A quote from the book Caffeine and Activation Theory: Effects on Health and Behavior by Barry D. Smith, Uma Gupta, B.S. Gupta
Interactive effects of caffeine, oestrogen and acetylcholine
Arnold et al., (1987) first suggested that an additional confound for female samples is a
possible caffeine-oestrogen interaction. This suggestion was based on the fact that their
female sample, who showed positive caffeine-related performance effects, were in fact tested
only during the menstrual cycle, to standardise hormonal influences. This is a particularly
interesting result, then, in the light of the increased evidence for changes in cognitive
competence as a consequence in oestrogen depletion in older female populations (e.g.
Paganinihill & Henderson, 1994; Williams, 1998; Gibbs & Aggarwal, 1998). If oestrogen depletion
is associated with memory impairment, that young women only show benefits of caffeine at that
point in their cycle when oestrogen levels take a substantive dip is entirely consistent with the view
that, for the most part, healthy adults are working with optimized systems whose efficiency, in
terms of cognitive processes at least, can not be boosted significantly by stimulants.
In fact, such potential interactions on memory measures between oestrogen and caffeine do
not appear to have been systematically considered in the published literature. As summarised
earlier, there appear to be no age x caffeine interactions on subjective assessments of mood
change, despite a main effect of caffeine on mood. Many of these studies, however, were run
on male only samples; where mixed sex samples were used, sex differences were not
anticipated, and sex was rarely incorporated as a factor in the analyses. Similarly, on
measures of memory, sex differences have rarely been systematically explored as a possible
source of differential effects. Rees et al., (1999) tested a mixed older age sample of 24 males
and 24 females, and reported no significant effects of caffeine on digit span (a measure of
working memory) or on immediate or delayed free recall of a 20 -item word list. Rogers &
Derncourt, (1998) tested 11 women and 7 male volunteers aged between 55 and 84 years on
an immediate free recall task; there were no significant effects of caffeine on recall scores. Yu
et al., (1991) tested 20 elderly volunteers on a paired associate learning task. They did not
specify the sex ratio of their sample, but again found no significant effects of caffeine on
cognitive performance levels. It remains possible that these null results may mask sex
differences in caffeine-related performance effects, and the interesting possibility that women
may be substantially more sensitive to caffeine-induced performance benefits during the
menstrual cycle.
Oestrogen-related effects on memory have been associated with the modulatory effects of this
hormone on the cholinergic neurotransmitter system, this being the neurotransmitter system
most closely associated with effective acquisition and storage of new memories (see Everitt
and Robbins, 1997, for an excellent review). One study, Riedel, et al. (1995) explored the
pharmacological basis of caffeine's cognitive-enhancing effects by testing its ability to reverse
the robust impairments induced by the drug scopolamine. Scopolamine is a cholinergic
antagonist which produces transient dose dependent impairments in both memory and
attention when administered to healthy volunteers. It is commonly used as a model of ageand
dementia-related changes in cognitive performance, since changes in efficiency of the
cholinergic system are robustly associated with both age- and dementia- related cognitive
decline. (Riedel, et al. 1995) reported that moderate doses of caffeine (250 mg) reversed the
scopolamine-induced deficit in immediate and delayed recall of unrelated word lists, while
having no effect on memory scanning times, visual search, simple, choice or incompatible
choice RT measures. In a control condition, co-administration of nicotine (a cholinergic
agonist) with scopolamine reversed the scopolamine-induced deficits in incompatible choice
RT and in immediate but not delayed recall. The authors conclude that the cognitive
enhancing properties of caffeine and nicotine are therefore distinct, and that while nicotine
may affect primarily speeded and sustained attentional processes, caffeine's effects appear to
be more memorial than attentional in nature. They conclude that caffeine may have
cognitive-enhancing effects via its cholinergic connections, and not solely via its adenosine
antagonism, as has generally been assumed (Yu et al., 1991; Nehlig, Daval, & Debry, 1992).
This could be the reason why more women than men suffer from PET and why hormonal contraception worsens PET.
Estrogen, which was promoted so intensively as prevention or treatment for Alzheimer's disease, was finally shown to contribute to its development. One of the characteristic effects of estrogen is to increase the level of growth hormone in the blood. This is just one of many ways that estrogen is associated with cholinergic activation. During pregnancy, it's important for the uterus not to contract. Cholinergic stimulation causes it to contract; too much estrogen activates that system, and causes miscarriage if it's excessive. An important function of progesterone is to keep the uterus relaxed during pregnancy. In the uterus, and in many other systems, progesterone increases the activity of cholinesterase, removing the acetylcholine which, under the influence of estrogen, would cause the uterus to contract.
Progesterone is being used to treat brain injuries, very successfully. It protects against inflammation, and in an early study, compared to placebo, lowered mortality by more than half. It's instructive to consider its anticholinergic role in the uterus, in relation to its brain protective effects. When the brain is poisoned by an organophosphate insecticide, which lowers the activity of cholinesterase, seizures are likely to occur, and treatment with progesterone can prevent those seizures, reversing the inhibition of the enzyme (and increasing the activity of cholinesterase in rats that weren't poisoned) (Joshi, et al., 2010). Similar effects of progesterone on cholinesterase occur in menstrually cycling women (Fairbrother, et al., 1989), implying that this is a general function of progesterone, not just something to protect pregnancy. Estrogen, with similar generality, decreases the activity of cholinesterase. DHEA, like progesterone, increases the activity of cholinesterase, and is brain protective (Aly, et al., 2011).
So progesterone, pregnenolone (as a precursor to progesterone) and DHEA could ameliorate PET.
