hypogonadism chromosomal sex chromosomal sex (46 xy male _ 46 xx female ) (46 xy male _ 46 xx female...

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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

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