The buspirone challenge test clearly distinguishes ME/CFS patients from healthy controls: why is it not being developed and deployed?

Ravn said:
What would a bare bones study design look like if the goal was just to learn enough to know whether this line of research is worth pursuing further? And if it's a yes, what would an ideal study look like, one that could give solid answers to all the questions raised in this thread?
Click to expand...
Good discussion topic.

I think it's clear that the research is worth pursuing further in some way. Something is happening that led to very consistent findings for buspirone, and I think it's important that this is explored until we figure out what it is. Even if it's something less "interesting", like maybe the time that ME/CFS participants woke up was different compared to the controls, it'd still be important to know so that future studies control for that. But I think there's a good chance this is a lot more interesting than that, potentially highlighting a specific hormonal or neural pathway involved in ME/CFS.

For an ideal initial study, these are just some quick thoughts that could be improved upon, and might have to be adjusted to fit with resource availability:
  • It'd be a study of post-infectious ME/CFS with PEM, excluding cases with comorbid depression or other significant health issues. Controls would be healthy and sedentary, and matched for age, weight, and sex.

  • In the same study, on different days (randomized per individual), test the prolactin response to: placebo, buspirone, d-fenfluramine, thyrotropin-releasing hormone, and domperidone.

  • Measure plasma levels of the drugs and their metabolites to check for differences in drug metabolism.

  • Analyze males and females separately.

  • Probably too speculative at this stage, but possibly test prolactin response after participants already were taking an estrogen receptor blocker or an aromatase inhibitor (inhibits conversion of androgens to estrogens), to see if the difference between groups is made smaller.
Possibly also a PET scan study of the pituitary or hypothalamus, looking at markers such as the D2 dopamine receptor, which may be altered in abnormally sensitive lactotrophs.
 
Last edited:
I think the buspirone/prolactin response finding is past the point of replicating to make sure it's not a false positive. The replication has been done. At least 3 or 4 different study teams have seen the same (Behan/Dinan et al., Richardson et al., Sharpe/Cowen et al., and maybe the Italian team of Racciatti et al. but they didn't give much detail.).

We're at the point where if someone does a new buspirone/prolactin response study and doesn't find a difference, it'd raise new questions rather than just suggesting a problem in the original studies. There'd still be the open question of why it happened in the earlier studies.

So I think "increased prolactin response to buspirone" can potentially be considered one of the few known "facts" about ME/CFS. Possibly it deserves a place in the fact sheets.
 
Last edited:
Kitty said:
If we expect to find it does replicate, perhaps we should think about what happens then. Maybe that’s just moving forward to imaging - but maybe there other questions too that could be explored?
Click to expand...
Yes, I think the most straightforward thing is just testing other probes. If dopamine drugs and TRH both lead to an altered prolactin response, then it suggests that the prolactin-secreting cells are abnormally sensitive to any stimuli. If neither causes altered response, the abnormality may be further upstream, for example in the hypothalamus.

I don't know much about what imaging methods are feasible. It might be good to get advice from someone with experience in PET.

Looking for something in cerebrospinal fluid might be good, but I don't know what exactly to look for. Maybe an abnormality in sex hormone levels, but I don't have high hopes for that, since nothing about sex hormones in blood seems to be consistently abnormal in ME/CFS.

An endocrinology expert might be good to consult for big picture questions about where to go from here.
 
I wrote up a rough draft of a quick outline of what is known about prolactin response (well, what I know about it), as it relates to ME/CFS. I wanted to make something to get across the important details to someone who doesn't know anything about it, and hopefully get them interested in exploring further.

It could probably be improved in various ways, for example by including other mechanistic prolactin-related findings that may be relevant. And the structure/style could probably be improved. So I welcome any suggestions to make this better. Though no promises on when I'll be able to work on it further.

Feel free to share this text if you'd like.

Introduction​

Abnormal prolactin response is a consistent and replicated finding in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but the implications of this finding have only been minimally explored. Further research into this phenomenon could potentially uncover hormonal, neural, or other abnormalities which help illuminate the pathophysiology of ME/CFS.

Prolactin response to buspirone​

Strikingly, every single study that has tested prolactin response to buspirone in ME/CFS has reported a significantly larger increase of prolactin in the patient group.

The first study of prolactin response in ME/CFS came from Bakheit et al. in 1992. The findings from this study were reported both in Bakheit’s thesis (1), as well as in a peer-reviewed paper (2). The authors were studying postviral fatigue syndrome, which, as indicated in the thesis, also required that the fatigue was made worse by exercise and which did not improve after bed rest. The study found that the patient group had a larger increase in plasma prolactin after administration of the anti-anxiety drug, buspirone, when compared to healthy controls or individuals with depression. This was seen in patients of both sexes. Figure 1 illustrates the study results, using the individual level data provided in Bakheit’s thesis. Notably, and as seen in virtually all other studies of this topic, baseline prolactin was not significantly different from controls.

Figure 1:
1787182330090.webp

Further evidence was provided in a study from John Richardson in 1995, in which patients who fulfilled the CDC or Oxford criteria for ME/CFS were compared to family members without ME/CFS. Based on the ratio of prolactin after to before administration, the prolactin response to buspirone (50 mg, orally) in the patients was, on average, over 3 times higher than that of the controls. The study also found a correlation between prolactin response in patients and their degree of sleep disturbance (3). A later study from Richardson and Costa again suggested very high prolactin responses to buspirone (50 mg, orally) in ME/CFS patients, however this study did not include a control group, and it is unclear if high prolactin response was a criteria for inclusion in the study (4).

In 1996, Sharpe et al. reported increased prolactin response to buspirone (0.5 mg/kg orally, up to 45 mg) in patients fulfilling Oxford criteria for ME/CFS, but without depression. Plasma levels of buspirone and its metabolite, 1-(2-Pyrimidinyl)piperazine (1-PP), were not significantly different between groups, suggesting that the abnormal prolactin response was not due to differences in drug metabolism. The growth hormone response to buspirone did not significantly differ between groups (5).

Also in 1996, Tahir Majeed, under the supervision of Peter O. Behan, published a thesis testing hormonal responses to a variety of drug challenges. The study cohort included patients who fulfilled Fukuda and Oxford criteria, and who had fatigue which worsened after exercise. The control group was made up of healthy, sex-matched volunteers. The ME/CFS patients exhibited a significantly larger increase in prolactin after administration of buspirone (60 mg, orally). Further findings in ME/CFS patients included a normal growth hormone response to bromocriptine and baclofen, a larger growth hormone response to pyridostigmine, smaller growth hormone responses to desipramine and dexamethasone, and a smaller adrenocorticotropic hormone (ACTH) response to ipsapirone (6).

