HORMONE

REPLACEMENT THERAPY NATALIA FDAS 01073180026

IN YOUNG WOMEN
WITH PRIMARY PEMBIMBING:
DR. JULITA, SPOG
OVARIAN INSUFFICIENCY
AND EARLY MENOPAUSE
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 INTRODUCTION

many of the health

rare but important complications
cause of sex steroid characterized by: associated with POI
sPOI affects;
deficiency and • menopausal levels of are directly related
infertility in FSH • ~1% <40 yo to ovarian
• absent or irregular • ~0.1% <30 yo
premenopausal menstrual cycles < 40 yo hormone
woman deficiency
(primarily estrogen)

*sPOI (Spontaneous 46,XX POI): ovarian insufficiency <40 yo in woman with a normal46,XX karyotype 3
 Health complications of POI;

hot flashes ↓ BMD mood disorders

• ↑ fracture risk infertility • depression
vaginal
night sweats • anxiety
dryness

menopausal ↑ rates of
symptoms cognitive sexual
autoimmune
decline dysfunction
↓sexual
insomnia
disease
desire

dyspareunia ↑ risk if CVD & dry eye

type 2 DM syndrome

*BMD: Bone Mineral Density

 stroke

• Women’s Health Initiative (WHI) trial  shows adverse effects

breast
from a study of older postmenopausal woman, has dissuades ↑ risk of :
cancer
many from using estrogen therapy or estrogen/progestin therapy
EPT) in young women with POI or early menopause CVD

In contrast to woman with normal menopause, the situation in young women

with POI and early menopause is in fact a pathologic state of estrogen
deficiency compared with their peers with normal ovarian function.

HRT is replacing hormones that would normally be present

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• Physiologic EPT ameliorates health risks and is considered standard care for women with POI or early menopause.
• Generally recommended until age ~50yo (average age of natural menopause) unless specific contraindication exist; estrogen
dependent malignancy.

• This review discuss:

Management of HRT
The use of HRT in
in women with POI & HRT use in special
women with POI & Benefits & risks
early menopause populations with POI
early menopause
after age 50

Ovarian insufficiency as a result of oophorectomy present a unique situation which will be addressed in a
separate review

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 sPOI (Spontaneous 46,XX POI): ovarian
insufficiency <40 yo in woman with a normal46,XX
ETIOLOGIES OF POI karyotype for whom the conditions develops
spontaneously.

genetic autoimmune 90% idiopathic

lymphocytic
iatrogenic (related sPOI 4% autoimmune
to chemotherapy surgical oophoritis
or radiation)
Fragile X Mental
2-5% Retardation (14% of
spontaneous familial sPOI)

Most common genetic cause of POI  Turner

syndrome (45,X karyotype). ~1in 1500 girls. 7
BENEFITS AND RISKS OF HRT IN WOMAN WITH
POI AND EARLY MENOPAUSE

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MENOPAUSAL SYMPTOMS AND SEXUAL FUNCTION

• Symptoms experienced by POI are identical to those who proceed natural menopause.
• Due to: primarily E2↓, and likely to some extent ovarian T production.
• Appropriate physiologic estrogens replacement alleviates menopausal symptoms.
• Role for T replacement has not been clearly established.

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BONE MINERAL DENSITY AND FRACTURE RISK

• Peak bone mass is attained by the age of ~ 30 yo in women, prolonged estrogen deficiency
• before 30  ↓ peak bone mass accrual. Primary health concern among young
• After 30  early bone loss women with POI

• Lower BMD seen in women with POI or early menopause (age<45 years) due to any etiology is
associated with significantly ↑ risk of fracture.
• Fracture rates ↓ among POI or early menopause who are treated with HRT.

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• Compared with regularly menstruating woman [age-matched, mean 32], sPOI (46,XX)= significantly
lower BMD Z-scores [femoral neck].
• 21% sPOI  BMD Z-scores <-2.0 = risk factor for fractures
• 67% sPOI  BMD Z-scores <-1.0
• 47% were within 1.5 years of diagnosis

• Progressive ↓ in ovarian hormone production occurring well before the diagnosis of sPOI may perhaps
contribute to the high rates of low BMD in women who were recently diagnosed.

