General endocrinology
Endocrinology is the study of the endocrine system (i.e., the hypothalamus, pituitary gland, thyroid gland, adrenals, and gonads), metabolic diseases, and certain aspects of nutritional medicine. The endocrine glands are responsible for producing and secreting hormones, which influence the function of cells in certain tissues of the body. Hormone secretion is controlled by highly regulated pathways, the most important of which is the hypothalamic-pituitary axis . The hypothalamus secretes and stores nontropic hormones (e.g., ADH, oxytocin) and releasing hormones (e.g., TRH, CRH, GnRH). The pituitary gland is composed of the anterior pituitary, which secretes tropic hormones (e.g., ACTH, TSH, FSH, LH) and whose function is controlled by hypothalamic releasing hormones, and the posterior pituitary , which stores ADH and oxytocin. The gonads are the ovaries in female individuals and testicles in male individuals. Their function is controlled via the hypothalamic-pituitary-gonadal axis , as well as the secretion of sex hormone-binding globulin (SHBG). Disruption of the hypothalamic-pituitary axis can result in the development of various endocrine disorders, which are classified according to the level of pathway disruption: primary (disorders of the peripheral endocrine gland), secondary (pituitary dysfunctions), and tertiary (hypothalamic disorders). An understanding of these hormone pathways is important for the diagnosis and management of endocrine disorders, particularly when interpreting changes in hormone levels and the results of suppression and/or stimulation tests.
Overview of endocrinological diseases
This article focuses on the hypothalamic-pituitary axis. Other important structures, hormones, and metabolic diseases are discussed in their respective articles.
- Types of endocrinological diseases
- Primary disease: caused by disorders of the endocrine gland (e.g., Addison disease)
- Secondary disease: caused by disorders of the pituitary (e.g., Cushing disease)
- Tertiary disease: caused by disorders of the hypothalamus (e.g., hypothalamic trauma, hemorrhage)
- Diabetes mellitus
- Metabolic syndrome
- Osteoporosis (See “ Calcium homeostasis ” in “ Hypocalcemia ”)
- Pituitary gland
- Hypopituitarism
- Prolactinoma
- Acromegaly
- Diabetes insipidus
- SIADH
- Central precocious puberty
- Hypocortisolism
- Cushing syndrome
- Primary hyperaldosteronism
- Congenital adrenal hyperplasia
- Adrenal insufficiency
- Hypothyroidism
- Hyperthyroidism
- Hypogonadotropic hypogonadism
- Hypergonadotropic hypogonadism
Basics of endocrinology
Hormones
- Definition
- Hormones are endogenous messengers produced by endocrine glands or single cells that are responsible for signal transduction .
- They influence the function and metabolic rate of other organs and cells in the body.
- Complex regulatory circuits (e.g., the hypothalamic-pituitary axis ) control their secretion.
- Affect the neighboring cells via diffusion
- D cells of the stomach produce somatostatin to inhibit neighboring G cells from secreting gastrin.
- Affect the secreting cell itself
- Autocrine signaling is particularly important for the self-renewal of embryonic stem cells. [1]
- Secreted into the bloodstream to reach their targets
- Pancreaticβ cells secrete insulin directly into the bloodstream to stimulate the uptake of glucose by the hepatic, muscle, and adipose tissue cells.
- Derived from cholesterol
- Testosterone
- Progesterone
- Estrogen
- Glucocorticoids
- Mineralocorticoids
- Derived from a single amino acid such as phenylalanine, tyrosine, or tryptophan
- Catecholamines
- Thyroid hormones ( T3 and T4 )
- Derived from a few or many amino acids
- Oxytocin
- Vasopressin
- Prolactin
- Glucagon
- Insulin
- Diffuse through the lipid plasma membrane of cells, bind to intracellular receptors, and affect transcription
- Usually have long-term effects with delayed onset (e.g., sex hormones)
- Steroid hormones
- Thyroid hormones
- Water-soluble
- Bind to receptorproteins on the cellular membrane
- Amine and peptide hormones (except for thyroid hormones, which are lipophilic)
Hydrophilic hormones (e.g., catecholamines) are stored in secretory granules and released when needed. Lipophilic hormones (e.g., adrenocortical steroid hormones) pass into the bloodstream once synthesized without being stored in cells.
- Degradation of hormones
- Steroid hormones and thyroid hormones: inactivation and conjugation in the liver and excretion in bile
- Catecholamines: enzymatic degradation and excretion in urine (e.g., vanillylmandelic acid )
- Peptide/protein hormones: proteolytic degradation mainly in the liver and kidneys
Feedback control mechanisms
Hormone secretion is controlled by the following feedback mechanisms: [2]
- Negative feedback
- Hormone secretion by the endocrine gland suppresses the release of hypothalamic and pituitaryhormones.
