HYPOGONADISM
Chromosomal sex
(46 XY male _ 46 XX female)
gonadal 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 reactivation
nocturnal surges of LH and
FSH
Leptin, a hormone produced by
adipose cells, may play role
PUBERTY
First signs of pubertal maturation is :
-breast budding in girl
-increase in testicular
volume 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 capillaries
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 Ageing
Measuring total testosterone is unreliable
(increased SHBG )
Chronic illness
Taking medications
Free testostron
All levels of hypothalamic-pituitary-testicular
axis
Testis dysfunction
( andropause )
GnRH test
in Prepubertal period or severe GnRH
deficiency
only for secondary hypogonadism
with false positive
hCG stimulation test
in prepubertal boys
increase in testosterone indicates the
presence of testicular tissue
Spemen analyses
2 to 6 mL
sperm counts
>20 million/mL
motility
of >50%
>50% normal morphology
liquification
TESTICULAR BIOPSY
normal biopsy in azoospermic man &
normal FSH level
*
=obstruction of vas deferens,
(correctable surgically)
* for intracytoplasmic sperm injection (ICSI)
MALE HYPOGONADISM
Sperm production or Testosterone production


Hypothalamic-pituitary
Secondary = hypogonadotrophic
Gonadal
Primary = hypergonadotrophic

Androgen insensitivity
Primary or hypergonadotrophic
Testosterone & sperm count low
High FSH and LH
Sperm count is more damaged than testosterone levels
Secondary or hypogonadotrophic
Testosterone & sperm count
Low or normal FSH, LH
low
Sperm count level is proportional to testosterone levels
History
Puberty
Growth spurts
Systemic illness
Eating disorders, excessive exercise
Social and psychological problem
Decreased libido ,Erectile dysfunction,
Infertility
Osteoporosis/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 HYPOGONADISM
Congenital
• Klinefelter
• Cryptorchidism
undescended testes
• Varicocele
• anorchia
Acquired
Mumps Orchitis
Trauma
Radiation
Chemotherapy
drugs
Chronic 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 synthesis
LH receptor mutations
enzyme defects
5α-Reductase 2 deficiency
Aromatase overexpression
Disorders of androgen action
Androgen Insensitivity Syndrome
Other disorders of male reproductive tract
Persistent 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 length
Decreased facial, axillary hair
Decreased libido
Tall stature & increased leg length
= eunuchoid habitus
Gynecomastia high Breast cancer risk
Varicose veins
radiation damage
Mump
unilateral or bilateral
atrophy 6 months after acute ilness
Direct + ischemia due to edema pressure
Drugs interfere with testicular function
ketoconazole
spironolactone
marijuana
Cyclophospham
Alcohol
digitalis
inhibition testosterone synthesis
blockade of androgen action
increased estrogen
Direct inhibition of spermatogenesis
decreases testosterone
( independent of liver disease or malnutrition )
Elevated estradiol & decreased testosterone
Environmental hazards
microwaves and ultrasound
Chemical
nematocide dibromochloropropane
Cadmium
lead
Environmental
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
- Suppressing gonadotropin production.
Cirrhosis
Impaired hepatic extraction androstenedione leads
to extraglandular conversion to estrone
(gynecomastia)
suppresses LH
(Testicular atrophy)
chronic renal failure
* Androgen synthesis &sperm production decrease
*Hyperprolactinemia
(reduced clearance)
but Elevated LH due to reduced clearance
sickle cell anemia
testicular or hypothalamic-pituitary
Acute febrile illness
Sperm density decrease temporarily
Infertility in celiac disease
Androgen resistance
myotonic dystrophy
small testes
(impairment spermatogenesis , Leydig cell
function )
paraplegia
_temporary decreased
testosterone
&
spermatogenesis
_some retain capacity for erection & ejaculation
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)
obesity
Kallmann syndrome :
X-linked mutations in KAL1 gene
GnRH deficiency
anosmia , renal defects , neurologic abnormalities
OBESITY
SHBG decrease =lower total testosterone
insulin inhibits SHBG
production

