Iman Z.

Ahmed –MD

Professor of Endocrinology and Diabetes

Ain Shams University
• It is a common, but frequently unrecognized
and undiagnosed condition

• Can occur at all stages of life from infancy

to old age.

• Adversely affect multiple organ functions

and quality of life (QoL)
Epidemiology:

• The prevalence ranged from 2.1% to 12.8%

of middle-aged to older men.

• Prevalence increase in : older men,

obesity, or co-morbidities,
Epidemiology ....... Conti,

Approximately 10–12% of men with hypogonadism

were receiving testosterone treatment.

This may be the result of

-underdiagnosis of the disease,
-lack of awareness by patients or physicians,
- irregularities surrounding the diagnostic criteria,
- deficiency of long-term safety studies.
Objectives

 Basics
 Step by step diagnosis approach
 Step by step treatment approach
 Monitoring and follow up
So why is testosterone so important?
Role of testosterone for male health
 Development of male reproductive organs (intrauterine)
 Puberty
 male fertility
 male sexual function
 muscle formation
 body composition
 bone mineralization
 fat metabolism
 cognitive functions .
 Circulating testosterone

1. Mostly bound to SHBG (~60%)

2. Bioavailable testosterone:
 Weakly bound to albumin (~ 40%)
 Free testosterone (2%)
 Case 1
A 48-year-old man is referred for evaluation of decreased
libido and energy for the past 6 months. He denies
head or testicular trauma. He is married but does not
have any children. His medical history is notable for
hyperlipidemia for 6 years (controlled on atorvastatin
40 mg daily) and chronic lower back pain for 15
months for which he is on fentanyl 50 mcg patch.

On physical examination, the patient is normally virilized.

His visual fields are normal on confrontation. There is
no gynecomastia. He has normal external genitalia
and both testes are 20 mL.
Laboratory Results:
Total testosterone (morning) = 98 ng/dL

LH = 1.5 IU/L ,

FSH = 2.3 IU/L

Prl = 15 ng/mL

TSH = 1.1 mIU/L ,

FT4 = 1.2 ng/dL

S. cortisol = 17.4 μg/dL

Iron saturation and Pituitary MRI are normal.

Q: Which one of the following is responsible for
the patient’s hypogonadism?

A- Atorvastatin

B- Klinefelter’s syndrome

C- Congenital isolated hypogonadotropic

hypogonadism

D- Fentanyl
 Most common causes of male hypogonadism
Primary Hypogonadism Secondary Hypogonadism
ORGANIC
KS ,Cryptorchidism, Hypothalamic/pituitary tumor
myotonic dystrophy, anorchia Iron overload syndromes
Some types of cancer chemotherapy, Infiltrative/destructive disease of
testicular irradiation/damage, hypothalamus/pituitary
orchidectomy ,Orchitis Idiopathic hypogonadotropic hypogonadism
Testicular trauma, torsion
Advanced age
FUNCTIONAL
Medications (androgen synthesis Hyperprolactinemia
inhibitors) Opioids, anabolic steroid use,
End-stage renal disease glucocorticoids, Alcohol and
marijuana abuse
Systemic illness Nutritional
deficiency/excessive exercise
Severe obesity, some sleep disorders
Organ failure (liver, heart, and lung)a
Comorbid illness associated with aging
CLINICAL FEATURES

Depend on:
1. age of onset
2. severity of testosterone deficiency
3. decrease testosterone production and/or
sperm production.
1. Time of onset
First trimester 
 Ambiguous genitalia in a male at birth

Third trimester:
 A history of micropenis.
 A history of bilateral cryptorchidism is usually associated
with diminished spermatogenesis and sometimes with
low testosterone in adulthood.

Prepubertal: (during first decade)

 Failure to undergo or complete puberty.
Adult :
Within days to weeks:
decrease in energy and libido

Several years:
sexual hair, muscle mass, and bone mineral density

2. Severe deficiency
may cause a more rapid decline.

3. Decreased testosterone and/or sperm

production
Infertility……… etc
 Diagnosis
Hypogonadism is a common condition which
is unrecognised and undiagnosed

The diagnosis is based upon the presence of

BOTH
1. Signs and symptoms of male hypogonadism
2. Unequivocally low serum total testosterone
concentrations
- between 8 and 10 AM
- at least two occasions
 Symptoms/Signs of AD in Men

 Incomplete sexual development, eunuchoidism

  libido,  Spontaneous erections
 Breast discomfort, gynecomastia
  Body hair (axillary & pubic),  shaving
 Very small or shrinking testes (esp < 5 ml)
 Infertility
  Height, low-trauma fracture, low BMD
  Muscle bulk & strength
 Hot flushes, sweats
Less Specific Symptoms/Signs of AD
  energy, motivation, initiative,
aggressiveness, self-confidence
 Feeling sad or depressed mood
 Poor concentration and memory
 Sleep disturbance, increased sleepiness
 Mild anemia
 Increased body fat, BMI
 Diminished physical or work performance
Screening?