- Negative feedback loop types include:
- Ultrashort feedback loop: Hypothalamichormones inhibit their own secretion via autocrine effects.
- Short feedback loop: Pituitaryhormones inhibit the release of hypothalamichormones.
- Long feedback loop: Hormones from peripheral endocrine glands inhibit the release of hypothalamic and pituitaryhormones.
- Hormone secretion enhances its own production.
- Example: Uterine stretching during labor contractions under the influence of oxytocin triggers the release of more oxytocin from the posterior pituitary.
Diagnosis of endocrine diseases
- Direct measurement of hormone blood levels (e.g., measuring prolactin blood level upon suspicion of prolactinoma )
- Stimulation of glands to detect underactivity (e.g., ACTH stimulation test for Addison disease )
- Inhibition of glands to detect hyperactivity (e.g., dexamethasone suppression test for Cushing syndrome )
- Imaging of glands to determine:
- Morphological abnormalities (e.g., thyroid ultrasound)
- Functional abnormalities (e.g., thyroid scintigraphy)
Hypothalamus and pituitary gland
Hypothalamus
- Anatomy
- Ventral part of the diencephalon (see “ Diencephalon ”)
- Composed of multiple nuclei (e.g., lateral nucleus, preoptic nucleus)
- Regulation of hormonal secretion by the anterior pituitary gland via the hypothalamic-pituitary axis
- Secretion/storage of ADH and oxytocin
- ADH and oxytocin are produced in the supraoptic nucleus and paraventricular nucleus of the hypothalamus .
- Both hormones are transported to the posterior pituitary via neurophysins (a group of carrier proteins ) and released into the circulation as needed.
- Inhibiting hormones
- Function: decrease hormonal secretion from the pituitary gland
- Examples: somatostatin, dopamine
- Function: increase hormonal secretion from the pituitary gland
- Examples: thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH), growth hormone-releasing hormone (GHRH)
Pituitary gland (hypophysis)
- Anatomy
- Located in the sella turcica (midline depression of the sphenoid bone) of the middle cranial fossa
- Connected to the hypothalamus via the pituitary stalk (a tube-like structure between the median eminence of the hypothalamus and the posterior pituitary that contains the axons of the posterior pituitaryneurons)
- Consists of two major parts:
- Anterior pituitary gland ( adenohypophysis ): develops from oral ectoderm ( Rathke pouch)
- Posterior pituitary gland ( neurohypophysis ): develops from neural ectoderm
- Acidophil cells
- Secrete prolactin and growth hormone (GH)
- Stain well with acidic dyes such as eosin
- Secrete adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)
- Stain well with basic dyes (e.g., hematoxylin)
- Do not secrete hormones [3]
- Stain poorly with both acidic and basic dyes
- Anterior pituitary gland
- Regulation of endocrine gland function via the release of tropic hormones
- Secretion of nontropic hormones with direct peripheral effects
- Tropic hormones : act on endocrine glands to mediate their effects
- All pituitary glycoprotein hormones (e.g., FSH, LH, TSH) have a common alpha subunit .
- Each hormone has a unique beta subunit .
“ B-FLAT ”: B asophils secrete F SH, L H, A CTH, and T SH.
“ P i G on Acid”: P rolactin and G H are secreted by Acid ophils.
Hypothalamus and anterior pituitary
Tropic hormones
- CRH
- Stimulates ACTH, MSH, and β-endorphin secretion from proopiomelanocortin (POMC) precursor
- CRH levels decrease after long-term steroid treatment via negative feedback.
- ACTH
- Stimulates adrenalglucocorticoid and androgen production
- Cleaved in the corticotropic cells of the anterior pituitary
- ACTH and MSH share the common precursor POMC , which explains the hyperpigmentation seen in Cushing disease.
- Adrenal cortex
- TRH
- Stimulates TSH and prolactin secretion
- An increase in TRH levels (e.g., in primary/secondary hypothyroidism) may result in the development of galactorrhea because it stimulates prolactin secretion.
- TSH
- Stimulates thyroid hormone production
- TSH secretion is inhibited by dopamine, somatostatin, and glucocorticoids. [4]
- TSH levels are the best initial test in the workup of hypothyroidism.
- Thyroid gland
- GnRH
- Stimulates FSH and LH secretion
- During breastfeeding, high prolactin levels cause supressed GnRH secretion, which results in the development of lactational amenorrhea.
- Pulsatile GnRH secretion is responsible for puberty and reproductive function.
- Gonadotropins
- LH
- Female individuals: triggers ovulation
- Male individuals: stimulates testosterone synthesis in Leydig cells
- Gonads
- Female individuals: ovaries
- Male individuals: testicles
Nontropic hormones
- GHRH
- Stimulates GH secretion
- Synthetic forms of GHRH (tesamorelin) can be used for abdominal fat reduction in HIV-associated lipodystrophy.
