Table of contents :

Helper cytotype => prohormone =>
• glandular cell => hormone
• factor : any of several substances or activities that are necessary to produce a result, e.g., a coagulation factor. Often, use of the term “factor” indicates that the chemical nature of the substance or its mechanism of action is unknown, as in endocrinology, where “factors” are renamed as “hormones” when their chemical nature is determined.
• neuron => neurohormone
• uncharacterized hormone is termed factor
=> modifying cytotype
=> biological effect(s) on target cytotype(s) expressing hormone receptor(s)
Chemical structure :
• small peptides
• large proteins
• amino acid derivatives
• catecholamines
• iodothyronins
• steroids
• retinoids
Plasma concentration relates to :
• synthesis
• incretion, which in turn relates to
• circadian rhythms
• stress
Receptors : 10^3-4 per target cell
Feedbacks :
• negative feedback : R₀ down-regulation
• positive feedbacks : coagulation, ovulation, R₀ up-regulation, choleretic effect
• ultrashort loop feedback : autocrinia. E.g. :
• hypothalamic neurons
• lactotropic cells
• short loop feedback : hormone produced by hypophysis inhibits hypothalamic neurons
• long loop feedback : hormone produced by target organ inhibits hypothalamic neurons
[HR] = R₀ ^. [(K_a ^. [H]) / (K_a + I)]
Scatchard plot : [HR] / [H] vs. [H] is nonlinear when :
• R₁ and R₂ exist with K_a,R1 > K_{a, R2} but R_{0, 1} < R_{0, 2}
• negative cooperativity
Once internalized in clathrin-coated vesicles (CCV), R may be degraded or recycled.
Fractioned turnover ratio (K) = [metabolic clearance ratio] / [distribution volume] ~ 1 / t_1/2 ~ 1 / M_r ~ ([H] + [H-carrier]) / [H-carrier]
Only the quote unbound to carrier(s) can be eliminated by kidneys : the rest is catabolyzed by the liver or within target cell types.
[H] is measured with radioimmunoassays at rest or after challenging.
hormone incretion rate = ([H]_{venous plasma} - [H]_{arterial plasma}) ^. f_blood = CE_H = [H]_plasma ^. metabolic clearance_H = ([H]_urine ^. V_urine ^. metabolic clearance_H) / renal clearance_H. Sometimes there is circadian variability. The first part of the equation can be used to look for ectopic incretion.
Metabolism :
• energy metabolism
• fuel reserves of a healthy (70 kg) adult man :
• fats : 14 kg (125,000 kcal available for energy expenditures)
• protein
• skeletal muscles : 6 kg (24,000 kcal available for energy expenditures)
• other : 6 kg (24,000 kcal available for energy expenditures)
• glycogen
• muscle : 0.15 kg (600 kcal available for energy expenditures)
• liver : 0.075 kg (300 kcal available for energy expenditures)
• free glucose : 0.02 kg (80 kcal available for energy expenditures)
• respiratory quotient (RQ) = V_CO2 / V_O2 =Avogadro's principle=> n_CO2 / n_O2 =
• >1 (FFA synthesis)
• 1  (carbohydrate oxidation)
• 0.8 (protein oxidation)
• 0.7 (FFA oxidation)
On average RQ = 0.82 => 4.85 Kcal are produced for every L of O₂ consumed
• basal metabolic rate (BMR) / basal energy expenditure (BEE) = 4.85 Kcal/L_O2 ^. 371 L O₂/day = 1800 kcal/day = 1000 ^. S [(kcal ^. m²) / die] = 70 ^. m_{lean body}^0.75 [(kcal ^. kg^0.75) / day] (Kleiber's law from fractal geometry). It represents the minimum amount of energy required to keep your body functioning, including your heart beating, lungs breathing, and body temperature normal. BMR measurements are typically taken in a thermally neutral environment in a darkened room upon waking after 8 hours of sleep; 12 hours of fasting to ensure that the digestive system is inactive; and with the subject resting (not sleeping) in a supine or reclining position. Equations have been developed to estimate BMR when testing is not practical :
• Harris-Benedict formula, 1919 :
• for males : 13.7516 x weight(kg) + 500.33 x height(m) - 6.7550 x age(years) + 66.473
• for females : 9.5634 x weight(kg) + 184.96 x height(m) - 4.6756 x age(years) + 655.0955
• Harris-Benedict formula recalculated by Roza-Shizgal :
• for males : 13.707 x weight(kg) + 492.3 x height(m) - 6.673 x age(years) + 77.607
• for females : 9.740 x weight(kg) + 172.9 x height(m) - 4.737 x age(years) + 667.051
According to today's test standards the Harris-Benedict equation does not estimate BMR, but rather RMR. This is because the test subjects did not spend the night at the test facility. The test subjects used to create the Harris-Benedict equation did not include an adequate representation of obese people, nor of younger and older people. These omissions continue to become more significant as our population becomes older and heavier. While all equations for predicting energy expenditure only make estimates, the Harris-Benedict equation typically overestimates by 5% or more.
Approximate BMRs in adults :
• 50 kg : 1300 kcal/day
• 60 kg : 1450 kcal/day
• 70 kg : 1600 kcal/day
• 80 kg : 1750 kcal/day
• 90 kg : 1900 kcal/day
• 100 kg : 2050 kcal/day
• resting metabolic rate (RMR) / resting energy expenditure (REE) : measurements are typically taken under less restricted conditions than BMR, and do not require that the subject spend the night sleeping in the test facility prior to testing. Equations have been developed to estimate BMR when testing is not practical :
•  Mufflin equation :
• for men: 10 x weight(kg) + 625 x height(m) - 5 x age(years) + 5
• for women: 10 x weight(kg) + 625  x height(m) - 5 x age(years) - 161
• metabolic rate (MR) : BMR (60-75%) + physical activity (15-30%) + diet-induced thermogenesis (7-13%) = 2,700 Kcal/day. Every day we introduce 1 kg food, 1.5 kg H₂O and 15 kg air into our bodies
• sedentary males and females : BMR x 1,375
• active males and females : BMR x 1,55
The equations do not take into account your body composition (percent muscle vs. fat) and are therefore less accurate if you have a non-typical amount of muscle. This is because muscle burns more calories than fat.
• intermediate metabolism
• anabolism
• catabolism
• evacuative metabolism
Specific resources
• epiphysis / pineal gland (see also diseases of epiphysis)

Embryogenesis : epiphyseal arch : the embryonic structure in the roof of the third ventricle from which the pineal body develops.
2 forms of biomineralization
• mulberry-type hydroxyapatite crystals
• cubic, hexagonal, and cylindrical calcite crystals < 20 mm in length with sharp edges and very rough surfaces. The calcite microcrystals are probably responsible for the previously observed second harmonic generation in pineal tissue sections
It is believed that the presence of 2 different crystalline compounds in the pineal gland is biologically significant, suggesting 2 entirely different mechanisms of formation and biological functions. Studies directed toward the elucidation of the formation and functions, and possible nonthermal interaction with external electromagnetic fields are currently in progress^ref
Cell types :
• pinealocytes / chief cells / epithelioid cells produce
• melatonin

Secretion is :
• inhibited by
• stress
• awakening
• light (retina =retinosuprachiasmatic tract=> suprachiasmatic nucleus of hypothalamus => paraventricular nucleus => epithalamus)
• stimulated by
• rest
• sleeping
Biological effects via MLT₁ and MLT₂ :
• in adult amphibians it produces lightening of the dermal pigmentation by promoting aggregation of melanosomes
• in mammals it influences hormone production and in many species it regulates seasonal changes such as reproductive pattern and fur color
• in humans it is implicated in the regulation of sleep, mood, puberty, and ovarian cycles (inhibition of GnRH / LHRH incretion)
• adrenoglomerulotropin is a substance occurring in blood and CSF that is thought to be secreted by the brain or pineal gland and is reported to stimulate aldosterone secretion by the adrenal glands
• interstitial cells : cells with elongated nuclei and long cytoplasmic processes, found in the perivascular areas and between the cords of pinealocytes in the pineal body, and regarded by some to be glial elements
• hypothalamus : the ventral part of the diencephalon that forms the floor and part of the lateral wall of the third ventricle. Anatomically, it includes the
• preoptic area / area preoptica / preoptic region : several groups of cells in the median plane immediately below the rostral commissure of the telencephalon that are functionally related to the hypothalamus
• optic tract
• optic chiasm
• mammillary or mamillary bodies / corpora mamillares : either of the pair of small spherical masses situated close together in the interpeduncular space rostral to the posterior perforated substance in the posterior hypothalamic region, consisting of two main nuclei, lateral and medial, and smaller associated aggregations of gray matter. It forms a portion of the limbic system
• tuber cinereum / tuberculum cinereum / gray tubercle : a layer of gray matter which is part of the hypothalamus; forming a part of the floor of the third ventricle, it lies in front of and between the corpora mammillaria and merges anteriorly into the infundibulum
• infundibulum
• neurohypophysis (considered a distinct structure for physiological purposes)
The hypothalamus may be divided into 5 regions or areas
• area hypothalamica rostralis / anterior hypothalamic area / preoptic area or region / regio hypothalamica anterior / anterior hypothalamic region : the most anterior part of the hypothalamus, lying adjacent to the lamina terminalis and superior to the optic chiasm, and comprising the lateral and medial preoptic nuclei, the supraoptic and paraventricular nuclei; and the anterior hypothalamic nucleus
• area hypothalamica dorsalis / dorsal hypothalamic area / regio hypothalamica dorsalis / dorsal hypothalamic region : the most dorsal part of the hypothalamus, comprising the entopeduncular nucleus and the nucleus of the ansa lenticularis
• area hypothalamica intermedia / intermediate hypothalamic area / regio hypothalamica intermedia / intermediate hypothalamic region : the part of the hypothalamus comprising the lateral hypothalamic region and the following nuclei: arcuate, tuberal, ventromedial hypothalamic, dorsomedial hypothalamic, dorsal hypothalamic, posterior periventricular, and infundibular
• area hypothalamica lateralis / lateral hypothalamic area / regio hypothalamica lateralis and lateral hypothalamic region : a part of the intermediate hypothalamic area lateral to the fornix and the mammillothalamic fasciculus
• area hypothalamica posterior / posterior hypothalamic area / regio hypothalamica posterior / posterior hypothalamic region : the most posterior part of the hypothalamus, consisting of the lateral and medial nuclei of the mammillary body and the posterior hypothalamic nucleus
... or into 3 longitudinal zones :
• periventricular zone
• medial zone
• lateral zone
The hypothalamic nuclei constitute that part of the corticodiencephalic mechanism that activates, controls and integrates the peripheral autonomic mechanisms, endocrine activity, and many somatic functions, e.g., a general regulation of water balance, body temperature, sleep, and food intake, and the development of secondary sex characteristics.
• supraoptic and paraventricular nuclei secrete vasopressin (VP) / antidiuretic hormone (ADH) and oxytocin (from neurohypophysis), which are stored in the pituitary
• arcuate and periventricular nuclei secrete many hypophysiotropic hormones in a pulsatile manner, by means of which it exerts control over functions of the adenohypophysis :
• releasing factors / releasing hormones are termed -crinins or -liberins
• inhibiting factors / inhibiting hormones are termed -statins
• CRH-increting neuron. Secretion is :
• stimulated by :
• noradrenaline
• serotonin
• acetylcholine
• GABA
Biological effects via CRHR₁ and CRHR₂ :
• induction of ACTH secretion in corticotropic cells of adenohypophysis
• a maternal mouse will attack any intruder to her nest if she thinks her pups are in danger. This apparently selfless response may be due to low levels of CRH. High levels of CRH in the brain are linked to fear and anxiety. So without it, a mouse is more likely to leap towards an intruder without a thought for herself. Perhaps lactation stimulates the brain to produce less CRH. Or maybe the brain's cells simply become less responsive to the hormone. Human postnatal depression is often linked to high levels of stress hormones. Some 10-15% of new mothers experience depression lasting > 2 weeks after giving birth, and around 50% of these require treatment with existing antidepressant medications. The fact that many depressed new mothers seem not to care about their baby's wellbeing could be because their raised levels of stress hormones prevent the low levels of CRH that seem to be required for the care of offspring.
• GnRH / LHRH-increting neuron. Secretion is :
• inhibited by ...
• dopamine
• melatonin
• b-endorphin
• stimulated by ...
• noradrenaline
GnRH neurons receive pheromone signals from both odor and pheromone relays in the brain and may also receive common odor signals. Moreover, feedback loops are evident whereby GnRH neurons could influence both odor and pheromone processing. Remarkably, 800 GnRH neurons communicate with 50,000 neurons in 53 functionally diverse brain areas, with some connections exhibiting sexual dimorphism^ref. Injection of conditional pseudorabies virus into the brain of an LHRH::CRE mouse line led to the identification of neuronal networks connected to LHRH neurons. Remarkably, and in contrast to established notions on the nature of LHRH neuronal inputs, major olfactory projection pathways were identified originating from a discrete population of olfactory sensory neurons but fail to document any synaptic connectivity with the vomeronasal system. Accordingly, chemosensory modulation of LHRH neuronal activity and mating behavior are dramatically impaired in absence of olfactory function, while they appear unaffected in mouse mutants lacking vomeronasal signaling. Further visualization of afferents to LHRH neurons across the brain offers a unique opportunity to uncover complex polysynaptic circuits modulating reproduction and fertility^ref.
t_1/2 = 4' (degraded by both hypothalamic and pituitary peptidases) : small quantities are found in the peripheral blood of nonpregnant females during the menstrual cycle. Pulsatile incretion (every hour) :
• higher frequencies cause initial gonadotropin increase for 4 hours, then a decrease termed pituitary densensitization (medical castration) via down-regulation of pituitary GnRH-R
• lower frequencies cause increase of FSH concentration due to slower metabolic clearance than LH
Biological effects via GnRH-R : induction of FSH and LH secretion in gonadotropic cells of adenohypophysis
• GHRH-increting neuron. Secretion is :
• stimulated by
• high protein diet
• fasting
Biological effects via GRP39 and GRP38 / MTLR1: induction of GH incretion in somatotropic cells of adenohypophysis
• TRH-increting neuron. Secretion is :
• stimulated by :
• estrogens
• serotonin
• histamine
• low temperature
• feeding
• inhibited by :
• glucocorticoids
• GABA
• DA
• adrenalin
• ACh
Normal plasma concentration : 25-100 pg/mL
Biological effects via TRH-R : induction of PRL incretion in lactotropic cells and of TSH incretion in thyrotropic cells of adenohypophysis
Secretions are regulated by neurons using as neurotransmitters
• dopamine
• acetylcholine
• GABA
• b-endorphin
• PACAP
Vascularization : hypophysiotrophic factors are released into superior hypophysary plexus, while hypophysary hormones are relased into lower hypophysary plexus. A third capillary plexus joins the 2 abovementioned plexuses and vascularize anterior pituitary gland (rete mirabile venosa)
• hypophysis (cerebri) / pituitary gland is located outside of the blood-brain barrier (BBB)
• anterior hypophysis / adenohypophysis / anterior pituitary / anterior lobe of hypophysis / lobus anterior hypophyseos / lobus glandularis hypophyseos (see also diseases of adenohypophysis) : it  has its origin in the Rathke pouch of buccal epithelium of the embryo and comprises
• pars tuberalis (near tuber cinereum of hypothalamus)
• pars distalis, the main body of the adenohypophysis. Its hormones are said -tropins when they target other endocrine glands.

