Hormone Hypothesis Research Articles

Vitamin D and the Free Hormone Hypothesis

Vitamin D and the Free Hormone Hypothesis

The Effectiveness of Ketamine Treatment on Depression

As the diagnosis rate of depression continues to rise, effective treatment options for this condition have become one of the most researched areas in the field. Earlier antidepressants were primarily developed based on mechanisms that involve regulating imbalanced neurotransmitters. For example, the widely known Selective Serotonin Reuptake Inhibitors (SSRIs) and various tricyclic antidepressants work by adjusting the concentration of different neurotransmitters, such as dopamine and norepinephrine, in the synaptic cleft to alleviate depressive symptoms. Additionally, many therapeutic approaches have been developed and applied based on the widely accepted hormone hypothesis and neurotrophic factor hypothesis. Ketamine, a drug traditionally used as an anesthetic, has recently been discovered to possess antidepressant properties. Its efficacy and underlying neuroscientific mechanisms are currently under investigation. Unlike earlier antidepressants, Ketamine produces significant antidepressant effects within a short time after administration. Multiple studies have suggested that Ketamine's rapid and effective therapeutic results may be based on entirely new antidepressant mechanisms and targets that have yet to be fully understood. This provides a new solution for the treatment of treatment-resistant depression and offers new hope to patients who have tried various treatments without success. In this literature review, Ketamine's therapeutic effects and its underlying mechanisms will be thoroughly examined. The content will be divided into three sections: significant antidepressant effects, underlying principles and mechanisms, and factors relevant to the improvement of Ketamine therapy.

The Effect of Phototherapy on Systemic Inflammation Measured with Serum Vitamin D-Binding Protein and hsCRP in Patients with Inflammatory Skin Disease.

Vitamin D plays a role in inflammatory skin disease, but the exact mechanisms and the clinical significance remain unclear. According to the free hormone hypothesis, it is the free concentration of 25-hydroxy vitamin D (25(OH)D) that is biologically active. Vitamin D-binding protein (DBP) acts as the major transporter of vitamin D in the circulation, and DBP concentration defines the free 25(OH)D levels. DBP levels are elevated in various inflammatory conditions, including psoriasis. Narrowband-ultraviolet B (NB-UVB) is the most widely used phototherapy and is an established first-line treatment for psoriasis and atopic dermatitis (AD), often used before proceeding to systemic treatment. The aim of this study was to investigate the influence of NB-UVB phototherapy on DBP and high-sensitivity C-reactive protein (hsCRP) levels, as markers of systemic inflammation, in inflammatory skin disease. Thirty adults (psoriasis (n = 20) and AD (n = 10)) were treated with NB-UVB. Serum DBP, hsCRP, total and free 25(OH)D, and 1,25-dihydroxy vitamin D (1,25(OH)2D) were measured before and after NB-UVB. Disease severity was assessed with Psoriasis Area and Severity Index (PASI), SCORing Atopic Dermatitis (SCORAD), and Visual Analogue Scale (VAS). DBP decreased in psoriasis patients and varied with no clear trend in AD patients. HsCRP decreased in both groups, but this did not reach statistical significance. PASI, SCORAD, and VAS improved, and vitamin D levels increased after NB-UVB. Sub-analysis indicated a better response to NB-UVB for patients with vitamin D deficiency and insufficiency compared to vitamin D-sufficient patients. The decrease in DBP after NB-UVB in psoriasis patients suggests a potential systemic anti-inflammatory effect of phototherapy. Measurement of vitamin D levels may potentially serve as a tool to identify patients who would derive the greatest benefit from NB-UVB phototherapy.

Hormonal differences in perpetrators of intimate partner violence.

In order to gain a better understanding of the individual and joint impact of testosterone and cortisol on behavior, the present study was developed to test the differences in each hormone alone and conjointly between perpetrators of IPV and non-violent controls. Perpetrators of IPV on probation were compared to a control group of non-aggressive males from Hidalgo County in the Rio Grande Valley on baseline testosterone and cortisol, as well as several relevant questionnaires measuring aggression and trait anger. Differences in cortisol following exposure to a stressful event were also examined. Procedures included two laboratory visits consisting of questionnaires, a number of salivary testosterone and cortisol collections, and exposure to a stressor. Perpetrators had higher basal testosterone and post stressor cortisol levels than non- violent controls as well as a higher T/C ratio. In addition, trait anger moderated the relationship between both testosterone alone, and the testosterone/cortisol ratio and perpetration of IPV. Results are consistent with the hypothesis that testosterone leads to antisocial behavior, including perpetration of violence. The results are also consistent with the dual hormone hypothesis, i.e., that testosterone and cortisol work together to jointly regulate social dominance and aggression. Both the increased freestanding testosterone and the increased cortisol following exposure to stress places these men at risk for perpetrating violence. Clinical implications are discussed.

