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Male hypogonadism
Charunee
13/7/50
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Definition
A decrease in either of the two major functions of the testes: sperm production testosterone production
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Hypothalamic-Pituitary-Testis Axis
Inhibin B
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Testosterone
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Testosterone metabolism
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Testosterone
60 % - sex hormone binding globulin
38 % - albumin
cortisol binding globulin 2 % - free form
Bioavailable
Testosterone
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Testosterone function
Male sexual differentiation Secondary sex characteristic in
puberty and adult Spermatogenesis Muscle strength, Muscle volume Bone density Erythropoisis
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Androgen Deficiency Symptoms
Musculoskeletal Decreased vigour and physical energy Diminished muscle strength
Sexuality Decreased interest in sex Reduction in frequency of sexual activity Poor erectile function/arousal Loss of nocturnal erections Reduced quality of orgasm Reduced volume of ejaculate
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Androgen Deficiency Symptoms
Mood disorder and cognitive function Irritability & lethargy Decreased sense of well-being Lack of motivation Low mental energy Difficulty with short-term memory Depression Low self-esteem Insomnia Nervousness
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Androgen Deficiency Symptoms
Vasomotor and nervous Hot flushes Sweating
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Diminished muscle mass
Loss of body hair
Abdominal obesity
Gynæcomastia
Testes frequently normal, occasionally
small
Physical Signs
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Tanner staging
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Metabolic and Other Effects
Reduction in HDL and increase in LDL cholesterol
Impaired glucose metabolism
Increase in total body fat (change in lean:fat ratio)
Osteopenia
Osteoporosis
Reduction in red cell volume
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Male hypogonadism
Primary hypogonadism Testes Serum Testosterone↓, FSH & LH ↑
Secondary hypogodism Pituitary gland or Hypothalamus Serum Testosterone↓, FSH & LH ↔ , ↓
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Male hypogonadism: Onset
Prepubertal onset: Eunuchoidism Lack of adult male hair distribution
Sparse axillary, pubic hair Lack of temporal hair recession
High-pitched voice Infantile genitalia
Small penis, testes and scrotum ↑ fat deposition in pectoral, hip, thigh and lower
abdomen Eunuchoidal proportion
Arm span > Height > 5 cm Upper/ lower segment ratio < 1
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Postpubertal onset Loss of libido Impotence Infertility
Male hypogonadism: Onset
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Primary hypogonadism: Cause
Prepubertal onset Klinefelter's syndrome Other chromosomal abnormalities Mutation in the FSH and LH receptor genes Cryptorchidism Disorders of androgen biosynthesis Myotonic dystrophy Congenital anorchia Varicocele
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Klinefelter's syndrome
Most common congenital abnormality causing primary hypogonadism
Male who has an extra X chromosome Genotype
47,XXY (most common) 48,XXXY 46,XY/46,XXY mosaicism 46,XX
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Testes Hyalinization & fibrosis of seminiferous
tubule Sertoli cell → inhibin↓ → FSH ↑
Gynecomastia ↑ peripheral conversion of testosterone ↓ clearance of estradiol Intraductal hyperplasia
Klinefelter's syndrome
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Klinefelter's syndrome
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Cancer: CA breast, extragonadal germ cell tumor
Autoimmume: SLE, SS, RA Intelligent & psychology: IQ score,
development, memory, depression, psychosis
Others: DM, DVT, Pulmonary dz. (chronic bronchitis, bronchiectasis, emphysema)
Klinefelter's syndrome:Associated syndrome
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Postpubertal onset Infections — Mumps orchitis Radiation Drugs Trauma Bilateral orchiectomy Autoimmune damage Chronic systemic diseases
Cirrhosis Chronic renal failure HIV
Primary hypogonadism:Cause
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Drugs: 1° hypogonadism
↓ Leydig cell production of testosterone Corticosteroids, ethanol, ketoconazole
↓ Conversion of testosterone to DHT Finasteride
Androgen receptor blockers Spironolactone, flutamide, cimetidine
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Secondary hypogonadism:Cause
Prepubertal onset Isolated idiopathic hypogonadotropic
hypogonadism Kallmann's syndrome Idiopathic hypogonadotropic hypogonadism
associated with mental retardation Abnormal ß-subunit of LH Abnormal ß-subunit of FSH Idiopathic hypogonadotropic hypogonadism
associated with other hypothalamic pituitary hormonal deficits
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Kallmann's syndrome
Hypogonadotropic hypogonadism Sporadic (most common)
Familial; X-linked, AD, AR X-linked; deletion in KAL gene(Xp22.3)
Lack of expression of anosmin ( neural cell adhesion-like molecule )
inability of GnRH-secreting neurons, which arise in the olfactory placode early in embryogenesis, to enter the brain and occupy either the olfactory bulb or arcuate nucleus of the hypothalamus
anosmia and hypogonadotropic hypogonadism
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Hypogonadotropic hypogonadism Anosmia or hyponosmia Somatic abnormality
cleft lip, cleft palate, short metacarpal bone, pes carvus, renal agenesis, urogenital tract defect
Neurological abnormality Uncoordinated eye movement, synkinesia,
spatial attention, mental retard, sensoryneural deafness, seizure, cerebellar ataxia, red green color blinness
Kallmann's syndrome
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Genetic hypogodadotropic hypogonadal syndromes
Syndrome Clinical manifestation
Prader-Labhart-Willi hypomentia, hypotonia,short stature, Cupid’s-bow mouth, DM, obesity
Laurence-Moon Biedl retinitis pigmentosa, obesity, polydactyly, MR
Multiple lentigines multiple lentigines, cardiac defect, hypertelorism, short stature, deafness, genital and uro. defect
