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
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
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.
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
• 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