Micol S. Rothman

Reexamination of Testosterone, Dihydrotestosterone, Estradiol and Estrone Levels across the Menstrual Cycle and in Postmenopausal Women Measured by Liquid Chromatography Tandem Mass Spectrometry

Measuring serum androgen levels in women has been challenging due to limitations in method accuracy, precision sensitivity and specificity at low hormone levels. The clinical significance of changes in sex steroids across the menstrual cycle and lifespan has remained controversial, in part due to these limitations. We used validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays to determine testosterone (T) and dihydrotestosterone (DHT) along with estradiol (E2) and estrone (E1) levels across the menstrual cycle of 31 healthy premenopausal females and in 19 postmenopausal females. Samples were obtained in ovulatory women in the early follicular phase (EFP), midcycle and mid luteal phase (MLP). Overall, the levels of T, DHT, E2 and E1 in premenopausal women measured by LC-MS/MS were lower overall than previously reported with immunoassays. In premenopausal women, serum T, free T, E2, E1 and SHBG levels peaked at midcycle and remained higher in the MLP, whereas DHT did not change. In postmenopausal women, T, free T, SHBG and DHT were significantly lower than in premenopausal women, concomitant with declines in E2 and E1. These data support the hypothesis that the changes in T and DHT that occur across the cycle may reflect changes in SHBG and estrogen, whereas in menopause, androgen levels decrease. LC-MS/MS may provide more accurate and precise measurement of sex steroid hormones than prior immunoassay methods and can be useful to assess the clinical significance of changes in T, DHT, E2 and E1 levels in females.

Patients with Nontuberculous Mycobacterial Lung Disease Exhibit Unique Body and Immune Phenotypes

RATIONALE Among patients with nontuberculous mycobacterial lung disease is a subset of previously healthy women with a slender body morphotype, often with scoliosis and/or pectus excavatum. We hypothesize that unidentified factors predispose these individuals to pulmonary nontuberculous mycobacterial disease. OBJECTIVES To compare body morphotype, serum adipokine levels, and whole-blood cytokine responses of patients with pulmonary nontuberculous mycobacteria (pNTM) with contemporary control subjects who are well matched demographically. METHODS We enrolled 103 patients with pNTM and 101 uninfected control subjects of similar demographics. Body mass index and body fat were quantified. All patients with pNTM and a subset of control subjects were evaluated for scoliosis and pectus excavatum. Serum leptin and adiponectin were measured. Specific cytokines important to host-defense against mycobacteria were measured in whole blood before and after stimulation. MEASUREMENTS AND MAIN RESULTS Patients with pNTM and control subjects were well matched for age, gender, and race. Patients with pNTM had significantly lower body mass index and body fat and were significantly taller than control subjects. Scoliosis and pectus excavatum were significantly more prevalent in patients with pNTM. The normal relationships between the adipokines and body fat were lost in the patients with pNTM, a novel finding. IFN-γ and IL-10 levels were significantly suppressed in stimulated whole blood of patients with pNTM. CONCLUSIONS This is the first study to comprehensively compare body morphotype, adipokines, and cytokine responses between patients with NTM lung disease and demographically matched controls. Our findings suggest a novel, predisposing immunophenotype that should be mechanistically defined.

How should postmenopausal androgen excess be evaluated

Evidence of clinical and/or biochemical androgen excess connotes a unique differential diagnosis in postmenopausal women. Providers need to be able to discriminate between changes of the normal ageing process compared to potential pathology in older women. The evaluation and treatment of postmenopausal hirsutism and hyperandrogenism is reviewed. Androgen excess may have long‐term negative health consequences and as such should be detected and treated.

Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients

Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported.

Female hypogonadism: evaluation of the hypothalamic–pituitary–ovarian axis

Female hypogonadism refers to deficient or abnormal function of the hypothalamic–pituitary–ovarian axis that clinically presents with menstrual cycle disturbances. Female hypogonadism can be due to a congenital or acquired cause, and the defect can be at the level of the hypothalamus, pituitary or ovary. A careful history, physical exam and selected laboratory testing can often determine the locus of the defect and whether it results from a structural or hormonal problem. Laboratory testing generally relies on basal hormone levels; however, timing of blood sampling in relation to menses is important to interpretation of the data.

HIV Infection and Osteoporosis: Pathophysiology, Diagnosis, and Treatment Options

As the population with HIV continues to age, specialists in HIV care are increasingly encountering chronic health conditions, which now include osteoporosis, osteopenia, and fragility fractures. The pathophysiology of the bone effects of HIV infection is complex and includes traditional risk factors for bone loss as well as specific effects due to the virus itself, chronic inflammation, and HAART. Examining risk factors for low bone density and screening of certain patients is suggested, and consideration should be given to treatment for those considered high risk for fracture.

The role of gonadotropin releasing hormone in normal and pathologic endocrine processes.