Another 1996 paper, authored by Behan, reported increased prolactin response to buspirone (60 mg, orally) in individuals with an ME/CFS-like illness (including fatigue worsened by exercise, myalgia, and with onset after a flu-like illness) and who had previously been exposed to organophosphates (7). Note that while the paper indicates that the study included 10 male healthy controls, later court testimony from Behan in an organophosphate trial indicated that there was a mistake in the paper, and the actual control group was made up of 15 males and 15 females (8). However, as Behan noted in court, the inclusion of females in the control group would not be expected to lead to spurious differences between groups, and would instead more likely have led to a smaller difference, as females have larger prolactin responses to buspirone than males (9).

Additionally, two papers from Racciatti et al. suggest that they have also seen increased prolactin response to buspirone in ME/CFS, however one paper does not include a healthy control group (10), and the other is an abstract which we have not been able to access (11), and with the findings briefly mentioned in a later review (12).

Finally, a 2001 case report included details of a female patient with ME/CFS, according to Oxford criteria, who exhibited an abnormally large prolactin response to buspirone (30 mg, orally). After symptom improvement, which followed a graded exercise therapy intervention, the prolactin response was measured again on two occasions, and was found to be normal both times (13).

Prolactin response to other challenges​

Additional evidence related to prolactin response is provided by studies which tested fenfluramine, exercise, and insulin-induced hypoglycemia in ME/CFS patients.

In 1995, Bearn et al. tested the prolactin response in ME/CFS to both insulin-induced hypoglycemia and to the serotonin drug, d-fenfluramine (30 mg, orally). The prolactin response to d-fenfluramine did not significantly differ between groups. However, after administration of insulin, prolactin increased significantly less in the ME/CFS group (14).

Ottenweller et al. tested a maximal exercise challenge using a treadmill, and reported a significantly smaller increase of prolactin in ME/CFS patients (15).

Yatham et al. published a study of response to racemic fenfluramine in ME/CFS. The groups did not significantly differ in the magnitude of prolactin response (16).

Two later studies from separate groups tested the prolactin response to d-fenfluramine, and both of these studies found increased prolactin response in ME/CFS patients (17,18).

A 2001 study did not find a significant difference between ME/CFS patients and controls for prolactin response to the 5-HT2c receptor agonist, m-chlorophenylpiperazine (mCPP) (19).

Finally, a 2010 study reported a significantly increased prolactin response to tryptophan, but only in females with ME/CFS, and not in females with ME/CFS+fibromyalgia, or in either of the male patient groups (20).

Other conditions​

Abnormally increased prolactin response has been reported in several other conditions, such as migraine, irritable bowel syndrome (IBS), hormonal disorders, and gonadal disorders.

Migraine​

Abnormal prolactin response has been reported several times in migraine. Migraine patients may have an abnormally long return to baseline prolactin after administration of reserpine (21) or benserazide (22). Studies have reported abnormally increased prolactin response in migraine patients to the D2 antagonists sulpiride (22,23) and domperidone (23). An abnormally large decrease in prolactin has been noted after administration of L-deprenyl (24). In contrast, an abnormally small decrease was reported after administration of the dopamine reuptake inhibitor, nomifensine (23) and the dopamine precursor, L-DOPA (25). Cassidy et al. have published two studies showing increased prolactin response to buspirone in migraine (26,27). The prolactin response to mCPP was larger in a study that used a dosage of 0.5 mg/kg (28), but not in a study that used a smaller 0.25 mg/kg dosage of the drug (29). A larger prolactin response was noted after racemic fenfluramine (30).

A blunted prolactin response in migraine was seen after administration of 50 μg and 200 ug doses of thyrotropin-releasing hormone (TRH) (31). A different study found an increased prolactin response to TRH during migraine attacks (32). Awaki et al. found an increased prolactin response after administration of a cocktail which included TRH, gonadotropin-releasing hormone (GnRH), and insulin (33).

However, other studies of migraine did not find significant differences between groups, including after administration of domperidone (34), fenfluramine (22), lisuride (23), metaclopromide (35,36), morphine (37), piribedil (38), and sumatriptan (39).

Other disorders​

Increased prolactin response has been reported in only a small number of other conditions. The following paragraphs include examples of these, but this should not be considered exhaustive.

Several studies from the same research group have reported abnormally increased prolactin response to buspirone in IBS (40), and in non-ulcer dyspepsia (41–44).

An increased prolactin response was seen in primary testicular failure after administration of TRH (45) and metoclopramide (46). Prolactin response to TRH was also significantly larger in females with primary ovarian failure (47). An increased prolactin response to TRH was also reported in patients with polyendocrine metabolic ovarian syndrome (PMOS) (48).

Connection to sex hormones?​

As females are more likely than males to have ME/CFS (49), it may be useful to consider whether sex hormones influence prolactin response in a way that may explain the observations of increased prolactin response to buspirone and d-fenfluramine in ME/CFS.

Females have a higher prolactin response to buspirone than males (9). Similar sex differences have been observed after administration of thyrotropin-releasing hormone (TRH), phenothiazine, and possibly chlorpromazine (50–52).

Prolactin response to various drugs differs throughout the menstrual cycle. While baseline prolactin levels stayed relatively steady throughout the menstrual cycle, it was observed that prolactin response to d-fenfluramine was highest at mid-cycle, followed by luteal, then follicular phases. This mirrored the differing amounts of circulating estradiol present across the menstrual cycle (53). Prolactin response to buspirone in females was found to be larger during the luteal phase than during the follicular phase or mid-cycle (9). Prolactin response to TRH may be somewhat larger during the follicular phase (54), but findings are inconsistent (55).

Exogenous estradiol can modulate prolactin response. TRH-induced prolactin response is 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 (54). In male rats, a prolactin response to TRH was only detectable when the rats had previously been administered estradiol (56). Exogenous estradiol also causes an increased prolactin response to ghrelin in postmenopausal women (57).

Dinan et al. also reported that females had more symptoms of sedation in response to buspirone during the luteal phase than at other timepoints, when prolactin response was also found to be highest (9). This may relate to the finding that ME/CFS patients appear to have more side effects, such as fatigue and nausea, to buspirone, when compared to healthy controls (2,3).

Similar to the sex bias in ME/CFS (49), migraine appears to be more prevalent in females than males (58,59). As noted in the “Migraine” section, this is another health condition in which several studies have reported altered prolactin response to various neuroendocrine challenges.

Note that a hypothesis which ties estradiol to the abnormal prolactin response seen in ME/CFS would need to be explained by a mechanism which is independent of blood estradiol levels, as studies have shown that blood levels of this hormone do not appear to be significantly increased in ME/CFS (60–63).

