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Ambulatory Care Grand Rounds
Wes 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 af...
Case Report (continued)
Medical History:
   Type 2 Diabetes Mellitus (T2D): HbA1c not at goal (9.1%)
   Hypertension (HT...
Case Report (continued)
 Current Medications:
    Caduet® 10 mg / 20 mg po daily
    Metformin 1000 mg po BID with meal...
Case Report (continued)
 After further questioning, it is discovered that ES’s erectile
  dysfunction has been occurring ...
Case Report (continued)
 After his pharmacotherapy work-up and physical exam, ES
  is given a prescription for once-daily...
Learning Objectives
 Establish the prevalence of hypogonadotropic
  hypogonadism (HH) in type 2 diabetes mellitus (T2D)
 ...
Definitions
 Hypogonadism: Low testosterone (T) along with the presence
   of any of the following signs and symptoms:
  ...
Definitions (continued)
 When low T is associated with inappropriately low serum
   gonadotrophin hormones such as follic...
Brief Physiology Overview




              Image courtesy of: http://www.prostate-cancer.org/education/andeprv/Img
      ...
HH and Type 2 Diabetes Mellitus
 Dhindsa et al (2004) were the first to assess the
  prevalence of hypogonadism in T2D ba...
FIG. 3. Correlation of FT (nmol/liter) with BMI (kg/m2) and weight (kg)




Dhindsa, S. et al. J Clin Endocrinol Metab 200...
HH and Type 2 Diabetes Mellitus
 •Kapoor et al (2007) also found a
 high prevalence of HH in T2D
 patients [n=355]
 • 50% ...
Is Hyperglycemia or Age To Blame?
     Tomar et al (2006) compared the incidence of low-T in
        patients with type 1...
Obesity and Metabolic Syndrome
 Obesity in the absence of T2D is associated with low-T. In the Tomar
   et al investigati...
Adjusted Odds Ratios for developing type 2 diabetes mellitus based on
     tertiles of testosterone concentrations:

     ...
Insulin Resistance
Animal Data
    When insulin receptors are genetically removed from
     hypothalamic neurons in mice ...
Insulin Resistance (continued)
      Human Data
            LH is secreted in a pulsatile fashion
            When LH pu...
Estradiol and Leptin
 Testosterone is converted to estradiol by aromatase
  enzymes in adipose tissue, so increased adipo...
 T2D, obesity, and MetS are disorders of high oxidative stress
  associated with increased TNF-a and IL-1b
 These inflam...
Dandona P, et al. Curr Mol Med 2008;8:816-828.
HH and Atherogenesis
 In patients with T2D and CAD, the presence of low T has
  recently shown to double the risk of CV m...
HH and Anemia
 •Hematocrit is significantly
 lower in patients with T2D
 and HH

 •A recent investigation found
 a normoch...
HH and C-Reactive Protein
     (CRP)
•CRP has been shown to be
significantly higher in T2D
patients with HH compared to
th...
HH and Sexual Dysfunction
    Men with T2D are twice as likely to have ED
    HH in men with T2D is associated with redu...
TRT Clinical Pearls
    Indications:
          Improve sexual function
          Improve sense of well being
         ...
TRT Clinical Pearls (continued)
  Common Formulations:
       Route of Administrations                     Advantages     ...
TRT Clinical Pearls (continued)
    Adverse Effects:
       Polycythemia: Monitor CBC periodically
       Breast tendern...
Learning Objectives
 Establish the prevalence of hypogonadotropic
  hypogonadism (HH) in type 2 diabetes mellitus (T2D)
 ...
Was other etiologies for ES’s ED exist?
Was our decision to start a PDE-5 inhibitor
appropriate?
What other laboratory ass...
Case Report (continued)
 You also order the following labs:
    CBC w/ differential: R/O macrocytic/microcytic anemias
 ...
Case Report (continued)
 Lab Review (continued):
    Testosterone: 143 ng/dL (Range: 300 – 1100 ng/dL)
    PSA: 2.3 ng/...
Case Report (continued)
 Three months later….
 Clinic Note:
    Patient reports discontinuing daily Cialis® and Lexapro...
Testosterone Deficiency And Type 2 Diabetes Mellitus
Testosterone Deficiency And Type 2 Diabetes Mellitus
Testosterone Deficiency And Type 2 Diabetes Mellitus
Testosterone Deficiency And Type 2 Diabetes Mellitus
Testosterone Deficiency And Type 2 Diabetes Mellitus
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Testosterone Deficiency And Type 2 Diabetes Mellitus

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Transcript of "Testosterone Deficiency And Type 2 Diabetes Mellitus"

