Hypothalamic and Pituitary Hormones

The hypothalamic and pituitary hormones are the most important regulators of the endocrine system. The hypothalamus functions as the coordinating center between the CNS and endocrine system by integrating the signals received from the rest of the brain and releasing appropriate regulatory hormones to the pituitary gland. The pituitary gland then releases its own hormones in response to hypothalamic stimulation. Pituitary hormones regulate multiple endocrine organs, including the gonads, thyroid gland, adrenal glands, and mammary glands. Pituitary hormones also play a critical role in growth and water balance.

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Overview

Definitions

Hormones are messenger molecules that are synthesized in one part of the body and exert specific regulatory effects on another part of the body.

Hypothalamic hormones:

  • Secreted directly by neurons from the hypothalamus 
  • Act on the pituitary gland
  • Represent the point of integration between the CNS and endocrine system

Pituitary hormones:

  • Secreted from both the anterior and posterior regions of the gland
  • Stimulate the secretion of hormones from peripheral endocrine organs
  • Regulated by both the hypothalamus and via negative feedback from peripheral endocrine hormones

Hypothalamic-pituitary axis and negative feedback

Many of the major endocrine hormones function within a multistep negative feedback loop known as an axis. These axes involve the hypothalamus, pituitary gland, and multiple different peripheral endocrine glands.

General structure and function of an axis:

  • Hypothalamus secretes releasing hormones.
  • The releasing hormones are transported to specific target cells within the pituitary gland.
  • The pituitary target cells release a 2nd hormone known as a tropic hormone.
  • Tropic hormones reach their target peripheral endocrine glands.
  • Peripheral endocrine glands secrete their hormones, which:
    • Act on target organs and exert a physiologic effect
    • Exert negative feedback on the hypothalamus and pituitary gland
Endocrine axis-driven negative feedback loops

Endocrine axis-driven negative feedback loops

Image by Lecturio.

Example: hypothalamic-pituitary-thyroid (HPT) axis:

  • The hypothalamus secretes thyrotropin-releasing hormone (TRH).
  • TRH stimulates pituitary thyrotropic cells to release thyroid-stimulating hormone (TSH).
  • TSH is transported to the thyroid to stimulate the production of thyroid hormones (e.g., thyroxine).
  • Thyroxine:
    • Stimulates metabolism in most cells in the body
    • Inhibits the release of TSH and TRH (negative feedback)

Hypothalamic Hormones

Hormones are synthesized directly within the neurons of the hypothalamus. Hormones are the primary regulators of the pituitary gland, and thus, the primary mechanism by which the CNS communicates with the endocrine system.

Hypothalamic control of the anterior pituitary

The hypothalamus secretes releasing factors that are transported to the anterior pituitary via the hypophyseal portal system (a vascular complex connecting the hypothalamus to the pituitary).

Stimulatory hypothalamic hormones:

  • TRH → stimulates pituitary thyrotropic cells to release TSH
  • Corticotropin-releasing hormone (CRH) → stimulates pituitary corticotropic cells to release adrenocorticotropic hormone (ACTH)
  • Gonadotropin-releasing hormone (GnRH) → stimulates pituitary gonadotropic cells to release:
    • Follicle-stimulating hormone (FSH)
    • Luteinizing hormone (LH)
  • Growth hormone-releasing hormone (GHRH) → stimulates pituitary somatotropic cells to release growth hormone (GH)
  • No “prolactin (PRL)-releasing hormone” has been definitively identified; PRL is primarily controlled through inhibition.

Inhibitory hypothalamic hormones:

  • Somatostatin:
    • At the anterior pituitary gland, somatostatin inhibits:
      • GH
      • TSH
    • Inhibits additional hormones throughout the body
  • Dopamine:
    • Inhibits PRL release
    • Other functions: role in executive function, motor control, motivation, arousal, reinforcement, and reward

Hypothalamic control of the posterior pituitary

Unlike the anterior pituitary, there are no hypothalamic hormones released into the circulation to stimulate the posterior pituitary. Rather, the hypothalamus has axons directly connected to the posterior pituitary.

  • Posterior pituitary hormones are synthesized within the neurons in the hypothalamus.
  • Posterior pituitary hormones are transported down the neuronal axons, through the hypophyseal stalk, to the posterior pituitary.
  • The hormones are released into the circulation within the posterior pituitary.
Anterior and posterior pituitary gland

Diagrams of the anterior and posterior pituitary and their respective communication pathways with the hypothalamus

ADH: antidiuretic hormone
OT: oxytocin
Image: “Anterior and posterior pituitary gland” by Phil Schatz. License: CC BY 4.0

Pituitary Hormones

The pituitary gland is the “master gland” of the endocrine system. The pituitary gland secretes hormones that stimulate other endocrine organs throughout the body.

Anterior pituitary

Anterior pituitary hormones include:

  • GH:
    • Does not target a specific organ
    • Stimulates cellular growth and differentiation throughout the body
    • Released from somatotropic cells (50% of anterior pituitary cells)
    • GH regulation:
      • Stimulated by GHRH
      • Inhibited by somatostatin
  • ACTH:
    • ACTH stimulates the adrenal cortex to secrete corticosteroids.
    • Released from corticotropic cells (15%–20% of anterior pituitary cells) 
    • Regulation: stimulated by CRH
  • TSH:
    • Stimulates the thyroid gland to release the thyroid hormones thyroxine and triiodothyronine
    • Released from thyrotropic cells (5% of anterior pituitary cells) 
    • Regulation: stimulated by TRH
  • Gonadotropins:
    • Act on the gonads (i.e., ovaries and testes), stimulating them to secrete sex hormones:
      • Androgens (e.g., testosterone)
      • Estradiol
      • Progesterone
    • Released from gonadotropic cells (10% of anterior pituitary cells)
    • Regulation: stimulated by GnRH
    • The 2 gonadotropin hormones are:
      • FSH: stimulates the development of eggs in the ovaries and sperm production in the testes
      • LH: stimulates ovulation in women and androgen production in both sexes
  • PRL:
    • Functions:
      • Stimulates the production (but not secretion) of breast milk during lactation
      • Has effects on LH sensitivity
    • Released from lactotropic cells (15%–20% of anterior pituitary cells)
    • Regulation:
      • Primarily regulated by dopamine (the major PRL inhibitor)
      • Stimulated by nipple stimulation

