Menopause-Tibolone and beyound

1. Dr.Fahmida Rashid
Assistant Professor
Chittagong Medical college
E-mail-
dr.fahmidaswati@gmail.com

3. HRT
Women's Life Cycle
Menopause

4. Transition

5.  Greek: menos:month, pausis:cessation
Permanent cessation of menstruation resulting
from loss of ovarian follicular activity(WHO)
(Amenorrhea for 1 year)
Marks the end of reproductive life
RETROSPECTIVE DIAGNOSIS(1 year from FMP)

6.  Peri-menopause is a period before and
after the menopause.
 Encompasses the years leading up to
menopause-anywhere from 2-8 yrs-plus the
first years after final period

7. Staging of women climacteric
period
adolescence 40yrs Final period
1yrs
after the
Final
period
60-65
yrs
Life
stop
Pre menopause Post menopause
Peri menopause
Transitional phase
climacteric period

8.  Premature Menopause- aged below 40 years.
 Menopause -aged 50 - 59 years.
 Late Menopause –aged 60 years or over
 Surgical menopause- surgical removal of both
ovaries in a woman.
 Medical menopause- permanent damage to both
ovaries in a woman following either chemotherapy
or radiotherapy.
Types of Menupause:

11.  Hot flushes
 Night sweats
 Headaches
 Panic attacks
 Mood swings
 Indecisiveness
 Insomnia leading
to:
 irritability
 poor short term
memory
 difficulty with
concentration

12. Management

14.  Vaginal dryness
 Dyspareunia
 Reduced libido
 Thinning skin/ hair
 Skin formication
 Urethral syndrome (frequency, nocturia &
urge incontinence)

15.  CARDIOVASCULAR DISEASE
 OSTEOPOROSIS
 CEREBROVASCULAR DISEASE

16. DIAGNOSIS OF MENOPAUSE
a. Clinical Criteria
1. age around menopause ( around 50 years )
2. no periods for 12 months
3. menopausal symptoms
If doubt, FSH estimation support diagnosis
b. Laboratory Criterion
FSH level > 35miu/ml
Estrogen<20pg/ml
Cytologic smear from the vaginal wall

17. Management

18. 0
10
20
30
40
50
60
70
80
90
1850 1900 1950 2000
Life expectancy
Age at menopause
Why so Important?

20. NON PHARMACOLOGCAL
 Lifestyle modification
 Natural herbs & remedies
 Complementary therapy-
acupuncture, reflexology,
magnetism
 Diet & supplements-vit C,E
PHARMACOLOGICAL
HRT
 alpha2 agonist,
 beta blocker,
 SNRI
 gabapentin,
 DHEA,

22. Uterus
Sequential therapy without tablet break
Regular bleeding at end of cycle
Estrogen
Progestogen
Day 14
De Villiers TJ et al. Climacteric 2013;16:316–337.
.
Continuous Estrogen
Estrogen
No tablet break
No bleeding as no uterus
Uterus
Estrogen
Progestogen
Day 14 Combined therapy without tablet
break
No bleeding at end of cycle
Combined sequential therapy(E+P)
Continuous combined therapy(E+P
Tibolone

23. Most Potent
natural
synthetic
ethinylestradiol
mestranol
Conjugated
estrogen

24. Equivalent dose for bone endpoints*
Estrogen Ultra Low Low Standard High
Conjugated equine estrogens
(mg)
0.151 0.3 0.625 1.25
17β-estradiol (mg) 0.52 1 2 4
Estradiol valerate (mg) 1 2
Transdermal 17β-estradiol (μg) 143 25 50 100
*Estrogenic effects may vary for other endpoints
The Estrogen Dose Counts
Note: For many women, low-doses of estrogen provide adequate
relief of symptoms with high rates of amenorrhea

25. standard low
Medroxyprogesterone
acetate
2.5-5 mg/day 1.5 mg
Micronised progesterone 100-300 mg/day 50mg/day
Dydrogesterone
Noethisterone acetate
5-10mg/day
0.5mg/day 0.5 mg/day

