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NGUYEN THI NGOC PHUONG
PROFESSOR

TREATMENT OF MENOPAUSE:
HORMONAL and NON-HORMONAL THERAPY
Prof. NGUYEN THI NGOC PHUONG, MD.
Vice President of Vietnam Asociation of Gynecologists and Obstetricians
President of Ho Chi Minh City Society for Reproductive Medicine

THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
MHT – MENOPAUSE HORMONE THERAPY -
A DECADE AFTER WHI
▸ WHI – Women' Health Initiative ▸ Published on July 2002 ▸ Resulting in many negative effects – "shock" in attitudes and practices toward MHT ▸ Many limitations, bias and drawbacks of this research were revealed afterward ▸ Many well-designed and scientific have been induced after WHI, concentrated on: advantages – disadvantages, positive and negative effects, risks and side effects of MHT

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ON OBSTETRICS AND GYNECOLOGY 2016
MHT, A DECADE AFTER WHI
▸ The benefits of MHT outweighs the risks
• Indicated as soon as possible – perimenopause or within 10 years of menopause • Patient's age: not over 60 y/o ▸ MHT is an effective treatment for moderate to severe menopausal symptoms and may be one of the way for preventing osteoporosis, cardiovascular diseases and Alzheimer disease.

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ON OBSTETRICS AND GYNECOLOGY 2016
MHT, A DECADE AFTER WHI
▸ To women with premature ovarian failure: MHT is recommended at least until the age of natural menopause. ▸ Using MHT after 60 y/o or over 10 years of menopause : potential risks of MHT should be taken into account. ▸ Various routes for estrogen administration to consider: oral – transdermal – vaginal routes ▸ Oral administration: liver first-pass leads to increased embolism and decreased bioavailability => transvaginal / transdermal routes are more efficient alternatives

