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Dyslipidemia: Hormone Therapies

Dyslipidemia: Hormone Therapies. Thierry Hertoghe, MD.  Total & LDL cholesterol. Dyslipidemia.  HDL cholesterol.  Antibodies against oxidized LDL cholesterol.  Triglycerides.  Lipoprotein a.  Homocysteine. American Heart association. Total Cholesterol.  Serum Cholesterol

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Dyslipidemia: Hormone Therapies

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  1. Dyslipidemia: Hormone Therapies Thierry Hertoghe, MD

  2.  Total & LDL cholesterol Dyslipidemia HDL cholesterol Antibodies against oxidized LDL cholesterol  Triglycerides  Lipoprotein a Homocysteine

  3. American Heart association Total Cholesterol

  4.  Serum Cholesterol =>  Coronary Insufficiency 10 to 15 %  serum cholesterol = 20 to 30 %  risk of coronary heart disease (Angies N, NY, 1995, Aug 3)

  5. Serum cholesterol 1 mmol/l = 39 mg/dl (38,647 mg/dl)3 mmol/l= 115 mg/dl5 mmol/l = 193 mg/dl8 mmol/l = 308 mg/dl

  6. American Heart association HDL Cholesterol

  7. American Heart association LDL Cholesterol

  8. LDL cholesterol => all-cause mortality SUBJECTS:the Munster Heart Study, 10,856 men aged 36 to 65 yearsat study entry (46.8+/-7.3 years [mean+/-SD]) were followed for 4 to 14 years(7.1+/-2.4 years). RESULTS:Total cholesterol, LDL cholesterol, and the LDL/HDL ratio showed a J-shaped relationship with total mortality. At high total and LDL cholesterol concentrations, increased mortality was due to increased coronary deaths. Cowan LD, O'Connell DL, Criqui MH, Barrett-Connor E, Bush TL, Wallace RB. Cancer mortality and lipid and lipoprotein levels. Lipid Research Clinics Program Mortality Follow-up Study. Am J Epidemiol. 1990 Mar;131(3):468-82. Department of Biostatistics and Epidemiology, College of Public Health,University of Oklahoma Health Sciences Center, Oklahoma City. Wolters M, Strohle A, Hahn A. [Age-associated changes in the metabolism of vitamin B(12) and folic acid: prevalence, aetiopathogenesis and pathophysiological consequences] Z Gerontol Geriatr. 2004 Apr;37(2):109-35 Universitat Hannover, Hannover, Germany

  9. LDL Men LDL Cholesterol  with age Women HDL HDL Cholesterol  with age in men LDL/HDL Atherogenic ratio LDL/HDL Cholesterol with age

  10. American Heart association Triglycerides

  11. Homocysteine   • What Is Homocysteine? • = an amino acid in the blood. Epidemiological studies => Excess serum levels of homocysteine =>  risk of • Coronary heart disease • Stroke • Peripheral vascular disease. • Other evidence suggests that homocysteine may have an effect on atherosclerosis by damaging the inner lining of arteries and promoting blood clots. However, a direct causal link hasn’t been established. American Heart association website

  12. Homocysteine Serum homocysteine => should be < 14 µmol/L Bostom AG, Silbershatz H, Rosenberg IH, Selhub J, D'Agostino RB, Wolf PA, Jacques PF, Wilson PW. Tufts Jean Mayer Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med. 1999 May 24;159(10):1077-80. USDA Human Nutrition Research Center on Aging, Boston, Mass, USA. abostom@loa.com

  13. Lipoprotein a Lp(a) = a particle of LDL + apolipoprotein(a), a large glycoprotein, structurallysimilar to plasminogen. • apolipoprotein(a) => couldpromotethrombogenesis • LDL-cholesterol => couldpromoteatherogenesis 1. Loscalzo J, Weinfeld M, Fless GM, et al. Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis 1990; 10:240-245.; 2. Stein JH, Rosenson RS. Lipoprotein Lp(a) excess and coronary heart disease. Arch Intern Med 1997; 157:1170-1176; 3. Kostner G, Krempler F. Lipoprotein(a). Curr Opin Lipidol 1992; 3:279-284; 4. Naruszewicz M, Selinger E, Davignon J. Oxidative modification of lipoprotein and the effect of beta-carotene. Metabolism 1992; 41:1215-1224; 5. Lawn RM, Wade DP, Hammer RE, et al. Atherogenesis in transgenic mice expressing human apolipoprotein(a). Nature 1992; 360:670-672; 6. Sorensen KE, Celermajer DS, Georgakopoulos D, et al. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J Clin Invest 1994; 93:50-55.