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 • Delay in diagnosis
• Inadequate Calcium intake (49%)  1200 mf of elemental calcium daily
• Inadequate Vitamin D intake (58%)  1,000-2,000 IU vitamin D3
(cholecalciferol) daily
Modifiable risk factors • 25-hydroxy vitamin D level has to be maintained within normal range
that may contribute to ↓ (>30ng/mL) Regular routine weight-bearing exercise (1 out of 4 had no
bone mass [in woman regular exercise program)
with POI]:

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• National Institutes of Health (NIH)
• 3 years prospective RCT; in standard regimen of HRT in BMD [lumbar spine and femoral neck] sPOI
• At the end of 3-year intervention, BMD did not differ between women with sPOI and a group of contemporaneously
recruited normally cycling control woman. Additional transdermal T replacement provided no additional beneficial
effect on BMD. 13
CARDIOVASCULAR DISEASE

• Evidence points to estrogen deficiency as a driver of ↑ CVD risk associated with POI.
• Compared with age-matched normal women, sPOI have ↓ endothelial function, an early sign of
atherosclerosis. Treatment with the use of HRT for 6 months significantly improved endothelial function
in these women.
• Benefit of HRT on cardiovascular health largely in naturally postmenopausal women;
• No long-term data exist on cardiovascular outcomes in young women with POI treated with the use of
HRT.

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EMOTIONAL HEALTH

• POI is associated with an ↑ risk of depression and anxiety (in large part owing to the diagnosis of
infertility & perceived psychosocial support.)
• A study comparing 154 women with 46,XX sPOI with control  significantly lower perceived social
support and self-esteem, (↑social anxiety and shyness, more symptoms of depression)
• Physiologic HRT, particularly the E2 component has been shown to alleviate symptoms of depression and
even lead to remission when initiated during perimenopause or very early menopause

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COGNITIVE FUNCTION

• Evidence suggest that estrogen is neuroprotective and therefore estrogen deficiency at an early age
would theoretically heighten a woman’s risk for cognitive decline and dementia
• Studies in older postmenopausal woman estrogen replacement therapy is protective against
development of dementia.
• Data on cognitive benefit benefits of HRT come exclusively from older post menopausal populations
• No data exists showing direct cognitive benefits of HRT in young women with POI

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 INFERTILITY
• For many, infertility is the most devastating aspect of the diagnosis.
• Spontaneous pregnancy occurs in ~5%-10% in sPOI
• POI in most cases is not a “failure” if the ovary, but rather intermittent and unpredictable ovarian
function that can persist for decades
• Tonic serum LH ↑  premature luteinization of growing antral follicles  ↓ chances for spontaneous
ovulation, therefore theoretically;
• HRT ↓LH levels
• E2 ↓FSH (chronically ↑ FSH level has been shown to down-regulate granulosa cell FSH receptors)

Despite this theoretic fertility enhancing effect of HRT, clinical

investigations have demonstrated little to no benefit in practice.
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DRY EYE SYNDROME

• Women with POI suffer from dry eye syndrome significantly > age-matched control women with normal
ovarian function (20% vs. 3%)
• No investigations to date have explored a role for androgen or estrogen replacement therapy in
ameliorating symptoms in women with POI.

not associated potential

with this, as sex hormone mechanism by
typically seen receptors in which ovarian
↓ tear
ocular
production in older hormone
surface
individuals tissues could alter
(>65 yo) function

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HORMONE REPLACEMENT THERAPY

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TRANSDERMAL OR TRANSVAGINAL ESTRADIOL

Recent study shows, 52% young women with POI either never take HRT, start HRT many years after diagnosis, and/or
discontinue HRT use before age 45.

The Women’s Health Initiative (WHI) study involved menopausal woman who ± 63 yo  should not be applied to young
women with POI or early menopause.

HRT in POI is ”replacement”, whereas in normal menopause is “extension”.