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ON OBSTETRICS AND GYNECOLOGY 2016
HRT, A DECADE AFTER WHI
▸ The optimal treatment duration for combined therapy (EPT) : 5 years without increased breast cancer risks. ▸ Estrogen – alone therapy: 7 years duration is safe. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
MENOPAUSE HORMONE THERAPY
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ON OBSTETRICS AND GYNECOLOGY 2016
MENOPAUSE HORMONE THERAPY
▸ Systemic estrogen has been used more than half a century for the treatment of pre-menopausal disorders ▸ Many observational studies showed that MHT reduces cardiovascular morbidity = > RCTs conducted studies to verify : WHI and HERS ▸ Data from WHI and HERS: no effects for using MHT , but risks for stroke and coronary heart diseases increased THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
MENOPAUSE HORMONE THERAPY
▸ Re – analysis of WHI: unreasonable conclusions as the result of unsuitable population selection, inclusion criteria and incongruous treatment choice. ▸ KEEPS - the Kronos Early Estrogen Prevention Study: the timing hypothesis - " the window of opportunity" where HRT may be beneficial for preventing CVD in younger women THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
MENOPAUSE HORMONE THERAPY
MHT INDICATION
PATIENT ASSESSMENT
MHT INITIATION
TIMING HYPOTHESIS
POTENTIAL
BENEFITS AND RISKS
WHICH MHT SHOULD BE
PRESCIBED
MHT TREATMENT FOLLOW-UP
TREATMENT CANCELLATION
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ON OBSTETRICS AND GYNECOLOGY 2016
MENOPAUSE HORMONE THERAPY
MHT INDICATION
▸ Individual assessment PATIENT ASSESSMENT
▸ Issues to be taken into account: The onset of menopause
Family history
Symptoms that the patient
Patient's history
must suffer
Patient's age
Age and health of her husband
Desires for her own future life
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ON OBSTETRICS AND GYNECOLOGY 2016
MHT INDICATION
PATIENT ASSESSMENT
Universal assessment: Gynaecologic and breast ultrasound Cancers screening Blood tests: total blood count, fibrinogen, D-dimer, liver - kidney function tests THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
MHT INITIATION
TIMING HYPOTHESIS
▸ Most suitable time for MHT initiation:
Window of opportunity
* Within 10 years after the onset of menopause ‣ The initiation of MHT in women over 60: risks
outweight benefits
‣ Women with premature ovarian insuffficiency: MHT is recommended at least until the age of natural menopause, low dose OCP may be used. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
MENOPAUSE HORMONE THERAPY
POTENTIAL
BENEFITS AND RISKS
Individual consideration should be noticed
▸ Vasomotor symptoms: MHT remains the most effective therapy
▸ Osteoporosis: MHT is a first-line therapy for the prevention of
fracture in at-risk women before age 60 years or within 10 years after menopause, but not indicating solely for osteoporosis prevention. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
MENOPAUSE HORMONE THERAPY
POTENTIAL
BENEFITS AND RISKS
Individual consideration should be noticed
▸ Cardiovascular diseases: For women < 60 and menopause <10
years, MHT has the potential for improving the cardiovascular risk profile through its beneficial effects on vascular function, cholesterol levels and glucose metabolism. ▸ Coronary heart diseases: young women, 50 - 59 y/o, or < 10 years
from the onset of menopause, using MHT, have a trend of significant reduction in mortality and in hospitalization for myocardial infarction and congestive heart failure. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
POTENTIAL
BENEFITS AND RISKS
‣ Stroke: depends on age – progestins – route of administration – current
• Excess absolute risk of MHT lower among women < 60. • UK General practice research database: the risk of VTE and stroke is less with transdermal than with oral estradiol. • Micronized progesterone and dydrogesterone associated with 17β-
estradiol may have a better risk profile.
• MHT related with stroke in those who have current hypertension. • Women with premature ovarian failure: increased risk for stroke unless THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
Breast cancer
POTENTIAL
BENEFITS AND RISKS
▸ No increased risk in first-time users of MHT SIDERATION
during the 5 - 7 years since initiation of treatment. ▸ WHI study: 7.1 years of treatment with unopposed CEE decreased the risk of breast cancer diagnosis and mortality in hysterectomized women. ▸ Risks are related to: time of the initiation – duration of administration – BMI. ▸ Micronized progesterone or dydrogesterone may be associated
with a better risk profile for breast cancer than synthetic
progestogens.
▸ The risk of breast cancer attributable to MHT is small and becomes normal after discontinuation of treatment. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
POTENTIAL
BENEFITS AND RISKS
▸ Venous thromboembolism
• A contra–indication for MHT
• Micronized progesterone or dydrogesterone may be associated with a better risk profile for VTE than synthetic progestogens. • Transdermal estrogen may avert some risk associated with oral MHT by avoiding first-pass hepatic metabolism. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
POTENTIAL
BENEFITS AND RISKS
▸ Low- dose local estrogens are more preferable for atrophy or recurrent lower urinary tract infections management. ▸ Systemic risks have not been identified with local low- potency/low-dose and short - term estrogen treatment. ▸ Local estrogens within 12 months: no need for progestogen THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
POTENTIAL
BENEFITS AND RISKS
Cognition
▸MHT initiated around the time of menopause and/or in postmenopausal women < 60 is associated with a reduced risk of Alzheimer disease (29 - 44 % for young women, 50 - 59 years old, or < 10 years from the onset of menopause, bilateral oophorectomy) ▸WHI: with respect to Alzheimer risk, starting MHT in later life is harmful. ▸Mood: HRT is effective at alleviating short-term menopausal
symptoms such as hot flashes, insomnia, mood swings, and irritability.
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ON OBSTETRICS AND GYNECOLOGY 2016
POTENTIAL
BENEFITS AND RISKS
Diabetes :
MHT is likely to decrease the serum glucose level. The mechanism, however, is not clear. Insulin – resistance reduction is supposed to be the reason. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
MENOPAUSE HORMONE THERAPY
Hormonal selection THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
ESTROGEN SELECTION
Hormonal selection
‣ Decision for estrogen administration:
Young age < 60 y/o, onset of menopause < 10 yrs (window of opportunity). Quality of Life
Vasomotor disorders Autonomic nervous system disorders ‣ Estrogen must be asociated with progestin, if uterus intact ‣ Hysterectomy=> estrogen – alone therapy, except for : • Hysterectomy for endometrial cancer • Hysterectomy for endometriosis • Subtotal hysterectomy THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
Hormonal selection
‣ Types of estrogen:
Estradiol valeriate ‣ Routes: oral, transdermal and vaginal administration (estriol)
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ON OBSTETRICS AND GYNECOLOGY 2016
Hormonal selection and
routes of administration
Transdermal
Fluctuating serum concentration
Relatively stable serum concentration

