Defining Non-Classical Primary or Secondary Hypogonadism:

Time for a Reset?

Mohit Khera, M.D., M.B.A., M.P.H.Associate Professor of Urology

Scott Department of Urology

Baylor College of Medicine

Houston, TX

GnRH

LH FSHTestosterone

Testosterone

Sperm

Hypothalamus

Pituitary

Testis

Testosterone Testing and Initiation

Layton et al. J Clin Endocrinol Metab 2014; 99(3):835-842

Diagnosis of Androgen Deficiency and Late Onset Hypogonadism (LOH)

Biochemical Signs and Symptoms

+

Diagnosing Hypogonadism Defined by 2010 Endocrine Guidelines

Prevalence of Androgen Deficiency

T = testosterone.

Mulligan T, et al. Int J Clin Pract. 2006;60(7):762-769.

Overall, 38.7% of men >45y

have T-levels<300 ng/mL

Percen

t Lo

w T

esto

stero

ne

0

10

20

30

40

50

60

>85

Patient Age Range

45 to

54

55 to

64

65 to

74

75 to

84

Results

Araujo et al., J Clin Endocrinol Metab 2007 Nov;92(11):4241-7

Pre March 3, 2015 Testosterone Label

Post March 3, 2015 Testosterone Label

LH

(U

/L)

Testosterone (nmol/L)Corona et al. J Sex Med. 2104. Jul;11(7):1823-34

Hypogonadal status in 4173ED subjects studied at the

University of Florence

LH

(U

/L) Compensated

hypogonadism

(4.1%)

Primary

hypogonadism

(2.5%)

Secondary hypogonadism

(17.3%)

LH

= 9

.4 U

/L

Eugonadism

(76.1%)

Testosterone (nmol/L)

Corona et al. J Sex Med. 2104. Jul;11(7):1823-34

Hypogonadal status in 4173ED subjects studied at the

University of Florence

Unknown

Secondary

Primary

Eugonadism

Prevalence of Hypogonadism in Men

with ED

69.2%

Specific medical

conditions

3.2%

17.4%

50.4% 49.6%

89.1% 10.9%

Maseroli et al J Sex Med 2015 Apr;12(4):956-65.

Radiotherapy

Surgery

Genetic

Specific Medical Conditions Associated with

Secondary Hypogonadism

1.1

3.4

1.1 1.7

1.1

0.1

2.4

89.1% 10.9%

Trauma

PRL-adenomas

Empty sella DrugsUnknown

Specific medical conditions

Maseroli et al J Sex Med 2015 Apr;12(4):956-65.

Unknown

Concomitant metabolic disease

(Obesity, T2DM or MetS)

Specific Medical Conditions Associated with

Secondary Hypogonadism

71.8%28.2%

89.1% 10.9%

Unknown

Specific medical conditions

Maseroli et al J Sex Med 2015 Apr;12(4):956-65.

Traish, J Androl 2009

Low Testosterone Levels and Diabetes/Metabolic Syndrome

Relationship Between Total Testosterone and the Number of MS Components

To

tal

Testo

ste

ron

e (

nM

)m

ean

an

d 9

5%

co

nfi

den

ce i

nte

rval

Number of Metabolic Syndrome Components

Corona G et al. Eur Urol. 2006; 50: 595-604

SMSNA Colloquium

• August 2015 expert colloquium commissioned by the Sexual Medicine Society of North America (SMSNA) convened in Washington, DC

• Panel consisted of 17 experts in men’s health, sexual medicine, urology, endocrinology, and methodology

• Purpose: To discuss hypogonadal men with associated signs and symptoms accompanied by low or normal gonadotropin levels and do not have classical hypogonadism

• AOH is a clinical and biochemical syndrome characterized by a deficiency of testosterone with signs and symptoms that can be caused by testicular and/or hypothalamic-pituitary dysfunction

• AOH is clinically distinct from classical primary and secondary hypogonadism

• AOH is characterized by T deficiency and the failure to mount an adequate compensator pituitary response to low T levels; gonadotropin levels are low or in the normal range

• AOH more often occurs in men who have chronic medical conditions

• AOH is not a new category of hypogonadism; but rather, a condition we had been treating with TTh that we previously classified as idiopathic hypogonadism