Purpose of reviewGonadotropin releasing hormone is the hypothalamic hormone that activates pituitary gonadotropin production and, ultimately, determines reproductive competence. This review will highlight advances in the basic biology of the gonadotropin releasing hormone neuron that give insight into disorders of pubertal development, and clinical studies with gonadotropin releasing hormone analogs in infertility and prostate cancer treatment. Recent findingsFactors that control gonadotropin releasing hormone neuronal migration such as fibroblast growth factor receptor-1 and others that modulate secretion at puberty including kisspeptin/G-protein-coupled receptor 54 have been identified. Mutations in these pathways cause disorders during puberty. Clinical trials have defined the utility of gonadotropin releasing hormone agonists and antagonists for ovulation induction, and the effects of long-term administration for prostate cancer. SummaryResearch into the role of the fibroblast growth factor receptor-1 and kisspeptin/G-protein-coupled receptor 54 pathways in gonadotropin releasing hormone neuronal development may identify the molecular defects in idiopathic hypogonadotropic hypogonadism and refine our understanding of normal negative and positive feedback by sex steroids. Clarification of the advantages and disadvantages of gonadotropin releasing hormone analog use in ovulation induction may improve the cost and success of infertility treatment. Insight into long-term effects of gonadotropin releasing hormone analogs in prostate cancer may lead to directed therapies to combat these consequences. Together these studies outline effects of modulation of gonadotropin releasing hormone in normal and pathophysiologic states.

Bone Density Testing: Science, the Media, and Patient Care

Dual-energy X-ray absorptiometry (DXA) is an inexpensive, noninvasive, widely available method for diagnosing osteoporosis, assessing fracture risk, and monitoring the effects of therapy. By diagnosing high-risk patients before a fracture occurs, clinicians can intervene early to reduce fracture risk. Appropriate use of DXA results in money saving for healthcare systems that might otherwise be spent for fracture-related care. Recent reports of studies evaluating DXA screening criteria and intervals for retesting have received considerable media coverage, sometimes suggesting that DXA is expensive, over-utilized, and unnecessary. This may lead to more patients who might benefit from early detection of osteoporosis remaining undiagnosed. We advocate for the use of current clinical practice guidelines with individualization of patient care factors to determine the optimal intervals for DXA testing.

Osteoporosis for the practicing neurologist

SummaryOsteoporosis is a common condition of impaired bone strength leading to fractures. A targeted history, physical exam, and blood work can help elucidate potentially reversible causes of low bone mass. In the neurology office, particular attention should be paid to the patient on glucocorticoids or antiepileptic medications, as these have distinct detrimental effects on bone. Patients can be risk-stratified by using the FRAX calculator, a tool that can help determine whether the patient is at sufficient risk of fracture to warrant pharmacologic therapy. Nonpharmacologic treatments such as calcium, vitamin D, and exercise should be discussed with the patient. The cornerstone of pharmacologic therapy has been treatment with bisphosphonates, but newer medications are available as well for the high-risk patient.

Natural History of Neuroendocrine Dysfunction after Traumatic Brain Injury during Inpatient Rehabilitation

Disclosures: M. E. Wierman, No Answer Objective: To assess changes in hormone function in men undergoing acute rehabilitation after TBI. Design: Prospective evaluation of the gonadal, adrenal, thyroid and growth hormone axes inmenwith normal and low testosterone (T) levels. Setting: Inpatient brain injury unit in a private, not-for-profit rehabilitation hospital in the United States. Participants: Men ages 18 e 65 enrolled in inpatient rehabilitation following moderate to severe TBI,within 6months from thedate of injury. Interventions: Not applicable. Main Outcome Measures: Serum hormones at baseline and every 2 weeks until discharge. Results or Clinical Course: 498 patients were screened, for a final N of 61. 38 subjects had normal T, 23 had low T levels (<260ng/dl). At baseline, LH, FSH, T, estradiol (E), SHBG prolactin, TSH, fT4, ACTH, cortisol, DHEAS and, IGF1 levels were measured. Men with low T demonstrated lower LH levels (P1⁄4.003) and a trend towards lower FSH levels than those with normal T, suggesting that hypogonadism was related to central dysfunction. TSH was also lower (P1⁄4.035) in subjects with low testosterone. Hormone levels in those with normal T remained stable. In those with low T, only 50% normalized their T levels by 4-8 wks. Other hormone deficits were infrequent and transitory. Conclusion: After TBI, men with hypogonadism had lower gonadotropin and TSH levels suggesting central dysfunction. Testosterone levels remained low in 50% of subjects with low T at 4-8 wks. Associated neuroendocrine dysfunction was transient. These data suggest that hypogonadism detected during acute rehabilitation often does not resolve without intervention. Monitoring for hormonal deficits is appropriate. Future studies are needed to determine if T replacement modulates functional or cognitive outcomes after TBI.