Comprehensive Physiology Wiley Online Library

Role of Pulsatility in Hormonal Action

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Abstract

The sections in this article are:

1 Rhythmicity, Cyclicity, and Organization of Function
1.1 Context of Pulsatile Events
1.2 Mathematical Models With the Properties of Biological Rhythms
1.3 Modeling of Endocrine Systems to Show Rhythmic Behavior
1.4 Pulses as Signals
2 Experimental Studies in Endocrine Pulsatility
2.1 Hypothalamic Studies
2.2 Pulses of Pituitary Hormones in Peripheral Blood
2.3 Pulsatility in Stimulation of End Organ Responses
2.4 Cellular Studies
3 Analysis of Time Series of Hormone Concentrations
3.1 What Is a Pulse?
3.2 Considerations in Analyzing Biological Pulses
3.3 Methods of Analyzing Pulses
4 Conclusion
Figure 1. Figure 1.

Coordinated cycles/pulses of major components in cyclic ovulation, and some of their interactions. Some of the different frequencies of action and response in cycles/pulses are indicated. [Adapted from McIntosh and McIntosh 109 with permission from Springer‐Verlag.]

Figure 2. Figure 2.

Stability in a closed dynamic system. a: Topological metaphor. b: Trajectories of a stable system in phase space showing monotonic or oscillatory movement to a steady state. This metaphor does not describe most biological behavior.

Figure 3. Figure 3.

Limit cycle stability in an open system. Values of two variable components y and z showing limit cycle behavior with time, as defined by the Zhabotinski‐Zaikin equations with diffusion terms omitted. In the equations, A and B equal 1 and 3, respectively. The period of the cycle/pulses is approximately 7.1 time units. Such stable cyclicity is typical of many biological behaviors. [Adapted from Mcintosh and McIntosh 109 with permission from Springer‐Verlag.]

Figure 4. Figure 4.

Further limit cycle behaviors. The limit cycle of Figure 3 has been plotted with axes y and z in phase space. Equal time intervals are marked on the cycle (0–7). Also shown (light lines) are changes in y and z with time when started from values either inside or outside the stable cycle values; the limit cycle is approached. When begun at precisely y = 1 and z = 3, their values remain constant at this point (S, an unstable steady state). However, on displacing the values slightly to y = 1.001 and z = 3.003, y and z spiral out to the limit cycle. The dotted line represents changes in values of y and z when A = 2 and B = 4.5. With these different parameters, damped oscillations move the variables toward a stable, constant steady state. [Adapted from McIntosh and McIntosh 109 with permission from Springer‐Verlag.]

Figure 5. Figure 5.

Entrainment of a limit cycle. A continuous forcing function, dz/dt = Esin (2π / P) with amplitude (E) = 0.5 and period (P) = 6.7 (lowest curve), is added to the cycle shown in Figure 1. Initial values of y = 1 and z = 2 were on the original cycle. A new cycle was rapidly approached (upper curves), having the same period as the forcing function (6.7 time units). [Adapted from McIntosh and McInosh 109 with permission from Springer Verlag).

Figure 6. Figure 6.

Model showing network of known interactions, neuroendocrine, pituitary, and systemic, which determine secretion of growth hormone (GH). This was used to design equations producing stable pulsatile behavior of growth hormone release in rats. Up‐regulatory interactions are indicated by lines with T endings (⊣); down‐regulatory interactions are indicated by lines with ball endings (——•). GHRH, growth hormone‐releasing hormone; SRIH, somatostatin; IGF, insulin‐like growth factor; BP, binding proteins; F+ and F–, modifier functions, up‐regulatory and down‐regulatory, respectively; R, release; S, synthesis. [Adapted from Chen et al. 27 with permission from Academic Press Inc.]

Figure 7. Figure 7.

A hormone (or any stimulant or inhibitor) interacts with a cell receptor. The biochemistry of this event and its many possible consequences depend on the state of the cell. Also, there are dynamic aspects. The signal for action is encoded in how the hormone is presented over time to the cellular response mechanisms, which have their own inherent timing. Dynamic aspects of this interaction are the focus of this chapter.

