HIPOGONADISMO MASCULINO Clasificación extendida basada en un enfoque de la endocrinología del desarrollo

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1 HIPOGONADISMO MASCULINO Clasificación extendida basada en un enfoque de la endocrinología del desarrollo Rodolfo Rey Centro de Investigaciones Endocrinológicas Dr. César Bergadá (CEDIE) CONICET FEI División de Endocrinología, Hospital de Niños "Ricardo Gutiérrez Buenos Aires Argentina

2 HYPOGONADISM Definition Non specific term for decreased testicular or ovarian function that could include a disorder of gamete production or function and sex hormone production or action. Usually, male hypogonadism indicates testicular failure associated with androgen deficiency. HW Gordon Baker Clinical Management of Male Infertility Endocrinology 5 th Ed. (2006). DeGroot L & Jameson JL (eds) Elsevier Saunders, Philadelphia, PA, USA

3 MALE HYPOGONADISM : Definition Interstitial tissue Leydig cell Testosterone HYPOGONADISM Seminiferous tubules Germ cells Sertoli cells Spermatozoa AMH Inhibin B

4 Ontogeny of the H P G axis Circulating levels 3 6 mo. T LH FSH Foetal BIRTH Childhood Puberty Adulthood

5 The Prepubertal Testis Birth Palpation Volume 2 ml 9 yr Palpation Volume 2 ml Serum Testosterone Low or Undetectable CHILDHOOD = QUIESCENCE hcg Test

6 Testicular Volume : from birth to adulthood Sertoli cells Interstitial tissue Germ cells TESTICULAR VOLUME 0.5 ml BIRTH 1.5 ml 9 yr PRE PUBERTY ml LATE PUBERTY ADULTHOOD Rey Endocrine Dev (2003) Adapted from: Nistal M et al. J Anat (1982) Müller & Skakkebaek. Int J Androl (1983) Rey R et al. J Clin Endocrinol Metab (1993) Berensztein et al. J Clin Endocrinol Metab (2002)

7 Morphometric study of the testes in Cebus monkeys from birth to puberty Testicular volume (ml) 0,12 Seminiferous tubule volume (ml) Seminiferous tubule diameter (µm) Seminiferous tubule length (m) 0,20 0, ,10 0, , , Age (months) Age (months) During infancy and childhood, testicular volume increases moderately due to seminiferous tubule increase in length Sertoli cell number per testis (million) Germ cell number per testis (million) Sertoli cell number per section Germ cell number per section Age (months) Age (months) Seminiferous tubule increase in length is due to Sertoli cell proliferation Beware of cell number per section!!! Rey et al. JCEM (1993)

8 Testicular activity during childhood BIRTH 9 yr 0.40 ml SERTOLI CELLS 1.60 ml 0.05 ml Interstitial tissue 0.15 ml 0.05 ml Germ cells 0.25 ml 0.5 ml TESTIS VOLUME 2 ml Spermatogonial proliferation Sertoli cell proliferation FSH

9 Sertoli cell markers (pmol/l) 2000 Serum AMH (ng/l) 600 Serum Inhibin B AMH/MIS ELISA Beckman Coulter Immunotech Grinspon RP et al. Int J Androl (2011) Inhibin B ELISA Oxford BioInnovation Bergadá I et al. Clin Endocrinol (1999)

10 Ontogeny of the H P G axis CHILDHOOD : physiologic hypoandrogenism Serum levels 3 6 m. AMH hypogonadism T LH FSH Inhibin B Fetal BIRTH Childhood Puberty Adulthood

11 MALE HYPOGONADISM Revised definition Decreased testicular function, as compared to what is expected for age, involving an impaired hormone secretion by Leydig cells (androgens, INSL3) and/or Sertoli cells (AMH, inhibin B) and/or a disorder of spermatogenesis. R. Rey et al. Andrology 1: 3 16 (2013)

12 MALE HYPOGONADISM : Classification Congenital Acquired Testicular or Primary (Hypergonadotrophic) Hypoth Pituitary or Central (Hypogonadotrophic) Combined or "dual" (Testicular + H P) Whole gonadal dysfunction (Sertoli Germ Leydig) Cell specific gonadal dysfunction

13 MALE HYPOGONADISM : Classification HYPOGONADISM IN FETAL LIFE 1 st Trimester Testicular Central 2 nd 3 rd Trimesters Testicular Central

14 Fetal Male Sex Differentiation Undifferentiated Stage Intermediate Mesoderm Gonadal ridge TESTIS Leydig cell Sertoli cell T AMH Wolffian ducts DHT Müllerian ducts Epididymis Vas deferens Seminal vesicle Urogenital Sinus External Genitalia REGRESSION Fallopian tubes Uterus Upper Vagina MALE

