66 M with erectile dysfunction and abnormal labs RAJESH JAIN ENDORAMA 10/29/2015

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1 66 M with erectile dysfunction and abnormal labs RAJESH JAIN ENDORAMA 10/29/2015

2 HPI 66 M presenting as a referral for erectile dysfunction and abnormal labs Has been seeing a facility specializing in ED. Previously failed Viagra, Cialis, and Muse Has been told his testosterone and estrogen were elevated and that he should see an endocrinologist Denies history of testosterone supplementation. Admits to fatigue but denies issues with libido, difficulty conceiving children in the past Denies changes in weight, muscle mass, hair/skin changes, vision changes, thirst, urinary frequency

3 Extended History PMH: Erectile dysfunction, elevated LFTs LFT workup: previous workup - everything was normal PSH: None Meds: None Allergies: NKDA Family history: Thyroid disease ( Goiter ), Parkinson s in mother. Stroke in father. Social: Non-smoker, drinks 1-2 beers per month. No drug use. Retired pipe fitter.

4 Physical Exam BP 163/90, P 75, Ht 5 10, Wt 175 LB, BMI 25.1 Constitutional: Appears well developed HEENT: Normocephalic, atraumatic, normal EOM Neck: Neck supple, no thyromegaly CV: RRR, no m/g/r Pulm: CTAB Abd: Soft, non-tender, BS present GU: Normal testicular exam Neuro: A&O x 3 Skin: Tan skin, whole body, no tan lines noted Psych: Normal mood and affect

5 Outside Labs 3 months prior Lab Value Reference SHBG > nmol/l Total testosterone ng/dl Free testosterone pg/nl Estradiol pg/ml LH IU/L

6 Questions What is the differential for elevated SHBG? What is the significance of elevated SHBG?

7 Differential for elevated SHBG? Endo Society Guidelines Testosterone Therapy in Men with Androgen Deficiency Syndromes

8 What is SHBG? Synthesized by hepatocytes of the liver Single competitive binding site per molecule, binds dihydrotestosterone and testosterone with high affinity and estradiol less avidly SHBG production by the liver is increased under the influence of estrogens and thyroid hormones and decreased by androgens and insulin Williams Textbook of Endocrinology, 12 th ed

9 Binding of testosterone

10 Sex hormone binding globulin In men with intact hypothalamic-pituitary-testicular axis, alterations in SHBG do not have an effect on physiology and action of androgens However, alterations in SHBG may alter free testosterone levels in men with reproductive disorders who have impaired negative feedback regulation or are receiving testosterone replacement therapy Williams Textbook of Endocrinology, 12 th ed

11 SHBG in endocrine disorders In PCOS, SHBG is reduced by as much as 50% due to the liver s response to elevated testosterone and insulin

12 Low SHBG and DM risk? 1,128 men in the Massachusetts Male Aging Study, followed for average 13 years Lakshman et al. Sex hormone-binding globulin as an independent predictor of incident diabetes mellitus in men. J Gerontol 2010;65A(5):

13 Diabetes Prevention Program and SHBG Men Pre-menopausal women Mather et al. Steroid sex hormones, sex hormone-binding globulin, and Diabetes incidence in the Diabetes Prevention Program. JCEM 2015;100:

14 Significance of elevated SHBG? Elevated fracture risk? Leblanc et al. The effects of serum testosterone, estradiol, and sex hormone binding globulin on fracture risk in older men. JCEM 2009;94:

15 Significance of elevated SHBG? Why elevated fracture risk? - May reflect decreased availability of sex hormones to the tissues when SHBG levels are high? - SHBG may directly influence cellular signaling - Marker for non-skeletal factors? Lower insulin or IGF-1 could increase SHBG, resulting in SHBGfracture risk associations Leblanc et al. The effects of serum testosterone, estradiol, and sex hormone binding globulin on fracture risk in older men. JCEM 2009;94:

16 Repeat Labs / Lab Value Reference Ferritin ng/ml Prolactin ng/ml SHBG nmol/l Total testosterone ng/dl Free testosterone pg/nl

17 Case continued Patient referred to liver clinic where further labs reveal: / Lab Value Reference INR Hep B Surf Ab Negative Negative Ferritin ng/ml Iron ug/dl TIBC < Percent saturation Unable to calculate 14-50% Alpha-1 antitrypsin mg/dl Alpha-1 antitrypsin phenotype SZ (heterozygote) Previous labs demonstrate LFT abnormality since 2012 with negative Hep C Ab IgG, Hep B Core Ab IgM, Hep A Ab IgM. Previous iron saturation 39%.

