PENYAKIT KARDIO VASKULER DENGAN HORMON TERAPI

PENYAKIT KARDIO VASKULER DENGAN HORMON TERAPI Noor Pramono Noerpramana Obstetri Ginekologi Indonesia Ke-XIII Kongres Obstetri Ginekologi Manado 7-127 Juli 2006 RABU, 12 JULI 2006. PKL 11.30 12.30

SKEMA MEKANISME KERJA AKSIS HIPOTALAMUS-HIPOFISIS HIPOFISIS-OVARIUMOVARIUM PADA MASA REPRODUKSI

SKEMA PERUBAHAN AKSIS HIPOTALAMUS-HIPOFISIS HIPOFISIS-OVARIUMOVARIUM PADA MENOPAUSE

DEFISIENSI ESTROGEN SINTESIS SEROTONIN fl KATABOLISME SEROTONIN PREKURSOR ESTROGEN- KATEKOLAMIN fl SISTEM LIMBIK KENDALI SIMPATO- HIPOTALAMIK fl TERMOREGULASI SISTEM KARDIOVASKULER MOOD fl AFEK fl MEMORI fl LIBIDO fl MOTIVASI fl HOT FLUSHES KERINGAT MALAM PALPITASI

GEJALA DAN TANDA MENOPAUSE

TERAPI HORMON IDEAL

FAKTOR RISIKO PENYAKIT KARDIO VASKULER Potentially modifiable risk factors High total cholesterol (>240mg/dl =>6.2mm0l/dl) Low serum high density lipoprotein cholesterol (<35mg/dl=<0.9mmol/L) Hypertension (>140/>90 mm Hg) Obesity (> 130% normal body weight) Physical inactivity Smoking Alcohol abuse Diabetes mellitus Unmodifiable risk factors Premature menopause (<45 years) Family history of premature CVD Male sex Male age (> 45 Years)

FAKTOR RISIKO PENYAKIT KARDIO VASKULER DYSLIPIDEMIA HYPERTENSION & ATHEROSCLEROSIS OBESITY DIABETES MELLITUS HEMOSTASIS SYSTEM PHYSICAL INACTIVITY SMOKING AND ALCOHOL ABUSE OTHER

DYSLIPIDEMIA DIWASPADAI PENYAKIT KARDIO VASKULER Total Kolesterol Serum > 240 mg/dl LDL HDL (>= 62 mmol/l ) Kolesterol Serum > 160 mg/dl Kolesterol Serum < ( =< 0.9 mmol/l) HDL-2 Kolesterol Serum < 35 mg/dl 30 mg/dl

HYPERTENSION & ATHEROSCELORIS DIWASPADAI PENYAKIT KARDIO VASKULER Tekanan Darah >140 / > 90 mm Hg Atherosclerosis

ATHEROSCLEROSIS MERUPAKAN PENYEBAB UTAMA PENYAKIT KARDIO VASKULER

MEKANISME TERJADINYA ATHEROSCLEROSIS

SEL ENDOTEL VASKULER Sel endotel vaskuler menghasilkan prostasklin ( Vasodilator) dan Endotelin (Muscle relaxant) Stabilisator tekanan diastolik Post menopause Produksi prostasiklin dan endotelin?, Transport kalsium pada otot vaskuler? Tekanan darah tak stabil dan kejadian atheroma? PKV

OBESITY DIWASPADAI PENYAKIT KARDIO VASKULER Obesity ( >= 130 % normal body weight) Obesitas Androgenik ( ANDROID FAT?) PKV? Post Menopause Proporsi Android FAT/GYNECOID FAT? RESISTENSI INSULIN? HIPERGLIKEMIA PKV

DIAGNOSIS PKV ANAMNESIS PEMERIKSAAN FISIK PEMERIKSAAN PENUNJANG ELEKTROKARDIOGRAFI EKHOKARDIOGRAFI ANGIOGRAFI KORONER THALLIUM EXERCISE MYOCARDIAL IMAGING LABORATORIUM (CKMB, LDH, AST)

DIABETES MELLITUS Diwaspadai penyakit kardio vaskuler oleh karena komplikasinya Post menopause Sekresi insulin? & sensitivitas jaringan terhadap insulin? Resistensi insulin? Hiperglikemia