First line therapy of HRT for young women with POI or early menopause: transdermal or transvaginal E2 therapy
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Transdermal E2+cyclic progestin vs. combination oral contraceptive

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Transdermal E2+cyclic progestin vs. combination oral contraceptive

PROGESTIN

• Most women with POI have an intact uterus, so the recommended hormone replacement is both
estrogen and progestin.
• Cyclical progestin is recommended for endometrial protection.
• Medroxyprogesterone acetate  available evidence demonstrating capability to fully induce secretory
endometrium in conjunction with a full replacement dose of estrogen when used in regular monthly
cycles.
• Transdermal E2 (100mcg/d) + oral medroxyprogesterone acetate (10 mg/d for 12 days per month) this
regimen was tolerated well.

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TESTOSTERONE

• Currently there is insufficient evidence to recommend T replacement.

• 12 months randomized-placebo-controlled trial of physiologic T replacement in women with 46,XX
sPOI No benefit of T on quality of life, self-esteem, mood .
• Small study in women with Turner syndrome (n=14; ages 17-27), 1 year 1.5 mg oral methyl T  BMD
improvement.

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DEHYDROEPIANDROSTERONE

• Is an endogenous androgen produced by the ovaries and adrenal glans, plays a role in ovarian
folliculogenesis.
• Findings regarding fertility-enhancing effect of DHEA in women with ovarian insufficiency are still
controversial and show minimal clinical benefit at most.

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SPECIAL POPULATIONS

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TURNER SYNDROME

• Is the most common genetic cause of POI.

• Ovarian function lost early in life, many girls with Turner syndrome require estrogen replacement for
induction of puberty and menarche, to promote bone accrual early in life, and later to for maintenance
of bone density.
• In girls with Turner syndrome who do not enter puberty spontaneously, estrogen replacement therapy
for puberty induction should start at approx. age of 12, gradually increasing doses until full ohysiologi c
replacement doses are achieved usually over ~ 2 years of titration.

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• Preferred HRT regimen: 100 mc transdermal or transvaginal E2 daily + 10 mg cyclic
medroxyprogesterone acetate daily for 12 days per month.
• Benefits: bone protection, relief of menopausal symptoms related to estrogen deficiency, likely
protection from CVD

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BREAST AND OVARIAN CANCER

• HRT is considered to be unsafe, alternate measures should be used,

• Vulvovaginal atrophy associated with estrogen deficiency:
• low-dose vaginal estrogen
• Selective estrogen receptors modulators

• Reduction of cardiometabolic risk by lifestyle changes

• Bone health: calcium and vitamin D supplementation + regular weight-bearing exercise
• Depressed mood: antidepressant and/or psychotherapy

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BREASTFEEDING

• According to FDA-approved drug labels  neither E2 oral or transdermal, hormonal contraceptives are
recommended to be used during breast feeding
• Small amounts of hormone are transmitted via breast milks  jaundice or breast enlargement in neonates
• Estrogen may interfere with lactation by ↓ quantity & quality of breast milk
• A nursing mother with POI should be advised not to use HRT, until she has completely weaned her child

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 AFTER AGE OF 50

• Mean age of natural menopause 50 ± 4 years.

• The decision of when and how to discontinue HRT in women with POI needs to be individualized;
• Strong family history of breast cancer  stop HRT at age 45 (early age of menopause is associated with a ↓ risk
of breast cancer)
• Strong family history if osteoporosis or cardiovascular disease  continue HRT until age 55 (later age of
menopause is associated with a ↓ risk if osteoporosis and CVD)
• Lower postmenopausal doses of HRT, when initiated within 10 years after menopause onset, have been
associated with overall favorable risk-benefit profiles (↓menopausal symptoms, fractures, CVD, type 2
DM, mortality)

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CONCLUSION

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• HRT choice should closely mimic normal ovarian hormone production.
• Provide sufficient E2 level to ↓ symptoms & risks
• Progestin component  cyclical by inducing regular withdrawal bleeds, protect endometrium.
• Continue HRT until, age of natural menopause, then tapered off or stopped based on individual risks
and needs.

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THANK YOU

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