Medical Hypotheses 84 (2015) 557–569

Contents lists available at ScienceDirect

Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy

A theoretical model of biochemical control engineering based on the relation between oestrogens/progestagens and prostaglandins P.H.E. van der Veen ⇑ Chronic Pain Science Foundation, The Netherlands

a r t i c l e

i n f o

Article history: Received 6 December 2014 Accepted 27 February 2015

a b s t r a c t A biological complex organism is involuntarily guided from all sides by measure and regulation systems. The human being is such a complex organism. Many cyclical processes are simultaneously at work, making it unclear how and why which process takes place at which moment. Noticeable examples are the 28-day menstrual cycle and the 40-week pregnancy. The time of activation in the middle of the menstrual is fairly clear. Hormonal changes also occur in this period. Why the hormonal changes occur, and what their relationship is with the activation of the processes is unclear. That is also the case during pregnancies. What is it that determines that a pregnancy should last an average of 40 weeks? What causes the changes in a complicated pregnancy? What are those changes? Prostaglandin concentrations have been found to have some relationship with these changes, but the activation of these changes and how to examine them is unknown. Using an example from practical experience, this article illustrates what Horrobin and Manku already reported in 1977, namely, the properties of prostaglandin E1 and 6-keto pgF1a: reversal effect with elevated concentration. The properties described is exceptionally suitable for the time of activation in a biochemically regulated measure and regulation system. These properties can help explain the occurrence of physiological cycles. The known electronic sawtooth wave has a biochemical analogue with this. This paper describes the presumed relationship between hormones and the accompanying prostaglandins with the hormone effects based on what is known regarding their concentrations progress. This relationship reveals the practical consequences of the experimentally found sensitivity of biochemical effects with regard to the accompanying prostaglandins. This paper shows how the theoretical relationship between effects of oestrogens and progestagens result in a curve that comprise observable aspects of the Basal Body Temperature Curve. The modulating and activating prostaglandins also affect local changes in blood circulation. These changes are visible on specific sites on the abdominal skin via viscerocutaneous reflex pathways. Changes in blood circulation at specific areas of the skin can be representative of pain. Pain that also frequently arises during activation processes. These changes can be seen and measured with non-contactual infrared thermography on the cutaneous surface, and moments of activation and pain can be determined. Ó 2015 Elsevier Ltd. All rights reserved.

Statements: What is already known about this topic? Systemic regulation and feedback mechanisms of the hormonal and nervous systems. Local concentrations of prostaglandin and hormones in blood and reproductive organs in diverse stages of the hormonal cycle. ⇑ Address: Onyx 13, 1703 CD Heerhugowaard, The Netherlands. Tel.: +31 725720430; fax: +31 848330847. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2015.02.021 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.

The existence of viscerocutaneous reflex pathways in vivo in human beings. Measurement possibilities of viscerocutaneous reflex pathways with non-invasive methods. What does this study add? It provides a model that adds insight on the impact of a local measure and regulation system, and its impact systematic feedback mechanisms. A method to reveal the effects and the time of activation of a measure and regulation system.

558

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

Introduction Not much is known regarding pain processes and cyclical changes in an organism. The processes themselves and the influence of the central nervous system on them has already been reported in the past, even exhaustively summarised in a textbook published in 1962 [1]. However, these local processes, activation moments and activation systems have not been sufficiently explained. Much is still unclear with regard to how and why certain events take place when they do. Noticeable examples are the 28-day menstrual cycle and the 40-week pregnancy. What causes hormonal concentrations to change at crucial moments, and what causes the biological effects to occur to the degree that they do? In 1977, Horrobin and Manku [2–4] reported on the properties of prostaglandins, which at that time were recently discovered. These properties are extremely well suited for activation and regulation functions. Prostaglandins are ubiquitous substances that are synthesized from cholesterol and released through cell walls [5,6]. They work as cofactors of all biological active substances in the body [4,5]. They have a purpose in pain generation, and have been shown to affect blood circulation. Complementary medical literature has for a long time assumed the dysregulation of biological processes. Pischinger called it the Grundsystem [7]. That is where pathology begins to develop after damage. That damage can be mechanical, chemical, caused by trauma, infection, vascular accidents and the like. Most of the processes recover without leaving any visible harm. More severe chronic pathology is only expressed after repetitive damage at the same site. Speransky introduced the concept of Zweitschlag for this in 1950 [8]. Local dysregulation implies local regulation too. The hypothesis of this article assumes that at a minimum, all local measure and regulation systems are controlled and guided by prostaglandins. These substances are ubiquitous, are synthesized locally, have intrinsic activation effects and mediate between local biochemical processes, and transmit their effects to the central nervous system, and vice versa. A recognisable result, as a living example, develops when the properties of these prostaglandins are connected with hormone concentrations. The hypothesis was developed in 1981 and served as the basis for the development of a non-invasive measurement system of effects of this measurement and regulation system. Measurement and regulation effects of the prostaglandins themselves are extremely difficult to measure. Each modification in the system influences its concentrations and hence its effects. The basic principles from 1981 were tested in 2012 with new data from 1981 to 2012. It turned out that adjustments were needed that could be substantiated by newly published data.