One could test the estradiol hypothesis by measuring the prolactin response to buspirone in ME/CFS and healthy controls both before and after administration of estrogen receptor antagonists or aromatase inhibitors. If the difference between groups were found to be diminished after blocking the influence of estrogens, this would provide evidence of sex hormone involvement in the abnormal prolactin response. It may be necessary to prescribe an extended course of these drugs prior to the second test, as estrogens are capable of inducing long term changes in prolactin-secreting cells, for example through genomic regulation or by increasing the number of prolactin-secreting cells, as reviewed in (64).

Where to go from here?​

The implications of abnormal prolactin response in ME/CFS are far from clear. While several of the ME/CFS studies cited above suggested abnormalities in serotonin receptors, the evidence is far from conclusive. A PET study of 5-HT receptors found the opposite of what the authors had expected based on prolactin findings (65). Additionally, while abnormal prolactin response could involve the receptors directly affected by the neuroendocrine probes, it could also be highlighting any of a number of possible downstream abnormalities, such as altered dopaminergic tone or sensitized prolactin-secreting cells. For example, serotonin drugs may exert at least part of their influence on prolactin through altering hypothalamic dopamine release (66).

What is clear is the importance of further exploration of these findings. ME/CFS is a condition with notoriously few well-replicated, specific findings. Some of the few potential other replicated findings include female sex bias (49) and potentially decreased NK cell cytotoxicity (67). With so few clues into the underlying pathophysiology, it is important to thoroughly investigate every possible avenue available.

A straightforward next step would be testing prolactin response to other neuroendocrine probes. If dopaminergic drugs and TRH both lead to abnormal responses, this would suggest abnormally sensitized lactotrophs, as dopamine and TRH both directly affect lactotrophs (68). If neither demonstrates altered responses, but responses to serotonin-related drugs are altered, this may indicate upstream abnormalities.

One ME/CFS study has reported increased levels of alpha-melanocyte-stimulating hormone (ɑ-MSH), albeit with substantial overlap between groups (69). ɑ-MSH is known to alter prolactin response, both in vitro and in vivo (70–73). Thus, it may be valuable to attempt to replicate increased ɑ-MSH in ME/CFS, and to test for a correlation to prolactin response in these patients.

In a study of increased prolactin response to TRH in primary ovarian failure, the authors speculated that the patients might have increased conversion of androgens to estrogens within the hypothalamus (74). This was not based on direct evidence, so should be interpreted cautiously, but it may be worth examining this possibility.

It may be possible to explore this finding further using PET scans, for example by measuring DRD2 binding in the pituitary gland. If the ME/CFS abnormality does relate to sex hormones, then DRD2 levels may be altered, as is seen when estradiol is applied to anterior pituitary cells in vitro (74).

Edit: Added missing image.

Edit: Updated version in post #426.
 
Last edited:
I couldn't include the references in the last post because it went over the character limit, so here they are:
1.Bakheit AMO. Hypothalamic Dysfunction and Neutrotransmitter Abnormalities in the Postviral Fatigue Syndrome [MD] [Internet]. [Ann Arbor :]: ProQuest Dissertations & Theses,; 1992 [cited 2026 Jul 21]. Available from: https://theses.gla.ac.uk/75589/

2.Bakheit AM, Behan PO, Dinan TG, Gray CE, O’Keane V. Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. BMJ. 1992 Apr 18;304(6833):1010–2. PubMed PMID: 1586780; PubMed Central PMCID: PMC1881733.

3.Richardson J. Disturbance of Hypothalamic Function and Evidence for Persistent Enteroviral Infection in Patients with Chronic Fatigue Syndrome. Journal Of Chronic Fatigue Syndrome. 1995 Jan 1;1(2):59–66. doi:10.1300/J092v01n02_05

4.Richardson J, Costa DC. Relationship Between SPECT Scans and Buspirone Tests in Patients with ME/CFS. Journal of Chronic Fatigue Syndrome. 1998 Jan;4(3):23–38. doi:10.1300/J092v04n03_04

5.Sharpe M, Clements A, Hawton K, Young AH, Sargent P, Cowen PJ. Increased prolactin response to buspirone in chronic fatigue syndrome. Journal of Affective Disorders. 1996 Nov 4;41(1):71–6. doi:10.1016/0165-0327(96)00075-4

6.Majeed T. Neuroendocrine Alterations in Chronic Fatigue Syndrome [PhD] [Internet]. [Ann Arbor :]: ProQuest Dissertations & Theses,; 1996 [cited 2026 May 15]. Available from: https://theses.gla.ac.uk/75796/

7.Behan PO. Chronic Fatigue Syndrome as a Delayed Reaction to Chronic Low-dose Organophosphate Exposure. Journal of Nutritional & Environmental Medicine. 1996 Jan 1;6(4):341–50. doi:10.3109/13590849609007262

8.The Herald [Internet]. 1997 [cited 2026 Aug 7]. Professor’s future in doubt. University inquiry blames academic’s sloppy preparation for court fiasco. Available from: https://www.heraldscotland.com/news...cademics-sloppy-preparation-for-court-fiasco/

9.Dinan TG, Barry S, Yatham LN, Mobayed M, O’Hanlon M. The reproducibility of the prolactin response to buspirone: relationship to the menstrual cycle. Int Clin Psychopharmacol. 1990 Apr;5(2):119–23. doi:10.1097/00004850-199004000-00006 PubMed PMID: 2380543; PubMed Central PMCID: 2380543.

10.Racciatti D, Vecchiet J, Ceccomancini A, Ricci F, Pizzigallo E. Chronic fatigue syndrome following a toxic exposure. Science of The Total Environment. 2001 Apr 10;Environment, Human Health and Immune System (selected papers from International Symposium on Occupational and Environmental Allergy and Immune Diseases,Chieti(Italy),April 27-30,1999270(1):27–31. doi:10.1016/S0048-9697(00)00777-4

11.Racciatti D, Barberio A, Pizzigallo E, others. Neuroendocrine perspective of chronic fatigue syndrome. Journal of Musculoske Pain. 1998;6(S2):152.

