Neuroendocrinological Control Systems Model to Help Understand the Normalizing Effect of Acupuncture on the Female Reproductive Cycle

Transcription

1 Neuroendocrinological Control Systems Model to Help Understand the Normalizing Effect of Acupuncture on the Female Reproductive Cycle Author: David Johnson Advisor: Prof Wayne Smith Courses Involved: ECE714 (DSP), ECE633 (Systems and Signals) MATH527 (Diff Equations) Date: May 21, 2014 Abstract: The objective presented here is to produce a working model that can accurately represent the ovarian cycle and how stress and acupuncture can affect it. Acupuncturists know that acupuncture can help in stabilizing the ovarian cycle, but they are not sure as to why it has these properties. The model represented here is able to simulate the effects of stress on the body and how acupuncture might reverse the negative results stress has on the body.

2 Introduction: Even though women have been experiencing the menstrual cycle for tens of thousands of years, we are only just starting to learn about how everything works in unison. Studies have been conducted to find out which hormones contribute to this process, but not a lot is known about how these hormones interact. Sometimes, the menstrual cycle becomes erratic and the cycle becomes irregular. Acupuncture has been found to restore that regularity with an overwhelmingly degree of success. 4 Our goal is to try to develop an accurate model for the ovarian process and create possible scenarios that may explain how acupuncture is affecting that process. Background: I. Ovarian Cycle During the menstrual cycle, there are primarily five hormones that interact. For simplicity, it makes sense to focus on only two of these, Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). Both of these hormones are produced by the pituitary gland. FSH is primarily responsible for stimulating the growth of the ovarian follicle, which includes the developing egg, the cells surrounding the egg that produce the hormones needs to support a pregnancy, and the fluid around the egg (Micromedex). The main function of LH is to cause ovulation by a sharp rise in blood levels. After ovulation, the groups of hormone-producing follicle cells become the corpus luteum, which will produce estrogen and large amounts of progesterone.

3 Progesterone causes the endometrium to mature so that it can support implantation of the fertilized egg or embryo. If implantation of a fertilized egg does not occur, the levels of estrogen and progesterone decrease, and menstruation occurs. Figure 1 illustrates how the hormone levels change throughout the thirty day period. Figure 1 7 Comparisons of the level of concentration of each hormone in the blood during the thirty day cycle. II. Ovarian Cycle and Acupuncture There have been studies pertaining to rats concerning the effects of acupuncture. Since the 1960s scientists have used acupuncture with appropriate electro-stimulation to cure patients with anovulation disorder (sterility), the rate of EA induction of ovulation was increased from 50% initial to 80% presently. 4 There is evidence that acupuncture has an effect on sterility in women, but why it has an effect is still unknown. Other authors in China also reported that acupuncture was successful in treating patients with sterility and the lying-in women with subnormal contraction of uterus. 4

4 Knowing how all the hormones in the ovarian cycle interact is illustrated in Figure 2. What we don t know is how acupuncture fits in to the aforementioned diagram. There is also the chance that acupuncture may not directly have any effect on any of these hormones, but instead affects some other system which in turn affects the ovarian cycle. Menstruation Corpus Luteum FSH Growth Follicle Hypothalamus Pituitary Corpus Luteum LH Preovulatory Follicle Ovulation Acupuncture Figure 2 4 Phases of the menstrual cycle with gonadotropin hormones, LH and FSH, and ovarian hormones, E2, P4, and Ih (2). The interaction with the acupuncture block and cycle phase is to be investigated in this study.

5 III. Stress One of the main causes of irregular ovulation is continued stress on the body. Stress causes the adrenal glands to release a hormone called cortisol. Though, it is important to clarify that cortisol is one of the few hormones in which humans need to survive. 9 Cortisol levels rise and fall throughout the day, and that is normal. But, in today s society, some people are exposed to long durations of stress that can last weeks or even months, and the body is not built to handle that much stress. When your adrenal glands are overworked, your body converts progesterone into adrenal hormones. This depletes you of the progesterone you need for other functions such as estrogen balance. Instead of progesterone being processed for ovarian needs, it is being processed to compensate for increased cortisol production. 9 Another situation we considered is instead of focusing on where cortisol is being synthesized, we could focus on where it is being metabolized. 5 The metabolization process for cortisol occurs in the liver. The liver also processes other hormones, one of which is estrogen. Increased cortisol production forces the liver s attention to processing cortisol instead of the estrogen hormones needed for the ovarian cycle.

