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

Rodolfo Reyrodolforey@cedie.org.ar

Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE)CONICET – FEI – División de Endocrinología, Hospital de Niños "Ricardo Gutiérrez“Buenos Aires ‐ Argentina     www.cedie.org.ar

HYPOGONADISM

DefinitionNon‐specific term for decreased testicular or ovarian functionthat could include a disorder of gamete production or functionand sex hormone production or action.

Usually, male hypogonadism indicates testicular failure associated

with androgen deficiency.

HW Gordon BakerClinical Management of Male Infertility

Endocrinology 5th Ed. (2006). DeGroot L & Jameson JL (eds)Elsevier Saunders, Philadelphia, PA, USA

Interstitialtissue

Leydig cell Testosterone

Sertoli cells AMHInhibin B

Germ cells SpermatozoaSeminiferoustubules

HYPOGONADISM

MALE HYPOGONADISM : Definition

Childhood Puberty AdulthoodBIRTH

Circulating  levels

Foetal

T 

LH

FSH

3‐6 mo.

Ontogeny of the H‐P‐G axis

Palpation Volume 2 ml

Palpation Volume 2 ml

The Prepubertal Testis

Birth

9 yr

Serum TestosteroneLow or Undetectable

CHILDHOOD = QUIESCENCEhCG Test

BIRTH

0.5 ml

9 yrPRE‐PUBERTY

1.5 mlTESTICULARVOLUME

Sertolicells

Germcells

Interstitialtissue

15‐25 ml

LATE PUBERTYADULTHOOD

Rey  Endocrine  Dev (2003)

Testicular Volume : from birth to adulthood

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)

0

40

80

120

0 3 6 9 12 15

Sertoli cell numberper testis (million)

Age (months)

0

4

8

0 3 6 9 12 15

Germ cell numberper testis (million)

0

10

20

30

40

0 3 6 9 12 15

Age (months)

Sertoli cell numberper section

0

1

2

3

4

0 3 6 9 12 15

Germ cell numberper section

0,00

0,04

0,08

0,12

0 3 6 9 12 15

Seminiferous tubulevolume (ml)

0,00

0,10

0,20

0 3 6 9 12 15

Testicular volume (ml)

Age (months)

0

40

80

0 3 6 9 12 15

Seminiferous tubulediameter (µm)

0

10

20

0 3 6 9 12 15

Seminiferous tubulelength (m)

Age (months)

Morphometric study of the testes in Cebus monkeys from birth to puberty

During infancy and childhood, testicular volume increases moderatelydue to seminiferous tubule increase in length

Seminiferous tubule increase in length is due to Sertoli cell proliferationBeware of “cell number per section” !!!

Rey et al. JCEM (1993)

BIRTH

0.5 ml

9 yr

2 mlTESTIS VOLUME

• Spermatogonial proliferation

• Sertoli cell proliferationFSH

Testicular activity during childhood

SERTOLI CELLS0.40 ml 1.60 ml

Germ cells0.05 ml 0.25 ml

Interstitial tissue0.05 ml 0.15 ml

Sertoli cell markers

AMH/MIS ELISA ®Beckman‐Coulter‐Immunotech

Grinspon RP  et al.   Int J Androl (2011)

1500

1000

500

0

(pmol/L)Serum AMH

2000

Bergadá I  et al.   Clin Endocrinol (1999)

0

150

300

450

600(ng/l)

Serum Inhibin B

Inhibin B  ELISA ®Oxford BioInnovation

Childhood Puberty AdulthoodBIRTH

Serum levels

Fetal

T

LH

FSH

3‐6 m.