Figure 8. Figure 8.

Characteristics of a hormone pulse which may be significant to the form of cell responses. [Adapted from McIntosh and McIntosh 113 with permission from the Journal of Endocrinology Ltd.]

Figure 9. Figure 9.

Synchrony between hypothalamic and pituitary activities. Volleys of hypothalamic multiunit electrical activity (MUA) and luteinizing hormone (LH) pulses in the peripheral circulation were measured during the follicular phase (day 5), mid‐cycle luteinizing hormone surge (day 12), and luteal phase (day 26) of the menstrual cycle of a rhesus monkey. On day 12 there was an absence of both luteinizing hormone peaks (using “cluster methods” of analysis) and volleys during the sampling period. [Adapted from O'Byrne et al. 133 with permission from Endocrinology.]

Figure 10. Figure 10.

Pituitary hormone pulses in the peripheral circulation. Variation of luteinizing hormone concentration in serial plasma samples (squares) from four cycles of one woman measured around onset of menstruation (M) on selected days during the transition from the luteal to the follicular phases and the results of fitting a secretory episode model to the data using deconvolution. Solid lines, results of fitting the model; vertical solid lines, timing and amplitude of secretory episodes seen in plasma. [Adapted from McIntosh and McIntosh 114 with permission from the Journal of Endocrinology Ltd.]

Figure 11. Figure 11.

Quantitative variation of pituitary hormone pulses in an individual with peripheral blood sampling repeated in the same healthy physiological conditions. a: Amplitudes of episodic luteinizing hormone (LH) release. b: Intervals between releases on different days of the menstrual cycle around onset of menstruation (M). Raw data are shown in Figure 10. Four menstrual cycles sampled are shown: open bars, cycle 1; lightly hatched bars, cycle 2; heavily hatched bars, cycle 3; solid bars, cycle 4. Arrowheads indicate incomplete peaks at the beginning or end of the sampling period; the size shown is less than actual and has been inferred from trends in the data. [Adapted from McIntosh and McIntosh 114 with permission from the Journal of Endocrinology Ltd.]

Figure 12. Figure 12.

Differences in pulse characteristics of two hormones secreted by the pituitary. Luteinizing hormone (LH, empty squares) and growth hormone (GH, filled squares) were measured in the same blood samples at two phases of the menstrual cycle: a, 10 days after and, b, 3 days before menstruation began. Luteinizing hormone peaks rose more rapidly and were cleared more slowly than growth hormone peaks. Timing of pulse onset of the different hormones is not correlated. Error bars represent S.E.M. of triplicate assays of each sample. The dotted line in b is the minimum detectable level of luteinizing hormone in the assay. [Adapted from McIntosh et al. 116 with permission from the Journal of Endocrinology Ltd.]

Figure 13. Figure 13.

Illustration of the more rapid rise of luteinizing hormone (LH) pulses secreted by the pituitary into the peripheral circulation compared to growth hormone (GH) pulses. Data are expressed as cumulative frequency distributions of the observed times for the concentrations of the hormones to increase from minimum levels in blood to the maxima of peaks. [Adapted from McIntosh et al. 116 with permission from the Journal of Endocrinology Ltd.]

Figure 14. Figure 14.

Regularity and entrainment of pulsatile secretion in health compared to disease. Profiles of glucose infusion rates, plasma glucose levels, and insulin secretion rates (ISR) from patients with non‐insulin‐dependent diabetes mellitus (NIDDM), or impaired glucose tolerance (IGT) and a weight‐matched control subject. Glucose was infused in an oscillatory fashion with a period of 144 min. ISRs entrained to the glucose periodicity in control subject but not patients. [Adapted from The journal of Clinical Investigation, 1993, 92: 262–271 134 by copyright permission from The American Society for Clinical Investigation.]

Figure 15. Figure 15.

Basic components of apparatus perifusing single cells or tissue pieces. [Adapted from McIntosh et al. 111, 128 with permission from Academic Press, Inc.]

Figure 16. Figure 16.

