hormone replacement therapy new advance.ppt

HRT

1. Hormone Replacement
Therapy And Menopause
Mikael D. Jones, Pharm.D, BCPS
College of Pharmacy
College of Nursing
University of Kentucky

2. Objectives
Discuss the current recommendations for
the
 use of  hormone replacement therapy
Compare and contrast the various dosage
forms available for hormone replacement
therapy

3. Facts and Figures
35 million women are >50 years of age
50-85% of menopausal women will
experience symptoms of estrogen
deficiency
25% of these women will have significant
distress from these symptoms
Endocrine Practice Vol 12 No. 3 May/June 2006
Fertility and Sterility Vol. 86, Suppl 4, November 2006

4. Fertil Steril 2001;76:875

5. Clinical Presentation
Vasomotor Symptoms
Vaginal Dryness
Sleep Disturbances
Mood Symptoms
Cognitive Disturbances
Uterine Bleeding
Sexual Dysfunction
Quality of Life
I
n
c
r
e
a
s
in
g

E
v
id
e
n
c
e

S
y
m
p
t
o
m
s

A
t
t
r
ib
u
t
a
b
le

t
o

M
e
n
o
p
a
u
s
e
NIH Consensus State Sci Statements. 2005. Mar 21-23; 22(1) 1–38.

6. Vasomotor Symptoms
Hot flash (or flush)
Few minutes or several minutes
Occur every hour to several per week
Narrowing of threshold between sweating and
shivering
Risk Factors
Cigarette smoking
BMI  30 kg/m
2

Menopause <52 years
Abrupt Menopause
Endocrine Practice Vol 12 No. 3 May/June 2006

7. Vaginal Atrophy
Vaginal dryness
Vaginal itching
Dyspareunia
Persists and may worsen with age
Urologic symptom may not always be
menopause

8. Reproductive Menopausal TransitionPost Menopause
Early Peak Late Early Late* Early* Late
Perimenopause
Prevalence of Hot
Flashes
10% 40% 65% 65% 10-15%
Prevalence of
Vaginal Symptoms
30% 47%
N Engl J Med 2006;355:2338-47.

9. Treatment of Menopause
Goals of Therapy
Reduce symptoms resulting from estrogen
imbalance
Treat urogenital atrophy and vaginal dryness
Minimize risk of disorders that may be more
frequent during hormone replacement therapy
Fertility and Sterility Vol. 86, Suppl 4, November 2006

10. Therapeutic Options
Non-pharmacologic
Maintain cool environment
Cotton Clothing
Exercise/ stretching
Vaginal lubricants/moisturizers (vaginal sxs)
Pharmacologic
Hormone Replacement Therapy (HRT)
Antidepressants
Clonidine
Gabapentin

11. Hormone Replacement Therapy
Contraindications
Current, past, or suspected breast cancer
Known or suspected estrogen-sensitive malignant
conditions
Undiagnosed genital bleeding
Untreated endometrial hyperplasia
Previous idiopathic or current venous
thromboembolism
Active or recent arterial thromboembolic disease
(angina, MI)
Untreated hypertension
Active liver disease

12. Estrogen Therapy
Conjugated equine estrogen
Synthetic conjugated estrogen
Estradiol & Ethinyl Estradiol
Esterified estrogen
Estropipate
Estrone

13. Progestogen Therapy
Medroxyprogesterone acetate
Progesterone
Norethindrone acetate
Norgestimate

14. Hormone Replacement Therapy
Systemic Dosing strategies
E
s
t
r
o
g
e
n

O
n
ly
P
r
o
g
e
s
t
o
g
e
n
s
1
0
-
1
4

d
a
y
s
S
e
q
u
e
n
t
ia
l
T
h
e
r
a
p
y
E
s
t
r
o
g
e
n

D
a
ily

+
C
o
n
t
in
u
o
u
s

T
h
e
r
a
p
y
E
s
t
r
o
g
e
n

+
P
r
o
g
e
s
t
o
g
e
n
s
D
a
ily Local
Estroge
n

15. Risk Associated with ERT/HRT
Use
Effect on RiskERT HRT
Venous
Thromboembolism
Endometrial
Cancer
Unopposed
with uterus
Breast Cancer ? ?
Stroke