 The Endocrine Society, 2018

recommends against screening for
androgen deficiency in the general
population.
Candidates for evaluation:
• Diseases of the sellar region,
• Medications that affect testosterone production
• HIV -associated weight loss
• ESRD and maintenance hemodialysis
• Moderate to severe chronic obstructive lung disease
• Infertility
• Osteoporosis or low-trauma fracture, especially
in a young man
• Type 2 diabetes mellitus
Men with acute or subacute illness should not
be assessed for hypogonadism,

Reason ?
 The ADAM Questionnaire
1.  Do you have a decrease in libido (sex drive)?
2.  Do you have a lack of energy?
3.  Do you have a decrease in strength and/or endurance?
4.  Have you lost height?
5.  Have you noticed a decreased "enjoyment of life?"
6.  Are you sad and/or grumpy?
7.  Are your erections less strong?
8.  Have you noticed a recent deterioration in your ability to
play sports?
9.  Are you falling asleep after dinner?
10.  Has there been a recent deterioration in your work
performance?
If you answered YES to questions 1 or 7 or any 3 other
questions, you may have low testosterone.
**Adapted from Morley JE, et al. Validation of a screening questionnaire for androgen deficiency in aging
males. Metabolism. 2000;49(9):1239-1242.
Step-by-step diagnostic approach

1. Screen and document hypogonadism

2. Level

3. cause
 Coffee slide
 Case 2
 A 55-year-old man is referred for evaluation of
increasing fatigue for the past 15 months. He also
reports morning headaches and daytime somnolence.
He recently saw his primary provider who checked
total testosterone level that was 284 ng/dL. He has
normal libido. His medical history is only significant for
hypertension that is treated with hydrochlorothiazide.
He is married and has 3 children.
 On physical examination, the patient is obese.
No moon face or facial plethora are noted. His
BMI is 37.4 kg/m2. His visual fields are normal.
Acanthosis nigricans is present on the back of
the neck and in the axillae. Thin pinkish
abdominal striae are present. His testes are 20
mL bilaterally. Proximal muscle strength is
normal.
Laboratory Results:
 Total testosterone (AM) = 290 ng/dL (mass
spectrometry)
 FBG = 110 mg/dL
 S. Cortisol = 15.6 ug/dl
 Hematocrit = 42.6%
Q: Measurement of which of the following
should be the next diagnostic step?

A- Iron saturation
B- Gonadotropins
C- Free testosterone
D- Prolactin
1.Screen and document hypogonadism

 Serum total testosterone

PRECAUTIONS RESULT
•Check between 6 a.m.- 8 < 300 ng/dl
a.m. (up to 11 a.m.) Twice
•Fasting

•Not during acute or

subacute illness
 When to measure FT or SHBG ?
A- Conditions that are associated with
decreased SHBG concentrations
• Obesity, DM, IR, hypothyroidism or acromegaly
• Use of glucocorticoids, some progestins, and
androgenic steroids
• Nephrotic syndrome
• Polymorphisms in the SHBG gene
B. Conditions associated with increased
SHBG concentrations

• Aging, Use of some anticonvulsants or

Use of estrogens
• HIV disease, cirrhosis or hepatitis
• Hyperthyroidism
• Polymorphisms in the SHBG gene
C. Total testosterone concentrations
equivocal or in the borderline zone
around the lower limit of the normal
range (e.g., 200-400 ng/dL)
• serum free testosterone and SHBG

Test precautions Result

Free •Same as Total < 5 ng/dl

testosterone testosterone

SHBG 10-57 nmol/L

The calculated free testosterone (using serum SHBG

and an online calculator) is a more accepted approach
due to laboratory inaccuracies for serum
free testosterone.
• serum bioavailable testosterone
The ammonium sulfate precipitation method should be
used if possible, although this may not be available in all
centers.
:

<70 ng/dl = hypogonadism

•
2. Level of hypogonadism:
• serum LH/FSH

3. Cause
. serum prolactin
• Serum Fe, TIBC, and ferritin
• Pituitary hormones
• MRI pituitary:
- Micro or macro-adenoma
- Empty sella or partially empty sella
- Parasellar mass
Semen analysis
Check if fertility is an issue.

Genetic testing
• Karyotype check for Klinefelter syndrome (47XXY,
46XY/47XXY) if azoospermia and small testes detected.

• Evaluate for Y-chromosome microdeletions if severe

oligozoospermia.