No evidence for relationship between paternal post-partum depressive symptoms and testosterone or cortisol in first-time fathers.

Male life history strategies are regulated by the neuroendocrine system. Testosterone (T) and cortisol regulate male behaviors including parenting and facilitate managing tradeoffs at key transitions in development such as first-time fatherhood. Both hormones demonstrate marked fluctuations in the postnatal period, and this presents an opportunity to investigate the role of T and cortisol in postpartum depressive symptoms-comparably less studied in fathers than in mothers in the evolutionary literature. Prior work on depressive symptoms has yet to integrate insights from the "dual hormone hypothesis (DHH)" which has focused on how T and cortisol interact to jointly regulate traits associated with dominance and status-seeking (i.e., mating effort) but has yet to be included in models of parenting effort. In this research, we use secondary data to investigate the relationship between DHH and traits ostensibly opposed to status seeking (i.e., depressive symptoms). First-time fathers (n = 193) provided morning saliva samples 10 months following parturition and reported on the presence of depressive symptoms (BDI-II). Responses were decomposed into three factors: cognitive, affective, and somatic. Using hybrid latent variable structural equation modeling, we did not find evidence that T predicted variability in cognitive, affective, or somatic depressive symptom factors. We found a null effect for cortisol as well. Finally, we could not find evidence that the DHH variable (T × cortisol interaction) predicted any variability in cognitive, affective, or somatic depressive symptoms. While we did not find evidence to support our hypotheses using a secondary data set, this study contributes to research on the neuroendocrinology of depression in fathers. Discussion focuses on the limitations of sample demographics, timing of saliva and self-report collection, and the lack of extant theory specific to paternal postpartum depression.

Free and bioavailable 25-hydroxyvitamin D thresholds for bone metabolism and their associations with metabolic syndrome in Chinese women of childbearing age.

The free hormone hypothesis suggests that free and bioavailable 25-hydroxyvitamin D [25(OH)D] may better reflect vitamin D bioactivity. This study aimed to determine the free and bioavailable 25(OH)D characteristics, estimate their thresholds based on parathyroid hormone (PTH) and bone turnover markers (BTMs), assess their associations with the risk of metabolic syndrome (MetS), and evaluate their potential advantages. A cross-sectional study was conducted using a nationally representative database (n = 1,505, female, 18-45 years). Serum total 25(OH)D, vitamin D-binding protein, albumin, PTH, and BTMs [osteocalcin, β-CrossLaps of type 1 collagen containing cross-linked C-telopeptide (β-CTX), and procollagen type 1 N-terminal propeptide (P1NP)] were measured. Free 25(OH)D and bioavailable 25(OH)D were calculated. The threshold associations of 25(OH)D with PTH and BTMs were analyzed. The relationship between 25(OH)D and MetS risk was examined. An intervention study was then performed in 39 women (18-47 years) to assess the associations of increasing 25(OH)D with PTH and BTMs after vitamin D supplementation. In the cross-sectional study, the three forms of 25(OH)D were found to have similar distribution characteristics. Free and bioavailable 25(OH)D correlated well with total 25(OH)D. Significant total 25(OH)D cutoffs were observed for PTH (14.19 ng/mL and 18.03 ng/mL), osteocalcin (15.14 ng/mL), β-CTX (14.79 ng/mL), and P1NP (15.08 ng/mL). Free and bioavailable 25(OH)D cutoffs were only found for P1NP (3.47 pg/mL and 1.66 ng/mL, respectively). A total 25(OH)D of <15.14 ng/mL was marginally associated with a higher risk of reduced high-density lipoprotein cholesterol (HDL-C) [odd ratios (OR) = 1.371 (0.991-1.899)]. The ORs of higher versus lower free and bioavailable 25(OH)D levels for reduced HDL-C were 0.770 (0.621-0.956) and 0.772 (0.622-0.958), respectively. The results of the intervention study indicated that PTH and BTMs responded more sensitively to total 25(OH)D than to free or bioavailable 25(OH)D. Free and bioavailable 25(OH)D only had a threshold effect on P1NP. The active 25(OH)D thresholds could be used for risk assessment of reduced HDL-C. However, no superiority of free or bioavailable 25(OH)D was found based on the response of PTH and BTMs to changes in 25(OH)D in Chinese women of childbearing age following vitamin D supplementation. http://www.chictr.org.cn, ChiCTR2200058290.

