Smart Hormone Management
Smart hormone management relates to the diagnosis and treatment of diseases characterized by abnormal levels of circulating sex steroids. These diseases are common, varied in nature, spanning everything from aging to cancer to infertility to menopause. Determining free and bioavailable levels of sex steroids is key to diagnosis and treatment.
The sex steroid androgens of interest are testosterone, dihydrotestosterone, androstenediol, androstenedione, androsterone, dihydroandrosterone, and DHEA, while the estrogens of interest include estrone, estradiol, and estriol. These androgens and estrogens circulate free and bound in various fractions to plasma proteins. Some of these protein bound fractions allow the androgens and estrogens to remain biologically active, while other proteins bind so tightly that androgen and estrogen bound fractions become biologically inactive. Measurement of the total androgen or estrogen alone can be misleading in many clinical situations; therefore, measurement of the free and bioavailable fractions yield a more accurate assessment of the androgen and estrogen status.
Estrogens are sex hormones that are responsible for the development and maintenance of the female sex organs and female secondary sex characteristics. In conjunction with progesterone, they also participate in the regulation of the menstrual cycle and breast and uterine growth, and in the maintenance of pregnancy. Estradiol is the major estrogen hormone secreted by the ovaries. Measurements of estradiol may be useful in women to assess ovarian function in women with menstrual disorders, precocious or delayed puberty, menopause, and useful in men to assess gynecomastia. Free and bioavailable estradiol levels have also shown a clinical relationship with a woman’s lifetime risk of breast cancer. Measurements of estrone are primarily used for assessment of estrogen status in postmenopausal women. Normally, blood estrone levels parallel estradiol levels throughout the menstrual cycle, but at one-third to one-half their magnitude.
Greater than 97% of circulating androgens and estrogens are bound to plasma proteins. They are bound specifically with high affinity and low capacity to Sex Hormone Binding Globulin (SHBG) and nonspecifically with low affinity and high capacity to albumin. SHBG concentrations are increased by estrogens and therefore are higher in women than in men. They are also increased during pregnancy, oral contraceptive use, hyperthyroidism, and administration of certain antiepileptic drugs such as dilantoin. SHBG concentrations may decrease in hypothyroidism, obesity, or androgen excess.
For many years, the free fraction of androgens and estrogens was thought to be the biologically active fraction. Current thought is that dissociation of the albumin-bound fractions occurs within a capillary bed. Therefore the bioavailable fraction is equal to the free fraction plus the albumin-bound fraction. The albumin-bound fraction is referred to as the “non-SHBG-bound” fraction or the weakly bound fraction. In cases where the SHBG concentrations are altered, measurement of bioavailable fraction is believed to be a better reflection of circulating status.
Various methods are available for determining the concentration of free and bioavailable fraction in serum or plasma: (1) estimation of the free fraction by equilibrium dialysis or ultra filtration; (2) estimate of the free fraction using a direct (“analog tracer”) immunoassay; (3) estimation of the combined free and weakly bound (“bioavailable”) fraction by selective precipitation of the tightly bound form; (4) calculation of androgen index using indices that reflect ratios of the circulating fractions; and (5) calculation of the free and bioavailable fractions by mathematical modeling. The mathematical modeling approach uses mass action equations to calculate free and weakly bound fraction concentrations from the total androgen or estrogen, SHBG, and albumin concentrations, and from the association constants for the binding of the androgen or estrogen to SHBG and albumin.
All of the above methods (except 2) require that the selected total androgen or estrogen concentration be measured in order to estimate the free and bioavailable fraction concentrations. There are many methods for determining the total androgen or estrogen concentration: (1) radioimmunoassay with extraction and/or purification, (2) mass spectrometry, and (3) immunoassays with chemiluminescence (including automated platforms). The free fraction method utilizing the direct “analog tracer” does not require the measurement of the total androgen or estrogen, but comparisons with other free fraction methods has shown extremely poor correlation with the conclusion that this method not be used for measuring free androgens or estrogens.
Methods using the laws of mass action modeling compared very well with equilibrium dialysis and ultra filtration methods often referred to as the “gold standards” for free fraction estimations. These “gold standard” methods are however, extremely labor intensive, time consuming, and require the use of radioactive materials which greatly reduces the availability of testing. An accurate and simple method for calculating the free and bioavailable fraction concentrations from the laws of mass action has the potential to save time, money, and reduce the usage of radioactive material.
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