0 ng
/dL
0%
20%
40%
60%
80%
100%
OA > 20 M/mL < 20 M/mL ASD
45%42.9%35.3%
16.7%
Hypogonadotropic Hypogonadism
Pubertal onset1
Eunuchoid habitus and deficient GnRH (and LH/FSH) secretion
“Kallmann syndrome” classic form: KAL1, X-linked, anosmia
1:10,000-60,000 live births
AR and AD also observed, and GnRHR, FGFR1/KAL2, PROKR2/PROK2, NELF, GPR54/kisspeptin, Convertase 1 genetic anomalies also observed
Adult onset2
Hypoandrogenism with inadequate pituitary response
Observed in half of males with azoospermia from spermatogenic
1Sokol RZ. In: Lipshultz LI, Howards SS, Niederberger CS, eds. Infertility in the Male 4th ed., 2009; 202-203, 2Sussman EM, Chudnovsky A, Niederberger CS. Urol Clin North Am. 2008 May;35(2):147-55.
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Hammoud AO, et al. Fertil Steril. 2008 Oct;90(4):897-904.
Obesity
Decreased testosteroneIncreased aromatase activity = estradiolDecreased SHBG
Schoor RA, Elhanbly S, Niederberger CS, Ross LS. J Urol. 2002 Jan;167(1):197-200.
FSH and Testis Size
0%
20%
40%
60%
80%
100%96%89%
ASD: FSH > 7.6, TLA < 4.6 OA: FSH < 7.6, TLA > 4.6
You don’t need to do a biopsy for diagnosis only!
Diagnose Azoospermia
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Gordetsky J, van Wijngaarden E, O’Brien J. BJU Int 2011;110:568–572.
FSH and Semen Analysis
Gordetsky J, van Wijngaarden E, O’Brien J. BJU Int 2011;110:568–572.
FSH and Semen Analysis
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What We Do
“Big 6”: morning testosterone, LH, FSH, SHBG, albumin, estradiol Prolactin if symptoms (visual field defects, headaches, ED, etc.)If testosterone is borderline, morning testosterone & LH x 3, 30 minutes apart for average
Consequences
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Morley JE, et al. Metabolism. 1997 Apr;46(4):410-3.
New Mexico Aging Process
Study
Men 61 - 87 years110 ng/dL/decade testosterone decline
Bhasin S, Bremner WJ. J Clin Endocrinol Metab. 1997 Jan;82(1):3-8.
Pathophysiology of Aging
Diminished testicular response to gonadotropins (! Leydig cell production)Attenuation of gonadotropins in response !to decreased androgen level (! LH)Altered function (pulsatility) of GnRH pulse generator
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Harman SM, et al. J Clin Endocrinol Metab. 2001 Feb;86(2):724-31.
Baltimore Longitudinal
Study of AgingAs testosterone falls,
SHBG rises and bioavailable
testosterone plummets
Bhasin S, Bremner WJ. J Clin Endocrinol Metab. 1997 Jan;82(1):3-8.
ConsequencesSexual dysfunction Muscle wasting Increased fat to lean body mass OsteopeniaHip and vertebral fractures Loss of body hair Impaired hematopoiesis
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Donaldson LJ, Cook A, Thomson RG. J Epidemiol Community Health. 1990 Sep;44(3):241-5.
Annual Fracture Index
Sperm
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Cooper TG, et al. Hum Reprod Update. 2010 May-Jun;16(3):231-45.
Cooper TG, et al. Hum Reprod Update. 2010 May-Jun;16(3):231-45.
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Guzick DS, et al. N Engl J Med. 2001 Oct 26;345(19):1388–93.
Semen Analysis is Poor
ROC AUC 0.60 0.59 0.66
WHO. WHO Manual for the Examination and Processing of Human Semen. World Health Organization; 2010. p9.
SA Variability
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Leushuis E, et al. Hum Reprod. 2014 Jul;29(7):1360–7.
Leushuis E, et al. Hum Reprod. 2014 Jul;29(7):1360–7.
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Leushuis E, et al. Hum Reprod. 2014 Jul;29(7):1360–7.
“Using the results of two semen analyses did not lead to a better goodness-of-fit. Discriminative capacity was rather poor, with an area under the ROC curve (AUC) ranging from 0.51 to 0.56.”
Morbeck DE, et al. Fertil Steril. 2011 Dec;96(6):1350–4.
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Morbeck DE, et al. Fertil Steril. 2011 Dec;96(6):1350–4.
“Accepting <30% normal forms as the threshold for WHO 3rd criteria, 31 (25.8%) of 120 patients were teratozoospermic in era 1 compared with 85 (77.3%) of 110 patients in era 2. Similarly, with a strict criteria threshold of % 4% normal forms, 24 (31.6%) of 76 patients were teratozoospermic in era 1 compared with 75 (56.4%) of 133 patients in era 2.”
Male Endocrine System
Consequences
Sperm
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Thank You