Relación de Laboratorios de Prueba Terceros Autorizados
51. LABORATORIO DE SALUD PÚBLICA DEL ESTADO DE PUEBLA
MFO
In agreement with prior research regarding the relationship between the menstrual cycle and substrate oxidation during exercise, a trend for a greater MFO during the luteal than the follicular phase of the cycle was observed (Nicklas, Hackney, and Sharp 1989; Jurkowski et al. 1978; Campbell, Angus, and Febbraio 2001; Zderic, Coggan, and Ruby 2001). Additionally, a greater MFO in women using hormonal contraceptives were seen than the MFO in regularly menstruating non-contraceptive users (McNeill and Mozingo 1981; Bonen, Haynes, and Graham 1991; Bemben et al. 1992), with an interaction, such that either amenorrhoeic women using a progesterone only form of contraceptive, or combined E+P users in the luteal
phase had a greater MFO than regularly menstruating women in the follicular phase. These findings will be discussed further below.
Our inconclusive finding of only a trend (p=0.06 and p=0.08) for a lower absolute and relative MFO respectively in the FOL vs the LUT phase unfortunately only adds to the inconsistency in the literature. When a difference has been reported in substrate oxidation by the phase of the menstrual cycle, a greater reliance of lipid and possibly protein has been seen in the luteal phase - when both oestrogen and progesterone levels are elevated. When oestrogen is administered in isolation to ovariectomized rodents, to men, amenorrhoeic women or women with pharmacologically suppressed ovarian hormone levels (D'Eon et al. 2002), then a greater reliance on fat oxidation has been documented. Although oestrogen supplementation doesn't seem to impact whole body lipolysis (Ruby et al. 1997), it seems to promote lipid oxidation through several other mechanisms such as through the upregulation of genes and transcription factors responsible for greater IMTAG storage (Fu et al. 2009), lipid membrane transport and mitochondrial biogenesis (Schulz et al. 2005; D'Eon et al. 2005) which should enhance oxidative lipid metabolism. Oestrogen supplementation also has an impact on carbohydrate metabolism, reducing hepatic glucose output, muscle glucose uptake and/or plasma metabolic clearance rate (Ruby et al. 1997; Carter et al. 2001; Devries et al. 2005). However, whilst oestrogen concentrations are greatest throughout the luteal phase of the menstrual cycle and so could explain the greater preference for lipid oxidation during this phase, progesterone levels are also elevated in comparison to the follicular phase, the independent impact of which is less clear, but could act antagonistically
It was perhaps most surprising that we saw the greatest rate of lipid oxidation in the amenorrhoeic group who presumably (not measured) had a lower oestrogen level than both the FOL and LUT group. This group of women largely consisted of PROGEST only users (15/16), who had a similar MFO to those using a combined form (E+P) of contraceptive, both of whom had a greater MFO than those not using any contraceptive (REG). Taking this all into account, it implies that when the phase of the menstrual cycle is not accounted for, exogenous hormonal administration in general, dis-regarding the type per se, has a stronger positive association with MFO than no contraceptive use at all.
Considering the assumed oestrogen suppressive effect of the PROGEST contraceptive, it was hypothesized that this group would show the lowest MFO during exercise, it was therefore quite surprising to find the opposite. However, in support of this somewhat contentious finding, the groups did not differ in other known determinants of lipid oxidation, such as SRPAL, FFM, FM, O2max, and dietary intake (data not shown). The only significant (p<0.05) difference between the groups was in carbohydrate intake (g/day), specifically, the REG-FOL (239.8 70.1) vs E+P-FOL (310.5 70.6) and the REG-FOL vs E+P+LUT (310.7 67.6). The higher carbohydrate intake in the E+P-FOL and the E+P+LUT group would however be expected to be associated with a lower MFO, and so it is unlikely carbohydrate intake is influencing the findings. To my knowledge there are no human studies that have directly investigated the effects of progesterone administration in isolation on substrate oxidation during rest or exercise. This perhaps reflects the historically lower prevalence of PROGEST
type contraception’s, with E+P more commonly prescribed. From studies in rodents however, showing oestrogen to enhance and progesterone diminish the maximal activity of key lipid oxidising enzymes and transcription factors that upregulate lipid oxidation (Campbell and Febbraio 2001; Campbell et al. 2003), our positive association of PROGEST and MFO that did not differ to the relationship of E+P with MFO, is somewhat surprising.
