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firmed the importance of SHBG, finding that

women in the upper one-third level of SHBG had

twice the risk of those in the lower one-third.

Moreover, those women with both low estradiol

and high SHBG levels were at considerably

increased risk of fracture, compared with those

without these characteristics.

CLINICAL TRIALS OF LOW-DOSE

ESTROGEN

For the purpose of this review, 0.625 mg conju-

gated estrogens/day or its equivalent is consid-

ered standard dosage; 0.3 mg conjugated estro-

gens or its equivalent (e.g. 0.5 mg/day oral

micronized estradiol or 25

µg/day transdermal

estradiol) is considered low dosage; and half this

amount (0.25 mg/day oral micronized estradiol

or 14

µg/day transdermal estradiol) is considered

very low or microdosage. Currently, the only

microdosage estrogen marketed for osteoporosis

prevention is the transdermal 14

µg/day product.

Recent studies designed to test various doses

of estrogen have uniformly shown a linear dose

response of the skeleton from the lowest to the

highest doses tested

6–12

. This dose effect extends

down to very low levels of plasma estradiol

(10–20 pg/ml), and has been shown for various

estrogen formulations and routes of administra-

tion. Similar results are seen with lower doses in

the elderly to those in the early postmeno-

pause

7,13

. In toto, these studies indicate that there

is no threshold level for estrogen activity on the

skeleton, but rather a small incremental effect

with each increment in dose.

Estrogen’s skeletal benefit is mediated by its

antiresorptive effect, and thus can be measured

by reductions in biochemical markers of bone

turnover. Typically, standard doses of estrogens

Relative risk of fracture

adjusted for age and weight

Estradiol < 5 pg/ml

2.5

(1.4–4.6)

2.5

(1.4–4.2)

2.0

(1.1–3.9)

2.3

(1.2–4.4)

6.9

(1.5–32)

7.9

(2.2–28)

Hip fracture

Vertebral fracture

Figure 2 Age- and weight-adjusted relative risks (95% confidence intervals) of hip or vertebral fracture in

postmenopausal women with undetectable serum estradiol levels (< 5 pg/ml), high serum sex hormone-binding

globulin (SHBG) levels (≥ 1 µg/dl) or both, compared with women without these factors. Adapted from reference 5

(5–6)

(7–9)

(≥ 10)

0.8

0.6

0.4

0.2

Relative risk of fracture

Quartiles of serum estradiol (pg/ml)

Hip fracture

< 0.01 for trend

Vertebral fracture

< 0.005 for trend

Figure 1 Age-adjusted relative risk of fracture in

postmenopausal women ≥ 65 years of age versus

quartile of baseline serum estradiol levels. p for trend

< 0.01 for hip fracture and < 0.005 for vertebral

fracture. Hip fracture analysis included 317 women;

vertebral fracture analysis included 282 women.

Reproduced with permission from reference 5

https://t.me/med1917

reduce turnover by 40–50%

, while low doses of

oral estrogens

11,13

or transdermal estradiol

sup-

press bone turnover markers by about 25–30%.

The ultimate measure of estrogen’s skeletal

protection is reduction in fracture risk. The

Women’s Health Initiative showed that an aver-

age of 5.2 years of standard-dose estrogen com-

bined with 2.5 mg medroxyprogesterone acetate

reduced the risk of hip and clinical spine fractures

by one-third

. In a parallel study of unopposed

standard-dose estrogen lasting 7 years, similar

fracture risk reductions were observed

. No sim-

ilar clinical trial of low-dose estrogen on fracture

risk has been conducted. One case–control study,

with relatively small numbers of subjects, was

not able to show that the use of lower doses of

estrogen was associated with lower hip fracture

risk

. Thus, while the links between antiresorp-

tive effect, preservation of bone density and frac-

ture risk reduction are well understood, clinical

trial evidence is lacking for fracture risk reduc-

tion with the use of low-dose estrogen.

CLINICAL TRIALS OF VERY LOW

ESTROGEN

In a short-term study, delivery of 7.5 µg/day by

a transvaginal ring system showed modest

suppression of bone turnover and small incre-

ments in radial BMD

; this route and formula-

tion causes, at most, a few pg/ml rise in serum

estradiol. Among women 65 years and older,

relative to placebo, 0.25 mg oral micronized

estradiol increased spine BMD by 2% and hip

BMD by 4% over 3 years of study

. Unfortu-

nately, the immunoassay used in this study did

not provide accurate assessment of estradiol lev-

els produced by this treatment.

