Hypogonadism:

Diagnosis & Testosterone Replacement

Therapy

dr. Adi Santosa Maliki, SpAnd(K)

 Testosterone for Life
• Testosterone is essential for Men’s
Body, Mind and Sexual Function.

• Symptoms associated with

hypogonadism may cause significant
reduction of patients’ quality-of-life.

• Testosterone Replacement Therapy

indicated progressive improvement
of HRQoL.

The Aging Male, 2012; 15(4): 198–207

Hypothalamic–Pituitary–Testicular Axis

Bagatell CJ, Bremner WJ. N Eng J Med 1996; 334: 707-714.

Griffin JE & Wilson JD. In Williams Text book of Endocrinology. 2003: 709-753.
Testosterone
• Metabolism
– Primarily by the liver • Major androgen in man
– Two active metabolites • 95% synthesized by Leydig
cells, from cholesterol
• Secreted into the
bloodstream
Testosterone 5 alpha-reductase • Necessary for
– fetal male sexual
differentiation
aromatase – puberty
– maintenance of
Dihydrotestosterone secondary male sex
(DHT) characteristics

Estradiol
M:male
F: female
Endogenous Testosterone
Sex Hormone
Usual distribution in the blood Binding Globulin
(SHBG)
45%

Albumin and
Free Testosterone
other Proteins
<4%
50%

Bioavailable Testosterone

Total testosterone : 300 - 1,000 ng/dL (10.4 – 41.6 nmol/L)

Free testosterone : 50 - 210 pg/mL (1.7 – 166.7 nmol/L)
Serum testosterone levels a day (Circadian Rhythm )
in men

MMESOR = midline estimate statistic of rhythm, defined as the rhythm-adjusted mean or the average
value of the rhythmic function fitted to the data. * A significant difference between the young and older
mean total testosterone was shown at three sampling times: 06:00, 07:00 and 07:30.

Reference: Diver MJ, Imtiaz KE, Ahmad AM, Vora JP, Fraser WD. Diurnal rhythms of serum
total, free and bioavailable testosterone and of SHBG in middle-aged men compared with
those in young men. Clin Endocrinol (Oxf). 2003; 58: 710-717.
 Organs and tissues throughout the
male body that affected by Testosterone
Physiologic effects of androgens
Sexual differentiation:

Figure from Molina PE. Male Reproductive System. In: Raff H, Levitzky M, eds. Medical
Physiology: A Systems Approach: The McGraw-Hill Companies; 2011: 683-694.
Physiologic effects of androgens
Puberty:
– Triggered by:
•  pulsatile secretion of GnRH   serum gonadotropins   testosterone production by
Leydig cells

– Associated physiologic changes:

• initiation of spermatogenesis
• testes and penis enlargement
• pubic, facial, extremities hair growth
• prostate, seminal vesicle, epididymis growth
• larynx enlargement, vocal cord thickening, deepening of voice
• increased linear growth
• increased muscle mass, haematocrit
• increased libido and sexual potency

References: Molina PE. Male Reproductive System. In: Raff H, Levitzky M, eds. Medical Physiology: A Systems Approach: The McGraw-Hill Companies;
2011: 683-694. Figure from Koeppen BM, Stanton BA, Berne RM. Berne and Levy Physiology. 6th ed. London: Mosby; 2008.
 Physiologic effects of androgens
Sexual maturity:
– sperm production optimal, most sexual anatomic changes completed
– testosterone and DHT required for:
• maintenance of reproductive tissues
• maintenance of male secondary sex characteristics

– testosterone has major effects on:

• libido and erectile function
• muscle mass and strength
• fat distribution
• bone mass
• erythropoiesis
• skin and hair
– testosterone may also enhance:
• general metabolism
• mood
• sense of well-being
References: 1. Molina PE. Male Reproductive System. In: Raff H, Levitzky M, eds. Medical Physiology: A Systems Approach: The McGraw-Hill Companies; 2011:683-694. 2.
Griffin JE, Wilson JD. Disorders of the testes and the male reproductive tract. In: Larson PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of
Endocrinology. Philadelphia: W. B. Saunders; 2003: 709-769. 3. Bagatell CJ, Bremner WJ. Androgens in men--uses and abuses. N Engl J Med. 1996; 334: 707-714. Figure
from Koeppen BM, Stanton BA, Berne RM. Berne and Levy Physiology. 6th ed. London: Mosby; 2008.
 Age-related Decline in Testosterone Level
(Hypogonadism or Hypoandrogenism in male)

Testosterone levels in adult male begins to

decline at an average of 1.25% per year.
Surampudi PN, Wang C, Swerdloff R. Hypogonadism in the aging male
diagnosis, potential benefits, and risks of testosterone replacement therapy.
Int J Endocrinol. 2012; 2012:625434
 Age-specific prevalence of hypogonadism in men:
Results from the HIM study

Mulligan T, Frick MF et al. Int J Clin Pract. 2006; 60:762-769.

