Tracer Methods in Hormone Research, Softcover reprint of the original 1st ed. 1975 Monographs on Endocrinology Series, Vol. 8

The purpose of this monograph is to describe theoretical aspects of the interpretation of data obtained from experiments performed with labeled hormones. Quantitative endocrinologic studies involving the use of tracers include the determination of rates at which hormones are secreted by endocrine glands and are produced outside these glands by conversion of other secreted hor­ mones. Tracer experiments are also performed with the purpose of measuring rates of metabolic reactions. These measurements reveal the contribution of secreted hormones to the formation of circulating compounds and urinary metabolites. The estimation of rates of fetal and placental production and exchange of hormones characterizes a class of in vivo quantitative studies performed with isotopically labeled hormones (radioactive or not). In addi­ tion, tracers are used to measure permeability and rates of reaction in in vitro systems, and to study the uptake of hormones by tissues, both in vivo and in vitro. The stability of the steroid nucleus carrying the isotopic label and the large number of reversible metabolic reactions in which steroids are involved, both facilitated and motivated the development of a sophisticated theoretical treat­ ment of tracer experiments in the field of endocrinology. Although the prac­ tical examples used to illustrate the concepts and calculations presented in this monograph involve labeled hormones, the theory is presented in a general symbolic manner and is applicable to other fields of investigation.

1. Rates in Open System in the Steady State: Definitions and Relations.- A. One Pool Embedded in a Multicompartmental System.- Rates of Entry.- Production Rate.- Rates of Removal.- B. Two Related Pools Embedded in a Multicompartmental System.- Rates of Entry, Exit, and Transfer.- The Transfer Factor.- Calculations of Rates from Values of Production Rates (PR’s) and Transfer Factors (?’s).- Further Description of the Rate of Transfer of Material from One Pool to Another.- The Contribution Factor.- Application of the Two-Pool Analysis to a Hormonal System.- C. Three Related Pools Embedded in a Multicompartmental System.- Rates of Entry, Exit, and Transfer.- Production Rates.- Contribution Factor.- Calculation of Rates from Values of PR’s and ?’s.- Application of the Three-Pool Analysis to a Hormonal System.- D. General Systems of m Related Pools.- Expanded Subsystems of Pools.- 2. Infusion of Tracers at a Constant Rate.- A. Multicompartmental System in Which Only One Pool is Studied.- B. Multicompartmental System in Which Two Pools are Studied.- Rates.- Transfer Factors (?).- Contribution Factors (?).- Rates of Transfer Which Exclude Recycle.- C. Multicompartmental System in Which Three Pools are Studied.- Rates.- Contribution Factors.- “Non-Recycling” Transfer Rates.- Transfer Factors in a Subsystem of Three Primary Pools Connected in Series.- D. General m-Primary-Pool Subsystem.- Rates.- Rates in Terms of PR’s and ?’s.- Contribution Factors.- Proof of the Relationship PR1 = v01 + ?21 v02 +...+ ?m1 v0m.- Relationships Between Rates in a System of m-Primary Pools and a Subsystem of Some of these Pools.- 3. Rapid Injection of Tracers.- A. Calculations Based on Areas under Specific Activity Curves.- Production Rates (PR) and Transfer Factors (?).- Rates.- B. Relationships Between Data Obtained by Rapid Injection and by Constant Infusion of a Tracer.- C. Calculations Based on the Shape of Specific Activity Curves.- Total Number of Pools in the System Undetermined.- Pool Size.- Rates of Exit.- Rates of Reentry, Fractional Loss.- “Turnover Times”.- Mean Residence Time (T?).- Mean Transit Time (t?).- Mean Number of Cycles (v).