Pulsatile secretion

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Pulsatile secretion is a biochemical phenomenon observed in a wide variety of cell and tissue types, in which chemical products are secreted in a regular temporal pattern. The most common cellular products observed to be released in this manner are intercellular signaling molecules such as hormones or neurotransmitters. Examples of hormones that are secreted pulsatilely include insulin, thyrotropin, TRH, gonadotropin-releasing hormone (GnRH) and growth hormone (GH). In the nervous system, pulsatility is observed in oscillatory activity from central pattern generators. In the heart, pacemakers are able to work and secrete in a pulsatile manner. A pulsatile secretion pattern 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. Variations of the concentration in a certain frequency 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 (tonic) 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.

Contents

Pulsatile secretion in its various forms is observed in:

Neuroendocrine Pulsatility

Nervous system control over hormone release is based in the hypothalamus, from which the neurons that populate the pariventricular and arcuate nuclei originate. [1] These neurons project to the median eminence, where they secrete releasing hormones into the hypophysial portal system connecting the hypothalamus with the pituitary gland. There, they dictate endocrine function via the four Hypothalamic-Pituitary-Glandular axes. [1] 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 their associated releasing hormone from the hypothalamus in a similar pulsatile 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 hypophyseal vessels of Gonadotropin Releasing Hormone (GnRH). [2] [3]

Luteinizing Hormone & Follicle Stimulating Hormone (HPG axis)

LH is released from the pituitary gland along with FSH in response to GnRH release into the hypophyseal portal system. [4] 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 subject to the requirements of a superior feedback loop. [3] 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. [5] [6] [7]

ACTH and Glucocorticoids (HPA axis)

Regular pulses of glucocorticoids, mainly cortisol in the case of humans, are released regularly from the adrenal cortex following a circadian pattern in addition to their release as a part of the stress response. [8] [9] Cortisol release follows a high frequency of pulses forming an ultradian rhythm, with amplitude being the primary variation in its release, so that the signal is amplitude modulated. [8] Glucocorticoid pulsatlity has been observed to follow a circadian rhythm, with highest levels observed before waking and before anticipated mealtimes. [8] [9] This pattern in amplitude of release is observed to be consistent across vertebrates. [9] 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. [8] 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. [8]

Thyrotropin and thyroid hormones (HPT axis)

Circadian and ultradian rhythms of thyrotropin (TSH) concentration. Simulated time series created with SimThyr. TSH rhythms.svg
Circadian and ultradian rhythms of thyrotropin (TSH) concentration. Simulated time series created with SimThyr.

The secretion pattern of thyrotropin (TSH) is shaped by infradian, circadian and ultradian rhythms. Infradian rhythmis are mainly represented by circannual variation mirroring the seasonality of thyroid function. [10] Circadian rhythms lead to a peak secretion (acrophase) around midnight and nadir concentrations around noon and in the early afternoon. [11] [12] A similar pattern is observed for triiodothyronine, however with a phase shift. [12] Pulsatile release contributes to the ultradian rhythm of TSH concentration with about 10 pulses per 24 hours. [13] [14] [15] The amplitude of the circadian and ultradian rhythms is reduced in severe non-thyroidal illness syndrome (TACITUS). [16] [17]

Contemporary theories assume that autocrine and paracrine (ultrashort) feedback mechanisms controlling TSH secretion within the anterior pituitary gland are a major factor contributing to the evolution of its pulsatility. [18] [19] [20]

Insulin

Insulin release from The Islet of Langerhans is pulsatile with a period of 3-6 minutes. Pancreas insulin oscillations.svg
Insulin release from The Islet of Langerhans is pulsatile with a period of 3-6 minutes.

Pulsatile insulin secretion from individual beta cells is driven by oscillation of the calcium concentration in the cells. In beta cells lacking contact (i.e. outside islet of Lagerhans), 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). [21] 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. [22]

Related Research Articles

Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses during childhood and after menopause.

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

Follicle-stimulating hormone Gonadotropin that regulates the development of reproductive processes

Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

Anterior pituitary Anterior lobe of the pituitary gland

A major organ of the endocrine system, the anterior pituitary is the glandular, anterior lobe that together with the posterior lobe makes up the pituitary gland (hypophysis). The anterior pituitary regulates several physiological processes, including stress, growth, reproduction, and lactation. Proper functioning of the anterior pituitary and of the organs it regulates can often be ascertained via blood tests that measure hormone levels.

Posterior pituitary Posterior lobe of the pituitary gland

The posterior pituitary is the posterior lobe of the pituitary gland which is part of the endocrine system. The posterior pituitary is not glandular as is the anterior pituitary. Instead, it is largely a collection of axonal projections from the hypothalamus that terminate behind the anterior pituitary, and serve as a site for the secretion of neurohypophysial hormones directly into the blood. The hypothalamic–neurohypophyseal system is composed of the hypothalamus, posterior pituitary, and these axonal projections.

Gonadotropin-releasing hormone Mammalian protein found in Homo sapiens

Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.