Relevance In the pathogenesis of most disease processes it is presumed that structural defects of organs resulting in functional impairments of organ systems. In automatically regulated systems, however, it is not the hardware, but rather the software (the functional part of the regulation system) which is the source of most impairments in the activation process. In the medical analogues, this focus on the activation process is addressed mainly in the field of complementary medicine, which is a form of medicine that is scarcely taken seriously. There is absolutely no reason to assume that it would be anything other than the technique when it involves a complex automated biological system. In quantity as well as quality. There is a difference. Biological systems have a built-in regeneration

capability. This enables most functional impairments to recover on their own, in some cases ad integrum. The measure and regulation system engages somewhat differently. The many complaints with which patients visit their medical advisors indicates that something such as this does not occur without its problems. Chronic pain without a known substrate is the most common example of this. Vrancken called her Dutch dissertation Het kruis van de geneeskunde (the cross of medicine) in 1989. However, a measure and regulation system is not only qualitatively important. A very severe conditions such as Complex Regional Pain Syndrome (CRPS) can, in the end, be explained as a dysregulated measure and regulation system. Medical models can provide insight into the medical measure and regulation system, and vice versa, which is what the model described in this article aims to do. Fundamental assumptions This theoretical model has three fundamental assumptions, which will be explained first for the purpose of understanding the model. The adjustments to the state of the science in 2012 follows after the discussion. 1: Horrobin and Manku [2–4] wrote: ‘‘It may be that it is a mistake to look for direct actions of prostaglandins themselves. What one should be looking for is a modulation of the action of another agent known to affect the system concerned’’ [2]. The prostaglandins in de second group (bell shaped) may have powerful potentiating effects on a biological response at one concentration and powerful inhibiting effects at another’’ [3]. To have a functional definition for a measure and regulation system for substances that only activate cofactor effects, there has to be a relationship between the concentration of PGs and the concentration of their buddy. A one-to-one relationship is the fundamental assumption for this article. 2: An antagonistic effect between PGF and PGE [9] is assumed, although this can only be factually established in a pure bellshaped prostaglandin system. The literature found in 1981 states: PGF: relationship with: oestrogens, proliferation, antiatherosclerosis. PGE: relationship with: progesterone, oedema, anti-proliferative, atherosclerosis, hyperthermia. The oestrogen hormone variations are correlated with the PGF concentrations and the progesterone variations with PGE. 3: PGE influences central temperature regulation. PGE is correlated with hyperthermia. Conversion forms The oestrogen-progesterone concentration is converted to PGFPGE concentration in the model. Graphically: in a time-concentration graph. Subsequently, the ‘‘concentration in time’’ is converted to ‘‘effect per time’’ based on the concentration-effect curve of Horrobin and Manku [4]. Graphically: time-effect graph. Finally, the values of PGF reduce the values of the effect of PGE: PGE–PGF. Result: a result of the prostaglandin effects in time. This is compared with the body temperature curve in time, such as was known in 1981. Keep in mind: the peak of prostaglandin concentration is not equal to the peak of the maximum prostaglandin effect, such as indicated in the curve of Horrobin and Manku. The maximum prostaglandin effect is approximately half of the increasing and decreasing legs of the concentration–time curve.

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

559

With the maximum concentration in time, the parabola of the concentration-effect curve intersects the basis line. The effect is therefore null. Higher concentration causes the effect to reverse. Prostaglandins in general Prostaglandins (PG), located throughout the body, are substances that are synthesised from unsaturated fatty acids [5,6]. Diverse biologically active substances form them. Several publications on prostaglandins have appeared over time (January 2012: Google: 5.5 ⁄ 106 hits in 0.25 s; PubMed: 96797, of which 17787 were available as free full texts. Of these PubMed publications, 77470 (80%) were published after 1982, which is after this article was first conceptualised. An evaluation from 2012 can therefore not be missed. Functions PGs fulfil a mediating and modulating role in almost every area of mammalian functioning [4,5] and as such, they have a activating effect. PGs have no biologically effect as a cofactor [2]. They only carry out their function when in combination with other biological substances. The other substance follows the dosage–effect pattern of the PG involved. The PGs have this activating role by pain, and also on hormones [4,10–15]. The fact that the activity of certain types of prostaglandins is not only dependent on its concentration, but also dependent on the fact that an agonistic can become an antagonistic effect, these types of substances have biochemical activation potential. This can be of great importance in an organism which contains many cyclical processes. The menstruation cycle is such an example in which functionality is active periodically and it is often accompanied by pain. A high level of prostaglandins are found in menstrual blood. This raises the questions about how this cycle is activated and if prostaglandins could possibly fulfil that activating role. The hypothalamic-pituitary systems direct the hormonal cycle. Straightforward direction of the cycle is improbable because PGs have a brief half-life (they are destroyed after passing through the lungs once [16,17]). Moreover, there are several tissue systems that can neutralize the PGs [18]. This mainly means there is a brief, local activation that can induce effects via the central nervous system remotely. (This could also play a role with Complex Regional Pain Syndrome (CRPS)). These possibilities were already addressed back in 1963 [19]. PGs also affect the activity of the central nervous system not only peripherally, but also centrally [19]. The hypothalamus area can be stimulated by hormones in combination with prostaglandins [10–12,14,19–21]. The PGE, which gets connected with the prolactin level, has exudative properties [10–12] and the ability to induce hyperthermia via stimulation of the hypothalamus [22–26], although this lacks complete consensus [27,28]. Both properties can be found in the second part of the menstrual cycle. This hypothesis assumes that the local released oestrogens and progestagens activate the peripheral nervous system through the influence and mediation of PGs. This activation can release PGs in central areas such as the hypothalamus. The PGS mediate the release of releasing factors, which in turn regulate pituitary activity. The feedback can then take place by way of the trope hormones, central nervous system, and PGs through which a feedback mechanism develops at the local level.

