hipogonadismo masculino - smep.org.mx · bilateral orchitis castration chemotherapy / pelvic...
Post on 27-Oct-2020
4 Views
Preview:
TRANSCRIPT
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
top related