Hypopituitarism Medical condition

Hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. If there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism is used.

Neuroendocrine cells are cells that receive neuronal input and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bring about an integration between the nervous system and the endocrine system, a process known as neuroendocrine integration. An example of a neuroendocrine cell is a cell of the adrenal medulla, which releases adrenaline to the blood. The adrenal medullary cells are controlled by the sympathetic division of the autonomic nervous system. These cells are modified postganglionic neurons. Autonomic nerve fibers lead directly to them from the central nervous system. The adrenal medullary hormones are kept in vesicles much in the same way neurotransmitters are kept in neuronal vesicles. Hormonal effects can last up to ten times longer than those of neurotransmitters. Sympathetic nerve fiber impulses stimulate the release of adrenal medullary hormones. In this way the sympathetic division of the autonomic nervous system and the medullary secretions function together.

Releasing hormones and inhibiting hormones are hormones whose main purpose is to control the release of other hormones, either by stimulating or inhibiting their release. They are also called liberins and statins (respectively), or releasing factors and inhibiting factors. The principal examples are hypothalamic-pituitary hormones that can be classified from several viewpoints: they are hypothalamic hormones, they are hypophysiotropic hormones, and they are tropic hormones.

Neuroendocrinology is the branch of biology which studies the interaction between the nervous system and the endocrine system; i.e. how the brain regulates the hormonal activity in the body. The nervous and endocrine systems often act together in a process called neuroendocrine integration, to regulate the physiological processes of the human body. Neuroendocrinology arose from the recognition that the brain, especially the hypothalamus, controls secretion of pituitary gland hormones, and has subsequently expanded to investigate numerous interconnections of the endocrine and nervous systems.

Hypothalamic–pituitary–gonadal axis Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

Hypothalamic–pituitary–thyroid axis Part of the neuroendocrine system

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

A Combined rapid anterior pituitary evaluation panel or triple bolus test or a dynamic pituitary function test is a medical diagnostic procedure used to assess a patient's pituitary function. A triple bolus test is usually ordered and interpreted by endocrinologists.

Functional hypothalamic amenorrhea (FHA) is a form of amenorrhea and chronic anovulation and is one of the most common types of secondary amenorrhea. It is classified as hypogonadotropic hypogonadism. It was previously known as "juvenile hypothalamosis syndrome," prior to the discovery that sexually mature females are equally affected. FHA has multiple risk factors, with links to stress-related, weight-related, and exercise-related factors. FHA is caused by stress-induced suppression of the hypothalamic-pituitary-ovarian (HPO) axis, which results in inhibition of gonadotropin-releasing hormone (GnRH) secretion, and gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Severe and potentially prolonged hypoestrogenism is perhaps the most dangerous hormonal pathology associated with the disease, because consequences of this disturbance can influence bone health, cardiovascular health, mental health, and metabolic functioning in both the short and long-term. Because many of the symptoms overlap with those of organic hypothalamic, pituitary, or gonadal disease and therefore must be ruled out, FHA is a diagnosis of exclusion; "functional" is used to indicate a behavioral cause, in which no anatomical or organic disease is identified, and is reversible with correction of the underlying cause. Diagnostic workup includes a detailed history and physical, laboratory studies, such as a pregnancy test, and serum levels of FSH and LH, prolactin, and thyroid-stimulating hormone (TSH), and imaging. Additional tests may be indicated in order to distinguish FHA from organic hypothalamic or pituitary disorders. Patients present with a broad range of symptoms related to severe hypoestrogenism as well as hypercortisolemia, low serum insulin levels, low serum insulin-like growth factor 1 (IGF-1), and low total triiodothyronine (T3). Treatment is primarily managing the primary cause of the FHA with behavioral modifications. While hormonal-based therapies are potential treatment to restore menses, weight gain and behavioral modifications can have an even more potent impact on reversing neuroendocrine abnormalities, preventing further bone loss, and re-establishing menses, making this the recommended line of treatment. If this fails to work, secondary treatment is aimed at treating the effects of hypoestrogenism, hypercortisolism, and hypothyroidism.

Hypothalamic–pituitary hormones are hormones that are produced by the hypothalamus and pituitary gland. Although the organs in which they are produced are relatively small, the effects of these hormones cascade throughout the body. They can be classified as a hypothalamic–pituitary axis of which the adrenal (HPA), gonadal (HPG), thyroid (HPT), somatotropic (HPS), and prolactin (HPP) axes are branches.

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

Exercise amenorrhoea is a medical condition in which women involved in heavy exercise experience absence of menstruation of varying periods of time. It occurs because of neuroendocrine dysfunction and is usually reversible. Exercise amenorrhoea is a component of female athlete triad.

Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.

Gonadotropin-inhibitory hormone (GnIH) is a RFamide-related peptide coded by the NPVF gene in mammals.

References

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  7. ↑ WHO International Standard, Luteinizing Hormone, Human, Recombinant. National Institute for Biological Standards and Control.
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