Salivary/Serum progesterone ratio differs between menstrual cycle phases but not between populations : implications for health, reproductive, and behavioral research

Abstract

ABSTRACT Objectives: Many investigations of human health, behaviors, and adaptations require an indicator of ovarian cycle functioningas a causal, outcome, or confounding variable in the study design and analyses. Because the dynamic fluctuations in cycle hor-mones can rarely be adequately characterized by a single measurement, but repeated blood sampling can be onerous, salivaryfree progesterone (P Free- SAL) concentration is widely used in both clinical and research contexts as an alternative to total pro-gesterone concentration in venous blood samples (P Total-VEN ). However, some doubts have been raised about the use of P Free- SALbecause of suggestions that Bolivian and other populations and/or individuals might differ markedly in the ratio of P Free- SAL toP Total-VEN (the apparent uptake fraction, UF). If there are such differences, several decades of comparative population researchbased on P Free- SAL would require reconsideration, and a seemingly useful tool in both clinical and research contexts would belost or require additional extensive pre-use evaluations. Such impacts would fall disproportionally on clinical monitoring andresearch studies of menstruating persons, a segment of the population that has long been underrepresented in research and clin-ical trials, especially in low resource conditions. Therefore, we tested three hypotheses: (H1) UF differs by ovarian cycle phase;(H2) UF differs in Bolivian women from that of non-Bolivian women; and (H3) within a population, UF is consistently higher orlower in some individuals than in most others.Methods: We collected mid-follicular and mid-luteal near-concurrent samples of venous blood and saliva from 36 healthy pre-menopausal Bolivian women. P Total-VEN and P Free- SAL were measured using commercial enzyme immunoassays. To test the studyhypotheses, we used graphical and statistical methods to analyze these new data and to analyze data from several previouslypublished studies.Results: In our study sample of Bolivian women, P Free- SAL and P Total-VEN concentrations (n = 66 pairs) were significantly and highlycorrelated (Spearman's rho = 0.858; mixed model: intercept = 77.4 pmol/L [(p < 0.001), β = 0.0191 (p < 0.001)]). An individual's