15 H P Testicular axis in fetal life 1. Ambiguous genitalia (DSD) Testosterone Testosterone level Growth of External Genitalia Leydig cell activity Differentiation of External Genitalñia Testicular descent Sertoli cell activity Regression of Müllerian ducts Differentiation of Wolffian ducts 2. Micropenis / Cryptorchidism Semana Gestación 1 Trimester Placental hcg dependent 2 3 Trimesters Fetal LH dependent Klonisch et al. Dev Biol (2004)

16 MALE HYPOGONADISM : Classification HYPOGONADISM IN FETAL LIFE 1 st Trimester Testicular Central DSD / Ambiguous genitalia Male genitalia (cryptorchidism, micropenis) 2 nd 3 rd Trimesters Testicular Central Male genitalia (cryptorchidism, micropenis)

17 MALE HYPOGONADISM : Classification TESTICULAR WHOLE GONADAL DYSFUNCTION (Sertoli Germ Leydig) Testicular dysgenesis CELL SPECIFIC GONADAL DYSFUNCTION Leydig: LH R mutation Steroidogenic proteins Sertoli: FSH R mutation Germ: DAZ deletion Virilización normal Micro orquidismo Virilización normalal nacer (Hipoplasia cél. Sertoli) Oligo/azoospermia Testículos normales al nacer Oligo/azoospermia Rey et al. Andrology (2013)

18 Gonadal function in patients with Klinefelter syndrome: Hypergonadtropic hypogonadism FSH (IU/L) LH (IU/L) Lanfranco et al. Lancet (2008) 0 I II III-V Pubertal stages 0 I II III-V Inhibina B (ng/l) I II III-V Pubertal stages Bastida et al. Clin Endocrinol (2007) Pacenza et al. Int J Endocrinol (2012)

19 Sertoli cell markers in cryptorchid boys Serum AMH SDS Normal % 68 % 10 % BILATERAL CRYPTORCHIDISM n = 78 Serum FSH SDS % Low N.D. 3 4 Normal function n = 17 Hypogonadism n = 53 Agonadism n = Normal function n = 17 Hypogonadism n = 53 Agonadism n = 8

20 Gonadotropins in childhood FSH levels in patients with Turner syndrome Conte et al. JCEM (1975)

21 Gonadotropins in childhood Gonadotrophin levels in boys with anorchidism Grinspon et al. Clin Endocrinol (2012) Primary Hypogonadism (childhood) Hypergonadotropic

22 MALE HYPOGONADISM : Classification Congenital Acquired Testicular or Primary (Hypergonadotropic) Hypothal Pituitary or Central (Hypogonadotropic) Combined or "dual" (Testicular + H P) Whole gonadal dysfucntion (Sertoli Germ Leydig) Dissociated dysfunction (cell specific)

23 Central Hypogonadism CONGENITAL Micropenis Crypptorchidism Microorchidism Absence of puberty

24 Central Hypogonadism GnRH cell migration GnRH release and action Pituitary development PROP1, HESX1, SOX2, SOX3, LHX3 Crowley, Mol Cel Endoc 2011

25 Central Hypogonadism GnRH cell migration GnRH release and action Pituitary development PROP1, HESX1, SOX2, SOX3, LHX3 Crowley, Mol Cel Endoc 2011

26 Gene defects affecting GnRH cell migration Kallmann syndrome ANOSMIN (KAL1) X-linked, recessive MRI Agenesis of Olfactory bulbs Esteroide sulfatasa Anosmina GnRH insufficiency Sarfati et al. Front Horm Res (2010)

27 Gene defects affecting GnRH cell migration Diagnosis Costa Barbosa et al. JCEM 2013

28 Central hypogonadism with global testicular dysfunction FSH FSH regulates Sertoli cells AP2 P P PKA IκB AC α AMPc P SF1 SOX9 NFκB Sertoli cell pmol/l AMH in boys with Congenital Multiple Pituitary Hormone deficiency Normal Range AP2 P SAP62 P NFκB P AMH Cell Prolif. 0 Normal genitalia Cryptorchidism and/or Micropenis Increase in testicular AMH output Lasala et al. Am J Physiol Endo Metab (2011) D. Braslavsky et al. Horm Res Paediatr (2015)

29 Effect of rhfsh and rhlh on testicular hormone secretion in boys with congenital central hypogonadism Bougnères et al. JCEM (2008)

30 MALE HYPOGONADISM : Classification Congenital Acquired Testicular or Primary (Hypergonadotropic) Hypothal Pituitary or Central (Hypogonadotropic) Combined or "dual" (Testicular + H P) Whole gonadal dysfunction (Sertoli Germ Leydig) Dissociated dysfunction (cell specific)

