Diagnosis

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Since the description by Cushing at the beginning of the 20th century, it is well known that hypogonadism is common in active Cushing's disease (62).

Men have loss of libido, impotence, oligospermia, and histological damage to the testes. Basal LH and FSH levels are commonly decreased, the response to GnRH is impaired, and testosterone levels are low. However, hypogonadism occurs with other clinical features (see Table 3) secondary to chronically elevated cortisol production (47,63).

When Cushing's syndrome is suspected, initial laboratory testing to detect hyper-cortisolism includes measurement of 24-h urinary-free cortisol (UFC) excretion, and/or the 1-mg overnight dexamethasone suppression test (64). The sensitivity and specificity of the first test in detecting cortisol excess are 95% and 98%, respectively. Because of the difficulty in obtaining 24-h urine collection in many outpatients, some physicians use the 1-mg overnight dexamethasone suppression test (sensitivity 98% and specificity 80%). A newer diagnostic approach is the late-night (11 pm) salivary cortisol determination (65). In fact, cortisol in the saliva is highly stable and correlated with free serum or plasma cortisol levels and is independent of the rate of the saliva flow (65).

Once the diagnosis of Cushing's syndrome is established, the source of the excess cortisol production must be determined. The ACTH plasma level in the late afternoon is useful in identifying the ACTH-dependent pathologic state in almost half of cases. At this time of day, plasma ACTH levels exceed 10 ng/L in Cushing's disease, whereas

Acth Testosterone

Testosterone Spermatozoa

Fig. 3. Mechanisms involved in the induction of hypogonadism secondary to Cushing's disease.

plasma ACTH levels are generally suppressed in Cushing's syndrome secondary to adrenal disease (66). The standard high-dose dexamethasone test (8 mg) and the corti-cotropin-releasing hormone (CRH) test are performed to obtain a clearer differential diagnosis. In Cushing's disease, serum cortisol levels and 24-h UFC excretion are suppressed after the 8-mg dexamethasone test and ACTH levels respond to CRH stimulation. The combination of these two tests may identify 60-80% of patients with Cushing's disease (66).

Pituitary ACTH-secreting adenomas are most often microadenomas with a diameter less than 5 mm in 45% of cases, and only 10-20% of patients with Cushing's disease have a macroadenoma (67). Therefore, pituitary MRI is often normal in patients with corticotropinomas. However, MRI of the pituitary is required in all patients with ACTH-dependent Cushing's syndrome. MRI should be performed with thin overlap-

Table 3

Clinical Features of Cushing's Syndrome

Centripetal obesity Buffalo hump Moon face Facial plethora Purple striae Skin thinning Easy bruising Acne, oily skin Skin infections Proximal myopathy Lethargy

Psychiatric disturbances Hypertension

Backache, vertebral collapse, and fracture

Polydipsia and polyuria

Renal calculi

Hyperpigmentation

Abdominal pain ping sections and high field strength (1.5 tesla) magnets (68). In the absence of a detectable pituitary tumor, bilateral inferior petrosal venous sinus and peripheral vein catheterization with simultaneous collection of samples for measurement of ACTH should be performed to establish the diagnosis of Cushing's disease, as well as identify the location of ACTH production (69,70). Stimulation with CRH, together with bilateral and simultaneous sampling, increases the sensitivity of this procedure (65,71).

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