Rud MR, epilepsy, congenital icthyosis
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Postpubertal onset Sella or suprasellar tumor Infiltrative disease
Sarcoidosis, eosinophilic granuloma → hypothalamic hypogonad
Hemochromatosis → pituitary hypogonad Infection: meningitis Trauma Critical illness: surgery, MI, head trauma Chronic systemic illness : cirrhosis, CKD, HIV Drugs
Secondary hypogonadism:Cause
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Drugs: 2° hypogonadism
↓ Pituitary secretion of gonadotropins corticosteroids ethanol GnRH analogs estrogen, progestrins medication that raise prolactin levels
( opiate, metoclopramide )
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Investigation Serum testosterone : 8.00 AM
Free testosterone: Equilibrium dialysis Bioavailable testosterone Total testosterone
SHBG ↑ SHBG ↓ moderate obesity nephrotic syndrome hypothyroidism use of glucocorticoids, progestins, androgenic steroids
aging cirrhosis hyperthyroidism use of anticonvulsants, estrogen HIV
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Serum FSH,LH Semen analysis Others
Peripheral leukocyte karyotype Other pituitary hormones Serum prolactin Iron saturation MRI brain
Investigation
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Hx + PE
Morning Total T Normal T
Low T (< 300 ng/dL)
Exclude reversible illness, drugs, nutritional deficiency
Repeat T ( use free or bio T, if suspect altered SHBG )
LH + FSH
Confirmed low T
Low T, Low or normal FSH + LH
Secondary hypogonadism
Low T, High FSH + LH
Primary hypogonadism
Normal T, FSH + LH
Follow up
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Treatment
Testosterone replacement Rx. Underlying disease
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Testosterone replacement
Intramuscular preparations Transdermal patch Transdermal gel Oral agent Testosterone pellet Buccal testosterone tablets
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Intramuscular injection
Short-acting: Testosterone propionate
Intermediate-acting: Testosterone enanthate Testosterone cypionate
Long-acting: Testosterone undecanoate
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Testosterone enanthate
250 – 300 mg IM q 3 wk Advantage:
Relatively inexpensive Flexibility of dosing
Disadvantage: Peak and valley in serum T level
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Oral testosterone undecanoate ( Andriol )
Dose: 40-80 mg po 2-3 times daily Advantage:
Convenience Disadvantage:
Variable clinical response Variable serum T levels
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Monitoring treatment
Serum testosterone IM: Measured midway between injection Oral: Measured after intake 3-5 hr 1° hypogonad
Normalization of serum LH
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Desirable effect Normal and maintained virilization Improvement of libido Improvement of energy Improvement of muscle strength Improvement of BMD
Monitoring treatment
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AdSoS m/s
Weeks
0 50 100 150 200 250 300 350 400 450 5002000
2050
2100
2150
2200
2250
2300
2350
2400
* Testosterone Undecanoate (Nebido)
Bone Density Changes with Long-term Treatment*
Zitzmann M et al. J Sex Med 2006, 3 (Suppl. 1): 68 (Abstract).
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Undesirable effects Effects on the prostate
Benign prostatic hypertrophy
Prostate cancer
Effect on cardiovascular risk Lipids
Effect on haemopoiesis Polycythaemia
Effects on the liver
Monitoring treatment
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Androgens and BPH Hypogonadal men have small prostates
In hypogonadal men receiving testosterone
treatment, prostatic volume increases, but to no
greater volume than that of normal age-matched
controls
PSA levels rise with androgen therapy but should
remain within the reference range
Maximal increase in volume and PSA occurs by
three months and does not continue with long-
term therapy
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Androgens and Prostate Cancer There is no evidence that testosterone
treatment causes a prostate cancer
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Androgens and Cardiovascular Risk
Both androgen deficiency and androgen excess are
associated with unfavourable lipid profiles and
increased CV risk
Maintaining androgen levels in the physiological range
promotes a favourable lipid profile
Early studies have been conducted in hypogonadal
men with angina and chronic heart failure showing
benefit from normalisation of testosterone levels
More research is needed on CV risk
Pugh et al. Eur Heart J 2003, 24: 909-915.English et al. Circulation 2000, Oct 17;102(16):1906-11.
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Androgens and Polycythaemia Clinically significant polycythaemia has been
associated with androgen replacement
More common with conventional injectable (up to
44%*) therapy, where high peak plasma
concentrations are found immediately after
administration
Much less common with transdermal (8%) therapy
or long-acting injection (Nebido)
*Dobs AS, et al. J Clin Endocrinol Metab 1999, 84(10);3469-3478.
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Androgens and the Liver Only alkylated testosterone
preparations have been associated
with liver disease
Modern testosterone preparations,
either biologically identical
testosterone or testosterone esters
are NOT associated with liver disease
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Rarely Reported Side Effects Others side effects are rare
Acne
Male pattern hair loss
Hirsutism
Mood changes
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Follow up
Hct q 3 month then annually Lipid profile LFT ( if alkylated testosterone
preparations used) PSA ( if age > 50 yr )
> 4 ng/ml ↑ > 1.4 ng/ml within 12 month after Rx. ↑ > 0.4 ng/ml/yr
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Time course of effect ↑ fat-free mass, prostate volume,
erythropoiesis, energy, and sexual function within 3-6 month
Monitoring treatment
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Infertility treatment
2° hypogonad only1. GnRH pulsatile infusion
2. hCG (~ LH ) + Leydig cell → testosterone
hMG (~ FSH+LH ) + Seminiferous tubule→ spermatogenesis
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