HYPOGONADISM
Chromosomal sex Chromosomal sex
(46 XY male _ 46 XX(46 XY male _ 46 XX femalefemale))
gonadal sexgonadal sex
phenotypic sex phenotypic sex
Increased FSH suggests damage to the seminiferous tubules low testosterone level high LH = hypergonadotropic hypogonadism
low testosterone
low or inappropriately normal LH = hypogonadotropic hypogonadism
Puberty• Sensitivity to steroid inhibition is gradually lost • GnRH reactivationreactivation• nocturnal surges of LH and FSHLeptin, a hormone produced by adipose cells, may play role
PUBERTY
First signs of pubertal maturation First signs of pubertal maturation is :is :
-breast budding in girl-breast budding in girl
-increase in testicular -increase in testicular volume in boysvolume in boys
Lab tests
Total testosterone
unbound or free testosterone (1-3%)
SHBG-bound testosterone (30-45%)
albumin-bound testosterone (50-70%)
Bioavailable testosterone:
( both free and albumin-bound
testosterone)
dissociates readily in the capillariess
low SHBG :
androgens - obesity - insulin - nephrotic syndrm - congenitaly
high SHBG :
estrogen - hyperthyroidism - chronic inflammatory dis - aging
Measuring Testosterone Levels
when total testostrone is borderline:
Calculate free testosterone from total
testosterone and SHBG
FSH, LH , prolactin , thyroid tests
Androgens and AgeingAndrogens and Ageing
Measuring total testosterone is
unreliable (increased SHBG )
Chronic illness Chronic illness
Taking medicationsTaking medications
Free testostron All levels of hypothalamic-pituitary-testicular axis Testis dysfunction ( andropause )
in Prepubertal period or severe GnRH deficiency
only for secondary hypogonadism
with false positivewith false positive
GnRH test
hCG stimulation test
in prepubertal boys
increase in testosterone indicates the presence of testicular tissue
2 to 6 mL
sperm counts >20 million/mL
motility of >50%
>50% normal morphology
liquification
Spemen analyses
* normal biopsy in azoospermic man & normal FSH level =obstruction of vas deferens, (correctable surgically)
*for intracytoplasmic sperm injection (ICSI)
TESTICULAR BIOPSY
MALE HYPOGONADISMMALE HYPOGONADISM
Sperm production or Testosterone Sperm production or Testosterone
productionproduction
Hypothalamic-pituitary Hypothalamic-pituitary Secondary = hypogonadotrophic
GonadalGonadal Primary = hypergonadotrophic
Androgen insensitivity Androgen insensitivity
Primary or hypergonadotrophicTestosterone & sperm count low High FSH and LHSperm count is more damaged than testosterone Sperm count is more damaged than testosterone
levelslevels
Secondary or hypogonadotrophicTestosterone & sperm count lowLow or normal FSH, LHSperm count level is proportional to testosterone levels
HistoryPuberty Growth spurts Systemic illnessSystemic illnessEating disorders, excessive exerciseEating disorders, excessive exerciseSocial and psychologicalSocial and psychological problemproblemDecreased libido ,Erectile dysfunction, InfertilityOsteoporosis/fractures/Asthenia
Physical examination Secondary sex characteristics hair growth (face, axilla chest , pubic )
Gynecomastia
Testicular volume Testicular size >2.5 cm indicates child entered puberty
Varicocel Phallic size, and scrotal reddening and thinning.
Height & body proportions
Eunuchoidal =arm span >2 cm greater than height (when androgen deficiency occurred before epiphyseal fusion.)
PRIMARY MALE PRIMARY MALE HYPOGONADISMHYPOGONADISM
Congenital
• Klinefelter• Cryptorchidism
undescended testes
• Varicocele
• anorchia
Acquired
Mumps Orchitis Trauma RadiationChemotherapy drugsChronic diseases
Undervirilized Males (46 XY DSD)
=Male Pseudohermaphroditism
defect in androgen production or action
Disorders of testis development True hermaphroditism (46,XY) testicular dysgenesis Disorders of androgen synthesisDisorders of androgen synthesis LH receptor mutations enzyme defects 5α-Reductase 2 deficiency Aromatase overexpression
Disorders of androgen actionAndrogen Insensitivity SyndromeOther disorders of male reproductive tractPersistent müllerian duct syndrome Isolated hypospadias Cryptorchidism
Klinefelter Syndrome
Extra X chromosome.common genotype is 47 XXY
Mosaic forms has less severe phenotype.
Klinefelter Syndrome
Small firm testes , azoospermia
Decreased penile lengthDecreased facial, axillary hairDecreased libidoTall stature & increased leg length = eunuchoid habitusGynecomastia high Breast cancer risk
Varicose veins
radiation damage
MumpMumpunilateral or bilateralunilateral or bilateralatrophy 6 months after acute ilnessatrophy 6 months after acute ilness Direct + ischemia due to edema pressure
Drugs interfere with testicular functionn ketoconazole inhibition testosterone synthesis spironolactone blockade of androgen actionmarijuana increased estrogen Cyclophospham Direct inhibition of spermatogenesis Alcohol decreases testosterone ( independent of liver disease or
malnutrition ) digitalis Elevated estradiol & decreased
testosterone
Environmental hazards microwaves and ultrasoundmicrowaves and ultrasound
ChemicalChemical nematocide dibromochloropropane nematocide dibromochloropropane
CadmiumCadmium
lead lead
Environmental estrogens or antiandrogensEnvironmental estrogens or antiandrogens
Polyglandular autoimmune insufficiency
Sperm antibodies isolated male infertility
in some , secondary phenomena to duct obstruction or vasectomy.