- GH (growth hormone, somatotropin)
- Direct effects
- ↓ Glucose uptake into cells ( ↑ insulin resistance )
- ↑ Lipolysis
- ↑ Protein synthesis in muscle
- ↑ Amino acid uptake
- Growth stimulation
- Anabolic effect on body
- ↑ GH secretion: exercise, deep sleep, puberty, hypoglycemia, CKD , thyroid hormone, estrogen, testosterone, and short-term glucocorticoid exposure
- ↓ GH secretion: glucose, somatostatin, somatomedin , free fatty acids, and chronic glucocorticoid therapy [6] [7]
- Somatostatin
- Inhibits GH and TSH secretion
- Synthetic forms of somatostatin are used in the treatment of acromegaly (e.g., octreotide).
- Dopamine ( prolactin-inhibiting hormone ): inhibits secretion of prolactin in the pituitary gland
- Prolactin (secreted by lactotropic cells )
- ↑ Breast tissue growth and lactation
- Inhibits GnRH secretion
- Female individuals
- Inhibition of ovulation
- Amenorrhea
- Galactorrhea
- Decreased libido
- Inhibition of spermatogenesis
- Decreased libido
- TRH: stimulates the secretion of prolactin (but is not part of the hypothalamic-pituitary-prolactin axis )
- Melanocyte-inhibiting hormone : inhibits release of MSH
- α-MSH
- Cleaved in the arcuate nucleus
- Regulation of appetite and metabolism: promotes satiety [8]
- Stimulates melanogenesis → melanocyte stimulation → hyperpigmentation
“No PRO-B L AM :” Derivatives of PRO opiomelanocortin are B eta- endorphin , A CTH, and M SH.
Hypothalamus and posterior pituitary
- Plasma osmolality: sensed by hypothalamic osmoreceptors
- Hypovolemia: sensed by the atrial stretch receptors
- Hypotension: sensed by the peripheral baroreceptors
- Angiotensin II : sensed by hypothalamicreceptors
- Regulation of plasma osmolality
- Mediated by V2 receptors
- Insertion of aquaporin channels in the principal cells of the renal collecting duct and DCT [10]
- Results in increased water reabsorption
- Mediated by V1 receptors
- Vasoconstrictive effects at higher levels
- Elevated in SIADH despite plasma hypoosmolality
- ADH deficiency or resistance can lead to diabetes insipidus.
- Alcohol inhibits ADH release and causes diuresis. [12]
- Nipple stimulation
- Stretching of the vagina or cervix
- Promotes uterine contractions during labor
- Facilitates milk ejection reflex via myoepithelial cell contraction
- Involved in the neuromodulation of social and reproductive behavior, fear, anxiety, and depression
- Goserelin
- Leuprolide
- Nafarelin
- Histrelin
- Excessive pituitary stimulation → ↓ GnRHreceptors → ↓ LH and FSH secretion → ↓ estradiol production in ovaries, ↓ testosterone in male individuals [13]
- Transient agonist effects are followed by the suppression of the hypothalamic-pituitary-gonadal axis .
- Cancer (continuous administration)
- Breast cancer
- Prostate cancer
- Hypogonadism
- Decreased libido
- Vaginal dryness
- Hot flashes
- Degarelix
- Block GnRHreceptors on pituitary to decrease FSH and LH secretion
- Prostate cancer
- In vitro fertilization [14]
- Hypogonadism
- Hot flashes
- Elevated liver enzymes
- Nausea, vomiting
- Octreotide
- Lanreotide
- Inhibit GH secretion
- Inhibit the release of splanchnicvasodilatoryhormones (e.g., gastrin, glucagon, insulin, VIP)
- Acromegaly
- Carcinoid tumor
- VIPoma
- Acute esophageal variceal bleeding
- Glucagonoma
- Gastrinoma
- Insulinoma
- General
- Fatigue, weakness
- Depressed mood
- Steatorrhea
- Nausea , vomiting
- Abdominal pain, cramps
- Cholelithiasis (due to inhibition of cholecystokinin)
- Tesamorelin
- Stimulate GHreceptors
- Growth hormone deficiency
- Turner syndrome
- HIV-associated lipodystrophy
- Short stature (e.g., in children with CKD) [16]
- Idiopathic intracranial hypertension
- Increased insulin resistance
- Prepubertal gynecomastia
- Slipped capital femoral epiphysis
- Progression of scoliosis
- Pegvisomant
- Block GHreceptor
- Acromegaly
- Hepatotoxicity
- Bromocriptine
- Cabergoline
- Stimulate dopaminereceptors
- Prolactinoma
- Parkinson disease
- Neuroleptic malignant syndrome
- Malignant hyperthermia
- Nausea, vomiting
- Orthostatic hypotension
- Confusion, hallucination
- Dyskinesia
- Conivaptan
- Tolvaptan
- Demeclocycline (a tetracycline)
- Block V2 receptors and decrease water reabsorption in the renal collecting duct
