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.

For more information, see the articles "Thyroid gland and parathyroid glands" and “Adrenal gland.”

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)
• Metabolic diseases
  • Diabetes mellitus
  • Metabolic syndrome
  • Osteoporosis (See “Calcium homeostasis” in “Hypocalcemia”)
• Diseases of the endocrine glands of the hypothalamic-pituitary axis
  • Pituitary gland
    • Hypopituitarism
    • Prolactinoma
    • Acromegaly
    • Diabetes insipidus
    • SIADH
    • Central precocious puberty
  • Adrenal cortex
    • Hypocortisolism
    • Cushing syndrome
    • Primary hyperaldosteronism
    • Congenital adrenal hyperplasia
    • Adrenal insufficiency
  • Thyroid gland
    • Hypothyroidism
    • Hyperthyroidism
  • Gonads
    • Hypogonadotropic hypogonadism
    • Hypergonadotropic hypogonadism

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.
• Types of hormones

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 pituitary hormones.
  • Negative feedback loop types include:
    • Ultrashort feedback loop: Hypothalamic hormones inhibit their own secretion via autocrine effects.
    • Short feedback loop: Pituitary hormones inhibit the release of hypothalamic hormones.
    • Long feedback loop: Hormones from peripheral endocrine glands inhibit the release of hypothalamic and pituitary hormones.
  • Example: Thyroid hormone signaling decreases the production of thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH).
• Positive feedback
  • 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)
• Specific laboratory studies (e.g., determination of thyrotropin receptor antibodies; HbA_1c for diabetes mellitus)

Hypothalamus

• Anatomy
  • Ventral part of the diencephalon (see “Diencephalon”)
  • Composed of multiple nuclei (e.g., lateral nucleus, preoptic nucleus)
• Function
  • 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.
  • Reception and integration of sensory inputs (e.g., from area postrema, OVLT)
  • Thirst and hunger regulation
  • Autonomic function control
  • Thermoregulation
• Hormones
  • Inhibiting hormones
    • Function: decrease hormonal secretion from the pituitary gland
    • Examples: somatostatin, dopamine
  • Releasing hormones
    • 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 pituitary neurons)
  • Consists of two major parts:
    • Anterior pituitary gland (adenohypophysis): develops from oral ectoderm (Rathke pouch)
    • Posterior pituitary gland (neurohypophysis): develops from neural ectoderm
  • The three major types of pituitary cells are:
    • Acidophil cells
      • Secrete prolactin and growth hormone (GH)
      • Stain well with acidic dyes such as eosin
    • Basophilic cells
      • Secrete adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)
      • Stain well with basic dyes (e.g., hematoxylin)
    • Chromophobe cells
      • Do not secrete hormones ^[3]
      • Stain poorly with both acidic and basic dyes
• Function
  • Anterior pituitary gland
    • Regulation of endocrine gland function via the release of tropic hormones
    • Secretion of nontropic hormones with direct peripheral effects
  • Posterior pituitary gland: storage/release of ADH and oxytocin in pituicytes (glial cells)
  • Intermediate pituitary gland: secretion of melanocyte-stimulating hormone (MSH)
• Hormones
  • 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.
  • Nontropic hormones: act directly on target-tissue cells

“B-FLAT”: Basophils secrete FSH, LH, ACTH, and TSH.

“PiG on Acid”: Prolactin and GH are secreted by Acidophils.

Hypothalamus and anterior pituitary

Tropic hormones

Nontropic hormones

“No PRO-BLAM:” Derivatives of PROopiomelanocortin are Beta-endorphin, ACTH, and MSH.

Hypothalamus and posterior pituitary

• 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)
• Feedback control mechanism
  • ↑ 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.
• See “Hormones of the adrenal cortex” in “Adrenal gland.”

• The thyroid gland cells produce the following hormones: ^[20]
  • Follicular cells: the thyroid hormones T₃ (triiodothyronine) and T₄ (tetraiodothyronine)
  • Parafollicular cells: calcitonin
• The main function of the thyroid hormones is the regulation of basal metabolism and growth, while calcitonin is involved in calcium and phosphate homeostasis.
• Feedback control mechanism
  • ↑ 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 Ca²⁺ levels.
• See “Thyroid gland and parathyroid glands.”

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.
• Sex hormones
  • Male individuals: testosterone, dihydrotestosterone
  • Female individuals: estrogen, progesterone
• Regulation: The secretion of sex hormones is controlled by the pituitary and hypothalamic hormones.
  • LH
  • FSH
  • GnRH

Physiological effects of LH and FSH

Physiological effects of sex hormones

• See “Female sex hormones” and “Male 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.
  • Peripheral regulation via feedback inhibition of GnRH, FSH, and LH secretion by the following hormones:
    • Androgen
    • Estrogen
    • Progesterone
    • Inhibin
• Sex hormone-binding globulins (SHBGs): a group of transporter proteins required for the transport of lipophilic sex hormones
  • 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.

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
  • Fat tissue: leptin hormone released into the circulation
• Integrating center: arcuate nucleus (hypothalamus)
• Projection: The arcuate nucleus relays signals to other hypothalamic nuclei via orexigenic and anorexigenic neurons.
  • Orexigenic neurons
    • Stimulate appetite
    • Release neuropeptide Y and agouti-related peptide
  • Anorexigenic neurons
    • Suppress appetite
    • Release POMC
• Output
  • Lateral nucleus of the hypothalamus (hunger center): appetite stimulation
  • Ventromedial nucleus of the hypothalamus (satiety center): appetite suppression
• Clinical relevance
  • 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 Gain weight. Leptin makes you Lose weight.

Appetite regulators