Offie P. Soldin

Sex Differences in Pharmacokinetics and Pharmacodynamics

Significant differences that exist between the sexes affect the prevalence, incidence and severity of a broad range of diseases and conditions. Men and women also differ in their response to drug treatment. It is therefore essential to understand these reactions in order to appropriately conduct risk assessment and to design safe and effective treatments. Even from that modest perspective, how and when we use drugs can result in unwanted and unexpected outcomes. This review summarizes the sex-based differences that impact on pharmacokinetics, and includes a general comparison of clinical pharmacology as it applies to men, women and pregnant women. Sex-related or pregnancy-induced changes in drug absorption, distribution, metabolism and elimination, when significant, may guide changes in dosage regimen or therapeutic monitoring to increase its effectiveness or reduce potential toxicity. Given those parameters, and our knowledge of sex differences, we can derive essentially all factors necessary for therapeutic optimization.Since this is a rapidly evolving area, it is essential for the practitioner to review drug prescribing information and recent literature in order to fully understand the impact of these differences on clinical therapeutics.

Steroid Hormone Analysis by Tandem Mass Spectrometry

BACKGROUND New high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) methods are among the most successful approaches to improve specificity problems inherent in many immunoassays. CONTENT We emphasize problems with immunoassays for the measurement of steroids and review the emerging role of LC-MS/MS in the measurement of clinically relevant steroids. The latest generation of tandem mass spectrometers has superior limits of quantification, permitting omission of previously employed derivatization steps. The measurement of steroid profiles in the diagnosis and treatment of congenital adrenal hyperplasia, adrenal insufficiency, chronic pelvic pain and prostatitis, oncology (breast cancer), and athletes has important new applications. CONCLUSIONS LC-MS/MS now affords the specificity, imprecision, and limits of quantification necessary for the reliable measurement of steroids in human fluids, enhancing diagnostic capabilities, particularly when steroid profiles are available.

Methods for Quantification of Exposure to Cigarette Smoking and Environmental Tobacco Smoke: Focus on Developmental Toxicology

Active and passive smoking have been associated with an array of adverse effects on health. The development of valid and accurate scales of measurement for exposures associated with health risks constitutes an active area of research. Tobacco smoke exposure still lacks an ideal method of measurement. A valid estimation of the risks associated with tobacco exposure depends on accurate measurement. However, some groups of people are more reluctant than others to disclose their smoking status and exposure to tobacco. This is particularly true for pregnant women and parents of young children, whose smoking is often regarded as socially unacceptable. For others, recall of tobacco exposure may also prove difficult. Because relying on self-report and the various biases it introduces may lead to inaccurate measures of nicotine exposure, more objective solutions have been suggested. Biomarkers constitute the most commonly used objective method of ascertaining nicotine exposure. Of those available, cotinine has gained supremacy as the biomarker of choice. Traditionally, cotinine has been measured in blood, saliva, and urine. Cotinine collection and analysis from these sources has posed some difficulties, which have motivated the search for a more consistent and reliable source of this biomarker. Hair analysis is a novel, noninvasive technique used to detect the presence of drugs and metabolites in the hair shaft. Because cotinine accumulates in hair during hair growth, it is a unique measure of long-term, cumulative exposure to tobacco smoke. Although hair analysis of cotinine holds great promise, a detailed evaluation of its potential as a biomarker of nicotine exposure, is needed. No studies have been published that address this issue. Because the levels of cotinine in the body are dependent on nicotine metabolism, which in turn is affected by factors such as age and pregnancy, the characterization of hair cotinine should be population specific. This review aims at defining the sensitivity, specificity, and clinical utilization of different methods used to estimate exposure to cigarette smoking and environmental tobacco smoke.

Sex Differences in Drug Disposition

Physiological, hormonal, and genetic differences between males and females affect the prevalence, incidence, and severity of diseases and responses to therapy. Understanding these differences is important for designing safe and effective treatments. This paper summarizes sex differences that impact drug disposition and includes a general comparison of clinical pharmacology as it applies to men and women.

Controversies in urinary iodine determinations

Iodine deficiency (ID) is associated with increased prevalence of goiter, increased risk for neurodevelopmental disorders, and is the worlds leading cause of intellectual deficits. Iodine nutritional status of a population is assessed by measurements of urinary iodine concentrations which are also used to define, indicate, survey and monitor iodine deficiency and consequently its treatment. Several methods are available for urinary iodine determination. Discussed here are some of the limitations and controversies related to urinary iodine determinations, and recent findings with emphasis on measurements of urinary iodine concentrations in children and during pregnancy.