Association of circulating serum free bioavailable and total vitamin D with cathelicidin levels among active TB patients and household contacts

The free hormone hypothesis postulates that the estimation of free circulating 25 (OH)D may be a better marker of vitamin D status and is of clinical importance compared to total vitamin D fraction. The unbound fraction is involved in biological activities since it is able to penetrate into the cell. Studies have shown that cathelicidin/LL-37 inhibits the growth of Mycobacterium tuberculosis in a vitamin D-dependent manner and therefore adequate vitamin D is required for its expression. The study aimed to determine the association between serum bioavailable and total vitamin D with LL-37 levels in ATB patients, LTBI, and individuals with no TB infection. This was a cross-sectional study in which bioavailable vitamin D and LL-37 levels were measured using competitive ELISA kits and total vitamin D was measured using electrochemilumiscence and consequently determined their association. The mean (SD) bioavailable vitamin D levels of the study participants were 3.8 ng/mL (2.6) and the median (IQR) of LL-37 levels were 320 ng/mL (160, 550 ng/mL). The mean (SD) of total vitamin D levels was 19.0 ng/mL (8.3) ng/mL. Similar weak correlations were observed between the bioavailable and total vitamin D with LL-37 levels, therefore, deviating from our hypothesis.

Endogenous sex steroid hormones and risk of liver cancer among US men: Results from the Liver Cancer Pooling Project

Background & AimsIncidence rates of liver cancer in most populations are two to three times higher among men than women. The higher rates among men have led to the suggestion that androgens are related to increased risk whereas oestrogens are related to decreased risk. This hypothesis was investigated in the present study via a nested case-control analysis of pre-diagnostic sex steroid hormone levels among men in five US cohorts. MethodsConcentrations of sex steroid hormones and sex hormone-binding globulin were quantitated using gas chromatography–mass spectrometry and a competitive electrochemiluminescence immunoassay, respectively. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% CIs for associations between hormones and liver cancer among 275 men who subsequently developed liver cancer and 768 comparison men. ResultsHigher concentrations of total testosterone (OR per one-unit increase in log2 = 1.77, 95% CI = 1.38–2.29), dihydrotestosterone (OR = 1.76, 95% CI = 1.21–2.57), oestrone (OR = 1.74, 95% CI = 1.08-2.79), total oestradiol (OR = 1.58, 95% CI=1.22–20.05), and sex hormone-binding globulin (OR = 1.63, 95% CI = 1.27–2.11) were associated with increased risk. Higher concentrations of dehydroepiandrosterone (DHEA), however, were associated with a 53% decreased risk (OR = 0.47, 95% CI = 0.33–0.68). ConclusionsHigher concentrations of both androgens (testosterone, dihydrotestosterone) and their aromatised oestrogenic metabolites (oestrone, oestradiol) were observed among men who subsequently developed liver cancer compared with men who did not. As DHEA is an adrenal precursor of both androgens and oestrogens, these results may suggest that a lower capacity to convert DHEA to androgens, and their subsequent conversion to oestrogens, confers a lower risk of liver cancer, whereas a greater capacity to convert DHEA confers a greater risk. Impact and implicationsThis study does not fully support the current hormone hypothesis as both androgen and oestrogen levels were associated with increased risk of liver cancer among men. The study also found that higher DHEA levels were associated with lower risk, thus suggesting the hypothesis that greater capacity to convert DHEA could be associated with increased liver cancer risk among men.

Development of free 25-hydroxyvitamin D3 assay method using liquid chromatography-tandem mass spectrometry.