AMH

Inhibin B

CHILDHOOD : physiologic hypoANDROGENISM ≠ hypoGONADISM

Ontogeny of the H‐P‐G axis

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)

Whole gonadal dysfunction (Sertoli‐Germ‐Leydig)

Cell‐specific gonadal dysfunction

Testicular or Primary  (Hypergonadotrophic) Hypoth‐Pituitary or Central  (Hypogonadotrophic) Combined or "dual" (Testicular  +  H‐P)

Congenital Acquired

MALE HYPOGONADISM : Classification

HYPOGONADISM  IN  FETAL LIFE

1st TrimesterTesticular    Central   

2nd – 3rd TrimestersTesticular    Central

MALE HYPOGONADISM : Classification

Fetal Male Sex Differentiation

TESTIS

Urogenital SinusExternal Genitalia

Müllerianducts

Wolffianducts

IntermediateMesoderm

Gonadalridge

Fallopian tubesUterus

Upper Vagina

DHT

MALE

EpididymisVas deferensSeminal vesicle

TLeydigcell

AMH REGRESSIONSertolicell

Undifferentiated Stage

H‐P‐Testicular axis in fetal life

Klonisch et al.Dev Biol (2004)

1° TrimesterPlacental hCG‐dependent

2° – 3° TrimestersFetal LH‐dependent

Testosterone level

Leydig cell activity

Sertoli cell activity

Semana Gestación

Testicular descent

Differentiation ofWolffian ducts

Regression of Müllerian ducts

Differentiation ofExternal Genitalñia

Growth of External Genitalia

Testosterone

2. Micropenis / Cryptorchidism

1. Ambiguous genitalia (DSD)

HYPOGONADISM  IN  FETAL LIFE

MALE HYPOGONADISM : Classification

1st TrimesterTesticular  DSD / Ambiguous genitaliaCentral  Male genitalia (cryptorchidism, micropenis)

2nd – 3rd TrimestersTesticular    Central Male genitalia (cryptorchidism, micropenis)

TESTICULAR

WHOLE GONADAL DYSFUNCTION(Sertoli‐Germ‐Leydig)

CELL‐SPECIFICGONADAL DYSFUNCTION

Testicular dysgenesis Leydig: LH‐R mutationSteroidogenic proteins

Sertoli: FSH‐R mutationGerm:   DAZ deletion

MALE HYPOGONADISM : Classification

Rey  et al. Andrology (2013)

Virilización normalMicro‐orquidismo al nacer (Hipoplasia cél. Sertoli)Oligo/azoospermiaVirilización normalTestículos normales al nacerOligo/azoospermia

Lanfranco et al. Lancet (2008)

Pacenza et al. Int J Endocrinol (2012)

Gonadal function in patients with Klinefelter syndrome:“Hypergonadtropic” hypogonadism

LH (IU/L)

I II III-V0

10

20

30

40

50

60

FSH (IU/L)

I II III-V0

10

20

30

40

50

60

Inhibina B (ng/L)

I II III-V0

100

200

300

400

500

600

Bastida et al. Clin Endocrinol (2007)

Pubertal stages

Pubertal stages

Sertoli cell markers in cryptorchid boys

Serum AMH SDS

‐4

‐3

‐2

‐1

0

1

2

3

BILATERAL  CRYPTORCHIDISMn = 78

Agonadismn = 8

Hypo‐gonadism

n = 53

Normal

Low

N.D.

Normalfunction

n = 17

22 % 68 % 10 %

‐4

0

4

8

12

16

20

356085

Serum FSHSDS

Agonadismn = 8

Hypo‐gonadism

n = 53

Normalfunction

n = 17

17 %

Gonadotropins in childhood

Conte  et al.   JCEM  (1975)

FSH levels in patients with Turner syndrome

Primary Hypogonadism (childhood)  ≠  Hypergonadotropic

Gonadotrophin levels in boys with anorchidism

Grinspon  et al.   Clin Endocrinol  (2012)

Gonadotropins in childhood

Whole gonadal dysfucntion (Sertoli‐Germ‐Leydig)

Dissociated dysfunction (cell‐specific)

Testicular or Primary  (Hypergonadotropic) Hypothal‐Pituitary  or Central  (Hypogonadotropic) Combined or "dual" (Testicular  +  H‐P)