Fig. 1. (A) long stable phase for homoeostatic situations (B). A brief steeply declining phase for transitions situations (B-C) and a long run-up and run-off at A. The last prevents accidents in the sense of function impairment due to scarcity. There is a built-in break, as it were, when there are low concentrations.

The question remains why activation moments occur at diverse points such that hormone concentrations are smoothly synthesized and why this production occurs in fixed cycles. An ideal biological active inducing agent would have to match the following profile: (Fig. 1) A long stable phase for homoeostatic situations (B). A brief steeply declining phase for transitions situations (B–C) and a long runup and run-off at A. The last prevents accidents in the sense of function impairment due to scarcity. There is a built-in break, as it were, when there are low concentrations. A long plateau phase at B, whereby B is the point where the effect of the activation substance decreases in strength when there is increasing concentration (Fig. 2a). Horrobin and Manku [4] described an intriguing and remarkable finding regarding the relationship between PG concentration and effect. Particularly noticeable is the bell curve of PGE1 and the logarithmic progressing dosage–effect curve of PGE2. (in linear dosage: plateau phased) (Fig. 2b) PGF2a is synthesized from PGE2 with similar properties compared with the dosage–effect curve. 6-keto PGF1a is not made enzymatically from PGI. PGI is in an unstable phase. 6-keto PGF1 is created enzymatically from 6-keto PGF1a. It can be expected that 6-keto PGF1 as well as 6-keto PGF1a have the same dosage–effect curves because of the same manner with which they are created. The literature refers to a number of effects of oestrogens and progestagens [29].

Fig. 2a. The original representation of Manku, Mtabaji and Horrobin. The lowest curve in the combination of PGE2 and PGE1. The phase shift in comparison with PGE1 is clearly visible with the plateau on the top of the effect.

560

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

Fig. 2b. On the left shows the dosage–effect curve of PGE2. Middle: that of PGE1. A is the effect with the start dosage. B is the maximum effect and C is the turning point towards vasoconstriction. When PGE1 and PGE2 appear simultaneously, then the effects of PGE1 and PGE2 are added up together until the ‘‘B’’ effect is reached. The X axis shifts, so to speak, in the direction of point B. Points A and C then shift towards each other. The curve is more narrow, smaller and steeper. The new point A: A1 has shifted to the right in comparison with A. The top at B becomes lower. (A1C1 is the new X axis.) A phase shift takes place. According to Manku and Horrobin, both prostaglandins inhibit each other’s effects after reaching the B effect. Result: the curve delays and runs by B are longer (Fig. 1).

Just as oestrogen, PGF also has a proliferative, stimulating effect on the endometrium as well as an anti-atherosclerotic effect. Both PGF and progesterone can promote oedema, have anti-proliferating effects and atherosclerotic effects. (The side effects that can develop while taking oral contraception is not considered a standard for this because they could be attributed to a relative overdose, as represented in the diagram of Horrobin and Manku). The comparison is relevant if the effects of PGF and PGE compared with those of oestrogens and progestagens. If the mechanism of action of the oestrogens and progestagens unfold with PGs as modulator and co-factor, then there should be a relationship between both concentrations. The progress of concentration of oestrogens and progestagens in the 28-day cycle is known: The two upper curves Fig. 3/I. A one-to-one relationship between the concentration of hormones and the co-factors (PGs) is assumed. This is why they are identical to the hormone concentration in time. This proves to be incorrect. The progesterone concentration curve is far above the oestrogen curve. The measurement is

2000/75 pg/ml to a maximum of 13,000/240 pg/ml (26.6–54.2). The assumption is that the influence of PGF on that of PGE is only 2–4%. A second weak point is the short duration of the top of the concentration of progesterone over time compared with the total duration of the second part of the cycle. That can make a substantial difference on the outcome of the resulting PGE effect. These aspects are thoroughly examined in the 2012 evaluation. Fig. 3/II. Fig. 3/III the effect curves of PGE and PGF are in this case in agreement with the effects of oestrogens and progesterone as time progresses. Fig. 3/IV is the resultant effect of PGE-PGF. Because PGF and PGE are assumed to have opposite effects [9], a resultant remains with subtraction. The prostaglandin effect resultant has an unexpected remarkable agreement with the Basal Temperature Curve [30]. The literature [29] reports that there is a LH peak around the 11th–12th day. In addition, a relationship is assumed between PGs and LH [21,14], whereby PGF as well as PGE have an inducing function.

