hormone replacement therapy: practical considerations marco gambacciani and nick panay

Hormone replacement therapy: Hormone replacement therapy: practical considerationspractical considerations

Marco Gambaccianiand Nick Panay

HRT HRT governing principlegoverning principle

• HRT should be part of an overall strategy including lifestyle recommendations regarding diet, exercise, smoking and alcohol for maintaining the health of postmenopausal women

IMS Updated Recommendations, February 2007

The emerging concepts in HRTThe emerging concepts in HRT

• Timing (window of opportunity)– Early start – Maintenance of estrogenic benefits

• Patient selection – Avoiding generalized prescribing

• Personalization– Tailoring dose to patient– Continuation and tapering the dose with age

17

48

10

25

0

10

20

30

40

50

60

Years since menopause

Pe

rce

nta

ge

Age-specific HRT useAge-specific HRT useUSA 1988–94

SOURCE : CDC/NCHS:NHANES IIIHRT: Factors Associated with HRT use, NIH, Office of Research of Women’s Health, March 2001

IMS Position Statement, Climacteric 2004;7:333–7

Before < 1 2–4 ≥ 5

Percentage

Menopause-relatedsymptoms

Osteoporosis, bone loss,fracture prevention

Doctor prescribed it,told me to take it

Cardiovascular diseaseprevention

Other

Depression, anxiety,emotional distress

0 10 20 30 40 50 60

Reasons women gave for Reasons women gave for initiating or continuing HRTinitiating or continuing HRT

Newton KM, et al. J Women’s Health 1997;6:459–65

Estrogen deprivation andEstrogen deprivation and symptomatic postmenopausal womensymptomatic postmenopausal women

• 75% of women report hot flushes (HF) around menopause

• 25% remain symptomatic for > 5 years

• Not all women will experience HF when they become menopausal

• HF are not just a symptom

• In postmenopausal women suffering from HF, the brain sensitivity to estrogen depletion is higher

The International Menopause SocietyHRT in climacteric and aging brain, Pisa 15–18 March, 2003

Estrogen deprivation andEstrogen deprivation andsymptomatic postmenopausal womensymptomatic postmenopausal women

• HRT:– Can cure HF and improve sleep, mood

and quality of life– May have the potential to prevent/delay

cognitive decline, Alzheimer’s disease, Parkinson’s disease, schizophrenia through multiple neuroprotective actions

The International Menopause SocietyHRT in climacteric and aging brain, Pisa 15–18 March, 2003

Emerging directions in HRTEmerging directions in HRT

• Early start

• Patient selection

• Personalization

• Lower HRT doses

Why lower HRT doses?Why lower HRT doses?

• Continued efficacy with fewer side-effects and possibly fewer risks

• Potential for greater acceptance by women

• Improved continuance to achieve potential long-term health benefits

• Efficacy in prevention of osteoporosis is not compromised

Estrogenic side-effectsEstrogenic side-effects

HRT: maximizing efficacy, minimizing problemsHRT: maximizing efficacy, minimizing problems


• Problems– Breast tenderness – especially in those

over 60– Fluid retention– Nausea– Heavy withdrawal bleeds– Breakthrough bleeding– Endometrial hyperplasia

HRT: maximizing efficacy, minimizing problems HRT: maximizing efficacy, minimizing problems

Estrogenic side-effectsEstrogenic side-effects• Management

– Start with low-dose estradiol in most cases– 1.0 mg p.o. (0.5 mg)/0.3 mg CEE/25–50 µg t.d./25

mg implant– Warn re possibility of side-effects initially and

reassure– Monitor E2 levels if poor response to therapy– Consider local use of estrogens for new/persistent

urogenital symptoms, e.g. vaginal dryness, even when systemic therapy has been initiated

Mammographic density: Mammographic density: comparative datacomparative data

• Marchesoni et al. Maturitas 2005– CEE 0.625 mg/MPA 5 mg, 45% had

increase in mammographic density– Tibolone 4%

• Christodoulakos et al. Maturitas 2006 – CEE 0.625 mg/MPA 5 mg

13.2% – E2 2 mg/NETA 1 mg

31.8%– E2 1 mg/NETA 0.5 mg

12.2%

Effect of ultra-low-dose HRT onEffect of ultra-low-dose HRT onmammographic breast densitymammographic breast density

Digitized quantificationDigitized quantification

No significant difference between groups

ALD 0.1: 0.5 mg 17β-estradiol + 0.1 mg NETAALD 0.25 : 0.5 mg 17β-estradiol + 0.25 mg NETA

Lundström E, et al. Climacteric 2007;10:249–56



• Exceptions to low starting dose of E2– Premature ovarian failure– Severe osteoporosis– Predominance of psychological

problems, e.g. climacteric depression

Maintaining benefitsMaintaining benefits

Low-dose HRT

Dose response to estrogen therapyDose response to estrogen therapyNumber of moderate–severe hot flushes