Granulomatous diseases
Systemic disease- primary testis dysfunction - primary testis dysfunction - Suppressing gonadotropin production. - Suppressing gonadotropin production.
Cirrhosis Impaired hepatic extraction androstenedione Impaired hepatic extraction androstenedione
leadsleads to to extraglandular extraglandular conversion toconversion to estroneestrone
(gynecomastia)(gynecomastia)
suppresses suppresses LHLH (Testicular atrophy)(Testicular atrophy)
chronic renal failure
* * Androgen synthesis &sperm production Androgen synthesis &sperm production decrease decrease
**Hyperprolactinemia (reduced clearance)Hyperprolactinemia (reduced clearance)
but Elevated LH due to reduced clearancebut Elevated LH due to reduced clearance
sickle cell anemia testictesticular ular or or hypothalamic-pituitaryhypothalamic-pituitary
Acute febrile illness
Sperm density decrease temporarilySperm density decrease temporarily
Infertility in celiac diseaseAndrogen resistance
myotonic dystrophy small testes (impairment spermatogenesis , Leydig cell function ) paraplegia paraplegia _temporary decreased testosterone & spermatogenesis_some retain capacity for erection &
ejaculation
Secondary hypogonadism Secondary hypogonadism
Congenital
Isolated idiopathic
Kallman Syndrome
Prader-Willi , Laurence-Moon syndrome
Acquired
Pituitary tumors , Mass , Hyperprolactinemia Infiltrative diseases , Apoplexy ,Trauma
Critical and chronic illness
STRESS ,MALNUTRITION ,EXERCISE
Marijuana (decreased GnRH secretion)(decreased GnRH secretion)
obesity
Kallmann syndromeKallmann syndrome : :
X-linked mutations in KAL1 geneX-linked mutations in KAL1 gene
GnRH deficiency GnRH deficiency
anosmia , renal defects , neurologic abnormalities
OBESITYOBESITY
SHBG decrease =lower total testosteroneSHBG decrease =lower total testosterone
insulin inhibits SHBGinsulin inhibits SHBG production production
higher Estradiol in obese menhigher Estradiol in obese men
hypothalamic-pituitary axis defecthypothalamic-pituitary axis defect
DELAYED PUBERTY boys age 14boys age 14
Constitutional delay of growth & puberty ( 60%)
Functional hypogonadotropic hypogonadism ((2020%%((
systemic illness ,Chronic disease - Malnutrition,Anorexia nervosa
Hypergonadotropic hypogonadism ( 15%)
Hypogonadotropic hypogonadism ( 10%)
Constitutional delay PUBERTY+ delayed bone age and short stature :
family history
blunted responses to exogenous GnRH
diagnosis of exclusion
requires ongoing evaluation until onset of
puberty &growth spurt.
ANDROGEN INSENSITIVITY SYNDROMESANDROGEN INSENSITIVITY SYNDROMES (AIS)(AIS)
Resistance to action of testosterone Resistance to action of testosterone and and DHTDHT , , 5α-reductase5α-reductase
X-linked mutations X-linked mutations
• Variable degrees of defective male Variable degrees of defective male phenotypic development and phenotypic development and undervirilizationundervirilization
• tall stature , eunuchoidal tall stature , eunuchoidal proportionsproportions
complete complete AIS AIS (testicular feminization syndrome)
• Female phenotypeFemale phenotype
• breast developmentbreast development
• short vaginashort vagina but no uterus , because MIS production Is but no uterus , because MIS production Is
normal normal • scanty pubic and axillary hairscanty pubic and axillary hair
High Gonadotropins and testosterone High Gonadotropins and testosterone levelslevels
Partial AIS Partial AIS ( ( Reifenstein syndrome Reifenstein syndrome ) )
hypospadias , cryptorchidismhypospadias , cryptorchidism Gynecomastia Gynecomastia
More severely undervirilized patients present with More severely undervirilized patients present with clitoral enlargement and labial fusion as femalesclitoral enlargement and labial fusion as females..
MildMild mutations in the androgen receptor:mutations in the androgen receptor:
Azoospermia , infertilityAzoospermia , infertility gynecomastiagynecomastia
Metabolic and Other Effectsin androgen deficiency
• Reduced HDL , increased LDL
• Increased total body fat = viceral fat
• Impaired glucose metabolism (ins.