higher Estradiol in obese men

hypothalamic-pituitary axis defect
DELAYED PUBERTY boys age 14
Constitutional delay of growth & puberty ( 60%)
Functional hypogonadotropic hypogonadism (20%(
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 SYNDROMES (AIS)
Resistance to action of testosterone and
DHT , 5α-reductase
X-linked mutations
•
Variable degrees of defective male
phenotypic development and
undervirilization
•
tall stature , eunuchoidal proportions
complete AIS
(testicular feminization syndrome)
•
Female phenotype
•
breast development
•
short vagina
but no uterus , because MIS production Is normal
•
scanty pubic and axillary hair
High Gonadotropins and testosterone levels
Partial AIS ( Reifenstein syndrome )
hypospadias , cryptorchidism
Gynecomastia
More severely undervirilized patients present with
clitoral enlargement and labial fusion as females.
Mild
mutations in the androgen receptor:
Azoospermia , infertility
gynecomastia
Metabolic and Other Effects
in 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 of
Osteoporotic fracture
cardiovascular disease
diabetes

Reduced wellbeing ,Depression

Reduced physical strength

Sexual dysfunction
Risks of Therapy
Effects on the prostate
Benign prostatic hypertrophy
Prostate cancer
Effect on cardiovascular risk (unknow)
HDL (depend on dose , route of administration & formulation)
haemopoiesis ,Polycythaemia
( less common with transdermal)
Effects on the liver
Only alkylated testosterone
Gynecomastia
Testicular atrophy & inhibition spermatogenesis
Early fusion of epiphisial plate
Hepatoma , pleosis hepatis
Sodium , water retention
Priapism,Acne
Contraindications for Androgen
•
presence of prostate cancer
Baseline PSA ≥ 4 ng/mL
Palpable abnormality of prostate
Severe symptoms of lower urinary tract obstruction
•
•
•
Baseline hematocrit > 52%
Severe sleep apnea
Class IV congestive heart failure
PRECOCIOUS PUBERTY
Puberty in boys before age 9
Isosexual precocity =premature sexual development
with phenotypic sex such as the development of facial
hair and phallic growth.
1- gonadotropin-dependent
2- gonadotropin-independent causes of androgen excess.
Heterosexual precocity =premature development of
feminizing features in boys, such as breast development
Gonadotrop dependent
central precocious puberty (CPP)
gonadotropin levels inappropriately elevated for age
1. Idiopathic
2. Hypothalamic hamartoma or
other lesions CNS tumor or inflammatory state
Gonadotropin independent
CAH
HCG-secreting tumor
Hormon producing tumor(adrenal ,testis)
Exogenous androgens
McCune-Albright syndrome
Familial male-limited precocious puberty
(testotoxicosis)
FAMILIAL MALE-LIMITED PRECOCIOUS PUBERTY
autosomal dominant or mutations in the LH receptor,
leading to stimulation of the cyclic AMP and testosterone
production called testotoxicosis
premature virilization in boys, growth
acceleration in early childhood, advanced bone age
followed by premature epiphyseal fusion.
Testosterone elevated and LH suppressed.
McCUNE-ALBRIGHT SYNDROME
sporadic disorder mutations in the Gsα subunit.
impair guanosine triphosphatase activity leading to
activation of adenylyl cyclase.
Like activating LH receptor mutations, stimulates
testosterone production .
- sexual precocity
- autonomy in adrenals, pituitary, and thyroid
- Café au lait spots.
- Polyostotic fibrous dysplasia is caused by activation of
parathyroid hormone receptor in bone
Heterosexual Sexual Precocity
Breast enlargement in prepubertal boys ( gynecomastia )
Familial aromatase excess
Estrogen-producing tumors in the adrenal
Sertoli cell tumors in the testis
Germ cell tumors that secrete hCG
excessive stimulation of estrogen production
Marijuana, Smoking ,Estrogen use