The free hormone hypothesis has triggered controversies regarding the measurement of free vitamin D metabolites, such as free 25-hydroxyvitamin D (25(OH)D), as a suitable indicator for total vitamin D for clinical use. This issue can be addressed by developing a precise and accurate method for free 25(OH)D measurement. In the present study, a novel assay method for free 25(OH)D3 based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Sample preparation first involved ultrafiltration to remove vitamin D-binding protein-bound and albumin-bound 25(OH)D, followed by extraction with a column, derivatization, evaporation, dissolution, and injection into the LC-MS/MS system. The coefficient of variation of repeatability and reproducibility obtained were 3.8–4.5% and 4.8–5.9%, respectively. Satisfactory linearity (r=0.999) was obtained up to 80 pg/ml. The lower quantification limit was 0.97 pg/ml and the S/N ratio on the peak of 1.0 pg/ml sample was 24.8 (which is more than the acceptable value of 10). The recovery rate was between 84.5 and 92.4% with a negligible matrix effect (94.5–104.9%). Levels of free 25(OH)D3, but not total 25(OH)D3, in the serum of the patients with chronic kidney disease (CKD) and hepatic cirrhosis (HC) were substantially lower than those in healthy subjects. The correlation coefficient between total and free 25(OH)D3 was 0.738 in all samples, while the linear regression equations were different between the patients with CKD and HC. In conclusion, LC-MS/MS assay for free 25(OH)D3 might be useful to evaluate high-throughput methods, including ELISA.

Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology.

According to the free hormone hypothesis, biological activity of a certain hormone is best reflected by free rather than total hormone concentrations. A crucial element in this theory is the presence of binding proteins, which function as gatekeepers for steroid action. For testosterone, tissue exposure is governed by a delicate equilibrium between free and total testosterone which is determined through interaction with the binding proteins sex hormone-binding globulin and albumin. Ageing, genetics and various pathological conditions influence this equilibrium, hereby possibly modulating hormonal exposure to the target tissues. Despite ongoing controversy on the subject, strong evidence from recent in vitro, in vivo and human experiments emphasizes the relevance of free testosterone. Currently, however, clinical possibilities for free hormone diagnostics are limited. Direct immunoassays are inaccurate, while gold standard liquid chromatography with tandem mass spectrometry (LC-MS/MS) coupled equilibrium dialysis is not available for clinical routine. Calculation models for free testosterone, despite intrinsic limitations, provide a suitable alternative, of which the Vermeulen calculator is currently the preferred method. Calculated free testosterone is indeed associated with bone health, frailty and other clinical endpoints. Moreover, the added value of free testosterone in the clinical diagnosis of male hypogonadism is clearly evident. In suspected hypogonadal men in whom borderline low total testosterone and/or altered sex hormone-binding globulin levels are detected, the determination of free testosterone avoids under- and overdiagnosis, facilitating adequate prescription of hormonal replacement therapy. As such, free testosterone should be integrated as a standard biochemical parameter, on top of total testosterone, in the diagnostic workflow of male hypogonadism.

Consistent Inverse Associations of Total, "Bioavailable", Free, and "Non-Bioavailable" Vitamin D with Incidence of Diabetes among Older Adults with Lower Baseline HbA1c (≤6%) Levels.

Background: Serum 25-hydroxyvitamin (25(OH)D) levels are inversely associated with risk of diabetes. The “free hormone hypothesis” suggests potential effects to be mainly related to concentrations of “bioavailable” and free rather than total 25(OH)D. We assessed associations of serum concentrations of vitamin D-binding protein (VDBP), as well as total “bioavailable”, complementary “non-bioavailable”, and free 25(OH)D, with the risk of developing diabetes among non-diabetic older adults in a large population-based cohort study in Germany. Methods: We included 4841 non-diabetic older adults aged 50–75 years at the baseline exam from the ESTHER cohort conducted in Saarland, Germany, in 2001–2002. Concentrations of “bioavailable” and free 25(OH)D were derived from serum concentrations of VDBP, total 25(OH)D, and albumin. Incidence of diabetes was ascertained during up to 14 years of follow-up. Associations were quantified by multivariable Cox proportional hazards regression models with comprehensive confounder adjustment. Results: During a median follow-up of 10.6 years, 837 non-diabetic participants developed diabetes. We observed similar inverse associations with developing diabetes for VDBP (hazard ratio (HR) for lowest versus highest quintile: 1.37, 95% confidence interval (CI): 1.09, 1.72), total 25(OH)D (HR: 1.31, 95% CI: 1.03, 1.66), and “non-bioavailable” 25(OH)D (HR: 1.30, 95% CI: 1.02, 1.65). Associations were smaller and statistically insignificant for “bioavailable” and free 25(OH)D. However, associations of total “non-bioavailable”, “bioavailable”, and free 25(OH)D with incidence of diabetes were much stronger among, and essentially restricted to, participants with lower baseline HbA1c (≤6%) levels. Conclusions: This large prospective cohort study of older Caucasian adults, in agreement with results from randomized trials and Mendelian randomization studies, supports a protective effect of vitamin D against development of diabetes. The “free hormone theory” may not be relevant in this context. However, our results underline the importance of adequate vitamin D status among those who have not yet shown any sign of impaired glucose tolerance.