  14. Lipoprotein a Serum lipoproteine a => should be < 24 mg/dl (Cheng 2001) or < 30 mgdl (Koda 1999) Cheng SW, Ting AC. Lipoprotein (a) level and mortality in patients with critical lower limb ischaemia. Eur J Vasc Endovasc Surg. 2001 Aug;22(2):124-9. Department of Surgery, The University of Hong Kong Medical Centre, Hong Kong, China. Koda Y, Nishi S, Suzuki M, Hirasawa Y. Lipoprotein(a) is a predictor for cardiovascular mortality of hemodialysis patients. Kidney Int Suppl. 1999 Jul;71:S251-3. Kidney Center of Shinraku-en Hospital, Niigata University, School of Medicine, Japan. WG8Y-KUD@asahi-net.or.jp

  15.  Total & LDL cholesterol Hormone Therapies HDL cholesterol Antibodies against oxidized LDL cholesterol Triglycerides  Lipoprotein a Homocysteine

  16. 1stmost efficient hormone therapy of dyslipidemia =ThyroidTherapy

  17. The importance of Thyroid

  18. Hypothyroidism=>  Serum cholesterol,triglycerides, homocysteine & oxidized LDL

  19. Patients with overt hypothyroidism=> 77% with combined  serum cholesterol &  triglycerides 22 patients with primary hypothyroidism & hyperipidemia Primary hypothyroidism = the cause of hyperlipidemia in 2 2patients • 27% had vascular disease • 14% had xanthomas • 86% had thyroid antibodies • Familial involvement was shown in 3. • 77% had combined hyperlipidemia (high cholesterol & high triglycerides) • Lipoprotein phenotyping => • types IIB hyperlipoproteinemia in 11, • IIA in 5, III in 3 • IV in 3 patients. mean age: 46 yrs, 59% = males Mishkel MA, Crowther SM.Hypothyroidism, an important cause of reversible hyperlipidemia. Clin Chim Acta. 1977 Jan 17;74(2):139-51

  20. Serumcholesterol (mmol/l) Serum T3 =>  Serum cholesterol • 0.1 nmol/l serum T3 =  0.5 mmol/l 8.98 346 mg/l = serum cholesterol 269 mg/l = 6.73 5.78 192 mg/l = 1.05 1.49 1.73 serum T3 (mmol/l) Figure : Inverse correlation between serum T3 & serum cholesterol (Elder J et al, Ann Clin Biochem, 1990, 27 : 110 - 113)

  21. Positive association between serum TSH & serum cholesterol TSH 80.0 TSH40.1-80.0 TSH10.1-15.0 TSH5.1-10.8 TSH15.1-20.0 346 mg/d = TSH20.1-40.0 TSH3.1-5.0 TSH1.1-3.0 8.98 p0.01 269 mg/d = 8.01 p0.01 6.42 NS 6.73 NS 192 mg/d = 6.31 NS 6.51 NS 6.30 p0.01 5.78 p0.05 Cholesterol (mmol/l) TSH (mU/l) Figure: Existence of a positive correlation between serum TSH & serum cholesterol on 1018 female patients. In subjects over 40 years old with suspected hypothyroidism, thyroid hormones control about 15 % of the variability of serum cholesterol (Elder J et al, Ann Clin Biochem, 1990, 27 : 110 - 13)