Inflammatory index
No effect
(C-reactive protein- CRP)
Lipid metabolism
Triglycerides và HDL 
LDL 
Triglycerides 
HDL và LDL No
effect
Insulin-like growth factor 1
No effect
(ILGF-1)
Sex hormone-binding globulin
Embolism protein
No effect
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ON OBSTETRICS AND GYNECOLOGY 2016
PROGESTOGEN SELECTION
Hormonal selection
‣ Progestogen combined with systemic estrogen for endometrial hyperplasia and cancer prevention ‣ Sequential or 12 – 14 days/ cycle ‣ Origin: natural or sub-natural • Natural origin: progesterone • Semisynthesis: micronized progesterone, dydrogesterone THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016
Hormonal selection
‣ Progestogen and risk of breast cancer
▸ WHI: a breast cancer risk reduction with conjugated equine estrogens (CEE)
alone and a risk elevation with CEE plus medroxyprogesterone acetate (CEE +
MPA) were observed
▸ KEEPS:
KEEPS: HT in recently menopausal women is not associated with serious adverse effects in the first four years of use Group 1: micronized progesterone + transdermal 17β-estradiol Group 2: micronized progesterone + CEE Group 3 : placebo No increase for breast cancer risks observed
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ON OBSTETRICS AND GYNECOLOGY 2016 28
ORAL LOW-DOSE CONTINUOUS E2 0.5 MG/D 2.5 MG
EFFECTIVELY ALLEVIATE VASOMOTOR SYMPTOMS
Reduction of symptoms significantly different between 2 groups; n= 305
sever- -7
*p<0.05, **p<0.01, ***p<0.001 vs. placebo Figure reproduced from Maturitas, 67, Stevenson JC et al. Oral ultra-low dose continuous combined hormone replacement therapy with 0.5mg 17β-oestradiol and 2.5mg dydrogesterone for the treatment of vasomotor symptoms: Results from a double-blind, controlled study. 227–32, Copyright (2010), with permission from THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 29
BREAST CANCER RISKS ACCORDING TO PROGESTOGEN CHOICE
FRENCH E3N COHORT STUDY
Not statistically significantly different from risk Significantly different from the risk without HRT N = 80,377 women, for an average treatment duration of 8.1 years A et al. Breast Cancer Res Treat 2008;107:103–11; Fournier A et al. J Clin Oncol. 2008 ;26:1260–1268. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 30
BREAST CANCER RISKS ACCORDING TO PROGESTOGEN CHOICE
FINNISH COHORT STUDY