M300 LC-MS/MS analysis indicates a narrower reference interval of free 25(OH)D in elderly population: An indication for free hormone hypothesis

M300 LC-MS/MS analysis indicates a narrower reference interval of free 25(OH)D in elderly population: An indication for free hormone hypothesis

Clinical Utility and Analytical Aspects of Direct Measurements of Free Hormones Using Mass Spectrometry-Based Methods.

The free hormone (FH) hypothesis states that hormone action and the corresponding biological effects are mediated by the unbound (free) fraction of hormone in circulation. The in vivo relationship between protein-bound and FH is complex and dynamic. In most individuals, measurement of total hormone (TH) is usually adequate to reflect the hormone status; however, certain physiological conditions and/or medications can affect protein binding and alter FH concentration. In these cases, measurement of FH will provide a better measure of the bioactive hormone status than measurement of the TH. Measurement of FH presents many challenges, as the concentrations are very low and there are number of pitfalls, which may affect the measured concentrations. In this review, we discuss techniques used in the separation and direct quantitation of FH concentrations in biological samples using mass spectrometry for analysis. We also highlight clinical situations in which FH analysis is warranted and when mass spectrometry should be the preferred methodology over immunoassays. Equilibrium dialysis, ultrafiltration, or size-exclusion separation coupled with liquid chromatography-tandem mass spectrometry provides a sensitive and specific method to measure FH concentrations. These direct methods are useful in iatrogenic or physiological states that alter hormone binding or metabolism.

Vitamin D-Binding Protein and the Free Hormone Hypothesis for Vitamin D in Bio-Naïve Patients with Psoriasis.

High levels of vitamin D-binding protein (DBP) have been reported in patients with psoriasis and the possibility of DBP as a marker of inflammation has been discussed. Furthermore, high DBP levels might negatively affect free 25(OH)D concentrations. According to the free hormone hypothesis, only the free fraction of a steroid hormone is capable of exerting biological action. Thus, free 25(OH)D level could be a better biomarker of vitamin D status than total 25(OH)D level. The objectives of this study were to identify the strongest determinants for DBP levels and to test the free hormone hypothesis for vitamin D in psoriasis. Additionally, we also aimed to investigate correlations between directly measured free 25(OH)D levels in serum and psoriasis disease severity compared to total 25(OH)D levels. This was a retrospective cross-sectional study including 40 bio-naïve patients with mild to severe plaque psoriasis. Psoriasis disease severity was evaluated using high sensitivity C-reactive protein (hsCRP), Psoriasis Area Severity Index (PASI) and visual analogue scale (VAS). Vitamin D metabolites including directly measured free 25(OH)D and serum DBP levels were measured. DBP levels were higher in patients with self-reported arthropathy than those without irrespective of confounding factors like sex, age and body weight. Total and free 25(OH)D levels correlated well (ρ = 0.77, p < 0.0001) and both were inversely correlated to intact parathyroid hormone (iPTH) (ρ = −0.33, p = 0.038 for total 25(OH)D and ρ = −0.40, p = 0.010 for free 25(OH)D). Only total 25(OH)D correlated to serum calcium levels (ρ = 0.32, p = 0.047). No correlations between any of the vitamin D metabolites and psoriasis disease severity were observed. In conclusion, DBP might be a new inflammatory biomarker in psoriasis, especially in psoriatic arthritis. Total 25(OH)D was a reliable measure for vitamin D status in this psoriasis cohort. However, evaluation of free 25(OH)D in patients with psoriatic disease and multiple co-morbidities and/or ongoing biologic treatment should be considered.