  22. Thyroidectomy =>increases cholesterol & homocysteine  T4 therapy => back to normal

  23. Overt Hypothyroidism =>increases serum homocysteine  T4 therapy => back to normal

  24. Hypo- & hyperthyroidism =>  LDL oxidation =>  oxidized LDL cholesterol • L-T4 functions =n antioxidant in vitro => inhibits low density lipoprotein (LDL) oxidation in a dose-dependent fashion. • Patients with hypothyroidism & hyperthyroidism • The lag phase (mean hours) of the Cu+2-catalyzed LDL oxidation • hypothyroid state: 3.5x quicker = 4h => subsequent euthyroid state: 14h, resp. (P < 0.05). • hyperthyroid phase: 2x quicker: 6 h => euthyroid phase: 12 h (P <0.05). •  total & LDL cholesterol levels in hypothyroidism than in euthyroidism and were lower in hyperthyroidism than in the euthyroid state. Sundaram V, Hanna AN, Koneru L, Newman HA, Falko JM. Both hypothyroidism and hyperthyroidism enhance low density lipoprotein oxidation. J Clin Endocrinol Metab. 1997 Oct;82(10):3421-4 Department of Internal Medicine, Ohio State University, Columbus 43210, USA

  25. Thyroid treatmentfor Dyslipidemia 

  26. Serum total T3 = 198 µg/dl 7 healthy young adults Diet high in poly-unsaturated fat (calories from 10% protein, 55% fat, & 35% carbohydrate) Diet high in protein (with 35% protein, 30% fat, 35% carbohydrate) High Protein & PUFA diets => -30 & - 43%  serum total T3 Low-carbohydrate diets • - 43%  serum total T3 = 113 µg/dl.  more (P <0.05) • No sign. change of serum total T4 & reverse T3 •  Serum TSH declined equally after both diets • Sign.  serum triglycerides after the HF diet (HF 52 mg/dl, HP 67 mg/dl). • 30%  serum T3 = 138 µg/d • No sign. change of serum total T4 & reverse T3 •  Serum TSH declined equally after both diets • Sign.  serum insulin 30 minutes after the HP meal (148 microU/ml) than after the HF meal (90 microU/ml). • Sign.  serum insulin 30 minutes after the HP meal (148 µU/ml) than after the HF meal (90 µU/ml). • Sign.  2-hour glucose levelfor the HP meal, 85 mg/dl, than after the HF meal (103 mg/dl). A low-carbohydrate diet, frequently used for treatment of reactive hypoglycemia, hypertriglyceridemia, and obesity may affect thyroid function. We studied the effects of replacing the deleted carbohydrate with either fat or protein in seven healthy young adults. Subjects were randomly assigned to receive seven days of each of two isocaloric liquid-formula, low-carbohydrate diets consecutively. One diet was high in polyunsaturated fat (HF), with 10%, 55%, and 35% of total calories derived from protein, fat, and carbohydrate, respectively. The other was high in protein (HP) with 35%, 30%, and 35% of total calories derived from protein, fat, and carbohydrate. Fasting blood samples were obtained at baseline and on day 8 of each diet. A meal tolerance test representative of each diet was given on day 7. The triiodothyronine (T3) declined more (P less than .05) following the HF diet than the HP diet (baseline 198 micrograms/dl, HP 138, HF 113). Thyroxine (T4) and reverse T3 (rT3) did not change significantly. Thyroid-stimulating hormone (TSH) declined equally after both diets. The insulin level was significantly higher 30 minutes after the HP meal (148 microU/ml) than after the HF meal (90 microU/ml). The two-hour glucose level for the HP meal was less, 85 mg/dl, than after the HF meal (103 mg/dl). Serum triglycerides decreased more after the HF diet (HF 52 mg/dl, HP 67 mg/dl). Apparent benefits of replacing carbohydrate with polyunsaturated fat rather than protein are less insulin response and less postpeak decrease in blood glucose and lower triglycerides. The significance of the lower T3 level is unknown. • less insulin response • less postpeak  in blood glucose • lower triglycerides. Ullrich IH, Peters PJ, Albrink MJ. Effect of low-carbohydrate diets high in either fat or protein on thyroid function, plasma insulin, glucose, and triglycerides in healthy young adults. J Am Coll Nutr.1985;4(4):451-9

