Ambulatory Care Grand RoundsWes Pierce, Pharm.D. Candidate

Case Report

CC: ES is a 41 year-old WM presenting to the Cardiometabolic Clinic at UMMC for his 3-month follow-up after an increase in Lantus® from 10 units at bedtime to 20 units at bedtime, and an increase in atorvastatin from 10 mg to 20 mg

Case Report (continued)Medical History:

Type 2 Diabetes Mellitus (T2D): HbA1c not at goal (9.1%)Hypertension (HTN): Controlled; BP today 128/84 mmHgHyperlipidemia: Lipid parameters not at goal at last visit

Total cholesterol = 230 mg/dLHDL = 39 mg/dLLDL = 171 mg/dL

Depression: Controlled on SSRI for 3 yearsObesity: BMI at last visit 31 kg/m2

Case Report (continued)Current Medications:

Caduet® 10 mg / 20 mg po daily Metformin 1000 mg po BID with mealsLantus® 20 units SC at bedtimeLexapro® 10 mg po daily

ES reports compliance with all medicationsNo chest pain, headache, shortness of breath, or myalgias

Before completing your pharmacotherapy work-up, ES hesitantly asks if any of his medications “affect you….ya know…in the bedroom…….”

Case Report (continued)After further questioning, it is discovered that ES’s erectile

dysfunction has been occurring for the past 6 months and is causing significant strain in the relationship with his wife

He states he does not remember having any morning erections recently, so you feel confident in assuring him that his problem is vasogenic secondary to his metabolic conditions and is an common condition

Case Report (continued)After his pharmacotherapy work-up and physical exam, ES

is given a prescription for once-daily tadalafil 2.5 mg in order to avoid “planning” for intercourse and is sent to the lab for his lipid panel and HbA1c percentage

Was this appropriate? What other possible etiologies could explain ES’s erectile

dysfunction given his medical history? What other laboratory assessments are warranted for ES?

Learning ObjectivesEstablish the prevalence of hypogonadotropic

hypogonadism (HH) in type 2 diabetes mellitus (T2D) and its precipitating factors

List 4 underlying mechanisms by which HH occurs in patients with T2D, and visa versa

Indentify 4 complications associated with HH in T2D and the potential modifying impact of testosterone replacement therapy (TRT)

Briefly highlight pharmacologic options for TRT

DefinitionsHypogonadism: Low testosterone (T) along with the presence

of any of the following signs and symptoms: Decreased libido Erectile dysfunction (ED) Increased adipose tissue mass Decreased muscle and bone mass Depression Anemia (usually normocytic, normochromic)

Low T is clinically defined as total serum testosterone concentrations under 300 ng/dL (normal: 300-1,100 ng/dL)

Bhansin S, et al. J Endocrinol Metab 2006;91(7):1995-2010.

Definitions (continued)When low T is associated with inappropriately low serum

gonadotrophin hormones such as follicle stimulating hormone (FSH) and leuteinizing hormone (LH), the condition is referred to as hypogonadotropic hypogonadism, or HH.

The release of FSH and LH from the pituitary is governed by the hypothalamic release of gonadotropin-releasing hormone (GnRH).

Dandona P, et al. Curr Mol Med 2008;8:816-828.

Brief Physiology Overview

Image courtesy of: http://www.prostate-cancer.org/education/andeprv/Img/tisman_adjandrogenwthdrFig2.gif

HH and Type 2 Diabetes MellitusDhindsa et al (2004) were the first to assess the

prevalence of hypogonadism in T2D based on free-T concentrations

Included were 103 males with T2D, aged 31-75 years of age

Results showed that 33% of the cohort had subnormal free-T and that LH and FSH were significantly lower in these patients

Dhindsa S, et al. J Clin Endocrinol Metab 2004;89:5462-5468

Copyright ©2004 The Endocrine Society

Dhindsa, S. et al. J Clin Endocrinol Metab 2004;89:5462-5468

FIG. 3. Correlation of FT (nmol/liter) with BMI (kg/m2) and weight (kg)

HH and Type 2 Diabetes Mellitus•Kapoor et al (2007) also found a high prevalence of HH in T2D patients [n=355]• 50% of patients in the cohort had borderline-low T (250 – 350 ng/dL)•75% of patients with low-T also had low gonadotropin concentrations (FSH and LH)•As in the previous study, BMI and waist circumference were negatively correlated with T levels