Cell types :
• somatotrope or somatotroph or somatotropic cell / somatotroph increte growth hormone (GH) : secretion has zenit at 8 a.m. and nadir at 6 p.m.. Tissue-specific transcription factors : PROP-1, PIT1. Onset at fetal week 8. It is :
• stimulated by GH secretagogues (GHS) :
• hormonal stimuli
• GHRH
• ghrelin
• estrogens
• T₃
• cortisol
• glucagon
• vasopressin / ADH
• insulin
• prostaglandins
• metabolic stimuli
• L-Arg
• L-Lys
• L-Leu
• starvation
• hypoglycemia
• uremia
• ectopic CRF production
• inhibited by
• hormonal stimuli
• IGF-1
• SST / somatotropin release inhibiting factor (SRIF)
• metabolic stimuli
• hyperglycemia
• free fatty acids
• obesity
Secretion rate : 0.5-2 mg/die. Carrier proteins :
• albumin
• high affinity growth hormone binding protein (GHBP) is the soluble ectodomain of GHR (in other species it is a splice variant of the Ghr gene) generated by TNF-alpha converting enzyme (TACE) / ADAM17 and possibly related enzymes
t_1/2 = 20-25' .
Normal plasma concentration :
• fetus : 150 ng/mL
• birth : 40 ng/mL
• babies > 10 ng/mL or > 465 pmol/L
• adult : 1-5 ng/mL (100 pM)

	after physical effort	after Glc challenge
males	< 5 ng/mL or < 233 pmol/L	< 5 ng/mL or < 233 pmol/L
females	< 30 ng/mL or < 1395 pmol/L

Biological effects : the response to GH incretion is biphasic
• first indirect (IGF-1-dependent) insulin-like effects via IGF-1R / CD221 (also IGF-2-dependent effects via IGF-2R in embryo):
• stimulation of amino acids transport into cells
• stimulation of protein synthesis if amino acid are introduced with diet
• stimulation of increased muscle mass
• stimulation of bone growth
• stimulation of epiphysary cartilage growth acting on chondrocytes (they also have autocrine IGF-1 incretion)
• stimulation of nucleic acid synthesis and cell proliferation
Plasma carriers for IGFs :
• IGF-binding protein (IGFBP1)
• IGFBP2
• IGFBP3 (major carrying protein)
• IGFBP4
• IGFBP5
• IGFBP6
• IGFBP7
• IGFBP8 / connective tissue growth factor (CTGF)
• IGFBP9 / nephroblastoma overexpressed gene (NOV)
• IGFBP10 / cysteine-rich, angiogenic inducer, 61 (CYR61)
Normal IGF-1 plasma concentration :
• month 2 - age 5 : 17-250 ng/mL
• age 6-12 : 88-770 ng/mL = 0.08-2.8 U/mL
• age 13-15 : 200-1100 ng/mL
• age 16-24 : 180-780 ng/mL = 0.9-5.9 U/mL
• age 25-50 : 90-490 ng/mL
• adult male : 0.34-1.9 U/mL
• adult female : 0.45-2.2 U/mL
• age > 50 : 71-290 ng/mL
• then direct (IGF-1-independent) anti-insulin effects via GHR (glucagon-like effects, but systemic, hence adrenalin-like, important during first days of starvation) :
• diabetic ketoacidosis
• hyperglycemia
• insulin resistance => hyperinsulinism
• gluconeogenesis
• ketogenesis
• lipolysis
• stimulation of protein synthesis if amino acid are introduced with diet
• Na⁺ / H₂O retention
• stimulation of epiphysary cartilage growth acting on chondroblasts
• gonadotrope, gonadotroph or gonadotropic cells / gonadotroph (basophilic cells). Tissue-specific transcription factors : SF-1, DAX-1. Onset at fetal week 12.
• follicle-stimulating hormone (FSH)-increting cell.

Secretion is monophasic and
• stimulated by :
• GnRH / LHRH
• activin A (inhibited by follistatin)
• activin AB (inhibited by follistatin)
• inhibited by :
• inhibin
Secretion rate : 200 IU/day. Pulsations are slower than for LH : they occur every 1-2 hours in follicular phase and every 4 hours in luteal phase. t_1/2 = 180'.
Normal plasma concentration :
• males
• prepuberal males : < 3 mIU/mL
• adult males : 3-18 mIU/mL
• females
• prepuberal females : 0.8-7.2 mIU/mL
• adult females
• follicular stage : 2.9-10.2 mIU/mL
• half-cycle peak = 13-41 mIU/mL
• periovulatory stage : 4.4-22.4 mIU/mL
• luteinic stage : 1.3-7.1 mIU/mL
• postmenopause : 30-170 mIU/mL
Biological effects via FSH-R (up-regulated by estradiol / E₂) :
• induces granulosa cells to up-regulate aromatase / CYP19 expression (hence promoting conversion of testosterone into 17b-stradiol / E₂), and then LH / hCG-R (accompanied to down-regulation of FSH-R); also induces secretion of follicular fluid
• induces Sertoli cells to increte AMH
• luteinizing hormone (LH)-increting cell

Secretion is biphasic and stimulated by GnRH / LHRH and high dose estradiol / E₂. With onset of puberty LH concentratios become higher than FSH and pulsatile increation pattern of LH occurs even during daytime (no longer only during sleep)
Secretion rate : 1,000 IU/day. t_1/2 = 30'.
Normal plasma concentration :
• males :
• prepuberal males : < 1.7 mIU/mL
• adult males : 3-18 mIU/mL
• females
• prepuberal females : < 2.5 mIU/mL
• adult females
• follicular stage : 0.9-9.7 mIU/mL
• periovulatory stage : 5-57 mIU/mL
• pre- and postovulatory stage : 2.4-34.5 mIU/mL
• half-cycle peak : 43-187 mIU/mL
• luteinic stage : 0.6-9 mIU/mL
• postmenopause : 30-150 mIU/mL
Biological effects via LH / hCG-R :
• induces Leydig cells to produce testosterone
• induces granulosa cells and inner techa cells to produce testosterone and progesterone
• lactotrope or lactotroph or lactotropic cell / lactotroph increte prolactin (PRL) / lactotropin : secretion has zenit at 12 p.m. and nadir at 8 a.m. Tissue-specific transcription factors : PROP1, PIT1. Onset at fetal week 12. It is
• stimulated by :
• TRH (increase >> 100%)
• VIP
• estradiol / E₂
• suction of nipple of lactating breast
• sleep
• stress
• physical exercise
• inhibited by :
• DA
• SST
Both a reserve pool and a release pool exist.
Secretion rate : 50-200 IU/day. t_1/2 = 20-80'.
Normal plasma concentration : 2-15 ng/mL = 0.08-6 nmol/L
• prepuberal males : 25-350 mIU/L (1-20 ng/mL)
• adult males : 71-330 mIU/L
• prepuberal females : 88-590 mIU/L
• follicular stage : 93-467 mIU/L
• periovulatory stage : 145-261 mIU/L (5-25 ng/mL)
• luteinic stage : 106-551 mIU/L
• menopause : 69-360 mIU/L
Biological effects via PRLR : hypertrophy of mammary gland
• corticotrope cell / corticotrophlipotroph cell / corticotroph increte adrenocorticotropic hormone (ACTH) / corticotropin. Tissue-specific transcription factors : PTX-1, CUTE. Onset at fetal week 6. Secretion is :
• stimulated by
• stress and physical exercise
• insulin-induced hypoglycemia
• CRH
• vasopressin / ADH via V_{1b / 3}
• serotonin
• histamine
• acetylcholine
• inhibited by
• GABA
• cortisol
t_1/2 = 10-25'. Normal plasma concentration at 6 a.m. : 15-70 pg/mL (3.3-15.4 pmol/L)
Incretion rate : 25 mg/die.
Biological effects via MC2R / ACTHR :
• induction of cortisol secretion by zona reticularis, fasciculata, and glomerularis of adrenal cortex
• induction of lipolysis
• thyrotrope or thyrotroph or thyrotropic cell / thyrotroph secrete TSH / thyrotropin : secretion has zenit at 12 p.m. and nadir at 8 a.m. Tissue-specific transcription factors : PROP-1, PIT-1. Onset at fetal week 12. It is :
• stimulated by :
• TRH (15' after exogenous administration)
• estradiol / E₂
• prostaglandins
• inhibited by :
• DA
• 3,5,3'-triiodothyronine (L-T₃)
• SST
• cholecystokinin (CCK)
• gastrin
• serotonin
• cortisol
• testosterone
• neurotensin (induced by vasopressin / ADH)
Normal plasma concentration : 0.5-5.0 mU/mL. t_1/2  = 50' => very few fluctuations despite pulsating secretion.
Biological effects via TSH-R : induction of thyroid hormones incretion
• chromophobe cells / chromophobic cells / C cells / chief cells / g cells of hypophysis : small, faintly staining cells with scanty cytoplasm found often in clusters in the center of the cell cords in the adenohypophysis; their cytoplasm was formerly thought to be nongranular, but the granules are now known to be simply small and sparse. These cells are increased in chromophobic or null-cell adenomas
• pregnancy cell : an altered chromophobe cell found in the adenohypophysis in pregnant women
• S cells : mucoid cells of the adenohypophysis that contain a cysteine-rich protein
• pars intermedia  / intermediate hypophysis (sometimes considered to be part of the neurohypophysis; see also diseases of intermediate hypophysis)

Cell types :
• b-endorphin

Biological effects via  :
• inhibition of CRH incretion
• inhibition of GnRH / LHRH incretion
• inhibition of oxytocin (OT) incretion
• a-MSH- and g-MSH-increting cell. Secretion is :
• stimulated by :
• ADH
Biological effects via MC1R => ... => CREB => MITF => tyrosinase-related protein-1 (TRP-1) and tyrosinase-related protein 2 (TRP2) / dopachrome tautomerase (DCT) => increased melanin synthesis in melanocytes
• b-LPH- and g-LPH-increting cell

Biological effects via MC1R :
• pharyngeal hypophysis / pars pharyngea lobi anterioris hypophyseos / pharyngeal pituitary / hypophysis pharyngealis : a small median residual collection of adenohypophysial glandular tissue in the mucoperiosteum of the roof of the nasopharynx; it develops from Rathke's pouch in the embryo
• posterior hypophysis / neurohypophysis / posterior pituitary / posterior lobe of hypophysis or of pituitary gland / lobus posterior hypophysis (see also diseases of neurohypophysis) : the posterior lobe of the hypophysis (pituitary gland), the neural portion of the gland. It consists of
• neural stalk
• infundibulum which is continuous with the supraoptic and paraventricular nuclei in hypothalamus
• median eminence
• neural lobe : the main body of the neurohypophysis
It originates in the embryo as an evagination from the floor of the diencephalon.
Cell types : hormone-containing granules are seen at TEM as Herring bodies.

• oxytocin (OT)- and neurophysin I-increting cell

Biological effects via OT receptor
• induction of labor
• post-partum hemostasis
• lactation
Inactivated by OTase / oxytocinase / leucyl/cystinyl aminopeptidase (LNPEP)
• arginine vasopressine (VP) / antidiuretic hormone (ADH)- and neurophysin II-increting neurons are parvicellular neurons of paraventricular nucleus

Secretion is
• stimulated by :
• plasma hyperosmolarity (osmoceptors)
• hypovolemia => systemic arterial hypotension (baroceptors, far less sensitive)
• nausea and vomiting
• pain
• stress
• pregnancy
• hypoglycemia
• hypoxia
• drugs :
• morphine
• nicotine
• cyclophosphamide
• inhibited by
• plasma hypoosmolarity
• hypervolemia => systemic arterial hypertension
• drugs :
• ethanol
• clonidine
• haloperidol
Biological effects : induces expression of vasopressin-induced transcript (VIP32) and activates cullin 5 (CUL5) / vasopressin-activated calcium-mobilizing receptor-1 (VACM1)
• V_1a : ejaculation and arteriolar vasoconstriction
• V_1b / V₃ : stimulation of ACTH incretion
• V₂ : increased H₂O reabsorption from distal convoluted renal tubule and collecting duct via up-regulation of aquaporin 2 translocation into apical membrane of principal cells
Inactivated by OTase / oxytocinase / leucyl/cystinyl aminopeptidase (LNPEP)
The hypophysis root consists of pars tuberalis adenohypophysis and neural stalk.
• thyroid / glandula thyroidea (see also diseases of thyroid) : an endocrine gland normally situated in the lower part of the front of the neck, consisting of 2 lobes, one on either side of the trachea and joined in front by a narrow isthmus