Further proof of the concept that levels of

about 10 pg/ml are linked to bone benefit in the

elderly comes from a 2-year clinical trial of 417

women aged 60–80 years who received either

placebo or 14

µg estradiol/day via a transdermal

estradiol patch system

. Transdermal delivery of

µg/day estradiol raised median serum estra-

diol levels from 4.8 to 8.6 pg/ml during the

ultralow-dosage transdermal estradiol assess-

ment (ULTRA) study. Bone mineral density

measured at the lumbar spine and total hip

showed statistically significant increases from

baseline; relative to those receiving placebo, the

mean increase in BMD in women receiving the

µg patch was 2.0% and 1.2% at spine and

hip, respectively (Figure 5). The improvement in

BMD was linked to a 22% suppression of bone

turnover markers. Thus, levels of plasma estra-

diol that would be considered inconsequentially

Relative risk of any fracture

2.5

2.0

1.5

1.0

0.5

2.3

1.4

1.1

11)

(11–14)

(15–18)

(≥ 19)

Quartiles of serum estradiol (pg/ml)

Figure 3 Relative risk of any fracture in 435

postmenopausal women (mean age 64 years) by

quartile of baseline serum estradiol: the OFELY (Os

des Femmes de Lyon) study. Reproduced with

permission from reference 4

Odds ratio of

vertebral fracture

T1 E

T2 E

SHBG T3

SHBG T2

SHBG T1

Figure 4 Odds ratios for incident vertebral fracture

based on tertiles of serum estradiol (E

) and sex

hormone-binding globulin (SHBG) in 454 post-

menopausal women ≥ 55 years old: the Rotterdam

Study. Reproduced with permission from reference 2

https://t.me/med1917

low in premenopausal women prevented bone

loss.

Furthermore, the observed BMD increases and

bone turnover decreases in the ULTRA study were

related to the baseline level of endogenous estra-

diol

. Women who began the 2-year study with

serum estradiol below the median (< 5 pg/ml)

showed substantially greater skeletal response to

estradiol treatment compared with those with

higher levels of endogenous estradiol (Figure 6).

There is controversy over the ideal level of

bone turnover to be achieved by antiresorptive

therapy, many supporting the goal of reducing

bone turnover to a level at or below the mean of

healthy premenopausal women but not to exces-

sively low levels. Mean bone turnover reductions

seen with very low oral

or transdermal

estro-

gens (about 20–25%) are similar in magnitude

to those reported in women who received ralox-

ifene, a drug that reduces risk of vertebral frac-

ture by 36% during 3 years of treatment

Some limited fracture data suggest that very

low estrogen reduces the risk of clinical fractures.

In the oral very-low-estradiol study, after 3 years,

six fractures occurred among women receiving

placebo while two were noted in the estradiol-

treated group

. A similar ratio was observed

during 2 years in the ULTRA study (ten in the

placebo-treated group and four in the estradiol-

treated group)

. Although neither study alone

had sufficient statistical power for fracture out-

comes, combining the results of both studies

yields a significant reduction in risk (relative risk

0.4, p < 0.05).

Larger, long-term trials are needed to deter-

mine fracture risk reductions accurately as well

as other potential benefits and harms of very-

low-dosage estradiol therapy.

WHO SHOULD RECEIVE VERY LOW

ESTROGEN?

Women who have continued to take

hormone therapy

Despite the high rate of discontinuation in hor-

mone therapy (HT) since publication of the

Women’s Health Initiative (WHI) study, about

half of prior users remain on HT

. Most of these

continuing users remain on standard estrogen

doses in combination with daily progestin

. A

large body of clinical trial data show that low-

and very-low-estrogen therapies have far greater

tolerability

7,9,11,20

than standard regimens; this is

particularly important for achieving the lowest

incidence of bleeding and breast tenderness, the

major reasons for women’s discontinuation of

. These data, coupled with emerging effi-

cacy data, suggest that providers should consider

changing a woman’s hormone regimen over

time. Whereas standard dosages are often

required for troublesome symptoms at the time

–1

Baseline 1 year 2 years

Percentage change in BMD

2.1%

2.6%

0.5%

0.6%

< 0.001 p < 0.001

(a)