18 Hemochromatosis Can be genetic (i.e. hereditary hemochromatosis) or secondary Hereditary transmitted as autosomal recessive Secondary causes are most commonly related to repeated transfusions Incidence of hereditary hemochromatosis: 0.5% Typically presents in the 4 th or 5 th decade

19 Manifestations of Hemochromatosis

20 Endocrine manifestations of hemochromatosis Vantyghem et al. Endocrine manifestations related to inherited metabolic diseases in adults. Orphanet J Rare Dis 2012;7:11.

21 Endocrine involvement of hemochromatosis Direct infiltration of the pituitary gland Hypogonadotrophic hypogonadism Hemochromatosis, no hypogonadism Healthy Sparacia et al. Transfusional hemochromatosis: quantitative relation of MR imaging pituitary signal intensity reduction to hypogonadotropic hypogonadism. Radiology 2000;215:

22 Hypogonadotrophic Hypogonadism Mcdermott and Walsh. Hypogonadism in hereditary hemochromatosis. JCEM 2005;90:

23 Pituitary involvement of hemochromatosis Histologic and immunologic analysis of the pituitary show predilection of gonadotrophs for iron depositions increased expression of transferrin and transferrin receptors? Deficiency of other pituitary hormones has been described but is less common

24 Case Report Central hypothyroidism Hudec et al. Secondary hypothyroidism in hereditary hemochromatosis: recovery after iron depletion. Thyroid 2008;18.2:

25 Case continued Gene testing for the most common mutations of hemochromatosis were negative However, patient s liver biopsy reveals cirrhosis, alpha-1 anti-trypsin deficiency, steatohepatitis, and hemosiderosis Patient s pulmonary function tests within normal limits Patient being treated with every 2-3 months phlebotomy & screening for hepatocellular carcinoma and varices

26 What if.? Discussion What if his free testosterone was actually low? Would you treat?

27 Testosterone Therapy in Liver Disease Sinclair et al. Testosterone in men with advanced liver disease: abnormalities and implications. J Gastro Hepatol 2015; 30:

28 Largest Trial To Date almost 20 years old! Gluud et al. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. Hepatology 1986; 6.5:

29 Hepatocellular carcinoma and testosterone No HCC has been reported with currently used testosterone formulations Link between testosterone levels and HCC are conflicting GnRH agonists and anti-androgens do not have any benefit in HCC

30 References Endo Society Guidelines Testosterone Therapy in Men with Androgen Deficiency Syndromes Williams Textbook of Endocrinology, 12 th ed Leblanc et al. The effects of serum testosterone, estradiol, and sex hormone binding globulin on fracture risk in older men. JCEM 2009;94: Yaffe et al. Sex hormones and cognitive function in older men. J Am Geriatr Sox 2002; Lakshman et al. Sex hormone-binding globulin as an independent predictor of incident diabetes mellitus in men. J Gerontol 2010;65A(5): Siddique and Kowdley. Review article: the iron overload syndromes. Aliment Pharmacol Ther 2012;35: Sparacia et al. Transfusional hemochromatosis: quantitative relation of MR imaging pituitary signal intensity reduction to hypogonadotropic hypogonadism. Radiology 2000;215: Noetzli et al. Pituitary iron and volume predict hypodonadism in transfusional iron overload. Am J Hematol 2012;87: Vantyghem et al. Endocrine manifestations related to inherited metabolic diseases in adults. Orphanet J Rare Dis 2012;7:11. Mcdermott and Walsh. Hypogonadism in hereditary hemochromatosis. JCEM 2005;90: Sinclair et al. Testosterone in men with advanced liver disease: abnormalities and implications. J Gastro Hepatol 2015; 30: Gluud et al. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. Hepatology 1986; 6.5: Hudec et al. Secondary hypothyroidism in hereditary hemochromatosis: recovery after iron depletion. Thyroid 2008;18.2: Barton et al. Thyroid-stimulating hormone and free thyroxine levels in persons with HFE C282Y homozygosity, a common hemochromatosis gene: the HEIRS study. Thyroid 2008;18.8:

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