The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure

Figures & data

Table 1 Similar Characteristics of Primary ES, FM and CFS

1. Cerebrospinal Fluid Pressure Dysregulation		Primary ES	FM	CFS
	Patients with pressure ≥ 19 cm H2O	62%^Citation10	53%^Citation4	50%^Citation6- Brain MRI: 55% show optic nerve sheath dilation^Citation7
2. Hormonal anomalies		Primary ES versus controls	FM versus controls	CFS versus controls
HPA axis	ACTH and cortisol levels	Low ACTH and cortisol^Citation9,Citation13,Citation15,Citation16 Reduced cortisol in up to 62%^Citation14,Citation17	Reduced morning peak ACTH and cortisol^Citation18,Citation19 Reduced basal cortisol^Citation1	Reduced basal cortisol^Citation1
	Challenge tests	–	Blunted ACTH response to CRH^Citation20 Blunted ACTH response to hypoglycemia^Citation21	Blunted cortisol response to dexamethasone + CRH^Citation22 No difference in the ACTH and cortisol response to CRH or naloxone^Citation23
	Aldosterone levels	–	–	Reduced^Citation24,Citation25
Hypothalamo-pituitary somatotropic axis	Mean GH and IGF-1 levels	Reduced GH in up to 60%^Citation11,Citation14,Citation26,Citation27	Reduced basal GH or IGF-1 in 30–34%^Citation20,Citation28–34 No differences in IGF-1^Citation35,Citation36	Reduced nocturnal GH^Citation37–39 – Reduced basal IGF-1^Citation37,Citation40 No differences in basal IGF-1^Citation35,Citation38,Citation41
	Challenge tests	Blunted GH response to GH-releasing hormone + arginine in 8 of 20 primary ES patients (using BMI-related cutoff limits)^Citation42 Blunted GH response to GHRH + arginine in 11 of 28 patients^Citation27	Suboptimal response of IGF-1 to GH^Citation20,Citation31,Citation32	Reduced GH response to insulin-induced hypoglycemia^Citation40 Reduced GH response to insulin-induced hypoglycemia in 73 nonobese CFS patients versus 21 nonobese controls^Citation38
Prolactin	Mean prolactin levels	Mildly but significantly increased in 10–37%^Citation11,Citation26,Citation42	Decreased^Citation28,Citation43 No differences^Citation18 Mildly significantly increased^Citation29,Citation33,Citation44,Citation45 71% of patients with high PRL are diagnosed with FM^Citation46	No differences^Citation18,Citation39,Citation47 Significantly higher^Citation38,Citation48
	Challenge tests	–	Increased response to hypothalamic releasing-hormones or buspirone^Citation20,Citation49,Citation50 No differences in response to hypoglycemia^Citation44	Increased response to buspirone^Citation51
Hypothalamo-pituitary gonadal axis	Mean hormone levels	Decreased FSH, LH and sex hormone Erectile dysfunction in 100% of male patients Irregular menses in 40% of female patients^Citation10,Citation12,Citation14,Citation16	Increased LH and FSH^Citation43 Decreased estrogen^Citation20,Citation43 No difference in testosterone^Citation40 No differences in FSH, progesterone, or estradiol or the pulsatile secretion of LH^Citation18,Citation52	No significant differences in FSH, LH, estradiol, or progesterone levels were documented^Citation18,Citation52,Citation53
	Challenge tests	–	Blunted LH response to LHRH^Citation20	–
Hypothalamo-pituitary thyrotropic axis	Mean hormone levels	Decreased TSH, similar free T4 and free T3^Citation54 Decreased TSH, free T4 and free T3 37%^Citation14	Increased TSH^Citation33 Normal TSH, T3, and T4^Citation49	Increased TSH, normal thyroxine^Citation38 Normal TSH, decreased T3 in 16%^Citation55
	Challenge test	Abnormal (decreased or delayed/exaggerate) TSH response to TRH in 79%^Citation54	Decreased TSH and thyroxine response to TRH^Citation20,Citation49	–
3. Obesity	Prevalence	50% of patients^Citation10,Citation56	43% of patients in the USA, 32% in Europe, 22.1% in Asia^Citation57 Prevalence of FM in obese individuals: 37–51% versus 4% in the general population	Odds ratio of being obese in > 15,000 16-year-old CFS patients: 4.1^Citation58
4. Female sex	Female:male ratio	5:1–6:1^Citation9,Citation11,Citation26	9:1^Citation59	9:1^Citation60
5. Headaches	Prevalence	Nonspecified type: 59%^Citation11 to 88%^Citation10	Migraine alone: 48%, Tension type: 32–59%, (probable analgesic overuse: only 8%)^Citation61,Citation62	Migraine: 84% Tension type: 81% (compared to 5% and 45%, respectively, in healthy controls)^Citation63
6. Fatigue		Fatigue is reported (no percentages provided)^Citation12,Citation15,Citation27,Citation42	Core symptom	Core symptom
7. Ophthalmological abnormalities	Visual disturbances	Worse visual acuity: 13–37% Blurred vision: 29% Diplopia: 2% Oculomotor nerve defects: 1%	Blurred vision: 46% Peripheral visual field loss: 10% Oculomotor nerve defects: 3%^Citation64 Diplopia: 15%^Citation64	Eye movement dysfunction^Citation65,Citation66
	Retinal nerve fiber layer thickness	Thinner^Citation67	Thinner^Citation68	Not reported
8. Vestibulocochlear disturbances	Vertigo prevalence	Vertigo in 50%^Citation69 Prevalence of ES in Meniere’s disease: 46%^Citation70	Dix-Halpike maneuver in 24 patients elicited positional rotary vertigo in 21%^Citation71 Vertigo: 30% to 84%^Citation64,Citation72	Below average performance in dynamic posturography tests requiring patient to depend heavily on the vestibular system^Citation73
	Hearing loss prevalence	89% (78% of these have sensorineural hearing loss)^Citation69	Sensorineural hearing: 15% Abnormal auditory brain stem responses: 30%^Citation74 Audiological testing significantly worse in FM^Citation75 1.5-fold risk of hearing loss and greater sensorineural hearing loss^Citation76 Higher likelihood to report hearing loss (OR 4.6)^Citation77	Not reported
9. Bodily pain		Radicular pain^Citation78–83 Radicular pain + ES^Citation84 Allodynia in 50% of patients with intracranial hypertension^Citation85 No reports on small-fiber neuropathy	Radiculopathy^Citation86,Citation87 Small-fiber neuropathy in 41% vs 4% in healthy individuals^Citation88 Meta-analysis of 20 studies (903 patients): 49%^Citation89	Pain is common^Citation90,Citation91 Probable small-fiber neuropathy in 31% of CFS patients with low cardiac filling pressures during exercise^Citation92

