Wasunon Tinroongroj ,MD18 jun 2014

Outline

� regulation of hypothalamic-pituitary-testis axis

� normal male pubertal development

� definition and classification of hypogonadism

� delayed puberty

� disorders of the male reproductive axis during adulthood� Cause of secondary hypogonadism

(hypogonadotropic)

� Cause of primary hypogonadism (hypergonadotropic)

� Diagnosis and evaluation

� Testosterone therapy (contraindication, regimen, adverse effect, monitoring)

� Regulation of hypothalamic-pituitary-testis axis

normal male pubertal

development � Puberty : maturation of the reproductive axis and the

development of secondary sex characteristics

� initiated by adrenarche at 6 and 8 years of age

� The GnRH pulse generator� Inhibit by GABA, neuropeptide Y � Reactivated by GPR54, kisspeptin, leptin

� nocturnal surges of LH and FSH

� growth of the testes is the first sign � testosterone

Tanner stage

Definition

� Hypogonadism in men is a clinical

syndrome that results from failure of the

testis to produce physiological levels of

testosterone (androgen deficiency) and a

normal number of spermatozoa due to

disruption of one or more levels of the

hypothalamic-pituitary-testicular axis

classification

� Primary hypogonadism� low testosterone levels, impairment of

spermatogenesis, and elevated gonadotropin levels

� Secondary hypogonadism� low testosterone levels, impairment of

spermatogenesis, and low gonadotropin levels

� Classification due to� fertility can be restored with appropriate hormonal

stimulation in patients with secondary hypogonadism

� Uncover pituitary tumor or systemic illness

classification

� Prepubertal onset �Delayed puberty

� No secondary sex characteristics

� Enuchoid

� Arm spans > Ht 5 cm

� Decreased upper/lower segment ratio

� Postpubertal onset

� Congenital/acquired

60%

functional

hypogonadotropic

hypogonadism

(20%)

hypogonadotropic hypogonadism (10%)

hypergonadotropic hypogonadism(15%)

> 14 yr

More specific symptoms and

signs� Incomplete or delayed sexual

development,eunuchoidism

� Reduced sexual desire (libido) and activity

� Decreased spontaneous erections

� Breast discomfort, gynecomastia

� Loss of body (axillary and pubic) hair,reduced shaving

� Very small (especially < 5 ml) or shrinking testes

� Inability to father children, low/zero sperm count

� Height loss, low trauma fracture, low BMD

� Hot flushes, sweats

Orchidometry

Other less specific symptoms &

signs� Decreased energy, motivation, initiative, and

self-confidence

� Feeling sad or blue, depressed mood, dysthymia

� Poor concentration and memory

� Sleep disturbance, increased sleepiness

� Mild anemia (normochromic, normocytic, in the female range)

� Reduced muscle bulk and strength

� Increased body fat, body mass index

� Diminished physical or work performance

Cause of secondary hypogonadism

(hypogonadotropic)� Congenital

� genetic disorders associated with gonadotropin deficiency

� Kallman syndrome

� Prader-Wille syndrome

� Other mutation

� Acquired

� Severe illness, stress, malnutrition, and exercise

� Obesity

� Hyperprolactinemia

� Hemochromatosis and other infiltrative disease: sarcoidosis

� Sellar mass lesions: pituitary adenoma, craniopharyngioma, germ cell tumor

�

KALLMANN SYNDROME

� defective hypothalamic gonadotropin-releasing hormone (GnRH) synthesis

� associated with � anosmia or hyposmia due to olfactory bulb

agenesis or hypoplasia syndrome

� color blindness, optic atrophy

� nerve deafness, cleft palate

� renal abnormalities, cryptorchidism

� neurologic abnormalities such as mirror movements.

KALgene defect � prevent embryonic migration of GnRH neurons from the hypothalamic olfactory placode to the hypothalamus

Other Genetic abnormalities: GPR54 (autosomal recessive), FGFR1 (autosomal

dominant)

KALLMANN SYNDROME

� GnRH deficiency prevents progression through puberty� Males present with delayed puberty and pronounced

hypogonadal features, including micropenis

� Female patients present with primary amenorrhea and failure of secondary sexual development.

