Most commonly reported clinical and biochemical manifestations reported in milieus of REDs
| Physiological axis . | Manifestation . | Most common study type . | |
|---|---|---|---|
| Endocrine | Hypothalamic-pituitary-gonadal | Functional HA (12, 36, 61, 65, 68, 76-79) | Systematic review Society guidelines Consensus statements Prospective cohort Cross-sectional |
| Diminished gonadotropin (LH, FSH) concentrations and pulses (56, 80-84) | Open-label clinical trial Prospective cohort | ||
| Decreased testosterone concentrations (81-83, 85-91) | Prospective cohort Cross-sectional | ||
| Decreased motile sperm count (86, 92) Abnormal sperm morphology (93) | Cross-sectional | ||
| Hypothalamic-pituitary-thyroid | Reduced thyroid hormone concentrations (42, 57, 85, 94-97) | Case-control Prospective cohort Cross-sectional | |
| Blunted TSH pulse and response to TRH (42, 96) | Cross-sectional Prospective (short-term) | ||
| Hypothalamic-pituitary-somatotropic | Accentuated GH pulse peaks (short-term) (98, 99) | Prospective cohort | |
| Decreased IGF-1 levels (56, 85, 99-103) | Prospective cohort | ||
| Increased IGFBP-1 levels (104) | Clinical trial | ||
| Decreased IGFBP-4, IGFBP-6, GHBP levels (104) | Clinical trial | ||
| Hypothalamic-pituitary-adrenal | Elevated cortisol concentrations (105-109) | Review Prospective cohort | |
| Blunted diurnal salivary cortisol pulse (42, 110, 111) | Prospective cohort | ||
| Leptin, insulin, and ghrelin | Reduced insulin levels (112) | Prospective (short-term) | |
| Elevated ghrelin levels (113) | Cross-sectional | ||
| Reduced leptin levels (42, 45, 46, 104, 112, 114-116) | Clinical trial | ||
| Bone | Loss of BMD and premenopausal osteoporosis (17, 24, 25, 58, 70, 117, 118) | Randomized controlled trials Reviews, Society guidelines, consensus statements | |
| ↑ NTX, CTX, bone resorption markers (58, 70, 119) | Randomized and nonrandomized trials Cross-sectional | ||
| Stress fractures (120-136) | Systematic review Epidemiological Prospective cohort Case-control | ||
| Immunological | Diminished lymphocyte and increased neutrophil counts (137-139) | Review Randomized controlled trial Prospective cohort | |
| Increased white blood cell counts (73) | Prospective cohort | ||
| Increased IL-6 levels (140-142) | Prospective cohort | ||
| Decreased monocytes and T-cell subpopulation (143) | Prospective cohort | ||
| T-cell hyporesponsiveness (144) | Clinical trial | ||
| Neutrophil hyporesponsiveness and decreased phagocytic activity (145, 146) | Prospective cohort | ||
| Decreased IgA levels (64, 147) | Prospective cohort Cross-sectional | ||
| Increased likelihood of infections and illnesses (64, 147-151) | Cross-sectional | ||
| Muscle and performance | Decreased muscle mass and strength, increased risk of injuries (152-154) | Randomized controlled trial Cross-sectional Prospective | |
| Decreased explosive power (155) | Prospective | ||
| Dysregulation of myokines (156, 157) | Review | ||
| Reduced muscle glycogen content (158) | Crossover randomized controlled trial | ||
| Decreased muscle protein synthesis (159) | Clinical trial | ||
| Diminished activin and increased follistatin concentrations (43, 53, 111, 160, 161) | Clinical trial Prospective | ||
| Impaired sports performance (162) | Review | ||
| Hematological | Iron deficiency anemia (163, 164) | Cross-sectional | |
| Abnormal levels of ferritin and transferrin, elevated levels of hepcidin (73, 142, 165-167) | Cross-sectional Prospective Case-control | ||
| Cardiovascular | Endothelial dysfunction concurrent with HA—association with increased cardiovascular risk (168) | Cross-sectional | |
| Gastrointestinal | Nausea, regurgitation, upper abdominal bloating, diarrhoea, delayed gastric emptying and constipation (169, 170) | Systematic review | |
| Increased intestinal permeability (170, 171) | Systematic review | ||
| Physiological axis . | Manifestation . | Most common study type . | |
