Estradiol
Estradiol ranges depend on sex, cycle phase and menopause, from 30 pg/mL or less after menopause to several hundred at ovulation. Most routine immunoassays cannot measure the low levels found in men and postmenopausal women accurately. Higher levels after menopause go with more breast cancer, and undetectable levels with more fractures. Estrogen therapy trials cut fractures and raised strokes.
- Status
- A blood test ordered by a clinician and also sold direct to consumers by some US laboratories. FDA classifies estradiol test systems as class I devices [1]. The Centers for Disease Control and Prevention sets reference targets for estradiol through its Hormone Standardization Program, whose performance criterion is a result within 12.5% of the target [2].
- Measures
- The amount of estradiol, one of the main types of estrogen, in blood [3].
- Also called
- estradiol, E2, E2 test, serum estradiol, estradiol serum, estradiol blood test, 17-beta estradiol, oestradiol, estradiol LC/MS, estradiol by mass spectrometry, sensitive estradiol, ultrasensitive estradiol
- Tested for
- menopause, irregular or absent periods, fertility treatment monitoring, hormone therapy monitoring, breast growth in men, early or late puberty, low sex drive, bone loss
Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on
Linked in research4
- ModerateLinked to more breast cancer in postmenopausal women at higher levels, with twice the risk in the top fifth of estradiol against the bottom fifth.
- ModerateLinked to more fractures at low levels: 2.5 times the hip fracture risk in older women with undetectable estradiol, and more fractures in older men below 16 pg/mL.
- ModerateLinked to more deaths in men at very low estradiol, below 5.1 pmol/L or about 1.4 pg/mL, in pooled cohorts that used mass spectrometry.
- LimitedOne trial found that blocking estradiol production in men aged 20 to 50 increased body fat and contributed to lower sexual function, while lean mass and strength followed testosterone.
Reported risks0
No risks sourced yet.
Reference ranges
Each range is the one its source published, in pg/mL. Also reported in pmol/L. Where sources differ, each is shown.
US National Library of Medicine, MedlinePlus, premenopausal women
Premenopausal females, with no cycle phase stated · [3]
| Range | What the source calls it |
|---|---|
| below 30 pg/mL | No name given |
| 30 to 400 pg/mL | "normal" |
| above 400 pg/mL | No name given |
Printed as 30 to 400 pg/mL (110 to 1468.4 pmol/L). It is one range for the whole menstrual cycle, and MedlinePlus states that estradiol levels vary depending on the time of month. It states that ranges may vary slightly among laboratories and names no assay [3].
US National Library of Medicine, MedlinePlus, postmenopausal women
Postmenopausal females · [3]
| Range | What the source calls it |
|---|---|
| 30 or below pg/mL | "normal" |
| above 30 pg/mL | No name given |
Printed as 0 to 30 pg/mL (0 to 110 pmol/L), so the range has no lower band. It names no assay [3]. The Endocrine Society reports that the limit of quantitation of most direct immunoassays is 30 to 100 pg/mL, which it calls insufficient for measurements in postmenopausal women [4].
Anckaert and colleagues, 2021, Roche Elecsys Estradiol III immunoassay, follicular phase
Women aged 18 to 37 with natural menstrual cycles, follicular phase · [5]
| Range | What the source calls it |
|---|---|
| below 31.1 pg/mL | No name given |
| 31.1 to 90.4 pg/mL | "reference interval" |
| above 90.4 pg/mL | No name given |
Printed as 114 to 332 pmol/L and converted here to pg/mL by dividing by 3.671. These are the 5th and 95th percentiles, so a tenth of the reference women fall outside them by construction. The median was 198 pmol/L. From 85 women in the United States and Europe sampled about three times a week through one cycle, with cycle length standardized to 29 days and the luteinizing hormone peak placed at day 15. Within the phase, the median rose from 125 pmol/L in the early follicular sub-phase to 464 in the late one. Two authors were employees of the assay's maker, which also funded medical writing [5].
Anckaert and colleagues, 2021, Roche Elecsys Estradiol III immunoassay, ovulation
Women aged 18 to 37 with natural menstrual cycles, ovulation phase · [5]
| Range | What the source calls it |
|---|---|
| below 60.5 pg/mL | No name given |
| 60.5 to 533.6 pg/mL | "reference interval" |
| above 533.6 pg/mL | No name given |
Printed as 222 to 1959 pmol/L, the 5th and 95th percentiles in 81 women, and converted here to pg/mL by dividing by 3.671. The median was 757 pmol/L. See the follicular phase block for how the study was done [5].