12.Racciatti D, Barberio A, Vecchiet J, Pizzigallo E. Clinical and Pathogenetical Characterization of 238 Patients of a Chronic Fatigue Syndrome Italian Center. Journal Of Chronic Fatigue Syndrome. 1999 Jan 1;5(3–4):61–70. doi:10.1300/J092v05n03_05

13.Sharma A, Oyebode F, Kendall MJ, Jones DA. Recovery from chronic fatigue syndrome associated with changes in neuroendocrine function. J R Soc Med. 2001 Jan;94(1):26–7. doi:10.1177/014107680109400107

14.Bearn J, Allain T, Coskeran P, Munro N, Butler J, McGregor A, et al. Neuroendocrine responses to d-fenfluramine and insulin-induced hypoglycemia in chronic fatigue syndrome. Biological Psychiatry. 1995 Feb;37(4):245–52. doi:10.1016/0006-3223(94)00121-I

15.Ottenweller JE, Sisto SA, McCarty RC, Natelson BH. Hormonal Responses to Exercise in Chronic Fatigue Syndrome. Neuropsychobiology. 2001;43(1):34–41. doi:10.1159/000054863

16.Yatham LN, Morehouse RL, Chisholm BT, Haase DA, MacDonald DD, Marrie TJ. Neuroendocrine assessment of serotonin (5-HT) function in chronic fatigue syndrome. Can J Psychiatry. 1995 Mar;40(2):93–6. doi:10.1177/070674379504000207 PubMed PMID: 7788624.

17.Cleare AJ, Bearn J, Allain T, McGregor A, Wessely S, Murray RM, et al. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. Journal of Affective Disorders. 1995 Aug 18;34(4):283–9. doi:10.1016/0165-0327(95)00026-J

18.Sharpe M, Hawton K, Clements A, Cowen P. Increased brain serotonin function in men with chronic fatigue syndrome. BMJ. 1997 Jul 19;315(7101):164–5. doi:10.1136/bmj.315.7101.164

19.Vassallo CM, Feldman E, Peto T, Castell L, Sharpley AL, Cowen PJ. Decreased tryptophan availability but normal post-synaptic 5-HT2c receptor sensitivity in chronic fatigue syndrome. Psychol Med. 2001 May;31(4):585–91. doi:10.1017/S0033291701003580

20.Weaver SA, Janal MN, Aktan N, Ottenweller JE, Natelson BH. Sex Differences in Plasma Prolactin Response to Tryptophan in Chronic Fatigue Syndrome Patients With and Without Comorbid Fibromyalgia. Journal of Women’s Health. 2010 May 1;19(5):951–8. doi:10.1089/jwh.2009.1697

21.Nappi G, Savoldi F, Bono G, Martignoni E. Reserpine - Headache and PRL Release in Migraine. Headache: The Journal of Head and Face Pain. 1979;19(5):273–7. doi:10.1111/j.1526-4610.1979.hed1905273.x

22.Polleri A, Nappi G, Masturzo P, Martignoni E, Murialdo G, Bono G, et al. Neuroendocrine approach to headache. Advances in neurology. 1982;33:173–82. Available from: https://archive.org/details/headachephysiopa0000unse/page/172/mode/2up

23.Murialdo G, Martignoni E, Maria AD, Bonura ML, Sances G, Bono G, et al. Changes in the Dopaminergic Control of Prolactin Secretion and in Ovarian Steroids in Migraine. Cephalalgia. 1986 Mar 1;6(1):43–9. doi:10.1046/j.1468-2982.1986.0601043.x

24.Calabresi P, Silvestrini M, Stratta F, Cupini L, Argiro G, Atzei G, et al. L-Deprenyl test in migraine: neuroendocrinological aspects. Cephalalgia. 1993;13(6):406–9. doi:10.1046/j.1468-2982.1993.1306406.x

25.Nattero G, Corno M, Savi L, Isaia G c., Priolo C, Mussetta M. Prolactin and Migraine: Effect of L-Dopa on Plasma Prolactin Levels in Migraineurs and Normals. Headache: The Journal of Head and Face Pain. 1986;26(1):9–12. doi:10.1111/j.1526-4610.1986.hed2601009.x

26.Cassidy EM, Tomkins E, Dinan T, Hardiman O, O’Keane V. Central 5-HT receptor hypersensitivity in migraine without aura. Cephalalgia. 2003 Feb;23(1):29–34. doi:10.1046/j.1468-2982.2003.00441.x PubMed PMID: 12534577.

27.Cassidy EM, Tomkins E, Sharifi N, Dinan T, Hardiman O, O’Keane V. Differing central amine receptor sensitivity in different migraine subtypes? A neuroendocrine study using buspirone. Pain. 2003 Feb;101(3):283–90. doi:10.1016/S0304-3959(02)00335-4 PubMed PMID: 12583871.

28.Leone M, Attanasio A, Croci D, Ferraris A, D’Amico D, Grazzi L, et al. 5-HT1A receptor hypersensitivity in migraine is suggested by the m-chlorophenylpiperazine test. Neuroreport. 1998 Aug 3;9(11):2605–8. doi:10.1097/00001756-199808030-00033 PubMed PMID: 9721941.

29.Gordon ML, Lipton RB, Brown SL, Nakraseive C, Russell M, Pollack SZ, et al. Headache and Cortisol Responses to M-Chlorophenylpiperazine are Highly Correlated. Cephalalgia. 1993 Dec 1;13(6):400–5. doi:10.1046/j.1468-2982.1993.1306400.x

30.Glover V, Ahmed F, Hussein N, Jarman J, Peatfield R. Central 5-hydroxytryptamine supersensitivity in migraine. In: Migraine: Pharmacology and genetics [Internet]. Chapman & Hall; 1996. p. 117–23. Available from: https://archive.org/details/migrainepharmaco0000unse/page/116/

31.Murialdo G, Masturzo P, Filippi U, De Palma D, Balbi D, Polleri A, et al. Thyroid-Stimulating Hormone and Prolactin Responses to Thyrotropin-Releasing Hormone in Common Migraine. Cephalalgia. 1987 Dec 1;7(4):267–72. doi:10.1046/j.1468-2982.1987.0704267.x

32.Papakostas Y, Daras M, Markianos M, Stefanis C. Increased prolactin response to thyrotropin releasing hormone during migraine attacks. Journal of Neurology, Neurosurgery & Psychiatry. 1987 Jul 1;50(7):927–8. doi:10.1136/jnnp.50.7.927 PubMed PMID: 3114432.