|---|---|---|---|
| Endocrine | Hypothalamic-pituitary-gonadal | Functional HA (12, 36, 61, 65, 68, 76-79) | Systematic review Society guidelines Consensus statements Prospective cohort Cross-sectional |
| Diminished gonadotropin (LH, FSH) concentrations and pulses (56, 80-84) | Open-label clinical trial Prospective cohort | ||
| Decreased testosterone concentrations (81-83, 85-91) | Prospective cohort Cross-sectional | ||
| Decreased motile sperm count (86, 92) Abnormal sperm morphology (93) | Cross-sectional | ||
| Hypothalamic-pituitary-thyroid | Reduced thyroid hormone concentrations (42, 57, 85, 94-97) | Case-control Prospective cohort Cross-sectional | |
| Blunted TSH pulse and response to TRH (42, 96) | Cross-sectional Prospective (short-term) | ||
| Hypothalamic-pituitary-somatotropic | Accentuated GH pulse peaks (short-term) (98, 99) | Prospective cohort | |
| Decreased IGF-1 levels (56, 85, 99-103) | Prospective cohort | ||
| Increased IGFBP-1 levels (104) | Clinical trial | ||
| Decreased IGFBP-4, IGFBP-6, GHBP levels (104) | Clinical trial | ||
| Hypothalamic-pituitary-adrenal | Elevated cortisol concentrations (105-109) | Review Prospective cohort | |
| Blunted diurnal salivary cortisol pulse (42, 110, 111) | Prospective cohort | ||
| Leptin, insulin, and ghrelin | Reduced insulin levels (112) | Prospective (short-term) | |
| Elevated ghrelin levels (113) | Cross-sectional | ||
| Reduced leptin levels (42, 45, 46, 104, 112, 114-116) | Clinical trial | ||
| Bone | Loss of BMD and premenopausal osteoporosis (17, 24, 25, 58, 70, 117, 118) | Randomized controlled trials Reviews, Society guidelines, consensus statements | |
| ↑ NTX, CTX, bone resorption markers (58, 70, 119) | Randomized and nonrandomized trials Cross-sectional | ||
| Stress fractures (120-136) | Systematic review Epidemiological Prospective cohort Case-control | ||
| Immunological | Diminished lymphocyte and increased neutrophil counts (137-139) | Review Randomized controlled trial Prospective cohort | |
| Increased white blood cell counts (73) | Prospective cohort | ||
| Increased IL-6 levels (140-142) | Prospective cohort | ||
| Decreased monocytes and T-cell subpopulation (143) | Prospective cohort | ||
| T-cell hyporesponsiveness (144) | Clinical trial | ||
| Neutrophil hyporesponsiveness and decreased phagocytic activity (145, 146) | Prospective cohort | ||
| Decreased IgA levels (64, 147) | Prospective cohort Cross-sectional | ||
| Increased likelihood of infections and illnesses (64, 147-151) | Cross-sectional | ||
| Muscle and performance | Decreased muscle mass and strength, increased risk of injuries (152-154) | Randomized controlled trial Cross-sectional Prospective | |
| Decreased explosive power (155) | Prospective | ||
| Dysregulation of myokines (156, 157) | Review | ||
| Reduced muscle glycogen content (158) | Crossover randomized controlled trial | ||
| Decreased muscle protein synthesis (159) | Clinical trial | ||
| Diminished activin and increased follistatin concentrations (43, 53, 111, 160, 161) | Clinical trial Prospective | ||
| Impaired sports performance (162) | Review | ||
| Hematological | Iron deficiency anemia (163, 164) | Cross-sectional | |
| Abnormal levels of ferritin and transferrin, elevated levels of hepcidin (73, 142, 165-167) | Cross-sectional Prospective Case-control | ||
| Cardiovascular | Endothelial dysfunction concurrent with HA—association with increased cardiovascular risk (168) | Cross-sectional | |
| Gastrointestinal | Nausea, regurgitation, upper abdominal bloating, diarrhoea, delayed gastric emptying and constipation (169, 170) | Systematic review | |
| Increased intestinal permeability (170, 171) | Systematic review | ||
Abbreviations: BMD, bone mineral density; CTX, collagen type 1 C-telopeptide; GHBP, GH-binding protein; HA, hypothalamic amenorrhea; IGFBP, IGF binding protein; NTX, N-terminal telopeptide.
