This is a case report with tentative conclusions and speculative mechanisms of action. The observed outcome may prove to be transient or to have a different cause. The oral estradiol may have been one factor around several. The mechanism of action is plausible and fits with documented and understood principles, but put together in a slightly unusual way. There are other plausible mechanisms of action, which are a mess because the liver and first-pass metabolism of estrogens contain multitudes. Do not use anything here to make clinical decisions, but perhaps it may spark useful clinical questions.
The patient is a 45-year-old woman who is on a full replacement dose of estradiol (hereafter E2) taken orally. She has been on a well-formulated ketogenic diet for some time, and has experience being on ketogenic diets in the past. Her adherence to the ketogenic diet is confirmed with extensive logging. She is following a ketogenic diet with the intention of losing weight, and is losing weight. Her presenting concern is being hypoketotic, i.e. showing serum levels of betahydroxybutyrate (BHB) as measured through capillary blood of less than 0.5mmol/L despite adherence. She occasionally is ketotic (BHB greater than or equal to 0.5mmol/L), but surprisingly reports that she is more likely to be ketotic when fed than when fasted, and that she almost always wakes up hypoketotic.
The patient's hypothesis was that something was inhibiting lipolysis, which could have been checked by examining BHB and NEFA (free fatty acids) at the same time, however this testing was not performed. If lipolysis were impaired but ketogenesis were intact, we would expect to see low NEFA and consequently low BHB. We could also see defects in or downregulation of BDH1 causing a deranged AcAc:BHB ratio, with higher levels of acetoacetate (AcAc) in proportion to BHB, but this also was not tested. The patient additionally queried cortisol driving gluconeogenesis in a diurnal pattern, disrupting ketogenesis, and elevated insulin. No gross cortisol elevation was observed, however elevated fasting insulin was observed. Along with elevated fasting insulin, extremely low IGF-1 (z-score -2.5, if I recall correctly) was observed.