• Genetic analysis for KAL-1 gene

  Serum TSH
hypothyroidism can result in hyperprolactinemia

 Dual-energy X-ray absorptiometry (DEXA )

Long-term suppressed levels of testosterone

Step by step treatment approach

• The principal goal of androgen

replacement therapy is to restore a
physiologic pattern of androgen exposure
to all tissues

• Fertility
 Case 3
• A 25 yrs old man with history of CHH
is transferring endocrine care to your
practice. He was diagnosed at age
15 yrs when he demonstrated no
signs of pubertal development.
  At that time, his testicular volumes
were 5 mL each and had a normal
sense of smell. Genetic testing
revealed a mutation in the GNRHR
gene.

 Puberty was induced with GnRH

therapy, which he received for several
years. Then started i.m testosterone
injection
 The patient is married, has normal
libido ,erectile function and has no
gynecomastia. somewhat bothered by
changes in his mood several days before
his scheduled testosterone injection.

 He is curious to whether he is fertile but

does not desire children in the next few
years.
 His only current medication is
testosterone cypionate 150mg i.m /2
weeks
 O/E: BP 110/67 mm/Hg, Ht 180cm, Wt
77.3kg . Testes are 8ml bilaterally
without masses and well virilized

 Labs:
Testosterone level 7 days after injection
405 ng/dl
Which of the following would you
recommend next?
a) Obtain a baseline semen analysis
b) Increase the dose of testosterone cypionate
c) Reassess his reproductive axis after
stopping testosterone for 4 months
d) Switch to transdermal testosterone
e) Switch to hCG therapy
 For future fertility
, Suppression of spermatogenesis !!!

. Alternative therapy
 Human chorionic gonadotropin
 Clomiphine citrate,
 Aromatase inhibitors
 SERM
 combination
Choice of testosterone regimen
Who should not receive testosterone
therapy?
Contraindications to use 
• Men planning fertility in the near term
• Prostate cancer or breast cancer
• palpable prostate nodule or induration,
• PSA level > 4 ng/mL, or > 3 ng/mL combined with a high risk
of prostate cancer
• Severe Lower urinary tract symptoms (BPH)
• Erythrocytosis, Thrombophilia
• Sleep apnea that is severe and untreated.
• Uncontrolled heart failure , or Cardiovascular event …..
Testosterone for the Following Reasons
May be Harmful

 To improve strength/athletic performance

 For physical appearance
 To prevent aging
Patients with CHH

 Testosterone?
 Reversible / Relapse ?
 Fertility?

 hCG ?
 FSH+LH?
 FSH?
 What About Older Men with age related
decline in T?
• Recommend against offering T to all older men
(>65) with low T in the absence of symptoms
and conditions of Androgen deficiency

• Treat men with consistently unequivocal low T

and clinically significant symptoms
(individualized)

• Which T cutoff should be offered ?

- Depends on the severity of symptoms
- T<300 Vs T<200
Testosterone preparations
Copyrights apply
Copyrights apply
Copyrights apply
• Oral preparations 
- 17-alpha alkylated androgens (eg, methyltestosterone)
- May be not fully effective in producing virilization,
- side effects mainly hepatic :
. cholestatic jaundice,
. a hepatic cystic disease called peliosis hepatis,
.hepatoma

17-alpha alkylated androgens should generally not be

used to treat testosterone deficiency.
 Oral:

- Testosterone undecanoate 40mg

- Dose: 40 to 80 mg twice daily

- Disadv:

.gastrointestinal side effects

.does not keep the serum T conc normal

 Oral:

- Testosterone undecanoate 40mg cap

- Dose: 40 to 80 mg twice daily after food

- Disadvantages:

.gastrointestinal side effects

.does not keep the serum testosterone conc.
normal in hypogonadal men
Copyrights apply
Long-acting injections, continuation 

Pharmakokinetic profile:
Rise to supraphysiologic range, then
hypogonadal range by the end of the dosing interval

Disadv:
 Fluctuation in symptoms .
 Deep IM injection,
 Excessive erythrocytosis

Advantage: .
 Effective in initiating and maintaining normal virilization
 Inexp, self administered, Flexibility of dosing
Extra long acting injection: (T undecanoate in oil)

Pharmakokinetic profile:
T conc maintained in the normal range

Advantage:
 Infrequent injection

Disadvantages:
 Deep IM of large vol 3-4 ml
 trocher is needed
 Rarely: pulmonary oil microembolism,
restricted use in USA
Transdermal patches…. Cont,

Pharmacokinetics and advantage

Restores serum T, DHT, and E2 concentrations

to the physiological male range

Disadvantages:

 Skin irritation
 transdermal gels, pumps, solutions……. Cont,

Pharmacokinetics
- T and E2 conc. to the physiological range;
- less fluctuation of T conc. than injection