Fig. 3. 1st row: Known oestrogen-progesterone concentrations in the course of the cycle. 2nd row: expected concentrations of prostaglandins E and F in the course of the cycle (Theoretically a one-to-one bond with hormones). 3nd row: expected biological activity following the bell-shaped curve. Maximum concentration means null activity (Points C and H). That is where C intersects with the X axis. The peak activity lies under half of the maximum concentration (Points B, D, F, G, J, and K). 4nd row: resulting from PGE-PGF activity (PGE and PGF are antagonists). 5nd row is the known Basal Body Temperature curve.

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

561

Consequence of this resulting ‘‘Relative PGE activity curve’’ During the oestrogen phase, the PGE activity decreases to a minimum as a result of the decreasing progesterone, and as a result of the increasing oestrogen concentration, the PGF activity increased to a maximum, both at point b. The effect of PGF then reverses with an increasing concentration of the oestrogen. The level of the PGF activity curve decreases, as if less PGF and/or more of its antagonist (PGE) has been produced. The dip of PGF activity (at point c) can be regarded as a virtual peak of PGE activity, followed by a peak of PGF activity. The latter corresponds with ovulation (there is an FSH peak in the serum simultaneously [15]). Subsequently, an increase of PGE activity begins as a result of the increase of progesterone production and a second period of virtual PGE activity by the second peak of oestrogen production. The resulting PGE activity is maintained until menstruation. Functional model The following can occur as a result of the combined activity of the regulating and regulated hormones: The activity increases point a to point b, the FSH stimulation increases. This increase along with the presence of LH causes the oestrogen level to increase (Fig. 3I), through which the PGF activity and the FSH production further increase. At point b, PGF activity turns into relative PGE activity, through which LH stimulation is induced increasing the production of oestrogen. Simultaneously, the FSH production gets inhibited because of the increased PGE activity. The oestrogen and PGF concentrations increase because of the decreased FSH activity. Gradually a balance between PGE and PGF activity (point C) occurs. From point C to point D. At C (Fig. 4) and C (Fig. 5) the effect of PGF changes absolutely from PGF to PGE. The PGE effect stimulates the production of progesterone which in turn promotes the production of PGE. In course of C to D, the PGE effect increases as a result of the transition from PGF to PGE. The increase of PGE concentration as a result of the production of progesterone inhibits the production of PGF and/or oestrogen. First of all, because of this the PGE effect decreases until the PGF concentration reaches point C (Fig. 5) again. Then in the pathway of C to B. The concentration of PGF falls again and therefore the effect of PGF increases again. The FSH production increases. The LH stimulation reduces. The effect switches again at B (Fig. 5) of D (Fig. 4). The PGF concentration reduces further as does the effect. The LH concentration now surpasses the maximum. The FSH stimulation is maximal. The peak of the FSH production reduces along with ovulation. The peak of LH is a couple of days earlier [15]. At point C, the maximum PGE effect and LH concentration stimulates prolactin (LTH), which induces the production of progesterone (17 hydroxyprogesterone peaks when the LH peaks [15]). (It is not clear why in this table the FSH also peaks when the LH peaks, which is not expected).

Fig. 5. The effect of the prostaglandin concentration on vasocontriction and vasodilatation.

The FSH decrease is initially stronger than the LH increase which causes a temporary oestrogen decrease. The PGE and PGF concentrations are in balance at point e after which the oestrogen production increases again as a result of increasing LH stimulation, which is a result of increased PGE activity, which is a result of the increasing progesterone level. The same PGE activity stimulates the LTH production for the purpose of progesterone. In the identical way as described with oestrogens in the first part of the cycle, an effect shift takes place at point f and point g for oestrogens and progestagens, respectively, and consequently at point k and point j. In this case, the PGF effect as well as the PGE reversal effect. This results in an increased level of PGE activity with a dip at point h (Because the progesterone concentration rapidly increases the then oestrogen concentration decreases). The LTH stimulation then decreases because of the decrease of the PGE activity, which causes the progesterone concentration to decrease and the difference between PGF and PGE increases in favour of PGF: This increases the FSH stimulation. The contraction of the smooth muscles tissues around the arterioles is stimulated by the PGF, which causes the spiral arteries to contract and ischemia develops in the uterine wall. In accordance with the same rationale, the oestrogen concentration and the PGF concentration increase. The effect then switches so that a PGE effect develops at the start of menstruation. The vessels dilate and bleeding begins. The PGE effect inhibits the production of FSH, which inhibits the production of oestrogen along with the production of PGF. The PGF concentration decreases