The human data to support or refute our positive association between lipid oxidation and PROGEST contraceptive use is limited. D’ on et al (D'Eon et al. 2002) pharmacologically induced three tightly controlled hormonal environments representing; baseline (low oestrogen and low progesterone), oestrogen only (high oestrogen, low progesterone), and high oestrogen high progesterone to mimic the early follicular, late follicular and mid luteal phases, respectively. During exercise at 60% O2max, greater plasma NEFA concentrations and greater rates of fat oxidation were reported in the high oestrogen condition (0.30 0.04g/min) than either the low E+P (0.2 0.04g/min) or the high E+P condition (0.2 0.3g/min). Whilst this is in agreement with the suggestion that oestrogen promotes lipid oxidation, it is somewhat contradictory to trials reporting greater rates of lipid oxidation in the luteal phase of the menstrual cycle, when both oestrogen and progesterone would be elevated. Using 6,6-2H labelled glucose, (D'Eon et al. 2002) were also able to attribute the reciprocal reduction in carbohydrate oxidation in the high oestrogen condition to a ~ 32% lower estimated muscle glycogen use (compared to the E+P condition) with a trend for lower plasma glucose use in the high oestrogen condition which would be in agreement with others (Ruby et al. 1997; Carter et al. 2001). However, these effects were not corroborated
in 2 similar studies, with the main distinction being that the 3 divergent hormonal environments were achieved naturally using regularly menstruating women (Horton et al. 2002; Horton et al. 2006). This investigational group saw no effect of oestrogen/progesterone during the different menstrual cycle phases on rates of substrate oxidation, plasma glucose, insulin, glycerol, NEFA, cortisol or catecholamines over a 90min exercise bout at 50% O2max. Thus the independent impact of progesterone alone on substrate metabolism, gene expression and protein content of regulatory sites of lipid metabolism in humans is mixed and do not help clarify our findings.
The results and conclusions drawn from the analysis presented in this chapter must be viewed with caution. The simple approach used to split the menstrual cycle into 2 phases ignores the fluctuations in oestrogen and progesterone within the follicular and luteal phase (Figure 4-4), with oestrogen concentration 5 fold higher in the late follicular (days 10-14) than early follicular (days 0-7). Furthermore, with the substantial inter-individual and intra- cycle variation in hormonal concentration, without measuring hormonal concentration, simply using the calendar approach to determine the phase limits the validity of our results. Indeed, the intra-cycle hormonal variation, even when under “pharmacological control” is substantial and can lead to subjects being outside of expected ranges when quantified (D'Eon et al. 2002; Casazza et al. 2004). Indeed the inconsistency in the literature regarding the impact of either the phase of the menstrual cycle or hormonal contraceptive use on substrate metabolism is quite likely a reflection the large variation in hormone concentrations in typically small underpowered sample sizes (Syrop and Hammond 1987;
Furthermore, as highlighted in a recent review (Stachenfeld and Taylor 2014) many otherwise well controlled studies of substrate metabolism during exercise that compared the effects of a tri-phasic hormonal contraceptive, have incorrectly used the “dummy pill” days to compare users to the early follicular phase of regularly menstruating women. This model incorrectly assumes both endogenous and exogenous sex hormone concentrations are low and comparable (Casazza et al. 2004; Jacobs et al. 2005). However, although the administration of exogenous hormones is low over the 7 day “placebo” period, the endogenous oestrogens are highly variable over this time and so this might not be an appropriate model (Creinin et al. 2002).
Moreover, the approach taken to group contraceptive taking women into just 2 groups (either E+P or PROGEST) despite the differences in doses and types of synthetic oestrogen / progestogen was one of a pragmatism, based on the absence of detailed blood hormonal profiles. Notwithstanding these concerns, the finding of greater rates of lipid oxidation in amenorrhoeic hormonal contraceptive users is interesting and the absence of any human data of the independent effects of progesterone is worthy of follow up in future investigations.