Oestradiol (E2)

What oestradiol (E2) means in laboratory test results

Oestradiol (E2) is a sex steroid. A laboratory result is the outcome of a specific measurement procedure carried out in a particular laboratory. Analytical specificity, sensitivity and reproducibility are particularly crucial at low concentrations. A result should therefore be interpreted in conjunction with the measurement method, unit and the method-specific reference interval.

Why the measurement method makes such a big difference for men

A position paper on the measurement of sex steroids describes relevant analytical limitations of available chemiluminescence immunoassays and recommends mass spectrometric methods, in particular liquid chromatography–mass spectrometry (LC-MS), for low concentrations. Reference ranges should be validated on a method- and laboratory-specific basis.

In a comparative human study, serum samples from 101 healthy, asymptomatic men over the age of 40 were analysed using five direct immunoassays and LC-MS, each in duplicate. Two of the assays detected E2 in only 53 per cent and 72 per cent of the samples, respectively. All five assays showed positive deviations of between 6 per cent and 74 per cent compared with LC-MS. Only LC-MS correlated with testosterone and sex hormone-binding globulin (SHBG).

A further method comparison included samples from men and pre- and post-menopausal women, and compared eleven immunological methods with six mass spectrometric methods. The mean deviation per participant ranged from –2.4 per cent to +235 per cent, depending on the method. Only 3 out of 17 methods met the performance criteria applied, and most were unable to reliably measure concentrations below 10 pg/ml. Consequently, the blanket assertion that every immunoassay overestimates E2 is untenable.

Why there is no universal number range

A universally applicable male reference range in pg/ml cannot be derived from these method-dependent comparisons. Consequently, even a range of 10 to 40 pg/ml is not a universal figure supported by the body of evidence. The reference range stated on the individual test result, which has been validated for the method and laboratory used, is the decisive factor. Even a mass spectrometric method does not automatically eliminate all analytical uncertainty.

How experimentally reduced E2 levels affect men

In two 16-week studies involving 198 and 202 healthy men aged between 20 and 50, gonadal steroids were pharmacologically suppressed and different testosterone, anastrozole and placebo conditions were compared. A deficiency in oestradiol was the main contributor to the increase in body fat percentage. A deficiency in androgens reduced lean body mass, thigh muscle size and leg press strength. Both deficiencies contributed to the decline in sexual function assessed in the study.

This is a controlled causal finding under the hormonal conditions studied. The group did not correspond to either a population of strength athletes or AAS users. The study therefore does not establish an individual E2 threshold and does not demonstrate that every individual change in sexual function is attributable to a low E2 level.

What an anastrozole intervention can reveal about bone and blood markers

In a randomised, double-blind study, 69 men aged 60 years and over with low or borderline testosterone levels and symptoms of hypogonadism received 1 mg of anastrozole or a placebo daily for one year. Under anastrozole, E2 levels fell from 15 ± 4 to 12 ± 4 pg/ml. Anteroposterior bone density in the lumbar spine decreased significantly compared with the placebo (p = 0.0014): In the anastrozole group, it fell from 1.121 ± 0.141 to 1.102 ± 0.138 g/cm²; whilst in the placebo group it rose from 1.180 ± 0.145 to 1.189 ± 0.146 g/cm². The study demonstrates a change following this anastrozole intervention, but does not distinguish the isolated effect of oestradiol (E2) from the concurrent change in testosterone. The study examined bone density and markers of bone turnover, not joint pain, dry skin or individual patterns of symptoms.

Another randomised controlled trial involved 74 healthy older men whose testosterone levels were kept constant for the duration of the study. Following gonadotropin suppression, E2 levels of between 1.2 and 82 pg/ml were maintained for 22 ± 1 days. The differences in E2 levels, as measured by mass spectrometry, altered total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), lipoprotein(a) (Lp(a)), interleukin 6 (IL-6) or high-sensitivity C-reactive protein (hsCRP). This short-term finding of no effect applies to the markers investigated and the short time period; it does not constitute evidence of long-term safety.

What can be practically applied to strength training

The first practical question is whether the value is analytically useful, not whether it fits a pre-selected explanation. Where male concentrations are low, the measurement should be carried out using a validated, specific and sensitive method. Mass spectrometry is particularly suitable for this purpose.

• Measurement method: The report should specify the assay used and its reference range. Due to the assay-dependent detection limits and variability demonstrated, results from direct immunoassays should not be equated uncritically with LC-MS values.
• Complaints: The controlled hormone study indicates that oestradiol and androgen deficiency contribute to the sexual function under investigation, but does not establish any individual thresholds or typical lists of symptoms. There is a lack of direct, controlled evidence from human studies regarding joint pain and dry skin.
• Anastrozole: The study shows a decrease in spinal bone density in older men with low testosterone levels following a one-year intervention. Due to the concurrent change in testosterone levels, it is not possible to infer an isolated effect of E2 or to derive a recommended dosage for strength athletes.

The studies cited here do not provide any direct evidence that substances used for flavouring in bodybuilding, a high body fat percentage, regular alcohol consumption or liver disease are individual causes of elevated E2 levels.

Where the limits of what can be said lie

• There is no method-independent male reference range that generally justifies the figure of 10 to 40 pg/ml.
• There is a lack of direct, controlled data on bodybuilders or AAS users with regard to aromatisable substances, aromatase inhibitors and clinical endpoints.
• The long-term effects of reduced E2 levels on lipids, blood vessels and joints remain unclear. The finding of no significant changes in lipid and inflammatory markers was based on a study duration of 22 ± 1 days.
• On this basis, changes in libido, joint pain and dry skin do not allow for a clear calculation of an E2 level.

Conclusion

Where male E2 concentrations are low, the measurement method contributes to the result. In comparative studies, direct immunoassays showed varying degrees of reliability in detection and assay-dependent variations, but no consistent trend across all methods. A validated, sensitive method, particularly a mass spectrometric one, is therefore important for interpretation. Controlled human studies demonstrate the contribution of oestradiol to body fat and the sexual function under investigation under experimental conditions. A one-year anastrozole intervention in older men with low testosterone reduced spinal bone density, although the isolated effect of E2 was not distinguished. Short-term controlled variations in E2 did not alter the lipid and inflammatory markers investigated. This does not imply either a general reference range or a specific guideline for bodybuilding.

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