Desensitization of response from pituitary cells within a few minutes of application of a square wave of releasing hormone even at very low stimulant concentration. Sheep pituitary cells were stimulated in perifusion with gonadotropin‐releasing hormone at 5 pM (solid line) and 10 pM (dashed line) for 30 min every 2 h (heavy bars). Luteinizing hormone (LH) was measured by radioimmunoassay in fractions collected at 5 min intervals. Representative error bars only are shown (S.E.M.). Maximal luteinizing hormone release was produced by 5–10 nM GnRH in similar preparations. [Adapted from McIntosh and McIntosh 115 with permission from Endocrinology.]

Figure 17. Figure 17.

Biphasic stimulated release of pituitary hormone shown by higher time resolution of output (1 min fractions). Sheep pituitary cells were stimulated in perifusion by two 5 min square‐wave pulses of 1 nM gonadotropin‐releasing hormone (heavy bars). Luteinizing hormone (LH) release was measured by radioimmunoassay in each fraction. Error bars are S.E.M. [Adapted from McIntosh and Mcintosh 115 with permission from Endocrinology.]

Figure 18. Figure 18.

Effects of varying period and duration of stimulatory pulses of releasing hormone on output of hormone from perifused dispersed pituitary sheep cells. Timing and duration of stimulation with 850 pM gonadotropin‐releasing hormone are shown (solid bars). Effluent fractions of 0.4 ml were collected for 4 min, and luteinizing hormone (LH) was measured by radioimmunoassay. Nine columns were run simultaneously and contained equal aliquots of the same cell preparation. [Adapted from McIntosh and McIntosh 113 with permission from the Journal of Endocrinology Ltd.]

Figure 19. Figure 19.

Output of pituitary hormone per unit of applied releasing hormone increases with longer intervals between pulses and decreases with longer duration of pulses, using perifused dispersed pituitary sheep cells. In an experiment similar to that in Figure 18, square‐wave pulses of 423 pM gonadotropin‐releasing hormone (GnRH), with a range of durations and intervals between them, were applied for 8 h, using one pulse type for each of 13 columns containing equal aliquots of cells. Luteinizing hormone (LH, open circles) and follicle‐stimulating hormone (FSH, filled circles) were measured by radioimmunoassay in each 4 min output fraction. a: Variation of output with intervals between pulses. Numbers on the graph refer to the duration of the GnRH pulse at each interval. b: Variation of output with duration of pulses. Numbers on the graph show intervals between pulses. Hatching links results for luteinizing hormone and FSH measured in the same samples. [Adapted from McIntosh and McIntosh 110 with permission from the Journal of Endocrinology Ltd.]

Figure 20. Figure 20.

Specific response of luteinizing hormone (LH, open circles) and follicle‐stimulating hormone (FSH, filled circles) release from perifused sheep pituitary cells stimulated with three pulses of gonadotropin‐releasing hormone (GnRH), having a range of pulse durations and intervals. Output is plotted as functions of both pulse interval and duration. Smooth curves emphasize trends. Experimental procedure was similar to that described in Figure 19. [Adapted from McIntosh and McIntosh 110 with permission from the Journal of Endocrinology Ltd.]

Figure 21. Figure 21.

Shapes of responses of pituitary cells to ramped and square‐wave stimulations with releasing hormone. Gonadotropin‐releasing hormone concentration rose from 0 to 17 pM (dashed line) or from 0 to 423 pM (solid line) over 30 min (a) or within seconds (b) in columns containing equal aliquots of dispersed sheep pituitary cells perifused simultaneously. Luteinizing hormone (LH) responses from three pulses of stimulation from each column were normalized and combined; results are shown as means and, for illustrative purposes, S.E.M. [Adapted from McIntosh and McIntosh 115 with permission from Endocrinology.]

Figure 22. Figure 22.