Hypogonadism: Classification
Primary hypogonadism Late-onset
- Abnormality is in the testes hypogonadism/Andropause
– defined as “hypogonadism in a
male who has had normal
Secondary hypogonadism pubertal development and as a
- Abnormality lies above the level of the testes result developed normal male
secondary sex characteristics”
– often either secondary or mixed
Mixed hypogonadism hypogonadism
- Defects in the testes and the hypothalamic-
pituitary axis

References: Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes:
an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 2536-2559. Figure from Pantalone KM,
Faiman C. Male hypogonadism: more than just a low testosterone. Cleve Clin J Med. 2012; 79: 717-725.
 Secondary
Primary Hypogonadism Hypogonadism
• Low testosterone levels • Decreased gonadotropin
• Impairment of stimulation of potentially
spermatogenesis normal testes
• Elevated gonadotropin • Low testosterone levels
level • Low or low-normal
(Hypergonadotropic) gonadotropin levels
: High LH, FSH (Hypogonadotropic) : normal
• Also known as Primary or Low LH, FSH
Testiculare Failure (PTF) • Impairment of
spermatogenesis

Bagatell CJ, Bremner WJ. N Eng J Med 1996; 334: 707-714.

Griffin JE & Wilson JD. In Williams Text book of Endocrinology. 2003: 709-753.
Primary Hypogonadism

Causes of Primary Male Hypogonadism

Genetic: Kleinefelter (XXY) Testicular trauma

Enzymatic: 5α-reductase deficiency Bilateral torsion

Myotonic muscular dystrophy Orchidectomy

Cryptorchidism Toxic exposure

Orchitis Chemotherapy, radiation

Autoimmune disease Malnutrition

Bagatell CJ, Bremner WJ. N Eng J Med 1996; 334: 707-714.

Plymate S. In Androgens in Health and Disease. 2003: 45-75.
Secondary Hypogonadism

Causes of Secondary Male Hypogonadism

Genetic: Kallmann Syndrome Hypothyroidism

Prader-Willi syndrome Hyperprolactemia

Pituitary tumors Cirrhosis

Suprasellar tumors Hemochromatosis

Hypothalamic, pituitary lesions Massive obesity

Bagatell CJ, Bremner WJ. N Eng J Med 1996; 334: 707-714.

Plymate S. In Androgens in Health and Disease. 2003: 45-75.
Mixed Hypogonadism
• Combined defects in the
Causes of Mixed Male testes and the
Hypogonadism hypothalamic-pituitary
Severe systemic axis
Aging
illness
Occupational • Low testosterone levels
Cirrhosis
exposure
HIV / AIDS Medications • Variable gonadotropin
Sickle cell disease Alcohol levels
Uremia
• Impairment of
spermatogenesis

Bagatell CJ, Bremner WJ. N Eng J Med 1996; 334: 707-714.

Plymate S. In Androgens in Health and Disease. 2003: 45-75.
 Hypogonadism: Signs and symptoms

• Incomplete or delayed sexual development, eunuchoidism

• Reduced libido, decreased spontaneous erections
• Breast discomfort, gynaecomastia
• Loss of body hair, reduced shaving More specific
• Very small or shrinking testes
• Low or zero sperm count
• Height loss, low trauma fracture, low bone mineral density
• Hot flushes, sweats

• Decreased energy/motivation
• Depressed mood
• Poor concentration and memory
• Sleep disturbance, increased sleepiness Less specific
• Mild anaemia
• Reduced muscle bulk and strength
• Increased body fat, body mass index
• Diminished physical or work performance

Reference: Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society
clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 2536-2559.
Hypogonadism: Symptoms

Reference: Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic

risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006; 91: 4335-4343.
Hypogonadism: Laboratory Evaluation

• Hypogonadism is characterized by repeatedly low serum testosterone concentrations.

• Measurement of serum testosterone concentration requires consideration:2

– types/forms of testosterone to be measured
– time of measurement
– frequency of measurement

• Three different forms of testosterone can be measured: total testosterone, free testosterone,
bioavailable testosterone.1
– Most circulating testosterone is bound to SHBG (44%) and to albumin (54%), with only 0.5-3% being unbound or
‘free’.
– Bioavailable testosterone = free testosterone + albumin-bound testosterone.
– Total testosterone concentrations are affected by changes in SHBG concentrations.
– When total testosterone concentrations are near the lower limit of the normal range and alterations of SHBG are
suspected, measurement of free testosterone or bioavailable testosterone is indicated.

