The Use of Estrone-3-Glucuronide and Pregnanediol-3-Glucuronide Excretion Rates to Navigate the Continuum of Ovarian Activity

Abstract

The patterns of a woman's normal ovarian activity can take many forms from childhood to menopause. These patterns lie on a continuum ranging from no ovarian activity to a fully fertile ovulatory cycle, but among the other defined patterns are cycles with anovulatory ovarian activity, including luteinized unruptured follicles (LUFs), and ovulatory cycles with deficient or short luteal phases. For any woman, these patterns can occur in any order, and one can merge into the next, without an intervening bleed, or be missed entirely. Consequently, it is not yet possible to predict the pattern of a future cycle, but it is possible to use our knowledge of the continuum to interpret the current cycle, which has clear implications for the management of personal fertility. An individual's position in the continuum can be monitored directly in real time by daily monitoring of ovarian hormone excretion rates, without either calendar-type calculations or reference to population means and standard deviations. The excretion of urinary estrone glucuronide (E1G) gives a direct measure of follicular growth, and the post-ovulatory rise in urinary pregnanediol glucuronide (PdG) following an E1G peak provides good evidence of ovulation. Specific values of the PdG excretion rate can be used to determine whether a cycle is anovulatory with or without a LUF, or is ovulatory and infertile or ovulatory and fertile. These specific values are important signposts for navigating the continuum. For a woman to take advantage of the knowledge of the continuum, the data must be reliable, and their interpretation has to be based on the underlying science and provided in an appropriate form. We discuss the various factors involved in acquiring and providing such information to enable each woman to navigate her own reproductive life.

Expressing the quantity of urinary analytes: a discussion of some issues arising from the monitoring of the menstrual cycle

“…where s A and u A are the concentrations of A in blood and urine, respectively. Combining (8) and (9) yields (10) from which, since R can not be negative, it follows that u A ≥ s A , although u A is actually much greater than s A .…”

“…This means that while s A can depend significantly on where in the 'cycle of pulsation' the serum sample is obtained, J A is averaged over at least three hours, thereby providing a more reproducible measure by minimising the effects of the rapidly changing s A . Second, their concentrations vary systematically during the menstrual cycle [1,8], rising or falling over several days (an important exception to this is luteinising hormone which usually rises very rapidly just before ovulation [102]). In such cases the time averaging over a few hours (Δt ≥ 3 hours) that is associated with measuring urinary metabolites does not present any significant problem (Cooke, Blackwell and Brown, manuscript in preparation).…”

“…First, the daily blood sampling required is unacceptable to women, so it is more usual to monitor the urinary metabolites of E2 and P instead [2]. The most common metabolites to be used in this way are, respectively, oestrone 3-glucuronide (E1G) and pregnanediol glucuronide (PdG) [3][4][5][6][7][8]. Second, in monitoring the menstrual cycle what is actually relevant is the rate at which E2 and P are produced because that provides an insight into the dynamics of the process.…”

“…While it is agreed that E1G and PdG are practical urinary analytes to monitor for this purpose, there is some debate about what should actually be measured. In practice, there are at least four common alternatives: (i) the analyte concentration [6,7], (ii) concentration corrected by normalising to the creatinine concentration [10,11], (iii) concentration corrected by normalising to the specific gravity [10,11], or (iv) the analyte excretion rate [3,4,8]. On occasion, urinary analyte concentrations have been corrected by normalising to osmolality [12,13], but this is not common among reports of E1G and PdG levels.…”

“…Given their significance to so many women and their partners, it is important to consider the limitations of these commonly used measures of E1G and PdG. However, even in a 'normal' menstrual cycle these analytes have very complex kinetics [8] because the events in the ovaries from which E2 and P come result from interactions with the pituitary gland involving other hormones (including luteinising and follicle-stimulating hormones). As there is nothing unique about the excretion of E1G and PdG we choose to clarify some of the issues associated with the various measures by considering analytes that have fewer of the complexities associated with the menstrual cycle.…”