Fig. 4. During the oestrogen phase, the PGE activity decreases to a minimum as a result of the decreasing progesterone, and as a result of the increasing oestrogen concentration, the PGF activity increased to a maximum, both at point b. The effect of PGF then reverses with an increasing concentration of the oestrogen. The level of the PGF activity curve decreases, as if less PGF and/or more of its antagonist (PGE) has been produced. The dip of PGF activity (at point c) can be regarded as a virtual peak of PGE activity, followed by a peak of PGF activity. The latter corresponds with ovulation (there is an FSH peak in the serum simultaneously [15]). Subsequently, an increase of PGE activity begins as a result of the increase of progesterone production and a second period of virtual PGE activity by the second peak of oestrogen production. The resulting PGE activity is maintained until menstruation.

562

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

again, which reduces the PGE effect to the level of the switch. There is then another PGF effect and FSH is stimulated again. The oestrogen concentration increases. The vessels contract and the bleeding decreases, which completes the cycle. Evaluation 2012 In the model, the oestrogen relates to PGF and progesterone relates to PGE.

Fig. 6. Hormone levels in the menstrual cycle I.

Fig. 7. Hormone levels in the menstrual cycle II.

In many ways, PGE and PGF have opposing effects, including their effects on temperature. That is logical considering their relationships hormones. Current literature also refers to the opposing effect on body temperature that oestrogen and progesterone have, although that mechanism was still unclear in the year 2000 [31]. More was known in 2012 than in 1981 about the mechanism of action of prostaglandins as co-factor and the relationship of prostaglandins with hormones, which is the reason for testing this theoretical model using publications between 1981 and 2012. Google generates more than 250 figures with the progress of hormone concentration. Only the Elsevier graph is similar to the diagram used in 1982. All the others have the profile, such as in the three figures below. Wikipedia (2012) has the following graphs on hormone concentrations in the menstrual period [32] (Fig. 6). The representation is very similar to Fig. 7 [33] and Fig. 8 [34]. The commonly shared traits are the correlation between ovulation and the LH peak and the FSH peak, respectively. Other commonly shared traits are the biphasic progression of oestrogen with a second peak lower than the first, a progesterone concentration that has a peak gradually with the oestrogen after ovulation, and a progesterone concentration larger than the oestrogen concentration after ovulation. Fig. 6 and Fig. 7 suggest concentration levels that all lie in the nanogram range close together. This was also assumed when this hypothesis was established in 1981. Figs. 8 and 9a and Fig. 10 provide quantitative information that does not correspond with this. This raises questions: the progesterone peak is above the oestrogen peak, but the concentration is 3 ng/ml = 3000 pg/ml and the oestrogen concentration is almost 400 pg/ml. The measured peak values are also somewhat dispersed [35]: Fig. 9a,b and Fig. 10. Progesterone between 8000 and 20,000 pg/ml and oestrogen between 120 and 800 pg/ml. The mutual relationships could differ somewhat. The ovulation is brief after the LH/FSH peak in all of them. The moment of ovulation is not consistent: somewhere between the top and descent of the oestrogen level and somewhere at the start

Fig. 8. Hormone levels in the menstrual cycle III.

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

563

Fig. 9a. Is a simplified representation of Figs. 9b and 10 and shows the mean concentrations of progesterone (2000–13,000 pg/ml above) and oestrogen (75–240 pg/ml below) as it was known in 2012. The Y-axis represents the concentration on a logarithmic scale. The X-axis represents the daily distribution of the cycle. The logarithm clearly shows the large concentration difference between progesterone and oestrogen.

Fig. 9b. Show oestrogen concentrations in the course of the menstrual cycle with their distribution areas.

of the increasing leg of the progesterone level, hence between the 13th and 17th day of the cycle. (Figs. 8 and 9b). In each case the average concentrations and the concentration diverge somewhat from the model used in 1981, which is reason to repeat the procedure using the mean values. The best usable values for this are quantitative data from Wikipedia [35]: The following curve is in accordance with the theoretical considerations from 1981: Because the progress of progestagen concentration is measured in ng/ml and the progress of oestrogen concentration is measured in pg/ml, both curves overlie each other. The course of the activity

curve is determined by the progesterone concentration and PGE activity to a great degree. The resulting curve does not have much similarity with the BBT curve, which can be attributed to the predominant influence of progesterone. In one situation, the prostaglandin effects are proportional to the concentration, the effect of prostaglandin E should increase one thousand times compared to that of the prostaglandin F, which then no longer has influence on E. This situation assumes a proportional effect of the progesterone and oestrogen concentrations. This does not explain the consensus on the course of oestrogen and progestagen concentrations as they appear in Figs. 6 and 7.

564

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

Fig. 10. Show progesterone concentrations in the course of the menstrual cycle with their distribution areas.