Congenital Acquired

MALE HYPOGONADISM : Classification

Central HypogonadismCONGENITAL

•Micropenis

• Crypptorchidism

•Microorchidism

•Absence of puberty

Crowley, Mol Cel Endoc 2011

Pituitary developmentPROP1, HESX1, SOX2, SOX3, LHX3

GnRH release and actionGnRH cell migration

Central Hypogonadism

Crowley, Mol Cel Endoc 2011

Pituitary developmentPROP1, HESX1, SOX2, SOX3, LHX3

GnRH release and actionGnRH cell migration

Central Hypogonadism

MRIAgenesis of Olfactory bulbs

Gene defects affecting GnRH cell migration

Sarfati et al. Front Horm Res (2010)

GnRH insufficiency

Kallmann syndromeANOSMIN (KAL1)

Esteroide sulfatasa Anosmina

X-linked, recessive

Diagnosis

Costa Barbosa et al. JCEM 2013

Gene defects affecting GnRH cell migration

Central hypogonadism with global testicular dysfunction

NFκB

P

AP2NFκB

IκB

α

AC

AMPc

FSH

CellProlif.

AMH

Increase in testicular AMH output

SAP62

AP2

PKA

SF1

P

P

P

PP

SOX9 Sertolicell

Lasala et al. Am J Physiol Endo Metab (2011)

Normal genitalia Cryptorchidismand/or Micropenis

0

500

1000

1500

2000

2500

pmol/L

Normal Range

AMH in boys with  Congenital Multiple Pituitary 

Hormone deficiency

D. Braslavsky et al. Horm Res Paediatr (2015)

FSH regulates Sertoli cells

Bougnères et al. JCEM (2008)

Effect of rhFSH and rhLH on testicular hormone secretionin boys with congenital  central hypogonadism

Whole gonadal dysfunction (Sertoli‐Germ‐Leydig)

Dissociated dysfunction (cell‐specific)

Testicular or Primary  (Hypergonadotropic) Hypothal‐Pituitary  or Central  (Hypogonadotropic) Combined or "dual" (Testicular  +  H‐P)

Congenital Acquired

MALE HYPOGONADISM : Classification

Central Hypogonadism

Phillip et al. NEJM (1998)FSHβ mutations

Testis volume   1‐2 ml

Central Hypogonadism

≠  Hypogonadotropic

Bouligand et al.PLoS One (2011)

TACR3  mutation

Central Hypogonadism  ≠  Hypogonadotropic

Central Hypogonadism

Whole gonadal dysfunction (Sertoli‐Germ‐Leydig)

Dissociated dysfunction (cell‐specific)

Testicular or Primary  (Hypergonadotropic) Hypothal‐Pituitary  or Central  (Hypogonadotropic) Combined or "dual" (Testicular  +  H‐P)

Congenital Acquired

MALE HYPOGONADISM : Classification

HYPOGONADISM     Combined or "dual" (Primary + Central)

Bergadá I. et al. Clin Endo (2008)

Testicular hormones : low Gonadotropins inadequately normal or low

I II III

Tanner

I II III0

200

400

600

800

1000

1200

AMH

(pmol/L)

I II III0

100

200

300

400

500

600

Inhibina

 B(pg/mL)

0

4

8

12

16

20

Testosterona

(nmol/L)

Hora

LH

FSH

Patient # 3

0 2 4 6 8 10 120

1

2

3

4

5

IU/L

Patient # 2

0 2 4 6 8 10 120

1

2

3

4

5

IU/L

Patient # 1

0 2 4 6 8 10 120

4

8

12

16

20

IU/L

LH

LH

FSH

FSH

Delayed-onset X-linked Adrenal HypoplasiaCongenita

Mutation NR0B1(DAX1)

TESTICULAR

CENTRAL(H‐P)

COMBINED(“Dual”)

Multiple Pituitary Hormone deficiency

Isolated Hypogonadotropic Hypogonadism(Kallmann)