33.Awaki E, Takeshima T, Takahashi K. A Neuroendocrinological Study in Female Migraineurs: Prolactin and Thyroid Stimulating Hormone Responses. Cephalalgia. 1989 Sep 1;9(3):187–93. doi:10.1046/j.1468-2982.1989.0903187.x

34.Capellan JIL, Dacosta CV, Garcia JMG, Servan PR, Cermeño JCA. Tuberoinfundibular Dopaminergic Tonus in Common Migraine. Headache: The Journal of Head and Face Pain. 1990;30(5):282–4. doi:10.1111/j.1526-4610.1990.hed3005282.x

35.Klimek A. Growth Hormone and Prolactin Release in Migraine Patients. In: Pfaffenrath V, Lundberg PO, Sjaastad O, editors. Updating in Headache. Berlin, Heidelberg: Springer; 1985. p. 241–8. doi:10.1007/978-3-642-88581-5_40

36.Klimek A. Metoclopramide Tests in Headache Patients. Cephalalgia. 1985 Jul 1;5(3_suppl):354–5. doi:10.1177/03331024850050S3138

37.Bussone G, Boiardi A, Mantia LL, Frediani F, Vescovi A, Parati EA. Long-acting ergot: clinical and neuroendocrinological aspects in migraine patients. Cephalalgia. 1983 Aug 1;3(1_suppl):163–7. doi:10.1177/03331024830030S127

38.Bussone G, Frediani F, Lamperti E, LaMantia L, Vescovi A, Peccarisi C, et al. Piribedil test in migraine: neuroendocrinological aspects. Headache: The Journal of Head and Face Pain. 1986;26(9):482–5. doi:10.1111/j.1526-4610.1986.hed2609482.x

39.Rainero I, Valfrè W, Savi L, Gentile S, Pinessi L, Gianotti L, et al. Neuroendocrine effects of subcutaneous sumatriptan in patients with migraine. J Endocrinol Invest. 2001 May;24(5):310–4. doi:10.1007/BF03343866 PubMed PMID: 11407649.

40.O’Mahony S, Chua ASB, Quigley EMM, Clarke G, Shanahan F, Keeling PWN, et al. Evidence of an enhanced central 5HT response in irritable bowel syndrome and in the rat maternal separation model. Neurogastroenterol Motil. 2008 Jun;20(6):680–8. doi:10.1111/j.1365-2982.2007.01065.x PubMed PMID: 18194152.

41.Chua A, Keating J, Hamilton D, Keeling PW, Dinan TG. Central serotonin receptors and delayed gastric emptying in non-ulcer dyspepsia. BMJ. 1992 Aug 1;305(6848):280–2. doi:10.1136/bmj.305.6848.280 PubMed PMID: 1392859; PubMed Central PMCID: PMC1882744.

42.Dinan TG, Chua AS, Keeling PW. Serotonin and physical illness: focus on non-ulcer dyspepsia. J Psychopharmacol. 1993 Jan;7(1):126–30. doi:10.1177/026988119300700104 PubMed PMID: 22289664.

43.Dinan TG, Mahmud N, Rathore O, Thakore J, Scott LV, Carr E, et al. A double-blind placebo-controlled study of buspirone-stimulated prolactin release in non-ulcer dyspepsia—are central serotoninergic responses enhanced? Alimentary Pharmacology & Therapeutics. 2001;15(10):1613–8. doi:10.1046/j.1365-2036.2001.01090.x

44.Dinan TG, Yatham LN, Barry S, Chua A, Keeling PW. Serotonin supersensitivity: the pathophysiologic basis of non-ulcer dyspepsia? A preliminary report of buspirone/prolactin responses. Scand J Gastroenterol. 1990 May;25(5):541–4. doi:10.3109/00365529009095527 PubMed PMID: 2359983.

45.Spitz IM, Zylber E, Cohen H, Almaliach U, Leroith D. Impaired prolactin response to thyrotropin-releasing hormone in isolated gonadotropin deficiency and exaggerated response in primary testicular failure. J Clin Endocrinol Metab. 1979 Jun;48(6):941–5. doi:10.1210/jcem-48-6-941 PubMed PMID: 109459.

46.Spitz IM, Leroith D, Livshin Y, Zylber-Haran E, Trestian S, Laufer N, et al. Exaggerated Prolactin Response to Thyrotropin-Releasing Hormone and Metoclopramide in Primary Testicular Failure*. Fertility and Sterility. 1980 Dec 1;34(6):573–80. doi:10.1016/S0015-0282(16)45198-8

47.Hochner-Celnikier D, Zylber-Haran E, Shilo S, Palti Z, Spitz IM. Increased prolactin response to thyrotropin-releasing hormone in primary ovarian failure. Obstet Gynecol. 1982 Mar;59(3):280–4. PubMed PMID: 6804899.

48.Szilágyi A, Csermely T, Csaba IF. Increased prolactin response to TRH in polycystic ovary syndrome with low basal prolactin values. Gynecological Endocrinology. 1988 Jan;2(4):313–7. doi:10.3109/09513598809107654

49.Lim EJ, Ahn YC, Jang ES, Lee SW, Lee SH, Son CG. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med. 2020 Feb 24;18(1):100. doi:10.1186/s12967-020-02269-0

50.Buckman MT, Peak GT. Estrogen Potentiation of Phenothiazine-Induced Prolactin Secretion in Man. J Clin Endocrinol Metab. 1973 Dec 1;37(6):977–80. doi:10.1210/jcem-37-6-977

51.Noel GL, Dimond RC, Wartofsky L, Earll JM, Frantz AG. Studies of Prolactin and TSH Secretion by Continuous Infusion of Small Amounts of Thyrotropin-Releasing Hormone (TRH). J Clin Endocrinol Metab. 1974 Jul 1;39(1):6–17. doi:10.1210/jcem-39-1-6

52.Schwinn G, von zur Mühlen A, Köbberling J, Halves E, Wenzel KW, Meinhold H. Plasma prolactin levels after TRH and chlorpromazine in normal subjects and patients with impaired pituitary function. Acta Endocrinol (Copenh). 1975 Aug;79(4):663–76. doi:10.1530/acta.0.0790663 PubMed PMID: 808064.

53.O’Keane V, O’Hanlon M, Webb M, Dinan T. d-fenfluramine/prolactin response throughout the menstrual cycle: evidence for an oestrogen-induced alteration. Clin Endocrinol (Oxf). 1991 Apr;34(4):289–92. doi:10.1111/j.1365-2265.1991.tb03768.x PubMed PMID: 1879060.