Ontogenesis : at week 3 of pregnancy the gland on the floor of embryonary pharynx at the level of foramen caecum in the posterior part of the tongue invaginates into the Bochdalek, His or Vater thyroglossal or thyrolingual duct / ductus thyroglossalis; in 75% of people the distal part of the duct differentiates to form the pyramidal lobe the thyroid and the remainder becomes obliterated, but occasionally persists into adult life, giving rise to cysts, fistulas, or sinuses or small salivary glands in the last part
Lobes :
• left lobe
• right lobe (usually larger than left one)
• Morgagni-Lalouette's pyramidal lobe of thyroid gland / lobus pyramidalis glandulae thyroideae : an occasional third lobe (found in 15-80% of people) that extends upward from the isthmus of the gland across the thyroid cartilage to the hyoid bone; it is the residuum of the thyroid stalk of the fetus
Vascularization :
• upper thyroideal artery
• lower thyroideal artery
• Neubauer's artery
TFs essential for thyroid development : thyroid transcription factor 1 (TTF-1) / NKX2A, FOXE1 / TTF-2 / FKHL15, and PAX8
Cell types :
• follicular epithelial cells of the thyroid / thyrocyte form follicles 30 mm in diameter and secrete :
• thyroglobulin is a p330 monomer containing 134 Tyr residues : only 30-40 are iodated, but steric hindrance allows only 8-10 pairings, so that only 4 or 5 iodothyronin molecules are formed per thyroglobulin molecule. TG is arranged into 19S dimers or 27S tetramers. Thyroid peroxidase (TPo) catalyzes :
• the iodination of tyrosine residues to 3- or 5-monoiodothyronin (MIT) or 3,5-diiodothyronin (DIT) in thyroglobulin (iodine enters thyrocytes via NIS ; see also iodine metabolism)
• phenoxy-ester formation between pairs of iodinated tyrosines to generate
• the thyroid hormones
• 3,5,3'-triiodothyronine (L-T₃) (10%; 6.4 mg/die; 20% of total L-T₃)
• 3,5,3',5'-tetraiodothyronine / thyroxine (L-T₄) (80%; 90 mg/die)
• inactive hormone 3,3',5'-triiodothyronine (reverse T₃ / L-rT₃) (< 1%)
Secretion is :
• stimulated by :
• prostaglandins
• estradiol / E₂
• VIP
• gastrin-releasing peptide (GRP)
• helodermin-like peptide
• inhibited by :
• acetylcholine
• neuropeptide Y (NPY)
• noradrenaline
• somatostatin (SST)
• calcitonin
• katacalcin
• calcitonin gene-related peptide (CGRP)
• endothelin
• atrial natriuretic peptide (ANP)
• growth factors
• IGF-1
• EGF
• cytokines
• TGF-b
The prohormone L-T₄ is peripherally converted to bioactive 3,3',5-L-T₃ (25.6 mg/die; 80% of total L-T₃) via 5'-deiodination / outer ring deiodination (ORD) catalysed by :
• deiodinase 1 (D₁) (liver, kidney, thyroid; low affinity for L-T₄ ). It also degrades both L-T₄ and 3,3',5-L-T₃ by inner ring deiodination (IRD).
• deiodinase 2 (D₂) (brain, pituitary, brown adipose tissue, heart, skeletal muscle, and thyroid; high affinity for L-T₄)
20% of L-T₄ and 70% of 3,3',5-L-T₃ are located intracellulary.
Deiodinase 3 (D₃) (placenta, several fetal tissues, skin, brain) > deiodinase 2 (D₂) catalyzes the 5-deiodination (IRD) of
• L-T₄ to 3,3',5'-triiodothyronine (reverse T₃)
• 3,3',5-L-T₃ to 3,3'-T₂ (inactive metabolite)
All iodinated catabolytes are sulfated and glucunated in hepatocytes.

	t1/2	plasma concentration	plasma molarity
TT4	7 days	4-12 mg/dL	52-154 nM
FT4		0.7-2.3 ng/dL (0.02%)	9-20 pM
TT3	0.75 day	75-195 ng/dL	1.16-3 nM
FT3		0.25-0.58 ng/dL (0.3%)	4-8 pM
T3 resin captation		25-25%
TrT3	0.8 days	0.04 mg/dL
FrT3		13-53 ng/mL	0.2-0.8 nM
thyroxin-binding globulin (TBG) / SERPINA7 (it binds 67% of BT4 and 1% of BT3)		2 mg/dL
TBG-binding capacity		15-24 mg T4/dL	193-322 nM
transthyretin / thyroxin-binding prealbumin (TBPA)	< 2 days	15 mg/dL
albumin	20 hours	3.5-5.2 g/dL
thyroglobulin (TG)		3-30 ng/mL

thyroid function test : any of various diagnostic procedures measuring the functioning of the thyroid gland
• protein-bound iodine test (no longer used) : the amount of iodine firmly bound to protein in the serum was determined by precipitating the proteins, yielding an estimate of serum thyroid hormone concentration. Errors were introduced if iodine compounds from nonthyroid sources were present
• perchlorate discharge test : 1-2 hours after administration of radioiodine, perchlorate is administered to block further iodine uptake and flush from the thyroid gland any that has not bound to thyroid proteins. In euthyroid patients only trace amounts will be flushed out; the discharge of significant amounts indicates a defect in thyroid iodine binding.
• thyroid-stimulating hormone (TSH) stimulation test : a thyroid function test in which thyrotropin (TSH) is administered intramuscularly and the thyroid gland is monitored over time with scintiscanning or radioimmunoassays for a response or areas of decreased responsiveness. The test was formerly also much used for determining whether hypothyroidism was caused by thyroid gland failure or by deficiency in thyrotropin
• thyrotropin-releasing hormone (TRH) stimulation test (for pituitary release of thyrotropin): a bolus of TRH is administered and serum concentrations of thyrotropin are assessed at intervals; if serum levels do not increase within 30 to 40 minutes, the pituitary thyrotrophs are dysfunctional
• thyroid suppression test : after administration of liothyronine for several days, radioactive iodine uptake is decreased in normal persons but not in those with hyperthyroidism
• radioactive iodine uptake test : a known quantity of radioiodine is administered and 24 hours later the per cent is calculated that has been absorbed by the thyroid gland. Patients who have recently been exposed to iodine compounds, such as in dietary supplements, contrast media, medications, or antiseptics, may not be good candidates for this test
• triiodothyronine resin uptake test : measuring how many sites on TBG are occupied by endogenous T₃ and how many sites remain available. An excess of radioactive exogenous triiodothyronine is added to the sample, followed by the addition of a resin that also binds T₃. A portion of the radioactive T₃ binds to sites on TBG not already occupied by endogenous thyroid hormones, and the remainder binds to the resin. The amount of labeled hormones bound to the resin (the triiodothyronine resin uptake) can be subtracted from the total that was added and the remainder is the amount that bound to the unoccupied binding sites on the thyroxine-binding globulin.
• thyroid hormone binding ratio (THBR) at T₃ resin uptake text
• FT₃ index = THBR ^. FT₃  : an estimate of the physiologically active free triiodothyronine in serum
• FT₄ index = THBR ^. FT₄  : an estimate of the physiologically active free thyroxine in serum
Only T₃ binds TRs, ubiquitously expressed (pantropic hormone)
Biological effects of 3-iodothyronamine (T₁AM) via trace amine receptor 1 (TAR1) : profound hypothermia and bradycardiawithin minutes^ref
Biological effects of F3,5,3'-triiodothyronine (L-T₃) via T3Ra and T3Rb, the effects of which manifest over hours and days :
• differentiation of most organs (CNS, exocrine pancreas, liver, heart ventricles, skull, lungs, gametogenesis)
• increases in metabolic rate : proteolysis
• positive inotropic effect (up-regulation of b₁-AR)
• tachycardia
• hyperglycemia due to
• insulin resistance
• increased intestinal glucose absorption
• glycogenolysis
• gluconeogenesis
=> diabetic ketoacidosis
• hyperthermia :
• up-regulation of uncoupling proteins (UCP) in mitochondria
• lipogenesis => lipolysis => ketogenesis
• awakening
• calcitonin gene-related peptide (CGRP)

Biological effects via CGRP receptor :
• vasodilatation
• cardiac inotropism
• C-cells (for corpus ultimus branchialis = ultimobranchial body (UBB)) / parafollicular cells / light cells : ovoid cells with an irregular nucleus and many brown or black cytoplasmic granules, located in the follicular epithelium and interfollicular spaces along with the principal cells of the thyroid follicles, and which elaborate calcitonin (M_r = 3.4 kDa; see also calcium metabolism)


Procalcitonin (ProCT / PCT) is a protein consisting of 116 aminoacids with molecular weight 13-14 kDa encoded by the Calc-1 gene along with calcitonin and katacalcin. It a positive acute phase protein (APP). ProCT is cleaved enzymatically into free aminoprocalcitonin (N-ProCT) and the conjoined calcitonin:calcitonin-carboxypeptide-I (CT:CCP-I). The latter, in turn, is processed into free CCP-I and immature CT. In granules the 33 amino acid immature CT is then amidated by the enzyme peptidylglycine-
amidating-monooxygenase (PAM) to yield the 32 amino acid mature CT. All these peptides are found in the serum of normal persons.
Secretion is :
• stimulated by :
• CASR activation
• CCK₂ agonists : gastrin and cholecystokinin (CCK)
Normal plasma concentration :
• males : 0-14 pg/mL = 0-4.1 pmol/L
• females : 0-28 pg/mL = 0.8.2 pmol/L
Biological effects via calcitonin receptor :
• inhibition of Ca²⁺ reabsorption => hypocalcemia
• stimulation of P_i reabsorption => hyperphosphatemia
It is more important in salt-water animals.
They arise during embryonic life from the fifth pharyngeal pouches and are incorporated in the thyroid gland in mammals, but form discrete epithelial cell masses (ultimobranchial bodies) in submammalian vertebrates.
• parathyroids / Gley's glands / Sandström's bodies / epithelial or parathyroid bodies (4 or more) (see also calcium metabolism) (see also diseases of parathyroids) : small bodies (2 x 3 x 7 mm) apposed to the posterior surface of the thyroid gland (paler and harder), developed from the endoderm of the branchial clefts, for an overall weight of 150 mg


..., occurring in a variable number of pairs, commonly 2 :
• glandula parathyroidea superior (from the endoderm of the third branchial cleft)
• glandula parathyroidea inferior (from the endoderm of the fourth branchial cleft, as thymus, within which are sometimes found)

> 90% are located above the transjugular line.
The parenchyma comprises masses and cords of epithelial cells, which have been divided into 2 main types :
• chief cells / principal cells : the most abundant cells of the parathyroid glands, being polygonal epithelial cells rich in glycogen, having granular cytoplasm and vesicular nuclei, and arranged in plates or cords.They are sometimes divided between
• clear cells : more numerous, clear cytoplasm, large nuclei, and few granules
• wasserhelle cell / water-clear cell : a large clear cell found in the parathyroid gland; these cells have a ballooned appearance and are especially numerous in adenoma of the gland.
• dark cells : cytoplasm with smaller, darker nuclei and many fine granules
Intermediate forms also exist. They secrete :
• parathormone (PTH) (M_r = 9 KDa). Secretion is
• inhibited by
• activation of calcium-sensing mechanisms :
• voltage-dependent L-type calcium channels
• CASR
• G_iPCRs :
• a₂-AR
• EP₃
• parastatin
• activated by G_sPCRs :
• histamine via H₂ receptors
• adrenalin via b-AR
• dopamine via D₁ and D₅ receptors
Vitamin D status is the major factor determining the circulating levels of PTH^ref
Normal plasma concentration < 25 pg/mL or < 2.94 pmol/L. Serum levels of PTH, osteocalcin, and N-telopeptide of collagen cross-links have diurnal variations, with a peak in the early morning, between 3 a.m. and 5 a.m.; PTH levels also have a second peak at 5 p.m. Levels of both osteocalcin and N-telopeptide of collagen cross-links have nadirs in the afternoon and evening (between noon and 8 p.m.), whereas PTH levels have two nadirs — at 10 a.m. and 9 p.m. — that follow the two peaks^{ref1, ref2, ref3}
Biological effects via PTHR1 and PTHR2 :
• enhanced Ca²⁺ reabsorption => hypercalcemia
• intestinal
• proximal renal tubule, thick ascending limb of Henle's loop and distal renal tubule : PTH decreased VDR expression^ref
• bone (expressed on osteoblasts)
• enhanced P_i reabsorption to prevent precipitation of calcium phosphate during hypercalcemia => hypophosphatemia
• intestinal
• proximal renal tubule
• bone (expressed on osteoblasts)
• inhibited reabsorption of Na⁺ and HCO₃^-
It is more important in land animals.
• parastatin (a fragment of chromogranin A)
• PTH-related protein (PTHrp)

Biological effects via PTHR1 are the same as for PTH.
• oxyphil or oxyphilic cells are acidophilic APUD cells; they increase in number with age, have small dark nuclei and abundant finely granular cytoplasm, and are larger and have many more mitochondria than the chief cells
• adipose tissue (see also diseases of adipose tissue)

Cell types :
• adipocyte / fat cell / adipose cell / lipocyte : such cells are bloated with globules of triglycerides, the nucleus being displaced to one side and the cytoplasm seen as a thin line around the fat droplet.
• white fat adipocyte
• Imlach's fat plug : a mass of fatty tissue sometimes found at the mesial angle of the external inguinal ring.
• brown fat adipocyte : in a human newborn, multilocular or brown adipose tissue (BAT) constitutes 2-5% of the body weight and is distributed as shown. The black areas indicate multilocular adipose tissue; shaded areas are a mixture of multilocular and unilocular adipose tissue. BAT helps maintain normal body temperature in newborn infants. It is believed that this tissue regresses with increasing age and is completely lost by the time a person reaches adulthood^ref. However, the capacity to produce brown adipose tissue in adulthood has been shown in patients with catecholamine-secreting tumors such as pheochromocytomas and paragangliomas, in whom distinct brown-adipose-tissue depots develop^{ref1, ref2}. When scanning with a combination of PET and computed tomography (CT) — with the glucose analogue ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) as a tracer — is used in the diagnosis of neoplasms and their metastases, the results can be confounded by a high glucose uptake in the supraclavicular tissue; this increased glucose uptake has been thought to represent the presence of brown adipose tissue^ref. This view has been supported by the localization of the ¹⁸F-FDG in adipose tissue on CT images^ref and its sensitivity to propranolol^ref and to environmental temperature before PET scanning^ref; furthermore, this phenomenon occurs more often during the cold winter months than in the summertime^ref. However, to our knowledge and as has been noted in a recent review^ref, there are no direct data that clearly show that tissue from these areas of cold-induced ¹⁸F-FDG uptake in healthy adult subjects indeed has histologic features of brown adipose tissue and expresses mRNA and proteins that distinguish it from white adipose tissue. This is an important point, since such data would be necessary to identify bona fide brown adipose tissue in healthy adults and to indicate that such tissue is part of normal human physiology after infancy. Using PET, cold-induced glucose uptake was increased by a factor of 15 in paracervical and supraclavicular adipose tissue in five healthy subjects. Biopsy specimens of this tissue were obtained from the first 3 consecutive subjects and documented mRNA and protein levels of the brown-adipocyte marker, uncoupling protein 1 (UCP1). Together with morphologic assessment, which showed numerous multilocular, intracellular lipid droplets, and with the results of biochemical analysis, these findings document the presence of substantial amounts of metabolically active brown adipose tissue in healthy adult humans^ref. Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of 18F-FDG PET–CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism^ref. However, estimates suggest that if it were present, as little as 50 g of maximally stimulated brown adipose tissue could account for up to 20% of daily energy expenditure in an adult human^ref. The percentage of young men with brown adipose tissue is high, but its activity is reduced in men who are overweight or obese. Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity^ref