The curve at B lacks the convex soul of the BBT. The curve at D is concave instead of straight and is considerably shorter than the BBT. It is improbable that this assumption can explain the BBT sufficiently. If the progesterone concentration can have an effect during the entire second part of the cycle, the turning points on the curve lie on the 14th and the 30th days. A difference in sensitivity of tissue for prostaglandins is therefore still possible (see Figs. 11 and 12). Discussion

Fig. 11. The upper part shows the concentrations of oestradiol and progesterone over the course of the cycle. The lowest part of the resulting dosage–effect curve of PGE-PGF calculated on the basis of the one-to-one arrangement of 1981. The result, plotted against the BBT (2nd part) has scarcely any consistency. Therefore, the assumption that prostaglandin has proportionality with hormone concentrations cannot be correct.

In those figures, the oestrogen and progesterone curves bisect each other, and the differences between the concentrations is not calculated as it is in Fig. 8a and Fig. 10. If the assumption is correct that hormone concentration is proportional with prostaglandin concentration, then the possibilities remaining are: the concentration difference between prostaglandin and oestrogen potentially linked to a fixed concentration of prostaglandin E or F results in the represented BBT, or the related tissue – where hormones and prostaglandins are formed – have a difference sensitivity for different types of prostaglandins. Then even a proportionate relationship between hormone and prostaglandin concentration is possible. Both possibilities are investigated in the following section.

The BBT curve does not correspond with the hormone concentrations when the effect of the oestrogen and progestagen concentrations are opposed and proportional with the concentration. The BBT curve cannot be explained from the subtraction of the opposing progesterone-oestrogen levels. An addition of progesterone-oestrogen levels cannot explain the BBT curve either. The effect of the oestrogens then falls away completely within the amount of progesterone. From the notion that the effects of oestrogen-progesterone only come into existence via their co-factors: prostaglandin E, and respectively F, it can also be assumed to be a proportional effect of hormone-prostaglandin. This is only possible if the progesterone effect is capped off above a certain level, so to speak, such that the range effect of the prostaglandin E falls within the range of the range effect of prostaglandin F. In this situation there is a change of the effect of progesterone. Progesterone is guided by its co-factor PGE. PGE changes its effect in the direction of concentration level B. There is a plateau phase in which the effect on a large progression of concentration scarcely changes (Fig. 1). The effect of the combination of progesteronePGE to the switch point C decreases with increasing concentration at the end of the plateau phase. The effect switches again there (Figs. 1, 2b and 5). Point B is the point of maximum effect. That is not same as maximum concentration. The effect of the maximum concentration corresponds with point C in Fig. 2b. As the curves above have shown, it is difficult to determine the moment at which point B is reached based on theory. It is improbable that point B is reached at the same time in both oestrogen and progesterone because of the large concentration

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

565

Fig. 12. The balanced evaluation of whether the concentration difference of progesterone and oestrogen, related to a prostaglandin, can represent the structure of a BBT. Separate for the pre-ovulatory phase (A and B) and the post-ovulatory phase (C and D). The upper diagram in A shows the concentrations of progesterone; the middle diagram shows the concentrations of oestrogen, and the lower diagram shows the accompanying BBT part. The upper diagram in B shows the concentration of progesterone minus the concentration of oestrogen, and the BBT part. The upper diagram in C shows the post-ovulatory concentrations of progesterone, the middle shows the post-ovulatory concentrations of oestrogen, and the lower one shows the accompanying BBT part.

differences between them. It is more logical that the sensitivity of oestrogen versus prostaglandin lies at a different level than that of progesterone versus prostaglandin. A publication from 1980 provides a point of reference [36]. Measurements were taken in the early luteal phase: 16th–19th day, the mid-luteal phase: 20th–22nd day, the late-luteal phase: 23rd–26th day. The phase in which point B of the progesterone curve and the mirror image of point B of the first peak of the oestradiol curve (BB) should be, is the early-luteal phase. The mirror image of point B of the progesterone curve should be in the late-luteal phase. The mirror image of point B of the second oestradiol curve should be in this phase too. The mean concentration of the early-luteal phase and the late luteal phase should be almost equal because of the symmetrical progression of progesterone concentration in Fig. 10. In the article involved the progesterone concentration of the early-luteal phase is 16 micrograms/gram of tissue and the luteal phase is 7 micrograms/gram of tissue. This large difference makes it difficult to draw conclusions. There is a large inter-woman variability according to Fig. 10 that can explain the difference. However, the accompanying prostaglandin level should also change. The prostaglandin/progesterone proportion for the group in the early-luteal phase is 1:12400. This proportion is 1:1727 for the late-luteal phase, while this should be the same proportional size. Therefore, there is more happening with the outcomes of this publication than just a difference in the inter-woman validity. The question is which of these values is correct, and thus, which comes close to the truth. When we show all the measured values and proportions, then the early-luteal phase is strongly discordant with the mid-luteal and late-luteal phases with regard to hormone concentrations, prostaglandins and proportion figures. The tissue concentration of the late-luteal phase and the midluteal phase, 7 lg/gr and 22 lg/gr, respectively, are in reasonable concordance with each other regardless of the size differences in serum concentration of progesterone in this phase: from 1.5 ng/ ml increasing up to 13 ng/ml (Fig. 10). The prostaglandin/hormone proportion is also the same size (1:1727 and 1:1083 for progesterone, respectively; 1:18 and 1:14 for oestradiol). The measured differences are attributed to a combination of sensitivity of hormone for prostaglandin, which recedes with a high hormone concentration [37] and inter-woman variability.