CI)
5%
(9
io
rat
Standard
N = 50,210; women >50 years of age; treatment duration 5 years 5/18/2016 tinen H et al. Obst Gyn 2009;113:65–73. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 31
REDUCE THE CARDIOVASCULAR RISKS
‣ Population study based on UK-based General Practice Research Data (n=69,412) ‣ 6 years follow-up ‣ No increase in cardiovascular events when taking E/D THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 32
REDUCE THE CARDIOVASCULAR RISKS
Schneider C et al. Climacteric 2009;12:445–53. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 33
LIPID PROFILE
ESTRADIOL/DYDROGESTERONE VS. CEE/NORGESTREL
In a 24 weeks – study on 193 women at peri- or post- menopausal age: ‣ HDL significantly increased with E/D ‣ HDL decreased with CEE/norgestrel (0.625/0.15 mg) ne at w
li
se
Mean change
*p<0.05, **p=0.01, ***p=0.003, ****p=0.001 vs. baseline Cieraad D et al. Arch Gynecol Obstet 2006;274:74–80. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 34
LIPID PROFILE
ESTRADIOL/DYDROGESTERONE VS TIBOLONE
A further study on 140 healthy, postmenopausal women to evaluate the effects of sequential E/D on lipid profile after 24 months. E/D 2/10 group: significantly increased in mean HDL- cholesterol 7% in comparision with decrease in mean 26.8% HDL cholesterol in tibolone group 5/18/2016 vs. baseline Hänggi W et al. Brit J Obst Gyn 1997;104:708–17. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 35
BENIFICIAL EFFECTS OF CONTINUOUS
ESTRADIOL/DYDROGESTERONE IN IMPROVING
THE BONE MINERAL DENSITY (BMD)
• 1/5, 1/10 và 1/20 E/D continuous significantly increased BMD of lumbar spines and hip (n=214) ệ phầ l độ *p < 0,01 so với ban đầu 2016 enson J và cộng sự. Maturitas 2001;38:197–203. THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 36
Follow-up
‣ First follow-up visit:
assessment
Drug absorption and interaction? Symptoms improvement Switching (d osage - routes)? Re – assessment every 6 months – 1 year, including:
Physical and gynecologic check-up, Ultrasound (gynecology and breast); mammography; bone density assessment; blood tests (total blood count, liver and kidney functions); cancer screening tests; review and discussion of individual's risk:benefit ratio concerning MHTon every time check- THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 37
MHT DISCONTINUATION
‣ Duration: 5 yrs for combined therapy, 7 yrs for estrogen – alone therapy ‣ Special cases: ‣ Premature ovarian failure: low-dose OCs until the natural menopause ‣ Osteoporosis prevention, bisphosphonate intolerance: MHT used for
over 5 – 7 years => discussion with patient. ‣ Withdrawal: suddenly/ gradually; symptoms recur among 50% of patients => MHT or non-hormonal therapy consideration. ‣ IMS congress 2015 (4-6 December 2015 in Taipei) : whether MHT
should be stopped if it is being used effectively, without any side-effects for a duration of 5 -7 years? NON-HORMONAL THERAPY
HỘI NGHỊ VIỆT-PHÁP CHÂU Á-TBD – 20/05/2016 NON-HORMONAL THERAPY
‣ Shock caused by the release of the principal results of the WHI led to the sharp fall of the number of women taking MHT : • Germany: 40,2% (2003 – 2004 vs 1997 – 1999) ( Du et al.,2007)
• Australia: 55% in women aged 50 – 80 y/o (2003 vs 2001) (Travers et
• USA: 77% of starting MHT in women aged 50 – 79 y/o (2004 vs 2001)
(Weglenka et al., 2006). APPEARANCE OF NON-HORMONAL AGENTS
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ON OBSTETRICS AND GYNECOLOGY 2016 40
NON-HORMONAL THERAPY
NON-HORMONAL THERAPY
PRESCRIBED
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ON OBSTETRICS AND GYNECOLOGY 2016 41
UNPRESCRIBED THERAPY LIFESTYLE MODIFICATION
‣Increasing physical activities ‣Reducing body weight ‣Healthy diet and functional supplements ‣Meditation, deep breathing intermittent, relaxing THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 42
FUNCTIONAL SUPPLEMENTS
• Soya and products with soya origins • Dong quai and black cohosh THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 43
UNPRESCIBED THERAPY
FUNCTIONAL SUPPLEMENTS:
Maca is a plant that grows in central Peru in the high plateaus of the Andes Mountains. It has been cultivated as a vegetable crop in this area for at least 3000 years. Maca is a relative of the radish and has an odor similar to butterscotch. Its root is used to make medicine. Maca also appears to be a potent suppressor of prostate hypertrophy, with potency similar to finasteride, a synthetic drug for the treatment of enlarged prostates. Preliminary research also suggests that maca can protect the brain from damage, improve bone health, and even improve cognitive ability in healthy people. ( IMS Congress 2015; 4-6/12 in Taipei) THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 44
PRESCRIBED THERAPY
‣ Selective Serotonin Reuptake inhibitors (SSRI) & Serotonin- Norepinephrine Reuptake inhibitors (SNRI). ‣ Gabapentinoids THE FRANCE - VIETNAM – ASIA PACIFIC CONFERENCE

ON OBSTETRICS AND GYNECOLOGY 2016 45
OTHER THERAPY
▸ Stellate ganglion block HỘI NGHỊ VIỆT-PHÁP CHÂU Á-TBD – 20/05/2016 CONCLUSION
▸ Women, who experience spontaneous or iatrogenic menopause
and suffer severe vasomotor symptoms, should use MHT after
universal assessment to reduce symptoms and maintain quality
▸ Duration for MHT administration depends on the purposes
when indicated.
▸ To women with premature ovarian insufficiency: MHT is
recommended at least until the age of natural menopause.
▸ Women with mild symptoms or treatment completion: non –
hormonal therapy may be an alternative.
HỘI NGHỊ VIỆT-PHÁP CHÂU Á-TBD – 20/05/2016 CONCLUSION
‣ Issues to be considered when indicating MHT for patients:
Window of opportunity
Patients' history
Risks for thromboembolic events
Estrogen and progestin selection: The combination of 17β-
estradiol & dydrogesterone was proven not increase breast
cancer – venous thromboembolism and stroke risks.
Patients should be counseled carefully about the potential
benefits – risks and result of the treatment each visit for
follow-up assessment
‣ Lifestyle modifications include socializing and being
physically/mentally active; healthy diets; weight loss of 5 -10%
prove quality of life and ensure a healthy menopause.
Thanks for your attention
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ON OBSTETRICS AND GYNECOLOGY 2016 49
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