Most commonly reported clinical and biochemical manifestations reported in milieus of REDs
| Physiological axis . | Manifestation . | Most common study type . | |
|---|---|---|---|
| Endocrine | Hypothalamic-pituitary-gonadal | Functional HA (12, 36, 61, 65, 68, 76-79) | Systematic review Society guidelines Consensus statements Prospective cohort Cross-sectional |
| Diminished gonadotropin (LH, FSH) concentrations and pulses (56, 80-84) | Open-label clinical trial Prospective cohort | ||
| Decreased testosterone concentrations (81-83, 85-91) | Prospective cohort Cross-sectional | ||
| Decreased motile sperm count (86, 92) Abnormal sperm morphology (93) | Cross-sectional | ||
| Hypothalamic-pituitary-thyroid | Reduced thyroid hormone concentrations (42, 57, 85, 94-97) | Case-control Prospective cohort Cross-sectional | |
| Blunted TSH pulse and response to TRH (42, 96) | Cross-sectional Prospective (short-term) | ||
| Hypothalamic-pituitary-somatotropic | Accentuated GH pulse peaks (short-term) (98, 99) | Prospective cohort | |
| Decreased IGF-1 levels (56, 85, 99-103) | Prospective cohort | ||
| Increased IGFBP-1 levels (104) | Clinical trial | ||
| Decreased IGFBP-4, IGFBP-6, GHBP levels (104) | Clinical trial | ||
| Hypothalamic-pituitary-adrenal | Elevated cortisol concentrations (105-109) | Review Prospective cohort | |
| Blunted diurnal salivary cortisol pulse (42, 110, 111) | Prospective cohort | ||
| Leptin, insulin, and ghrelin | Reduced insulin levels (112) | Prospective (short-term) | |
| Elevated ghrelin levels (113) | Cross-sectional | ||
| Reduced leptin levels (42, 45, 46, 104, 112, 114-116) | Clinical trial | ||
| Bone | Loss of BMD and premenopausal osteoporosis (17, 24, 25, 58, 70, 117, 118) | Randomized controlled trials Reviews, Society guidelines, consensus statements | |
| ↑ NTX, CTX, bone resorption markers (58, 70, 119) | Randomized and nonrandomized trials Cross-sectional | ||
| Stress fractures (120-136) | Systematic review Epidemiological Prospective cohort Case-control | ||
| Immunological | Diminished lymphocyte and increased neutrophil counts (137-139) | Review Randomized controlled trial Prospective cohort | |
| Increased white blood cell counts (73) | Prospective cohort | ||
| Increased IL-6 levels (140-142) | Prospective cohort | ||
| Decreased monocytes and T-cell subpopulation (143) | Prospective cohort | ||
| T-cell hyporesponsiveness (144) | Clinical trial | ||
| Neutrophil hyporesponsiveness and decreased phagocytic activity (145, 146) | Prospective cohort | ||
| Decreased IgA levels (64, 147) | Prospective cohort Cross-sectional | ||
| Increased likelihood of infections and illnesses (64, 147-151) | Cross-sectional | ||
| Muscle and performance | Decreased muscle mass and strength, increased risk of injuries (152-154) | Randomized controlled trial Cross-sectional Prospective | |
| Decreased explosive power (155) | Prospective | ||
| Dysregulation of myokines (156, 157) | Review | ||
| Reduced muscle glycogen content (158) | Crossover randomized controlled trial | ||
| Decreased muscle protein synthesis (159) | Clinical trial | ||
| Diminished activin and increased follistatin concentrations (43, 53, 111, 160, 161) | Clinical trial Prospective | ||
| Impaired sports performance (162) | Review | ||
| Hematological | Iron deficiency anemia (163, 164) | Cross-sectional | |
| Abnormal levels of ferritin and transferrin, elevated levels of hepcidin (73, 142, 165-167) | Cross-sectional Prospective Case-control | ||
| Cardiovascular | Endothelial dysfunction concurrent with HA—association with increased cardiovascular risk (168) | Cross-sectional | |
| Gastrointestinal | Nausea, regurgitation, upper abdominal bloating, diarrhoea, delayed gastric emptying and constipation (169, 170) | Systematic review | |
| Increased intestinal permeability (170, 171) | Systematic review | ||
| Physiological axis . | Manifestation . | Most common study type . | |
