Dr Budi Wiweko, SpOG (K)

Tempat/Tgl Lahir : Jakarta, 15 Agustus 1971 Alamat : Vila Jatibening

Jl Villa Cendrawasih III Blok KH No .6 Bekasi

PENDIDIKAN 1. Fakultas Kedokteran Universitas Indonesia (1990-1996) 2. Spesialis Obgin FKUI (2001-2005) 3. Research Student di Hyogo College of Medicine, Japan (2006) 4. Spesialis Konsultan FER di FKUI (2009) PEKERJAAN

1. Staf Medis Departemen Obstetri Ginekologi FKUI-RSCM (2005Sekarang)

2. Asisten Manajer Pendidikan Dokter Spesialis Obgin FKUI (2006Sekarang)

HORMONAL THERAPY
What should we do after WHI study ?

Budi Wiweko

Division of Reproductive Immunoendocrinology Department of Obstetrics and Gynecology Faculty of Medicine University of Indonesia Dr. Cipto Mangunkusumo General Hospital
Jakarta

Outline of this talk

1. 2. 3. 4. Background Benefits and risks of hormonal therapy How to choose hormonal therapy ? Take home messages

Background

Benefits and risk of hormonal therapy

How to choose hormonal therapy

Take home messages

An epidemic of fear and distrust has infected women (and physicians) after publication of the Womens Health Initiative (WHI)
Graziottin. Maturitas, 2005

PROS AND CONS

Background

Benefits and risk of hormonal therapy

How to choose hormonal therapy This is RCT about combination of 0.625 mg Conjugated Equine Estrogen and 2.5mg Medroxyprogesterone Acetate on 16.608 post menopausal women between 50-79 years old

Take home messages

JAMA, July 17, 2002 Vol.288, 321-33

JAMA, July 17, 2002 Vol.288, 321-33

JAMA, July 17, 2002 Vol.288, 321-33

Background

Benefits and risk of hormonal therapy

How to choose hormonal therapy

Take home messages

Background

Benefits and risk of hormonal therapy

How to choose hormonal therapy

Take home messages

25.000

Speroff L, Glass R, Kase N. Clinical gynecologic endocrinology and infertility, 7th edition, 2005

Low level estrogen related symptoms

EARLY SYMPTOMS
Background

Benefits and risk of hormonal therapy

How to choose hormonal therapy

- Vasomotor - Hot flushes - Night sweat - Urogenital tract symptoms - Vaginal dryness and dyspareunia - Low sexual drive - Dysfunction of orgasm - Urinary incontinence - Psychological symptoms - Mood swings - Depression - Anxiety - Insomnia

Take home messages

LONG TERM EFFECT

Background

Benefits and risk of hormonal therapy

Osteoporosis Pelvic floor laxity Cardiovascular disease Colon cancer Alzheimers disease

How to choose hormonal therapy

Take home messages

Background

North American Menopause Society (NAMS)

No Terminology
EPT ET

Description
Combined estrogen-progestogen therapy Estrogen therapy

Benefits and risk of hormonal therapy

1 2

3
4 5 6

HT
Local therapy Progestogen Systemic therapy

Hormone therapy (encompassing both ET and EPT)

Vaginal ET administration Encompassing both progesterone and progestin HT administration that results in absorption in the blood

How to choose hormonal therapy

Take home messages

Menopause, 2010

Background

Indications for Hormonal Therapy

Relief of menopausal symptoms Long term prevention of cardiovascular disease, dementia, and osteoporosis

Benefits and risk of hormonal therapy

How to choose hormonal therapy

Take home messages

Background

Benefits and risk of hormonal therapy

How to choose hormonal therapy

Using validated methods of measuring well-being and quality of life, the authors showed that, after 1 year, significant improvements were observed in the following domains for those taking combined hormone therapy: vasomotor symptoms, sexual functioning, sleep problems, aching joints or muscles (p < 0.001 for all)

Take home messages

Health related quality of life after combined hormone replacement therapy: randomised controlled trial. BMJ. 2008