Khera et al. Mayo Clin Proc. 2016 Jul;91(7):908-26

Is it Safe and Beneficial to Treat AOH Patients with Testosterone

Therapy?Medical Benefits

• Diabetes

• Metabolic syndrome

• Obesity

• Osteoporosis

• Cardiovascular

Symptomatic Benefits

• Erectile dysfunction

• Libido

• Muscle strength

• Energy

• Mood/Depression

We have more safety and benefits data on patients with

AOH than we do with patients with classical primary or

secondary hypogonadism

Effects on Insulin Resistance From Testosterone Therapy: The Times 2 Study

• A 12-month, multicenter, prospective, randomized, double-blind, placebo-controlled study

Study Design

• 220 hypogonadal men with Type 2 diabetes and metabolic syndromePopulation

• Significant improvement in insulin resistance in all patients (15.2% at 6m and 16.4% at 12m)

• Significant improvement in HDL (-0.049 mmol/L) and LDL cholesterol (-0.210 mmol/L), lipoprotein a (-0.31 mmol/L) in selected groups

• Significant improvement in erectile function (IIEF increase of 4.8 points)

• CVE higher in placebo (10.7 vs. 4.6%; P = 0.095)

Results

Jones TH, et al. Diabetes Care. 2011;34(4):828-837.

IIEF = International Index of Erectile Function

Effects on HbA1c From Testosterone Therapy: BLAST Study

• 30 week double-blind placebo-controlled study of long-acting T undeconoatefollowed by open label 52 weeks

Study Design

• 211 male type 2 diabeticsPopulation

• Significant improvement in HbA1c at 6 and 18 weeks

• Significantly reduction in waist circumference, weight and BMI related to achieving adequate serum testosterone levels

• 1 patient with CAD died of an MI in open label

Results

Hackett et al J Sex Med.2014 Mar;11(3):840-56

Effects of Testosterone Treatment on BodyFat and Lean Mass in Obese Men on a

Hypocaloric Diet

• 56-week, randomised, double-blind, parallel, placebo-controlled study

Study Design

• 82 obese adult men (BMI ≥30 kg/m2) with median age 53 years Population

• TTh resulted in a significant reduction in fat mass (-2.9 kg) and visceral fat (-2678 mm2) over dieting alone

• 1 CVE in control group and 1 CVE in TRT group

Results

Fui et al. BMC Medicine (2016) 14:153

• 137 RPC studies assessing TTh and changes in IIEF

• 14 studies were included with 2,298 subject

• Mean follow-up 40.1 weeks

• Mean age 60.2 years

• “nearly all studies included in this meta-analysis were comprised of populations of men without classic hypogonadism”

Corona et al. Eur Urol. 2017 epub

Results

Corona et al. Eur Urol. 2017 epub

• RPC Trial of 790 men 65 years and older

• T gel or placebo for 12 months

• Participation in one or more of 3 trials

• Sexual Function Trial

• Physical Function Trial

• Vitality Trial

• 63% of subjects were obese

Snyder et al N Engl J Med. 2016 Feb 18;374(7):611-24

Results

• Significant improvement in sexual activity, sexual desire and erectile function

• Significant improvement in 6 min walking distance when all 3 trials were combined

• Improvement in mood and severity of depressive symptoms compared to placebo

• No improvement in vitality Snyder et al N Engl J Med. 2016 Feb 18;374(7):611-24

Snyder et al N Engl J Med. 2016 Feb 18;374(7):611-24

Results

• Year 1: 7 men in each group were adjudicated to have major CVE (MI, stroke, or death from CV causes

• Year 2: 2 men in the testosterone group and 9 men in the placebo group were adjudicated to have had major CVE

Conclusion• Most hypogonadal patients being treated

with TTh today are being treated off-label

• AOH is a true medical condition which comprises the majority of the patients that are being treated with TTh

• Historically, studies assessing the safety and benefits of TTh have consisted mainly of patients with non-classical secondary hypogonadism, or AOH

• Patients with non-classical and classical primary and secondary hypogonadism all appear to equally benefit from TTh, irrespective of the etiology of their disease

Thank You

Texas Medical Center, Houston