- Tolvaptan: selective V2 receptorantagonism
- Conivaptan: dual V1A and V2 receptorantagonism
- Demeclocycline seems to disrupt the intracellular second messenger cascade that follows after the binding of vasopressin to the V2 receptor in renal collecting ducts → ↓ ADH effect
- Euvolemic hyponatremia (e.g., SIADH )
- Hypervolemic hyponatremia (e.g., congestive heart failure, liver cirrhosis )
- Demeclocycline: bacterial infections
- Hypernatremia
- Nephrogenic DI (specific to demeclocycline)
- Hypotension
- Dry mouth
- Liver failure [19]
- Nausea, vomiting, stomachpain
- Increased thirst, hunger, urination
- Weight loss
- CYP3A (including CYP3A4) inhibition and CYP3A induction
- Demeclocycline
- Azotemia and nephrotoxicity
- Hepatotoxicity
- Skin reactions
- Desmopressin
- Terlipressin
- Act on the V1 and V2 receptors
- Release vWF stored in the endothelium
- Central DI
- Von Willebrand disease
- Hemophilia A
- Nocturnal enuresis
- Hyponatremia
- Oxytocin
- Mediates calcium influx → uterine contraction
- Induction of labor
- Augmentation of labor
- Postpartum hemorrhage
- Hyponatremia
- Tachysystole
- Hypotension
Adrenal cortex
- The adrenal cortex consists of three distinct layers:
- Zona glomerulosa: produces mineralocorticoids (i.e., aldosterone )
- Zona fasciculata: produces glucocorticoids (i.e., cortisol )
- Zona reticularis: produces androgens (i.e., dehydroepiandrosterone )
- ↑ Hypothalamic secretion of CRH → ↑ ACTH secretion from the pituitary → ↑ synthesis of glucocorticoids and androgens from the adrenal cortex
- Mineralocorticoids are secreted as a result of renin-angiotensin-aldosterone system activation.
Thyroid gland
- The thyroid gland cells produce the following hormones: [20]
- Follicular cells: the thyroid hormones T3 (triiodothyronine) and T4 (tetraiodothyronine)
- Parafollicular cells: calcitonin
- ↑ Hypothalamic secretion of TRH → ↑ TSH secretion from the pituitary → ↑ thyroid hormone production
- Calcitonin is not controlled by the hypothalamic-pituitary-thyroid axis . It is released in response to increased serum Ca 2+ levels .
Gonads
Overview
- Definition
- Gonads are reproductive organs that produce gametes and sex hormones.
- The male gonad is the testicle and the female gonad is the ovary.
- Male individuals: testosterone, dihydrotestosterone
- Female individuals: estrogen, progesterone
- LH
- FSH
- GnRH
Physiological effects of LH and FSH
Physiological effects of sex hormones
Feedback control mechanisms
- Hypothalamus
- Central regulation
- Pulsatile release of GnRH during puberty stimulates secretion of FSH, LH, and sex hormones.
- GnRH secretion may be influenced by competitive sports, malnutrition, or stress, any of which can lead to amenorrhea in women.
- Androgen
- Estrogen
- Progesterone
- Inhibin
- Hyperestrogenism (e.g., pregnancy, OCP use) causes increased SHBG levels.
- Female individuals with low levels of SHBG (e.g., PCOS) have higher levels of free testosterone, which is responsible for the development of hirsutism in these patients.
- Male individuals with high estrogen levels (e.g., in liver cirrhosis) are at risk of developing gynecomastia because of increased SHBG levels and decreased free testosterone levels.
Regulation of appetite and satiety
Overview [22] [23] [24]
- Input
- Gastrointestinal system
- Endocrine hormones: released into the circulation in response to feeding/fasting state
- Vagal afferents: relay signals from intestinal mechanoreceptors to the nucleus tractus solitarius
- Orexigenic neurons
- Stimulate appetite
- Release neuropeptide Y and agouti-related peptide
- Suppress appetite
- Release POMC
- Lateral nucleus of the hypothalamus (hunger center): appetite stimulation
- Ventromedial nucleus of the hypothalamus (satiety center): appetite suppression
- Polyphagia : excessive hunger (e.g., in hyperthyroidism, Prader-Willi syndrome )
- Anorexia: a loss of appetite (e.g., in cancer, HIV)
Regulation of appetite
Regulation of satiety [22] [24]
Ghrelin makes you G ain weight. Leptin makes you L ose weight.
Appetite regulators
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- Gastrointestinal system
- Central regulation
- Female individuals
- Direct effects
- LH