� Long-term treatment� Men: human chorionic gonadotropin (hCG) or

testosterone

� women: cyclic estrogen and progestin.

� Fertility: gonadotropins or by using a portable infusion pump to deliver subcutaneous, pulsatile GnRH

Prader-Willi syndrome

� deletions of the proximal portion of

paternally derived chromosome 15q

� Clinical feature

� obesity

� hypotonic musculature

� mental retardation

� Hypogonadism

� short stature

� small hands and feet

Laurence-Moon syndrome

� autosomal recessive

� characterized by obesity,

hypogonadism, mental retardation,

polydactyly, and retinitis pigmentosa

Obesity

� SHBG levels decrease in proportion to the degree of obesity

� lower total testosterone levels

� free testosterone levels remain within the normal range

� Estradiol levels are higher because of aromatization of testosterone to estradiol in adipose tissue

� defect in the hypothalamic-pituitary axis

Hyperprolactinemia

� PRL inhibits hypothalamic GnRH

secretion

Hemochromatosis

� suggested by the association of

� skin discoloration

� hepatic enlargement or dysfunction,

� diabetes mellitus

� Arthritis

� cardiac conduction defects

� hypogonadism

Sellar mass lesions

� Invade gonadotrope in anterior pituitary

� Invade hypothalamus � ↓ GnRH secretion

� Invade pituirary stalk � ↓ dopamine � ↑

Prolactin � ↓ GnRH secretion

Cause of primary hypogonadism

(hypergonadotropic)

� Klinefelter’s syndrome

� uncorrected cryptorchidism

� cancer chemotherapy

� radiation to the testes

� Trauma

� Testicular torsion

� infectious orchitis

� HIV infection

� anorchia syndrome

� myotonic dystrophy

Klinefelter syndrome

� characterized by small testes, infertility,

gynecomastia, eunuchoid proportions, and

poor virilization in phenotypic Males

� 47,XXY, Mosaic forms (46,XY/47,XXY)

� Hyalinized testes

Clinical feature of Klinefelter

syndrome� Small testes

� � Testes are small and firm [median length 2.5 cm (4 mL volume); almost always <3.5 cm (12 mL

� azoospermia

� decreased facial and axillary hair

� decreased libido

� tall stature & increased leg length

� decreased penile length

� increased risk of breast tumors

� thromboembolic disease

� learning difficulties

� obesity, diabetes mellitus

� varicose vein

Klinefelter syndrome

� Treatment

� Gynecomastia should be treated by surgical reduction if it causes concern

� Androgen supplementation improves virilization, libido, energy, hypofibrinolysis, and

bone mineralization

Cryptorchidism

� incomplete descent of the testis from the

abdominal cavity into the scrotum

� associated with increased risk of

malignancy and infertility

� Management: Sx if failed to descend at 1-

2 yr

Viral orchitis

� mumps virus, echovirus, lymphocytic

choriomeningitis virus, group B

arboviruses

� Orchitis occurs in as many as one-

fourth of adult men with mumps

� the orchitis is unilateral in about two-thirds

and bilateral in the remainder

radiation damage

� >200 mGy (20 rad) � increased FSH

and LH levels and damage to the

spermatogonia

� > ∼800 mGy (80 rad) � oligospermia or

azoospermia

Drug, chemiccal, environment

� Drugs interfere with testicular function by several Mechanisms� inhibition of testosterone synthesis (e.g., ketoconazole)� blockade of androgen action (e.g., spironolactone)� increased estrogen (e.g., marijuana� direct inhibition of spermatogenesis (e.g., chemotherapy).� Alcohol� Digitalis

� microwaves and ultrasound

� chemicals such as nematocide dibromochloropropane, cadmium, phthalates, and lead

Systemic illness

� Suppress testicular function

� PGA

aging-related changes in male

reproductive function

� Begin at 3rd decade of life

� defects at all levels of the hypothalamic-

pituitary-testicular axis

� Testicular dysfunction is the main cause

� gradual rise in LH

Diagnosis and evaluation

� consistent symptoms and signs and unequivocally low serum testosterone levels

� Suggest measure serum testosterone level in pts

symptom

Diagnosis and evaluation

� Initial test: morning total testosterone level

� Confirmation test: repeating measurement of (morning ) total testosterone

� free or bioavailable testosterone level … in whom� total testosterone concentrations are near the lower limit of

the normal range � alterations of SHBG

� The diagnosis of androgen deficiency should not be made during an acute illness.

