Prof. Dr. Michael Zitzmann Internal Medicine Endocrinology, Diabetology, Andrology University of Muenster, Germany

Induction of fertility in hypogonadal men Prof. Dr. Michael Zitzmann Internal Medicine Endocrinology, Diabetology, Andrology University of Muenster, Germany

Induction of fertility in hypogonadal men Prof. Dr. Michael Zitzmann Andrologist, Endocrinologist, Diabetologist Sexual Medicine (FECSM) Clinical Andrology / Centre for Reproductive Medicine and Andrology, University Clinics Muenster Germany WHO Collaborating Centre for Research in Human Reproduction Training Centre of the European Academy of Andrology

Depression and Sexuality in Aging Men Prof. Dr. Michael Zitzmann Andrologist, Endocrinologist, Diabetologist Sexual Medicine (FECSM) Clinical Andrology / Centre for Reproductive Medicine and Andrology, University Clinics Muenster Germany WHO Collaborating Centre for Research in Human Reproduction Training Centre of the European Academy of Andrology

Depression and Sexuality in Aging Men Prof. Dr. Michael Zitzmann Andrologist, Endocrinologist, Diabetologist Sexual Medicine (FECSM) Clinical Andrology / Centre for Reproductive Medicine and Andrology, University Clinics Muenster Germany WHO Collaborating Centre for Research in Human Reproduction Training Centre of the European Academy of Andrology

Hypothalamicpituitarygonadal axis Nieschlag, Andrology, Springer, 2000

Pat. J.E. 190 cm Age?

Pat. J.E.

Pat. J.E.

Pat. J.E.

Hormones Testosterone (nmol/l) 1,8 (>12) Free Testo. (pmol/l) 46 (>250) Estradiol (pmol/l) 26 (<250) SHBG (nmol/l) 43 (11-71) LH (U/l) < 0,2 (2-10) FSH (U/l) < 0,5 (1-7) Prolactin (mu/l) 127 (<500)

Hormone Constellations in Hypogonadism Hypergonadotropic Hypogonadism T LH Normogonadotropic Hypogonadism Hypogonadotropic Hypogonadism

Further results GnRH Test (0.1 mg GnRH i.v.) Baseline after 30` after 45` LH (IU/l) < 0.2 3.3 3.7 FSH (IU/l) < 0.2 1.5 2.1 Further hormone axes: intact MRI: normal findings Ophthalmologic investigation: not done

Diagnosis? Hypogonadotropic (secondary) Hypogonadism Kallmann - Syndrom

Fertility related symptom: hypogonadotropic azoospermia

Localisation of disorder Forms of therapy Hypothalamus GnRH GnRH-R pulsatile GnRH Gonadotropin substitution Testosterone substitution Pituitary LH FSH Effect of therapy Fertility induction yes yes no Androgenisation yes yes yes

Retrospective study in 83 men with secondary hypogonadism Zitzmann et al. 2005 Induction of fertility Target parameters: Appearance of sperm in the ejaculate Sperm concentration and total number of sperm Number of induced pregnancies Time until pregnancy achieved

Patient characteristics Zitzmann et al. 2005 Hypothalamic disorder Pituitary disorder Diff. n: 54 Age: 29 ± 6 years Height: 179 ± 9 cm Weight: 79 ± 12 kg BMI: 24 ± 3 kg x m -2 Maldesc (n) 26 n: 31 Age: 33 ± 6 years n.s. Height: 181 ± 9 cm n.s. Weight: 86 ± 15 kg n.s. BMI: 26 ± 4 kg x m -2 n.s. Maldesc (n) 3 **

Patient characteristics Zitzmann et al. 2005 Hypothalamic disorder Baseline characteristics Pituitary disorder Baseline characteristics Diff. Bitestic. vol.: 7.4 ± 7.4 ml LH: 0.3 ± 0.6 U/L FSH: 0.6 ± 0.9 U/L Testosterone: 4.5 ± 3.3 nmol/l Azoospermia: all patients Bitestic. vol.: 13.2 ± 12.2 ml ** LH: 0.3 ± 0.4 U/L n.s. FSH: 0.3 ± 0.4 U/L * Testosterone: 3.9 ± 2.2 nmol/l n.s. Azoospermia: all patients

