ANATOMIE

Structura testicului - reprezentat de:

reeaua de tubi -produc i transport sperma n
canalele excretorii - ejaculatoare
celulele interstiiale Leydig -secret hormoni
androgeni
Reeaua de tubi - format din:
tubii seminiferi contorti
cile spermatice
Tubii seminiferi contorti - conducte sinuoase,
ncolcite, n care se desfoar spermatogeneza;
n numr de 400 - 800 n fiecare testicul
formai din:
celule germinale
celule Sertoli
Cile spermatice - continua tubii seminiferi contorti
intratesticulare
tubii contorti drepi - 20-30/testicul (se continu
cu rete testis)

extratesticulare
- ductele eferente (15-20)
+
- ductul epididimar (6-7 m)
+
- epididim (corp, cap)
+
- ductul deferent (50 cm) -pleac de la coada
epididimului, se termin la baza prostatei, unde se unete cu
- ductul excretor al veziculei seminale
+
- ductul ejaculator (2 cm) - strbate prostata, se deschide
n uretra prostatic, prin orificul ductului ejaculator

FIZIOLOGIE
Funciile testiculului:
spermatogeneza
hormonosinteza
SISTEMUL HIPOTALAMO-HIPOFIZO-
TESTICULAR

HI POTALAMUSUL
secret GnRH, un decapeptid secretat pulsatil, (8-
14 pulsuri/24 ore)
Frecvena i amplitudinea pulsaiilor este:
intrinsec, declaat de generatorul de puls situat n:
nucleul arcuat
aria preoptic
modulat, de alte regiuni ale creierului, prin ci:
catecolaminergice
- dopaminergice
- -endorfinice (efect inhibitor)


GnRH - este transportat n adenohipofiz, unde:
- acioneaz pe receptorii membranari ai celulelor
gonadotrofice
- stimuleaz sinteza de LH i FSH

LH i FSH - glicoproteine formate din 2 lanuri polipeptidice:
- lanul o - comun pentru LH, FSH, TSH, hCG
- lanul | - confer particularitile funcioonale i
imunologice
FSH - are un turn-over mai lent dect LH

hCG - are un timp de njumtire mai lung dect LH


LH acioneaz pe receptorii membranari ai celulelor
Leydig
stimuleaz sinteza andogenilor

FSH acioneaz pe receptorii membranari ai celulelor
Sertoli
stimuleaz sinteza de:
- aromataz
- proteine de transport pentru androgeni
rol n controlul spermatogenezei
rol indirect n hormonosintez, prin cretere numrului de
receptori LH ai celulelor Leydig



Secreia de GnRH i de FSH i LH
- reglat prin feed-back negativ de steroizi testiculari

Reglarea secreiei de LH
- la nivelul hipotalamusului
- feed-back negativ exercitat de T,DHT i E
2

- la nivelul SNC
- testosteronul + activitatea generatorului de puls
hipotalamic, determinnd + frecvenei plusurilor de LH

- la nivelul hipofizei

_
-

feed-back negativ al testosteronului

Reglarea secreiei de FSH

- inhibina
secretat de celulele Sertoli
aciune supresoare asupra secreiei de FSH
asemntoare structural cu TGF | i MIH
- activina
dimer al unei subuniti | a inhibinei
stimuleaz eliberarea de FSH
HORMONOSINTEZA TESTICULARA
Hormonii testiculari sunt:
testosteronul (T), principalul produs
dihidrotestosteronul (DHT)
androstendionul (A)
estradiolul - E
2
- cantiti foarte mici
17 HO progesteronul, progesteronul, pregnenolonul -
cantiti extrem de mici
+ inhibina, activina, h. antimullerian (h. proteici)
Precursorul hormonilor steroizi testiculari - colesterolul
sintetizat de novo
provenit din plasma prion endocitoza receptor-
mediata a LDL-colesterolului
5 reductaza
DHT
5o reductaza
Estradiol
aromataza (CYP 19)
TESTOSTERONUL
Sinteza testosteronului poate urma i calea:

pregnenolon 17 HO pregnenolon DHEA


A T


Reacia limitativ a sintezei de T
- transformarea colesterolului n pregnenolon -
sub controlul LH-ului