 
• fatty tissue stem cells
Adipocytes secrete :
• free fatty acids (FFAs) : adipose triglyceride lipase / desnutrin catalyzes the initial step in triglyceride hydrolysis in mouse fat cells; diglycerides are then hydrolyzed to monoglycerides (FFAs) by hormone-sensitive lipase (HSL). The former is more related to plant lipases than it is to mammalian lipases, and it has a patatin domain on the C-terminal site responsible for the lipid hydrolase activity^{ref1, ref2}
• adipocytokines / adipokins :
• leptin, a 16-kDa peptide derived principally from white adipose tissue, is believed to serve an “adipostat” function, being released in proportion to fat cell mass^ref. Although extra-adipocyte sites of leptin production are well documented (stomach^ref, placenta^ref, brain^ref, and pituitary gland^ref), it is the leptin released by adipocytes and circulating in plasma that is thought to regulate fat mass by acting within the brain.

Secretion is stimulated by :
• adiposity, which, along with gender, is the dominant long-term determinant of leptin gene expression and release
• important short-term regulators of leptin synthesis and release have been identified^{ref1, ref2} :
• sympathetic system, which has been suggested to be a key regulatory inhibitor of leptin production, mediating, for example, the reduction of leptin synthesis accompanying exposure to cold^{ref1, ref2}. An inhibitory effect on leptin synthesis and release has been demonstrated for the catecholamines, norepinephrine (NE), and epinephrine, and for isoprenaline, both in adipocyte cell cultures and in intact experimental animals^{ref1, ref2}. Although the high plasma leptin levels of human obesity are often accompanied by sympathetic nervous activation, this sympathetic stimulation does not involve all outflows, sparing the sympathetic nerves directed to the heart, whereas the stimulation of epinephrine secretion expected with high leptin levels is not seen in obesity^{ref1, ref2}. The most direct evidence for catecholaminergic inhibition of leptin release in humans, reduction of plasma leptin levels during infusion of isoprenaline, alternatively might perhaps be attributable to an increase in leptin clearance by the kidneys^{ref1, ref2} because of the drug’s increasing renal blood flow^ref. Although the importance of leptin as an antiobesity factor in rodents seems well established, its contribution to human energy balance is uncertain. There are fundamental differences between rodents and humans in mechanisms of thermogenesis, perhaps primarily because of the importance of brown adipose tissue in the former. Thus, there seems to be a 2-way interaction between leptin and the sympathetic nervous system, perhaps constituting a regulatory feedback loop, with leptin acting within the hypothalamus to cause activation of central sympathetic outflow and stimulation of adrenal medullary release of epinephrine^ref and conversely, with the sympathetic nervous system inhibiting leptin release from white adipose tissue^ref. Some studies find no support for the presence of a regulatory leptin–sympathetic nervous feedback loop in humans, previously documented in experimental animals, in which leptin activates central sympathetic outflow and the sympathetic nervous system inhibits leptin release. An earlier hypothesis of obesity causation was that weight gain in obesity is caused in part by sympathetic nervous underactivity and reduced secretion of epinephrine by the adrenal medulla reducing thermogenesis and contributing to a positive energy balance. The findings of normal epinephrine secretion rates in obesity accompanied by activated sympathetic activity in some sympathetic outflows argue strongly against this, perhaps weakening the case for the development and clinical use of b₃-adrenergic agonists as thermogenic antiobesity drugs. Leptin is rather rapidly cleared from plasma by the kidneys. Findings in heart failure of reduced renal clearance of leptin, thus elevating its plasma concentration, illustrate that the plasma concentration of leptin and its release rate are not strictly equivalent, with the high plasma leptin levels reported in renal failure providing another example of this phenomenon.
Biological effects via LEPR :
• short-term and long-term control of body weight
• reduce food intake and stimulate thermogenesis^ref
• activation of the sympathetic nervous system by leptin is the primary mechanism mediating this increase in energy expenditure. Leptin administered intravenously, intracerebroventricularly, and into hypothalamic nuclei in rodents has been demonstrated to increase the sympathetic outflow to the kidneys, adipose tissue, and the skeletal muscle vasculature and the neural traffic to the adrenal^{ref1, ref2, ref3}.
• promotion of neoangiogenesis^{ref1, ref2, ref3, ref4, ref5}
• adiponectin (APM1) / adipocyte complement-related protein of 30 kDa (ACRP30) / adipocyte, C1Q and collagen domain containing (ACDC) : found in multimeric complexes in circulation at relatively high levels in healthy human subjects (2-10 mg/mL^{ref1, ref2, ref3}). Levels are decreased in visceral adiposity, coronary artery disease^{ref1, ref2}, and impaired glucose tolerance. Levels are increased by PPARg antagonists. Adiponectin exists in the circulation as a full-length protein (fAd) as well as a putative proteolytic cleavage fragment consisting of the globular C-terminal domain (gAd), which may have enhanced potency^ref. It binds to collagen type I, III and V, improves insulin sensitivity in muscle and liver.

Biological effects via :
• adipoR1 :
• enhances fat oxidation in tissues and weight loss, protects against development of type 2 diabetes mellitus
• in the vasculature :
• enhanced endothelium-dependent vasodilation^{ref1, ref2, ref3}
• enhanced endothelium-independent vasodilation (in response to nitroglycerin^ref)
• suppression of atherosclerosis
• suppressed expression of vascular adhesion molecules scavenger receptors (VCAM-1 and class A scavenger receptors) => inhibits monocyte adhesion to endothelial cells
• suppresses macrophage transformation into foam cells => anti-atherogenic effects
• supression of leukocytic colony formation, reduction of phagocytic activity, and reduction of TNF-a secretion from macrophages^{ref1, ref2}
• reduced levels of TNF-a and suppression of inflammatory TNF-a effects on endothelial function^ref (blockage of NFkB phosphorylation and NFkB activation^ref => lack of up-regulation of VCAM-1, E-selectin, and ICAM-1)
• attenuation of growth factor effects on smooth muscle cells
• inhibition of endothelial cell effects of oxidized LDL, including suppression of proliferation, superoxide generation and the activation of MAPK^ref
• enhanced NO production^{ref1, ref2, ref3}
• stimulation of angiogenesis (the reduction in signalling effects of PDGF is possibly caused at least in part by binding of adiponectin to PDGF-BB, which inhibits PDGF cellular association)^{ref1, ref2, ref3, ref4}
• reduced neointimal thickening and proliferation of smooth muscle cells in mechanically injured arteries^{ref1, ref2}
• inhibition of endothelial cell proliferation and migration
• adipoR2 :
• adipsin / D component of complement
• resistin is produced by white and brown adipose tissues but has also has been identified in several other tissues, including the hypothalamus, pituitary and adrenal glands, pancreas, gastrointestinal tract, myocytes, spleen, white blood cells and plasma. The tissue level of resistin is decreased by insulin, cytokines such as TNF-a, endothelin-1 and increased by growth and gonadal hormones, hyperglycaemia, male gender and some proinflammatory cytokines, such as IL-6 and LPS. Resistin antagonizes insulin action, and it is downregulated by rosiglitazone and PPAR-g agonists. Since evidence of a direct link between resistin genotype and human diabetes is still weak, more molecular, physiological and clinical studies are needed to determine the role of resistin in the aetiology of type 2 diabetes^ref.

Biological effects via ? :
• mediates glycemia in obesity^ref
• promotes endothelial cell activation, with increased endothelin-1 transcription and release and increased expresion of the adhesion molecule VCAM-1 and the chmotactic protein VCAM-1 (inhibited by adiponectin)^{ref1, ref2}
• PAI-1
• visfatin, an hormone produced by visceral fat, correlates with obesity. Surprisingly, visfatin has beneficial, insulin-like activity and is able to bind to the insulin receptor, lowering blood glucose levels. It is highly enriched in the visceral fat of both humans and mice and whose expression level in plasma increases during the development of obesity. Visfatin corresponds to a protein identified previously as pre-B cell colony-enhancing factor (PBEF), a 52 kilodalton cytokine expressed in lymphocytes. Visfatin exerted insulin-mimetic effects in cultured cells and lowered plasma glucose levels in mice. Mice heterozygous for a targeted mutation in the visfatin gene had modestly higher plasma glucose levels compared with wild-type littermates. Surprisingly, visfatin binds to and activates the insulin receptor. Further study of visfatin's physiological role may lead to new insights into glucose homeostasis and/ or new therapies for metabolic disorders like diabetes^{ref1, ref2}.
• EGF

