Androgen Supplementation in Older Women: Too Much Hype, Not Enough Data: Part 4

MEASUREMENT OF TOTAL AND UNBOUND TESTOSTERONE

In healthy women, approximately, 50 to 60 percent of testosterone is bound to sex hormone binding globulin (SHBG), 30 to 40 percent to albumin and only 0.5 to 3 percent is unbound. The free hormone
hypothesis assumes that only the free and loosely bound (testosterone bound to albumin) exerts
biologic effects.

SHBG is affected by many factors; it is increased by thyroid hormone, estrogen
and aging, and decreased by testosterone, glucocorticoids, growth hormone and insulin. Ideally,

measurements of unbound testosterone should provide a better estimate of the biologically
relevant fraction. However, in practice, some measurements of free and bioavailable testosterone
have been hampered by methodological difficulties, particularly in women.

The commercially available assays for the measurement of unbound testosterone include the equilibrium dialysis method, the bioavailable testosterone by the ammonium sulfate precipitation method, free testosterone indices calculated from the measured total testosterone and SHBG concentrations, and tracer analog methods for estimates of free testosterone.

Of these methods, the equilibrium dialysis method for the measurement of unbound testosterone, and ammonium sulfate precipitation method for the measurement of albumin-bound and unbound testosterone (bioavailable testosterone) are both acceptable methods that have good clinical correlation, are accurate, independent from the effects of SHBG concentrations, and available at specialized commercial endocrinology laboratories.

The estimates of free testosterone, calculated from total testosterone and SHBG concentrations, have also been shown to correlate with free testosterone concentrations measured by dialysis in men. These algorithms have not been extensively tested in women. Tracer analog methods of measuring free testosterone are widely available but are affected by SHBG concentrations and do not provide an accurate measure of unbound testosterone and are not recommended.

A recent commentary by Rosner emphasized that direct radioimmunoassay of free testosterone by the tracer analog method may underestimate its concentration.

ANDROGEN DEFICIENCY STATES IN WOMEN

Currently, there is no consensus on a clinical or biochemical definition of androgen deficiency in women. A physical and behavioral symptom complex termed “female androgen deficiency syndrome” includes impaired sexual function, loss of energy and depression.

Based on the distribution of serum total and free testosterone concentrations in healthy, menstruating
women, androgen deficiency could be defined by serum total testosterone concentrations less than
15 ng/dl, the lower end of the normal female range in our laboratory.

The causes of androgen deficiency in women can be divided into ovarian, adrenal, central
and systemic causes. Ovarian causes include premature ovarian failure, Turner’s syndrome and
surgical or chemical ovariectomy. Turner’s syndrome is characterized by gonadal dysgenesis, streak gonads, estrogen deficiency and low circulating levels of androstenedione, testosterone,
free testosterone and SHBG.

Most of these women are receiving estrogen and progesterone replacement, which further decreases their free androgen levels by increasing the SHBG concentrations; in addition, LH suppression by the hormone replacement therapy may further decrease the stimulus for ovarian androgen production.

It is possible that the reduction in free androgen levels induced by the traditional hormone replacement therapy might adversely affect sexual function in post-menopausal women. Primary adrenal insufficiency is associated with deficiencies of glucocorticoids as well as adrenal androgens.

Central causes of androgen deficiency include disorders affecting the pituitary or the hypothalamus. Panhypopituitarism affects androgen secretion from both adrenal and ovarian sources; not surprisingly, patients with panhypopituitarism have lower circulating concentrations of total and free testosterone, and androstenedione than those found in patients with either adrenal or ovarian failure alone.

GnRH agonist or antagonist analogs, often used for treating endometriosis and other reproductive disorders, suppress gonadotropin secretion. Glucocorticoid therapy suppresses corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) and leads to low levels of cortisol, DHEA, DHEAS and androstenedione. In addition, pharmacologic doses of glucocorticoids in amounts greater than 10 mg prednisone daily or equivalent doses of other glucocorticoids directly inhibit ovarian
steroidogenesis. Human immunodeficiency virus infection and chronic illness are examples of systemic causes of androgen deficiency.

Link to article: http://www.goodhormonehealth.com/symptoms/androgen.pdf

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• Turner Syndrome