E
2

DHT


Valoarea maxim a testosteronului este dimineaa =
ritm circadian de secreie

Numai 25 g T este depozitat n testiculele normale

- Coninutul total de hormon:
- nlocuit de peste 200 de ori/zi, pentru a
asigura media de 6 mg T /zi n plasm la un brbat
normal

Reglarea secreiei de testosteron este realizat:
LH
controlul paracrin la nivelul testiculului,
exercitat de:
- IGF 1
- IGF | i o
- EGF
- FGF
- inhibina
- interleukina 1
- TNF o
- CRH, ADH, angiotensina II



Transportul plasmatic al testosteronului
Testosteronul circul:
predominant legat de proteine plasmatice
- albumine 54%
- TeGB (SHBG) 44% - sex hormone binding globuline
2% liber

Albumina
- afinitate de 1000 de ori mai mic pentru T
dect SHBG;
- concentraia n snge mult mai mare dect
cea a SHBG
Ipoteza conform creia T liber ar fi fracia activ
biologic, ce intr n celul i interacioneaz cu
receptorii este perimat.

Astzi se cunoate c disocierea T de albumine se
poate produce i n capilare

fracia activ a T > fracia liber msurat
(aproximativ 1/2 din T plasmatic)
SHBG - este o | globulin
Reglarea sintezei hepatice de SHBG:
+ estrogenii
- insulina
testosteronul
GH

Femeile au valori plasmatice de 2 -3 ori > de SHBG,
comparativ cu brbaii

METABOLISMUL EXTRAGLANDULAR AL
TESTOSTERONULUI
Reprezentat de:

aromatizare, cu formare de E
2

aciunea 5 o reductazei, cu formare de DHT
aciunea 17 | HSD, cu formare de 17 CS
hidroxilare, conjugare, cu formare de dioli,
trioli, conjugai
E
2
(producie zilnic de 45 g/zi):
37,7% provine din aromatizarea T circulant
48,8% provine E
1

13,3% provine direct din testicul

Aromatizarea T i E
2
are loc n esutul
adipos
crete proporional cu creterea greutii i
cu naintarea n vrst




DHT (are o potent dubl fa de T)
- Exist 2 izoenzime de 5 o reductaz
- tip I - n cantiti crescute n:
- glandele sebacee
- ficat
Gena specific localizat la nivelul cromozomului 5
- tip 2 - n cantiti crescute n:
- tractul urogenital masculin
- pielea genital
- ficat
- prezent n tractul urogenital precoce, avnd rol n
masculinizarea OGE
Gena specific localizat la nivelul cromozomului 2

- tip 2 - n cantiti crescute n:
- tractul urogenital masculin
- pielea genital
- ficat

- prezent n tractul urogenital precoce, avnd rol
n masculinizarea OGE
Gena specific localizat la nivelul
cromozomului 2

Reglarea 5 o reductazei - realizat de:
- androgeni (cu aciune stimulatoare)
- factori genetici

ACIUNILE ANDROGENILOR
1. Formarea fenotipului masculin:
sexualizarea OGI i OGE n viaa intrauterin
promovarea caracterelor sexuale secundare masculin
saltul statural pubertar
2. Iniierea i meninerea spermatogenezei
3. Dezvoltarea i meninerea n funcie a veziculelor
seminale, a glandelor bulbo-uretrale i a prostatei
4. Controlul comportamentului sexual i al potentei
5. Stimuleaz secreia glandelor sebacee
6. Stimuleaz secreia de proteine (rol anabolizant proteic)
7. Rol n reglarea secreiei de gonadotropi




Receptorii hormonilor androgeni :

- sunt receptori citoplasmatici, comuni pentru
T i DHT
- complexul hormon-receptor - transportat n
nucleu
- receptorul este codat de o gen situat n
braul lung al cromozomului X
- exist numeroase similitudini cu receptorii
pentru progesteron, cortizol, aldosteron
SPERMATOGENEZA
Cuprinde 3 procese:

- multiplicarea celulelor germinale
- reducerea nr. de cromozomi de la un set diploid la
un set haploid (meioza)
- formarea une suprastructuri, ce permite:
motilitatea
generarea de energie necesar motilitii
protecia ncrcturii cromozomiale
mpotriva agresiunilor din mediul
nconjurtor
Spermatogeneza:
- ncepe din luna a 2-a a vieii intrauterine,
cnd n fiecare testicul exist 3 x 10
5
celule
germinale (spermatogonii)

la pubertate exist 6 x 10
8
spermatogonii/testicul

dup pubertate, proliferarea celular este masiv;
se produc zilnic 10
8
spermatozoizi (peste un
trilion pn la btrnee) - spermatogeneza nu
nceteaz complet niciodat



~ 70 zile
Spermatogonia 1
+ +
Spermatocit primar 16
+ meioza +
Spermatocit secundar 32
+ meioza +
Spermatida 64
+ +
Spermatozoid 64
Durata spermatogenezei - aproximativ 70 zile
Transportul spermei - prin epididim, pn la
canalul ejaculator este de 12 - 21 zile
Este asigurat de :
micrile peristaltice ale ductelor spermatice
fluidul de secreie
motilitatea intrinsec a spermei
Spermatozoizii prsesc testiculul cnd sunt nc
imaturi i au o capacitate sczut de fetilizare
n timpul pasajului prin epididim sufer procesul de
maturare, care se completeaz n tractul genital
feminin


spermatogeneza - nu se produce la hipofizectomizai
restaurarea sau iniierea sa n perioada pubertar
necesit LH i FSH

FSH -
- acioneaz direct pe tubii spermatogenetici
- are receptori pe spermatogonii

acioneaz pe celulele Sertoli, stimulnd:
maturarea lor
dezvoltarea jonciunilor strnse ntre celulele
Sertoli

- secreia de androgen-binding protein:
- transferina
- inhibina
- aromataza
- activatori ai plasminogenului
- captarea glucozei i transformarea glucozei n lactat





LH - influeneaz spermatogeneza indirect, prin
stimularea sintezei de T n celulele Leydig

T - are receptori pe:
- celulele Sertoli
- celulele Leydig
- celulele mioide peritubare
Ali factori:
- acid retinoic
- factori de cretere i citokine
Dup hipofizectomie, restaurarea spermatogenezei
necesit FSH i hCG

Meninerea spermatogenezei dup restaurare,
necesit doar hCG

FSH-ul este deci esenial pentru iniierea, dar nu i
meninerea spermatogenezei
INVESTIGAII N PATOLOGIA GONADIC
I. FUNCIA TESTICULAR
A. FUNCIA CELULELOR LEYDIG

1. EXAMENUL CLINIC I ANAMNESTIC

Urmrete:
- anormaliti la natere
- momentul i gradul maturrii sexuale
- rata de cretere a barbii
- libidoul
- aspectul scheletului
- tipografia esutului adipos

2. DOZRI HORMONALE
- LH plasmatic
- testosteron plasmatic
- testosteron plasmatic liber
- dihidrotestosteron (DHT) plasmatic
- 17 CS urinari
- testul de stimulare a LH cu GnRH
- testul de stimulare a testosteronului cu hCG
B. FUNCIA TUBILOR SEMINIFERI
1. EXAMENUL CLINIC AL TESTICULELOR

- se realizeaz n ortostatism
- diametrul longitudinal - prepubertar 2 cm
- postpubertar, 4, 6 cm
-volumul testicular - prepubertar 2 ml
- postpubertar, 12 - 15 ml
2. SPERMOGRAMA
- exploreaz funcia tubular a testiculului
- se recolteaz dup 3 - 5 zile de repaus sexual
- fluidul seminal se analizeaz la 30 - max
60 dup recoltare
Caracteristicile fluidului seminal:
- volumul - N = 2 - 6 ml =normospermie
+ = parvispermie
0 = aspermie
| = multispermie
- Aspectul:
- N: opalescent, lactascent
- dens
- apos, transparent
- Aspecte patologice: - mucos
- glbui
- roz-brun
- pH-ul - N: uor alcalin (7 - 8,7)
-Numrul de spermatozoizi/ml
N: 60 - 120 milioane/ml
polizoospermie > 120 milioane/ml
oligospermie < 30 milioane/ml
azoospermie - secretorie
- excretorie
Motilitatea spermatozoizilor
N: 60-90% din spermatozoizi sunt mobili la
o or dup recoltare
- anormal: astenospermie
akinezie
- necrospermie
- Morfologia spermatozoizilor:
- N: 80 - 85% din spermatozoizi au forma
normal
- anormal - teratospermie