26. Progestogen
Progestog
enic
Estroge
nic
Androge
nic
Anti-
androgenic
Glucocorti
coid
Anti-
mineralo-
corticoid
Dydrogesterone1
+ – – ± – ±
Progesterone1
+ – – ± + +
MPA1
+ – ± – + –
Norethisterone1
+ + + – – –
Drospirenone1
+ – – + – +
CPA1
+ – – ++ + –
Dienogest1
+ ± – + – –
Levonorgestrel1
+ – + – – –
Norgestrel1
+ – + – – –
Tibolone2
+ ± + – – –
1. Schindler AE. Maturitas 2003;46(S1):7–16; 2. De Gooyer ME et al. Steroids 2003;68:21–30.
+ Effective; ± Weakly effective; – Not effective.
•Dydrogesterone highly selective
progestogen which binds almost
exclusively to the progesterone receptor.
Due to its selectivity, effects not
mediated by the progesterone receptor -
are minimal or absent.1

27.  Combined Sequential oestrogen and progestogen
 The addition of the progestogen protects the
endometrium from stimulatory effect of
unopposed estrogen and leads to a regular bleed
Oestrogen for
28 days
Progestogen
for 14 days
Next month
Withdrawal
bleeding
Stop

29. Estrogen continuously
MPA continuously
No Withdrawal bleeding
 This should not be started until 1 year
after the LMP
 No monthly bleed
Oestrogen combined with
progestogen for 28 days

31.  If subtotal Hysterectomy - progestogens may
need (some endometrium may be left behind)
 If the hysterectomy for endometriosis -
progestogens continuously along with oestrogen
should be used at least initially(MPA/DEPO)
 In 1st 12-18 month –HRT given cyclically to prevent
Breakthrough bleeding.
 Reduce number and severity of hot flush by 85%

32. Oral
Transdermal:
patch or gel
Subcutaneous(i
mplant)
Intramuscular
(depot)
Intra-uterine
(Mirena)
Intra-vaginal
(tablets, ring or
cream)

34.  Set realistic goals!
 Lower the ambient temperature
 Alternative therapies
 High dose progestin
 Tibolone
 SSRI’s (Paroxetine, Fluoxetine(+/-))
 SNRI (Venlafaxine (+/-))
 Gabapentin
 Clonidine (+/-)

35. Treatment of POI
 HRT- higher dose

36.  Irregular uterine bleeding
 Breasts tenderness
 Progestogen-related symptoms
(abdominal bloating,edema)

37. Benefits
Relief of
Menopause
Symptoms
Risks
Breast
Cancer
Do evaluation every year may find any abnormals，
reduce the incidence of the above risk

38. vascular thrombosis
hypertension
diabetes
 chronic liver disease
myoma, endometriosis,
breast disease
 gallbladder disease
Uncontrolled
Uncontrolled

40. Endorsed by –
The American Society for Reproductive Medicine,
The Asia Pacifi c Menopause Federation,
The Endocrine Society,
The European Menopause and Andropause Society,
The International Menopause Society,
The International Osteoporosis Foundation and
The North American Menopause Society.

41. The option of MHT is individual decision in terms of
quality of life and health priorities as well as
personal risk factors such as –
age,
time since menopause and
the risk of venous thromboembolism,
stroke,
ischemic heart disease and
breast cancer.

42. Indian Menopause
Society, 2013
International Menopause
Society, 2013
North American
Menopause Society,
2012
Indication  Most effective forVasomotor symptoms
 For sleep disturbances & urogenital atrophy
Potential
Benefits
 Positive effects on lipid profile
 Metabolic syn (Type 2 DM, abdominal obesity)

43. Indian Menopause
Society, 2013
International Menopause
Society, 2013
North American
Menopause Society,
2012
Age of
Initiation
 Begins within 10 years of menopause or <60 years of age
“Window of opportunity”
Duration
of Use
 Premature menopause: MHT up to natural age of menopause
 3-5 years

44. Indian Menopause
Society, 2013
International Menopause
Society, 2013
North American
Menopause Society,
2012
Monit
oring
• Pre-HT work-up (Indian MS)
 Initial visit,
 3 months,
 6 months,
 Yearly------
 BP, breast examination and vaginal
examination (3 yearly smears to age 60
and 3 yearly mammography aged 50-64),
 Invite earlier visit for specific problems

45. RCT and meta-analyses –
standard-dose estrogen-alone MHT may decrease
coronary heart disease in women younger than 60
years of age and within 10 years of menopause.
Data on E + P- MHT - no significant increase or
decrease in coronary heart disease has been found.

46.  Local low-dose estrogen therapy is preferred for
women whose symptoms are limited to vaginal
dryness or associated discomfort with intercourse.
 Estrogen as a single systemic agent is
appropriate in women after hysterectomy but
additional progestogen is required in the presence
of a uterus.