|---|---|---|---|
| Endocrine | Hypothalamic-pituitary-gonadal | Functional HA (12, 36, 61, 65, 68, 76-79) | Systematic review Society guidelines Consensus statements Prospective cohort Cross-sectional |
| Diminished gonadotropin (LH, FSH) concentrations and pulses (56, 80-84) | Open-label clinical trial Prospective cohort | ||
| Decreased testosterone concentrations (81-83, 85-91) | Prospective cohort Cross-sectional | ||
| Decreased motile sperm count (86, 92) Abnormal sperm morphology (93) | Cross-sectional | ||
| Hypothalamic-pituitary-thyroid | Reduced thyroid hormone concentrations (42, 57, 85, 94-97) | Case-control Prospective cohort Cross-sectional | |
| Blunted TSH pulse and response to TRH (42, 96) | Cross-sectional Prospective (short-term) | ||
| Hypothalamic-pituitary-somatotropic | Accentuated GH pulse peaks (short-term) (98, 99) | Prospective cohort | |
| Decreased IGF-1 levels (56, 85, 99-103) | Prospective cohort | ||
| Increased IGFBP-1 levels (104) | Clinical trial | ||
| Decreased IGFBP-4, IGFBP-6, GHBP levels (104) | Clinical trial | ||
| Hypothalamic-pituitary-adrenal | Elevated cortisol concentrations (105-109) | Review Prospective cohort | |
| Blunted diurnal salivary cortisol pulse (42, 110, 111) | Prospective cohort | ||
| Leptin, insulin, and ghrelin | Reduced insulin levels (112) | Prospective (short-term) | |
| Elevated ghrelin levels (113) | Cross-sectional | ||
| Reduced leptin levels (42, 45, 46, 104, 112, 114-116) | Clinical trial | ||
| Bone | Loss of BMD and premenopausal osteoporosis (17, 24, 25, 58, 70, 117, 118) | Randomized controlled trials Reviews, Society guidelines, consensus statements | |
| ↑ NTX, CTX, bone resorption markers (58, 70, 119) | Randomized and nonrandomized trials Cross-sectional | ||
| Stress fractures (120-136) | Systematic review Epidemiological Prospective cohort Case-control | ||
| Immunological | Diminished lymphocyte and increased neutrophil counts (137-139) | Review Randomized controlled trial Prospective cohort | |
| Increased white blood cell counts (73) | Prospective cohort | ||
| Increased IL-6 levels (140-142) | Prospective cohort | ||
| Decreased monocytes and T-cell subpopulation (143) | Prospective cohort | ||
| T-cell hyporesponsiveness (144) | Clinical trial | ||
| Neutrophil hyporesponsiveness and decreased phagocytic activity (145, 146) | Prospective cohort | ||
| Decreased IgA levels (64, 147) | Prospective cohort Cross-sectional | ||
| Increased likelihood of infections and illnesses (64, 147-151) | Cross-sectional | ||
| Muscle and performance | Decreased muscle mass and strength, increased risk of injuries (152-154) | Randomized controlled trial Cross-sectional Prospective | |
| Decreased explosive power (155) | Prospective | ||
| Dysregulation of myokines (156, 157) | Review | ||
| Reduced muscle glycogen content (158) | Crossover randomized controlled trial | ||
| Decreased muscle protein synthesis (159) | Clinical trial | ||
| Diminished activin and increased follistatin concentrations (43, 53, 111, 160, 161) | Clinical trial Prospective | ||
| Impaired sports performance (162) | Review | ||
| Hematological | Iron deficiency anemia (163, 164) | Cross-sectional | |
| Abnormal levels of ferritin and transferrin, elevated levels of hepcidin (73, 142, 165-167) | Cross-sectional Prospective Case-control | ||
| Cardiovascular | Endothelial dysfunction concurrent with HA—association with increased cardiovascular risk (168) | Cross-sectional | |
| Gastrointestinal | Nausea, regurgitation, upper abdominal bloating, diarrhoea, delayed gastric emptying and constipation (169, 170) | Systematic review | |
| Increased intestinal permeability (170, 171) | Systematic review | ||
Abbreviations: BMD, bone mineral density; CTX, collagen type 1 C-telopeptide; GHBP, GH-binding protein; HA, hypothalamic amenorrhea; IGFBP, IGF binding protein; NTX, N-terminal telopeptide.
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