Female Androgen Deficiency Syndrome: A Hard Look at a Sexy Issue

John F. Randolph, Jr, MD, Lorraine Dennerstein, AO, MBBS, PhD, FRANZCP, DPM

Disclosures

Introduction

The evolution of a validated clinical syndrome from an initial recognition of a cluster of symptoms to the clear delineation of a defining set of biochemical, biobehavioral, and physical findings is a convoluted process influenced by a complex interplay of social, medical, and technical factors. Such is the case with female androgen deficiency syndrome, an evolving entity whose time appears to have come. In view of a growing interest in the evaluation and treatment of this variably defined disorder, it seems timely and appropriate to examine the factors influencing its evolution.

The symptoms associated with female androgen deficiency syndrome have included low libido, blunted motivation, fatigue, and a lack of well being,[1] although no consensus has been reached. A biochemical definition of a low serum bioavailable testosterone level with a normal estradiol concentration in association with symptoms leads to the name of the syndrome. Again, consensus regarding normal ranges has not been reached.[2]

The convergence of several recent medical and social trends has amplified the visibility of female androgen deficiency syndrome. Widespread dissemination of the results of the 1992 National Health and Social Life Survey (NHSLS) highlighted the surprising prevalence of sexual dysfunction in the United States[3] and revealed it to be more common in women (43%) than in men (31%). Media attention surrounding the release and subsequent demand for sildenafil has broken the silence regarding male erectile dysfunction and underscored both the lack of a comparably effective therapy for women and the gaps in our understanding of the underlying physiology and pathophysiology of female sexual function.

Recommendations for the therapeutic use of androgens[4] have followed reports of clinical trials demonstrating the benefits of such therapy on sexual function,[5,6] mood and energy level,[7] and the maintenance of bone density,[8] among others. The interest is clearly present, but specific criteria for the diagnosis, much less therapy, are sorely lacking.

The association between androgens and sexual function was made over 2 generations ago[9] but remains incompletely characterized. It was followed decades later with the development of specific radioimmunoassays to measure total serum testosterone.[10] Assay development focused on the identification of high serum levels to identify hyperandrogenic disorders, and was challenged by the concentration disparities between men and women. Despite the advent of efficient, automated assay systems with improved sensitivity at lower concentrations, the reliable measurement of androgens at the lower range of sensitivity remains a concern. Moreover, current assays use normal ranges defined from small convenience samples of incompletely characterized women and men without regard to known influences on androgen metabolism such as age, menopausal status, and body size.[11]

In addition, the binding of testosterone to plasma proteins limits the hormone available to enter cells and bind to intracellular receptors. It is not yet clear which subfraction or metabolite of testosterone is most associated with sexual function and, therefore, of most clinical utility in the evaluation of sexual dysfunction. Direct and indirect methods of measuring total, free, and bioavailable (not bound to sex hormone-binding globulin) testosterone are available, but no consensus has been reached on which is the gold standard for defining female androgen deficiency syndrome. Despite the lack of known correlation with specific measures of sexual function, it has been recommended that women with sexual dysfunction and a serum-free testosterone concentration in the lower third of the normal range be considered for androgen replacement therapy.

Some consensus has been reached on definitions and classifications of both male[12] and female[13] sexual dysfunction, and instruments to measure mood have been well validated.[14] But the standards for female sexual dysfunction are too recent to have achieved uniform use in research reported to date. Moreover, other symptoms ascribed to female androgen deficiency syndrome, such as fatigue and blunted motivation, lack accepted objective measures to use for diagnosis or in clinical studies.

Thus, we are faced with a syndrome characterized by: (1) a variable cluster of symptoms, some nonspecific and without validated measures; (2) a biochemical definition hampered by low assay sensitivity, a lack of defined population norms, and a lack of a clear correlation with specific measures of sexual dysfunction; and (3) an imprecise understanding of the relationship of androgens to sexual function in women, leading to uncertainty about what to measure. What is clear is that women are presenting to healthcare providers with symptoms that include sexual dysfunction, and providers are seeking answers and possible therapy for a syndrome that has not yet achieved full validation.

Fortunately, we have the wherewithal to validate female androgen deficiency syndrome and to guide the use of androgen replacement therapy. First, we must implement the use of androgen assays with sensitivity in the lower concentrations seen in women after iatrogenic menopause and as they age. Second, we must establish the normal ranges for those assays in the specific populations of interest, accounting for the variables known to affect those hormone levels, such as body size and ethnicity. Third, we must associate specific hormones, subfractions, and metabolites with specific and validated measures of sexual function, mood, and "vitality" to verify the relationships and determine which measures will best guide clinical decision making. Fourth, we can then proceed to clinical trials of therapy based on known relationships between hormones and function.

We also must be cognizant of the paucity of data on long-term risks of androgen therapy in women. Unlike estrogen replacement, which has been used for 2 generations to treat a more easily identifiable, biologically explainable clinical syndrome and which still has uncertain long-term effects, androgen therapy has no documented track record in women to present when counseling potential recipients. Until better information is available on the effects of androgens on the breast, liver, and cardiovascular system in women, we must carefully inform prospective patients and conduct rigorous long-term follow-up of women who choose to use androgen therapy.

Female androgen deficiency syndrome needs to be defined and validated before the identification and treatment of it becomes a part of the medical standard of care. We must not fall into the trap of chasing an ephemeral disorder without a clear biological basis and specific clinical indicators, or we run the risk of doing more harm than good.

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