- Leucocite, celulele epiteliale - sunt n mod
normal s 2%
3. TESTUL DE PENETRAIE A MUCUSULUI
CERVICAL
- se utilizeaz mucus cervical bovin introdus
ntr-un tub capilar
- sperma penetreaz >15 mm n 90

4. BIOPSIA TESTICULAR
- indicat la brbaii cu:
- infertilitate, azoospermie i FSH plamatic normal
- infertilitate, azoospermie, i FSH plasmatic crescut
5. DOZAREA FSH-ului PLASMATIC
- valorile crescute indic leziuni ale epiteliului
germinal
6. INVESTIGAII CROMOZOMIALE
a) testul Barr
b) corpusculul F
c) Cariotipul
HIPOGONADISMUL
MASCULIN
ALGORITMUL DE DIAGNOSTIC AL HIPOGONADISMULUI
SIMPTOMATOLOGIA
HIPOGONADISMULUI
MASCULIN
DEFICITUL DE ANDROGENI SI
MANIFESTARILE CLINICE IN
FUNCTIE DE MOMENTUL
APARITIEI DEFICITULUI
FETAL ANDROGEN DEFICIENCY
Symptoms Signs
Ambiguous genitalia
Ambiguous genitalia (47,XY DSD)
Normal female genitalia
Microphallus (resembling clitoromegaly)
Pseudovaginal perineoscrotal hypospadias
Bifid scrotum
Cryptorchidism
PREPUBERTAL ANDROGEN DEFICIENCY
Symptoms Signs
Delayed puberty Eunuchoidism
Lack of sexual interest or desire (libido) Infantile genitalia
Reduced nighttime or morning spontaneous erections Small testes
Breast enlargement and tenderness Lack of male hair pattern growth, no acne
Reduced motivation and initiative Disproportionately long arms and legs relative to height
Diminished strength and physical performance Pubertal fat distribution
No ejaculate or ejaculation (spermarche) Poorly developed muscle mass
Inability to father children (infertility)
High-pitched voice
Reduced peak bone mass, osteopenia or osteoporosis
Gynecomastia
Small prostate gland
Aspermia, severe oligozoospermia or azoospermia
ADULT ANDROGEN DEFICIENCY
Symptoms Signs
Incomplete sexual development Eunuchoidism
Lack of sexual interest or desire (libido) Small or shrinking testes
Reduced nighttime or morning spontaneous
erections
Loss of male hair (axillary and pubic hair)
Breast enlargement and tenderness Gynecomastia
Inability to father children (infertility)
Aspermia or azoospermia or severe
oligozoospermia
Height loss, history of minimal-trauma fracture
Low bone mineral density (osteopenia or
osteoporosis)
Hot flushes, sweats
Height loss, minimal-trauma or vertebral
compression fracture
Reduced shaving frequency Unexplained reduction in prostate size or PSA
Less Specific Symptoms Less Specific Signs
Decreased energy, vitality
Mild normocytic, normochromic anemia (normal
female range)
Decreased motivation, self-confidence Depressed mood, mild depression or dysthymia
Feeling sad or blue, irritability Reduced muscle bulk and strength
Weakness, decreased physical or work
performance
Increased body fat or body mass index
Poor concentration and memory
Fine facial skin wrinkling (lateral to orbits and
mouth)
Cause Examples
BRAIN DISORDERS
Psychogenic disorders
Stress or preoccupation, performance anxiety, depression,
major psychiatric illness
Chronic systemic illness Heart, respiratory, kidney, or liver failure; cancer
CNS-active drugs
Alcohol; antihypertensive, narcotic, sedative-hypnotic,
anticonvulsant, antidepressant, antipsychotic medications
Structural brain disease
Temporal lobe or limbic system disorders, Parkinson's or
other neurodegenerative brain disease, vascular brain
disorders
Androgen deficiency Primary and secondary hypogonadism
Other endocrine disorders
Hyperprolactinemia, Cushing's syndrome,
hyperthyroidism, hypothyroidism
SPINAL CORD AND PERIPHERAL DISORDERS
Spinal cord disorders
Trauma, vascular compromise, spinal stenosis, epidural
abscess, tumor, transverse myelitis, multiple sclerosis,
other spinal cord lesions
Peripheral nerve disorders
Diabetes mellitus; pelvic, prostate, or retroperitoneal
surgery or damage; other causes of peripheral neuropathy
PNS-active drugs
Anticholinergic, antihistamine, antidepressant,
sympathomimetic, -adrenergic agonist, -adrenergic
antagonist medications
Peripheral vascular disease
Aorto-iliac atherosclerosis, diabetes mellitus, trauma,
surgery, vasculitis, venous incompetence (venous leakage),
smoking
Antihypertensive drugs
Diuretics, - and -adrenergic antagonists, ACE inhibitors,
calcium channel antagonists
Penile abnormalities
Peyronie's disease, chordee, micropenis, trauma, priapism,
phimosis
Causes of Hypoactive Sexual Desire Disorder and Erectile Dysfunction
Cause Examples
PHYSIOLOGIC CAUSES
Maternal estrogen exposure Neonatal gynecomastia
Transient increase in estrogen to androgen concentrations Pubertal gynecomastia
ESTROGEN EXCESS
Estrogens or estrogen receptor agonists
Estrogens, marijuana smoke, digitoxin, testosterone or other
aromatizable androgens
Increased peripheral aromatase activity Obesity, aging, familial
Estrogen-secreting tumors Adrenal carcinoma, Leydig or Sertoli cell tumor
hCG-secreting tumors Germ cell, lung, hepatic carcinoma
