(I've made the reference numbers in the quotes link directly to the papers.)
Females have larger prolactin response than males
The clearest connection of prolactin response findings to the sex bias in ME/CFS comes from observations that females tend to have larger prolactin responses to various neuroendocrine probes than males. For example, healthy females have a larger prolactin response to buspirone [
28,
35]. Similar sex differences in prolactin response magnitude have been observed after administration of d-fenfluramine [
106], thyrotropin-releasing hormone (TRH) [
107], phenothiazine [
108], and possibly chlorpromazine [
109].
Apart from references 35 (baseline difference not reported) and 108 (non-significant difference), all the references above found higher baseline prolactin in females.
Prolactin response varies through menstrual cycle
O’Keane et al. observed that while baseline prolactin levels in healthy females stayed relatively steady throughout the menstrual cycle, prolactin response to d-fenfluramine was highest at mid-cycle, followed by the luteal, then follicular phase, which mirrored the differing amounts of circulating estradiol measured at different phases [
110]. Prolactin response to buspirone in females was found to be larger during the luteal phase than during the follicular phase or at mid-cycle [
35]. Prolactin response to TRH may be somewhat larger during the
follicular [periovulatory] phase [
111], though findings are inconsistent [
112].
(Note that I wrote follicular phase for TRH response, but
@EndME notified me that was incorrect and should say "periovulatory". I'll fix in a future version. [Edit: The reason was I mixed up periovulatory and preovulatory.])
For 110 and 111, baseline prolactin did not differ between menstrual phases. 35 didn't report baseline prolactin levels in females. For 112, quoted below, there might have been a couple dips in prolactin, after menses and after ovulation.
No difference was observed between basal PRL concentrations during the proliferative and secretory phases of the menstrual cycle although there was a consistent dip after menses and immediately after ovulation.
[On smaller subset of women tested every day] While the standard errors were too wide to make the values statistically significant, again prolactin appears to decline soon after menses and for a second time just beyond mid-cycle.
Other studies: For
Bäckström 1982, it looks like prolactin was lowest at early-mid luteal phase.
Franchimont 1976: Lowest during follicular phase.
However, for each of the women it was confirmed that the mean levels of prolactin during the ovulatory phase were always greater than those during the follicular phase and the mean level during the luteal phase was greater than that of the follicular phase in twelve of fourteen cases and lower than that in the ovulatory phase in ten of fourteen. For the whole group these differences were highly statistically significant.
Tanner 2011: Lowest during follicular phase.
Within premenopausal women, the prolactin median and upper limits were significantly higher in ovulatory phase compared to follicular/non-cycling and luteal phases and in luteal phase compared to follicular/non-cycling phase.
Reference 111 says findings from studies have been inconsistent:
a cyclical pattern of serum prolactin, similar to that of endogenous oestrogens, has been reported during the normal menstrual cycle (Robyn et al., 1973), but this is questioned by other authors (Jaffe et al., 1973; McNejlly & Chard, 1974; Fournier et al., 1974).
So it's not consistent, but some studies found variation in baseline prolactin throughout the menstrual cycle. Though it's interesting that in the study of prolactin response to d-fenfluramine at different phases, baseline prolactin did not differ while prolactin response to the drug did.
Direct effect of estradiol on prolactin response
TRH-induced prolactin response was seen to be substantially larger in females taking a short course of exogenous estradiol, as well as after subsequent short-term combined contraceptive use, but not in those taking long-term combined contraceptives [
111]. In male rats, a prolactin response to TRH was only detectable when the rats had previously been administered estradiol [
113]. Exogenous estradiol causes an increased prolactin response to ghrelin in postmenopausal women [
114]. Administration of estradiol to ovariectomized rats resulted in substantially larger prolactin responses to the dopamine antagonist, thioproperazine [
115].
For 111, in females taking sequential contraceptives (16 days estradiol, then 7 days estradiol+progestogen), prolactin response to TRH was higher than in normally cycling females at the end of both phases of treatment, but baseline prolactin was only higher during the estradiol-only phase.
However, long term combined estradiol+progestogen that did not follow an estradiol-only phase did not appear to cause increased prolactin response.
For 113, where prolactin response to TRH was only detectable in male rats after estradiol treatment, the paper doesn't give the baseline prolactin for the rats that weren't treated. There were two other experiments in the study, and it seems like in one, estradiol increased baseline prolactin, while in the other, it did not. Maybe it's related to dose or specific form of estradiol (one study used 25 mcg 17B-estradiol, the other used 50 mcg estradiol-benzoate).
For 114, where estradiol valerate increased prolactin response to ghrelin in post-menopausal females, baseline prolactin was also increased.
For 115, where estradiol increased prolactin response to thioproperazine, they don't describe baseline prolactin and it's hard to figure out the values from the plot.