Anckaert and colleagues, 2021, Roche Elecsys Estradiol III immunoassay, luteal phase
Women aged 18 to 37 with natural menstrual cycles, luteal phase · [5]
| Range | What the source calls it |
|---|---|
| below 60.5 pg/mL | No name given |
| 60.5 to 232.6 pg/mL | "reference interval" |
| above 232.6 pg/mL | No name given |
Printed as 222 to 854 pmol/L, the 5th and 95th percentiles in 85 women, and converted here to pg/mL by dividing by 3.671. The median was 412 pmol/L. See the follicular phase block for how the study was done [5].
Verdonk and colleagues, 2019, mass spectrometry, early follicular phase
Premenopausal women, early follicular phase, 15 to 6 days before the luteinizing hormone peak · [6]
| Range | What the source calls it |
|---|---|
| below 8.4 pg/mL | No name given |
| 8.4 to 210 pg/mL | "reference interval" |
| above 210 pg/mL | No name given |
Printed as 31 to 771 pmol/L and converted here to pg/mL by dividing by 3.671. From 30 premenopausal women the study classed as healthy, sampled daily through one menstrual cycle and measured by liquid chromatography tandem mass spectrometry shown to be traceable to the reference method of the Centers for Disease Control and Prevention. The abstract does not state which percentiles the interval covers. The authors state that the intervals can be used for all traceable mass spectrometry methods [6].
Verdonk and colleagues, 2019, mass spectrometry, late follicular phase
Premenopausal women, late follicular phase, 5 days to 1 day before the luteinizing hormone peak · [6]
| Range | What the source calls it |
|---|---|
| below 28.3 pg/mL | No name given |
| 28.3 to 474.5 pg/mL | "reference interval" |
| above 474.5 pg/mL | No name given |
Printed as 104 to 1742 pmol/L and converted here to pg/mL by dividing by 3.671. See the early follicular phase block for how the study was done [6].
Verdonk and colleagues, 2019, mass spectrometry, day of the luteinizing hormone peak
Premenopausal women, on the day of the luteinizing hormone peak · [6]
| Range | What the source calls it |
|---|---|
| below 74.9 pg/mL | No name given |
| 74.9 to 780.2 pg/mL | "reference interval" |
| above 780.2 pg/mL | No name given |
Printed as 275 to 2864 pmol/L and converted here to pg/mL by dividing by 3.671. See the early follicular phase block for how the study was done [6].
Verdonk and colleagues, 2019, mass spectrometry, early luteal phase
Premenopausal women, early luteal phase, 1 to 4 days after the luteinizing hormone peak · [6]
| Range | What the source calls it |
|---|---|
| below 25.9 pg/mL | No name given |
| 25.9 to 323.6 pg/mL | "reference interval" |
| above 323.6 pg/mL | No name given |
Printed as 95 to 1188 pmol/L and converted here to pg/mL by dividing by 3.671. See the early follicular phase block for how the study was done [6].
Verdonk and colleagues, 2019, mass spectrometry, mid luteal phase
Premenopausal women, mid luteal phase, 5 to 9 days after the luteinizing hormone peak · [6]
| Range | What the source calls it |
|---|---|
| below 41.1 pg/mL | No name given |
| 41.1 to 528.7 pg/mL | "reference interval" |
| above 528.7 pg/mL | No name given |
Printed as 151 to 1941 pmol/L and converted here to pg/mL by dividing by 3.671. See the early follicular phase block for how the study was done [6].
Verdonk and colleagues, 2019, mass spectrometry, late luteal phase
Premenopausal women, late luteal phase, 10 to 14 days after the luteinizing hormone peak · [6]
| Range | What the source calls it |
|---|---|
| below 10.6 pg/mL | No name given |
| 10.6 to 481.9 pg/mL | "reference interval" |
| above 481.9 pg/mL | No name given |
Printed as 39 to 1769 pmol/L and converted here to pg/mL by dividing by 3.671. See the early follicular phase block for how the study was done [6].