–1

Baseline 1 year 2 years

Percentage change in BMD

0.7%

0.4%

–0.2%

–0.8%

= 0.001

< 0.001

(b)

Transdermal estradiol, 14

µg/day

Transdermal placebo

Transdermal estradiol, 14 µg/day

Transdermal placebo

Figure 5 Percentage change from baseline lumbar

spine bone mineral density (BMD) (a) and total hip

BMD (b) over 2 years in postmenopausal women

(60–80 years old) using transdermal estradiol 14 µg

(n = 208) or placebo patch (n = 209). Reproduced

with permission from reference 20

https://t.me/med1917

of the menopausal transition, switching to lower

dosages may become acceptable after some

months of therapy. Half-strength regimens

appear to be adequate to control vasomotor

symptoms

26–28

as well as prevent bone loss

7–13

Low-dosage estrogen is likely to become the pre-

ferred HT option because of its superior tolera-

bility and because of greater potential for patient

acceptance and continuation. Health-care

providers should now make every attempt to

reduce the dosage to the lowest that is acceptable

(i.e. controls menopausal symptoms) and is likely

to promote health. A trial of reducing dosage in

long-term users of standard HT to half-strength

estrogen dosage found that only 6.5% returned

to the standard dosage because of unacceptable

vasomotor symptoms

. This same study showed

that long-cycle progestin (14 days every 6

months) was adequate to protect the

endometrium. Gradual tapering of the dose can

be accomplished by alternate-day oral therapy or

by reduction in transdermal patch strength.

Women who have recently stopped

using hormone therapy

Approximately one in five women who stopped

HT after learning of the Women’s Health Initia-

tive results report persisting and troublesome

vasomotor symptoms

. These women have

made the choice to live with the symptoms and

lose bone density rather than return to HT. It is

not known how many of them have been given

counseling about low- and very-low-dosage HT.

Adequate proof exists for the efficacy of low-dose

estrogen in the relief of hot flushes and other

menopausal symptoms, but only anecdotal evi-

dence is thus far available for symptom relief

using very low doses.

New starts for very low estrogen

In today’s climate of increased concern about

adverse effects of HT, many women would rather

avoid starting standard HT. Lower doses of

estrogen may not be effective in the control of

severe vasomotor symptoms, especially in young

oophorectomized women. However, for women

well beyond the menopausal transition, who are

not very troubled by vasomotor symptoms and

who are at risk for osteoporosis, very low estro-

gen may be acceptable. The otherwise healthy

woman who is at increased risk for osteoporosis

can be identified by using the easily obtained

National Osteoporosis Foundation (NOF) key

risk factors: thinness, smoking, mother or sister

with hip fracture and personal history of frac-

ture

. Given the choice between bisphospho-

nates, raloxifene and the three levels of estrogen

% Change

in BMD

% Change in

osteocalcin

–5

–10

–15

–20

–25

–30

(< 2.7)

(2.7–4.7)

(4.8–8.2)

(> 8.2)

–19.5

–3.5

1.5

0.7

1.2

2.11.9

3.9

2.2

2.8

–28

–21.2

Spine BMD

Hip BMD

Osteocalcin

Te st for

trend

p = 0.02

p = 0.22

p = < 0.01

Figure 6 Mean differences in lumbar spine bone mineral density (BMD), total hip BMD and serum osteocalcin

levels between women receiving transdermal estradiol 14 µg (n = 208) or placebo patch (n = 209) by quartile of

baseline estradiol. Adapted from reference 21

https://t.me/med1917

therapy, many women meeting these NOF crite-

ria would choose very low estrogen.

HOW SHOULD UNOPPOSED VERY

LOW ESTROGEN BE MONITORED?

Use of serum estradiol

Ideally, serum estradiol measurement could be

used to guide initiation and follow-up of very-

low-dose estrogen therapy, but only a few labo-

ratories use the sensitive radioimmunoassay

capable of accurately measuring very low levels

of estradiol. Most clinical laboratories in the USA

use the automated enzyme-linked immunosor-

bent assay (ELISA), for which the Food and Drug

Administration (FDA)-approved lower limit of

sensitivity is 15 pg/ml

For skeletal effects

Ideally, antiresorptive therapy should be moni-

tored for its effects using biochemical measures

of bone turnover; usually, after 3–6 months of

therapy, turnover markers reach a nadir. If the

marker level is not at or below the pre-

menopausal mean, then adjustment in dosage

could be considered.