Differences and similarities in dynamics of release of a pituitary hormone from stimulation of the same cells with two releasing hormones activating distinct transduction pathways. a–d: Ten minute pulses of stimulant at hourly intervals to perifused aliquots of sheep pituitary cells. Stimulants: a, 100 nM corticotropin‐releasing factor (CRF); b, 200 nM arginine vasopressin (AVP); c, three pulses of 100 nM CRF, then one of 200 nM AVP; d, three pulses of 200 nM AVP, then one of 100 nM CRF; e, continuous infusion of 20 nM CRF followed by 2 μM CRF; f, continuous infusion of 100 nM AVP, followed by 2 μM AVP. Five minute fractions were collected and analyzed for adrenocorticotropic hormone (ACTH) by radioimmunoassay. Different rates of decline are seen on removal of each releasing hormone, desensitization to one stimulant does not inhibit response to the other, and cells desensitized to one level of stimulant develop responsiveness to a higher concentration of the same stimulant. [Adapted from Evans et al. 41 with permission from the Journal of Endocrinology Ltd.]

Figure 23. Figure 23.

Example of a hormonally controlled rhythm appropriate for analysis by methods based on a sine‐wave model; pulsatile rhythms with relatively sharply rising edges and variable intervals between events are less suitable. Early morning body temperature was recorded daily in a normal woman with 27‐day ovulatory cycles. Smooth curve represents results of fitting a sine curve model over data collected for 349 days. [Adapted from McIntosh and McIntosh 109 with permission from Springer‐Verlag.]

Figure 24. Figure 24.

Illustration of aliasing. If samples are taken at intervals longer than the period in a time series (filled circles), a false picture will be obtained of its true period. [Adapted from McIntosh and McIntosh 109 with permission from Springer‐Verlag.]

Figure 25. Figure 25.

Example of the result of deconvolution of hormone measurements in blood. Luteinizing hormone (LH) was measured at 10 min intervals in a woman 2 days after the start of menstruation. Secreted pulses of luteinizing hormone were assumed to be discrete and less than 10 min long; therefore, the summed equation in the text could be applied. Output of the model was estimated amplitude of peaks (vertical bars) and estimated single exponential decay of hormone clearance. Decays of individual secretory episodes (thin curves) are shown, and these when summed gave the best fitted description (heavy curves) of the stepped experimental data. [Adapted from Murray‐McIntosh and McIntosh 128 with permission from Academic Press, Inc.]

Figure 26. Figure 26.

Principles of convolution and deconvolution applied to a secretory episode broader than sampling intervals. At each time interval (t), convolution sums successive decay curves (y, responses) calculated for each increment of the known or chosen secretory (input) pulse. Deconvolution takes the summed response y(t) (measured data) and, by the reverse process, selects the best fitted (unknown) secretory pulse. [Adapted from McIntosh and McIntosh 109 with permission from Springer‐Verlag.]



Figure 1.

Coordinated cycles/pulses of major components in cyclic ovulation, and some of their interactions. Some of the different frequencies of action and response in cycles/pulses are indicated. [Adapted from McIntosh and McIntosh 109 with permission from Springer‐Verlag.]



Figure 2.

Stability in a closed dynamic system. a: Topological metaphor. b: Trajectories of a stable system in phase space showing monotonic or oscillatory movement to a steady state. This metaphor does not describe most biological behavior.



Figure 3.

Limit cycle stability in an open system. Values of two variable components y and z showing limit cycle behavior with time, as defined by the Zhabotinski‐Zaikin equations with diffusion terms omitted. In the equations, A and B equal 1 and 3, respectively. The period of the cycle/pulses is approximately 7.1 time units. Such stable cyclicity is typical of many biological behaviors. [Adapted from Mcintosh and McIntosh 109 with permission from Springer‐Verlag.]



Figure 4.

Further limit cycle behaviors. The limit cycle of Figure 3 has been plotted with axes y and z in phase space. Equal time intervals are marked on the cycle (0–7). Also shown (light lines) are changes in y and z with time when started from values either inside or outside the stable cycle values; the limit cycle is approached. When begun at precisely y = 1 and z = 3, their values remain constant at this point (S, an unstable steady state). However, on displacing the values slightly to y = 1.001 and z = 3.003, y and z spiral out to the limit cycle. The dotted line represents changes in values of y and z when A = 2 and B = 4.5. With these different parameters, damped oscillations move the variables toward a stable, constant steady state. [Adapted from McIntosh and McIntosh 109 with permission from Springer‐Verlag.]