HEMOSTASIS SYSTEM Pada gangguan hemostasis sebagai akibat dari peningkatan PAI-1 1 (Plasminogen( activator inhibitor-1) Hipofungsi Fibrinolitik PKV Post Menopause Estrogen? Produksi Prostasiklin? Adhesi Trombocit?,, Faktor Koagulasi VII Dan Fibrinogen?,, Faktor Anti Koagulan Antitrombin III? dan Inhibitor Fibrinolisis PAI-1? PKV

The Role of Estrogen & Progestin in Hormone Therapy Estrogen Progestin Positive Effect Negative Effect Positive Effect Negative Effect Hot Flushes Skin Dyslipidemia (HDL?, LDL?) Hemostasis syst Cardio Vascular Endothel Vasc Metabolism Advantage Bone Turn Over CNS, etc Proliferation: Endometrium Breast, mitosis? RAAS Adverse : Aldosterone?? Body Weight? Blood Pressure?? Anti Estrogen Proliferation? & Aldosterone? Androgen, Proliferation, Metabolism Acne SHBG?? Proliferation of Breast Gland Metabolism Adverse RAAS = Renin Angiotensin Aldosterone System

PENGARUH ESTROGEN PADA METABOLISME LIPOPROTEIN

PENGARUH ESTROGEN PADA PEMBULUH DARAH (Estrogen Menghambat Atherosclerosis) Menghambat Oksidasi LDL Kolesterol Meningkatkan reseptor LDL Hepatik Meningkatkan produksi EDRF ( Endothelium-Dependent Relaxing Factor)

PENGARUH ESTROGEN PADA SISTEM HEMOSTASIS Pemberian Estrogen Produksi Prostasiklin? Adhesi Trombocit?, Faktor Koagulasi VII & Fibrinogen?, Faktor Anti Koagulan Antitrombin III?&& Inhibitor Fibrinolisis PAI-1? Proteksi PKV

PENGARUH ESTROGEN PADA ENDOTEL VASKULAR Pemberian Estrogen produksi Prostasiklin dan Endotelin?, Transport Kalsium pada otot Vaskuler? Tekanan darah stabil dan kejadian Atheroma? cegah PKV

METABOLISM ADVANTAGE OF ESTROGEN Pemberian Estrogen Sekresi Insulin & Sensitivitas jaringan terhadap insulin? Resistensi Insulin? cegah Hiperglikemia

NEGATIVE EFFECT OF ESTROGEN PENGARUH ESTROGEN PADA RAAS Aldosterone? Body Weight? Blood Pressure?

POSITIVE EFFECT OF PROGESTIN PENGARUH PROGESTIN (Anti Estrogen) Aldosterone? Aldosterone? ( BW?, BP?)

NEGATIVE EFFECT OF PROGESTIN PENGARUH PROGESTIN (Metabolism Adverse) Progestin sekresi insulin pankreas?& resistensi insulin? hiperglikemia PKV

PENELITIAN TERAPI HORMON PADA MENOPAUSE 1. PEPI 2. NHLBI 3. HERS 4. WHI 5. NURSES HEALTH STUDY ( NHS) 6. PROSPECTIVE EPIDEMIOLOGICAL RISK FACTORS ( PERF STUDY)

Relative and absolute risks (hazard ratio,hr) for preventable postmenopausal diseases. * An estrogen monotherapy study, randomized and controlled against placebo: hysterectomized women; mean age at start of treatment 63.86 years (50-79 years); mean duration of treatment 6.8 years; 0.625 mg conjugated d estrogens treatment and in part not healthy Disease Breast cancer Relative risk againts placebo (HR); nominal 95% confidence limits 0.77 (0.59-1.01) Absolute risk no.of probands/ 10,000 women years Conjugated estrogen 26 Placebo 33 Risk ERT 1 - Benefit ERT 1 7 Coronary infarction 0.91 (0.75-1.12) 49 54-5 Stroke 1.39(1.01-1.77) 2 44 32 12 - Thromboembolism 1.33 (0.99-1.79) 28 21 7 - Colorectal cancer 1.08(0.75-1.55) 17 16 1 - Osteoporotic fractures 0.70 (0.63-0.79) 3 139 195-56 Sum of events - - - 20 68 Mortality 0.98 - - - - * Source; WHI Steering Committee. JAMA 2004; 291:1701-1212