54.Reymond M, Lemarchand‐Béraud Th. Effects of oestrogens on prolactin and thyrotrophin responses to TRH in women during the menstrual cycle and under oral contraceptive treatment. Clinical Endocrinology. 1976 Sep;5(5):429–37. doi:10.1111/j.1365-2265.1976.tb01973.x

55.Tyson JE, Friesen HG. Factors influencing the secretion of human prolactin and growth hormone in menstrual and gestational women. American Journal of Obstetrics and Gynecology. 1973 Jan 1;116(3):377–87. doi:10.1016/S0002-9378(15)31297-7

56.De Léan, A, Ferland L, Drouin J, Kelly PA, Labrie F. Modulation of Pituitary Thyrotropin Releasing Hormone Receptor Levels by Estrogens and Thyroid Hormones. Endocrinology. 1977 Jun 1;100(6):1496–504. doi:10.1210/endo-100-6-1496

57.Messini CI, Malandri M, Anifandis G, Dafopoulos K, Georgoulias P, Sveronis G, et al. Submaximal doses of ghrelin do not inhibit gonadotrophin levels but stimulate prolactin secretion in postmenopausal women. Clinical Endocrinology. 2017;87(1):44–50. doi:10.1111/cen.13349

58.Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of Migraine Headache in the United States: Relation to Age, Income, Race, and Other Sociodemographic Factors. JAMA. 1992 Jan 1;267(1):64–9. doi:10.1001/jama.1992.03480010072027

59.Victor T, Hu X, Campbell J, Buse D, Lipton R. Migraine prevalence by age and sex in the United States: A life-span study. Cephalalgia. 2010 Sep;30(9):1065–72. doi:10.1177/0333102409355601

60.Cevik R, Gur A, Acar S, Nas K, Sarac AJ. Hypothalamic-pituitary-gonadal axis hormones and cortisol in both menstrual phases of women with chronic fatigue syndrome and effect of depressive mood on these hormones. BMC Musculoskelet Disord. 2004 Dec 8;5(1):47. doi:10.1186/1471-2474-5-47

61.Studd J, Panay N. Chronic fatigue syndrome. The Lancet. 1996 Nov 16;348(9038):1384. doi:10.1016/S0140-6736(05)65448-7 PubMed PMID: 8918295.

62.Thomas N, Ubhayasekera SJKA, Armstrong CW, Huang K, Bergquist J. Steroid dynamics in myalgic encephalomyelitis / chronic fatigue syndrome: a case-control study using ultra performance supercritical fluid chromatography tandem mass spectrometry. J Transl Med. 2025 Jul 25;23(1):829. doi:10.1186/s12967-025-06841-4

63.Wyller VB, Evang JA, Godang K, Solhjell KK, Bollerslev J. Hormonal alterations in adolescent chronic fatigue syndrome. Acta Paediatrica. 2010;99(5):770–3. doi:10.1111/j.1651-2227.2010.01701.x

64.Grattan DR. 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-prolactin axis. Journal of Endocrinology. 2015 Aug;226(2):T101–22. doi:10.1530/JOE-15-0213

65.Cleare AJ, Messa C, Rabiner EA, Grasby PM. Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635. Biological Psychiatry. 2005 Feb;57(3):239–46. doi:10.1016/j.biopsych.2004.10.031

66.Lynch CO, Johnson MD, Crowley WR. Effects of the serotonin agonist, quipazine, on luteinizing hormone and prolactin release: Evidence for serotonin-catecholamine interactions. Life Sciences. 1984 Oct 1;35(14):1481–7. doi:10.1016/0024-3205(84)90165-6

67.Baraniuk JN, Eaton-Fitch N, Marshall-Gradisnik S. Meta-analysis of natural killer cell cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome. Front Immunol. 2024;15:1440643. doi:10.3389/fimmu.2024.1440643 PubMed PMID: 39483457; PubMed Central PMCID: PMC11524851.

68.Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: Structure, Function, and Regulation of Secretion. Physiological Reviews. 2000 Jan 10;80(4):1523–631. doi:10.1152/physrev.2000.80.4.1523

69.Shishioh-Ikejima N, Ogawa T, Yamaguti K, Watanabe Y, Kuratsune H, Kiyama H. The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients. BMC Neurol. 2010 Aug 23;10:73. doi:10.1186/1471-2377-10-73 PubMed PMID: 20731841; PubMed Central PMCID: PMC2933583.

70.Hill JB, Nagy GM, Frawley LS. Suckling Unmasks the Stimulatory Effect of Dopamine on Prolactin Release: Possible Role for α-Melanocyte- Stimulating Hormone as a Mammotrope Responsiveness Factor*. Endocrinology. 1991 Aug;129(2):843–7. doi:10.1210/endo-129-2-843

71.Khorram O, Bedran De Castro JC, McCann SM. Physiological role of alpha-melanocyte-stimulating hormone in modulating the secretion of prolactin and luteinizing hormone in the female rat. Proc Natl Acad Sci USA. 1984 Dec;81(24):8004–8. doi:10.1073/pnas.81.24.8004

72.Newman CB, Wardlaw SL, Frantz AG. Supression of basal and stress-induced prolactin release and stimulation of luteinizing hormone secretion by α-melanocyte-stimulating hormone. Life Sciences. 1985 Apr;36(17):1661–8. doi:10.1016/0024-3205(85)90369-8

73.Nuñez L, Frawley LS. α-MSH potentiates the responsiveness of mammotropes by increasing Ca2+ entry. American Journal of Physiology-Endocrinology and Metabolism. 1998 Jun 1;274(6):E971–7. doi:10.1152/ajpendo.1998.274.6.E971

74.Pasqualini C, Bojda F, Kerdelhué B. Direct Effect of Estradiol on the Number of Dopamine Receptors in the Anterior Pituitary of Ovariectomized Rats. Endocrinology. 1986 Dec 1;119(6):2484–9. doi:10.1210/endo-119-6-2484

Edit: Previously cited the wrong Yatham paper, so I fixed ref 16.
 
Last edited:
forestglip said:
I wrote up a rough draft of a quick outline of what is known about prolactin response (well, what I know about it), as it relates to ME/CFS. I wanted to make something to get across the important details to someone who doesn't know anything about it, and hopefully get them interested in exploring further.

It could probably be improved in various ways, for example by including other mechanistic prolactin-related findings that may be relevant. And the structure/style could probably be improved. So I welcome any suggestions to make this better. Though no promises on when I'll be able to work on it further.

Feel free to share this text if you'd like.

Introduction​

Abnormal prolactin response is a consistent and replicated finding in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but the implications of this finding have only been minimally explored. Further research into this phenomenon could potentially uncover hormonal, neural, or other abnormalities which help illuminate the pathophysiology of ME/CFS.

Prolactin response to buspirone​

Strikingly, every single study that has tested prolactin response to buspirone in ME/CFS has reported a significantly larger increase of prolactin in the patient group.

The first study of prolactin response in ME/CFS came from Bakheit et al. in 1992. The findings from this study were reported both in Bakheit’s thesis (1), as well as in a peer-reviewed paper (2). The authors were studying postviral fatigue syndrome, which, as indicated in the thesis, also required that the fatigue was made worse by exercise and which did not improve after bed rest. The study found that the patient group had a larger increase in plasma prolactin after administration of the anti-anxiety drug, buspirone, when compared to healthy controls or individuals with depression. This was seen in patients of both sexes. Figure 1 illustrates the study results, using the individual level data provided in Bakheit’s thesis. Notably, and as seen in virtually all other studies of this topic, baseline prolactin was not significantly different from controls.

