Pulsatile secretion is a biochemical phenomenon observed in a wide variety of cell types, in which chemical products are secreted in a regular pattern. The most common cellular products observed to be released in this manner are intercellular signaling molecules such as hormones or neurotransmitters. The most common examples of hormones that are secreted pulsatilely include insulin, thyrotropin, TRH, gonadotropin-releasing hormone (GnRH) and growth hormone (GH). In the nervous system, pulatlility is observed in oscillatory activity from pacemakers and central pattern generators. Pulsatile activity is critical to the function of many hormones in order to maintain the delicate homeostatic balance necessary for essential life processes, such as development and reproduction. Pulsatile secretion can be critical to hormone function, as evidenced by the case of GnRH agonists, which cause functional inhibition of the receptor for GnRH due to profound downregulation in response to constant stimulation. Pulsatility may function to sensitize target tissues to the hormone of interest and upregulate receptors, leading to improved responses. This heightened response may have served to improve the animal's fitness in its environment and promote its evolutionary retention.
Pulsatile secretion in its various forms is observed in:
Nervous system control over hormone release is based in the hypothalamus, from which the neurons that populate the pariventricular and arcuate nuclei originate. These neurons project to the pituitary gland via the hypophysial portal system, and dictate endocrine function via the four Hypothalamic-Pituitary-Glandular axes. Recent studies have begun to offer evidence that many pituitary hormones which have been observed to be released episodically are preceded by pulsatile secretion of its associated releasing hormone from the hypothalamus in a similar pulastile fashion. Novel research into the cellular mechanisms associated with pituitary hormone pulsatility, such as that observed for Leutinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) have indicated similar pulses into the hypophesial vessels of Gonadotropin Releasing Hormone (GnRH).
Leutinizing Hormone & Follicle Stimulating Hormone
Main Article: Leutinizing Hormone
LH is released from the pituitary gland along with FSH in response to GnRH release into the hypophesial portal system. Pulsatile GnRH release causes pulsatile LH and FSH release to occur, which modulates and maintains appropriate levels of bioavailable gonadal hormone, testosterone in males and estradiol in females. In females the levels of LH is typically 1–20 IU/L during the reproductive period and is estimated to be 1.8–8.6 IU/L in males over 18 years of age.
Regular pulses of glucocorticoids, mainly cortisol in the case of humans, are released regularly from the adrenal cortex at following a circadian pattern in addition to its release as a part of the stress response. Cortisol release follows a high frequency of pulses, with amplitude being the primary variation in its release. Glucocorticoid pulsitlity has been observed to follow a circadian rhythm with highest levels observed before waking and before anticipated mealtimes. This pattern in amplitude of release is observed to be consistent across vertebrates. Studies done in humans, rats and sheep have also observed a similar circadian pattern of release of adrenocorticotropin (ACTH) shortly preceding the pulse in the resulting corticosteroid. It is currently hypothesized that the observed pulsatility of ACTH and glucocorticoids is driven via pulsatility of corticotropin-releasing hormone (CRH), however there exists little data to support this due to difficulty in measuring CRH.
Main Article: Insulin Oscillation
Oscillations of intracellular calcium concentration in beta cells within the pancreas produces a basal pulsatile secretion of insulin form the pancreas. Secretion pulses emanating form free beta cells not located within an islet of Lagerhans has been observed to be highly variable (2 to 10 minutes). Beta cells within an islet, however, become synchronized via electrical coupling resulting from gap junctions, and osculate more regularly (3 to 6 minutes). ATP signalling has also been proposed as a method of coordination between beta cells.
Pulsatile insulin secretion from individual beta cells is driven by oscillation of the calcium concentration in the cells. In beta cells lacking contact, the periodicity of these oscillations is rather variable (2-10 min). However, within an islet of Langerhans the oscillations become synchronized by electrical coupling between closely located beta cells that are connected by gap junctions, and the periodicity is more uniform (3-6 min). In addition to gap junctions, pulse coordination is managed by ATP signaling. α and δ cells in the pancreas also share secrete factors in a similar pulsatile manner.
- Kandel ER, Jessell TM, Schwartz JH, Siegelbaum SA, Hudspeth AJ (2013). Principles of neural science (5th ed.). New York. ISBN 9780071390118. OCLC 795553723.
- Wetsel WC, Valença MM, Merchenthaler I, Liposits Z, López FJ, Weiner RI, Mellon PL, Negro-Vilar A (May 1992). "Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons". Proceedings of the National Academy of Sciences of the United States of America. 89 (9): 4149–53. Bibcode:1992PNAS...89.4149W. doi:10.1073/pnas.89.9.4149. PMC 525650. PMID 1570341.
- Stamatiades GA, Kaiser UB (March 2018). "Gonadotropin regulation by pulsatile GnRH: Signaling and gene expression". Molecular and Cellular Endocrinology. 463: 131–141. doi:10.1016/j.mce.2017.10.015. PMC 5812824. PMID 29102564.
- Mayo Medical Laboratories - Test ID: LH, Luteinizing Hormone (LH), Serum, retrieved December 2012
- World Health Organization Proposed International Standard for Luteinizing Hormone. WHO Expert Committee on Biological Standardization. World Health Organization. Geneva. 2003.
- WHO International Standard, Luteinizing Hormone, Human, Recombinant. National Institute for Biological Standards and Control.
- Gjerstad JK, Lightman SL, Spiga F (September 2018). "Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility". Stress. 21 (5): 403–416. doi:10.1080/10253890.2018.1470238. PMC 6220752. PMID 29764284.
- Kalsbeek A, van der Spek R, Lei J, Endert E, Buijs RM, Fliers E (February 2012). "Circadian rhythms in the hypothalamo-pituitary-adrenal (HPA) axis". Molecular and Cellular Endocrinology. 349 (1): 20–9. doi:10.1016/j.mce.2011.06.042. PMID 21782883.
- Hellman B, Gylfe E, Grapengiesser E, Dansk H, Salehi A (August 2007). "[Insulin oscillations--clinically important rhythm. Antidiabetics should increase the pulsative component of the insulin release]". Lakartidningen. 104 (32–33): 2236–9. PMID 17822201.
- Hellman B (2009). "Pulsatility of insulin release--a clinically important phenomenon". Upsala Journal of Medical Sciences. 114 (4): 193–205. doi:10.3109/03009730903366075. PMC 2852781. PMID 19961265.