Vitamin D in dairy cows: metabolism, status and functions in the immune system

ABSTRACT The function of vitamin D in calcium homoeostasis in dairy cows, such as in other vertebrates, is known for many years. In recent years, new and interesting, non-classical functions of vitamin D have been elucidated, including effects on the immune system. The major aim of this review is to provide an overview of effects of vitamin D or its metabolites on the immune system in dairy cows. The first part of the review provides an overview of vitamin D metabolism, with particular reference to the role of various proteins (25- and 1-hydroxylases, vitamin D binding protein, vitamin D receptor) in vitamin D signalling. The second part deals with the role of the concentration of 25-hydroxyvitamin D [25(OH)D] in plasma as an indicator of the vitamin D status in dairy cows, and its dependence on sunlight exposure and dietary vitamin D supplementation. In this part also the “free hormone hypothesis” is discussed, indicating that the concentration of free 25(OH)D might be a more valid indicator of the vitamin D status than the concentration of total 25(OH)D. The third part deals with classical and the non-classical functions of vitamin D. Among the non-classical functions which are based on an autocrine vitamin D signalling, particular reference is given to the effects of vitamin D and vitamin D metabolites on the immune system in bovine immune cells and in dairy cows. Recent findings provide some indication that vitamin D or its metabolite 25(OH)D could enhance the immune function in dairy cows and be useful for the prevention and therapy of mastitis. However, the number of studies reported so far in this respect is very limited. Thus, much more research is required to yield clear concepts for an optimised usage of vitamin D to improve the immune system and prevent infectious diseases in dairy cows.

Hormonal and neural correlates of prosocial conformity in adolescents

The dual hormone hypothesis, which centers on the interaction between testosterone and cortisol on social behavior, offers a compelling framework for examining the role of hormones on the neural correlates of adolescent peer conformity. Expanding on this hypothesis, the present study explored the interaction between testosterone and cortisol via hair concentrations on adolescents’ conformity to peers. During fMRI, 136 adolescents (51 % female) ages 11–14 years (M = 12.32; SD = 0.6) completed a prosocial decision-making task. Participants chose how much of their time to donate to charity before and after observing a low- or high-prosocial peer. Conformity was measured as change in behavior pre- to post-observation. High testosterone with low cortisol was associated with greater conformity to high-prosocial peers but not low prosocial peers. Focusing on high prosocial peers, whole-brain analyses indicated greater activation post- vs. pre-observation as a function of high testosterone and low cortisol in regions implicated in social cognition, salience detection, and reward processing: pSTS/TPJ, insula, OFC, and caudate nucleus. Results highlight the relevance of hormones for understanding the neural correlates of adolescents’ conformity to prosocial peers.

Growth hormone deficiency, acromegaly and COVID-19: Transitioning from media reports to knowledge and a growth hormone hypothesis

• Rapid media coverage of COVID-19 has prompted new hypotheses for research of its impact in patients with GH disorders. • Adherence of GH therapy in children and adults with GH deficiency remains unexpectedly high during the COVID-19 pandemic. • Risk factors of COVID-19 may be associated with decreased GH secretion suggesting a role of GH therapy in COVID-19 patients with GH deficiency. • Increased vigilance should be paid to COVID-19 acromegaly patients, as normalizing GH levels might improve outcomes. • The proposed hypotheses of normalizing GH levels in COVID-19 acromegaly should encourage further studies in these patients.

The Free Hormone Hypothesis: When, Why, and How to Measure the Free Hormone Levels to Assess Vitamin D, Thyroid, Sex Hormone, and Cortisol Status.