Posterior pituitary

Axons from the hypothalamus release these hormones directly into the circulation. The posterior pituitary hormones include:

  • Oxytocin:
    • Synthesized in the paraventricular nuclei of the hypothalamus
    • Stimulates:
      • Uterine contractions in labor
      • Milk let-down/secretion during lactation
    • Surges during sexual arousal and orgasm
    • May play a role in the propulsion of semen through the male reproductive tract
    • Known as the “love hormone”: Creates feelings of emotional bonding and sexual satisfaction
  • Antidiuretic hormone (ADH):
    • Synthesized in the supraoptic nuclei of the hypothalamus
    • Acts on the kidneys to increase water retention

Summary of the Hypothalamic-Pituitary Axis

Table: Hypothalamic-pituitary axis hormones and targets
Hypothalamic hormonePituitary target cellPituitary hormoneTarget organEnd effects
CRHCorticotropesACTHAdrenal cortexRelease of corticosteroids
TRHThyrotropesTSHThyroid glandRelease of thyroid hormones
GnRHGonadotropesFSHGonads: ovaries, testesDevelopment of ovarian follicles and production of sperm
LHGonads: ovaries, testesAndrogen production (both sexes), stimulates ovulation (women)
GHRHSomatotropesGHMany organsAnabolic effects
Somatostatin (inhibitor)SomatotropesGH (inhibited)Many organsAnabolic effects inhibited with somatostatin
Dopamine (inhibitor)LactotropesProlactin (inhibited)Mammary glandsMilk production inhibited with dopamine
ACTH: adrenocorticotropic hormone
CRH: corticotropin-releasing hormone
GH: growth hormone
GHRH: growth hormone-releasing hormone
FSH: follicle-stimulating hormone
LH: luteinizing hormone
TRH: thyrotropin-releasing hormone
TSH: thyroid-stimulating hormone

Clinical Relevance

  • Functional hypothalamic amenorrhea: a primary cause of secondary amenorrhea (cessation of menses). Functional hypothalamic amenorrhea results from the decreased pulsation of GnRH that occurs during times of severe physical or psychological stress and is most commonly associated with eating disorders or overexercise (common in women athletes). Management usually requires nutritional support and counseling.
  • Hypopituitarism: a condition characterized by a deficiency of all the pituitary hormones. As pituitary hormones regulate multiple organs, the effects of pituitary hypofunction are multisystemic. Causes include pituitary masses, congenital syndromes, trauma, infections, and vascular damage. Diagnosis is via a combination of clinical findings, hormone levels, provocation tests, and brain imaging. Treatment is by hormone replacement and addressing the underlying etiology.
  • Pituitary adenoma: tumors that develop within the anterior lobe of the pituitary gland. Pituitary adenomas are classified by size (either micro- or macroadenomas) and their ability to secrete hormones. Nonfunctioning or nonsecretory adenomas do not secrete hormones but can compress the surrounding pituitary tissue and lead to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism.
  • Hyperprolactinemia: elevated levels of PRL in the blood. The most common cause is a PRL-secreting pituitary adenoma known as a prolactinoma. Presentations can include galactorrhea (milky discharge), oligomenorrhea, erectile dysfunction, and, in the case of large tumors, headaches and visual changes. Diagnosis is made by determining serum PRL levels and imaging the pituitary gland. Management typically involves dopamine agonists as 1st-line therapy, although surgery and/or radiation may be required.
  • Acromegaly and gigantism: conditions caused by the excess production of pituitary GH. Typically, gigantism refers to the tall stature seen in excess GH states in children before growth-plate closure. Acromegaly is the result of excess GH after growth-plate closure, which leads to large extremities and characteristic facies. Diagnosis is by laboratory analysis and neuroimaging of the pituitary gland.
  • Central diabetes insipidus (CDI): a condition in which the kidneys are unable to concentrate urine due to a lack of circulating ADH. Low levels of ADH are due to either decreased production within the hypothalamus or decreased release from the posterior pituitary gland. Individuals present with polyuria, nocturia, and polydipsia. Central and nephrogenic diabetes insipidus are differentiated based on ADH levels and response to the water-deprivation test. Treatment of CDI is with desmopressin.
  • SIADH: a disorder of impaired water excretion due to the inability to suppress ADH secretion. The inappropriate secretion of ADH can be due to various causes, including increased production by the pituitary gland due to trauma or disease, certain medications, ectopic secretion in cancer, or hereditary causes (nephrogenic SIADH). Syndrome of inappropriate antidiuretic hormone should be suspected in any individual presenting with hyponatremia, hypoosmolality, and high urine osmolality.

References

  1. Welk, C.K. (2021). Hypothalamic-pituitary axis. In Martin, K.A. (Ed.), UpToDate. Retrieved July 30, 2021, from https://www.uptodate.com/contents/hypothalamic-pituitary-axis 
  2. Sadiq, N. (2021). Physiology, pituitary hormones. Tadi, P. (Ed.), Statpearls. Retrieved August 11, 2021, from Physiology, Pituitary Hormones Article (statpearls.com)
  3. Saladin, K.S., Miller, L. (2004). Anatomy and physiology. (3rd Ed. Pp. 638–646).

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