Kapoor D, et al. Diabetes Care 2007; 30 (4):911-917

Is Hyperglycemia or Age To Blame?Tomar et al (2006) compared the incidence of low-T in

patients with type 1 and type 2 diabetes mellitus with high baseline HbA1c (>7.5%) and found that only 6% of type 1 patients were hypogonadal compared to 26% of men with type 2 diabetes

Chandel et al (2008) found that even young men, aged 18-35 years, with T2D have a high prevalence of low-T (33%)

Tomar R, et al. Diabetes Care 2006;29(5):1120-1122.Chandel A, et al. Diabetes Care 2008;31(10):2013-2017

Obesity and Metabolic SyndromeObesity in the absence of T2D is associated with low-T. In the Tomar et al

investigation, BMI was inversely related with T in both T2D and T1D populations

Kaplan et al (2006) studied 864 men with a mean age of 52 years and found that obese men with the metabolic syndrome (MetS) have up to 300 ng/dL less total T than their metabolically healthy counterparts

Laaksonen et al (2003) demonstrated that men with T concentrations in the lowest tertile (<100 – 500 ng/dL) were almost twice as likely to develop MetS

Kaplan SA, et al. J Urol 2006;176:1524-1528.Laaksonen DE, et al. Euro J Endocrinol 2003;149:601-608.

Selvin E, et al. Diabetes Care 2007;30:234-238.

Lowest Tertile Middle Tertile Highest Tertile(reference)

Estimated FreeTestosterone

4.12 2.86 1.00

Est. Bioavailable Testosterone

3.92 3.05 1.00

Adjusted Odds Ratios for developing type 2 diabetes mellitus based ontertiles of testosterone concentrations:

Insulin ResistanceAnimal Data

When insulin receptors are genetically removed from hypothalamic neurons in mice models, HH ensues with a 60-90% decrease in LH secretion

This implies that GnRH release, and subsequent gonadotrophin release, is mediated by insulin action

Hypothalamic insulin action also mediates the following:Suppression of appetite Decrease hepatic glucose production

Bruning JC, et al. Science 2000;289:2122-2125.Watanobe H. Endocrinology 2003;144:4868-4875.

Insulin Resistance (continued)Human Data

LH is secreted in a pulsatile fashionWhen LH pulse frequency and amplitude (amount

secreted) are compared between obese and lean men, LH pulse frequencies were similar, however the amplitude of LH secretion is significantly decreased in the obese population

Weight LOSS has been shown to increase LH and FSH concentrations

Vermeulen A, et al. J Clin Endocrinol Metab 1993;76:1140-1146.Pitteloud N, et al. J Clin Endocrinol Metab 2005;90:2636-2641.Lima N, et al. Int J Obes Relat Metab Disord 2000;24;1433-1437.

Estradiol and LeptinTestosterone is converted to estradiol by aromatase enzymes in adipose

tissue, so increased adiposity leads to increased aromatization and estradiol formation

Estradiol, like testosterone, can decrease FSH and LH release through negative feedback

Leptin regulates LH and FSH secretion much like insulinObese individuals (with and without T2D) have high circulating leptin

levels due to leptin resistance, much like T2D have high insulin levels due to insulin resistance

Khosla S, et al. J Clin Endocrinol Metab 1998;83:2266-2274Pitteloud N, et al. J Clin Endocrinol Metab 2005;90:2636-2641

T2D, obesity, and MetS are disorders of high oxidative stress associated with increased TNF-a and IL-1b

These inflammatory mediators interfere with insulin signal transduction

As we have already noted, insulin dysfunction results in decreased GnRH and subsequent HH

These effects are underscored by the fact that T supplementation results in reduced levels of inflammatory mediators and increases anti-inflammatory cytokines such as IL-10.

Katsuki A, et al. J Clin Endocinol Metab 1998;83:859-862.Malkin CJ, et al. J Clin Endocrinol Metab 2004;89:3313-3318.

Dandona P, et al. Curr Mol Med 2008;8:816-828.