Screening for androgen

deficiency� Sellar mass, radiation to the sellar region, or

other diseases of the sellar region

� Treatment with medications that affect testosterone production or metabolism �glucocorticoids and opioids

� HIV-associated wt loss

� ESRD & maintenance HD

� Moderate to severe COPD

� Infertility

� Osteoporosis or low trauma fx, esp. in a young man

� T2DM

Pituitary imaging (MRI)

� Perform to exclude pituitary and/or

hypothalamic tumor or infiltrative disease if

� severe secondary hypogonadism (serum T

150 ng/dl)

� Panhypopituitarism

� persistent hyperprolactinemia

� symptoms or signs of tumor mass effect

� headache, visual impairment, or visual field defect

are present

Dysmorphic features

� secondary hypogonadism should be examined for dysmorphic features—such as

� extreme obesity (e.g.PraderWilli syndrome)

� polydactyly, anosmia (e.g.Kallmann

syndrome)

� short stature (e.g.contiguous gene deletions of

chromosome X)

� kidney abnormalities (e.g.Kallmann syndrome)

Karyotype

� useful in excluding Klinefelter syndrome

� especially in those with testicular volume less than 6 ml

� The lower limit of the normal testosterone

range in healthy young men is

approximately 280 –300 ng/dl (9.8 –10.4

nmol/liter)

Infertility evaluation

� at least two seminal fluid analyses

� separated by an interval of several weeks

� semen samples collected within 1h of

ejaculation after at least 48 h of

abstinence.

Bone mineral density

� dual-energy x-ray absorptiometry

scanning in men with severe androgen

deficiency or low trauma fracture

Testosterone therapy

� Goal

� inducing & maintaining 2˚sex

characteristics

� improving sexual function

� sense of well-being

� bone mineral density

Contraindication of testosterone

Rx� Very high risk of serious adverse outcomes

� Breast cancer

� Metastatic prostate cancer

� Moderate to high risk of adverse outcomes

� Unevaluated prostate nodule or induration

� PSA > 4 ng/ml (> 3 ng/ml in high risk for prostate

cancer, such as African Americans, men with 1˚ relatives with prostate cancer)

Contraindication of testosterone

Rx� Moderate to high risk of adverse

outcomes

� Hct > 50%

� Untreated severe OSA

� Severe lower urinary tract symp. associated

with BPH as indicated by AUA / IPSS >19

� Uncontrolled or poorly controlled HF

� Desiring fertility

Testosterone therapy

regimens� testosterone enanthate or cypionate

� 75–100 mg IM weekly, or 150–200 mg q 2

wk

� testosterone patches

� One or two 5-mg nongenital patches

applied nightly over the skin of the back,

thigh, or upper arm, away from pressure

areas.

Testosterone therapy regimens

� testosterone gel

� 5–10 g 1% testosterone gel applied daily

over a covered area of nongenital skin

(should wash hands after application)

� bioadhesive buccal testosterone

� 30 mg of a bioadhesive buccal

testosterone tablet applied to buccal

mucosa every 12 h.

Testosterone therapy regimens

� Testosterone pellets implanted sc at intervals

3-6 months

� Oral testosterone undecanoate

� injectable testosterone undecanoate

� testosterone-in adhesive matrix patch

References

� J. Lary jameson, Harrison endocrinology

3rd edition

� Testosterone Therapy in Adult Men with

Androgen Deficiency Syndromes 2010 :

An Endocrine Society Clinical Practice

Guideline