Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic ovary syndrome (PCOS), a common chronic condition that affects up to 10% of all women. Identification of women with non-PCOS pathology within large cohorts of patients presenting with androgen excess represents a diagnostic challenge for the endocrinologist, and rare pathology including nonclassic congenital adrenal hyperplasia, severe insulin resistance syndromes, Cushing's disease or androgen-secreting tumours of the ovary or adrenal gland may be missed in the absence of a pragmatic screening approach. Detailed clinical history, physical examination and biochemical phenotyping are critical in risk-stratifying women who are at the highest risk of non-PCOS disorders. Red flag features such as rapid onset symptoms, overt virilization, postmenopausal onset or severe biochemical disturbances should prompt investigations for underlying neoplastic pathology, including dynamic testing and imaging where appropriate. This review will outline a proposed diagnostic approach to androgen excess in women, including an introduction to androgen metabolism and provision of a suggested algorithmic strategy to identify non-PCOS pathology according to clinical and biochemical phenotype.

Abstract. The delivery systems of two long-acting formulations of methylphenidate (MPH) were designed for different durations. Diffucaps bead-delivery system (DBDS)-MPH was designed to last 8 h and osmotically controlled-release oral delivery system (OROS)-MPH was designed to last 12 h. While the plasma pharmacokinetics and timing of efficacy have been studied, the corresponding central nervous system dopamine transporter (DAT) occupancies are unknown. In this study, 21 healthy volunteers underwent PET imaging with 11 C Altropane before and after administration of oral doses of DBDS-MPH and OROS-MPH. Each subject received 40 mg DBDS-MPH and 36 mg OROS-MPH on different days. PET imaging occurred at 10 h after dosing. Each subject was injected with 5 mCi of 11 C Altropane and serial images of the brain were acquired over 60 min with a Siemens HR + PET camera. Binding potentials (BP, k 3 /k 4 ) were calculated from time-activity curves using the simplified reference region method with cerebellum as reference. Transporter occupancy was calculated by standard methods. At 10 h, plasma d-MPH levels were lower (3.8±1.2 vs. 5.2±2.0) and brain DAT occupancy was lower (34.8 ±12.9 vs. 44.3±11.8) for DBDS-MPH than OROS-MPH. Across the range of values, for each unit of change in plasma d-MPH level there was a larger change in DAT occupancy with the DBDS-MPH formulation than with the OROS-MPH formulation. As predicted from previous pharmacokinetic and efficacy data, the average plasma level and DAT occupancy of 36 mg OROS-MPH was >40 mg DBDS-MPH at 10 h. Moreover, a relatively small difference in plasma levels (1.4 ng/ml at 10 h) was associated with a more impressive difference in DAT occupancy (~10% at 10 h). IntroductionThe stimulant methylphenidate (MPH) remains a mainstay of treatment for attention deficit hyperactivity disorder (ADHD) with over a hundred studies documenting its safety and efficacy in pediatric and adult ADHD (1). Because of the short half life of MPH, a new generation of long acting MPH formulations has emerged that has greatly improved the management of patients with ADHD across the lifecycle. While the pharmacokinetic (PK) data from studies using these formulations support their longer duration of action, whether peripheral plasma kinetics match their effects in the brain remain unknown.Since the main target of MPH in the brain is the striatal dopamine transporter (DAT), (2) measuring central DAT binding can elucidate the central kinetic effects of MPH formulations. A highly sensitive methodology has been developed to measure drug occupancy of the DAT in the brain using the radioligand 11 C Altropane to label the DAT and positron emission tomography (PET) for detection (3). Because of the sensitivity of this methodology, low radiation exposure permits repeated imaging, allowing for the examination of the kinetics of CNS DAT receptor occupancy in the living human brain. Similar PET methodology has been previously used to document the CNS pharmacokinetics of other psychiatric drugs (4-8).Using this method...

Polycystic ovary syndrome (PCOS) is the most common endocrine condition affecting women. It has traditionally been viewed as a primarily reproductive disorder; however, it is increasingly recognized as a lifelong metabolic disease. Women with PCOS are at increased risk of insulin resistance (IR), type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular disease. Although not currently a diagnostic criterion, IR is a cardinal pathophysiological feature and highly prevalent in women with PCOS. Androgens play a bidirectional role in the pathogenesis of IR, and there is a complex interplay between IR and androgen excess in women with PCOS. Skeletal muscle has a key role in maintaining metabolic homeostasis and is also a metabolic target organ of androgen action. Skeletal muscle is the organ responsible for the majority of insulin-mediated glucose disposal. There is growing interest in the relationship between skeletal muscle, androgen excess and mitochondrial dysfunction in the pathogenesis of metabolic disease in PCOS. Molecular mechanisms underpinning defects in skeletal muscle dysfunction in PCOS remain to be elucidated, but may represent promising targets for future therapeutic intervention. In this review, we aim to explore the role of skeletal muscle in metabolism, focusing particularly on perturbations in skeletal muscle specific to PCOS as observed in recent molecular and in vivo human studies. We review the possible role of androgens in the pathophysiology of skeletal muscle abnormalities in PCOS, and identify knowledge gaps, areas for future research and potential therapeutic implications. Despite increasing interest in the area of skeletal muscle dysfunction in women with PCOS, significant challenges and unanswered questions remain, and going forward, novel innovative approaches will be required to dissect the underlying mechanisms.