Mutation DAX1Prader‐Willi

Total Body Irradiation

Leydig: Mutation LHSertoli: Mutation FSH

Rey  et al. Andrology (2013)

WHOLE GONADAL DYSFUNCTION(Sertoli‐Germ‐Leydig)

DISSOCIATED GONADALDYSFUNCTION

TESTICULAR Testicular dysgenesis Leydig:  Mutation  LH‐R Steroidogenic proteins

Sertoli:   Mutation FSH‐RGerm.:    Deletion DAZ

MALE HYPOGONADISM : Classification

Testicular or Primary  (Hypergonadotropic) Hypothal‐Pituitary  or Central  (Hypogonadotropic) Combined or "dual" (Testicular  +  H‐P)

Congenital Acquired

MALE HYPOGONADISM : Classification

Childhood Few or no signs Subdiagnosis (if no AMH/Inhibin B measured)Puberty Absence / Delayed / IncompleteAdulthood Low libido, erectile dysfunction, infertility, etc.

Primary HypogonadismACQUIRED

CongenitalAnorchidismCryptorchidism 

Whole testicular dysfucntion

Leydig cell‐specificdysfunction

Whole testicular dysfucntion

Testosterone synthesis defectsLH‐R mutationAndrogen insensitivity

AcquiredBilateral OrchitisCastrationChemotherapy / Pelvic Radiotherapy

Serrtoli cell‐specificdysfunction

AMH or AMH‐R mutation

• 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

Central HypogonadismADQCQUIREDPermanent

Underlying cause identified and treated Reversible

EndocrineGH deficiencyHypothyroidismHyperprolactinemiaHypercortisolemiaDiabetes mellitus 1

GastrointestinalCeliac diseaseInflammatory bowel diseaseParasitic diseases

NutritionalAnorexia nervosa

RespiratorySevere Asthma

RenalNephrotic syndrome

HematologyThalassemia

CardiacChronic heart failure

OncologyNeuroblastomaALLHodgkin disease

CNSCerebral palsySeizure syndromes

Central HypogonadismADQCQUIRED

Transient (Functional)

POST‐NATAL HYPOGONADISM

Rey  et al. Andrology (2013)

Constitutional delay of Puberty   vs.   Hypogonadism

Differential Diagnoses

1) Gold Standard: clinical evolution

2) Testosterone

3)Basal  LH y FSH

4) Dynamic tests

Sedlemeyer & Palmert.  JCEM (2002)

Constitutional delay of puberty                                                    

Unclassified

Functional Central Hypogonadism

Primary hypogonadism

CongenitalCentral Hypogonadism

Constitutional delay of Puberty   vs.   Hypogonadism

1 ‐ Gold Standard: clinical evolution

18 yr: ¿started puberty?

HHFollow‐up  4 years

Completed puberty?

YES

NO

Constitutional delay of puberty

HH partial

NOYES

346 ng/dl

34.6 ng/dl

3.46 ng/dl

Ankarberg-Lindgren et al. Eur J Endocrinol (2004)

Testicular Volume (ml)

2 – Testicular volumen and basal Testosterone

Prepubertal boys between 10 and 16 yr-old:

Testosterone (morning) ≥ 20 ng/dl 100 % entered puberty within 15 months.

Testosterone (morning) < 20 ng/dl 25 % entered puberty within 15 months

Wu et al. JCEM (1993)

CHH PHH SP0

1

2

3

4

Basal LH(IU/L)

CHH PHH SP0

1

2

3

4

Basal FSH(IU/L)

Grinspon, Ropelato et al. JCEM (2010)

FSH < 1.2 UI/L (IFMA)PPV 100% for HHNPV 54% for HH

LH < 0.4 UI/L (IFMA)PPV 95% for HHNPV 60% for HH

FSH <1.11 IU/l (IRMA)Sensitivity 97% (IC95% 89–100) 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)