Biological effects via ERBB1 / EGFR :
• IL-6 (30% of plasma IL-6 under basal conditions^ref; visceral > subcutaneous^ref)
The visceral fat accumulation is characterised by the increased, abundant secretion of a number of peptides such as leptin, insulin-like growth factor (IGF), adiponectin and the recently reported resistin and visfatin hormones^ref.
Adipose is a proinflammatory tissue : increasing evidence indicates that adipose tissue is an important source of cytokines (1) and that adiposity
contributes to a proinflammatory milieu (2). Fat is both a dynamic endocrine organ, as well a highly active metabolic tissue. Fat produces and secretes inflammatory factors, which are well known to play important roles in the atherosclerotic process (Fig. 1). Collectively, these factors are called adipocytokines or adipokines. These include TNF-a, leptin, plasminogen activator inhibitor-1 (PAI-1), IL-6, resistin, and angiotensinogen (1). Serum adipokine levels are elevated in humans and animals with excess adiposity (2–5), and visceral fat appears to produce several of these adipokines more actively than sc adipose tissue (6 –9). Reduction in fat mass correlates with decrease in the serum levels of many of these adipokines (10 –14), implying that approaches designed to promote fat loss should be useful in attenuating the proinflammatory milieu associated with obesity. Some of these adipokines, in addition to their proinflammatory actions, also affect insulin action. For example, TNF
inhibitstyrosine kinase phosphorylation of the insulin receptor, resulting in defects in insulin signaling and ultimately leading to insulin resistance and impaired glucose transport (15). Leptin has recently been shown to enhance cellular immune responses (16), as well as to increase blood pressure (17, 18). Leptin also tends to decrease insulin sensitivity when given to obese rats (19), although it markedly improves insulin sensitivity in patients with lipodystrophy, who tend to have low circulating levels of leptin (20). Resistin administration also markedly decreases insulin-mediated glucose uptake (21). Adiponectin (Acrp30), a recently described adipokine of emerging importance, is distinct from other known adipokines in that it alone among them appears to improve insulin sensitivity and inhibits vascular inflammation (22–24). Serum adiponectin levels are low in obese subjects but increase upon weight loss (25, 26). Undoubtedly, other adipokines produced by fat are yet to be discovered. A potentially important therapeutic strategy for the treatment of obesity and the metabolic syndrome will be to alter the ratio of proinflammatory, insulin-desensitizing adipokines to antiinflammatory, insulin-sensitizing adipokines, to both attenuate the inflammatory milieu and improve the metabolic state.
The monocyte and inflammation are integral components of the atherosclerotic process
Monocyte migration is integral to the development of atherosclerosis. Early in the process of atherosclerosis, circulating monocytes adhere to the endothelial layer of the vessel wall, migrate into the vascular interstitium, and phagocytize oxidized low-density lipoprotein cholesterol (LDLC; Ref. 27).
This process results in the formation of lipid-laden foam cells, which accumulate within the arterial wall to form fatty streaks. Ultimately, these early lesions evolve into advanced atherosclerotic plaques that contain necrotic lipid cores surrounded by proteoglycan matrix and covered by a fibrous
cap and thickened intima. This structure defines an organized atherosclerotic plaque. A number of approaches have been used to cripple macrophage
activity in genetically prone mouse models of atherosclerosis, all of which attenuated the atherosclerotic process. These include mouse models deficient for expression of 1) macrophage chemoattractive protein-1 (MCP-1; Ref. 28), which stimulates macrophage movement into the vessel wall; 2) chemokine receptor-2 (29), a macrophage receptor that binds MCP-1; 3) macrophage colony stimulating factor (M-CSF; Ref. 30), which enhances conversion of monocytes to macrophages; 4) macrophage osteopontin, which may prevent macrophage apoptosis, similar to its effects on endothelial cell survival (31). These observations underscore the prominent role of the macrophage in the pathogenesis of atherosclerosis. Adipokines enhance the attachment and migration of monocytes into the vessel wall and their conversion into macrophages. In particular, TNF
activates the transcriptionfactor nuclear factor-, which orchestrates a series of inflammatory changes in vascular tissue, including expression of adhesion molecules on the surface of the endothelial cells and vascular smooth muscle cells (VSMC). This includes elevated expression of ICAM-1 and VCAM-1 (32–35), which enhance monocyte adhesion to the vessel wall (36–40); endothelial cells and SMC production of MCP-1 and M-CSF (32, 41–43); and activation of a proinflammatory macrophage state resulting in increased macrophage expression of iNOS, interleukins, superoxide dismutase, etc. (44–47). T lymphocytes are also activated and enhance macrophage atherosclerotic activity (48). Leptin is also reported to stimulate cholesterol accumulation by the macrophage, particularly in the presence of high glucose (49). The cytokine, IL-6, also has proinflammatory activity by itself and through increasing the levels of IL-1 and TNF
; allof these have been implicated in atherogenesis (CRP; Ref. 50). Importantly, IL-6 stimulates liver production of CRP (51). Serum CRP measured by a highly sensitive assay (hsCRP) has become an important marker of vascular inflammation and predictor of atherosclerosis (52–56). Recent data suggest that hsCRP is as important a predictor of atherosclerosis as circulating LDLC (57). Thus, inflammation may be potentially as important as cholesterol in contributing to atherosclerosis. High levels of hsCRP in obesity also predict later development of diabetes (58). Angiotensinogen is a precursor to a major vasconstrictive, proatherogenic peptide, angiotensin II (AngII). This product of the renin-angiotensin system enhances multiple steps leading to foam cell formation. AngII directly stimulates intracellular adhesion molecule-1, vascular cell adhesion molecule-1, MCP-1, and M-CSF expression in the cells of the vessel wall (59). When infused into animal models, an early increase in arterial macrophage accumulation occurs in the vessel wall (60). In addition, another important affect of AngII is to enhance the metabolism of NO into oxygen free radicals, which damage the vascular tissue. AngII accomplishes this effect by stimulating nicotinamide adenine dinucleotide phosphate (reduced) oxidase, resulting in decreased bioavailability of NO (61). Importantly, NO is not only a vasodilator, but protects the vessel wall from macrophage
adhesion and accumulation (62), decreases VSMC growth (63), and decreases platelet adherence to the endothelium (64). An imbalance between AngII and NO leads to endothelial dysfunction with not only a loss of vasodilator capacity, but also increased monocytes/macrophage platelet
activity in the vessel wall. PAI-1 has two important actions in the vessel wall. First, it inhibits the breakdown of fibrin clots and, therefore, plays
a key role in promoting thrombus formation upon rupture of unstable atherosclerotic plaques (65). In addition, elevated PAI-1 activity, by altering the fibrinolytic balance, also contributes to remodeling of the vascular architecture (66–69). In human population studies, circulating PAI-1 levels correlate
with atherosclerotic events and mortality, and some studies suggest that PAI-1 may be an independent risk factor for coronary artery disease (CAD; Ref. 70–72). Hyperglycemia (73, 74), AngII (75, 76), and VLDL-Ch (77), in addition to obesity (78), contribute to elevated serum PAI-1 levels. All
of these factors increase PAI-1 gene expression (79–83). High levels of PAI-1 in patients with diabetes are a major contributor to the prothrombotic state in diabetes, which leads to enhanced atherosclerotic mortality (84). Use of aspirin to attenuate this prothrombotic state is associated with attenuation of CAD (85). Diabetes is an atherosclerotic risk equivalent. Both are the end result of two important parallel pathways (Fig. 2): 1) the progression of insulin resistance to the metabolic syndrome, prediabetes, and, ultimately, diabetes and 2) the progression of endothelial dysfunction with progressive inflammation, thrombosis, and oxidation at the vessel wall to fatty streak formation and, ultimately, to development of advanced
atherosclerotic plaques. Indeed, in the prediabetic state (impaired glucose tolerance), there is a 2-fold increased atherosclerosis risk, and, in frank diabetes, the risk is increased 3- to 4-fold (86). The metabolic syndrome, itself, is also associated with increased CAD risk (87). Early in the insulin
resistant, hyperinsulinemic state, there is also evidence of brachial artery endothelial dysfunction, as well as abnormal coronary artery vasomotion, which appears to result from the endothelial dysfunction (88). Thus, insulin resistance, itself, appears to be an endothelial dysfunction risk equivalent. The pathways are clearly interdigitated and sparked in obesity, in large part by excess adipokine production.
Is decreasing adipokine production useful? Reducing adipocyte mass is associated with a reduction in proinflammatory, insulin-desensitizing adipokines and a rise in circulating adiponectin. Exercise and weight loss improve endothelial function and prevent diabetes (89–91). Thus, there is a strong association between changes in adipokines, endothelial function, and prevention of diabetes through lifestyle modifications. Treatment with PPARg agonists, is reported to decrease serum hsCRP (92), leptin (5), PAI-1 (93), and TNF-a (94) levels and to increase circulating adiponectin (95, 96). These agents also improve endothelial function (97–99). The TRIPOD study suggested that an early PPARg ligand, troglitazone, prevented type 2 diabetes in a high-risk cohort (100). The PPARligands currentlyin clinical use, rosiglitazone and pioglitazone, are being tested in clinical trials for their ability to prevent diabetes and decrease CAD events. In mice that are genetically prone to develop atherosclerosis, PPAR ligands consistently attenuatevascular lesions (101, 102). Statins decrease hsCRP by 30–40%, which is not correlated with their cholesterol-lowering capability (103); they consistently improve endothelial function, decrease cardiovascular events and mortality, and in the West of Scotland study decreased new onset type 2 diabetes (104, 105). Statins are reported to have additive and possibly synergistic effects with PPARg ligands on vascular inflammation (106). Statins have also been reported to decrease plasma TNFa (107) andmay also lower plasma PAI-1 (108). Angiotensin converting enzyme inhibitors and AngII AT1 receptor blockers (ARBs) lower hsCRP, although inconsistently, and angiotensin converting enzyme inhibitors are reportedly better at lowering serum PAI-1 than ARBs, although ARBs have been reported to have this effect (109–112). Both classes of agents improve endothelial function and reduce atherosclerosis-associated events. In the HOPE trial, Ramipril administration was associated with 32% less newonset diabetes than placebo (113), and, in the LIFE trial, Losartan administration was associated with less new-onset diabetes than its comparator, Atenolol (114, 115). These agents tend to decrease circulating TNF
, but their effects onleptin and adiponectin are unknown (116–118). AngII is reported to increase leptin secretion from cultured adipocytes through a prostaglandin-independent mechanism but has no effect on adiponectin expression in these cells.
Clearly, much more investigation is needed, but insight into mechanisms by which the adipocyte communicates with both insulin target tissues and the vasculature allows us to better understand the relationships between obesity and cardiovascular disease. Furthermore, study of the regulation of
these mechanisms will help us to develop treatment strategies to prevent diabetes and heart disease in the growing epidemic of obesity^ref.
Ideal body weight (IBW) [kg] :
• standard formula : (2.3 kg x (height(in) - 60)) + (45.5 kg if female, 50.0 kg if male)
• Broca formula :
• for males : height (cm) - 100
• for females : height (cm) - 104
• Lorentz formula, 1929 : valid for age > 18 years and height = 140-220 cm (55-87 in)
• for males : [height(cm) - 100] - [(height(cm) - 150) / 4]
• for females : [height(cm) - 100] - [(height(cm) - 150) / 2] ^. 0.9  OR [height(cm) - 100] - [(height(cm) - 150) / 4] ^. 0.9
• normal : 90-110%
• overweight : 110-130%
• obesity : > 130%
• modified Lorentz formula = 50 + [height(cm) - 150]/4 + [age(years) - 20]/4
• Devine formula, 1974 : valid for age > 18 years and height = 140-220 cm (55-87 in)
• for males : 50 + 2.3 ^. [height(in) - 60]
• for females : 45.5 + 2.3 ^. [height(in) - 60]
• Peck formula : results in pounds (x0.454 = Kg); valid for any age and height = 45-220 cm (17-86 in)
• if age < 18 years :
• for males : -130.736 + [4.064 ^. height(in)]
• for females : - 111.621 + [3.636 ^. height(in)]
• if age > 18 years :
• for males : -59.6035 + [5.2878 x height(in)] - [0.123939 x height(in)²] + [0.00128936 x height(in)³]
• for females : -77.55796 + [6.93728 x height(in)] - [0.171703 x height(in)²]+ [0.001726 x height(in)³]
• total adiposity
• body mass index (BMI) = weight [kg] / height² = [704.5 x weight [pound]]/[(height(cm)]² : it overestimates adiposity in musculous subjects
• for males : 19.1-25.8 kg/m²
• for females : 20.7-26.4 kg/m²

Weight : lbs.

Height : Ft. In.

Body Mass Index

According to the Panel on Energy, Obesity, and Body Weight Standards published by American Journal of Clinical Nutrition, your category is:

• fat mass
• body fat distribution
• estimate the amount of adipose tissue stored specifically in the abdominal region : obesity contributes to the risk of several chronic diseases, including coronary heart disease (CHD)^{ref1, ref2, ref3}. However, obesity is a heterogeneous disorder in that the storage depot for excess calories differs widely between persons, and these differences in fat distribution confer differential health risks. Prior studies designed to assess the health risks of body fat distribution have used anthropometric measures such as waist circumference, sagittal diameter, or waist-to-hip ratio to estimate the amount of adipose tissue stored specifically in the abdominal region. The majority of these findings showabdominal fat measures are better predictors of incident CHD in both men and women than total adiposity assessed by body mass index (BMI)^{ref1, ref2, ref3, ref4, ref5, ref6}. The association between these anthropometric measures of abdominal fat and CHD most likely is due to a preponderance of adipose tissue stored in and around the visceral organs. Associations between CHD risk factors and amount of visceral adipose tissue, measured directly with computed tomography or magnetic resonance imaging, are stronger than associations observed with indirect measures of visceral adipose tissue, such as waist and waist-hip ratio^{ref1, ref2}. However, currently there are very few studies that show a cross-sectional association between directly measured visceral adipose tissue and actual coronary disease^{ref1, ref2}, and, to our knowledge, only one examined the prospective association between visceral adipose tissue and incident CHD. This study showed that visceral adipose tissue was predictive of CHD onset, independently of BMI, in 175 middle-aged Japanese-American men^ref. Data examining the association between visceral adipose tissue and onset of CHD in women or in elderly individuals were absent. Previous data show that the relative risk of a greater BMI on all-cause mortality^ref, cardiovascular disease mortality^ref, and CHD^ref declines with age. The fact that the relative accumulation of visceral adipose tissue is higher in older persons^{ref1, ref2} may explain the lower disease risk associated with overall body mass with aging. Indeed, there does not appear to be a difference by age in the associations of surrogate measures of visceral adipose tissue with CHD morbidity and mortality^{ref1, ref2, ref3, ref4}. While it is more practical to use a surrogate measure of visceral adipose tissue in the clinical setting to assess this risk factor, anthropometric measures provide poor estimates of visceral adipose tissue and are more reflective of total adiposity in older adults^ref. Thus, direct assessment of visceral adipose tissue may be important for additional evaluation of CHD risk in an older population. The amount of adipose tissue stored in the intraabdominal cavity is an important, independent risk factor for MI in wellfunctioning, elderly women^ref.
• sagittal diameter
• abdominal circumference
• < 88 cm for females
• < 102 cm for males
• waist hip ratio (WHR) : measured with the patient upright at the shortest level between xiphoid process and iliac crests (waist circumference) or the largest level below the iliac crest, usually at the level of the greater trochanters (hip ratio)
• < 0.9 in males
• > 0.8 in females
• abdominal fat depots (sc and visceral) are quantified by MRI using a clinical 1.5-T whole body magnetic resonance scanner (Gyroscan ACS/NT15, Philips, Best, The Netherlands). Briefly, patients are scanned in the supine position, and three transverse images were obtained at the abdominal level: the first at the anatomical marker (lower edge of the umbilicus), and one above and one below this position (slice thickness, 10 mm). The same investigator performed all scans, and one blinded, well-trained observer performed image analysis using a dedicated software program^ref. The areas of the abdominal fat depots were calculated by converting the number of pixels to square centimeters and taking the average of three abdominal images
• visceral adipose tissue (VAT) area [cm²]
• subcutaneous adipose tissue (SAT) area [cm²]
• VAT/SAT
• VAT/fat mass
• lean body mass (LBM) [kg] :
• James' formula (1981) : valid for age 18-80, weight = 35-130 kg, and height = 140-185 cm
• for males : 1.10 x weight [kg] - 128 [weight [kg]²/height(cm)²]
• for females : 1.07 x weight [kg] - 148 [weight [kg]²/height(cm)²]
• Hume's formula (1966) : for age 16-80
• for males : [0.32810 x weight [kg]] + [0.33929 x height(cm)] - 29.5996 (for age 16-80, weight = 45-140, and height = 150-185 cm)
• for females : [0.29569 x weight [kg]] + [0.41813 x  height(cm)] - 43.2933 (for age 30-80, weight = 35-130, and height = 145-180 cm)
• Forbes-Bruining formula : 29,08 x creatininuria_{24 hrs} [g/day] + 7.38
• Wang formula :
• 21,8 x creatininuria_{24 hrs} [g/day]
• 18,9 x creatininuria_{24 hrs} [g/day] + 4.1
Regulation of body weight :
• short-term (days and weeks) weight regulation depends on peptide hormones produced by the digestive tract:
• appetite stimulants
• ghrelin is a meal initiator : its plasma levels rise 1-2 hours before a meal and go down to trough levels afterward.
• activates neurons of arcuate nucleus producing agouti-related peptide (AgRP) and neuropeptide Y (NPY) (which stimulate appetite while reducing metabolism)
• galanin
• glucagon-like peptide (GLP)
• corticotropin-releasing hormone (CRH)
• anandamide acts on CB1 receptors located on capsaicin-sensitive sensory terminals^ref
• appetite suppressants
• peptide YY (PYY) is a meal terminator : its plasma levels rise during meals and signal satiety^{ref1, ref2}
• inhibits neurons of arcuate nucleus producing agouti-related peptide (AgRP) and neuropeptide Y (NPY) (which stimulate appetite while reducing metabolism)
• activates neurons of arcuate nucleus producing a-melanocyte stimulating hormone (a-MSH) (from POMC) and cocaine- and amphetamine-regulated transcript (CART) (which inhibit eating)
If you give injections under certain circumstances to one strain of mice, you can get a persistent 24-hour suppression of food intake that is more prominent in recently fasted mice^ref, but you don't see a persistent effect over 7 days. In 2004 42 scientists, from 12 labs, report that they have failed to replicate the effects described in the 2002 study. One potential reason PYY failed to work could be stress : if appetite is already low, PYY will have less room for influence. Recent work supports PYY's role in appetite, but only under certain, low-stress experimental conditions^ref and a new paper supports the effect of PYY on food intake and body mass in a variety of rodent models^ref.
• cholecystokinin (CCK)
• oleylethanolamide (OEA) is a satiety factor secreted by small intestine (increased by feeding and reduced by fasting^ref) that excites peripheral vagal sensory nerves via activation of PPAR-a^ref, inducing satiety (delayed feeding onset and reduced meal size) and regulation of body weight^{ref1, ref2}. It activates PKC => activation of capsaicin receptor (TRPV1)^ref
• nesfatin, corresponding to NEFA/nucleobindin2 (NUCB2), a secreted protein of unknown function, is expressed in the appetite-control hypothalamic nuclei in rats. Intracerebroventricular (i.c.v.) injection of NUCB2 reduces feeding. Rat cerebrospinal fluid contains nesfatin-1, an amino-terminal fragment derived from NUCB2, and its expression is decreased in the hypothalamic paraventricular nucleus under starved conditions. I.c.v. injection of nesfatin-1 decreases food intake in a dose-dependent manner, whereas injection of an antibody neutralizing nesfatin-1 stimulates appetite. In contrast, i.c.v. injection of other possible fragments processed from NUCB2 does not promote satiety, and conversion of NUCB2 to nesfatin-1 is necessary to induce feeding suppression. Chronic i.c.v. injection of nesfatin-1 reduces body weight, whereas rats gain body weight after chronic i.c.v. injection of antisense morpholino oligonucleotide against the gene encoding NUCB2. Nesfatin-1-induced anorexia occurs in Zucker rats with a leptin receptor mutation, and an anti-nesfatin-1 antibody does not block leptin-induced anorexia. In contrast, central injection of -melanocyte-stimulating hormone elevates NUCB2 gene expression in the paraventricular nucleus, and satiety by nesfatin-1 is abolished by an antagonist of the melanocortin-3/4 receptor^ref
• long-term (months and years) weight regulation :
• appetite stimulators : when fat stores and leptin (and to a lesser extent, insulin) levels are declining,
• neurons of arcuate nucleus producing agouti-related peptide (AgRP) and neuropeptide Y (NPY) (which stimulate appetite while reducing metabolism) are activated
• neurons of arcuate nucleus producing a-melanocyte stimulating hormone (a-MSH) (from POMC) and cocaine- and amphetamine-regulated transcript (CART) (which inhibit eating) are inhibited
... leading to weight gain. Our natural appetite could be built into our brains just after birth, and may then be set for the rest of our lives : when mice genetically engineered not to produce leptin (ob/ob) are left untreated, they grow fat as adults. But when given leptin in the first few week of their life, the growing mice eat much less. There are more neurons in the 2 distinct populations of neurons in the hypothalamic arcuate nucleus (one producing the appetite-stimulating NPY and the other producing appetite-suppressing POMC) in mice given the leptin dose and the changes are permanent : these extra neurons prompt a higher level of activity in that part of the brain, helping to stimulate the impulses that makes an animal feel full.
• appetite suppressors : conversely, at least in nonleptin-resistant animals, increasing fat stores and leptin (and to a lesser extent, insulin) levels lead to
• inhibition of the NPY/AgRP neurons
• activation of the POMC neurons
... resulting  in weight loss.
Leptin turns up the body's metabolism by altering the pathways through which fat is metabolized :
• activates muscle AMPK that inhibits acetylCoA carboxylase (ab), an enzyme that catalyzes a key step in fat synthesis. As a result, the building blocks that would otherwise go into fat formation are shifted into a pathway that oxidize them, providing energy for muscle cells.
• inhibits liver stearoyl-CoA desaturase-1 (SCD-1)
The NPY/AgRP and POMC/CART neurons then send their signals through certain other brain centers to the satiety center in nucleus tractus solitarius of the brain stem, and from there to the rest of the body.
• endocrine kidney