For endometrial safety

Endometrial proliferation is exceedingly rare

among women aged 60 years and older because

the production of estradiol in these women yields

levels below the stimulation threshold for the

endometrium. At the end of 2 years of 14

µg

transdermal estradiol given unopposed, < 2% of

women showed evidence of endometrial prolifer-

ation

. In this same study, the incidence of vagi-

nal bleeding was not significantly increased by

this dosage of estradiol. Thus, physiologic estro-

gen replacement should not require progestin

opposition and, consistent with this, the US FDA

has not required that concomitant daily or

monthly progestin be used; they have, however,

recommended the use of long-cycle progestin (14

days every 6–12 months) as a precaution against

the development of endometrial abnormalities.

CONCLUSIONS

The foregoing review supports redefining estro-

gen deficiency among elderly women – not in

comparison with premenopausal levels, but con-

sidering the physiologic effects of estradiol in this

age group. In premenopausal women, serum

estradiol ranges from about 50 to 200 pg/ml,

depending on the menstrual cycle phase; stan-

dard HT increases levels of estradiol into this

range. In marked contrast, most older post-

menopausal women have levels below

10 pg/ml

1,2,5,12,20

. Those below the mean (e.g.

5–9 pg/ml, depending on the assay) have lower

BMD, higher bone turnover and greater fracture

risk compared with their peers whose levels are

above the mean. Physiologic enhancement aimed

at increasing serum estradiol to an age-appropri-

ate level is able to reduce bone turnover and pre-

vent bone loss. Given the remarkable new

research showing that a small amount of circu-

lating estradiol is needed for bone health, and

having the means to restore levels to those

appropriate for age, providers can add micro-

dosage estradiol to their osteoporosis prevention

armamentarium.

WHAT IS THE FUTURE FOR

VERY-LOW-ESTROGEN THERAPY?

Further studies of very low estradiol will help to

provide additional long-term safety and efficacy

information. Both a head-to-head comparison of

BMD effects against raloxifene and a trial of

effectiveness for relief of hot flushes are under

way. A 3–5-year study is planned to examine its

effect on fracture risk and long-term endometrial

safety. Beyond these, a new generation of low-

dose estrogen studies will be required to docu-

ment adequately the risks and benefits.

ADDENDUM

This addendum is intended for readers of this

chapter interested in knowing more about

methodologies used to measure serum estra-

diol in very low concentrations, 0–20 pg/ml.

https://t.me/med1917

Differences in reported postmenopausal serum

levels should be considered by those intending to

use these assays for research or clinical applica-

tions. Without a practical method for standard-

izing assays, measuring low levels of estradiol

using such assays and interpreting results of

epidemiological studies

1–5,20

remain a challenge.

The purpose of this review is to compare results

of various estradiol assay methods and suggest a

means for standardization.

In an immunoassay system, measurement of

an analyte is generally based on the analyte bind-

ing the detection antibody and preventing the

antibody from binding to either a solid phase or

a tagged reporter molecule. The matrix is

defined as everything other than the analyte in

the immunoassay sample. Ill-defined matrix

effects can be due to substances interfering with

different aspects of the immunoassay, such as

inhibiting signaling detection or affecting bind-

ing of the labeled antibody to the solid phase, to

the analyte itself or to both. Thus, matrix effects

may falsely under- or overestimate the true con-

centration of the analyte

Estradiol immunoassays typically use either a

radioactive or a non-radioactive detection

marker, work by an excess-antigen/limited-anti-

body system (competitive immunoassay) and are

performed with (extraction-type) or without

(direct-type) purification steps. Extraction-type

assays employ initial solvent extraction and sub-

sequent chromatographic separation of estradiol

from other steroids; they typically use radioactive

estradiol as a marker. Direct immunoassays use

either chemiluminescent or colorimetric markers

and are typically faster and less labor-intensive

(automated) than extraction-type assays. The

presence of serum sex hormone-binding globulin

and the difficulty in obtaining appropriate

buffers have contributed to interference and

matrix effects, leading to greater inaccuracy

(higher or lower estradiol measurements) by

direct immunoassays than by extraction-type

assays. New methods are being developed to

characterize better and reduce sample matrix

effects in estradiol assays

. Extraction-chro-

matography may better remove estradiol from

sex hormone-binding globulin and minimize

potential cross-reacting steroids.

