Table 1.

Biphasic dose-effect or time-effect of endocrine factors

Hormone	Target	Effect	Reference
Parathyroid hormone	Bone	Constant high-level exposure causes bone loss, while intermittent exposure increases bone mass.	[65][66]
	Insulin secretion	Low-dose stimulates glucose-induced insulin release, while high-dose inhibits it.	[67][68]
Glucocorticoid	Muscle	Chronic treatment exacerbates muscle atrophy, while intermittent weekly treatment enhances muscle repair and improves muscle contractile function.	[69][70]
	Cognitive function	Chronic high-level exposure is associated with increased risk of cognitive decline, while the acute exposure improves memory consolidation but inhibits memory retrieval.	[72][73] [74]
Thyroid hormone	Heart	Hyperthyroidism increases the risk of coronary heart diseases, pulmonary hypertension, and atrial fibrillation. Hypothyroidism causes left ventricular diastolic dysfunction and increases carotid intima-media thickness.	[76]
	Metabolism	Thyroid hormone increases catabolism and energy expenditure. However, the T3 level is positively correlated with unfavorable metabolic parameters in some population.	[77,78]
Adiponectin	Metabolism	Adiponectin improves glucose tolerance and endothelial functions while reduces inflammation and atherosclerosis. But the adiponectin level is positively associated with mortality in coronary heart disease. Adiponectin may exacerbate chronic inflammatory conditions.	[80]
Estrogen	Tumor cell proliferation	Estrogen stimulates tumor cell proliferation at low doses but promotes cell apoptosis at high doses.	[81][82]
	Cardiovascular system	Low-dose activates, while high-dose inhibits, plasminogen activator in aortic endothelial cells.	[84]
	Bone	Estrogen stimulates endochondral bone formation at the start of puberty but induce epiphyseal closure at the end of puberty. In treating Turner syndrome, intermittent low-dose estrogen induces maximal ulnar growth, while high-dose estrogen fails to stimulate ulnar growth.	[86][87]
Progesterone	Memory	Progesterone, when administrated shortly before test, potentiates estradiol-induced effects on extinction recall or spatial memory. However, when administrated a day before the test, progesterone abolishes the estradiol effects.	[89][90]
	Immune response	Long exposure time is associated with poor immune responses to genital herpes. Short treatment is protective against HSV challenge.	[91]
Growth hormone (GH) and IGF-1	Lifespan	Both low and high IGF-I levels are associated with increased mortality. GH can increase muscle mass, reduce adiposity, and improve bone density. However, deficiencies in GH/IGf-1 signaling pathways increases lifespan and healthspan.	[92] [95,99]
Insulin	Blood glucose	Insulin lowers blood glucose levels in diabetes patients. However, suppressing hyperinsulinemia can improve insulin sensitivity and extend lifespan in diet-induced obesity.	[101] [102]
Irisin	Bone	Low-dose weekly treatment increases bone density. However, irisin deficiency also suppresses ovariectomy-induced bone resorption.	[106]