Table 2 Overview of the Hypothalamic and Pituitary Hormones

Axis	Hormones Secreted by the Hypothalamus	Hormones Secreted by the Anterior Lobe of the Pituitary Gland	Endocrine Glands	Most Important Hormones Secreted by the Endocrine Glands
Hypothalamo-pituitary adreno-cortical axis	Corticotropin- releasing hormone (CRH)	Adrenocorticotropic hormone (ACTH)	Adrenal glands	Glucocorticoids (cortisol) Mineralocorticoids (aldosterone)
Hypothalamo-pituitary somatotropic axis	GHRH (growth hormone-releasing hormone)	Growth hormone (GH)	Liver	Insulin-like growth factor-1 (IGF-1)
Prolactin (PRL) has no endocrine axis as it acts directly on nonendocrine cells	Dopamine inhibits PRL secretion Thyrotropin releasing hormone (TRH) stimulates PRL secretion	PRL	(Lactotrophic cells in the breast)
Hypothalamo-pituitary gonadal axis	Gonadotropin- releasing hormone (GnRH)	Luteinizing hormone (LH) Follicle-stimulating hormone (FSH)	Gonads	Gonadal steroid hormones (estradiol or testosterone) (Production of sperm and eggs)
Hypothalamo-pituitary thyrotropic axis	TRH	Thyroid-stimulating hormone (thyrotropin - TSH)	Thyroid gland	Thyroid hormones

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