Relative and absolute risks (hazard ratio,hr) for preventable postmenopausal diseases. * An estrogen + MPA study, randomized and controlled against placebo: mean age at start of treatment 63.2; mean age at end of treatment 69.4 years; mean duration of treatment 5.2 years with correction in 2003;0.625 mg conjugated estrogens + 2.5 mg MPA given combined and continuosly; n=8506 estrogen +MPA, n 8102 placebo Disease Relative risk againts placebo (HR); nominal 95% confidence limits Absolute risk no.of probands/ 10,000 women years Risk EPRT 1 Benefit EPRT 1 Conjugated Estrogens + MPA Placebo Breast cancer 1.24 (1.01-1.54) 2 41 33 8 0 Coronary infarction 1.24 (1.00-154) 3 37 30 7 0 Stroke 1.41(1.07-1.85) 4 29 21 8 0 Thromboembolism 2.11 (1.58-2.82) 34 16 18 0 Colon cancer 0.63(0.43-0.92) 5 10 16-6 Osteoporotic fractures 0.76 (0.69-0.83) 152 199-47 Diabetes 0.79 20 15-5 Sum of events - - - 41 59 Mortality 0.98 52 53-1 * Source; WHI Steering Committee. JAMA 2004; 291:1701-1212

Influence of age on the hazard ratio (HR) of preventable postmenopausal opausal disease with the intervention of conjugated estrogen. * An estrogen monotherapy study, randomized and controlled against placebo: mean duration of treatment 6.8 years; 0.625 mg conjugated estrogen given continously Disease Age (years) Total HR for all ages 50-57 1 60-69 70-79 Total of probands population (%) 33.4 45.3 27.3 - Coronary heart disease 0.56 0.92 1.04 0.91 Stroke 1.08 1.65 2 1.25 1.29 Venous Thromboembolism 1.22 1.31 1.44 1.33 Mammary cancer 0.72 0.72 0.94 0.77 Colorectal cancer 0.59 0.88 2.09 1.03 Hip fractures - 0.33 3 0.62 0.70 3 Mortality 0.73 1.01 1.20 1.08 * Source; WHI Steering Committee. JAMA 2004; 291:1701-1212

Data for manifold pre-existing existing disease, anomalies and medicaments of probands of the WHI study.* An estrogen monotherapy study, randomized and controlled againts placebo; mean duration of treatment 6.8 years; 0.625 mg conjugated estrogens given continuously; n = 5310 estrogen, n=5429 placebo. A high percentage of probands exhibited contraindications of estrogen medication and relevant risk factors were present, as evidenced by the use of specific medicaments. Probands were mostly too old for oral estrogen administration and no indication for replacement was existent in the majority of cases. No proof of estrogen deficiency was performed. Therefore the study was not one of replacement but of experimental medication, embedded in a worst-case scenario Anamnestic data No. of probands Probands (%) Hypertension 2308 48 Cholesterol increase 694 14.5 Medication of statins 394 7.4 Medication of acetyl salicyclic acid 1030 19.4 History of myocardial infarction 165 3.1 1 Angina pectoris 308 5.8 1 History of stroke 76 1.4 1 Bypass operation (angioplasty) 120 2.3 1 History of thromboembolism 87 1.6 1 Diabetes mellitus 410 7.7 Smokes 2529 47.6 2 Overweight (BMI>30) 2376 45.0 2 ERT before study 2540 47.8 Nulliparae 489 9.3 2 First child 30 years of age 210 4.9 2 Breast cancer in family 836 18.0 2 * Source; WHI Steering Committee. JAMA 2004; 291:1701-1212

Ispection of the year by year analysis of incidence of coronary heart disease (CHD) in the treatment and placebo groups of the women s Health Initiative (WHI) study No. of CHD events Hazard rate ( risk ratio) Treatment Placebo Year 1 43 23 1.78 1 Year 2 36 30 1.15 Year 3 20 18 1.06 Year 4 25 24 0.99 Year 5 23 09 2.38 1 Year 6 17 18 0.78 * Source; WHI Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004; 291:1701-1212

The timing of the initiation of HT may well be critical for the effects on the coronary arteries estrogen is now beneficial if started at the right time ( the pendulum swings back), table below