31 Central Hypogonadism FSHβ mutations Phillip et al. NEJM (1998) Central Hypogonadism Hypogonadotropic Testis volume 1 2 ml

32 Central Hypogonadism Bouligand et al. PLoS One (2011) TACR3 mutation Central Hypogonadism Hypogonadotropic

33 MALE HYPOGONADISM : Classification Congenital Acquired Testicular or Primary (Hypergonadotropic) Hypothal Pituitary or Central (Hypogonadotropic) Combined or "dual" (Testicular + H P) Whole gonadal dysfunction (Sertoli Germ Leydig) Dissociated dysfunction (cell specific)

34 HYPOGONADISM Combined or "dual" (Primary + Central) Delayed-onset X-linked Adrenal Hypoplasia Congenita Mutation NR0B1 (DAX1) AMH (pmol/l) I II III Inhibina B (pg/ml) I II III IU/L Patient # Patient # 2 FSH LH Testosterona (nmol/l) IU/L Patient # 3 FSH LH 0 I II III Tanner IU/L 3 2 Testicular hormones : low Gonadotropins inadequately normal or low Hora FSH LH Bergadá I. et al. Clin Endo (2008)

35 MALE HYPOGONADISM : Classification WHOLE GONADAL DYSFUNCTION (Sertoli Germ Leydig) DISSOCIATED GONADAL DYSFUNCTION TESTICULAR Testicular dysgenesis Leydig: Mutation LH R Steroidogenic proteins Sertoli: Mutation FSH R Germ.: Deletion DAZ CENTRAL (H P) COMBINED ( Dual ) Multiple Pituitary Hormone deficiency Isolated Hypogonadotropic Hypogonadism (Kallmann) Mutation DAX1 Prader Willi Total Body Irradiation Leydig: Mutation LH Sertoli: Mutation FSH Rey et al. Andrology (2013)

36 MALE HYPOGONADISM : Classification Congenital Acquired Testicular or Primary (Hypergonadotropic) Hypothal Pituitary or Central (Hypogonadotropic) Combined or "dual" (Testicular + H P) Childhood Few or no signs Subdiagnosis (if no AMH/Inhibin B measured) Puberty Absence / Delayed / Incomplete Adulthood Low libido, erectile dysfunction, infertility, etc.

37 Primary Hypogonadism ACQUIRED Congenital Anorchidism Cryptorchidism Testosterone synthesis defects LH R mutation Androgen insensitivity Whole testicular dysfucntion Leydig cell specific dysfunction AMH or AMH R mutation Serrtoli cell specific dysfunction Acquired Bilateral Orchitis Castration Chemotherapy / Pelvic Radiotherapy Whole testicular dysfucntion

38 Central Hypogonadism ADQCQUIRED Permanent Infections / Tumors of CNS (craniopharyngiomas, germinomas, etc.) Histiocytosis X Cranial Radiotherapy Cranial Surgery / Traumatism Symptoms Headache, Visual defects, vomit Other pituitary deficiencies History of Radiotherapy Polydipsia/polyuria

39 Central Hypogonadism ADQCQUIRED Transient (Functional) Underlying cause identified and treated Reversible Endocrine GH deficiency Hypothyroidism Hyperprolactinemia Hypercortisolemia Diabetes mellitus 1 Gastrointestinal Celiac disease Inflammatory bowel disease Parasitic diseases Nutritional Anorexia nervosa Respiratory Severe Asthma Renal Nephrotic syndrome Hematology Thalassemia Cardiac Chronic heart failure Oncology Neuroblastoma ALL Hodgkin disease CNS Cerebral palsy Seizure syndromes

40 POST NATAL HYPOGONADISM Rey et al. Andrology (2013)

41 Constitutional delay of Puberty vs. Hypogonadism Differential Diagnoses 1) Gold Standard: clinical evolution 2) Testosterone 3)Basal LH y FSH 4) Dynamic tests

42 Constitutional delay of Puberty vs. Hypogonadism Unclassified Primary hypogonadism Congenital Central Hypogonadism Functional Central Hypogonadism Constitutional delay of puberty Sedlemeyer & Palmert. JCEM (2002)

43 1 Gold Standard: clinical evolution 18 yr: started puberty? YES NO Follow up 4 years HH Completed puberty? NO HH partial YES Constitutional delay of puberty

44 2 Testicular volumen and basal Testosterone Ankarberg-Lindgren et al. Eur J Endocrinol (2004) 346 ng/dl 34.6 ng/dl 3.46 ng/dl Testicular Volume (ml) Prepubertal boys between 10 and 16 yr-old: Wu et al. JCEM (1993) Testosterone (morning) 20 ng/dl 100 % entered puberty within 15 months. Testosterone (morning) < 20 ng/dl 25 % entered puberty within 15 months