Adapted from Notelovitz M, et al. Obstet Gynecol 2000;95:726–31

Nu

mb

e r

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9 10 11 12

** *

**

*

*

*

Placebo

0.25 mg E2

0.5 mg E2

1 mg E2

2 mg E2

Significantly (p < 0.05)different from placebo

*

0

2

4

6

8

10

1 2 3 4 5 6 7 8 9 10 11 12 13Cycle

Ad

jus

ted

me

an

nu

mb

er*

0

2

4

6

8

10

1 2 3 4 5 6 7 8 9 10 11 12 13Cycle

Ad

jus

ted

me

an

nu

mb

er*

0.625

0.45

0.3

Placebo

0.625/2.50.45/2.50.45/1.50.3/1.5

PlaceboCEE/MPACEE

Women's HOPE StudyWomen's HOPE StudyNumber of hot flushes over 13 cyclesNumber of hot flushes over 13 cycles

Adapted from Utian W, et al. Fertil Steril 2001;75:1065–79

*Adjusted for baselineMean number of hot flushes at baseline = 12.3 (range 11.3–13.8)

Number of hot flushesNumber of hot flushes

0

10

20

30

40

50

60

70

80

Baseline 2 4 6 8 10 12 14 16

Treatment week

Me

an

nu

mb

er

of

ho

t fl

us

he

s p

er

we

ek Placebo

1 mg 17β-estradiol + 2mg drospirenone

Modified from Schürmann R, et al. Climacteric 2004;7:189–96

*

*

* significantly (p = 0.001)different from placebo

*

**

*

*

*

*

*

Panay N, et al. Climacteric 2007;10:120–31

CHOICE TrialCHOICE TrialNumber of moderate to severe hot flushes by weekNumber of moderate to severe hot flushes by week

-4

-3

-2

-1

0

1

2

3

4

Baseline 6 12 18 24

Months

Me

an

ch

an

ge

fro

m b

as

elin

e (

%)

CEE 0.625 mg/day

CEE 0.45 mg/day

CEE 0.3 mg/day

Placebo-4

-3

-2

-1

0

1

2

3

4

Baseline 6 12 18 24

CEE 0.625/MPA 2.5 mg/day




Placebo

CEE CEE/MPA

Spine BMD: ITT populationSpine BMD: ITT population

Lindsay R, et al. JAMA 2002;287:808

*

*

*

* Significantly (p < 0.005) different from placebo

*

*

*

Lumbar spinePercentage change over placebo after 26 months

Effects of oral E2/NETA and E2 alone vs. placebo Effects of oral E2/NETA and E2 alone vs. placebo in prevention of osteoporosis in postmenopausal in prevention of osteoporosis in postmenopausal

women (mean age 52.8)women (mean age 52.8) Multicenter RCT studyMulticenter RCT study

Greenwald MW, et al. Menopause 2005;12:741–8

Progestogenic side-effectsProgestogenic side-effects

Intolerance


Progestogen intolerance: Progestogen intolerance: mineralocorticoid effectsmineralocorticoid effects

• Symptoms– Edema, weight gain, bloating, migraine

• Etiology– Competition for mineralocorticoid

receptors– Possible effect on renin-angiotensin-

aldosterone cascade


Progestogen intolerance:Progestogen intolerance:mild androgenic effectsmild androgenic effects

• Symptoms– Acne, greasy skin, hirsutism, etc.

• Competition for androgen receptor – Especially C19 nortestosterone-

derived progestogens


Progestogen intolerance: Progestogen intolerance: CNS effectsCNS effects

• Stimulation of progesterone receptors in CNS may lead to negative mood effects

• Mediation by neurotransmitter pathways– GABA receptors stimulated – Serotonin levels reduced– Increased monoamine turnover

Progestogen intolerance:Progestogen intolerance:minimizing progestogenicminimizing progestogenic

side-effectsside-effects

• Progestogenic side-effects may resolve after first few weeks

• Direct treatment– Mild diuretics – Linolenic acid for breast tenderness– ?Mifepristone (anti-progesterone)


Minimizing progestogenicMinimizing progestogenicside-effectsside-effects

• Action– Change progestogen

• Drospirenone may offer additional benefits– Lower dose and duration (7–10 days)– Switch to: ccHRT, tibolone, intermittent

progestogen, LNG-IUS• Transvaginal ultrasonography ±

endometrial biopsy if bleeding problems

Minimizing side-effectsMinimizing side-effects

Bleeding

HRT: maximizing efficacy, HRT: maximizing efficacy, minimizing problems minimizing problems

• Heavy/prolonged bleeding

• Increase dose/duration of progestogen (13–21 days)

• Avoid bleeds altogether• Continuous combined HRT • Tibolone• LNG-IUS

Panay N, Studd J. Hum Reprod Update 1997;3:159

Women’s HOPE StudyWomen’s HOPE StudyCumulative amenorrhea rates: CEE/MPACumulative amenorrhea rates: CEE/MPA