Background

Benefits and risk of hormonal therapy

Vasomotor
ET, with or without a progestogen, is the most effective treatment for menopause-related vasomotor symptoms (ie, hot flashes and night sweats) and their potential consequences (eg, diminished sleep quality, irritability, and reduced QOL)

How to choose hormonal therapy

Take home messages

Menopause, 2010

Background

Benefits and risk of hormonal therapy

Urogenital tract

How to choose hormonal therapy

Take home messages

1. Relief of moderate to severe vaginal atrophy with systemic or local HT can be effective in relieving dyspareunia, a common cause of intercourse avoidance 2. Local ET may help reduce the risk of recurrent urinary tract infection (UTI)
Menopause, 2010

Background

Benefits and risk of hormonal therapy

Cardiovasvular
1. HT is currently not recommended as a sole or primary indication for coronary protection in women of any age 2. Initiation of HT by women ages 50 to 59 years or by those within 10 years of menopause to treat typical menopause symptoms (eg, vasomotor, vaginal) does not seem to increase the risk of CHD events
Menopause, 2010

How to choose hormonal therapy

Take home messages

Background
10 years Estrogen + MPA

Benefits and risk of hormonal therapy

How to choose hormonal therapy

Take home messages

Drive J. Curr Op Obste Gynecol, 2005

HORMONAL THERAPY
Background Benefits and risk of hormonal therapy

ESTROGEN
1. Oral (tablet) 2. Transdermal Patch Gel 3. Vaginal Vaginal ring Vaginal cream

How to choose hormonal therapy

PROGESTIN
Tablet Levonorgestrel intrauterine system (LNG-IUS)

Take home messages

Low estrogen

Hyperinsulinemia

Increase PAI-I Increase VLDL Decrease HDL

Resistensi Insulin

will improved

Background

Benefits and risk of hormonal therapy

How to choose hormonal therapy Increasing HDL Lowering VLDL Take home messages Increase NO and prostacyclin
Sitruk et al. Maturitas, 2007 Bonasi. Contraception, 2010

Antagonis

Negative Effects of Progestin

Water retention

Cardiovascular a. Decreasing HDL and increasing VLDL b. Decreasing NO intravascular

Lopez et al. Maturitas, 2008

PROGESTERONE AND PROGESTINS

Natural Synthetic

Retroprogesterone Dydrogesterone

Progesterone

19-norprogesterone
Trimegestone Nestorone Nomegestrol Acetate Promegestone

17-hydroxyprogesterone
Medroxyprogesterone acetate (MPA)

19-nortestosterone

Medrogestone Chlormadinone acetate Cyproterone acetate

Norethindrone (Estranes) Norethindrone acetate (NETA)

Levonorgestrel (gonanes) Desogestrel Norgestimate Gestodene

Spirolactone Drospirenone

Norethynodrel Lynestrenol Ethynodiol diacetate

Norgestrel

Anti-aldosterone action of drospirenone

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

Background

Drospirenone increases endothelial nitric oxide synthesis via a combined action on progesterone and mineralocorticoid receptors
T. Simoncini, X-D. Fu, A. Caruso, S. Garibaldi, C. Baldacci, M.S. Giretti, P. Mannella, M.I. Flamini, A.M. Sanchez and A.R. Genazzani

Benefits and risk of hormonal therapy

How to choose hormonal therapy

Endogenous estrogens seem to play a protective role on cardiovascular cells, including endothelial, smooth muscle cells and cardiomyocytes, explaining part of the gender-related differences in coronary heart disease (CHD)
This study assess the effects of DRSP on eNOS activity and expression in human endothelial cells and compare it with P and the synthetic progestogen MPA

Take home messages

Hum Reprod, 2007

Background

Benefits and risk of hormonal therapy

How to choose hormonal therapy

DRSP blocks the reduction of eNOS expression associated with aldosterone through its anti-mineralocorticoid activity

Take home messages

This action might result in beneficial cardiovascular actions in women, particularly in the presence of endothelial dysfunction, such as in hypertension

