The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing’s syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing’s syndrome). Endogenous Cushing’s syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing’s syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control.

Cushing’s syndrome is a rare disorder resulting from prolonged exposure to excess glucocorticoids. Early diagnosis and treatment of Cushing’s syndrome is associated with a decrease in morbidity and mortality. Clinical presentation can be highly variable, and establishing the diagnosis can often be difficult. Surgery (resection of the pituitary or ectopic source of adrenocorticotropic hormone, or unilateral or bilateral adrenalectomy) remains the optimal treatment in all forms of Cushing’s syndrome, but may not always lead to remission. Medical therapy (steroidogenesis inhibitors, agents that decrease adrenocorticotropic hormone levels or glucocorticoid receptor antagonists) and pituitary radiotherapy may be needed as an adjunct. A multidisciplinary approach, long-term follow-up, and treatment modalities customized to each individual are essential for optimal control of hypercortisolemia and management of comorbidities.

Prolactin measurement and evaluation of the venogram can improve diagnostic accuracy when IPSS results suggest EAS but is not necessary with positive IPSS results. Confirmation of hypercortisolemia remains a prerequisite for IPSS. A normalized ratio of 0.7-1.3 was not diagnostic.

IntroductionCushing’s disease is a rare disorder characterized by overproduction of ACTH from a pituitary adenoma leading to hypercortisolemia that in turn leads to increased morbidity and mortality.MethodsHere we review the comorbidities associated with Cushing’s disease and their impact on quality of life and mortality.ResultsRecent evidence suggests that correction of hypercortisolemia may not lead to complete resolution of comorbidities associated with this condition. In particular, increased cardiovascular risk may persist despite long-term remission of hypercortisolemia. This may be related to persistence of visceral adiposity, adverse adipokine profile, glucose intolerance, hypertension, dyslipidemia, atherosclerosis and a procoagulant phenotype. Prior prolonged exposure to glucocorticoids also may have irreversible effects on the central nervous system, leading to persistent cognitive and mood alterations. Osteoporosis and fractures, especially vertebral fractures, can further add to morbidity and a poor quality of life. Normalization of cortisol levels leads to significant improvement in comorbidities but long-term data regarding complete resolution are lacking and need further study.ConclusionEarly diagnosis and treatment of hypercortisolemia, aggressive management of comorbidities along with long-term follow-up is crucial for the optimal recovery of these patients.

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In our cohort, early, profound hypocortisolemia could be used as a clinical prediction tool for durable remission. Achievement of hypocortisolemia ≤2 µg/dL before 21 post-operative hours appeared to accurately predict durable remission in the intermediate term.

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Insulin resistance is an important pathophysiological feature of the polycystic ovary syndrome (PCOS). Insulin resistance and its compensatory hyperinsulinemia contribute to the anovulation, hyperandrogenism, infertility and early pregnancy loss suffered by women with PCOS. Current evidence supports the role of metformin in the treatment of anovulation in PCOS, both in monotherapy and concomitantly with clomiphene in clomiphene-resistant patients. In addition, novel evidence suggests that insulin sensitizers may also play a role in reducing the risk of early pregnancy loss. The insulin-sensitizing agents available commercially include metformin, rosiglitazone and pioglitazone. Compared with the thiozolidinediones, metformin is the agent that has been most frequently studied in PCOS, and has the most favorable pregnancy safety profile. In conclusion, there is strong evidence supporting the use of metformin as a primary ovulatory agent in women with PCOS.