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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.
Disclosures
These drugs are off-label:
rFSHhMGClomipheneTamoxifenAnastrozoleTestolactone
Male Endocrine System
Consequences
Sperm
Male Endocrine System
GnRH+
Clomiphene Tamoxifen
Anastrozole Testolactone
HCG rFSH hMG
LH+ FSH+
Activin+ Inhibin-
Testosterone
Estradiol-
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-
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
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
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.
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
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
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
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
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
Donaldson LJ, Cook A, Thomson RG. J Epidemiol Community Health. 1990 Sep;44(3):241-5.
Annual Fracture Index
Sperm
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.
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
Leushuis E, et al. Hum Reprod. 2014 Jul;29(7):1360–7.
Leushuis E, et al. Hum Reprod. 2014 Jul;29(7):1360–7.
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.
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
Thank You