Number of cases of selected coronary events over 7 year s treatm ent with either conjugated equine estrogens (CEE) or placebo in women aged 50-59 59 years at baseline (from WHI) Coronary event CEE (n=1673) Placebo (n=1637) Hazard ratio (95 % confidence interval) Coronary heart disease 23 34 0.63 (0.36-1.08) (MI or coronary death) CABG or PCI MI, coronary death, CABG and PCI 29 42 52 65 0.55 ( 0.35-0.86) 0.66 (0.44-0.97) MI, coronary death,cabg, PCI and angina 46 70 0.66 ( 0.45 0.96) MI myocardial infraction; CABG, coronary artery bypass grafting; g; PCI, percutaneous coronary intervention Adapted from Hisa et.al Arch intern Med 2006;357-65. 65.

A META-ANALYSIS OF CARDIAC EVENTS IN 23 RANDOMIZED, CONTROLLED TRIALS ON HT A significant reduction in younger women OR 0.68 ; CI 0.48-0.96. When RCT are divided into the initiation of HT before or after age 60 years, a significant reduction in all-cause mortality is seen in younger users, compared to placebo HR 0.61; CI 0.39-0.95 Adapted from Salpeter SR, et.al J.gent Intern Med 2004;19: 791-804.

MORE DATA ON HT & CORONARY HEART DISEASE (CHD): COMMENTS ON RECENT PUBLICATIONS FROM THE WHI & NHS EP & E WHI Study Actually HT does not? the risk of CHD in the PERI & Early Menopause, may carry beneficial effect NHS : Starting HT near the Menopause reduced risk of CHD RR 0.66, CI 0.54-0.80 for ET; RR 0.72, CI 0.56 0.92 for EPT

MORE DATA ON HT & CORONARY HEART DISEASE (CHD): COMMENTS ON RECENT PUBLICATIONS FROM THE WHI & NHS Sub group WHI study: no relation between HT & CHD among women who initiated therapy at least 10 years after the menopause RR 0.87, CI 0.68 1.10 FOR ET; RR 0.90, CI 0.62 1.29 FOR EPT. Initiating HT in older women with established atherosclerosis is not likely to produce any cardiac or neuro protection not to be recommended for those indication; for younger age groups of WHI & NHS study are in line with the Window of opportunity theory, Based on the assumption that estrogen is cardio protective when the arterial endothelium is still intact

THE LONG-TERM IMPACT OF 2-32 3 YEARS OF HT ON CARDIOVASCULAR MORTALITY & ATHEROSCLEROSIS IN HEALTHY WOMEN (PERF STUDY) In 2000 &2001, Subjects of the original randomized control trial were invited to partipate in a follow-up examination at research institute PERF study The subjects show in table below

Tahun 2000 dan 2001 PERF Study Penelitian di PERF StTUDY (Prospective Epidemiological Risk Factors) Hormone replacement therapies used in randomized, placebo-controlled, controlled, clinical trials for the present analysis Age range Years of Years of Study n (years) Estrogen Progestin treatment follow-up Reference.A 226 44-70 17ß-estradiol, norethisterone acetate, 1977-79 2000 16 estradiol valerate cyproterone acetate B 154 44-54 17ß-estradiol, norethisterone acetate, 1983-85 2000 17,18 *17ß-estradiol, cyproterone acetate progesterone C 11 45-53 17ß-estradiol, norethisterone acetate, 1983-84 2000 17 D 160 45-55 17ß-estradiol, cyproterone acetate 1987-90 2000 19 estradiol valerate levonorgestrel, desogestrel, Medroxyprogesterone Acetate E 338 44-62 17ß-estradiol, gestodene 1993-95 2000 20 F 70 56-75 17ß-estradiol, norethisterone acetate, 1985-86 2000 21 G 314 49-68 17ß-estradiol, norethisterone acetate, 1993-94 2000 22 piperazine estrone sulfate H 185 56-71 17ß-estradiol, norethisterone acetate, 1994-95 2000 23 All hormone regimens were oral, except for the 17ß-estradiol, indicated by asterisk (8) which as transdermal

