Diagnosis of Overtraining Syndrome: Results of the Endocrine and Metabolic Responses on Overtraining Syndrome Study: EROS-DIAGNOSIS

Table 3

Biochemical parameters evaluated for the development of the Endocrine and Metabolic Responses on Overtraining Syndrome diagnostic tools.

Study/tests	Markers	p-score	Highest NPV or PPV (%) and accuracy (%)	Ranges of the maximum accuracy and maximum true positive and true negative values	Useful for any of the questionnaires (no/potentially/yes)
EROS-HPA axis
Response to an ITT	Basal ACTH levels (pg/mL)	n/s	n/a	n/a	No
	ACTH levels during hypoglycemia (pg/mL)	n/s	n/a	n/a	No
	ACTH levels 30 min after hypoglycemia (pg/mL)	<0.001	Cutoff: <35 pg/mL; PPV: 75%; NPV: 81.5%; accuracy: 79.5%	OTS: 13/14 if <106 pg/mL or 9/14 if <35 pg/mL; ATL: 22/25 if >35 pg/mL; accuracy: 31/39 if >35 pg/mL	Yes
	ACTH increase during an ITT (pg/mL)	<0.001	Cutoff: <20 pg/mL; PPV: 66.7%; NPV: 83.3%; accuracy: 76.9%	OTS: 14/14 if <75 pg/mL, 12/14 if <35 pg/mL, or 10/14 if <20 pg/mL; ATL: 25/25 if >3 pg/mL or 20/25 if >20 pg/mL; accuracy: 30/39 if 1–3 pg/mL or 20 pg/mL	Potentially
	Basal serum cortisol levels (µg/dL)	n/s	n/a	n/a	n/a
	Cortisol levels during hypoglycemia (µg/dL)	0.015	Cutoff: <13.5 μg/dL; PPV: 62.5%; NPV: 82.6%; accuracy: 74.4%	OTS: 12/14 if <16.9 µg/dL, 11/14 if <13.7 µg/dL, or 10/14 if <13.2 µg/dL; ATL: 17/25 if >13.7 µg/dL or 19/25 if >13.5 µg/dL; accuracy: 29/39 if 13.2–13.5 µg/dL	No (10/39 overlapping results)
	Cortisol levels 30 min after hypoglycemia (µg/dL)	0.002	Cutoff: <19.1 µg/dL; PPV: 72.2%; NPV: 95.2%; accuracy: 84.6%	OTS: 13/14 if <19.1 µg/dL; ATL: 25/25 if <17 µg/dL or 20/25 if <19.1 µg/dL; accuracy: 33/39 if <19.1 µg/dL	Yes
	Cortisol increase during an ITT (µg/dL)	0.008	Cutoff: <9 µg/dL; PPV: 57.1%; NPV: 89.9%; accuracy: 71.8%	OTS: 14/14 if <10 µg/dL, 12/14 if <9 µg/dL, or 11/14 if <8 µg/dL; ATL: 16/25 if >9 µg/dL, 13/25 if >10 µg/dL, or 10/25 if >11 µg/dL; accuracy: 28/39 if <9 µg/dL	No (11/39 overlapping results)
Response to a CST	Cortisol levels 30 min after cosyntropin (µg/dL)	n/s	n/a	n/a	No
	Cortisol levels 60 min after cosyntropin (µg/dL)	n/s	n/a	n/a	No
SCR	Waking salivary cortisol (ng/dL)	n/s	n/a	n/a	No
	Salivary cortisol 30 min after waking (ng/dL)	0.002	Cutoff: >390 ng/dL; PPV: 68.7%; NPV: 87%; accuracy: 79.5%	OTS: 14/14 if <520 ng/dL or 11/14 if <390 ng/dL; ATL: 20/25 if >390–400 ng/dL; Accuracy: 31/39 if <390–400 ng/dL	Yes
	4 PM salivary cortisol (ng/dL)	n/s	n/a	n/a	No
	11 PM salivary cortisol (ng/dL)	n/s	n/a	n/a	No
	CAR (%)	n/s	n/a	n/a	No
EROS-STRESS
Response to an ITT	Basal GH levels (µg/L)	0.009	Cutoff: <0.1 µg/L; PPV: 87.5%; NPV: 77.4%; accuracy: 79.5%	OTS: 11/14 if <0.2 µg/L or 7/14 <0.07 µg/L; ATL: 24/25 if >0.1 µg/L or 18/25 if >0.2 µg/L; Accuracy: 31/39 if <0.1 µg/L	Yes