Verdonk and colleagues, 2019, mass spectrometry, postmenopausal women
Postmenopausal women · [6]
| Range | What the source calls it |
|---|---|
| below 7.1 pg/mL | "reference interval" |
| 7.1 or above pg/mL | No name given |
Printed as below 26 pmol/L and converted here to pg/mL by dividing by 3.671, so the interval has no lower band. From 33 postmenopausal women measured by mass spectrometry [6]. This upper limit is about a quarter of the 30 pg/mL that MedlinePlus prints for postmenopausal women [3].
US National Library of Medicine, MedlinePlus, men
Males · [3]
| Range | What the source calls it |
|---|---|
| below 10 pg/mL | No name given |
| 10 to 50 pg/mL | "normal" |
| above 50 pg/mL | No name given |
Printed as 10 to 50 pg/mL (36.7 to 183.6 pmol/L). It names no assay or age group [3]. The Endocrine Society states that estradiol levels in men are at or below the sensitivity of available direct assays [4].
Verdonk and colleagues, 2019, mass spectrometry, men
Men · [6]
| Range | What the source calls it |
|---|---|
| below 3.3 pg/mL | No name given |
| 3.3 to 37 pg/mL | "reference interval" |
| above 37 pg/mL | No name given |
Printed as 12 to 136 pmol/L and converted here to pg/mL by dividing by 3.671. From 64 men measured by mass spectrometry. The abstract does not give their ages or state which percentiles the interval covers [6].
What has been shown to move it
Shown to lower it1
Lower estradiol over 12 weeks
One small trial found estradiol fell 16% from baseline over 12 weeks at 6 g a day in men.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- Over 12 weeks at 6 g a day, estradiol fell 16% (95% CI -27% to -5%) from baseline. The placebo group showed improved spinal responsiveness at the gastrocnemius that the supplement group did not [4].
- Population
- 10 men analyzed in the supplement group and 9 on placebo [4].
- Sources
- [4]
- Caveats
- One small trial. The authors received no specific funding [4].
Shown to raise it2
Testosterone and estradiol levels in postmenopausal women
Shown to raise testosterone by about 24 ng/dL and estradiol by about 8 pg/mL in postmenopausal women.
The numbers and sources
- Effect
- DHEA raised serum testosterone by 24.31 ng/dL (95% CI 15.22 to 33.40) and estradiol by 7.86 pg/mL (95% CI 6.33 to 9.40). Trials using 50 mg a day or more showed larger rises in testosterone (29.65 ng/dL) [10].
- Population
- Postmenopausal women in 21 RCTs [10].
- Sources
- [10]
- Caveats
- These are blood levels, not symptoms or outcomes. Subgroup confidence intervals overlapped [10].
Testosterone in men: clomiphene
Shown to raise total testosterone in men with low testosterone, by about 274 ng/dL against placebo, in pooled trials of clomiphene or enclomiphene.
Compared with placebo [13]; testosterone gel [13]; human chorionic gonadotropin [13]; the same men before treatment [14]
Across 17 studies pooled in a second review, total testosterone rose during treatment (pooled estimate 2.60, 95% CI 1.82 to 3.38, unit not given in the abstract), along with free testosterone, LH, FSH, SHBG and estradiol.
The numbers and sources
- Effect
- Against placebo, clomiphene or enclomiphene raised total testosterone by 273.76 ng/dL (95% CI 191.87 to 355.66, I² 89%), LH by 4.66 IU/L and FSH by 4.59 IU/L. Total testosterone did not differ from testosterone gel. Levels were higher than with hCG alone [13]. Across 17 studies pooled in a second review, total testosterone rose during treatment (pooled estimate 2.60, 95% CI 1.82 to 3.38, unit not given in the abstract), along with free testosterone, LH, FSH, SHBG and estradiol. Symptom scores on the Androgen Deficiency in Aging Males questionnaire improved. Side effects were reported by fewer than 10% of study populations and no serious adverse events were reported [14].
- Population
- Men with functional hypogonadism in randomized trials [13]. 1,642 men with hypogonadism in 19 studies, 4 randomized and 15 observational, treated for 1.5 to 52 months [14].
- Sources
- [13], [14]
- Caveats
- The first review pooled clomiphene with enclomiphene and heterogeneity was high [13]. The second rests mostly on before-and-after observational studies [14]. Use in men is off-label in the US [1]. Neither abstract reports fractures, heart events or fertility.