HH and AtherogenesisIn patients with T2D and CAD, the presence of low T has

recently shown to double the risk of CV mortality in 19 monthsA recent prospective study in elderly men [n=794, median

age=73.6] found that men in the lower quartile of T (<294 ng/dL) had 1.4 times higher risk of overall mortality, and 1.38 times higher risk of CV mortality than the highest quartile

In LDL-receptor deficient mice models, testosterone administration reduces atherosclerosis and VCAM-1 expression (anti-inflammatory and anti-atherogenic)

Ponikowska B, et al. Int J Cardiol 2009 [published ahead of print]Laughlin GA, et al. J Clin Endocrinol Metab 2008;93:68-75Rosano GM, et al. Circulation 1999;99:1666-1670Nathan L, et al. Proc Natl Acad Sci USA 2001;98:3589-3593.

HH and Anemia•Hematocrit is significantly lower in patients with T2D and HH

•A recent investigation found a normochromic, normocytic anemia in 38% of men with HH and in only 3% normal controls

Bhatia V, et al. Diabetes Care 2006;29(10):2289-2294.Dandona P, et al. Curr Mol Med 2008;8:816-828.

HH and C-Reactive Protein (CRP)

•CRP has been shown to be significantly higher in T2D patients with HH compared to those without HH

•6.12 mg/dL vs. 3.1 mg/dL

•This CRP value places T2D patients with HH in the highest CV risk category

Bhatia V, et al. Diabetes Care 2006;29(10):2289-2294.Dandona P, et al. Curr Mol Med 2008;8:816-828.

HH and Sexual DysfunctionMen with T2D are twice as likely to have ED HH in men with T2D is associated with reductions in

blood flow in the penile arteriesRestoration of T to even the low range of normal can

restore sexual function and penile rigidity through directly enhanced vasodilation

Energy and libido are also increased The efficacy of PDE-5 inhibitors can also be increased

Kapoor D, et al. Diabetes Care 2007;30:911-917Isidori AM, et al. J Clin Endocrinol Metab 1999;84:3673-3680Shabsigh R, et al. J Urol 2004;172:658-663

TRT Clinical PearlsIndications:

Improve sexual functionImprove sense of well beingIncrease muscle massReduce adiposity

Contraindications: Prostate cancer Breast cancer

Dandona P, et al. Postgrad Med 2009;121(3):45-51.

TRT Clinical Pearls (continued)

Route of Administrations Advantages Disadvantages

Intramuscular injections Once every 2 weeks Peaks/troughsPain

Topical Patch Ease of administrationNo hygiene requirements

Application site irritation and rash

Topical Gel Most physiologicBest tolerated

Hygiene requirements

Common Formulations:

Dandona P, et al. Postgrad Med 2009;121(3):45-51.

TRT Clinical Pearls (continued)Adverse Effects:

Polycythemia: Monitor CBC periodicallyBreast tenderness, gynecomastia:

Aromatase activityBPH and Prostate Cancer: Perform yearly

PSA

Dandona P, et al. Postgrad Med 2009;121(3):45-51.

Learning ObjectivesEstablish the prevalence of hypogonadotropic

hypogonadism (HH) in type 2 diabetes mellitus (T2D) and its precipitating factors

List 4 underlying mechanisms by which HH occurs in patients with T2D, and visa versa

Indentify 4 complications associated with HH in T2D and the potential modifying impact of testosterone replacement therapy (TRT)

Briefly highlight pharmacologic options for TRT

Was other etiologies for ES’s ED exist?Was our decision to start a PDE-5 inhibitor appropriate?What other laboratory assessments would you order?

Case Report (continued)You also order the following labs:

CBC w/ differential: R/O macrocytic/microcytic anemiasTestosterone concentrationPSA

During chart checks the next day, the following results are obtained:CBC w/ diff:

Hematocrit: 39% (Range: 42 – 52%) MCV: 84 μm3 (Range: 80 – 95 μm3 ) MCH: 30 pg (Range: 27 – 31 pg)

Case Report (continued)Lab Review (continued):

Testosterone: 143 ng/dL (Range: 300 – 1100 ng/dL)PSA: 2.3 ng/mL (Range: <4 ng/mL)

Assessment:HypogonadismSecondary normochromic, normocytic anemia

Plan:Call patient with lab resulstsInitiate Androgel® 1%; apply 5 g to arms, shoulders, and

chest daily Keep f/u appointment in 3 months

Case Report (continued)Three months later….Clinic Note:

Patient reports discontinuing daily Cialis® and Lexapro® as he “no longer needs them”

Reports joining a gym to which he goes 3 times per week15 lb. weight loss since last visitPlan:

Reschedule next appointment; patient will be in Tahiti renewing vows with wife……