Figure 5.

Entrainment of a limit cycle. A continuous forcing function, dz/dt = Esin (2π / P) with amplitude (E) = 0.5 and period (P) = 6.7 (lowest curve), is added to the cycle shown in Figure 1. Initial values of y = 1 and z = 2 were on the original cycle. A new cycle was rapidly approached (upper curves), having the same period as the forcing function (6.7 time units). [Adapted from McIntosh and McInosh 109 with permission from Springer Verlag).



Figure 6.

Model showing network of known interactions, neuroendocrine, pituitary, and systemic, which determine secretion of growth hormone (GH). This was used to design equations producing stable pulsatile behavior of growth hormone release in rats. Up‐regulatory interactions are indicated by lines with T endings (⊣); down‐regulatory interactions are indicated by lines with ball endings (——•). GHRH, growth hormone‐releasing hormone; SRIH, somatostatin; IGF, insulin‐like growth factor; BP, binding proteins; F+ and F–, modifier functions, up‐regulatory and down‐regulatory, respectively; R, release; S, synthesis. [Adapted from Chen et al. 27 with permission from Academic Press Inc.]



Figure 7.

A hormone (or any stimulant or inhibitor) interacts with a cell receptor. The biochemistry of this event and its many possible consequences depend on the state of the cell. Also, there are dynamic aspects. The signal for action is encoded in how the hormone is presented over time to the cellular response mechanisms, which have their own inherent timing. Dynamic aspects of this interaction are the focus of this chapter.



Figure 8.

Characteristics of a hormone pulse which may be significant to the form of cell responses. [Adapted from McIntosh and McIntosh 113 with permission from the Journal of Endocrinology Ltd.]



Figure 9.

Synchrony between hypothalamic and pituitary activities. Volleys of hypothalamic multiunit electrical activity (MUA) and luteinizing hormone (LH) pulses in the peripheral circulation were measured during the follicular phase (day 5), mid‐cycle luteinizing hormone surge (day 12), and luteal phase (day 26) of the menstrual cycle of a rhesus monkey. On day 12 there was an absence of both luteinizing hormone peaks (using “cluster methods” of analysis) and volleys during the sampling period. [Adapted from O'Byrne et al. 133 with permission from Endocrinology.]



Figure 10.

Pituitary hormone pulses in the peripheral circulation. Variation of luteinizing hormone concentration in serial plasma samples (squares) from four cycles of one woman measured around onset of menstruation (M) on selected days during the transition from the luteal to the follicular phases and the results of fitting a secretory episode model to the data using deconvolution. Solid lines, results of fitting the model; vertical solid lines, timing and amplitude of secretory episodes seen in plasma. [Adapted from McIntosh and McIntosh 114 with permission from the Journal of Endocrinology Ltd.]



Figure 11.

Quantitative variation of pituitary hormone pulses in an individual with peripheral blood sampling repeated in the same healthy physiological conditions. a: Amplitudes of episodic luteinizing hormone (LH) release. b: Intervals between releases on different days of the menstrual cycle around onset of menstruation (M). Raw data are shown in Figure 10. Four menstrual cycles sampled are shown: open bars, cycle 1; lightly hatched bars, cycle 2; heavily hatched bars, cycle 3; solid bars, cycle 4. Arrowheads indicate incomplete peaks at the beginning or end of the sampling period; the size shown is less than actual and has been inferred from trends in the data. [Adapted from McIntosh and McIntosh 114 with permission from the Journal of Endocrinology Ltd.]



Figure 12.

Differences in pulse characteristics of two hormones secreted by the pituitary. Luteinizing hormone (LH, empty squares) and growth hormone (GH, filled squares) were measured in the same blood samples at two phases of the menstrual cycle: a, 10 days after and, b, 3 days before menstruation began. Luteinizing hormone peaks rose more rapidly and were cleared more slowly than growth hormone peaks. Timing of pulse onset of the different hormones is not correlated. Error bars represent S.E.M. of triplicate assays of each sample. The dotted line in b is the minimum detectable level of luteinizing hormone in the assay. [Adapted from McIntosh et al. 116 with permission from the Journal of Endocrinology Ltd.]