hCG treatment
ANDROGEN DEFICIENCY OR RESISTANCE
Androgen deficiency Primary of secondary hypogonadism
Hyperprolactinemia causing androgen deficiency
Androgen resistance disorders Congenital and acquired androgen resistance
Drugs that interfere with androgen action
Spironolactone, androgen receptor antagonists, marijuana, 5-
reductase inhibitors, histamine 2 receptor antagonists
SYSTEMIC DISORDERS
Organ failure Hepatic cirrhosis, chronic kidney disease
Endocrine disorders
Hyperthyroidism, acromegaly, growth hormone treatment,
Cushing's syndrome
Nutritional disorders
Refeeding, recovery from chronic illness (hemodialysis, insulin,
isoniazid, antituberculous medications, HAART)
IDIOPATHIC CAUSES
Drugs Adultonset idiopathic gynecomastia
HAART, calcium channel antagonists, amiodarone,
antidepressants (SSRIs, taricyclic antidepressants), alcohol,
amphetamines, penicillamine, sulindac, phenytoin, omeprazole,
theophylline
Persistent prepubertal macromastia
Causes of Gynecomastia
Cause Examples
HYPOGONADISM
Isolated impairment of sperm production or function
Androgen deficiency and impaired sperm production
Androgen resistance
DISORDERS OF SPERM TRANSPORT
Genital tract obstruction
Congenital bilateral absence of the vas deferens, cystic fibrosis, other
congenital defects, vasectomy, postinfectious fibrosis, Young
syndrome
Accessory gland dysfunction
Androgen deficiency or resistance, infection or inflammation, anti-
sperm antibodies (immunologic)
Sympathetic nervous system dysfunction
Autonomic neuropathy, sympatholytic drugs, sympathectomy,
retroperitoneal or abdominopelvic surgery, spinal cord injury or
disease, vasovasostomy
EJACULATORY DYSFUNCTION
Premature or retarded ejaculation
Retrograde ejaculation
Prostatectomy, bladder neck surgery, autonomic neuropathy, SNS
dysfunction
Reduced ejaculation
Androgen deficiency or resistance, SNS dysfunction, ureteral
abnormalities
COITAL DISORDERS
Erectile dysfunction
Defects in coital technique
Infrequent intercourse, excessive intercourse or masturbation, poor
timing in relation to ovulation, premature withdrawal of penis
Causes of Male Infertility
Common Causes Uncommon Causes
ANDROGEN DEFICIENCY AND IMPAIRMENT OF SPERM PRODUCTION
Congenital or Developmental Disorders
Klinefelter's syndrome (XXY) and variants Myotonic dystrophy
Uncorrected cryptorchidism
Noonan syndrome
Bilateral congenital anorchia
Polyglandular autoimmune syndrome
Testosterone biosynthetic enzyme defects
CAH (testicular adrenal rest tumors)
Complex genetic syndromes
Down syndrome
LH receptor mutation
Acquired Disorders
Bilateral surgical castration or trauma Orchitis
Drugs (spironolactone, ketoconazole, alcohol, chemotherapy agents)
Ionizing radiation
Systemic Disorders
Chronic liver disease (hepatic cirrhosis)* Malignancy (lymphoma, testicular cancer)
Chronic kidney disease* Sickle cell disease*
Aging* Spinal cord injury
Vasculitis (polyarteritis)
Infiltrative disease (amyloidosis, leukemia)
ISOLATED IMPAIRMENT OF SPERM PRDUCTION OR FUNCTION
Congenital or Developmental Disorders
Cryptorchidism Myotonic dystrophy
Varicocele Sertoli cellonly syndrome
Y chromosome microdeletions Primary ciliary dyskinesia
Down syndrome
FSH receptor mutation
Acquired Disorders
Orchitis Environmental toxins
Ionizing radiation
Chemotherapy agents
Thermal trauma
Systemic Disorders
Acute febrile illness Spinal cord injury
Malignancy (testicular cancer, Hodgkin's disease)*
Idiopathic azoospermia or oligozoospermia
of Primary Hypogonadism
Common Causes Uncommon Causes
ANDROGEN DEFICIENCY AND IMPAIRMENT OF SPERM PRODUCTION
Congenital or Developmental Disorders
Constitutional delayed puberty IHH and variants
Hemochromatosis IHH
Kallmann's syndrome
Congenital adrenal hypoplasia
Isolated LH deficiency, LH mutations
Complex genetic syndromes
Acquired Disorders
Hyperprolactinemia
Opiates
Androgenic anabolic steroids, progestins, estrogen excess
GnRH agonist or antagonist
Hypopituitarism
Pituitary or hypothalamic tumor
Surgical hypophysectomy, pituitary or cranial irradiation
Vascular compromise, traumatic brain injury
Granulomatous or infiltrative disease
Infection
Pituitary stalk disease
Lymphocytic hypophysitis
Systemic Disorders
Glucocorticoid excess (Cushing's syndrome)* Chronic systemic illness*
Chronic organ failure* Spinal cord injury
Chronic liver disease (hepatic cirrhosis), chronic kidney disease,
chronic lung disease, chronic heart failure
Transfusion-related iron overload (-thalassemia)
Chronic systemic illness* Sickle cell disease
Diabetes mellitus Cystic fibrosis
Malignancy
Rheumatic disease (rheumatoid arthritis)
HIV disease
Starvation,* malnutrition,* eating disorders, endurance exercise
Morbid obesity, obstructive sleep apnea
Acute and critical illness
Aging*
Secondary Hypogonadism