6 Methods: Considering that none of the team members are qualified to experiment on human subjects with acupuncture, a program called MATLAB was used extensively. This piece of software is capable of modeling systems using sets of differential equations and producing an output. Using the information found in Schlosser and Selgrade, the team was able to recreate the ovarian cycle in a controlled environment. 1 In the equations below, let RP LH denote the state variable which represents the amount of LH in the reserve pool and let LH denote the serum concentration of LH. The system of differential equations governing the synthesis (s LH ), release (r LH ) and clearance (c LH ) of LH has the form 1 ( 1 ) (2.1) Where (3.2) (4.3) (5.4)

7 The corresponding synthesis, release, and clearance terms for FSH are: ( 2 ) ( 2.1) ( 2.2) The ovarian hormone equations control the feedback that in turn controls the levels of FH and FSH. It is clear from equations 3 to 3.8 that the ovarian hormones (E 2 (t), P 4 (t), Ih(t)) rely on negative feedback to help in the stabilization of the production of LH and FSH. ( 3) [ ] ( 3.1) ( 3.2) ( 3.3) ( 3.4) ( 3.5)

8 (3.6) (3.7) (3.8) The below ovarian equations (4, 4.1, 4.2) are dependent on the negative feedback of equations above. The purpose of this negative feedback is to correct any irregularities that may be introduced into the cycle. Sometimes, though, this negative feedback loop can be rendered useless when a positive feedback (cortisol) occurs for extended periods of time. ( 4) ( 4.1) ( 4.2)

9 Ovarian Equations b L day -1 c L µg -1 day -1 c day -1 c day -1 c day -1 c day -1 d day -1 d day -1 k day -1 k day -1 k day -1 k day -1 α ß Ý Table 1: Parameter values for ovarian equation

10 Auxiliary Equation e ng L -1 e kl -1 e kl -1 e kl -1 p nmol L -1 µg -1 p nmol L -1 µg -1 h U L -1 h U L -1 µg -1 h U L -1 µg -1 h U L -1 µg -1 Table 2: Parameter Values for Auxiliary Equations ( 5) ( 5.1) ( 5.2) ( 5.3)

11 LH Equation K LH 2.49 day -1 a LH 14.0 day -1 V 0,LH µgday -1 V 1,LH µgday -1 Km LH 360 ng L -1 Ki LH,P nmol L -1 C LH,E L ng -1 c LH,P 0.07 L nmol -1 d P 1.00 day Table 3: Parameter values for LH equations FSH Equation V FSH 5700 µgday -1 a FSH 8.21 day -1 k FSH 7.29 day -1 d Ih 2.00 days c FSH,E 0.16 (L/ng) 2 Ki FSH,Ih 641 U L -1 c FSH,P 644 L nmol -1 v 2.50 L Table 3.1: Parameter values for FSH equations Using these equations, it is possible to create a working model in MATLAB. This model can be easily manipulated to represent different inputs, like cortisol and acupuncture.

12 Results: Through much reading, it was clear that the irregular cycle that can occur is mainly caused by stress. Our first goal was to create a working model for the regular, thirty day, ovarian cycle. The components of the model can be seen in Figure 3 and Figure 4. After achieving this initial objective, we could proceed to simulate how cortisol could affect the body and, therefore, the ovarian cycle.

13 Figure 3 Overview of model, emphasizing FSH and LH being fed back into ovarian hormones.

14 Figure 4 Model for the ovarian hormones. These are constantly fed back into the system for stabilization.

15 During normal ovulation, it is appropriate to repeat the cycle every twenty-eight days on average. Without changing the cortisol or acupuncture inputs (which are shown in red and green, respectively), the model produces waveforms of FH and E2 about every thirty days. These values are representative of the daily mean serum levels. 8 This can be seen in Figure 5 and Figure 6. Figure 5 Output of LH during normal ovulation Figure 6 Output of E2 during normal ovulation After creating a stable environment for the ovarian cycle, we could then easily manipulate our equations to produce an output that might coincide with how cortisol would affect the system. Cortisol can affect the cycle in two ways: distracting the liver from processing ovarian hormones and stealing P4 to help in the production of cortisol. These two methods are outlined in Figure 4 by the red boxed inputs. Changing these inputs produce a cycle representing the ones in Figure 7 and Figure 8.