Tested, and not shown to change it5
Testosterone
Shown to raise testosterone in men, by about 57 ng/dL in one review, with no change in women. Rises stayed within physiological ranges.
A hormone meta-analysis found testosterone rose by 57.43 ng/dL in men but not in women (5.09 ng/dL), and estradiol did not change.
The numbers and sources
- Effect
- Across 20 trials of cognitive and physical outcomes, testosterone rose (SMD 0.33, 95% CI 0.13 to 0.54, I² 20.8%) [8]. A hormone meta-analysis found testosterone rose by 57.43 ng/dL in men but not in women (5.09 ng/dL), and estradiol did not change [6]. In 57 overweight men aged 40 to 70 with mild fatigue, 8 weeks of an ashwagandha extract was associated with a 14.7% greater rise in salivary testosterone and an 18% greater rise in DHEA-S than placebo. Fatigue, vigor and sexual well-being did not differ between groups [9].
- Population
- 1,249 participants in 20 RCTs [8]. 1,706 adults in 23 RCTs [6]. 57 men, crossover, 43 completed all 16 weeks [9].
- Sources
- [8], [6], [9]
- Caveats
- The 57-man trial tested one branded extract and was funded by its maker, Arjuna Natural Ltd [9]. In healthy adults, testosterone rises stayed within physiological ranges [7].
Testosterone and estrogen in men
Not shown to change total or free testosterone, estrogen or SHBG in men eating soy foods, soy protein or isoflavones, in two pooled analyses of clinical studies.
Compared with placebo groups [15]; values before intake in the same men, in simpler models [15]; control and baseline values the abstract does not detail [14]
The numbers and sources
- Effect
- Across 41 studies, soy protein or isoflavone intake had no significant effect on total testosterone, free testosterone, estradiol, estrone or SHBG, regardless of the statistical model, dose or study duration [14]. An earlier analysis of 15 placebo-controlled treatment groups, and 36 groups in simpler models, found no effect on testosterone, SHBG, free testosterone or free androgen index [15].
- Population
- Total testosterone measured in 1,753 men, free testosterone in 752 and estradiol in 1,000 [14]. Adult men in 32 reports [15].
- Sources
- [14], [15]
- Caveats
- Several authors of both analyses overlap. Studies included isoflavone extracts from soy or red clover as well as soy foods [14][15].
Testosterone
Mixed results: one 12-day trial found testosterone up 42% from baseline in untrained men, while trials in trained men found no rise or a fall at 6 g.
In resistance-trained men, 3 g a day for 28 days did not change total or free testosterone, LH or estradiol.
The numbers and sources
- Effect
- In 23 men aged 27 to 37 given 3.12 g of sodium D-aspartate a day for 12 days, testosterone rose from 4.5 to 6.4 ng/mL, a 42% increase over baseline, and LH rose 33%. Twenty men on placebo did not change [1]. In resistance-trained men, 3 g a day for 28 days did not change total or free testosterone, LH or estradiol [2]. In 24 trained men over 14 days, 3 g a day had no effect, and 6 g a day lowered total and free testosterone [3]. In 22 trained men over 12 weeks, 6 g a day did not change total or free testosterone [4]. In 16 boxers at simulated altitude, 6 g a day for 14 days did not change resting testosterone or LH [5]. A systematic review of 4 human studies found the results inconsistent and the studies few and of poor quality [6].
- Population
- Healthy men in Italy [1]; resistance-trained men [2][3][4]; male boxers [5].
- Sources
- [1], [2], [3], [4], [5], [6]
- Caveats
- The rise in [1] was reported against the same men's baseline, and the product was a commercial preparation also containing vitamins B6, B12 and folic acid. All trials were small and lasted 2 to 12 weeks.
Polycystic ovary syndrome
Shown to raise progesterone and endometrial thickness in women with PCOS. These are hormone and ultrasound measures, not pregnancy rates.
Estradiol, SHBG and FSH did not differ.
The numbers and sources
- Effect
- Across 22 studies (2,515 women), NAC was associated with higher progesterone (SMD 0.95, 95% CI 0.13 to 1.77) and thicker endometrium (SMD 0.58, 95% CI 0.10 to 1.06) than placebo and other drugs. Estradiol, SHBG and FSH did not differ [7].