	GH levels during hypoglycemia (µg/L)	0.018	Cutoff: <0.1 µg/L; PPV: 100%; NPV: 73.5%; accuracy: 76.9%	OTS: 12/14 if <1.8 µg/L, 8/14 if <0.7 µg/L, 6/14 if <0.4 µg/L, or 5/14 if <0.25 µg/L; ATL: 25/25 if >0.1 µg/L, 24/25 if >0.17 µg/L, 22/25 if >0.3 µg/L, 18/25 if >0.4 µg/L, or 16/25 if >0.5 µg/L; accuracy: 30/39 if <0.1 µg/L	Yes
	GH levels 30 min after hypoglycemia (µg/L)	0.001	Cutoff: <5–6 µg/L; PPV: 81.8%; NPV: 82.1%; accuracy: 82%	OTS: 14/14 if <14.4 µg/L, 12/14 if <10.7 µg/L, 9/14 if <6 µg/L, or 7/14 if <1.5 µg/L; ATL: 23/25 if >6 µg/L; accuracy: 32/39 if <1.5–560 µg/L	Potentially
	Basal prolactin levels (ng/mL)	0.014	Cutoff: <7.1 ng/mL; PPV: 85.7%; NPV: 75%; accuracy: 76.9%	OTS: 13/14 <14.5 ng/mL or 6/14 if <7.1 ng/mL; ATL: 25/25 if >6.6 ng/mL, 24/25 if >7.1 ng/mL, or 23/25 if >7.7 ng/mL; accuracy: 30/39 if <6.6–7.7 ng/mL	Yes
	Prolactin levels during hypoglycemia (ng/mL)	0.001	Cutoff: <11.5–12 ng/mL; PPV: 83.3%; NPV: 85.2%; accuracy: 84.6%	OTS: 12/14 if <17.5 ng/mL or 10/14 if >11.5–12 ng/mL; ATL: 23/25 if <12 ng/mL; accuracy: 33/39 if <11.5–12 ng/mL	Yes
	Prolactin levels 30 min after hypoglycemia (ng/mL)	0.001	Cutoff: <10 ng/mL; PPV: 100%; NPV: 78.1%; accuracy: 82.1%	OTS: 7/14 if <14 ng/mL or <10 ng/mL; ATL: 25/25 if 10 ng/mL or 18/25 if >20 ng/mL; accuracy: 32/39 if <10 ng/mL	No (11/39 overlapping results)
	Prolactin increase during an ITT (ng/mL)	0.047	Cutoff: <0–2.5 ng/mL; PPV: 61.5%; NPV: 76.9%; accuracy: 71.8%	OTS: 14/14 if <14 ng/mL, 10/14 if <4 ng/mL, or 8/14 if <0 ng/mL; ATL: 20/25 if > 0–2.5 ng/mL; accuracy: 28/39 if <0–2.5 ng/mL
Glucose behavior and related symptoms during an ITT	Basal serum glucose (mg/dL)	n/s	n/a	n/a	No
	Serum glucose during hypoglycemia (mg/dL)	n/s	n/a	n/a	No
	Time to hypoglycemia (min)	n/s	n/a	n/a	No
	Adrenergic symptoms (0–10)	0.034	Cutoff: ≤3: PPV: 56.2%; NPV: 78.3%; accuracy: 69.2%	OTS: 13/14 if ≤6 or 9/14 if ≤3; ATL: 20/25 if ≥3 or 18/25 if ≥4; accuracy: 27/39 if ≤3	No (12/39 overlapping results)
	Neuroglycopenic symptoms (0–10)	n/s	n/a	n/a	No
EROS-BASAL
Hormonal markers	Total testosterone (ng/dL)	0.008	Cutoff: <400 pg/mL; PPV: 72.7%; NPV: 78.6%; accuracy: 76.9%	OTS: 10/14 if <440 pg/mL, 8/14 if <380 pg/mL; ATL: 24/25 if >350 ng/mL or 22/25 if >400 ng/mL; accuracy: 30/39 if <380–410 pg/mL	Potentially
	Estradiol (pg/mL)	0.007	Cutoff: >35 pg/mL; PPV: 66.7%; NPV: 75%; accuracy: 75.7%	OTS: 13/14 if >28 pg/mL or 10/14 if <35.5 pg/mL; ATL: 18/23 if <34 pg/mL; accuracy: 28/37 if >34–35.5 pg/mL	Potentially
	IGF-1 (pg/mL)	n/s	n/a	n/a	No
	TSH (µUI/mL)	n/s	n/a	n/a	No
	free T3 (pg/mL)	n/s	n/a	n/a	No
	Total catecholamines (µg/12 h)	0.032	Cutoff: >220 µg/12 h; PPV: 58.3%; NPV: 74.1%; accuracy: 69.2%	OTS: 14/14 if >130 µg/12 h, 11/14 if >155 µg/12 h, 8/14 if >200 µg/12 h, 7/14 if >220 µg/12 h, or 5/14 if >270 µg/12 h; ATL: 20/25 if <220 µg/12 h, 15/25 if <200 µg/12 h, 11/25 if <150 µg/12 h, or 10/25 if <130 µg/12 h; accuracy: 27/39 if >220 µg/12 h	No (12/39 overlapping results)
	Noradrenaline (µg/12 h)	n/s	n/a	n/a	No