  1. 1. Ambulatory Care Grand Rounds Wes Pierce, Pharm.D. Candidate
  2. 2. 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
  3. 3. Case Report (continued) Medical History:  Type 2 Diabetes Mellitus (T2D): HbA1c not at goal (9.1%)  Hypertension (HTN): Controlled; BP today 128/84 mmHg  Hyperlipidemia: Lipid parameters not at goal at last visit  Total cholesterol = 230 mg/dL  HDL = 39 mg/dL  LDL = 171 mg/dL  Depression: Controlled on SSRI for 3 years  Obesity: BMI at last visit 31 kg/m2
  4. 4. Case Report (continued)  Current Medications:  Caduet® 10 mg / 20 mg po daily  Metformin 1000 mg po BID with meals  Lantus® 20 units SC at bedtime  Lexapro® 10 mg po daily  ES reports compliance with all medications  No 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…….”
  5. 5. 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
  6. 6. 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?
  7. 7. Learning Objectives  Establish 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
  8. 8. Definitions  Hypogonadism: 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.
  9. 9. 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.
  10. 10. Brief Physiology Overview Image courtesy of: http://www.prostate-cancer.org/education/andeprv/Img tisman_adjandrogenwthdrFig2.gif
  11. 11. HH and Type 2 Diabetes Mellitus  Dhindsa 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
  12. 12. FIG. 3. Correlation of FT (nmol/liter) with BMI (kg/m2) and weight (kg) Dhindsa, S. et al. J Clin Endocrinol Metab 2004;89:5462-5468 Copyright ©2004 The Endocrine Society
  13. 13. 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
  14. 14. 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
  15. 15. Obesity and Metabolic Syndrome  Obesity 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.
  16. 16. Adjusted Odds Ratios for developing type 2 diabetes mellitus based on tertiles of testosterone concentrations: Lowest Tertile Middle Tertile Highest Tertile (reference) Estimated Free 4.12 2.86 1.00 Testosterone Est. Bioavailable 3.92 3.05 1.00 Testosterone Selvin E, et al. Diabetes Care 2007;30:234-238.
  17. 17. Insulin Resistance Animal 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.
  18. 18. Insulin Resistance (continued) Human Data  LH is secreted in a pulsatile fashion  When 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.
  19. 19. Estradiol and Leptin  Testosterone 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 insulin  Obese 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;83:2266-2274
  20. 20.  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.
  21. 21. Dandona P, et al. Curr Mol Med 2008;8:816-828.
  22. 22. HH and Atherogenesis  In patients with T2D and CAD, the presence of low T has recently shown to double the risk of CV mortality in 19 months  A 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;93:68-75 Rosano GM, et al. Circulation 1999;99:1666-1670 Nathan L, et al. Proc Natl Acad Sci USA 2001;98:3589-3593.
  23. 23. 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.
  24. 24. 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.
  25. 25. HH and Sexual Dysfunction  Men with T2D are twice as likely to have ED  HH in men with T2D is associated with reductions in blood flow in the penile arteries  Restoration 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;30:911-917 Isidori AM, et al. J Clin Endocrinol Metab 1999;84:3673-3680 Shabsigh R, et al. J Urol 2004;172:658-663
  26. 26. TRT Clinical Pearls  Indications:  Improve sexual function  Improve sense of well being  Increase muscle mass  Reduce adiposity  Contraindications:  Prostate cancer  Breast cancer Dandona P, et al. Postgrad Med 2009;121(3):45-51.
  27. 27. TRT Clinical Pearls (continued) Common Formulations: Route of Administrations Advantages Disadvantages Intramuscular injections Once every 2 weeks Peaks/troughs Pain Topical Patch Ease of administration Application site irritation No hygiene requirements and rash Topical Gel Most physiologic Hygiene requirements Best tolerated Dandona P, et al. Postgrad Med 2009;121(3):45-51.
  28. 28. TRT Clinical Pearls (continued) Adverse Effects:  Polycythemia: Monitor CBC periodically  Breast tenderness, gynecomastia: Aromatase activity  BPH and Prostate Cancer: Perform yearly PSA Dandona P, et al. Postgrad Med 2009;121(3):45-51.
  29. 29. Learning Objectives  Establish 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
  30. 30. 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?
  31. 31. Case Report (continued)  You also order the following labs:  CBC w/ differential: R/O macrocytic/microcytic anemias  Testosterone concentration  PSA  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)
  32. 32. 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:  Hypogonadism  Secondary normochromic, normocytic anemia  Plan:  Call patient with lab resulsts  Initiate Androgel® 1%; apply 5 g to arms, shoulders, and chest daily  Keep f/u appointment in 3 months
  33. 33. 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 week  15 lb. weight loss since last visit  Plan:  Reschedule next appointment; patient will be in Tahiti renewing vows with wife……
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