Rabih Hijazi, MD, FACP, FACEConsultant EndocrinologistCleveland Clinic Abu Dhabi

October 7, 2017

Objectives

Provide an overview of male hypogonadism in adults

Raise awareness of a growing and related healthproblem commonly seen in clinical practice

Alert clinicians of potential pitfalls in the evaluationand management of male hypogonadism using clinicalvignettes

Disclosure

No conflicts

Case Presentation

27-year old male presents with complaints of fatigue, reduced physical strength, and decreased libido over the past two months

He is otherwise healthy and denies taking any medications

Case Presentation

BMI is 26 kg/m2

Normal breast exam, no goiter

Muscular man

Normal axillary and pubic hair

Normal sense of smell

12 cc soft testes bilaterally (normal average 18 cc)

Case Presentation

CBC, Metabolic panel, Cortisol, TSH, and Free T4 all normal

Total morning fasting Testosterone levels low at

5.5 nmol/l and 6.9 nmol/l (normal 11-35)

LH 1.6 IU/L (normal 2-11)

FSH 1.1 IU/L (normal 2-11)

Does our patient have hypogonadism?

Definition

Hypogonadism in adult men is a clinical syndrome characterized by decline of one or both primary functions of the testes: sperm and testosterone production

This occurs when there is dysfunction in the hypothalamic-pituitary-testicular axis

Physiology

The testes contain two anatomical units: the seminiferous tubules composed of germ cells and Sertoli cells, and the interstitium, containing Leydig cells

Testosterone is derived from cholesterol and synthesized primarily in the Leydig cells

Role of Androgens in Men

Promotion of sexual maturation at puberty and its maintenance thereafter

Increase in lean body mass and decrease in fat mass

Regulate secretion of gonadotropins

Initiation and maintenance of spermatogenesis

Androgens in Men

Binds directly to the androgen receptor (AR)

In certain tissues that expresses 5-alpha-reductase (prostate, external genitalia, and sexual hair), testosterone (T) is converted to DHT which binds more avidly to AR

Testosterone also requires conversion to estradiol by aromatase (found in brain, liver, and adipose tissues) for much of its action on the bones

H-P-T Axis

The amount of testosterone synthesized is regulated by the hypothalamic–pituitary–testicular axis (through a feedback mechanism)

Inhibin B, a glycoprotein produced by the germ cells, inhibits GnRH-stimulated FSH release

Inhibin B, Testosterone, and FSH are all required for normal spermatogenesis

What is the typical clinical presentation of hypogonadism?

Clinical Presentation

The main presenting symptoms in adulthood are:

Loss or reduction of libido

Fatigue

Erectile dysfunction

Reduced physical strength

Clinical Presentation Decreased muscle mass and body hair may not occur

for years

Hot flashes occur only when the degree of hypogonadism is severe

Gynecomastia, tender or not, and infertility are more likely to occur in primary than secondary hypogonadism

Signs and symptoms may be nonspecific, or overlap with symptoms of other common conditions such as aging or depression

Who should be screened for hypogonadism?

Screening for hypogonadismUniversal screening is not recommended or cost-effective

Screen in individuals with:

Sexual symptoms Infertility Diseases of the sellar region Osteoporosis HIV-associated weight loss Severe COPD ESRD Medications that alter testosterone levels (e.g.

glucocorticoids or opioids)

How should we evaluate these patients?

Initial Assessment Comprehensive evaluation is key

History should focus on current symptoms, information about possible causes of hypogonadism, medications, and developmental milestones of sexual development

Physical examination should look whether the patient has normal genitalia and is normally virilized. If either is abnormal, look for clues as to whether hypogonadism is primary or secondary and if it began before or after puberty

Diagnosis

Based on two low fasting serum total testosterone concentrations between 8 and 10 AM in the presence of signs and symptoms of male hypogonadism

Evaluation should not be made during periods of acute illness as these patients will have a transient functional secondary hypogonadism