Cell types :
• juxtaglomerular cells (JGCs) in the walls of afferent arterioles of renal glomeruli secrete :
• renal erythrogenic factor (REF) / erythrogenin which activates erythropoietinogen to erythropoietin (EPO).

Secretion is
• stimulated by
• chronic hypoxia
• phlebotomy
• androgens
• TSH / thyrotropin
• adrenocorticotropic hormone (ACTH) / corticotropin
• angiotensin II
• adrenalin
• growth hormone (GH)
• inhibited by
• estrogens
Normal plasma concentration :

age (years)	males (mIU/mL)	females (mIU/mL)
1-3	1-3	2.1-15.9
4-6	3.5-21.9	2.9-8.5
7-9	1.0-13.5	2.1-8.2
10-12	1.0-14.0	1.1-9.1
13-15	2.2-14.4	3.8-20.5
adults	4.2-27.8	4.2-27.8

Biological effects via EPOR:
• on hematopoietic cells => erythropoiesis
• since the normal kidney is essentially unresponsive to EPO, EPO's cytokine effects in the kidney are revealed when tubular cells are induced to proliferate by a prior insult, as occurs in acute renal failure (ARF).
• renin

Normal peripheral vein plasma renin activity (PRA) :
• 0-1 months: 2.0-35.0 ng/mL/hour
• 2-11 months: 2.4-37.0 ng/mL/hour
• 1-3 years: 1.7-11.2 ng/mL/hour
• 4-5 years: 1.0-6.5 ng/mL/hour
• 6-10 years: 0.5-5.9 ng/mL/hour
• 11-15 years: 0.5-3.3 ng/mL/hour

adults	sodium-replete diet (sodium intake 100-150 mmol/day, potassium intake 50-100 mmol/day)	sodium-depleted diet (3 g/die for 3 days before the test)	sodium-depleted diet and diuretics
supine	0.15-2.33 ng/mL/hr = 0.9±0.6 nmol/L/hr	2.7±1.8 = 2.1±1.4	10.0±3.7 = 7.7±2.9
upright	1.31-3.95 = 1.5±1.3  age 20-39 : 0.1-4.3 08.00h, after overnight recumbency: 1.1 - 2.7 pmol/mL/hr 08.30h, after 30 min mobility: 2.8 - 4.5 pmol/mL/hr age > 40 : 0.1-3	6.6±2.5 = 5.1±1.9  age 20-39 : 2.9-24 age > 40 : 2.9-10.8

Salt excretion (Na mEq/24 h)
• Na = 0.30 : 8.82-23.86
• Na = 30-75 : 4.09-7.73
• Na = 75-150 : 1.44-2.80
• Na >150 : 0.39-1.31
Biological effects : it converts angiotensinogen into proangiotensin / angiotensin I. Then ACE / CD143 in the caveolae of pulmonary capillary endothelial cells converts angiotensin I into angiotensin II, which exercts biological effects via AT_1a, AT_1b, and AT₂ :
• generalized peripheral arteriolar vasoconstriction, but vasoconstriction of efferent arteriole 10 folds more than vasoconstriction of afferent arteriole
• increased Na⁺ reabsorption in proximal renal tubule
• induction of aldosterone incretion from zona glomerularis cells of adrenal cortex
• stimulation of pressure centres
• stimulation of thirst centre (subfornical organ)
• stimulation of ADH incretion
• stimulation of norepinephrine release by SNS
• inhibition of renin secretion (negative feedback)
=> increased ABP.
The Asp cleavage in angiotensin II generates angiotensin III.
• proximal convoluted renal tubule cells
• secrete : C-type natriuretic peptide (CNP)

Biological effects via NPR2 / ANP-B / GC-B :
• natriuresis
• vasodilatation
• negative inotropic effect
• inhibition of exocytosis of endothelin, vasopressin (VP) / antidiuretic hormone (ADH), renin, and aldosterone
• express :
• CYP27B1 / steroid 1a-hydroxylase (up-regulated by PTH during hypocalcemia) which hydroxylates calcifediol / 25-hydroxycholecalciferol to create the hormone 1a,25-(OH)₂-vitamin D₃ / calcitriol

Normal plasma concentration : 26-65 pg/mL = 62-155 pmol/L
Biological effects via VDR :
• enhanced Ca²⁺ and PO₄ absorption in bowels
• enhanced Ca²⁺ and PO₄ reabsorption from bone (together with PTH) => hypercalcemia
• immunosuppressant :
• promotion of monocyte/macrophage cytotoxicity but inhibition of differentiation and maturation (including antigen presentation) of DCs (see here)
• inhibition of cytokine production by T lymphocytes and cell mediated immune reactions
• inhibition of T lymphocyte proliferation and cytokine secretion
• stimulation of NK cell mediated cytotoxicity
• inhibition of B lymphocyte proliferation and immunoglobulin secretion
• CYP24 / steroid 24-hydroxylase (during hypercalcemia) which hydroxylates calcifediol / 25-hydroxycholecalciferol creating the inactive metabolyte 24R,25-dihydroxyvitamin D₃
• endocrine myocardium (see also nonendocrine mycoardium)

Cell types :
• atrial cardiomyocytes increte atrial natriuretic peptide (ANP)
• specific atrial granules : membrane-bound spherical granules with a dense homogeneous interior that are concentrated in the core of sarcoplasm of the atrial cardiac muscle, extending in either direction from the poles of the nucleus, usually near the Golgi complex; they also may be found in limited numbers in other regions of the cell. They are the storage site of ANP
Biological effects via NPR1 / ANP-A / GC-A :
• decreased Na⁺ reabsorption in thick ascending limb of Henle's loop, distal renal tubule, and collecting duct => natriuresis
• vasodilatation
• negative inotropic effect
• inhibition of exocytosis of endothelin, vasopressin (VP) / antidiuretic hormone (ADH), renin, and aldosterone
• ventricular cardiomyocytes increte brain natriuretic peptide (BNP)

Secretion is stimulated by : myocardial tension and increased intravascular volume
Normal plasma concentration : 0.5–30 pg/ml (0.15–8.7pmol/l)^ref. For NT-proBNP a suggested reference range is 68–112 pg/ml (8.2–13.3pmol/l)^ref
Biological effects via NPR1 / ANP-A / GC-A :
• atriuresis
• vasodilatation
• negative inotropic effect
• inhibition of exocytosis of endothelin, vasopressin (VP) / antidiuretic hormone (ADH),renin, and aldosterone
• enteroendocrine system
• endocrine stomach (see also exocrine stomach)

Cell types :
• d-cells / D cells / a₁ cells (in fundus and pylorus) increte somatostatin (SST) (secretion granules of 350 nm)
• d₁ cells / D₁ cells (in fundus and pylorus) increte an unknown product (secretion granules of 160 nm)
• EC cells (in fundus and pylorus) increte serotonin and various peptides (secretion granules of 300 nm)
• enterochromaffin-like (ECL) cells (in fundus) increte histamine (secretion granules of 450 nm) and express  CCK₂
• G cells (in pylorus) increte gastrin (secretion granules of 300 nm). normal plasma concentration : 0-200 pg/mL = 0-95 pmol/L.
• P cells (in fundus and pylorus) increte an unknown product (secretion granules of 120 nm)
• PP cells / F cells (in fundus and pylorus) increte pancreatic polypeptide (PPY) (secretion granules of 180 nm)
• X cells (in fundus and pylorus) increte an unknown product (secretion granules of 300 nm)
• endocrine liver (see also exocrine liver)

Cell types : hepatocyte
• express
• CYP27A1 / steroid 25-hydroxylase which hydroxylates vitamin D₃ to create calcifediol / 25-hydroxycholecalciferol. Normal plasma concentration : 8.9-80 ng/mL = 19.4-200 nmol/L (as high as 100 ng/mL = 250 nmol/L after excessive sunlight exposure). t_1/2 = 21 days.
• produce
• angiotensinogen
• erythropoietinogen, which is activated by erythrogenin (produced by iuxtaglomerular cells) to erythropoietin (EPO) (10%; see at endocrine kidney). Then Epo binds to EPOR on hematopoietic cells.
• endocrine pancreas (Langerhans' islets) (see also diseases of endocrine pancreas and exocrine pancreas)

Cell types :
• a-cells / A cells / a₂ cells increte
• glicentin
• GRPP
• C-terminal peptide / major proglucagon fragment (MPGF)
• glucagon (M_r = 3,500 Da, no plasma carrier => t_1/2= 6').

Secretion of granules of 250 nm is :
• inhibited by :
• glucose
• free fatty acids
• insulin
• secretin
• GLP-1
• SST
• Zn released from the simultaneously activated b-cells.
• stimulated by
• Arg
• Ala
• stress
• pyruvate, a glycolytic intermediate and principal substrate of mitochondria
No change occurs after meals. Normal plasma concentration = 50-150 pg/mL (20 pM).
Biological effects (mainly on hepatocytes : same effects at a systemic level are guaranteed by adrenalin) :
• induction of
• cardiac output
• liver glycogenolysis
• gluconeogenesis
• lipolysis
• ketogenesis
• proteolysis
• inhibition of
• glycolysis
• glycogenosynthesis
• lipogenesis
• b-oxidation of free fatty acids (FFA)
• (re-)uptake of P_i, Na⁺, K⁺, and Mg²⁺
• b-cells / B cells undergo hyperplasia in response to GH, estrogens, progestins, cortisol, hPL, and T₃. They increte ...
• insulin. The gene is highly conserved among vertebrates. Proinsulin conversion to insulin occurs in a multistep process within granules of the regulated secretory pathway. In this compartment, the combined action of 2 subtilisin-like prohormone convertases, PC2 and PC3, is responsible for excision of the connession (C)-peptide from the A- (21 amino acids) and B- (30 amino acids) chains, which remain kept together by 2 disulfide bonds, creating a 5,8 kDa molecule. Mature insulin, together with the C-peptide and the processing machinery, is then retained in the late endosomes under the b cell membrane. Hexameric Zn-insulin is found at the centre of secretion granules of 350 nm with C-peptides in periphery : secretory granules also contain proinsulin, which has just 5-10% activity on receptors but is cross-reactive in immunoassays. The C-terminal region or B-chain and the N- and C-terminal residues of A-chain bind the receptor : isolated chains are not effective agonists. In solution insulin may exist as monomer or dimer or hexamer (2 Zn²⁺-coordinated trimer of dimers). Zn²⁺- allows the formation of crystals and the conversion of proinsulin in insulin and hormone storage. The whole pancreas may contain up to 8 mg of insulin = 200 biological units. The IU was initially defined on the basis of the hypoglycemizing activity of rabbit insulin, while currently it is referred to weight, ie 28 IU/mg.

