There are few systematic studies of the relationship between blood testosterone concentrations and the symptoms of overt androgen deficiency. Because most testosterone preparations are relatively short-term, the rapid changes in blood testosterone concentrations they cause make it difficult to define any testosterone threshold. By contrast, subdermal testosterone implants provide stable blood testosterone concentrations over days to weeks, while gradually declining to baseline over 5-7 months. Hence, this provides an opportunity to define a blood testosterone threshold for androgen deficiency symptoms by observing androgen-deficient men as their familiar androgen deficiency symptoms return as testosterone pellets slowly dissolve. Among 52 androgen-deficient men who underwent 260 implantations over 5 yr, at the time of return of androgen deficiency symptoms the blood total and free testosterone concentrations were highly reproducible within individuals (F ؍ 0.8, P ؍ 0.49 and F ؍ 1.4, 0.24, respectively) but varied markedly between men (F ؍ 167 and F ؍ 138, both P < 0.001), indicating that each person had a consistent testosterone threshold for androgen deficiency symptoms that differed markedly between individuals. The most reported symptoms of androgen deficiency were lack of energy, lack of motivation, and reduced libido. The symptomatic threshold was significantly lower in men with secondary hypogonadism compared with men with primary or mixed hypogonadism (total, 9.7 ؎ 0.5 nmol/liter vs. T HE EFFECTS OF androgen deficiency and replacement on objective endpoints, notably bone (1, 2) and muscle (3-7), are well known and increasingly studied. Yet, whereas symptoms of androgen deficiency are discussed in textbooks and form the basis for practical clinical monitoring of androgen replacement therapy (8), there is a paucity of systematic studies of the symptoms of, and symptomatic threshold for, androgen deficiency. The subjective effects of androgen deficiency and replacement have generally been studied as objectively recorded measures of mood, behavior and cognitive responses (9 -11), but symptoms themselves are more difficult to study objectively. As a result, subjective effects of androgens have received most attention in the psychology literature, where empirical studies are, however, largely observational and restricted to eugonadal men limiting the salience of any inferences regarding relationships of blood testosterone concentrations to symptoms of overt androgen deficiency. A major limitation of interventional clinical research on androgen deficiency symptoms is that the available relatively short-term testosterone preparations produce swings in blood testosterone levels over days to weeks, which make it difficult or impossible to distinguish reliably symptom resolution and reappearance from pharmacological effects. The present study overcomes this limitation by using a long-acting depot testosterone preparation, which maintains stable blood testosterone concentrations over days to weeks but, as the biodegradable implants erode, allows them to decline slowly back to baseline over 5-7 months (12-15). Because the treated men return for blood testosterone measurement and reimplantation when their familiar androgen deficiency symptoms return, this allows a prospective evaluation of the relationships between individual androgen deficiency symptoms and the blood testosterone concentrations that accompany them. Subjects and Methods Patients We reviewed prospectively collected data from patients having regular androgen replacement therapy with a standard dose (four 200-mg pellets) of subdermal testosterone implants for androgen deficiency as described previously Procedures Implantation procedure. Testosterone pellet implantation procedures are booked throughout the week. At visits, men have a blood sample drawn JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community