Free or bioavailable Testosterone

Approximately 2 percent of plasma testosterone is free or unbound, 44 percent is bound to SHBG, and 54 percent is loosely bound to albumin and other proteins

The term bioavailable testosterone refers to the sum of free testosterone plus albumin-bound testosterone

This represents the fraction of circulating testosterone that readily enters cells and better reflects the bioactivity of testosterone

Free or bioavailable Testosterone

Recommended in men in whom total testosterone concentrations are near the lower limit of normal and alterations of SHBG are suspected e.g. older men, obesity, diabetes mellitus, chronic illness, or thyroid disease

Evaluation

If diagnosis is confirmed, serum LH and FSH should be measured to distinguish primary and secondary hypogonadism

Classification Primary hypogonadism occurs when the serum

testosterone concentration and/or the sperm count are below normal and the serum luteinizing hormone (LH) and/or follicle stimulating hormone (FSH) concentrations are above normal

Secondary hypogonadism occurs when the serum testosterone concentration and/or the sperm count are subnormal and the serum LH and/or FSH concentrations are normal or low

Does our patient have primary or secondary hypogonadism and what additional tests are

needed?

Case Presentation

CBC, Metabolic panel, Cortisol, TSH, and Free T4 all normal

Total morning fasting Testosterone levels low at

5.5 nmol/l and 6.9 nmol/l (normal 11-35)

LH 1.6 IU/L (normal 2-11)

FSH 1.1 IU/L (normal 2-11)

Case Presentation

Iron studies and Prolactin were normal

Seminal fluid analysis: 8 million sperm/ml (normal >14 million sperm/ml)

MRI of Pituitary is normal

What is the cause of secondary hypogonadism in our patient?

Case Presentation

The patient is a recreational athlete (bodybuilder)

He admits on his second visit that he has been using chronically androgenic steroids (AS)

He stopped androgens when he recently got engaged as he was concerned about its effects on infertility and sperm count

How should we manage our patient?

Challenges Individuals using AS are unlikely to seek treatment

Most think that they know more about it than clinicians

They are unlikely to tell their physicians about its use until a trusting relationship has been built

Clinicians should educate their patients about the potential harms of these agents

Pope HG Jr, et al. Endocr Rev 2014; 35:341

Kanayama G, et al. Drug Alcohol Depend 2010; 109:6

Potential Side effects of AS ? CV safety Low HDL, high LDL ? Risk of thrombosis as it activates hemostatic system Erythrocytosis and risk of hyper viscosity syndrome Aggressive or even criminal behavior Low sperm count Gynecomastia Infection Tendon rupture ? Risk of BPH/Prostate cancer Hepatic side effects like peliosis hepatis and cholestatic

jaundice

Other challenges

Stopping AS is very challenging as many struggle with body image disorders and prolonged hypogonadal symptoms from the suppression of the hypothalamic-pituitary-testicular axis

Gonadotropin and testosterone secretion usually recovers in a few months

Sperm count returns to normal within four months but may take more than a year

Younger men tend to recover faster than older men Hcg or Clomiphene has been used to hasten this process but

there is no evidence that either does so

Rahnema CD, et al. Fertil Steril 2014; 101:1271Knuth UA, et al. Fertil Steril 1989; 52:1041Gazvani MR, et al. Hum Reprod 1997; 12:1706

How common is this problem?

Scope of the problem More common in men than women

Higher among recreational athletes than professional athletes

Average age of onset of use is in the early 20

By region, rate is highest in the Middle East (22%) compared to the rest of the world (2 to 5%)

One retrospective study found that 21% of men presenting for TRT in clinical practice had previously taken these drugs

Coward RM, et al. J Urol 2013; 190:2200

Sagoe D, et al. Ann Epidemiol 2014; 24:383

Ip EJ, et al. Pharmacotherapy 2011; 31:757

Patterns of use AS are most often obtained from the internet

Some users obtain drugs intended for veterinary purposes or from laboratories that are not regulated

The most common AS used are testosterone, trenbolone, stanozolol, nandrolone, and boldenone (a veterinary steroid)