16. Use of HRT/ERT to Prevent
Disease
Effect on RiskERT HRT
Fracture
Dementia
Cardiovascular
Disease
? ?
Colon Cancer
Stroke

17. Current Recommendations
FDA Indications for HRT
Treatment of moderate to severe vasomotor
symptoms associated with menopause
Treatment of moderate to severe symptoms of
vulvar and vaginal atrophy
Prevention of postmenopausal osteoporosis

18. Current Recommendations
Decision to use HRT should be based on
patient specific risk vs benefit
Use the lowest dose to control symptoms
for the shortest duration
Reevaluate dose as patient ages
Use progestogen with estrogen in women
with a uterus
HRT should not be used to prevent
chronic diseases
Ann Intern Med. 2005;142:855-860.
Endocrine Practice Vol 12 No. 3 May/June 2006

19. Treatment Modalities
Transdermal/Topical
Oral Therapy
Focus on Low Dose
Vaginal
Rings
Creams
Bioidentical

20. Focus on New HRT
Dosage Forms

21. Transdermal
Advantages
Avoids first-past effect
Avoids induction of triglyceride production
Does not increase production of angiotensinogen
May reduce thromboembolic risk associated with
oral estrogen

22. Transdermal
Transdermal Patches
17-estradiol (e.g. Menostar

, Vivelle Dot

,
Estraderm

)
Doses 0.014 mcg to 0.1 mcg
17-estradiol + Norethindrone acetate
(CombiPatch

)
17-estradiol + levonorgestrel acetate
(Climara Pro

)
Once or twice weekly application

23. Transdermal
Transdermal Gel
All 17-estradiol products
EstroGel

0.06% Metered pump (0.035mg/day)
Elestrin

0.06% Metered pump (0.0125mg/day)
Divigel

0.1% Gel Packets (0.25-1 mg/day)
Transdermal Emulsion
Estrasorb

Emulsion packets (0.05 mg/day)
Transdermal Spray
Evamist

1.7% solution

24. Transdermal Gels
All products are once a day
Apply at the same time each day
Apply after bath, shower, sauna use
Wash hands after application
No currently available products with a
progestogen
Women with a uterus still require a progestogen
All Gels and spray are not approved for
osteoporosis prevention or treatment

25. Reduction in Daily Hot Flash
Frequency (12 weeks)
-12
-10
-8
-6
-4
-2
0
M
e
a
n

C
h
a
n
g
e

f
r
o
m

B
a
s
e
l
i
n
e

E
s
t
r
o
g
e
l
E
l
e
s
t
r
i
n
D
i
v
i
g
e
l
E
s
t
r
a
s
o
r
b
E
v
a
m
i
s
t
Placebo
Product
*<0.01
*
*
*
*
*
Prescribing Information for respective product

26. Transdermal Gel Application
Product Application Procedures
EstroGel
 1 pump of gel applied to 1 arm (wrist to
shoulder); Dries in 2-5 mins
Elestrin
 Pump gel onto upper arm; Spread on
upper arm and shoulder with 2 fingers
Divigel
 Cut open packet; Apply to right or left
upper thigh (alternate daily); Spread gel
over 5-7 inches
Estrasorb
2 packet = dose; Apply one packet per
leg; Start at upper thigh and massage into
thigh and calf area
Prescribing Information for respective product

27. Transdermal Spray Application
Evamist Prescribing Information 8/2007
•Remove Cover
•Hold upright and rest
cone flat against the skin
•Depress pump fully once
•If a second or third dose
has been prescribed,
apply in area next to
original dose

28. Low Dose Oral Regimens
What is considered low dose?
0.3mg of oral conjugated estrogens
0.25-0.5 mg oral micronized 17 -estradiol
0.025mg transdermal 17 -estradiol patch
Effectiveness
Hot flash reduction similar
Dose-related effects on bone
Fracture risk reduction not clear
Maturitas 57 (2007) 81–84

29. Reduction in Hot Flash
Frequency
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
R
e
d
u
c
t
i
o
n

i
n

F
r
e
q
u
e
n
c
y
C
E
E
O
r
a
l

1
7
b
e
s
t
r
a
d
i
o
l
T
r
a
n
s
d
e
r
m
a
l
1
7
b
e
s
t
r
a
d
i
o
l
Placebo
Traditional
Dose
Low Dose
N Engl J Med 2006;355:2338-47.