Secretion is :
• stimulated by :
• plasma glucose (from diet or endogenous mobilization) > 70 mg/dL (3.9 mmol/L) ...
• ... induces secretion of incretins / glucoincretins, gut-derived peptides that potentiate insulin secretion from the pancreatic islets :
• glucagon-like peptide 1 (GLP-1) from L cells
• gastric inhibitory polypeptide / glucose-dependent insulinotropic peptide (GIP) from K cells
... which then act on b-cells via G_qPCRs and G_sPCRs. However, incretin secretion can also be induced by non-digestible carbohydrates and involves the autonomic nervous system and endocrine factors such as GIP itself and cholecystokinin. In addition, GLP-1 is involved in glucose sensing by the autonomic nervous system of the hepato-portal vein controlling muscle glucose utilization and indirectly insulin secretion. GLP-1 has been shown to decrease glucagon secretion, food intake and gastric emptying, preventing excessive hyperglycaemia and overfeeding. Another remarkable feature of GLP-1 is its secretion by the brain. Recently, elegant data showed that cerebral GLP-1 is involved in cognition and memory. Experiments using knockout mice suggest that the lack of the GIP receptor prevents diet-induced obesity. The actions of GLP-1 include :
• a stimulation of insulin secretion in a glucose-dependent manner
• a suppression of glucagon
• a reduction in appetite and food intake
• a deceleration of gastric emptying, gastric acid secretion and exocrine pancreatic secretion, indicating that the hormone acts as an enterogastrone--a hormone released from the distal portion of the small intestine that inhibits proximal gastrointestinal events
• a stimulation of b-cell neogenesis
• growth and differentiation in animal and tissue culture experiments
• an in vitro inhibition of b-cell apoptosis induced by different toxins
• cardioprotection
• neuroprotection
• induction of learning and memory
• stimulation of afferent, sensory nerves
• stimulation of surfactant production in the lung, dilatation of pulmonary vessels, induction of diuresis, and also under some conditions, induction of antidiabetic actions unrelated to islet function.

• ... enters the b cell via GLUT-2 and mitochondrial oxidation generates intracellular ATP. The increased ATP:ADP ratio inhibits the ATP-inactivated KCNJ11 channel (associated to ABCC8 / sulfonylurea receptor 1 (SUR1)), resulting in membrane depolarization, opening of voltage-gated calcium channels and exocytosis of insulin-filled granules into circulation.
• Arg
• Lys
• Gln^ref
• a endosulfine binds to ABCC8 / sulfonylurea receptor 1 (SUR1) and inhibits KCNJ11
• adrenaline via b₂-AR
• inhibited by :
• pancreastatin
• G_iPCRs
• under physiological conditions, a endosulfine mainly acts to block voltage-gated calcium channels
b-cell stimulation induces the nucleocytoplasmic translocation of polypyrimidine tract-binding protein (PTB) : activated cytosolic PTB binds and stabilizes mRNAs encoding proteins of secretory granules, thus increasing their translation, and restoring their granule pool^ref.
Secretion rhythms : 18-40 IU/day = 0.2-0.5 IU/kg (50% basal incretion = 0.5-1 IU/hr, 50% after meals = 6 IU/hr), peaks every 10', larger peaks every 80-150' (returning to basal levels within 2-3 hours), postprandial, related to physical activity. Biphasic incretion (the first phase is lost in IDDM). C-peptide has a metabolic clearance slower than insulin, so that [C-peptide]_plasma = 1-2 ng/mL = 5-15 [insulin]_plasma = 6-26 mIU/mL (43-187 pmol/L) during fasting. t_1/2 = 5-8'.
Once secreted in portal vein, 50% is removed and catabolyzed in liver. Insulin-degrading enzyme (IDE), a Zn²⁺-metalloprotease, is involved in the clearance of insulin and amyloid-b. Loss-of-function mutations of IDE in rodents cause glucose intolerance and cerebral accumulation of amyloid-b, whereas enhanced IDE activity effectively reduces brain amyloid-b. Structures of human IDE in complex with 4 substrates (insulin B chain, amyloid-b peptide (1–40), amylin and glucagon). The amino- and carboxy-terminal domains of IDE (IDE-N and IDE-C, respectively) form an enclosed cage just large enough to encapsulate insulin. Extensive contacts between IDE-N and IDE-C keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains enables substrate access to the catalytic cavity. IDE uses size and charge distribution of the substrate-binding cavity selectively to entrap structurally diverse polypeptides. The enclosed substrate undergoes conformational changes to form b-sheets with 2 discrete regions of IDE for its degradation. Consistent with this model, mutations disrupting the contacts between IDE-N and IDE-C increase IDE catalytic activity 40-fold. The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-b and blood sugar concentrations^ref
When exogenous insulin is injected and concentrations drops after absorption, the hormone dissociates into monomers which are probably the biologically active form.
Biological effects via insulin receptor :
• induction of
• Glc uptake in skeletal muscle and liver (not in CNS, which uses Glc independently from insulin stimulation !), promoting glucose utilization (turnover : 2 mg Glc / kg / min)
• glycogenosynthesis
• glycolysis
Staub-Traugott phenomenon : after a glucose load is administered, subsequent loads, given after a short interval, are disposed of at an accelerated rate.
• Staub-Traugott effect or test : a second dose of glucose by mouth to a normal person 1 hour after a first dose does not elevate the blood glucose level
• lipogenesis
• (re-)uptake of P_i, Na⁺, K⁺
• proteosynthesis
• inhibition of
• gluconeogenesis
• glycogenolysis
• lipolysis
• ketogenesis
• proteolysis
Embryonic proinsulin expression is subject to fine, stringent regulation to ensure sufficient protein levels for its antiapoptotic role, but not in excess, which would prevent necessary developmental cell death : the embryonic proinsulin transcript is 32 bp longer than the pancreatic version and includes 2 upstream AUGs open reading frames (upORFs) that influence the translational efficiency of the cellular pool of mRNA
• pancreastatin (a fragment of chromogranin A)
• islet amyloid polypeptide (IAPP) / amylin
• d-cells / D cells / a₁ cells increte somatostatin (SST). Secretion of granules of 350 nm is :
• stimulated by :
• glucose
• amino acids
• low protein diet
• free fatty acids
• enteric nervous system
• autonomous nervous system
• inhibited by
• adrenalin
• insulin
t_1/2 = 1'.
Biological effects via SST₁, SST₂, SST₃, SST₄, and SST₅ : inhibition of
• growth hormone (GH), PRL, and of TSH incretion
• gastric motility
• H⁺Cl^- secretion
• pepsinogen secretion
• exocrine pancreas secretions
• d₁ cells / D₁ cells increte an unknown product (secretion granules of 160 nm)
• EC cells increte serotonin and various peptides (secretion granules of 300 nm)
• PP cells / F cells in pancreas head increte pancreatic polypeptide (PP) (secretion granules of 180 nm). Secretion is
• stimulated by
• GEP
• parasympathetic nervous system
• inhibited by : glucose
Hormones are carried to liver by pancreatic veins and then porta vein.
[insulin]_plasma / [glucagon]_plasma ratio =
• = 2 at rest
• = 0.5 during fasting, physical activity, and in newborns
• = 10 after meals
• endocrine bowel (see also exocrine bowel)

Cell types :
• d-cells / D cells / a₁ cells (in jejunum, ileum, and colon) increte somatostatin (SST) (secretion granules of 350 nm)
• d₁ cells / D₁ cells (in jejunum, ileum, and colon)  increte an unknown product (secretion granules of 160 nm)
• EC cells / Kulchitsky's cells : argentaffin cells situated between the cells that line the glands of Lieberkühn of the intestine that increte serotonin and various peptides (secretion granules of 300 nm)
• G cells (in duodenum) increte gastrin (secretion granules of 300 nm)
• I cells (in jejunum and ileum) increte cholecystokinin (CCK) (secretion granules of 250 nm)
• K cells (predominantly in the midzone of the duodenal, jejunal and ileal mucosa) increte gastric inhibitory peptide (GIP) (secretion granules of 350 nm)
• large granule (L) cells (in jejunum, ileum, and colon) are a type of argyrophilic cells with large cytoplasmic granules in the mucosa of the upper intestine; their ultrastructure resembles that of the a cells of the islets of Langerhans, and they secrete glicentin, GLP-1, and GLP-2, smaller amounts of oxyntomodulin, GRPP, and IP-2 in response to ingestion of carbohydrates and lipids. Only oxyntomodulin and GLP-1 have proven biological activity; oxyntomodulin possibly because it interacts (but with lower potency) with GLP-1 and glucagon receptors. GLP-1 is the most potent insulinotropic hormone known and functions as an incretin hormone (secretion granules of 400 nm)
• Mo cells (in jejunum and ileum) increte motilin
• N cells (in ileum) increte neurotensin (secretion granules of 300 nm)
• P cells (in jejunum) increte an unknown product (secretion granules of 120 nm)
• PP cells / F cells (in colon) :increte pancreatic polypeptide (PP) (secretion granules of 180 nm)
• small granule (S) cells (in duodenum, jejunum and ileum) increte secretin (secretion granules of 200 nm)
• TG cells (in jejunum) increte a C-terminal gastrin-like product
• adrenal glands / suprarenal gland / glandula suprarenalis (see also diseases of adrenal glands) : located above and medially to the upper renal pole
• in the newborn : 7-9 g (33% of renal sizes)
• in the adult : 5-10 g (3-6 cm in width, 2-5 cm in height, 2-8 mm in thickness)
Ontogenesis : sympathochromaffin cells (small round cells in the fetal suprarenal gland, the forerunners of the sympathetic and medullary cells)
• accessory suprarenal or adrenal glands or rests / glandulae suprarenales accessoriae : adrenal glandular tissue, usually either cortical or medullary, found in the abdomen or pelvis
Cell types :
• adrenal medulla (10-20% of gland volume)
• adrenaline-increting cell (80%) : absent in the fetal period

Normal plasma value : 20-60 pg/ml; < 15 mg/day
Biological effects via b-ARs > a-ARs :
• b₁-AR
• positive inotropic, chronotropic, and batmotropic effects
• renin incretion
• b₂-AR
• peripheral vasodilatation
• bronchodilatation
• glycogenolysis
• lipolysis
• release of insulin
• relaxation of uterus
• short hypertensive course => orthostatic systemic arterial hypotension
• noradrenaline-increting cell (20%) : prevalent at birth

Normal plasma value : 200-400 pg/ml; 10-60 mg/day
Biological effects via a-ARs > b-ARs:
• glycogenolysis
• peripheral vasoconstriction
• stable or paroxysmal systemic arterial hypertension
• dopamine
• adrenomedullin (ADM)
Secretion is stimulated by pregangliar orthosympathetic neurons via M receptors. Urinary catabolites : vanylmandelic acid (VMA) (2-7 µg/day), metanephrine (300-900 µg/day) and normetanephrine
• adrenal cortex (80-90% of gland volume) : arising from the cranial pole of the mesonephros
• definitive zone of adrenal cortex : the smaller outer zone of the primordial adrenal cortex and that of the fetus and newborn, which develops into
• zona glomerulosa / glomerular zone (75%) : the thin outer layer of the adrenal cortex, contiguous with the capsule; it is the source of aldosterone.
• mineralocorticoids-increting cell. Secretion is :
• stimulated by :
• acetylcholine
• serotonin
• angiotensin II
• adrenoglomerulotropin
• hyperkalemia
• ACTH
• b-endorphin
• endothelin
• inhibited by
• atrial natriuretic peptide (ANP)
• dopamine
• hypernatremia
• ouabaine-like drugs
Daily incretion rate : 0.2 mg/die
Normal aldosterone plasma concentration : in orthostatism =  3-16 ng/dl

	diet = 210 mEq Na+	diet = 110 mEq Na+	diet = 10 mEq Na+
supine	48±29 pg/mL = 133±80 pmol/L	107±45 = 279±125	175±75 = 485±208
upright	65±23 pg/mL = 180±64 pmol/L	239±123 = 663±341	532±228 = 1476±632

Biological effects via MR :
• increased Na⁺ reabsorption and decreased K⁺ reabsorption from distal convoluted renal tubule and cortical collecting duct => hypernatremia and hypokaliemia
• metabolic alkalosis
• zona fasciculata / fascicular zone (15%) : the thick middle layer of the adrenal cortex; it is the major source of glucocorticoids.
• glucocorticoids-increting cell in zonae reticularis, fasciculata, and glomerularis : incretion has zenit at 8 a.m. and nadir at 6 p.m.