Figure 13.

Illustration of the more rapid rise of luteinizing hormone (LH) pulses secreted by the pituitary into the peripheral circulation compared to growth hormone (GH) pulses. Data are expressed as cumulative frequency distributions of the observed times for the concentrations of the hormones to increase from minimum levels in blood to the maxima of peaks. [Adapted from McIntosh et al. 116 with permission from the Journal of Endocrinology Ltd.]



Figure 14.

Regularity and entrainment of pulsatile secretion in health compared to disease. Profiles of glucose infusion rates, plasma glucose levels, and insulin secretion rates (ISR) from patients with non‐insulin‐dependent diabetes mellitus (NIDDM), or impaired glucose tolerance (IGT) and a weight‐matched control subject. Glucose was infused in an oscillatory fashion with a period of 144 min. ISRs entrained to the glucose periodicity in control subject but not patients. [Adapted from The journal of Clinical Investigation, 1993, 92: 262–271 134 by copyright permission from The American Society for Clinical Investigation.]



Figure 15.

Basic components of apparatus perifusing single cells or tissue pieces. [Adapted from McIntosh et al. 111, 128 with permission from Academic Press, Inc.]



Figure 16.

Desensitization of response from pituitary cells within a few minutes of application of a square wave of releasing hormone even at very low stimulant concentration. Sheep pituitary cells were stimulated in perifusion with gonadotropin‐releasing hormone at 5 pM (solid line) and 10 pM (dashed line) for 30 min every 2 h (heavy bars). Luteinizing hormone (LH) was measured by radioimmunoassay in fractions collected at 5 min intervals. Representative error bars only are shown (S.E.M.). Maximal luteinizing hormone release was produced by 5–10 nM GnRH in similar preparations. [Adapted from McIntosh and McIntosh 115 with permission from Endocrinology.]



Figure 17.

Biphasic stimulated release of pituitary hormone shown by higher time resolution of output (1 min fractions). Sheep pituitary cells were stimulated in perifusion by two 5 min square‐wave pulses of 1 nM gonadotropin‐releasing hormone (heavy bars). Luteinizing hormone (LH) release was measured by radioimmunoassay in each fraction. Error bars are S.E.M. [Adapted from McIntosh and Mcintosh 115 with permission from Endocrinology.]



Figure 18.

Effects of varying period and duration of stimulatory pulses of releasing hormone on output of hormone from perifused dispersed pituitary sheep cells. Timing and duration of stimulation with 850 pM gonadotropin‐releasing hormone are shown (solid bars). Effluent fractions of 0.4 ml were collected for 4 min, and luteinizing hormone (LH) was measured by radioimmunoassay. Nine columns were run simultaneously and contained equal aliquots of the same cell preparation. [Adapted from McIntosh and McIntosh 113 with permission from the Journal of Endocrinology Ltd.]



Figure 19.

Output of pituitary hormone per unit of applied releasing hormone increases with longer intervals between pulses and decreases with longer duration of pulses, using perifused dispersed pituitary sheep cells. In an experiment similar to that in Figure 18, square‐wave pulses of 423 pM gonadotropin‐releasing hormone (GnRH), with a range of durations and intervals between them, were applied for 8 h, using one pulse type for each of 13 columns containing equal aliquots of cells. Luteinizing hormone (LH, open circles) and follicle‐stimulating hormone (FSH, filled circles) were measured by radioimmunoassay in each 4 min output fraction. a: Variation of output with intervals between pulses. Numbers on the graph refer to the duration of the GnRH pulse at each interval. b: Variation of output with duration of pulses. Numbers on the graph show intervals between pulses. Hatching links results for luteinizing hormone and FSH measured in the same samples. [Adapted from McIntosh and McIntosh 110 with permission from the Journal of Endocrinology Ltd.]



Figure 20.