Resistance)
• Osteopenia , Osteoporosis
• Reduction in red cell volume
Consequences for Health
Increased risk ofIncreased risk of
Osteoporotic fractureOsteoporotic fracture
cardiovascular diseasecardiovascular disease
diabetesdiabetes
Reduced wellbeing ,DepressionReduced wellbeing ,Depression
Reduced physical strengthReduced physical strength
Sexual dysfunctionSexual dysfunction
Risks of Therapy
Effects on the prostateEffects on the prostate
Benign prostatic hypertrophyBenign prostatic hypertrophy
Prostate cancerProstate cancer
Effect on cardiovascular riskEffect on cardiovascular risk (unknow)(unknow)
HDLHDL (depend on dose , route of administration & formulation(depend on dose , route of administration & formulation))
haemopoiesis ,Polycythaemiahaemopoiesis ,Polycythaemia
( less common with ( less common with
transdermal)transdermal)
Effects on the liver Effects on the liver Only alkylated testosteroneOnly alkylated testosterone
GynecomastiaGynecomastia
Testicular atrophy & inhibitionTesticular atrophy & inhibition spermatogenesisspermatogenesis Early fusion of epiphisial plateEarly fusion of epiphisial plate
Hepatoma , pleosis hepatisHepatoma , pleosis hepatis
Sodium , water retentionSodium , water retention
Priapism,AcnePriapism,Acne
Contraindications for AndrogenContraindications for Androgen
• presence of prostate cancerpresence of prostate cancer Baseline PSA ≥ 4 ng/mL Palpable abnormality of prostate
Severe symptoms of lower urinary tract obstruction
• Baseline hematocrit > 52%Baseline hematocrit > 52%• Severe sleep apneaSevere sleep apnea• Class IV congestive heart failure Class IV congestive heart failure
PRECOCIOUS PUBERTYPRECOCIOUS PUBERTY Puberty in boys before Puberty in boys before age 9age 9
Isosexual precocity =Isosexual precocity =premature sexual premature sexual development with phenotypic sex such as the development with phenotypic sex such as the development of facial hair and phallic growth.development of facial hair and phallic growth. 1- gonadotropin-dependent 1- gonadotropin-dependent 2- gonadotropin-independent causes of androgen excess. 2- gonadotropin-independent causes of androgen excess.
Heterosexual precocityHeterosexual precocity ==premature premature development of feminizing features in boys, such development of feminizing features in boys, such as breast developmentas breast development
GonadotropGonadotrop dependentdependent
centralcentral precocious puberty (CPP)precocious puberty (CPP) gonadotropin levels inappropriatelygonadotropin levels inappropriately elevated elevated forfor ageage
1.1. Idiopathic Idiopathic 2.2. HypothalamicHypothalamic hamartoma orhamartoma or other other lesions CNS tumor or inflammatory lesions CNS tumor or inflammatory statestate
Gonadotropin independent CAH CAH HCG-secreting tumor HCG-secreting tumor Hormon producing tumor( Hormon producing tumor(adrenal ,testis)adrenal ,testis) Exogenous androgens Exogenous androgens McCune-AlbrightMcCune-Albright syndromesyndrome Familial male-limited precocious puberty Familial male-limited precocious puberty ( (testotoxicosistestotoxicosis))
FAMILIAL MALE-LIMITED PRECOCIOUS PUBERTYFAMILIAL MALE-LIMITED PRECOCIOUS PUBERTY
autosomal autosomal dominantdominant or or mutationmutations in the LH s in the LH receptor, receptor, leading to stimulation of the cyclic AMP and leading to stimulation of the cyclic AMP and testosterone productiontestosterone production calledcalled testotoxicosistestotoxicosis
premature virilization in boys,premature virilization in boys, growthgrowthacceleration in early childhood, advanced bone acceleration in early childhood, advanced bone age followed by premature epiphyseal fusion. age followed by premature epiphyseal fusion.
Testosterone elevated and LH suppressedTestosterone elevated and LH suppressed..
McCUNE-ALBRIGHT SYNDROMEMcCUNE-ALBRIGHT SYNDROME
sporadic disorder sporadic disorder mutationmutations in the Gss in the Gsαα subunit. subunit. impair guanosine triphosphatase activity leading impair guanosine triphosphatase activity leading to activation of adenylyl cyclase. to activation of adenylyl cyclase. Like activating LH receptor mutations, stimulates Like activating LH receptor mutations, stimulates testosterone productiontestosterone production ..
-- sexualsexual precocityprecocity - autonomy in adrenals, pituitary, and thyroid - autonomy in adrenals, pituitary, and thyroid - Café au lait spots.- Café au lait spots.- Polyostotic fibrous dysplasia is caused by - Polyostotic fibrous dysplasia is caused by activation of parathyroid hormone receptor in activation of parathyroid hormone receptor in bonebone
Heterosexual Sexual PrecocityHeterosexual Sexual PrecocityBreast enlargement in prepubertal boys ( gynecomastia )( gynecomastia )
Familial aromatase excess Familial aromatase excess
Estrogen-producing tumors in the adrenal Estrogen-producing tumors in the adrenal
SertoliSertoli cell cell tumors tumors in in thethe testis testis
Germ cell tumors thatGerm cell tumors that secrete hCGsecrete hCG excessive stimulation of estrogen excessive stimulation of estrogen
productionproduction Marijuana,Marijuana, Smoking ,Estrogen useSmoking ,Estrogen use