Correlations of Free Thyroid Hormones Measured by Tandem Mass Spectrometry and Immunoassay with Thyroid-Stimulating Hormone across 4 Patient Populations

BACKGROUND Accurate measurement of free thyroid hormones is important for managing thyroid disorders. Ultrafiltration liquid chromatography tandem mass spectrometry (LC-MS/MS) can reliably measure the concentrations of small molecules, including thyroid hormones. Our study was designed to compare free thyroid hormone measurements performed with immunoassay and LC-MS/MS. METHODS We studied the performance of LC-MS/MS in 4 different populations comprising pediatric patients, euthyroid adults, and healthy nonpregnant and pregnant women. The samples obtained from each population numbered 38, 200, 28, and 128, respectively. Free thyroxine, free triiodothyronine, and thyroid-stimulating hormone (TSH) concentrations were documented. RESULTS LC-MS/MS measurement of free thyroid hormones provided better correlation with log-transformed serum TSH in each population and also the populations combined. The correlations between free thyroxine measured by LC-MS/MS and log TSH in the pediatric outpatients and healthy adults were -0.90 and -0.77, respectively. The correlations for immunoassay were -0.82 and -0.48. The correlations between free triiodothyronine measured by LC-MS/MS and TSH for both pediatric and healthy adult populations were -0.72 and -0.68, respectively. CONCLUSIONS Free thyroid hormone concentrations measured by LC-MS/MS correlate to a greater degree with log TSH values compared to concentrations measured by immunoassay. This correlation was maintained across the patient populations we studied and may reflect the accuracy and specificity of LC-MS/MS. The superior ability of LC-MS/MS to enable documentation of the well-known thyroid hormone-TSH relationship supports the use of this measurement technique in a variety of clinical situations.

Steroid hormone levels associated with passive and active smoking

CONTEXT Cigarette tobacco smoke is a potent environmental contaminant known to adversely affect health including fertility and pregnancy. OBJECTIVE To examine the associations between second-hand cigarette tobacco-smoke exposure, or active smoking and serum concentrations of steroid hormones using tandem mass spectrometry. DESIGN Healthy women (18-45 y) from the general community in the Metropolitan Washington, DC were recruited at the follicular stage of their menstrual cycle. Participants were assigned to one of three study groups: active smokers (N=107), passive smokers (N=86), or non-smokers (N=100). Classifications were based on a combination of self-reporting and serum cotinine concentrations. METHODS Serum androgens, estrogens, progestins, androstenedione, aldosterone, cortisol, corticosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 11-deoxycortisol and 25-hydroxy-vitamin D3 (25-OHVitD3) and cotinine were measured by isotope dilution tandem mass spectrometry (LC/MS/MS) (API-5000). Kruskal-Wallis tests were used to assess median differences among the three groups, with Dunns multiple comparison test for post hoc analysis. RESULTS Serum estrone, estradiol, and estriol concentrations were lower in active and passive smokers than in non-smokers. The three study groups differed significantly in serum concentrations of 16-OHE1, aldosterone and 25-OHVitD3, as well as in the ratios of many of the steroids. Pair-wise comparison of the groups demonstrated significant differences in hormone concentrations between (i) smokers and non-smokers for aldosterone: (ii) passive smokers and non-smokers for aldosterone, progesterone and estriol. Moreover, for smokers and passive smokers, there were no significant differences in these hormone concentrations. CONCLUSIONS Smoke exposure was associated with lower than normal median steroid hormone concentrations. These processes may be instrumental in explaining some adverse effects of tobacco smoke on female health and fertility.

Gestation-specific thyroxine and thyroid stimulating hormone levels in the United States and worldwide.

Background: Euthyroid women experience dramatic changes in the demand for thyroid hormone production as early as the first trimester of pregnancy. These changes are important for fetal neurodevelopment and organ development as well as maternal health and succesful full term pregnancy. Therefore, gestation-specific reference intervals assist in appropriate clinical management of thyroid disease in pregnancy to ensure maternal and fetal health. Objective: To determine trimester-specific levels of serum thyroxine (T4) and thyroid stimulating hormone (TSH) in the U.S. population based on the National Health and Nutrition Survey III and compare these with published trimester-specific T4 and TSH means and medians obtained in other countries worldwide. Methods: Trimester-specific means and medians for T4 and TSH were determined for the U.S. population based on the National Health and Nutrition Survey III database (1988-1994). These were compared with trimester-specific means and medians of other countries in the published literature. Results: Mean serum T4 levels for the U.S. population were 141.35, 152.95, and 142.65 nmol/L in the three trimesters, respectively, whereas mean serum TSH levels were 0.91, 1.03, and 1.32 mIU/L. Conclusions: Gestation-specific mean T4 and TSH levels for the representative U.S. population are well within the trimester-specific reference intervals. T4 and TSH measured during pregnancy in longitudinal and cross-sectional studies of populations worldwide demonstrate that, in some populations, T4 and TSH levels are outside the normal trimester-specific reference intervals.