With 130 pg/ml oestradiol, a proportion of 1:13 for PGF/oestrogen results in 10 pg/ml PGF. That is the reported switch concentration [38]. This is an unexpected outcome because it is based on the values found in the mid-luteal phase and the switch points can be expected in the early-luteal and late-luteal phases. However, the oestradiol curve in the complete luteal phase has a rather flat progression with slight concentration differences. The scarcity of sensitivity shifts resulting from the concentration difference probably occurs because of that. This is different with the progesterone. The progesterone/ oestradiol proportion increases by a factor of 30 to a factor 70 in luteal tissue, and 50100 in serum. The increases of the tissue values found, and the serum values reported in the literature are in reasonable concordance with these amounts. That probably causes a sensitivity shift with high concentrations of progesterone. This will probably cause the switch in the low concentrations of progesterone to take place with a sensitivity larger than 1:1000 in the proportion of PGE/progesterone. For the switch point of progesterone, the study by Patwardhan et al. [36] only has minimal value because the low concentrations are for the 17th, respectively, after the 25th day of the cycle which is where these measurements are based on, and there is no switch points in the period between the early-luteal and late-luteal phases. The switch point should be between 10,830 pg/ml and 17,270 pg/ml in compliance with the measured sensitivity in the mid-luteal and late-luteal phases. These values are close to the peak of 20,000 pg/ml. According to the assumption (Fig. 2b), however, point C is there. There is no point B in this situation. Therefore, the switch points have to be before the early-luteal phase and after the late-luteal phase, which is before the 16th day and after the 26th day. This is in agreement with the estimated width of the progesterone curve at switch points around the 14th and 30th days (page 4, Fig. 3). This is why, to further the development of this theoretical hypothesis, switch points found for oestradiol and the proposed progesterone switch points were assumed: The progression of oestrogen has a concentration of 140 pg/ml twice in the pre-ovulatory peak: once on the increasing leg of the curve and once on the decreasing leg. The concentration of the increasing leg is reached on day 11. On the decreasing leg between day 14 and day 15 right before ovulation (Fig. 9).

566

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

Also the mid-luteal phase has two points of 140 pg/ml for oestradiol: at the 19th and 25th days. Day 16 and symmetrical day 29 are maintained for progesterone. The concept of sensitivity plays an important role for the choice. Sensitivity The word sensitivity has already been mentioned a couple of times. In their study, Manku et al. [37] report that a high dosage of an effector agent can reduce the sensitivity for prostaglandin co-factors. Noradrenaline 10 ng/ml with 10 pg/ml PGE gives a higher effect than noradrenaline 100 ng/ml with 10 pg/ml PGE. The switch point shifts with by a factor of 1000. That effect will scarcely appear here because the oestradiol concentration as well as de prostaglandin concentration are found to be pg/ ml. Progesterone, however, has a concentration of 13 ng/ ml, approximately 50 times higher than the maximum of oestradiol (250 pg/ml). The concentration of PGE from the proportion of 1:1083 can be estimated at 13 pg/ml [36]. 10 pg/ml is then around day 18. However, according to the findings of Manku et al. [37], the sensitivity with these concentrations of progesterone could be lower, and can easily amount to a difference of 103. In other words, with these high concentrations it can be such that the switch is reached at 100 pg/ml or even 10 ng/ml. De estimated value at day 18 is 10 pg/ml, which is too low for a switch point in that case.

De 10 pg/ml serum value of PGF has to therefore be reached in an earlier stage of the curve. Clearly, the accompanying sensitivity has to be higher than 1/1083. With a sensitivity of 1/300, the limit of 10 pg/ml is reached with a progesterone concentration of 3000 pg/ml = 3 ng/ml. That level is at day 16 of the cycle (Fig. 10). Assuming the same rationale as followed in 1981, and the concentration curves from Wikipedia (Figs. 9a and 10), the following series of curves emerge: Fig. 13. The upper curve is the mean progression of progesterone in time. Each vertical line is one day in the cycle. Under that in green (proportional) is the mean oestradiol concentration in time. (Fig. 14) There are clear agreements with the BBT curve: 1: 2: 3: 4: 5: 6:

Pre-ovulatory dip with a peak in the same span of time. A rapid increase of the curve in the peri-ovulatory time. A peak at the 16th day and at the 30th day. A fairly similar progression between the 16th and 30th days. A dip around the 23rd day. A steep decrease after the 30th day.

Measurement systems The thesis assumes the properties of two types of prostaglandins (PGs) described by Manku, Mtabaji and Horrobin in 1977: the bell shaped curve and the linear dosage–effect curve.