47. The risk of venous thromboembolism and ischemic
stroke increases with oral MHT
but the absolute risk is rare below age 60 years.
Observational studies point to a lower risk with
transdermal therapy.

48. Risk of breast cancer in women over 50 years
associated with MHT is a complex issue.
The increased risk of breast cancer primarily
associated with the addition of a progestogen to
estrogen therapy and related to the duration of use.
The risk of breast cancer attributable to MHT is small
and the risk decreases after treatment is stopped

49. The dose and duration - consistent with treatment
goals and safety issues and should be individualized.
In women with premature ovarian insuffi ciency,
systemic MHT is recommended at least until the
average age of the natural menopause

50. The use of custom-compounded bioidentical
hormone therapy is not recommended.
Current safety data do not support the use of MHT in
breast cancer survivors

51. Events Indian Menopause
Society, 2013
International Menopause
Society, 2013
The North American
Menopause Society,
2012/The Endocrine Society
2010
CVD  No/lower risk in healthy women <60 years of age or within 10 years of
menopause
Breast
Cancer
It does not
increase risk if
given for <5 yrs
Small increase in
risk (incidence of
<1.0/1000 women
/year of use)
Risk of events in younger
women is lower than that for
older women
Does not increase
breast cancer risk if
given for <5 yrs
Santen R et al. J Clin Endocrinol Metab 2010;95(Suppl1):S1–S66.

52. MHT is an effective treatment
for the prevention of fracture
(vertebral/hip) in
at-risk women before age 60
years or within 10 years after
the menopause
De Villiers TJ et al. Climacteric 2013;16:316–37.

59. HRT-
Used by the right woman, at the right dose & right age,
 Relieve vasomotor and other menopausal symptoms
 Provide protection against bone loss (second line)
 Provide acceptable bleeding patterns

61.  Synthetic steroid with weak -
 oestrogenic
 androgenic
 progestogenic agent
 STEAR ( SelectiveTissue Estrogen Activity
Regulator)

64.  It reduces endometrail hyperplasia ,so, Does
not need endometrial protection.
 improves symptoms of dryness and painful
intercourse.
 Licensed for vasomotor symptoms and
osteoporosis
 The risk: benefit ratio similar to HRT in
women under 60, but over 60 increased risk
of stroke

65.  Not safe in breast cancer survivor. But--
 Can be used in those with a personal history
of breast cancer.
 Standard-dose tibolone (2.5 mg/day) has
proven efficacy against postmenopausal
osteoporosis.
 • Low-dose tibolone (1.25 mg/day) is effective
in reducing vertebral and non-vertebral
fractures

66.  ↓ hot flushes
 ↓ headache, insomnia, fatigability
 Mood changes[increases endorphins]
 Increases sexual function[libido]
 Improves vaginal atrophy
 Improves urogenital symptoms

71.  Prevents endometrial proliferation
(Volker et al,2001; Climacteric)
 No increase in size or volume of myomas
 Addition of progestogen not required[as progestogenic]
 Standard endometrial surveillance not required
(InternationalTibolone ConsensusGroup; Maturitas,2005)

75.  Favorable effect on lipid profile:
 ↓Triglyceride- 25%
 ↓ HDL-C 34%
 No effect on LDL and Lipoprotein(a)
 No effect- Antithrombin3, Plasminogen, CRP
 J Clin Endo Metab; 2002
 Inconclusive evidence on cardiovascular clinical outcomes
andVTE with regard to risk or benefit.
InternationalTibolone Consensus Group; Maturitas,2005

78.  Leucorrhoea
 Abdominal pain
 Weight gain
 Vaginal bleeding( less than with continuous EPT)
 Breast pain( less than with continuous EPT)

79. Tibolone may have added value in
 Women with low sex drive
 Women with mood disorders
 Women with risk of accelerated bone loss
 Women with premenopausal breast tenderness
 Women with high breast density
 Women with fibroids
 Women with urogenital complaints

80.  Pregnancy n lactation [teratogenic]
 Estrogen dependant cancer
 Thrombophilic disorders
 VTE/CAD
 Liver diseases
 Porphyria
 Known/suspected ca breast/Ovary

81.  Better effects than HRT/ERT
 Tibolone 2.5mg starting dose
 Best for women with estrogen contraindication
 Better improvements in vasomotor symptoms,
osteoporosis
 No known toxicity
.

86. Angelina Jolie Doesn’t Mind Being In
Menopause