3 – Basal gonadotropins

4 – Dynamic tests

Short Tests• GnRH (100 ug/ 10 ug)• GnRH analogues (Leuprolide, Triptorelin)• hCG• GnRH with FAS assay

Long Tests• Pulsatile GnRH administration 36 h• GnRH infusion: 100 µg GnRH in 120 minutes: 0,83 µg/minute

Peak FSH

0.0 0.2 0.4 0.6 0.8 1.00.0

0.2

0.4

0.6

0.8

1.0

1 - Specificity

Sens

itivi

ty

Peak LH

0.0 0.2 0.4 0.6 0.8 1.00.0

0.2

0.4

0.6

0.8

1.0

1 - Specificity

Sens

itivi

ty

AUC: 0.62 (95% CI: 0.27 to 0.96) AUC: 0.70 (95% CI: 0.39 to 1.00)

CHH PHH SP0

5

10

15

20

Peak FSH(IU/L)

CHH PHH SP0

5

10

15

20

Peak LH(IU/L)

5,8 UI/L 4,6 UI/L

Peak FSH

Grinspon, Ropelato et al. JCEM (2010)

4 – Pruebas de estímulo

Absence of puberty / HH suspicion(> 12 yr)

FSH < 1.2 IU/L FSH ≥ 1.2 IU/L

CentralHypogonadism

Peak FSH < 4.6 IU/Land

Peak LH < 5,8 IU /L

Basal Gonadotropins

GnRH infusion

Peak FSH > 4.6 IU/LAnd/or

Peak LH > 5.8 IU/L

Constitutional delayof Puberty

Grinspon, Ropelato et al. JCEM (2010)

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

TRATAMIENTO

Objetivos del Tratamiento :

1) Adquisición de caracteres sexuales secundarios2) Adquisición de masa ósea3) Evitar compromiso psicológico4) Optimizar velocidad de crecimiento5) Fertilidad

Varón:  E.C. > 14 años (E.O. > 13 años)

Rey R.   Annales d’Endocrinologie (2017)

LH Leydig cells Intratesticular Testosterone

FSH Sertoli cells TV  2 ml  3 ml  4 ml(Tanner 2)

Sertoli cell maturation(Tanner 2‐3)  AMH      Inhibin B

Germ cell proliferation & meiosis

TV  4 ml  25 ml(Tanner 2   Tanner 5)

Pubertal Testis development

(Tanner 3‐5) Serum Testosterone

BIRTH

0.5 ml

9 yrPRE‐PUBERTY

1.5 ml

Sertolicells

Germcells

Interstitialtissue

15‐25 ml

LATE PUBERTYADULTHOOD

Serumlevels

T

LH

FSH

Childhood3‐6 mo.

Fetal

AMH

Inhibin B

Puberty

Young et al, JCEM (2005)

Effect of rhFSH on testicular AMH secretionin patients with congenital hypogonadotropic hypogonadism

rhFSHGonal-F 150 U/d sc

+ hCG1500 U 2/wk im

* **

T (ng/dl)302 ± 25

T (ng/dl)351 ± 34

Serum AMH (pmol/L)

0

250

500

750

1000

0 10 20 30 60 90Days

rhFSHGonal-F 150 U/d sc

*********

T (ng/dl)31 ± 5

T (ng/dl)39 ± 8

HIPOGONADISMO MASCULINO en INFANCIA y PUBERTAD

I. Definición  basada en endocrinología del desarrollo1) Gonadotrofinas – Testosterona – AMH – Inhibina B : 0‐6 m2) AMH – Inhibina B : 6 m – 10 años3) Pruebas de estímulo

II. Clasificación  basada en endocrinología del desarrollo1) Primario / Central / Dual2) Congénito : Fetal (1° vs 2°‐3° trimestres) 3) Adquirido : Infancia / Pubertad / Adultez4) Disfunción testicular global vs disociada

III. Hipogonadismo central (HH) vs Retardo Puberal Simple1) Diagnóstico2) Tratamiento

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 www.cedie.org.ar