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

nocturnal surges of LH and FSH 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

-breast budding in girl -increase in testicular volume in boys PUBERTY First signs of pubertal maturation is : -breast budding in girl -increase in testicular volume in boys 12

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

Chronic illness Taking medications 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

2 to 6 mL sperm counts >20 million/mL motility of >50% >50% normal morphology liquification Spemen analyses

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

Primary = hypergonadotrophic Androgen insensitivity 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 Low or normal FSH, LH 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 Decreased penile length 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

Drugs interfere with testicular function radiation damage Mump unilateral or bilateral atrophy 6 months after acute ilness Direct + ischemia due to edema pressure Drugs interfere with testicular function ketoconazole inhibition testosterone synthesis spironolactone blockade of androgen action marijuana 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 ultrasound Chemical nematocide dibromochloropropane Cadmium lead Environmental estrogens or antiandrogens Polyglandular autoimmune insufficiency

Granulomatous diseases Sperm antibodies isolated male infertility in some , secondary phenomena to duct obstruction or vasectomy. Granulomatous diseases

Systemic disease Cirrhosis - 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

Sperm density decrease temporarily Infertility in celiac disease 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

High Gonadotropins and testosterone levels 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