Specific response of luteinizing hormone (LH, open circles) and follicle‐stimulating hormone (FSH, filled circles) release from perifused sheep pituitary cells stimulated with three pulses of gonadotropin‐releasing hormone (GnRH), having a range of pulse durations and intervals. Output is plotted as functions of both pulse interval and duration. Smooth curves emphasize trends. Experimental procedure was similar to that described in Figure 19. [Adapted from McIntosh and McIntosh 110 with permission from the Journal of Endocrinology Ltd.]



Figure 21.

Shapes of responses of pituitary cells to ramped and square‐wave stimulations with releasing hormone. Gonadotropin‐releasing hormone concentration rose from 0 to 17 pM (dashed line) or from 0 to 423 pM (solid line) over 30 min (a) or within seconds (b) in columns containing equal aliquots of dispersed sheep pituitary cells perifused simultaneously. Luteinizing hormone (LH) responses from three pulses of stimulation from each column were normalized and combined; results are shown as means and, for illustrative purposes, S.E.M. [Adapted from McIntosh and McIntosh 115 with permission from Endocrinology.]



Figure 22.

Differences and similarities in dynamics of release of a pituitary hormone from stimulation of the same cells with two releasing hormones activating distinct transduction pathways. a–d: Ten minute pulses of stimulant at hourly intervals to perifused aliquots of sheep pituitary cells. Stimulants: a, 100 nM corticotropin‐releasing factor (CRF); b, 200 nM arginine vasopressin (AVP); c, three pulses of 100 nM CRF, then one of 200 nM AVP; d, three pulses of 200 nM AVP, then one of 100 nM CRF; e, continuous infusion of 20 nM CRF followed by 2 μM CRF; f, continuous infusion of 100 nM AVP, followed by 2 μM AVP. Five minute fractions were collected and analyzed for adrenocorticotropic hormone (ACTH) by radioimmunoassay. Different rates of decline are seen on removal of each releasing hormone, desensitization to one stimulant does not inhibit response to the other, and cells desensitized to one level of stimulant develop responsiveness to a higher concentration of the same stimulant. [Adapted from Evans et al. 41 with permission from the Journal of Endocrinology Ltd.]



Figure 23.

Example of a hormonally controlled rhythm appropriate for analysis by methods based on a sine‐wave model; pulsatile rhythms with relatively sharply rising edges and variable intervals between events are less suitable. Early morning body temperature was recorded daily in a normal woman with 27‐day ovulatory cycles. Smooth curve represents results of fitting a sine curve model over data collected for 349 days. [Adapted from McIntosh and McIntosh 109 with permission from Springer‐Verlag.]



Figure 24.

Illustration of aliasing. If samples are taken at intervals longer than the period in a time series (filled circles), a false picture will be obtained of its true period. [Adapted from McIntosh and McIntosh 109 with permission from Springer‐Verlag.]



Figure 25.

Example of the result of deconvolution of hormone measurements in blood. Luteinizing hormone (LH) was measured at 10 min intervals in a woman 2 days after the start of menstruation. Secreted pulses of luteinizing hormone were assumed to be discrete and less than 10 min long; therefore, the summed equation in the text could be applied. Output of the model was estimated amplitude of peaks (vertical bars) and estimated single exponential decay of hormone clearance. Decays of individual secretory episodes (thin curves) are shown, and these when summed gave the best fitted description (heavy curves) of the stepped experimental data. [Adapted from Murray‐McIntosh and McIntosh 128 with permission from Academic Press, Inc.]



Figure 26.

Principles of convolution and deconvolution applied to a secretory episode broader than sampling intervals. At each time interval (t), convolution sums successive decay curves (y, responses) calculated for each increment of the known or chosen secretory (input) pulse. Deconvolution takes the summed response y(t) (measured data) and, by the reverse process, selects the best fitted (unknown) secretory pulse. [Adapted from McIntosh and McIntosh 109 with permission from Springer‐Verlag.]

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Rosalind P. Murray‐Mcintosh. Role of Pulsatility in Hormonal Action. Compr Physiol 2011, Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology: 515-558. First published in print 1998. doi: 10.1002/cphy.cp070119