Figure 1:
View attachment 33790

Further evidence was provided in a study from John Richardson in 1995, in which patients who fulfilled the CDC or Oxford criteria for ME/CFS were compared to family members without ME/CFS. Based on the ratio of prolactin after to before administration, the prolactin response to buspirone (50 mg, orally) in the patients was, on average, over 3 times higher than that of the controls. The study also found a correlation between prolactin response in patients and their degree of sleep disturbance (3). A later study from Richardson and Costa again suggested very high prolactin responses to buspirone (50 mg, orally) in ME/CFS patients, however this study did not include a control group, and it is unclear if high prolactin response was a criteria for inclusion in the study (4).

In 1996, Sharpe et al. reported increased prolactin response to buspirone (0.5 mg/kg orally, up to 45 mg) in patients fulfilling Oxford criteria for ME/CFS, but without depression. Plasma levels of buspirone and its metabolite, 1-(2-Pyrimidinyl)piperazine (1-PP), were not significantly different between groups, suggesting that the abnormal prolactin response was not due to differences in drug metabolism. The growth hormone response to buspirone did not significantly differ between groups (5).

Also in 1996, Tahir Majeed, under the supervision of Peter O. Behan, published a thesis testing hormonal responses to a variety of drug challenges. The study cohort included patients who fulfilled Fukuda and Oxford criteria, and who had fatigue which worsened after exercise. The control group was made up of healthy, sex-matched volunteers. The ME/CFS patients exhibited a significantly larger increase in prolactin after administration of buspirone (60 mg, orally). Further findings in ME/CFS patients included a normal growth hormone response to bromocriptine and baclofen, a larger growth hormone response to pyridostigmine, a smaller growth hormone responses to desipramine and dexamethasone, and a smaller adrenocorticotropic hormone (ACTH) response to ipsapirone (6).

Another 1996 paper, authored by Behan, reported increased prolactin response to buspirone (60 mg, orally) in individuals with an ME/CFS-like illness (including fatigue worsened by exercise, myalgia, and with onset after a flu-like illness) and who had previously been exposed to organophosphates (7). Note that while the paper indicates that the study included 10 male healthy controls, later court testimony from Behan in an organophosphate trial indicated that there was a mistake in the paper, and the actual control group was made up of 15 males and 15 females (8). However, as Behan noted in court, the inclusion of females in the control group would not be expected to lead to spurious differences between groups, and would instead more likely have led to a smaller difference, as females have larger prolactin responses to buspirone than males (9).

Additionally, two papers from Racciatti et al. suggest that they have also seen increased prolactin response to buspirone in ME/CFS, however one paper does not include a healthy control group (10), and the other is an abstract which we have not been able to access (11), and with the findings briefly mentioned in a later review (12).

Finally, a 2001 case report included details of a female patient with ME/CFS, according to Oxford criteria, who exhibited an abnormally large prolactin response to buspirone (30 mg, orally). After symptom improvement, which followed a graded exercise therapy intervention, the prolactin response was measured again on two occasions, and was found to be normal both times (13).

Prolactin response to other challenges​

Additional evidence related to prolactin response is provided by studies which tested fenfluramine, exercise, and insulin-induced hypoglycemia in ME/CFS patients.

In 1995, Bearn et al. tested the prolactin response in ME/CFS to both insulin-induced hypoglycemia and to the serotonin drug, d-fenfluramine (30 mg, orally). The prolactin response to d-fenfluramine did not significantly differ between groups. However, after administration of insulin, prolactin increased significantly less in the ME/CFS group (14).

Ottenweller et al. tested a maximal exercise challenge using a treadmill, and reported a significantly smaller increase of prolactin in ME/CFS patients (15).

Yatham et al. published a study of response to racemic fenfluramine in ME/CFS. The groups did not significantly differ in the magnitude of prolactin response (16).

Two later studies from separate groups tested the prolactin response to d-fenfluramine, and both of these studies found increased prolactin response in ME/CFS patients (17,18).

A 2001 study did not find a significant difference between ME/CFS patients and controls for prolactin response to the 5-HT2c receptor agonist, m-chlorophenylpiperazine (mCPP) (19).

Finally, a 2010 study reported a significantly increased prolactin response to tryptophan, but only in females with ME/CFS, and not in females with ME/CFS+fibromyalgia, or in either of the male patient groups (20).

Other conditions​

Abnormally increased prolactin response has been reported in several other conditions, such as migraine, irritable bowel syndrome (IBS), hormonal disorders, and gonadal disorders.

Migraine​

Abnormal prolactin response has been reported several times in migraine. Migraine patients may have an abnormally long return to baseline prolactin after administration of reserpine (21) or benserazide (22). Studies have reported abnormally increased prolactin response in migraine patients to the D2 antagonists sulpiride (22,23) and domperidone (23). An abnormally large decrease in prolactin has been noted after administration of L-deprenyl (24). In contrast, an abnormally small decrease was reported after administration of the dopamine reuptake inhibitor, nomifensine (23) and the dopamine precursor, L-DOPA (25). Cassidy et al. have published two studies showing increased prolactin response to buspirone in migraine (26,27). The prolactin response to mCPP was larger in a study that used a dosage of 0.5 mg/kg (28), but not in a study that used a smaller 0.25 mg/kg dosage of the drug (29). A larger prolactin response was noted after racemic fenfluramine (30).

A blunted prolactin response in migraine was seen after administration of 50 μg and 200 ug doses of thyrotropin-releasing hormone (TRH) (31). A different study found an increased prolactin response to TRH during migraine attacks (32). Awaki et al. found an increased prolactin response after administration of a cocktail which included TRH, gonadotropin-releasing hormone (GnRH), and insulin (33).

However, other studies of migraine did not find significant differences between groups, including after administration of domperidone (34), fenfluramine (22), lisuride (23), metaclopromide (35,36), morphine (37), piribedil (38), and sumatriptan (39).

Other disorders​

Increased prolactin response has been reported in only a small number of other conditions. The following paragraphs include examples of these, but this should not be considered exhaustive.

Several studies from the same research group have reported abnormally increased prolactin response to buspirone in IBS (40), and in non-ulcer dyspepsia (41–44).

An increased prolactin response was seen in primary testicular failure after administration of TRH (45) and metoclopramide (46). Prolactin response to TRH was also significantly larger in females with primary ovarian failure (47). An increased prolactin response to TRH was also reported in patients with polyendocrine metabolic ovarian syndrome (PMOS) (48).