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13Cycle

Pa

tie

nts

(%

)

0.625/2.50.45/2.50.45/1.50.3/1.5

Placebo

Archer DF, et al. Fertil Steril 2001;75:1080–7

Clinical efficacy: low-dose c.c. HRTClinical efficacy: low-dose c.c. HRTAmenorrhea rates after 1 yearAmenorrhea rates after 1 year

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12 13

Cycle number

Pa

tie

nts

wit

h n

o b

lee

din

g (

%)

1 mg 17β-estradiol + 2 mg drospirenone

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

CHOICE TrialCHOICE TrialAmenorrhea rates in women treated withAmenorrhea rates in women treated with

oral E2 0.5 mg with NETA 0.25 (ALD 0.25) and oral E2 0.5 mg with NETA 0.25 (ALD 0.25) and NETA 0.1 mg (ALD 0.1)NETA 0.1 mg (ALD 0.1)

** **

* Significantly (p < 0.05) different from placebo

* ** *

Sturdee D, et al. Climacteric 2008;11:63

Unopposed ultra-low-dose Unopposed ultra-low-dose transdermal estradiol (14 µg/day)transdermal estradiol (14 µg/day)

Endometrial effects vs placebo:

• Proliferation 8.5% vs. 1.1% p = 0.6

• Bleeding 12.4% vs. 8.6% p = 0.3

• Atypical hyperplasia × 1

• Adenosarcoma × 1

Johnson SR, et al. Obstet Gynecol 2005;105:779–87

Conclusions:

“This therapy apparently causeslittle or no endometrial stimulation”

Management of breakthrough Management of breakthrough bleeding with c.c. HRT/tibolonebleeding with c.c. HRT/tibolone

• Usually in women – Recently menopausal – 1-year rule– Early menopause

• May be due to endogenous E2 production

• > 6 months breakthrough bleeding: investigate for pathology by ultrasonography (endometrial biopsy if endometrial thickness > 4 mm)

HRT indicationsHRT indications

• Vasomotor symptoms

• Urogenital symptoms

• Joint and muscle pains, mood swings, sleep disturbances and sexual dysfunction

• Prevention of osteoporosis and related fractures

• Prevention of atrophy – Epithelia– Skin– Connective tissue– Intervertebral disks


HRT contraindications IHRT contraindications I(as specified by regulatory authorities)(as specified by regulatory authorities)

• Current, past or suspected breast cancer

• Known or suspected estrogen-dependent malignant tumors (e.g. endometrial cancer)

• Undiagnosed genital bleeding

• Untreated endometrial hyperplasia

• Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)

Burger H, et al. Climacteric 2004;7:210–16

HRT contraindications IIHRT contraindications II(as specified by regulatory authorities)(as specified by regulatory authorities)

• Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)

• Untreated hypertension

• Active liver disease

• Known hypersensitivity to the active substances or to any of the excipients

• Porphyria cutanea tarda (an absolute contraindication)

Burger H, et al. Climacteric 2004;7:210–16

HRT potential benefits IHRT potential benefits I

• CVD– HRT improves many aspects of the metabolic

syndrome and reduces the risk of diabetes– There is evidence that HT may be cardioprotective

if started around the time of menopause and continued long-term (often referred to as the ‘window of opportunity’ concept)

– In women less than 60 years old, recently menopausal, without prevalent cardiovascular disease, the initiation of HT does not cause early harm, and may reduce cardiovascular morbidity and mortality


HRT potential benefits IIHRT potential benefits II

• CNS– HRT initiated around the time of menopause

or by younger postmenopausal women is associated with a reduced risk of Alzheimer’s disease

• Combined HRT may reduce the risk of colon cancer


Principles of hormone treatmentPrinciples of hormone treatment

• HRT should not be recommended without there being a clear indication for its use

• Counselling should convey the benefits and risks of menopausal HT in simple terms, e.g. absolute numbers rather than as percentage changes from a baseline

• This allows a woman and her physician to make a well-informed decision about HRT



• Women experiencing spontaneous or iatrogenic menopause before the age of 45, and particularly before the age of 40, are at higher risk for cardiovascular disease and osteoporosis

• They will benefit from hormone replacement, which should be given at least until the normal age of menopause



• Women taking HRT should have at least an annual consultation for a physical examination, update of medical history, relevant laboratory and imaging investigations and a discussion on lifestyle



• Whether or not to continue therapy should be decided at the discretion of the well-informed hormone user and her health professional, dependent upon the specific goals and an objective estimation of benefits and risks

• There are no reasons to place mandatory limitations on the length of treatment


hormone replacement therapy: practical considerations marco gambacciani and nick panay

Documents

hrt governing principle

age slide

continuing hrt newton

nick panay slide

agespecific hrt use

fewer sideeffects

reasons women

possibility of sideeffects