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

Transcription

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

2 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

3 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

4 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

5 Hypothalamicpituitarygonadal axis Nieschlag, Andrology, Springer, 2000

6 Pat. J.E. 190 cm Age?

7 Pat. J.E.

8 Pat. J.E.

9 Pat. J.E.

10 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)

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

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

13 Diagnosis? Hypogonadotropic (secondary) Hypogonadism Kallmann - Syndrom

14 Fertility related symptom: hypogonadotropic azoospermia

15 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

16 Retrospective study in 83 men with secondary hypogonadism Zitzmann et al 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

17 Patient characteristics Zitzmann et al 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 **

18 Patient characteristics Zitzmann et al 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

19 Patient characteristics Zitzmann et al 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

20 Bitesticular volume maximal ml Bitesticular volume during therapy 80 Induction of spermatogenesis Yes No Bitesticular volume baseline ml

21 Percent Induction of spermatogenesis time until appearance of first sperm in ejaculate Pituitary disorder Hypothalamic disorder Log rank test: p = Months

22 Percent Induction of pregnancies (spontaneous) Pituitary disorder Hypothalamic disorder Log rank test: p = Months

23 Percent Induction of spermatogenesis time until appearance of first sperm in ejaculate No maldescensus Maldescensus Log rank test: p = Months

24 Percent Induction of pregnancies (spontaneous) 100 Log rank test: p = 0.03 No maldescensus 80 Maldescensus Months

25 Log sperm concentration / ml Induction of pregancy Yes (spontaneous) Yes (ICSI) 2, , , , Normal range > 2 x 10 7 / ml No -1, , Months until pregnancy or Months of treatment until abandonment

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27 Initial After 2 years After 5 years

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

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

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

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

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

34 Clomiphene citrate for treatment of hypogonadism Moscovic et al BJU 2012

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

36 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: (2008)

37 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

38 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

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

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

41 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 nmol/l Free Testo >250 pmol/l Estradiol < 250 pmol/l PSA<4 µg/l Sniffing test: recognizes 8 of 15 substances

42 Case presentation Diagnosis?

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

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45 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 nmol/l Free Testo >250 pmol/l Estradiol < 250 pmol/l PSA<4 µg/l

46 Case presentation

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