- Population
- Women with PCOS, compared with placebo, metformin or clomiphene [7].
- Sources
- [7]
- Caveats
- Hormone and ultrasound measures, not pregnancy or live birth rates. Comparators were mixed.
Lower testosterone at 6 g a day
One small trial found 6 g a day for 14 days lowered total and free testosterone in 24 trained men. A 12-week trial found no change.
Estradiol, SHBG and albumin did not change.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- In trained men, 6 g a day for 14 days lowered total testosterone (p = 0.03), and free testosterone was lower than with the flour placebo (p = 0.005). Estradiol, SHBG and albumin did not change [3].
- Population
- 24 resistance-trained men [3].
- Sources
- [3]
- Caveats
- The 12-week trial at the same dose found no change in testosterone [4].
How it compares with the reference method
Mixed results1
Variation from one test to the next in men
Limited evidence: two hormone results from the same man differed by more than 18% to 28% about half the time, across eleven hormone measures that included estradiol.
The numbers and sources
- Compared with
- The same man's earlier result
- Effect
- In men sampled up to six times over 6 months, the within-person variation of eleven hormone measures, estradiol among them, implied that two measurements would differ by more than 18% to 28% about half the time and by more than 27% to 54% about a quarter of the time, depending on the hormone. Day to day biological variation accounted for more of the total than assay variation [14].
- Population
- 132 men aged 30 to 79 in Boston, 121 of whom completed all six visits [14].
- Sources
- [14]
- Caveats
- The percentage ranges cover all eleven hormone measures, and the abstract does not give the figure for estradiol alone [14].
Did not match the reference method2
Immunoassays at low concentrations
Not shown to match mass spectrometry at low levels: direct immunoassays read 6% to 74% high in men, and US laboratories averaged 34% high at 24 pg/mL.
The numbers and sources
- Compared with
- Liquid chromatography mass spectrometry, and reference targets set by the Centers for Disease Control and Prevention
- Effect
- The Endocrine Society reports that the limit of quantitation of most direct immunoassays is 30 to 100 pg/mL, which it calls insufficient for measurements in children, postmenopausal women, men and women taking aromatase inhibitors. It adds that even mass spectrometry methods may have difficulty below 5 pg/mL [4]. In 101 men, five commercial direct immunoassays all read higher than mass spectrometry, by 6% to 74%, and two of them detected estradiol in only 53% and 72% of samples [13]. When 76 laboratories measured five single-donor sera, the mean bias against the reference targets was 34% (range -17% to 175%) at 24.1 pg/mL, 40% (-33% to 386%) at 28.4, 16% (-45% to 193%) at 61.7, 5% (-27% to 117%) at 94.1 and -4% (-31% to 21%) at 127 pg/mL. Of nine measuring systems, none met the 12.5% criterion at the two lowest levels [2].
- Population
- 101 men older than 40 [13]. 76 clinical laboratories certified by New York State [2].
- Sources
- [4], [13], [2]
- Caveats
- A result near or below 30 pg/mL from a routine immunoassay may differ widely from a mass spectrometry result on the same sample. The proficiency survey's lowest sample was 24.1 pg/mL, above the levels in many men and postmenopausal women [2].
Day of the menstrual cycle
One study found median estradiol rose more than sixfold within one cycle, from 125 pmol/L in the early follicular phase to 817 at ovulation.
The numbers and sources
- Compared with
- The same women's samples from the early follicular phase
- Effect
- Median estradiol by sub-phase was 125 pmol/L early follicular, 172 intermediate follicular, 464 late follicular, 817 at ovulation, 390 early luteal, 505 intermediate luteal and 396 late luteal [5]. A mass spectrometry study that sampled women daily reported a different interval for each of six parts of the cycle [6].
- Population
- 85 women aged 18 to 37 sampled about three times a week through one natural cycle [5]. 30 premenopausal women sampled daily [6].
- Sources
- [5], [6]
- Caveats
- One immunoassay study with authors employed by the assay's maker [5]. A result from a premenopausal woman cannot be placed against a phase range without knowing the cycle day.