Advantages:
 Ease of application,
 less erythrocytosis than injectable T

Disadvantages:
 Potential of transfer by direct skin-to-skin contact;
 T conc. may be variable from application to
application
 skin irritation (infrequent)
 Pharmacokinetics of SC implants:
Sustained in normal range for 3–6 mo,

Advantage
 Requires infrequent administration

Disadvantage:
 Requires surgical incision for insertions;
 pellets may extrude spontaneously;
 rarely, local hematoma, infection or fibrosis
 No information for optimal dosing
 Buccal, Bioadhesive T Tablet

Pharmacokinetics and advantages

- serum T, DHT, and E2 conc, in physiological male range;
- convenience and discrete

Disadvantage
 Gum-related adverse events in 16% of treated men
 Alteration in taste
 Poor adherence
• Intermediate-acting S.C. injection 
  Testosterone enanthate 50 -100 mg once a week

• levels during the intervening week in the

normal range
 Time course of effects:

First three to six months.

 Increases in fat-free mass, erythropoiesis,
energy, sexual function and prostate enlargement

Within two years

 The full effect on bone mineral density did
 Monitoring of treatment
1. Is the testosterone dose therapeutic?

2. When to measure testosterone level?

3. What is the best timing for measurement ?

4. Are there any undesirable effects?

 
1. Is the testosterone dose therapeutic?
 Symptoms and signs
 Testosterone level in the mid tertile (400-600ng/dl)
 Normalization of the serum LH , in case of primary
hypogonadism

2. When to measure testosterone level?

 Two to three months after initiation/changing dose
 When the dose is stable; every 6 to 12 months
3.What is the best timing for measuring
testosterone ?
 Long acting injections (T enanthate or cypionate)
Midway between injections

 Extra long (T undecanoate):

At the end of dosing interval aiming at low-mid range

 Oral Undecanoate:
From 3-5 hours after injestion with fat containing meal

 Transdermal gel preparations: (twice)

From 2-8 hrs after gel application
 Transdermal patches
From 3-12 hours after application

 Buccal T biadhesive tablets:

Immediately before or after application

 Subcutanuous pellets:
At the end of the dosing interval
4.Are there any undesirable effects?
Pre and post treatment evaluation
Hematocrit
Baseline, after 3-6 months then annually

If >54%  stop T until safe level

Evaluate for hypoxia and OSA

Then restart at lesser dose

Smoking cessation

Phlebotomy
DEXA
 Lumber spine and/or femoral neck
 After 1-2 yrs of T therapy in hypogonadal
men with osteoporosis
 Reevaluation for prostate cancer
after treatment:

 Age 50 years (or 40 years ….)

 Three months and one year after beginning

treatment and thereafter according
Average PSA increase after starting T
0.3 ng/ml in young men, 0.44 ng/ml in older men

When to Consult a Urologist

 PSA increase 1.4 ng/ml in 1 year
 Confirmed PSA >4.0 ng/ml
 PSA velocity >0.4 ng/ml per year
 Two consequative years,
 Ref is PSA after 6 months of T therapy

 Abnormality on DRE
 prostate symptom score of >19
Venous thromboembolism
Related or unrelated to polycythemia

-Careful personal and family VTE history

before treatment.

- ???Routine screening for thrombophilias??

 Cardiovascular risks
  - Conflicting and inconclusive evidence

- Possibility of increased cardiovascular

risk associated with testosterone use.
 Screen only symptomatic patients & high risk
populations

 Diagnosis = S&S + unequivocal consistency

low T (standardized test)

 Evaluate for the underlying cause

Primary vs. Secondary

 Options: shots, patches, pills, buccal…..

Take home message…. Cont.

 Evaluate for contraindications before

starting therapy especially for older age

 Follow up treatment and Monitor for

adverse events

 Testosterone should not be given to men

planning fertility in the near term

 Alternative therapy
 References
• Endocrine Society (ES): Clinical practice guideline on tes
tosterone therapy in men with hypogonadism
 (2018)
• American Urological Association (AUA): Guidelines for t
he evaluation and management of testosterone deficie
ncy
(2018)
• Hypogonadism in men, BMJ Best practice, (2018)
• Uptodate , last updated, (2018)
• Induction of Spermatogenesis and Fertility during
Gonadotropin Treatment of Gonadotropin-Deficient
Infertile Men: Predictors of Fertility Outcome , JCEM,
2009
• European Consensus Statement on congenital hypog
onadotropic hypogonadism—pathogenesis, diagnosis
and treatment
(2015)
• European Association of Urology (EAU): Guidelines o
n male infertility
 (updated 2016)
• Endocrine Society of Australia (ESA): Position stateme
nt on male hypogonadism (part 1) – Assessment and
indications for testosterone therapy
 (2016)
• ESA: Position statement on male hypogonadism (part
2) – Treatment and therapeutic considerations
 (2016)
• Hammersmith Endocrine Protocols ( 2017)