Hum Reprod, 2007

No
Background

Estrogen Estradiol valerate 1 dan 2 mg Conjugated equine estrogen 0.625 mg Progestin

1 2

Benefits and risk of hormonal therapy

No 1 2 3 Norethisterone 5 mg

Medroxyprogesterone acetate 5 mg, 10 mg Nomegestrol acetate 5 mg

Estrogen Estradiol valerate 1 mg Estradiol valerate 2 mg Estradiol valerate 2 mg Progestin Drospirenone 2 mg Norgestrel 500 g Cyproterone Acetate 1mg Nama Paten Angeliq Cyclo progynova Climen

How to choose hormonal therapy

No 1 2 3

Take home messages

Background

HT Regimens
Women who have had a hysterectomy only need to take estrogen Women with an intact uterus must take progestogen for endometrial protection to prevent endometrial cancer or hyperplasia

Benefits and risk of hormonal therapy

How to choose hormonal therapy

Take home messages

Background

Continu
Estrogen and progestin were given since day 1st NO PERIODS

Benefits and risk of hormonal therapy

HORMONAL THERAPY
How to choose hormonal therapy

Sequential
Take home messages Progestin was given on last 10 days PERIODS

Clinical efficacy: Amenorrhea rates after 1 year

% patients with no bleeding

Angeliq: 88% cycle control after 1 year 64% of bleedings confined in 12 pill cycles In most cases spottings Mean number of bleeding days: 0.9 days

Cycle number

Archer DF et al. Menopause 2005; 12 (6): 716-727

Angeliq: Number of hot flushes

80 Mean number of hot flushes/week 70 60 50 40 30 20 10 0 BL 1 2 3 4 5 6 7 8 Treatment week 9 10 11 12 13 14 15 16 Placebo (n=46) Angeliq (n=38)

*P>0.001
*

BL, baseline
Schrmann R et al. Climacteric 2004;7:189-196

Angeliq: Incidence of menopausal CNS symptoms

Sweating episodes 100 Sleep problems

Baseline Week 16 Baseline Week 16

Placebo (n=61) Angeliq (n=52)

75 Patients (%) Depression

50

25

0 Placebo Angeliq Placebo Angeliq Placebo Angeliq

CNS, central nervous system

Schrmann R et al. Climacteric 2004;7:189-196

Effect on vertebral BMD in osteopenic patients

Change from baseline in lumbar spine BMD (%) 6 5 4 3 2 1 0 -1 -2 Months of treatment BL 3 6 12 18 24 Angeliq (n=18) Placebo (n=18)

Osteopenic women

BL: baseline; BMD: bone mineral density

Schering AG, data on file

Angeliq: Change in lipid levels

20 15 10 5 0,6 0 -0,2 -5 -10 -15 -12,8 Total C -6,7 -12,7 LDL-C HDL-C TG HDL/LDL Angeliq Estradiol 1 mg 17,5

4,2
1,4

0,1 0,1

Archer D et al. Menopause 2005;12:716-27

1.
Background

The best candidates for HT are early postmenopausal symptomatic women

Benefits and risk of hormonal therapy

2.

Those who should not be treated with HT include obese women (BMI of 30 or more) and women with high cardiovascular risk or previous coronary events Drospirenone is the progestogen of choice, given its anti mineralcorticoid and anti androgenic activity that prevent cardiovascular risk The benefits of reduction in bone fractures and reduction of colon cancer risk , constantly found in observational studies, are confirmed by WHI as well

How to choose hormonal therapy

3.

Take home messages

4.

Menopausal women

Hormonal therapy

Climacteric symptoms History of breast cancer USG Mammography Pap smear Liver function, lipid profile BMD

Anamnesis and physical examination Intact uterus E+P Periods EP Sequential No periods Starting lowest dosage EP Continu Estradiol valerate 1 mg CEE 0.375 mg Norethisterone 2.5 mg Nomegestrol acetate 2.5 mg No uterus Estrogen

E: D1-D21 P: D11-D21

Combination

ANGELIQ