PERF Study Baseline characteristic for women who received a few years of HRT (HRT+) or no HRT (HRT-). Data are mean ± 1SD HRT + HRT (n=553) (n=727) Age at baseline (years) 55.3 ± 5.6 55.9 ± 6.4 Body mass index (kg/m 2 ) 24.9 ± 3.9 25.6 ± 4.5 Serum total cholesterol (mmol//) 6.2 ± 1.6 5.9 ± 2.2 Serum triglycerides (mmol/l) 1.1 ± 0.6 1.2 ± 0.6 Fasting serum glucose (mmol/l) 5.3 ± 0.6 5.4 ± 1.3 White blood cell count (X10 9 /l) 5.4 ± 1.6 5.5 ± 1.5 Current smokers (%) 50.3 54.5

PERF Study Incidence of all-cause mortality due to cardiovascular disease (CVD) and coronary heart disease (CHD) in postmenopausal women stratified according to use of hormone replacement therapy (HRT) Cases HRT+ HRT- p Value All-cause mortality 174 51 (29.3%) 123 (70.7%) 0.024 CVD mortality 61 14 (23.0%) 47 (77.0%) 0.024 CHD mortality 39 8 (20.5%) 31 (79.5%) 0.025

PERF Study The impact of hormone replacement therapy on mortality rate of post menopausal women as a function of the follow-up period Cases HRT+ HRT- pvalue Follow-up = 5 years All cause mortality 45 17 28 0.637 CVD mortality 138 4 9 0.521 CHD mortality 8 3 5 0.901 Follow up > 5 years and = 10 years All cause mortality 38 9 29 0.843 CVD mortality 13 4 9 0.521 CHD mortality 8 3 5 0.901 Follow up > 10 years All cause mortality 91 25 CVD mortality 32 9 CHD mortality 20 5 CVD, cardiovascular disease: CHD, coronary heart disease HRT + designates users of HRT, and HRT - designates non-users of HRT 66 23 15 0.004 0.042 0.305

SUMMARY OF PERF STUDY Short term use of HT in healthy postmenopausal women provides longterm cardiovascular benefits as indicated by a decreased all cause and cardiovascular mortality rate and decelerated atherogenesis compared with non-users of HRT

ESTROGEN & PROGESTIN YANG DIPAKAI PADA HT Estrogen : - CEE - 17 ß-estradiol - Estradiol Valerate - Piperazine - Estrone sulfate Hasil penelitian mempunyai efek cukup baik Progestin : - pada tabel dibawah Progestin baru diperlukan untuk pengganti progestin lama yang mempunyai banyak efek samping Tibolone (bersifat progestogenik, estrogenik & androgenik) penelitian telah dilakukan

Comparison of Drospirenone With Other Progestins Progestins C-21 progestins 19-nortestosterone Spirolactone Pregnanes Medroxyprogesterone acetate Megestrol acetate Cyproterone acetate Estranes Norethindrone Noreth. acetate Ethynodiol diacetate Lynestrenol Norethynodrel Gonanes Norgestrel Levonorgestrel Norgestimate Desogestrel Gestodene Drospirenone

Related to progesterone Dydrogesterone 17-OH Progesterone Medroxyprogesterone Acetate Cyproterone Acetate Chlormadinone Acetate Megestrol Acetate Drospirenone 19-nor progesterone Nomegestrol Acetate Trimegestone Promegestone Klasifikasi Progestin (Progesteron sintetik) Related to testosterone Estranes Norethisterone Estrane/Pregnane Dienogest Gonanes Norgestrel Desogestrel Gestodene Norgestimate Pharmacological profile of progestins, R. Struck-Ware. Maturitas 47 (2004) 278

DIPERLUKAN PROGESTIN BARU YANG LEBIH BAIK 17-OH Progesterone Medroxyprogesterone Acetate Cyproterone Acetate Chlormadinone Acetate Megestrol Acetate Drospirenone (PARA = Progestogen with Aldosterone Receptor Antagonism mempengaruh RAAS) Tibolone ( bersifat progestogenik, estrogenik dan androgenik)

Comparison of Drospirenone With Other Progestins Progestogenic activity Androgenic activity Antiandrogenic activity Antialdosterone activity Glucocorticoid activity Progesterone + (+) + Drospirenone + + + CPA Desogestrel + + (+) + (+) Dienogest Gestodene Levonorgestrel MPA Norethisterone Norgestimate Tibolone + + + + + + + (+) (+) (+) (+) (+) + + (+) (+) + relevant activity; (+) activity not clinically relevant; no activity CPA: cyproterone acetate ; MPA: medroxy progesterone acetate Schindler AE et al. Maturitas. 2003;46(suppl 1):S7-S16; Rübig A. Climacteric. 2003;6(suppl 3):49-54.

