Future of HRT - how far can
we go
down with the dose?

?

3rd Chair and Department of Gynecology
Medical University of Lublin
Poland

Low-dose HRT

history

history



5th Century B.C.

„As to diseases, make a habit of

two things - to help, or at least to do no harm”
(„Primum non nocere”)

Hippocrates



1975

30 years after the introduction of the

1,25mgCEE drug for menopausal women, data are

published to prove osteoprotective efficacy of the

0,6mgCEE dose



1990

a term „compliance” gains popularity (6th

Menopausal Congress in Bangkok)



since 1996

rapidly growing popularity of low-

dose HRT formulations worldwide

Low-dose HRT – what is

it ?



0,5-1,0 mg E

2

– orally



0,3 mg CEE – orally



25-37,5 µg E

2

/24 h -

transdermally

Burger H et al. Climacteric 2004

Low-dose HRT

major issues

major issues



Is LD-HRT effective (are the effects
of HRT dose-dependent ?)



Is LD-HRT well tolerated ?



Does LD-HRT provide any benefits

over high-dose or standard-dose
HRT ?

Low-dose HRT – efficacy

symptom relief

symptom relief

Stadberg et al. Maturitas 1996;23:31.-

hot flushes

vaginal dryness

sweats

irritability

Low-dose HRT – efficacy

QoL improvement

QoL improvement

Modified Kupperman Index – subscale analysis after 6 mths of treatment

Loh et al. Maturitas 2002;41:123.-

Moderate and severe hot flushes

0

10

20

30

40

50

60

70

80

Placebo

0.25mg E
0.5mg E

1mg E
2mg E

N

u

m

b

e

r

significantly different (p < 0.05)

from placebo

*

*

*

*

*

*

*

*

*

0

1

4

5

6

7

8

9

10 11 12

3

Weeks

2

2

2

2

2

Low-dose HRT - efficacy

symptom relief

Low-dose HRT – efficacy

symptom relief

symptom relief

Speroff et al. J NAm Menop Soc 2000;7:383.-

mean number of hot flushes per week

Low-dose HRT – efficacy

bone resorption markers

bone resorption markers

difference in mean % change compared to placebo (vit.D+calcium)

Prestwood et al. J Clin Endocrinol Metabol 2000;85:4462.-

CTx – C-telopeptides of type I collagen
NTx – cross-linked N-telopeptides
Dpyr – total deoxypyridinoline cross-links

Low-dose HRT – efficacy

endothelial function

endothelial function

maximal forearm blood flow in response to reactive hyperemia

- strain-gauge plethysmography -

Sanada et al. J Clin Endocrinol Metab 2003;88:1303.-

Low-dose HRT

compliance

compliance

„Grant that my patients have

confidence in me and my art and

follow my directions and counsel”

Prayer of Maimonides (12th Century)

Why patients discontinue

HRT

?

Abnormal vaginal bleeding

44,8%

Fear of cancer 28,9%
Others

26,3%

Karakoc, Erenus. Menopause 1998;5:102.-

Over 50% of patients discontinue HRT
within the first year

Schneider, Gallagher. Maturitas 1999;33:S25.-

Why?

Low-dose HRT: tolerability

bleeding control

bleeding control

Loh et al. Maturitas 2002;41:123.-

%

Low-dose HRT:

tolerability

bleeding control

bleeding control

Delmas et al. Osteoporosis Int 2000;11:177.-

Low-dose HRT

endometrial safety

Bergeron, Ferenczy, Maturitas, 2001

Low-dose HRT:

tolerability

mastalgia

mastalgia

Loh et al. Maturitas 2002;41:123.-

%

2 mg E

2

+ 1 mg NETA

1 mg E

2

+ 0,5 mg NETA

Stadberg et al. Maturitas 1996;23:31.-

Low-dose HRT:

tolerability

mastalgia

mastalgia

Sanada et al. J Clin Endocrinol Metab 2003;88:1303.-

%

0,625 CEE + 2,5 mg MPA

0,300 CEE + 2,5 mg MPA

Low-dose HRT – adverse

effects

pronounced increase in

pronounced increase in

breast density

breast density

Junkermann H. Journal fűr Menopause 2001;1:7.-

1mgE2 + 0,5mgNETA-ccHRT0,600 CEE + 5mg MG-scHRT

HRT post WHI – a time for low-

dose ?

„

Women who choose to take estrogen should

start with a low dose and gradualy increase it
until symptoms are adequately controlled”

Grady. NEJM 2003;348:19.-

„The results do not necessarily apply to lower dosages
of these drugs, to other formulations of oral estrogens
and progestins or to estrogens and progestins
administered through the transdermal route”

Writing Group for the WHI Investigators. JAMA 2002;288:321.-

Low-dose HRT

benefits for the starters



Low-dose HRT is effective in reducing
climacteric symptoms even in highly
symptomatic women



Initiating HRT at the lowest effective dose
minimises the risk of hyperestogenic side
effects



Better tolerability of low-dose HRT may lead to
fewer early discontinuations



Starting HRT with low dose gives a physician the
ability to titrate doses to suit individual patient

Low-dose HRT

benefits for long-term users



Low-dose HRT provides an effective bone

protection in both perimenopausal and late-

postmenopausal women



Low-dose HRT is associated with a better

cardiovascular hazard/benefit ratio than

standard or high-dose HRT, even in women

with ACS (WHISP Study)



Fewer hyperestogenic side effects result in

better compliance



The use of low estrogen dose enables an

application of relatively low progestogen dose

thus minimising the risk of progestin-related

side effects