References:
1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an
Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 2536-2559.
2. Surampudi PN, Wang C, Swerdloff R. Hypogonadism in the aging male diagnosis, potential benefits, and risks of
testosterone replacement therapy. Int J Endocrinol. 2012; 2012:625434.
Hypogonadism: Diagnosis

• The 2010 Endocrine Society Guideline

and the 2012 EAU Guideline recommend
that the diagnosis of hypogonadism be
based on:
– the identification of signs and symptoms
suggestive of testosterone deficiency, and
– the presence of low testosterone levels
measured by a reliable assay on two or
more occasions

References: Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in

men with androgen deficiency syndromes: an Endocrine Society clinical practice
guideline. J Clin Endocrinol Metab 2010; 95: 2536-2559. Dohle GR, Arver S,
Bettocchi C, Kliesch S, Punab M, de Ronde W. Guidelines on Male
Hypogonadism. Arnhem, The Netherlands: EAU Guidelines Office; 2012.
Hypogonadism Management Diagram

Lunenfeld B, Arver S, Moncada I, Rees DA, Schulte HM. How to help the aging male? Current
approaches to hypogonadism in primary care. Aging Male. 2012;15:187-197.
Hypogonadism: Co-morbidities

• Epidemiological studies support associations of low serum testosterone with co-morbidities,

including:1,2,3,4
– the metabolic syndrome
• increased central abdominal obesity
• elevated triglycerides
• reduced HDL
• high blood pressure
• increased fasting glucose, hyperinsulinaemia
– obesity
– type 2 diabetes
– increased cardiovascular disease risk
– erectile dysfunction
• Low testosterone levels reported in up to 20% of men with symptomatic vertebral fractures
and 50% of elderly men with hip fractures. 5

References: 1. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract.
2006; 60: 762-769. 2. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010; 363: 123-135. 3.
Wang C, Jackson G, Jones TH, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk
in men with type 2 diabetes. Diabetes Care. 2011; 34: 1669-1675. 4. Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes,
cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation. 2007; 116:
2694-2701. 5. Francis RM. The effects of testosterone on osteoporosis in men. Clin Endocrinol (Oxf). 1999; 50: 411-414.
Hypogonadism and Co-morbidities

Insulin Resistance Obesity

Metabolic
Diabetes Hypogonadism
Syndrome

Erectile
Dysfunction

Figure adapted from Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2
diabetes and insulin resistance. J Androl. 2009; 30: 23-32.
 
 High Prevalence of Low Testosterone
Percentage in Men with Co-morbidities (HIM Study)

Mulligan T, Frick MF et al. Int J Clin Pract. 2006; 60:762-769.

Testosterone Therapy

• Major goal
= to alleviate the symptoms of hypogonadism by restoring serum testosterone levels to
normal physiologic levels, with a minimum of adverse effects

• Optimally, testosterone therapy should:

– raise circulating testosterone levels to normal physiologic ranges
– provide a daily release of testosterone that is similar to normal endogenous production
– reproduce testosterone fluctuations that match the circadian rhythm
– deliver serum testosterone that can be converted at tissue level to its metabolites at the
desired concentrations
– have little or no negative effects on the prostate, liver, lipid profile, or cardiovascular
system
– represent a convenient treatment option

Reference: Giagulli VA, Triggiani V, Corona G, et al. Evidence-based medicine update on

testosterone replacement therapy (TRT) in male hypogonadism: focus on new formulations.
Curr Pharm Des. 2011; 17: 1500-1511.
 TESTOSTERONE THERAPHY
DELIVERY SYSTEMS
• Trans-dermal: adequate T level, no
First-pass effect through the liver
1. Gels
2. Patches
3. Pellets
4. Buccal
• Orals
• Intra Muscular Injection
Drug Interactions of Testosterone
• Drugs which decrease levels of testosterone levels:
– Phenobarbital and Dilantin (seizure medicines)
– Rifampin
– Alcohol!