What studies tie it to
Linked in research4
Breast cancer after menopause
Linked to more breast cancer in postmenopausal women at higher levels, with twice the risk in the top fifth of estradiol against the bottom fifth.
The numbers and sources
- Effect
- In pooled individual data from nine prospective studies, the relative risks of breast cancer for the second to fifth fifths of estradiol, against the lowest fifth, were 1.42 (95% CI 1.04 to 1.95), 1.21 (0.89 to 1.66), 1.80 (1.33 to 2.43) and 2.00 (1.47 to 2.71). For free estradiol the top fifth had a relative risk of 2.58 (1.76 to 3.78). The increases remained after women diagnosed within 2 years of blood collection were excluded [7].
- Population
- 663 postmenopausal women who developed breast cancer and 1,765 who did not, none taking sex hormones when blood was drawn [7].
- Sources
- [7], [4]
- Caveats
- Observational. The Endocrine Society notes that median estradiol in the control women of such studies ran from 5.9 to 27.5 pg/mL from one study to the next, a spread it attributes largely to assay differences, so the fifths are not fixed levels [4]. In a trial of estrogen given alone, breast cancer did not rise (see the trial block below).
Fractures in older women and men
Linked to more fractures at low levels: 2.5 times the hip fracture risk in older women with undetectable estradiol, and more fractures in older men below 16 pg/mL.
The numbers and sources
- Effect
- Among women aged 65 or older, those with undetectable estradiol (below 5 pg/mL) had a relative risk of 2.5 for hip fracture (95% CI 1.4 to 4.6) and 2.5 for vertebral fracture (1.4 to 4.2) against women with detectable levels [8]. In older Swedish men measured by mass spectrometry, each standard deviation lower estradiol had a hazard ratio for fracture of 1.34 (1.22 to 1.49). The relation was nonlinear and strong below 16 pg/mL [9].
- Population
- 133 women with later hip fracture and 138 with later vertebral fracture, compared with randomly selected women from the same cohort, estrogen users excluded [8]. 2,639 men with a mean age of 75, followed for 3.3 years on average [9].
- Sources
- [8], [9]
- Caveats
- Observational. The women's results were adjusted for age and weight only [8]. Many routine assays cannot quantify levels this low [4].
Death from any cause in men
Linked to more deaths in men at very low estradiol, below 5.1 pmol/L or about 1.4 pg/mL, in pooled cohorts that used mass spectrometry.
The numbers and sources
- Effect
- In pooled individual data from cohorts of community-dwelling men, those with baseline estradiol below 5.1 pmol/L, about 1.4 pg/mL, had higher mortality from any cause. The abstract gives no hazard ratio for estradiol [11].
- Population
- 9 cohorts with individual data covering 255,830 participant-years, plus 11 studies with summary estimates [11].
- Sources
- [11], [4]
- Caveats
- Observational, with differences between studies and imputed missing data [11]. The level in question sits far below the 30 to 100 pg/mL limit of quantitation of most direct immunoassays [4].
Body fat and sexual function in a trial that lowered estradiol in men
One trial found that blocking estradiol production in men aged 20 to 50 increased body fat and contributed to lower sexual function, while lean mass and strength followed testosterone.
The numbers and sources
- Effect
- Men were given a drug that suppressed their own testosterone and estradiol, then placebo or one of four doses of testosterone gel for 16 weeks. A second group also took anastrozole, which blocks the conversion of testosterone to estradiol. The authors concluded that androgen deficiency accounted for the decreases in lean mass, muscle size and strength, that estrogen deficiency primarily accounted for the increases in body fat, and that both contributed to the decline in sexual function [12].
- Population
- 198 men aged 20 to 50 without anastrozole and 202 with it, treated for 16 weeks [12].
- Sources
- [12]
- Caveats
- One trial of 16 weeks in which hormone levels were set by drugs. The abstract gives no effect sizes for estradiol [12].
Mixed results1
Fractures, stroke and breast cancer in trials of estrogen therapy after menopause
Mixed results: in one large trial estrogen alone cut fractures by 27% and raised strokes by 33% in postmenopausal women, with little or no difference in breast cancer.