Renin Angiotensin - Aldosteron System

Effect of Drospirenone on the Renin- Angiotensin-Aldosterone Aldosterone System (RAAS) Estrogens Angiotensinogen Angiotensin I Angiotensin II Adrenal gland Aldosterone Sodium- and water retention - Increased plasma volume - Rise of blood pressure in susceptibles - Water retention-related symptoms (edema, bloating, weight gain) Receptor level DRSP

Pharmacological and Clinical Effects of Aldosterone and Anti-Aldosterone Aldosterone Action of DRSP

GLOMERULUS RBF JGA LIVER RENIN ANGIOTENSINOGEN + ANGIOTENSIN I CONVERTING ENZYM ADRENAL CORTEX ANGIOTENSIN II LUNG ALDOSTERON BRAIN S ARTERI retensi Na & H2O Intake H2O VASOKONSTRIKSI Blood Vol HEART COP x R SV H R RENIN-ANGIOTENSIN CONTROL BP BP

DROSPIRENONE & CARDIOVASCULAR DISEASE The beneficial effect on the cardiovascular system of drospirenon as demonstrated by control of blood pressure, and the prevention of estrogen induced sodium and water retention and body weight gain

THE POSSIBLE CARDIOVASCULAR BENEFITS ASSOCIATED WITH ALDOSTERONE ANTAGONISM INCLUDE: INCREASED SODIUM EXCRETION AND PREVENTION OF EDEMA AND WEIGHT GAIN LEADING TO: Decreased systolic and diastolic blood pressure Improved baroreceptor function Prevention of vascular and myocardial fibrosis Improved vascular compliance (elasticity/thickening)

THE POSSIBLE CARDIOVASCULAR. Improved diastolic function Improved endothelial function and nitric oxide availability Improved myocardial norepinephirine uptake Decreased ventricular ectopic activity Decreased levels of plasminogen activator inhibator (PAI-1) Reduced mortality and morbidity in patients with severe heart failure

Pharmacological and Clinical Effects of Aldosterone and Anti-Aldosterone Aldosterone Action of DRSP

Penelitian Drospirenon terhadap metabolisme karbohidrat Drospirenon shows : No glucocorticoid or antiglucocorticoid activity No relevant impairment of fasting glucose levels or oral glucose tolerance

EFFECTS OF TIBOLONE ON BLOOD FLOW RESISTANCE AND INTIMA-MEDIA MEDIA THICKNESS OF THE CAROTID ARTERIES: EFFECT OF TIME SINCE MENOPAUSE No significant effects of tibolone on either intima-media thickness or blood flow resistance in the carotid arteries in postmenopausal women. However, the results suggest that tibolone may have a positive effect on the vascular system if commenced within 18 months since menopause; this warrants further investigation. A.Somunkiran, B.Yazici,F.Demirci, Berdogmus and I.Ozdemir. Climacteric 2006;9:59-65

S I M P U L A N Patofisiologi: Pengaruh positif estrogen Metabolisme lipoprotein Menghambat atherosklerosis Sistem hemostasis Endotel vaskular Metabolisme karbohidrat cegah hiperglikemia Pengaruh negatif Estrogen RAAS Aldosterone? BB?&TD? Pengaruh positif Progestin tertentu RAAS Aldosterone? BB? &TD? Pengaruh negatif Progestin Metabolisme karbohidrat hiperglikemia

Penelitian S I M P U L A N Estrogen mempunyai pengaruh positif pada PKV apabila dimulai pada saat yang tepat ( umur 50-59 th) Estrogen-progestin mempunyai pengaruh posistif pada PKV apabila pemberiannya sebelum umur 60 th dimana umumnya endotel arteri masih utuh Pemakaian Terapi Hormon jangka pendek (5 th atau kurang) pada wanita postmenopause sehat berdampak positif jangka panjang terhadap Kardio Vaskuler Pemakaian Progestin baru yang berpengaruh positif terhadap PKV, sangat bermanfaat, masih perlu penelitian lanjut. Pengaruh negatif Terapi Hormon diluar Kardio Vaskular perlu ditelaah lebih teliti