Imbunatateste functia sexuala, restaureaza
libidoul, corecteaza disfunctia erectila




Creste masa musculara si forta musculara,
perfomanta fizica




Creste densitatea osoasa, reduce riscul de
fracturi





Amelioreaza energia, vitalitatea tonusul psihic
si motivatia






Creste hematocritul in intervalul normal pentru
adult






Restabileste cresterea parului de tip masculin

Tinta tratamentului substitutiv cu Testosteron
TRATAMENTUL SUBSTITUTIV AL
HIPOGONADISMULUI MASCULIN
PRIMAR: DERIVATI DE TESTOSTERON
SECUNDAR: - rFSH / rLH (HMG/HCG)*
TERTIAR: GnRH pulsatil / Clomifen citrat*


* numai pentru inductia spermatogenezei
Preparate de testosteron

Testosterone enanthate or cypionate, IM injections Adults:
150-200 mg IM every 2 wk or 75-100 mg IM every
wk.Prepubertal boys: 50-100 mg monthly or 25-50 mg every
2 wk, increasing to 50-100 mg every 2 wk and then to adult
replacement dosage over 2-4 yr OR until spontaneous
pubertal development occurs


Parenteral testosterone undecanoate Nebido - 1000 mg
IM initially and at 6 wk, then 1000 mg IM every 10-14 wk
DIAGRAMELE
SCHEMATIZATE ALE
HIPOGONADISMULUI
MASCULIN PRIMAR/
SECUNDAR/ TERTIAR/
CUATERNAR(REZISTENTA
LA ANDROGENI)