The numbers and sources
- Effect
- A Cochrane review drew its main results from the Women's Health Initiative. Among 10,739 women who had had a hysterectomy, oral conjugated equine estrogen for an average of 7 years, against placebo, gave relative risks of 0.73 for all clinical fractures (95% CI 0.65 to 0.80), 1.33 for stroke (1.06 to 1.67), 1.78 for gallbladder disease requiring surgery (1.42 to 2.24), 0.94 for coronary events (0.78 to 1.13), 1.32 for venous clots (1.00 to 1.74) and 0.79 for breast cancer (0.61 to 1.01). Among 16,608 women with a uterus, estrogen with a progestin for 5.6 years gave 0.78 for fractures (0.71 to 0.86), 1.39 for stroke (1.09 to 2.09), 2.03 for venous clots (1.55 to 6.64) and 1.27 for breast cancer (1.03 to 1.56) [10].
- Population
- 24 randomized trials with 45,660 women, most of them postmenopausal American women with a mean age over 60 [10].
- Sources
- [10], [7]
- Caveats
- A marker that tracks an outcome is not always one whose correction changes it. Higher estradiol went with more breast cancer in cohorts [7], and estrogen given alone did not raise it in this trial. The trials set a dose and did not target a blood level. The review's authors caution that the results rest on one study of oral therapy, and that only about 30% of the women were aged 50 to 59 [10].
Sources
- US Food and Drug Administration. 21 CFR 862.1260, Estradiol test system. Electronic Code of Federal Regulations. https://www.ecfr.gov/current/title-21/section-862.1260
- Cao ZT, Rej R, Vesper H, Astles JR. Accuracy-based proficiency testing for estradiol measurements. Clinical Biochemistry. 2024. https://doi.org/10.1016/j.clinbiochem.2023.110700
- US National Library of Medicine. Estradiol blood test. MedlinePlus Medical Encyclopedia. Reviewed August 18, 2025. https://medlineplus.gov/ency/article/003711.htm
- Rosner W, Hankinson SE, Sluss PM, Vesper HW, Wierman ME. Challenges to the Measurement of Estradiol: An Endocrine Society Position Statement. The Journal of Clinical Endocrinology and Metabolism. 2013. https://doi.org/10.1210/jc.2012-3780
- Anckaert E, Jank A, Petzold J, et al. Extensive monitoring of the natural menstrual cycle using the serum biomarkers estradiol, luteinizing hormone and progesterone. Practical Laboratory Medicine. 2021. https://doi.org/10.1016/j.plabm.2021.e00211
- Verdonk SJE, Vesper HW, Martens F, et al. Estradiol reference intervals in women during the menstrual cycle, postmenopausal women and men using an LC-MS/MS method. Clinica Chimica Acta. 2019. https://doi.org/10.1016/j.cca.2019.04.062
- Key T, Appleby P, Barnes I, Reeves G, Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous Sex Hormones and Breast Cancer in Postmenopausal Women: Reanalysis of Nine Prospective Studies. Journal of the National Cancer Institute. 2002. https://doi.org/10.1093/jnci/94.8.606
- Cummings SR, Browner WS, Bauer D, et al. Endogenous Hormones and the Risk of Hip and Vertebral Fractures among Older Women. New England Journal of Medicine. 1998. https://doi.org/10.1056/nejm199809103391104
- Mellström D, Vandenput L, Mallmin H, et al. Older Men With Low Serum Estradiol and High Serum SHBG Have an Increased Risk of Fractures. Journal of Bone and Mineral Research. 2008. https://doi.org/10.1359/jbmr.080518
- Bofill Rodriguez M, Yong LN, Mirkov S, et al. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database of Systematic Reviews. 2026. https://doi.org/10.1002/14651858.cd004143.pub7
- Yeap BB, Marriott RJ, Dwivedi G, et al. Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men: Individual Participant Data Meta-analyses. Annals of Internal Medicine. 2024. https://doi.org/10.7326/m23-2781
- Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men. New England Journal of Medicine. 2013. https://doi.org/10.1056/nejmoa1206168
- Handelsman DJ, Newman JD, Jimenez M, et al. Performance of Direct Estradiol Immunoassays with Human Male Serum Samples. Clinical Chemistry. 2014. https://doi.org/10.1373/clinchem.2013.213363
- Brambilla DJ, O'Donnell AB, Matsumoto AM, McKinlay JB. Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men. Clinical Endocrinology. 2007. https://doi.org/10.1111/j.1365-2265.2007.02976.x