  27. Thyroidtreatment = most efficient hypolipemictreatment

  28. Thyroid treatment = should be started low & progressively increasing … Slow Progress: takes 2-6months to  or cure thehypothyroidism-induceddyslipidemia (partiallybecause of the slow & progressive increase in dose)

  29. TIP 1: PreferablydesiccatedT3-T4 (animal) thyroid=> greaterefficacybecause of its more prolonged action • TIP 2: Relativelyhigherphysiologicalthyroid doses maybenecessary to totally cure dyslipidemia • than for otherdisorders: • ≥ 75 mg/day of dessiccatedthyroid • ≥ 1 tablet/day (100 µg T4, 20 µg T3) • ≥ 125 µg/day of L-thyroxine Usually: 75-180 mg/day for strong hypolipemic effect TIP 2: Relativelyhigherphysiological doses maybenecessary

  30. TIP 3: The more severe the dyslipidemia, the greater the hypolipemiceffects of thyroidtherapy, even at lower doses=> greatefficacyon severedyslipidemia TIP 3: With L-Thyroxine, TSH suppression mightbenecessary to achievesignificanthypolipemiceffects TIP 2: Relativelyhigherphysiological doses maybenecessary

  31. Thyroid Therapy=>  Dyslipidemia

  32. Hypothyroid Euthyroid after thyroid treatment Normalization of Hypercholesterolemia Hypercholesterolemia

  33. THYROID THERAPY in euthyroid subjects & SERUM CHOLESTEROL Serum cholesterolmg/dl DESSICATED THYROID 180 mg/d =114:27 µg/d   NOVOTHYRAL(185:37.5 µg/d)   L-THYROXINE (300 µg/d)   CYTOMEL(100 µg/d)   0 2 w -7 % 2 w -9 % 6 w 0 0 6 w -12 % 0 231 233 2 w  -20 % 230 2 w  -21 % 228 218 214 212 6 w  -31 % 206 180 6 w  -40 % 175 158 131 4,22 : 1 5 : 1 100 : 0 0 : 100 T4:T3 figure : Effects on serum cholesterol of different thyroid preparations administered to healthy euthyroid men : T3 alone and dessicated thyroidreduce serum cholesterol persistently (Allery RA et al, Metabolism, 1968, 17 (2) : 97-104)

  34. SYNTHETIC THYROID PREPARATIONS & SERUM CHOLESTEROL in enthyroid subjects NOVOTHYRAL (188 : 37.5) THYROXINE (300 mcg/d) EUTHYRAL(180 : 45) (150 : 50) 0 0 0 6 w 0 0 CYTOMEL 2w 2w 6 w 2w 6 w 233 serum Choles-terol (mg/dl) 230 230 228 231 6 w 2w 214 217 212 218 206 208 2w 195 194 6 w 100 : 0 5 : 1 4 : 1 3 : 1 0 : 100 T4:T3 ratio figure : effects on serum cholesterol of different synthetic thyroid preparations administered to healthy euthyroid men. T3 alone decreases serum total cholesterol considerably.( Alley RA et al, Metabolism 1968, 17 (2) : 97-104)

  35. Thyroid therapy => serum cholesterol PATIENTS with initial TSH  40 mU/l ALL PATIENTS PATIENTS with initial TSH  40 mU/l PRIOR T4 - 11 % T4-replacement therapy T4- 36 % PRIOR Serum cholesterol (mg.dl) (mmol/l) PRIOR 297 230 346 223 263 235 highly significant (7.72) (5.99) (8.99) (5.81) (6.84) (6.11) figure : in 139 hypothyroid patients, there is a highly significant correlation between serum cholesterol concentration & thyroid status (Elder J et al, Am Clin Biochem, 1990, 27 : 110 - 113)