Connection to sex hormones?​

As females are more likely than males to have ME/CFS (49), it may be useful to consider whether sex hormones influence prolactin response in a way that may explain the observations of increased prolactin response to buspirone and d-fenfluramine in ME/CFS.

Females have a higher prolactin response to buspirone than males (9). Similar sex differences have been observed after administration of thyrotropin-releasing hormone (TRH), phenothiazine, and possibly chlorpromazine (50–52).

Prolactin response to various drugs differs throughout the menstrual cycle. While baseline prolactin levels stayed relatively steady throughout the menstrual cycle, it was observed that prolactin response to d-fenfluramine was highest at mid-cycle, followed by luteal, then follicular phases. This mirrored the differing amounts of circulating estradiol present across the menstrual cycle (53). Prolactin response to buspirone in females was found to be larger during the luteal phase than during the follicular phase or mid-cycle (9). Prolactin response to TRH may be somewhat larger during the follicular phase (54), but findings are inconsistent (55).

Exogenous estradiol can modulate prolactin response. TRH-induced prolactin response is 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 (54). In male rats, a prolactin response to TRH was only detectable when the rats had previously been administered estradiol (56). Exogenous estradiol also causes an increased prolactin response to ghrelin in postmenopausal women (57).

(9) also reported that females had more symptoms of sedation in response to buspirone during the luteal phase than at other timepoints, when prolactin response was also found to be highest. This may relate to the finding that ME/CFS patients appear to have more side effects, such as fatigue and nausea, to buspirone, when compared to healthy controls (2,3).

Similar to the sex bias in ME/CFS (49), migraine appears to be more prevalent in females than males (58,59). As noted in the “Migraine” section, this is another health condition in which several studies have reported altered prolactin response to various neuroendocrine challenges.

Note that a hypothesis which ties estradiol to the abnormal prolactin response seen in ME/CFS would need to be explained by a mechanism which is independent of blood estradiol levels, as studies have shown that blood levels of this hormone do not appear to be significantly increased in ME/CFS (60–63).

One could test the estradiol hypothesis by measuring the prolactin response to buspirone in ME/CFS and healthy controls both before and after administration of estrogen receptor antagonists or aromatase inhibitors. If the difference between groups were found to be diminished after blocking the influence of estrogens, this would provide evidence of sex hormone involvement in the abnormal prolactin response. It may be necessary to prescribe an extended course of these drugs prior to the second test, as estrogens are capable of inducing long term changes in prolactin-secreting cells, for example through genomic regulation or by increasing the number of prolactin-secreting cells, as reviewed in (64).

Where to go from here?​

The implications of abnormal prolactin response in ME/CFS are far from clear. While several of the ME/CFS studies cited above suggested abnormalities in serotonin receptors, the evidence is far from conclusive. A PET study of 5-HT receptors found the opposite of what the authors had expected based on prolactin findings (65). Additionally, while abnormal prolactin response could involve the receptors directly affected by the neuroendocrine probes, it could also be highlighting any of a number possible downstream abnormalities, such as altered dopaminergic tone or sensitized prolactin-secreting cells. For example, serotonin drugs may exert at least part of their influence on prolactin through altering hypothalamic dopamine release (66).

What is clear is the importance of further exploration of these findings. ME/CFS is a condition with notoriously few well-replicated, specific findings. Some of the few potential other replicated findings include female sex bias (49) and potentially decreased NK cell cytotoxicity (67). With so few clues into the underlying pathophysiology, it is important to thoroughly investigate every possible avenue available.

A straightforward next step would be testing prolactin response to other neuroendocrine probes. If dopaminergic drugs and TRH both lead to abnormal responses, this would suggest abnormally sensitized lactotrophs, as dopamine and TRH both directly affect lactotrophs (68). If neither demonstrates altered responses, but responses to serotonin-related drugs are altered, this may indicate upstream abnormalities.

One ME/CFS study has reported increased levels of alpha-melanocyte-stimulating hormone (ɑ-MSH), albeit with substantial overlap between groups (69). ɑ-MSH is known to alter prolactin response, both in vitro and in vivo (70–73). Thus, it may be valuable to attempt to replicate increased ɑ-MSH in ME/CFS, and to test for a correlation to prolactin response in these patients.

In a study of increased prolactin response to TRH in primary ovarian failure, the authors speculated that the patients might have increased conversion of androgens to estrogens within the hypothalamus (74). This was not based on direct evidence, so should be interpreted cautiously, but it may be worth examining this possibility.

It may be possible to explore this finding further using PET scans, for example by measuring DRD2 binding in the pituitary gland. If the ME/CFS abnormality does relate to sex hormones, then DRD2 levels may be altered, as is seen when estradiol is applied to anterior pituitary cells in vitro (74).
Click to expand...
What a beautifully well-written summary you have written. I’m grateful you wrote this because I was losing sight of the bigger picture through all of these papers. When someone does this study, you should be an author on it. The level of detail and investigation you’ve put in is astounding.
 
forestglip said:
I wrote up a rough draft of a quick outline of what is known about prolactin response (well, what I know about it), as it relates to ME/CFS. I wanted to make something to get across the important details to someone who doesn't know anything about it, and hopefully get them interested in exploring further.
Click to expand...
Moderators have put a link to Forestglip's summary in the first post of the thread, to make it easier for people to find it as the thread moves on
 
Thank you for this detailed and well rounded summary, which is well worthy of publication. You have put in a lot of work and one can see that!

Having not followed the full discussion I was wondering if it was possible to include 2 smaller sections or additional links on the historical context which I find quite important given that these are old findings which have been lying around for some time.
- Why has prolactin response been studied in illnesses in general in the past?
- Why has it come out of favour of being studied and why in particular did it not get studied further in ME/CFS?

The second question might be particularly hard to answer as it might be related to unpublished results and historical context none of us might know, but in this case it might be worth writing something like "it is unclear why these results weren't further investigated". Perhaps it would also be wise to include a sentence on whether this response might be related to being physically less active or other variables like sleep patterns, timing of testing, drug usage, BMI as these are the usual candidates to explain results in ME/CFS research. If it for instances is impacted by stress then pwME/CFS might be under more stress during hospital visits. I know you've thought all of these things through, maybe the summary could have a section on these explanations, in a "limitations section" or similar. I understand that including all of this might also make the summary unattractively long and you've already gone over the character limit.

You mention other diseases where prolactin response has been measured. Have you been able to get a feel for how reliable these results are in other contexts, for example are there illnesses where you tend to always see the same results and where large replication studies have shown this or is it rather a bit mixed with spurious results appearing all over the place?
 
Last edited:
You must log in or register to reply here.
Back
Top Bottom