Patient characteristics Zitzmann et al. 2005 Hypothalamic disorder Pituitary disorder Treatment cycles Treatment cycles Total cycles: 67 Using GnRH: 7 Total cycles: 40 Using GnRH: 0 Desiring paternity: 45 Desiring paternity: 29

Bitesticular volume maximal ml Bitesticular volume during therapy 80 Induction of spermatogenesis Yes 70 60 50 40 No 30 20 10 0 0 10 20 30 40 50 60 70 80 Bitesticular volume baseline ml

Percent Induction of spermatogenesis time until appearance of first sperm in ejaculate Pituitary disorder Hypothalamic disorder 100 80 60 40 Log rank test: p = 0.02 20 0 0 10 20 30 40 50 60 Months

Percent Induction of pregnancies (spontaneous) Pituitary disorder Hypothalamic disorder 100 80 60 40 20 Log rank test: p = 0.03 0 0 10 20 30 40 50 60 70 80 Months

Percent Induction of spermatogenesis time until appearance of first sperm in ejaculate No maldescensus Maldescensus 100 80 60 Log rank test: p = 0.01 40 20 0 0 10 20 30 40 50 60 Months

Percent Induction of pregnancies (spontaneous) 100 Log rank test: p = 0.03 No maldescensus 80 Maldescensus 60 40 20 0 0 10 20 30 40 50 60 70 80 Months

Log sperm concentration / ml Induction of pregancy Yes (spontaneous) Yes (ICSI) 2,5 10 8 2 1,5 10 7 1 0,5 10 6 0-0,5 10 5-1 Normal range > 2 x 10 7 / ml No -1,5 10 4-2 -2,5 0 10 20 30 40 50 60 70 80 Months until pregnancy or Months of treatment until abandonment

Initial After 2 years After 5 years

Treatment of hypogonadism and/or infertility with clomiphen citrate or TMX Kim et al, Fertil Steril 2013 epub

Clomiphene citrate for treatment of hypogonadism N=86 Katz et al. BJU 2011

Clomiphene citrate for treatment of hypogonadism Katz et al. BJU 2011

Clomiphene citrate for treatment of hypogonadism Katz et al. BJU 2011

Clomiphene citrate for treatment of hypogonadism N=46 Moscovic et al BJU 2012

Clomiphene citrate for treatment of hypogonadism Moscovic et al BJU 2012

Use of aromatase inhibitors for treatment male infertility is under discussion and seems to have rare side effects Schlegel Fertil Steril 2012

Increase of LH and Testosterone in obese men receiving an aromatase inhibitor Total-Estradiol LH Total-Testo free-estradiol FSH free-testosterone Loves et al. Eur J Endocrinol 158: 741-747 (2008)

Subfertility: enhancement of positive outcome Using Tamoxifen 20 mg/d and Andriol 120 mg/d vs. Placebo Each group n= 106 Adamopoulos et al. 2003

Case presentation Patient 23 years. Feels exhaused and tired puberty has stopped at age of 14 years does not shave Maldescensus left side 2nd year of life treated with hcg no current medication, no history of other diseases

Case presentation Height:181 cm Arm span:185 cm weight 77 kg No facial hair Pubic hair Tanner II No clear voice mutation

Case presentation Horizontal hair lines Testicular volume right 4 ml, left 10 ml

Case presentation Lab Hemoglobin 13 g/dl, liver and kidney markers normal Karyotype (external): 46, XY LH-RH-Test: LH (2-10 U/l) FSH 1-7 U/l Prolactin < 500mU/l Testosterone >12 pmol/l SHBG 11-71 nmol/l Free Testo >250 pmol/l Estradiol < 250 pmol/l PSA<4 µg/l Sniffing test: recognizes 8 of 15 substances

Case presentation Diagnosis?

Case presentation Hypogonadotropic Hypogonadism incomplete Kallmann Syndrom or Mutation of GnRH Receptor

Case presentation Therapy 1. Testosterone Substitution with T-Gel 50 mg / d 2. Change to hcg/rhfsh-therapy after a partner was found LH (2-10 U/l) FSH 1-7 U/l Prolactin < 500mU/l Testosterone >12 pmol/l SHBG 11-71 nmol/l Free Testo >250 pmol/l Estradiol < 250 pmol/l PSA<4 µg/l

Case presentation

Case presentation Spontaneous pregnancy Birth of a healthy boy Further therapy: Switch to T-Gel