30. Low Dose Oral Regimens
Safety
Potential decrease in adverse effects
Stroke Risk
VTE Risk
More studies needed!
Progestogen Dose reduction
0.625mg dose of CEE
2.5mg of medroxyprogesterone acetate
0.3mg dose of CEE
1.5 mg of medroxyprogesterone acetate
Maturitas 57 (2007) 81–84

31. 17 -Estradiol +
Drospirenone
Angeliq

17 -Estradiol (1mg) +
Drospirenone (0.5mg)
Indicated for treatment of moderate to
severe vasomotor symptoms/ vulvar and
vaginal atrophy
May cause hyperkalemia
Only available in 1mg/0.5mg
Cannot provide low dose estrogen with this
product
Angeliq Package Insert Bayer 2007

32. 17 -Estradiol +
Drospirenone
Drospirenone
Spironolactone analog
Antimineralocorticoid and antiandrogenic effects
Prevents endometrial hyperplasia
Reduce Sodium/water retention
May reduce blood pressure
CLIMACTERIC 2007;10(Suppl 1):3–10

33. Vaginal Products
Local therapy is effective in treating vaginal
therapy
Cochrane Review suggests all vaginal estrogen
products are equally effective
Progestogen therapy is not needed for local
therapy
However systemic absorption does occur
Conjugated estrogens creams may have higher
incidence of adverse effect compared to the ring
or vaginal tablet delivery
Suckling J, Lethaby A, Kennedy R. Cochrane Database of
Systematic Reviews 2006, Issue 4. Art. No.: CD001500.

34. Vaginal Products
Creams
17-estradiol
Conjugated Equine Estrogens
Vaginal Tablet
Estradiol hemihydrate
Rings
17-estradiol (local therapy)
Estradiol acetate (systemic therapy)

35. Avoid Ring Confusion
17-estradiol (local
therapy)
Estring
Silicone Ring
7.5g/24H over 90 days
Patient can insert
Estradiol acetate
(systemic therapy)
Femring
Silicone Ring
0.05mg or 0.1mg/ day
over 90 days
Patent can insert
Patient’s with uterus
will require
progestogen therapy
Estring Package Insert Pfizer
Femring package Insert Warner Chilcott

36. Androgens
In 2003 FDA question the effectiveness of
conjugated estrogen/ methyltestosterone
products
Products never have been approved by FDA
Controversial when androgens should be
utilized
Difficult to determine true androgen deficiency
Endocrine Practice Vol 12 No. 3 May/June 2006
Federal Register: April 14, 2003 (Volume 68, Number 71)

37. Androgens
Androgen insufficiency
Loss of Libido
Decreased sexual motivation, enjoyment
Insomnia, depression, poor concentration
Adequate estrogen status
Very low free-testosterone levels
Testosterone typically does not decline in
menopause
Produced by ovaries
Endocrine Practice Vol 12 No. 3 May/June 2006

38. Androgens
Possible applications (more studies
needed)
Post-menopausal women with androgen
insufficiency despite adequate estrogen
replacement
Women who have undergone bilateral
oophorectomy and are on estrogen therapy
Generally not recommended
Endocrine Practice Vol 12 No. 3 May/June 2006

39. Questions

40. Women’s Health Initiative
JAMA 2002;288:321–33. N Engl J Med
2003;349:523–34. JAMA 2003;289:3243–53
JAMA 2004;291:1701–12.
Estrogen and progestinEstrogen Only
Outcome Relative
Hazard
95% CI Relative
Hazard
95% CI
CHD 1.2 0.97-1.60.95 0.79-1.16
Stroke 1.4 0.86-2.311.39 0.97-1.99
VTE 2.1 1.26-3.551.333 0.86-2.08
Breast Cancer1.2 0.97-1.590.77 0.57-1.06
Colon Cancer0.6 0.32-1.241.08 0.63-1.86
Hip Fracture0.6 0.33-1.330.61 0.33-1.11