• Drugs which increase levels of testosterone:

– Serzone, Prozac, Paxil (antidepressants)
– Sporanox, Diflucan (antifungals)
– Tagamet
– Biaxin, Zithromax (antibiotics)
– Protease Inhibitors (HIV treatment)

• Testosterone can also alter the effects of other drugs:

– Increase the blood thinning effect of Coumadin
– Decreases the effectiveness of Inderal (propranolol) a blood-pressure medicine
– Increases the effect of some oral medicines for diabetes and can cause
dangerously low blood sugar levels
Desirable Attributes of TRT
Desirable Attributes Gel IM Oral

Bio-identical Yes No No

High Efficacy Yes Yes No

Short Duration/Flexible Dosing Yes No Yes

Strict to Normal Physiologic Range Yes No No

Mimics Circadian Rhythm of Testosterone Yes No Yes

Self-Administration Yes No Yes

Adapted from U.S. PHARMACIST December 2011

Therapeutic potential of testosterone gels. Aging Health (2009) 5(3), 227-245
 Profile of Androgel 1%
• AndroGel® 1% is a testosterone in the form of clear and colorless
ointment like supplies

• AndroGel® 1% provides a conducting effect testosterone in a

transdermal manner continuously in 24 hours within granting a
single application.

• Keep at temperatue below 30oC

• Avoid from the children

How to Use Androgel 1%
Effects of AndroGel® 1% on increasing
testosterone levels
?

Kebiri kimia?
NOO!!!!
RELATIVE
CONTRAINDICATIONS: CONTRAINDICATIONS:
• PSA >4.0 or accelerated • Prostate CA
>0.75 • Breast CA
• Hb/Hc> 18/55 • Untreated prolactinoma
• Sleep Apnea
• Cardiac, Hepatic, Renal
Disease
Also for the long
term evaluation!!
Benefits of Testosterone Therapy

• Improved body composition1

– increased lean body mass
– increased muscle strength
– decreased fat mass

• Improvement in bone mineral density1

• Improved sexual function1
– increased libido
– improved erectile function

• Improved mood, sense of well-being1

• Improvement in MetS parameters2
–  fasting plasma glucose
–  insulin sensitivity
–  triglycerides
–  waist circumference

• Improved Quality of Life3,4

References: 1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J
Clin Endocrinol Metab 2010; 95: 2536-2559. 2. Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med. 2011; 8: 272-
283. 3. Behre HM, Tammela TL, Arver S, et al. A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in
men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. Aging Male. 2012;
15: 198-207. 4. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in
intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010; 95: 639-650.
Androgel 1% and Sexual Functions
Improvement
Androgel 1% and Mood Improvement
Androgel 1% and Body Composition (lean
body vs fat mass)
Hypogonadism: Summary

• The prevalence of hypogonadism in men increases with age

• There is an increased risk of hypogonadism in association with common medical conditions

such as obesity, type 2 diabetes, and hypertension1
– a strong relationship has been observed between hypogonadism and the metabolic syndrome

• If left untreated, hypogonadism can compromise the sexual function, body composition,
cardiometabolic profile, and healthy aging of men2

• At present, symptomatic hypogonadism is frequently undiagnosed and left untreated

– in the UK, Germany, France, Italy, Russia, and Australia, < 2% of hypogonadal men over 50 years receive
treatment3

• Testosterone therapy alleviates many of the symptoms of testosterone deficiency in

hypogonadal men4
– resulting in improved physical health, mental health, and sexual function

References: 1.Traish AM, Miner MM, Morgentaler A, Zitzmann M. Testosterone deficiency. Am J Med. 2011; 124: 578-587. 2. Giagulli VA, Triggiani V, Corona
G, et al. Evidence-based medicine update on testosterone replacement therapy (TRT) in male hypogonadism: focus on new formulations. Curr Pharm Des.
2011; 17: 1500-1511. 3. Carruthers M. Time for international action on treating testosterone deficiency syndrome. Aging Male. 2009; 12: 21-28. 4. Bhasin S,
Basaria S. Diagnosis and treatment of hypogonadism in men. Best Pract Res Clin Endocrinol Metab. 2011; 25: 251-270.
THANK YOU

AVOID
THIS !!!
!
Curriculum Vitae
Nama: dr Adi Santosa Maliki SpAnd(K)
Tempat/tgl lahir: Bogor, 9 Desember
Status: Menikah
Agama: Islam
Alamat: Jalan Sukanegara 36 Antapani Bandung
Riwayat Pendidikan dan Pekerjaan:
- Dokter Umum: FKUI lulus 2002
- Dokter Triase RSUPN Cipto Mangunkusumo 2003
- Staf Pendidik: FKIK UIN 2008
- Spesialis Andrologi: FK UNAIR 2013
- Pengukuhan Konsultan Seksologi dan Anti Aging
Medicine: 2019
- Staf Departemen Ilmu Kedokteran Dasar FK
UNPAD: sekarang
- Dokter praktek RSIA Limijati Bandung dan RS
Melinda 2/Morula IVF Melinda Bandung: sekarang