Some are taken by injection (like testosterone esters) while others are taken orally (17 alpha alkylated androgens like stanozolol)

SARM are novel non steroidal oral molecules (Andarine)

Starcevic B, et al. Drug Test Anal 2013; 5:377

Patterns of use

Suppliers often provide AS in “packages” that contain a additional medications:

Growth hormone- Additional anabolic effect

Hcg or Clomiphene- To recover H-P-G axis and increase testicular size during the “off cycle” period

Aromatase inhibitor/SERM-To counteract gynecomastia

5-alpha reductase inhibitor- To prevent balding and acne

Diuretics- To promote water lossHandelsman DJ, et al. JCEM 2006; 91:1646

Handelsman DJ, et al. Br J Pharmacol 2008; 154:598

Evans-Brown M, et al. BMJ 2014; 348:1476

Summary (1)

Comprehensive history and physical examination is key in evaluating patients with hypogonadism

The evaluation should always include a detailed list of medications used (past and current)

Laboratory and imaging tests are needed to confirm the diagnosis and to determine its etiology

Summary (2) Use of androgenic steroids (AS) is a common problem

among young men and recreational athletes

Clinicians should form a therapeutic alliance with their patients and educate them about the potential harms of these agents

Discontinuation of AS can prove to be challenging as many patients struggle with body image disorders and prolonged hypogonadal symptoms from the suppression of the H-P-T axis

Spontaneous recovery will take several months. Clomiphene or Hcg have been used to accelerate the process

Clinical Vignettes

1. A 26-year old firefighter presents for evaluation of gynecomastia and low Testosterone.

His past medical history is unremarkable and he is on no medications.

Physical exam: Height 188 cm

Breasts 4 cm non tender gynecomastia bilaterally

Skin scant facial and body hair

2 cc hard testes bilaterally

Total Morning Testosterone 12 nmol/L (normal 11-35), FSH 27 IU/L (normal 2-11), LH 10 IU/L

(normal 2-11). TSH and Prolactin were normal.

Which of the following tests will most likely lead to a diagnosis?

a- 17-OH Progesterone

b- Testicular biopsy

c- FSH receptor analysis

d- Karyotype

e- MRI of sella

1. A 32-year old pharmacist presents for evaluation of low Testosterone. He is complaining

of decreasing energy and libido associated with worsening hand arthralgias over the past

several years. He is otherwise healthy and denies taking any medications. He is divorced

and has an 8-year old girl from his first marriage.

Physical exam: BMI 29

Breasts and skin are normal

Normal secondary sexual characteristics

12 cc testes bilaterally

Total Morning Testosterone 9.2 nmol/l (normal 11-35), LH 1.6 IU/L (normal 2-11), FSH 1.1 IU/L

(normal 2-11). TSH, Free T4, and Prolactin were normal.

Sellar CT is normal and X ray of the hands reveals chondrocalcinosis of the small joints

bilaterally.

Which of the following tests will most likely lead to a diagnosis?

a- Urine screen for opiates

b- 24-hour urine free cortisol

c- Serum iron studies

d- GnRH stimulation test

e- Sellar MRI

1. A 36-year old police officer complains of decreased libido and breast tenderness for 6

months. He is otherwise healthy and is a father of a 6-year old boy. He denies taking any

medications including testosterone or anabolic steroids.

Physical exam: BMI 24 and Vital signs were normal

Well virilized and muscular

Breasts 6 cm tender gynecomastia bilaterally

10 cc right test and 12 cc left testis

Total Morning Testosterone 7 nmol/L (normal 11-35), FSH 1.0 IU/L (normal 2-11), LH 1.0 IU/L

(normal 2-11), estradiol 560 pmol/L (normal 37-220), serum hCG undetectable, Prolactin normal.

Which of the following test will most likely lead to a diagnosis?

a- Scrotal ultrasound

b- MRI of the sella

c- Abdominal and pelvic CT

d- TSH

e- Screen for anabolic steroid abuse

Thank you!

Thank you!