ABSTRACTThe free hormone hypothesis postulates that only the nonbound fraction (the free fraction) of hormones that otherwise circulate in blood bound to their carrier proteins is able to enter cells and exert biologic effects. In this review, I will examine four hormone groups—vitamin D metabolites (especially 25OHD), thyroid hormones (especially thyroxine [T4]), sex steroids (especially testosterone), and glucocorticoids (especially cortisol)—that are bound to various degrees to their respective binding proteins—vitamin D‐binding protein (DBP), thyroid‐binding globulin (TBG), sex hormone‐binding globulin (SHBG), and cortisol‐binding globulin (CBG)—for which a strong case can be made that measurement of the free hormone level provides a better assessment of hormonal status than the measurement of total hormonal levels under conditions in which the binding proteins are affected in levels or affinities for the hormones to which they bind. I will discuss the rationale for this argument based on the free hormone hypothesis, discuss potential exceptions to the free hormone hypothesis, and review functions of the binding proteins that may be independent of their transport role. I will then review the complications involved with measuring the free hormone levels and the efforts to calculate those levels based on estimates of binding constants and levels of both total hormone and total binding protein. In this review, the major focus will be on DBP and free 25OHD, but the parallels and differences with the other binding proteins and hormones will be highlighted. Vitamin D and its metabolites, thyroid hormones, sex steroids, and glucocorticoids are transported in blood bound to serum proteins. The tightness of binding varies depending on the hormone and the binding protein such that the percent free varies from 0.03% for T4 and 25OHD to 4% for cortisol with testosterone at 2%. Although the major function of the primary carrier proteins (DBP, TBG, SHBG, and CBG) may be to transport their respective lipophilic hormones within the aqueous media that is plasma, these proteins may have other functions independent of their transport function. For most tissues, these hormones enter the cell as the free hormone presumably by diffusion (the free hormone hypothesis), although a few tissues such as the kidney and reproductive tissues express megalin/cubilin enabling by endocytosis protein‐bound hormone to enter the cell. Measuring the free levels of these protein‐bound hormones is likely to provide a better measure of the true hormone status than measuring the total levels in situations where the levels and/or affinities of the binding proteins are altered. Methods to measure free hormone levels are problematic as the free levels can be quite low, the methods require separation of bound and free that could disturb the steady state, and the means of separating bound and free are prone to error. Calculation of free levels using existing data for association constants between the hormone and its binding protein are likewise prone to error because of assumptions of linear binding models and invariant association constants, both of which are invalid. © 2020 The Author. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Beyond the dual hormone hypothesis: Understanding risky and prosocial behavior in adolescence

Beyond the dual hormone hypothesis: Understanding risky and prosocial behavior in adolescence

Abstract B094: Regulation of megalin by vitamin D as the mechanism for differential levels of intra-prostatic androgens between African American and Caucasian men

Abstract Prostate cancer (PCa) is a hormonally driven cancer and is currently the third most common cancer in the US. African American (AA) men are disproportionately at risk for both PCa and vitamin D (vitD) deficiency compared to white men. The numerous chemopreventative properties of vitD and epidemiological relationship of vitD status with PCa aggressiveness and mortality has led to the hypothesis that vitD deficiency is a biological contributor to PCa disparity in AA men. Our lab recently reported an unexpected relationship between serum and intraprostatic vitD metabolites 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D in AA men. We also observed that Megalin, a multi-liganded endocytic membrane receptor encoded by the gene LRP2, was expressed in the prostate epithelium and is regulated by vitD. Extra-renal activity of Megalin has not been well studied as the widely accepted Free Hormone Hypothesis assumes passive diffusion of circulating free hormones into tissues. The presence of megalin suggests that globulin bound hormones from the circulation, including 25(OH)D bound to vitamin D binding protein (DBP) and testosterone (T) bound to sex hormone binding globulin (SHBG), are imported into the prostate in a regulated manner. Here we examine megalin as a potential mechanism to regulate globulin bound hormone import into the prostate. 25(OH)D decreased expression of LRP2 in primary prostate epithelial cells and fresh human prostate tissue slice explants. DBP-bound 25(OH)D and SHBG-bound T were imported into these prostate models and transcriptionally active. Lastly, we quantified T and its active metabolite dihydrotestosterone (DHT) in the patient cohort from our prior study. Prostatic DHT levels inversely correlated with serum 25(OH)D status. AA men had higher levels of DHT in prostate tissue compared to white men. These clinical findings support our hypothesis that vitD status regulates intraprostatic hormone levels. In summary, we report the presence of a negative feedback loop in which vitD deficiency increases hormone import into prostate epithelium via megalin. Therefore, the upregulation of megalin in the setting of vitamin D deficiency may facilitate increased import of circulating sex steroids into the prostate contributing to carcinogenesis in AA men. Citation Format: Jason Garcia, Zachary Richards, Morgan Zenner, Yancai Wang, Peter Gann, Gail Prins, Larisa Nonn. Regulation of megalin by vitamin D as the mechanism for differential levels of intra-prostatic androgens between African American and Caucasian men [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B094.