  36. T4 treatment =>   serum cholesterol & triglycerides 22 patients with primary hypothyroidism & hyperipidemia L-thyroxine, 0.05--0.2 mg/day fora mean of 16 months. • Normalized serum cholesterol(<265mg/dl) in 91% • Sign. -47 %  serum cholesterol:Initial mean pretreatment fasting serum cholesterol = 387 mg/dl => T4 => 205 mg/dl (p < 0.005) • Normalized serum triglycerides (<200 mg/dl) in 86% • Sign. -59 %  serum triglycerides: Initial mean pretreatment fasting serum triglycerides = 328 mg/dl => T4 => 133 mg/dl (p < 0.005) • Mean maintenance L-thyroxine dose = 150 µg mg/day, but smaller doses often showed marked hypolipidemic effect. Hypothyroidism = common reversible hyperlipidemia mean age: 46 yrs, 59% = males Mishkel MA, Crowther SM.Hypothyroidism, an important cause of reversible hyperlipidemia. Clin Chim Acta. 1977 Jan 17;74(2):139-51

  37. T4 must suppress serum TSH =>  total & LDL cholesterol in postmenop. women w / subcl. hypothyroidism 11 postmenopausal women with subclinical hypothyroidism ( TSH, normal free T4) Short-term T4 treatment before therapy & 6 weeks after T4 at incremental doses (50, 100, 150 µg/day) RESULTS: Short- termtreatment of womenwithsubclinicalhypothyroidism& Long-term T4 treatment of womenwithovert & subclinicalhypothyroidism • Sign.  total & LDL cholesterolwithincreasing T4 dose (P < 0.001) • WhenTSH wasrestored to normal revealedno significantdifference in lipidscompared to pretreatmentlevels & non-T4 treatedcontrols •  WhenTSH wassuppressedin the samesubjectswhen => sign.  total & LDL cholesterol => suggestthat patients withsubclinicalhypothyroidismshouldreceive replacement therapy => Doses of T4 whichsuppress TSH to below normal have a more sign. influence uponlipidsthan doses of T4 which restore TSH to the normal range. 105 postmenopausal women on T4 herapy for min. 1 yr vs 105 controls Crosssectional study of long-term (at least 1 yr) T4 treatment, Franklyn JA, Daykin J, Betteridge J, Hughes EA, Holder R, Jones SR, Sheppard MC. Thyroxine replacement therapy and circulating lipid concentrations. Clin Endocrinol (Oxf). 1993 May;38(5):453-9 Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, UK.

  38. Thyroid => Homocysteine

  39. T4 therapy: a target = serum TSH < 2 = optimal to lower serum CRP & homocysteine

  40. Thyroid => Liporotein a

  41. T4 => reduced Lp-a, LDL & total cholesterol

  42. 2ndmost efficient hormone therapy of dyslipidemia in Men =TestosteroneTherapy

  43. The importance of Testosterone

  44. Before Testosterone therapy Dry, thin hair Low

  45. Low Serum Testosterone=>  Dyslipidemia

  46.  SerumTestosterone =>  Serum HDL,  VLDL +17% Blood cholesterol levels (mg/dl) -28% HDL HDL VLDL VLDL men with low testosterone men with average testosterone men with high testosterone Figure : The blood HDL cholesterol level increases and the level of the VLDL cholesterol declines proportionately to the increase of testosterone in the blood. 247 men of middle age participated in this study. The extreme values of blood levels of testosterone were for the three groups respectively 780-5330, 6.420-7.610 and 9.370-16.500 pg/ml. (Gutai J et al, AM J Cardiol, 1981, 48 : 897-902)

  47.  SerumTestosterone =>  Serum HDL,  VLDL & Triglycerides • Serum testosterone: -  HDL cholesterol (+ 12 % for the highest quartile) in 391 men aged 30-79 years)( 1,2,3) -  VLDL cholesterol (1, 3) -  triglycerides (3)  serum DHT : =>  HDL cholesterol (4) in coronary heart disease patients (1) Khaw KIT et al, Arterioscler Thromb, 1991, 11(3): 489-94 for study in 391 men aged 30-79 yrs (2) Freedman DS et al, Arterioscler Thrombos, 1991, 11(2): 307-15 for study in 4.062 men (3)Gutai I et al, Am J Cardiology, 1981, 48: 897-902 (4) Hämäläinen E et al, Atheroscdlerosis, 1987, 67: 155-62

  48. Serum Testo => correlated negatively w/ Serum Triglycerides & Lipoprotein a

  49. Serum testo => neg assoc. w/ Lp-a

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