	Dopamine (µg/12 h)	0.042	Cutoff: >200 µg/12 h; PPV: 58.3%; NPV: 74.1%; Accuracy: 69.2%	OTS: 12/14 if >120 µg/12 h, 7/14 if >200 µg/12 h, or 4/14 if >230 µg/12 h; ATL: 20/25 if <200 µg/12 h, 13/25 if <160 µg/12 h, or 11/25 if <120 µg/12 h; accuracy: 27/39 if >200 µg/12 h	No (12/39 overlapping results)
	Epinephrine (µg/12 h)	n/s	n/a	n/a	No
	Total metanephrines (µg/12 h)	n/s	n/a	n/a	No
	Metanephrines (µg/12 h)	n/s	n/a	n/a	No
	Normetanephrines (µg/12 h)	n/s	n/a	n/a	No
Biochemical markers	ESR (mm/h)	n/s	n/a	n/a	No
	CRP (mg/dL)	n/s	n/a	n/a	No
	Vitamin B12 (pg/mL)	n/s	n/a	n/a	No
	Lactate (nMol/L)	0.007	Multiple cutoffs: >0.9, 0.92–0.93, 0.95–0.98, or 1.06–1.1 nMol/L; PVV: 77.8% if >1.08 nMol/L; NPV: 100% if <0.75 nMol/L; accuracy: 74.4%	OTS: 14/14 if >0.75 nMol/L; ATL: 21/25 if <1.05 nMol/L; accuracy: 29/39 if 0.9, 0.92–0.93, 0.95–0.98, or 1.06–1.1 nMol/L	No (10/39 overlapping results)
	Ferritin (ng/mL)	n/s	n/a	n/a	No
	Neutrophils (/mm^3)	0.035	Cutoff: 2700/mm^3; PPV: 61.5%; NPV: 76%; accuracy: 71.1%	OTS: 12/14 if <3500/mm^3 or 8/14 if <2700/mm^3; ATL: 19/24 if >2700/mm^3 or 14/24 if >3500/mm^3; accuracy: 27/38 if <2700/mm^3, 26/38 if <2900/mm^3, or 3500–3750/mm^3	No (accuracy <75%)
	Lymphocytes (/mm^3)	n/s	n/a	n/a	No
	Platelets (1000/mm^3)	n/s	n/a	n/a	No
	Hematocrit (%)	n/s	n/a	n/a	No
	Eosinophils (/mm^3)	n/s	n/a	n/a	No
	LDLc (mg/dL)	n/s	n/a	n/a	No
	HDLc (mg/dL)	n/s	n/a	n/a	No
	Triglycerides (mg/dL)	n/s	n/a	n/a	No
	CK (U/L)	0.043	Cutoff: 800–850 U/L; PPV: 85.7%; NPV: 75%; accuracy: 76.9%	OTS: 7/14 if >760 U/L or 6/14 if >880 U/L; ATL: 24/25 if <780–910 U/L or 22/25 if <580–730 U/L; accuracy: 30/39 if 730 U/L or between 800 and 850 U/L	Potentially
	Creatinine (mg/dL)	n/s	n/a	n/a	No
Ratios	Testosterone:estradiol ratio	<0.001	Cutoff: 13.3; PPV: 83.3%; NPV: 84%; accuracy: 83.8%	OTS: 14/14 if <17 or 10/14 if <13.3; ATL: 21/23 if >13 or 16/23 if >16; accuracy: 31/37 if 13.3	Yes
	Testosterone:cortisol ratio	n/s	n/a	n/a	No
	Neutrophil:lymphocyte ratio	0.017	Cutoff: <1.65; PPV: 54.2%; NPV: 92.3%; accuracy: 68.4%	OTS: 14/14 if <1.95 or 13/14 if <1.65; ATL: 13/24 if >1.65 or 11/24 if >1.95;	No (accuracy <75%)
	Platelet:lymphocyte ratio	n/s	n/a	accuracy: 26/38 if <1.65	No

Two missing data points. One missing data point. ACTH = adrenocorticotropic hormone; ATL = healthy athletes; CAR = cortisol awakening response; CK = creatine kinase; CRP = C-reactive protein; CST = cosyntropin stimulation test; EROS = Endocrine and Metabolic Responses to Overtraining Syndrome; ESR = erythrocyte sedimentation rate; GH = growth hormone; HDLc = high-density lipoprotein-cholesterol; HPA = hypothalamic–pituitary–adrenal; IGF-1 = insulin-like growth factor 1; ITT = insulin tolerance test; LDLc = low-density lipoprotein-cholesterol; n/a = nonapplicable; NPV = negative predictive value; n/s = nonsignificant; OTS = overtraining syndrome-affected athletes; PPV = positive predictive value; SCR, salivary cortisol rhythm; T3L = free T3; and TSH = thyroid-stimulating hormone.