16 Figure 7 Output of LH after cortisol input Figure 8 Output of E2 after cortisol input These figures clearly represent what an irregular ovarian cycle might look like. In both hormones (LH and E2) in can be seen that the cycle starts out normally, but then tapers off as cortisol takes its toll. It may be important to emphasize that small bursts of cortisol is not enough to throw off the cycle. As mentioned before, cortisol is one of the few hormones that humans need in order to survive and it fluctuates throughout the day. Long durations of cortisol exposure are what cause the cycle to become irregular and produce the outputs of Figure 7 and Figure 8. Now that we have a working model that can simulate the effects of cortisol on the cycle, our next goal was to implement a system that could successfully put the cycle back into a thirty day period with the correct amplitudes. This system can be seen in Figure 3 as the green input blocks labeled Acupuncture Inputs. These acupuncture inputs offset the effects of prolonged cortisol exposure. It is interesting to note that for acupuncture to have an effect, only one or two treatments may be needed.

17 As shown in Figure 10, the cycle starts out as tapering off because of prolonged stress having an effect. This tapering off is caused by prolonged exposure to cortisol instead of the normal bursts we experience throughout the day. We introduce an acupuncture input at day 150 that significantly increases E2 levels for that day only. That increase in E2 is enough to put the cycle back into a regular cycle of thirty days with the correct waveform. Figure 9 Output of LH after acupuncture input Conclusions: Figure 10 Output of E2 after acupuncture input It is well known that stress can have a substantial effect on the ovarian cycle, but not a lot is known as to why it has this effect. The model we have created can shed some light as to why acupuncture might have the effects that it does. Clearly, acupuncture does have some sort of effect. Through much research, the consensus is that acupuncture affects the central nervous system (CNS), which in turn has an effect on the hypothalamus. The hypothalamus is the link

18 between the nervous system and endocrine system. Our model assumes that acupuncture tells the hypothalamus to increase E2 production as to offset the influences set on by stress. Being in a stressed state of mind for a sustained period of time tells the adrenal glands to produce more and more cortisol. This overabundance of cortisol production is causing the adrenal glands to use more P4 that could have been used for the ovarian cycle. Also, the liver is processing more cortisol instead of estrogen, which in turn affects the ovarian hormones and how much is available to the ovaries. As is shown by the model, if acupuncture is applied is such a way as to increase E2 production, it can permanently stabilize the ovarian cycle. Unlike cortisol, which takes weeks to months to take effect, acupuncture can set the cycle back into a thirty day rhythm with as little as one treatment.

19 References: 1. Clark, Leona, Paul Schlosser, and James Selgrade. Multiple Stable Periodic Solution in a Model for Hormone Control of the Menstraul Cycle. Bulletin of Mathematical Biology (2002) Selgrade, James and Paul Schlosser. A Model for the Production of Ovarian Hormones during the Mentrual Cycle. Fields Institute Communications (2000). 3. Schlosser, Paul and James Selgrade. A Model of Gonadotropin Regulation during the Menstrual Cycle in Women: Qualatative Features. A Model of Gonadotropin Regulation (2000). 4. Chen, Bo-Ying. Acupunture Normalizes Dysfunction of Hypothalamic-Pituitary-Ovarian Axis. Acupuncture & Electro-Theraputics 22.0 (1997) Eshkevari, Ladan, Eva Permaul, and Susan Mulroney. Acupuncture blocks cold stressinduced increases in the hypothalamus-pituitary-adrenal axis in the rat. Acupuncture and the HPA 217:1 (2013): Cobelli, Claudio and Ewart Carson. Introduction to Modeling in Physiology and Medicine. Hartford: Elsevier, Print. 7. Ammi. Interaction of Diet and Exercise with the Menstrual Cycle. Not Just A Man s World. Sitemap, March 24, Web. 8. McLachlan, R. I., N. L. Cohen, K. D. Dahl,W. J. Bremner and M. R. Soules (1990). Serum inhibin levels during the periovulatory interval in normal women: relationships with sex steroid and gonadotrophin levels. Clin. Endocrinol. 32, Esposito, Alonzo and Vito Bianchi. Cortisol: Physiology, Regulation and Health Implications. Human Anatomy and Physiology (2012).