Secretion is stimulated by ACTH.
Daily incretion rate : 15 mg/die. Plasma carriers : albumin, cortisol-binding globulin (CBG) / SERPINA6
Normal cortisol plasma concentration :
• at 8 a.m. : 5-25 mg/dL = 0.14-0.69 nmol/L
• 8 hours after dexamethasone nocturnal suppression test < 5 mg/dL or < 0.14 nmol/L
• at h 2-4 p.m. : 3-13 mg/dL or 0.14-0.69 mmol/L
• at 8 p.m. : < 10 mg/dL or < 0.28 mmol/L
• 4 hours after 20 IU ACTH challenge test (4 hrs infusion) : 30-45 mg/dL = 0.83-1.24 mmol/L
Normal concentration of free urinary cortisol (FUC) = 10-100 µg/day
Biological effects :
• insulin-like effects on carbohydrates (=> insulin resistance; priming effect for glucagon and adrenalin : in the latter case it also upregulates PNMT expression in adrenal medulla)
• diabetic ketoacidosis
• gluconeogenesis
• glycogenosynthesis
• anti-insulin effects on proteins and lipids
• lipolysis
• proteolysis
• bone reabsorption
• embryo development
• natriuresis
• zona reticularis / reticular zone (10%) : the inner layer of the adrenal cortex, consisting of cells arranged as clearly anastomosing cords, and abutting the medulla.
• androgen-increting cell in zona reticularis produces testosterone
• fetal zone of adrenal cortex / fetal adrenal cortex / provisional cortex (80%) : the inner zone of the primordial adrenal cortex and that of the fetus and newborn, which begins to involute shortly after birth in the first month of extrauterine life
• adrenarche : augmentation of adrenal cortical secretion, involving especially androgens, a physiologic change that occurs at approximately the age of 7-8 years (puberty) in both sexes.
• endocrine gonads
• endocrine ovaria (see also diseases of ovaria) : the female gonad, one of the two sexual glands in which the ova are formed. It is a flat oval body along the lateral wall of the pelvic cavity, attached to the posterior surface of the broad ligament. It consists of
• stroma
• ovarian follicles in various stages of maturation
• cortex
• medulla
• covered by a modified peritoneum (mesovarium)
Cell types :
• ovarian follicle inner theca cell (estrogen-increting)

Normal plasma concentration of estradiol / E₂ :
• prepuberal females : < 20 pg/mL or < 73 pmol/L
• adult females : 23-361 pg/mL or 84-1325 pmol/L
• follicular stage : 22-300 pmol/L
• periovulatory stage : 55-1424 pmol/L
• luteinic stage : 111-1311 pmol/L
• postmenopause : < 30 pg/mL or < 110 pmol/L
Biological effects via ER :
• reproductive effects
• nonreproductive effects :
• cardioprotection
• arterial vasodilatation
• neuroprotection
• reduced incidence of CRC
• increased incidence of breast cancer
• increased LPL and CF
• increased BMD
• at menopause :
• LDL increased by 10% (ERT : p.o. -12-19%)
• HDL reduced by 8% (ERT : p.o. +9-13%; implants : +10%; transderm : +25%; T-Ch -4-8%)
• hypertriglyceridemia (ERT : +25% !)
• increased small LDLs
• granulosa-lutein cells / corpus luteus cell (increting progesterone since Graafian secondary ovarian follicle)

Normal plasma concentration :
• prepuberal females : < 1.9 nmol/L
• follicular stage : 0.2-0.6 ng/mL = 0.6-1.9 nmol/L
• half-cycle peak : 0.3-3.5 ng/mL = 0.95-11 nmol/L
• post-ovulatory stage : 6.5-32.2 ng/mL = 21-102 nmol/L
• periovulatory stage : 1.5-4.1 nmol/L
• luteinic stage : 8-84 nmol/L
• menopause : < 1.5 nmol/L
Plasma carriers : albumin (90%) and transcortin (10%)
Biological effects :
• inhibits proliferation and induces secretory differentiation of endometrium (expecially uterine body, retroplacental and periplacental areas), allowing nidation and development of pregnancy until week 9 (when progesterone is directly produced by syncitiotrophoblast)
• decreased cervical mucus secretion
• decreased growth of galactophorous ducts in breasts
• immunosuppression
• sedation and anaesthesia
• hyperthermy
• decreased vascular permeability (direct action or via histamine and prostaglandins)
Biological events :
• menarche : the establishment or beginning of the menstrual function (puberty), occurring in the age range 10.5-15.5. In the first 2 years after menarche 55-90% of ovarian cycles are anovulatory, 20% after 5 years.
• menopause
Androgens in females :

hormone	relative androgenic activity	sources			normal plasma concentrations
		adrenal glands	ovaries	other tissues
androstenedione	10-20	30-45%	45-60%	10%	3-12 nmol/L
DHT / androstanolone	250	0%	0%	100%	24-368 pg/mL (premenopausal)  10-181 pg/mL (postmenopausal)
testosterone	100	5-25%	5-25%	50-70%	25-95 ng/dL = 0.87-3.12 nmol/L  (free : 0.09-1.28 ng/dL = 3.1-44.4 pmol/L)
DHEA	5	80%	20%	0%	1.4-8.0 ng/mL = 4.9-28 nmol/L (adult)  0.3-4.5 ng/mL = 1.0-15.6 nmol/L (postmenopausal)
DHEA-S	1	>95%	< 5%	0%	84-433 mg/dL = 2.2-11.1 mmol/L (adult)  1.7-177 mg/dL = 0.04-4.5 mmol/L

• endrocrine testes (see also diseases of testes)

TFs required for normal testis development : sex determining region Y (SRY) / testis-determining factor (TDF), Wilms tumor 1 (WT1), steroidogenic factor 1 (SF-1), SRY (sex determining region Y)-box 9  (SOX9), NR0B1 / DAX-1.
Cell types :
• seminal cells : epithelial cells within the tubuli seminiferi
• interstitial cells of Leydig contain crystalloids of Reinke and elaborate
• androgens :
• normal testosterone (T) plasma concentration in males : 300-1100 ng/dL = 10.4-38.1 nmol/L (adolescent : > 100 ng/dL or > 3.5 nmol/L; free : 3.06-24.0 ng/dL = 106-832 pmol/L). In plasma : 80% bound to SHBG, 19% to albumin, free 1% in females, 2-3% in males. Incretion is stimulated by :
• a 5-minute chat with a twentysomething female increases testosterone levels up around 30%.
• men who are married or in long-term relationships have lower testosterone levels than those still playing the field. But it's not yet clear whether marriage drives testosterone down or if low-testosterone men are more likely to get married.
Catabolism by liver and extrahepatic tissues (30-35% in males and 10% in females)
• normal dihydrotestosterone (DHT) plasma concentration : 30-99 ng/dL. Catabolyzed to 3a-androstenediol and 3a-androstenediol glucuronide (3a-AG)
• normal DHEA plasma concentration : 0.5-5.5 ng/mL = 1.7-19 nmol/L. No plasma carrier
• normal DHEA-S plasma concentration : 151-446 mg/dL = 3.9-11.4 mmol/L. No plasma carrier.
• normal androstenedione (A) plasma concentration : 45-180 ng/dL = 2-10 nmol/L (< 3.5 nmol/L in prepuberal children). No plasma carrier. Androstenedione/testosterone ratio at all ages < 1.0
• normal progesterone plasma concentration : < 1.0 ng/mL or < 3.2 nmol/L
• normal estradiol / E₂ plasma concentration :
• prepuberal males : < 78 pmol/L
• adult males : < 50 pg/mL or < 184 pmol/L
Glucuroconjugates (90-95%) are excreted by renal route, while sulfoconjugates (5-10%) are excreted in bile.
Biological effects :
• male organogenesis
• distribution and growth of body hair (including the head's hair loss pattern, often seen at relatively young age), sebaceous glands, skeletal muscles and bone marrow
• inhibition of granulosa cell proliferation and induction of follicular atresia
• pitch of the male voice
• distribution of body fat
• libido
• androgens are the principal sex steroids controlling reproduction and aggression in male fish, but their production can also be affected by social interactions. Androgen concentrations are not significantly increased in cichlid fish (Oreochromis mossambicus) that are fighting their own image in a mirror, despite their aggressive behaviour towards the virtual intruder. Our results indicate that the hormonal response normally triggered in male contests is not induced under these circumstances by the act of fighting itself, and that it may therefore depend on some indicator of relative fighting ability that cannot be delivered by a mirror-image challenger^ref.
• oxytocin (OT)
• POMC
• nurse or nursing Sertoli's cells / sustentacular cells / nurse or nursing cells / foot cells / trophocytes : elongated cells in the seminiferous tubules, to which the spermatids become attached; they provide support, protection, and, apparently, nutrition until the spermatids become transformed into mature spermatozoa. They contain Charcot-Böttcher crystalloids and produce :
• antimullerian hormone (AMH) during embryogenesis
• activin A. Biological effects via activins and inhibin receptor : stimulation of FSHincretion
• activin AB. Biological effects via activins and inhibin receptor : stimulation of FSH incretion
• follistatin. Biological effects : inhibition of activin A and activin AB
• inhibin. Biological effects via activins and inhibin receptor : inhibition of FSH incretion
• Gley's cells : large glandular cells in the interstitial tissue of the testicle
• myoid cells / peritubular contractile cells : cells found in the seminiferous tubules of common laboratory rodents, which cytologically resemble smooth muscle and are presumed to be contractile and to be responsible for the rhythmic shallow contractions of the seminiferous tubules of these species
Biological events :
• climacteric / climacterium : the syndrome of endocrine, somatic, and psychic changes occurring in men owing to normal diminution of sexual drives with the aging process (andropause)
Biological events :
• primordial germ cells (PGC) : the earliest germ cells, originating extragonadally but migrating early in embryonic development to the gonads
• endocrine changes : activation of
• hypothalamus-pituitary-adrenal (HPA) axis : adrenarche =>
• pubarche : the beginning of puberty, signalled by growth of the pubic hair
• hypothalamus-pituitary-gonads (HPG) axis : gonadarche : the onset of gonadal functioning =>
• menarche
• thelarche
=> puberty : the period during which
• secondary sex characteristics begin to develop and the capability of sexual reproduction is attained
• penis development occurs in the age range 10.5-14.5 to 10.5-16.5
• testicular hypertrophy (> 4 ml, as measured with Prader orchidometer) occurs in the age range 9-14 to 13.5-17
• 1-3 ml for prepuberty
• 4 ml for entering puberty
• 8-10 ml for mid-puberty
• 15-25 ml for full puberty
The change from prepuberty to full reproductive capacity may take as little as 18 months or as long as 5 years. At age 13 years, boys can manifest the entire range.
• spermarche : the beginning of sperm production (50% at age 14) assessed by spermaturia
• pubertal spurt : growth velocity. Height growth occurs from age 10.5-16 to age 13.5-17.5 in males, and from age 9.5 to 14.5 in females
• mean height in males 175 cm (spurt at age 14), in females 162 cm (spurt at age 12)
• height curve
• height velocity curve
• predicted adult height (PAH) = (current height x 100) / (coefficient for bone age)
• Bayley-Pinneau table
• Tanner-Goldstein-Whitehouse mark I table
• Tanner-Whitehouse mark II table
• index of potential height table
• Roche-Wainer-Thissen table
• target height (TH) :
• (father's height + mother's height + 13)/2 +
• + 8.5 cm (for sons)
• - 13 cm (for daughters)
• = (height of the father + height of the mother) / 2 +
• + 6.5 cm (for sons)
• - 6.5 cm (for daughters)
• puberogenic bone age (BA) : appearance of sesamoid bone in thumb of left hand and stabilization of carpal bones
• in females : age 11
• in males : age 13
• peak bone mass (PBM)
In males every target is postponed by 2 years.
Tanner's stages :
• breast (B) (in girls only)
• B1 : flat, prepubertal breast
• B2 : a firm, tender lump under the center of the areola(e) of one or both breasts (thelarche)
• B3 : the swelling has clearly begun in both sides, softened, and can be felt and seen extending beyond the edges of the areolae
• B4 : breasts are approaching mature size and shape, with areolae and papillae forming a secondary mound
• B5 : this mound disappears into the contour of the mature breast
• pubic hairs (Ph)
• Ph2 : first few hairs. In about 15% of girls, the earliest pubic hair appears before breast development begins.
• Ph3 : hairs are too numerous to count and appear on the mons as well
• Ph4 : pubic hairs densely fill the "pubic triangle."
• Ph5 : spread of pubic hair to the thighs and sometimes upward towards the umbilicus
• genitalia (penis and testis) (G)
• G1 : a boy's penis grows little from the fourth year of life until puberty. Average prepubertal penile length is 6 cm.
• G2 : within months after growth of the testes begins, rising levels of testosterone promote growth of the penis and scrotum
• G3 :
• G4 :
• G5 :

Plasma carrier for sexual steroids : sex steroid-binding globulin (SSBG) / sex hormone-binding globulin (SHBG) / androgen-binding protein (ABP) (normal plasma concentration : 27-92 nmol/L; synthesis is upregulated by estrogens and T₃, and down-regulated by androgens and insulin)
Peptides produced by both gonads :
• activin A. Biological effects via activins and inhibin receptor : stimulation of FSH incretion
• activin AB. Biological effects via activins and inhibin receptor : stimulation of FSH incretion
• follistatin. Biological effects : inhibition of activin A and activin AB
• inhibin. Biological effects via activins and inhibin receptor : inhibition of FSH incretion
• relaxin 1. Biological effects via RLXR
• relaxin 2. Biological effects via RLXR
• relaxin 3. Biological effects via RLXR
• endocrine placenta

Cell types :
• cytotrophoblast is functionally equivalent to hypothalamus
• syncitiotrophoblast is functionally equivalent to pars distalis adenohypophysis
• human placental lactogen (hPL) / human chorionic somatomammotropin (hCS) replaces GH
• human chorionic gonadotropin (hCG)replaces LH. Normal urine concentrations of b subunit of hCG (BHCG) :
• males and nonpregnant females : 0-10 mIU/mL
• pregnancy
• week 5 : 60-7,100 mIU/mL
• week 5-6 : 110-16,200 mIU/mL
• week 6-7 : 530-62,200 mIU/mL
• week 7-8 : 3,000-130,000 mIU/mL
• week 8-9 : 17,800-207,400 mIU/mL
• week 9-10 : 30,600-254,600 mIU/mL
• week 10-11 : 34,400-244,800 mIU/mL
• week 11-12 : 29,100-213,300 mIU/mL
• week 12-13 : 25,900-208,400 mIU/mL
• week 13-14 : 30,600-189,000 mIU/mL
Qualitative serum pregnancy testing is performed when greater accuracy is sought, but only a "yes" or "no" answer is required. While the qualitative urine test can detect hCG levels > 25-50 mIU/mL, the serum tests can detect hCG levels > 5-10 mIU/mL
Normal plasma concentration of common a subunit :
• adult male or female : < 0.5-2.5 ng/mL or < 0.4-2.0 nmol/L
• post-menopausal female : < 0.5-5.0 ng/mL or < 0.4-4.0 nmol/L

carbohydrates
glycogenosynthesis => hypoglycemia	gluconeogenesis and glycogenolysis => hyperglycemia
insulin cortisol (but induces gluconeogenesis)	glucagon (only on hepatocytes)  adrenalin growth hormone (GH) T3
lipids
lipolysis => hyperlipidemia	lipogenesis
growth hormone (GH) glucagon cortisol	insulin
proteins
proteolysis	proteosynthesis (incretion is stimulated by essential amino acids)
cortisol	growth hormone (GH) IGF-1 insulin

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