Estradiol measurements from different assays

produce varying results at low estradiol lev-

els

35–39

. For example, the mean of 20 post-

menopausal women’s estradiol levels using dif-

ferent direct assays ranged from 8 to 43 pg/ml,

while an indirect assay measured a mean level

<3pg/ml

. Newer direct assays and rapid

extraction methods report improved accuracy

and precision at postmenopausal estradiol lev-

els

40,41

The assays used in the epidemiologic and

clinical studies reviewed in this chapter all share

excellent sensitivities (ability to distinguish dif-

ferences between a few pg/ml and none) as well

as excellent precision (coefficient of variation on

the order of 10% at levels of 10 pg/ml). The Rot-

terdam Study, STOP/IT study (Sites Testing

Osteoporosis Prevention/Intervention) and

ULTRA study all measured estradiol by direct

immunoassays, while the OFELY and SOF stud-

ies used extraction-based radioimmunoassay

(Table 1)

1–5,20

. Characteristic of direct

immunoassays, the direct assays used by the Rot-

terdam Study, the ULTRA study and the

STOP/IT study all report very low limits of

detection, 1.3 pg/ml, 1.4 pg/ml and 2.2 pg/ml,

respectively, which are lower than those of indi-

rect radioimmunoassays (3 pg/ml and 5 pg/ml in

the OFELY and SOF studies, respectively)

1–5,20

The key issue is accuracy: are results obtained

by the various assays really true? Examining the

estradiol cut-off point for clinical outcomes is a

useful way to compare these assays. Table 1

shows the lowest tertile or quartile cut-off points

that, in these studies, were associated with either

greater fracture risk or greater response to treat-

ment; note the critical values differ four-fold,

from < 2.7 pg/ml to < 11 pg/ml.

We conclude that there is substantial variabil-

ity in measurements of low serum estradiol con-

centrations across different estradiol immuno-

assay methods. For estradiol to be clinically

useful for discriminating risks of osteoporosis and

predicting response to therapy, assay methods

should be standardized. Mass spectrometry,

using gas or liquid chromatography, has been

suggested as a gold standard for measuring low

estradiol levels; this method is capable of

measuring to 0.1 pg/ml, but is not yet widely

https://t.me/med1917

available

. Just as manufacturers of cholesterol

assays have agreed to standardize their assays to

results obtained by ultracentrifugation, those

measuring estradiol could use mass spectrometry

to provide this much needed standardization.

Table 1 Characteristics of estradiol (E

) assays used in large epidemiologic studies of bone health in post-

menopausal women

Lowest E

detection tertile or quartile

Study Assay type

Manufacturer limit (pg/ml)

†

(pg/ml)

†

Cummings et al.

, 1998 extraction Endocrine Sciences, 5 < 5 (quartile)

Ettinger et al.

, 1998 Inc.

SOF

Garnero et al.

, 2000 extraction radioimmunoassay 3 < 11 (quartile)

OFELY study (in-house method)

Goderie-Plomp et al.

, 2004 direct Diagnostic Systems 1.3 < 11 (tertile)

Rotterdam Study Laboratories

Rapuri et al.

, 2004 direct Diagnostic Systems 2.2 7.1 ± 0.14

STOP/IT study Laboratories (tertile)

‡

Ettinger et al.

, 2004 direct Diagnostic Products 1.4 < 2.7 (quartile)

ULTRA study Corporation

Extraction-type assay consists of an initial extraction step;

†

multiply pg/ml by 3.67 to convert to pmol/l;

‡

mean ± standard deviation of lowest tertile; SOF, Study of Osteoporotic Fractures; OFELY, Os des Femmes de

Lyon; STOP/IT, Sites Testing Osteoporosis Prevention/Intervention; ULTRA, ultralow-dosage transdermal

estradiol assessment

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INTRODUCTION

Selective estrogen receptor modulators (SERMs)

are a group of compounds characterized by bind-

ing to the estrogen receptor. Chemically, they are

heterogeneous, and have been grouped into five