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