45 3 Basal gonadotropins Basal LH (IU/L) Basal FSH (IU/L) FSH < 1.2 UI/L (IFMA) PPV 100% for HH NPV 54% for HH 1 0 CHH PHH SP 1 0 CHH PHH SP LH < 0.4 UI/L (IFMA) PPV 95% for HH NPV 60% for HH Grinspon, Ropelato et al. JCEM (2010) FSH <1.11 IU/l (IRMA) Sensitivity 97% (IC95% ) Specificity 23% (IC95% 7 51) for the absence of LH pulses Odink et al. Horm Res (1998) LH <0.65 IU/l (IFMA) Sensitivity 91% Specificity 98% Sequera et al., J Ped Endocrinol Metab (2002)

46 Short Tests GnRH (100 ug/ 10 ug) GnRH analogues (Leuprolide, Triptorelin) hcg GnRH with FAS assay 4 Dynamic tests Long Tests Pulsatile GnRH administration 36 h GnRH infusion: 100 µg GnRH in 120 minutes: 0,83 µg/minute Sensitivity Peak LH Sensitivity Peak FSH 0.2 AUC: 0.62 (95% CI: 0.27 to 0.96) AUC: 0.70 (95% CI: 0.39 to 1.00) Specificity Specificity Peak LH (IU/L) CHH PHH SP Peak FSH Peak FSH (IU/L) 5,8 UI/L 4,6 UI/L CHH PHH SP Grinspon, Ropelato et al. JCEM (2010)

47 4 Pruebas de estímulo Absence of puberty / HH suspicion (> 12 yr) Basal Gonadotropins FSH < 1.2 IU/L FSH 1.2 IU/L GnRH infusion Peak FSH < 4.6 IU/L and Peak LH < 5,8 IU /L Peak FSH > 4.6 IU/L And/or Peak LH > 5.8 IU/L Central Hypogonadism Constitutional delay of Puberty Grinspon, Ropelato et al. JCEM (2010)

48 Objetivos del Tratamiento : TRATAMIENTO 1) Adquisición de caracteres sexuales secundarios 2) Adquisición de masa ósea 3) Evitar compromiso psicológico 4) Optimizar velocidad de crecimiento 5) Fertilidad Varón: E.C. > 14 años (E.O. > 13 años) Varón: Testosterona 50 mg IM cada 28 días durante 6 meses. Controlar el avance de la edad ósea (no > 1 año/6 meses) Aumento gradual cada 6 meses hasta la dosis adulta de 250 mg cada 28 días. En adulto buscando fertilidad se utiliza LH/hCG y FSHrh

49 Pubertal Testis development Sertoli cells Interstitial tissue Serum levels Fetal 3 6 mo. Childhood AMH Inhibin B Puberty T LH FSH Germ cells 0.5 ml BIRTH 1.5 ml 9 yr PRE PUBERTY ml LATE PUBERTY ADULTHOOD (Tanner 2 3) FSH Sertoli cells TV 2 ml 3 ml 4 ml (Tanner 2) LH Leydig cells Intratesticular Testosterone AMH Inhibin B Sertoli cell maturation TV 4 ml 25 ml (Tanner 2 Tanner 5) (Tanner 3 5) Serum Testosterone Germ cell proliferation & meiosis Rey R. Annales d Endocrinologie (2017)

50 Effect of rhfsh on testicular AMH secretion in patients with congenital hypogonadotropic hypogonadism Serum AMH (pmol/l) *** *** *** * ** 500 T (ng/dl) 302 ± 25 T (ng/dl) 351 ± T (ng/dl) 39 ± 8 T (ng/dl) 31 ± Days rhfsh Gonal-F 150 U/d sc rhfsh Gonal-F 150 U/d sc + hcg 1500 U 2/wk im Young et al, JCEM (2005)

51 HIPOGONADISMO MASCULINO en INFANCIA y PUBERTAD I. Definición basada en endocrinología del desarrollo 1) Gonadotrofinas Testosterona AMH Inhibina B : 0 6 m 2) AMH Inhibina B : 6 m 10 años 3) Pruebas de estímulo II. III. Clasificación basada en endocrinología del desarrollo 1) Primario / Central / Dual 2) Congénito : Fetal (1 vs 2 3 trimestres) 3) Adquirido : Infancia / Pubertad / Adultez 4) Disfunción testicular global vs disociada Hipogonadismo central (HH) vs Retardo Puberal Simple 1) Diagnóstico 2) Tratamiento

52 Muchas gracias por la atención! Centro de Investigaciones Endocrinológicas Dr. César Bergadá (CEDIE) CONICET FEI División de Endocrinología, Hospital de Niños "Ricardo Gutiérrez" Buenos Aires, ARGENTINA