Thyroid Hormone Levels Associated with Active and Passive Cigarette Smoking

BACKGROUND Active and passive cigarette smoking are a risk factor among women of reproductive age-leading to reproductive health morbidity, including fetal and infant death and developmental problems with the newborn. However, the underlying physiological mechanisms for these ill-effects are not fully understood. Smoke exposure may affect various metabolic and biological processes, including hormone biosynthesis and secretion, interfere with thyroid hormone release, binding, transport, storage, and clearance, associated with adverse effects on the thyroid resulting in changes in circulating hormone concentrations. We measured and compared serum thyroid hormone and thyroid stimulating hormone (TSH) concentrations in active, passive, and nonsmokers and determined their association with cigarette tobacco smoke exposure. We use a comprehensive approach to assess the interrelationships between active and passive tobacco smoke exposure and thyroid hormone levels by employing innovative hormone analysis techniques. METHODS Serum was obtained from women (18-44 years of age). Thyroxine (T4), triiodothyronine (T3), and cotinine concentrations were quantified using isotope dilution high performance liquid chromatography tandem mass spectrometry, and TSH concentrations by chemiluminescence. RESULTS Serum concentrations of the various hormones of active smokers, passive smokers, and nonsmokers (nonexposed), respectively, were as follows. Median TSH concentrations were 1.02, 1.06, and 1.12 mIU/L (p < 0.001 for the comparison of each group with the other two groups), and mean TSH levels were 1.40 mIU/L, confidence interval (CI) 0.07-6.83 mIU/L; 1.30 mIU/L, CI 0.25-3.01 mIU/L; and 1.50 mIU/mL, CI 0.71-4.00 mIU/L. Median serum T4 concentrations were 7.6, 7.9, and 8.7 microg/dL, and median serum T3 concentrations were 92.0, 84.0, and 102.0 ng/dL (p < 0.0001). Mean T3 levels were 99.1 ng/dL, CI 52.1-204.3 ng/dL; 87.6 ng/dL, CI 40.1-160.2 ng/dL; and 106.6 ng/dL, CI 46.4-175.0 ng/dL. Pair-wise comparisons of the three study groups indicate statistically significant differences in serum T4 (p < 0.01) and T3 (p < 0.001) means for the comparison of each group with the other two groups. CONCLUSIONS This study is unique in examining the association of serum cotinine and thyroid hormone concentrations using liquid chromatography tandem mass spectrometry in women smokers, passive smokers, and nonsmokers. Active and passive exposure to cigarette tobacco smoke is associated with a mild inhibitory effect on the thyroid reflected in higher serum T4 and T3 in nonsmokers compared to smokers in this cohort of women.

Hypothyroxinemia and pregnancy

OBJECTIVE To evaluate the peer-reviewed literature on iodine deficiency and hypothyroxinemia in pregnancy. METHODS We review published studies on isolated hypothyroxinemia in pregnancy, methodology of free thyroxine (T4) assays, impact of iodine deficiency on free T4 levels, and status of ongoing prospective randomized trials of isolated hypothyroxinemia during pregnancy. RESULTS Hypothyroxinemia during pregnancy is common. Studies have demonstrated the pivotal role exerted by maternal T4 on fetal brain development and the negative impact of hypothyroxinemia on neurobehavioral performance in offspring. Two intervention studies have demonstrated a positive effect on neurodevelopment in children of mothers promptly supplemented with iodine compared with the neurodevelopment in children of nonsupplemented mothers. Free T4 assays presently in clinical use have limitations. Preliminary results of the Controlled Antenatal Thyroid Study (CATS) are somewhat mixed, and the National Institutes of Health Maternal Fetal Medicine Thyrotropin Study (TSH Study) will be completed in 2015. Knowledge regarding the impact of isolated hypothyroxinemia has progressed, but major questions remain. An optimal diagnostic test for free T4 during pregnancy (accurate, inexpensive, and widely available) remains elusive. Trimester-specific normative data and normal ranges from different geographic regions do not exist. CONCLUSIONS Data published to date are insufficient to recommend levothyroxine therapy in pregnant women with isolated hypothyroxinemia. Adequate iodine intake should be recommended before conception and early in pregnancy.