- Mean Recycling Time (t?ii).- Mean Transfer Time (t?ij).- Two-Primary-Pool Subsystem.- D. Determination of Areas and Shapes of Specific Activity Curves.- Graphic Methods to Measure Areas.- Procedures to Determine Specific Activity Functions.- “Peel-off” Graphic Method.- Numerical (Computer) Methods.- 4. Tracer Kinetics in Compartmental Models.- Rate Constants (k’s).- Fractional Rates (h’s).- A. One-Pool System.- Rapid Injection of the Tracer.- Infusion of the Tracer at a Constant Rate.- B. Two-Pool Systems.- Rapid Injection of the Tracer.- Analysis of Two-Pool Systems with Equal Exponential Constants.- Analysis of a Two-Pool Closed System.- Calculation of Parameters of the Two-Pool System from Values of ?’s and D’s.- Infusion of Tracers into the Pools at a Constant Rate.- C. Multiple-Pool Systems.- h’s in Terms of ?’s and D’s.- Unrestricted Three-Pool Systems.- Irreducible System: Number of Pools Versus Number of Exponential Terms in Specific Activity Functions.- Linearly Dependent Specific Activities.- Repeated ?’s.- Complex ?’s.- 5. Interpretation of Isotopic Data from Blood-Borne Compounds.- I. Data: Isotopic Steady-State Values or Areas under Concentration Curves.- A. One Tracer Administered.- Production Rates.- Metabolic Clearance Rates.- Sources of a Circulating Hormone.- Measurement of Blood Flow.- B. Two Tracers Administered.- Conversion Factors (?’s).- Rates of Secretion and Metabolism.- Pathways of Conversion of a Circulating Hormone to Another.- Fetomaternal Transfer and Production of Hormones.- Rates of Metabolism in Specific Organs.- C. Three Tracers Administered.- II. Data: Specific Activity Functions.- Size of the Pool of Fast Initial Distribution of the Intravenously Injected Tracer.- “Volume” of the Space of Fast Initial Distribution.- Rates of Exit of a Compound from Circulation.- Reentry into Circulation.- Average Times of Transit, Residence, and Recycling of Hormones in Circulation.- III. Calculations Based on Models Involving a Limited Number of Compartments.- IV. Analysis of Systems that are Not at the Steady State.- Note 5.- “Peel-off” Method.- Computer Method (R. J. Bogumil).- Discussion of Results.- 6. Rates of Secretion and Metabolism of Hormones Estimated from Specific Activities of Urinary Metabolites.- A. Estimation of Hormone Secretion Rates.- Case 1. Metabolites Derived from one Secreted Precursor (e.g., Aldosterone).- Case 2. Metabolites Derived from Two Secreted Precursors (e.g., Dehydroisoandrosterone).- Case 3. Metabolites Derived from Several Secreted Precursors (e.g., Testosterone).- B. Interpretation of Specific Activity Data Obtained from Labeled Urinary Metabolites.- C. Parameters of Metabolism Estimated from Labeled Urinary Metabolites.- Conversion of a Precursor to Urinary Metabolites.- Relative Conversion of Two Precursors to a Metabolite.- Metabolites “Uniquely Derived5’ from a Circulating Compound.- Relation Between the Specific Activities of a Circulating Compound and of a Urinary Metabolite Uniquely Derived from It.- Measurement of Production Rates and Rates of Interconversion of Circulating Compounds.- Production Rates.- Rates of Interconversion.- D. Labeled Urinary Metabolites in Pregnancy.- Secretion Rates.- Fetomaternal Transfers.- E. Comments.- 7. In vitro Tracer Superfusion Experiments.- Superfusion Versus Batch Incubations.- Use of Two Metabolically Related Tracers in Superfusion Experiments.- Model.- Calculation of Rates of Entry of Superfused Tracer into Cells.- Fraction of a Superfused Tracer Returning from the Cells to the Medium.- Fraction of Superfused Tracer Appearing in the Perfusate as a Metabolite.- Conversion Factors.- Rates in the Superfusion Model.- Intracellular Clearance.- A Special Case: Nonsteroidogenic Tissue.- Validation of the Model.- Applications.- References.