Fig. 13. (A) The course of concentration of progesterone over the course of the cycle is shown in the uppermost graph. Underneath that is the course of concentration of oestrogen. The BBT curve is the lowermost graph. In the following second part, first the estimated – based on the literature – effect curve of PGE and then that of PGF. The cavity is estimated, and is possibly not completely correct. (B) The effect cure can be flat if the sensitivity decreases proportionally with the increase of the progesterone concentration. However, no data on this can be found in the literature. The degree to which the PGE effect curve is flatter and more narrow, the better the variations of the PGF curve are. (C) The result of the PGE-PGF effect curves are shown below.

Fig. 14. 1: Pre-ovulatory dip with a peak in the same span of time. 2: A rapid increase of the curve in the peri-ovulatory time. 3: A peak at the 16th day and at the 30th day. 4: A fairly similar progression between the 16th and 30th days. 5: A dip around the 23rd day. 6: A steep decrease after the 30th day.

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

Both types are in logarithmically increasing concentrations. If the thesis is true, then there are high concentrations of bell-shaped PGs. With a NULL hypothesis a contradictory linkage would be found in situations with mild concentrations of bell-shaped PGs and high concentrations of linear PGs at the time of switching. These moments are found, for example, at the time of ovulation, onset of menstruation, and onset of the birthing process. A technical problem is acquiring the respective prostaglandins in vivo at the right moment. Every damage of tissue, as the case may be, in the organism indeed releases all prostaglandins and causes unacceptable noise because of the low concentrations in which prostaglandins do their work. In addition, prostaglandins act locally in very low concentrations and are very rapidly broken down via venous transport. The question is if this could enable them to affect the body temperature and the gonadotropic hormones through the circulatory system to the effector area in the central nervous system. Measurements of concentration in venous blood should therefore have to take place regardless of the problems that brings with it. Signal transport of the local production site via the central nervous system is possible and shown. Prostaglandins play an essential role in this. It may therefore be beneficial to measure the effects of prostaglandins via an indirect non-invasive, and preferably, non-contactual method. That is why examination options are fall into two categories. Non-invasive The non-invasive examination options are mainly focused on the question of whether switch moments can be found, and if so, at which moments and in which situations. Additionally, they focus on whether these switch moments can be visibly influenced with prostaglandin concentration changes regardless of the type. Conversion of prostaglandin effects on skin temperature change. Non-invasive measurement of the local tissue temperature is possible by using viscerocutaneous reflex pathways in a living organism.

567

The processes in the tissue (Grundsystem, BBRS) can be transferred to the central nervous system via prostaglandin activity. This transferred activity is visible in the changes of the blood circulation in the accompanying segment through viscerocutaneous reflex transfer. This change is measurable with non-contactual infrared thermography [38,39]. That means that infrared thermography should be able to register the presumed (overall) effects of the prostaglandin activity described in this article. A basal temperature curve would be influenced by measuring the skin temperature of the genital zone while using the temperature of the abdominal wall as a comparison reference. Of course that would not be possible if the hypothesis were untrue, hence, the basal temperature would only be centrally determined in the central nervous system. The local skin temperature changes would not be patently obvious. Modification of the statistical calculations also seems possible at the individual level by using selective calculations (Fig. 15). Fig. 15 was created by entering data of an individual cycle in a statistical water drainage programme [40]. The programme registers significant changes in a data flow. This example shows the skin temperature measurements of a specific abdominal wall area of a young woman who wants to have a child from the first day of her cycle till the 40th day. The X axis represents the days from the first cycle day. The Y axis represents the temperature difference of the specific skin area with the abdominal wall temperature as reference in Celsius  1000. There is a significant temperature increase around the 23rd day. The programme is not validated for this application, but it illustrated the idea behind the measurability of the hypothesis. Each organ has its own ‘projection area’ on the skin. The temperature in this area of skin varies with the temperature in the accompanying organ area. It probably does not have a one-toone ratio. However, changes of the visceral circulation also change the accompanying cutaneous circulation. Switch effects in the internal organs cause a change in the local temperature and

Fig. 15. Statistically search for suddenly body temperature change in specific area.

568

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

therefore also in the accompanying skin temperature. That cannot be measured non-contactually with infrared thermography. Skin temperature measurement Modern devices are amply available, easy to place and transport, and are not taxing for the patient or volunteer. The sensitivity is usually 0.1 Celsius absolute. The disadvantage is that, just as with blood samples, it is a snapshot record, which means there is a great chance of missing the exact switching moment. It then continues to be a mode of analysis based on measurement variations. Theoretically that can be resolved by using thermocouples with the same precision of 0.1 degrees Celsius connected to a wearable data recorder. Actively influencing It is probably also possible to record the course of partus induction through vaginal gels containing prostaglandin with infrared thermography, or to record fixed configurations with thermocouples. Invasive examination possibilities One cannot operate without invasive methods to get an answer as to which prostaglandins are responsible for that. As yet, this phase is too invasive for endocrinological aspects to be carried out in an ethically responsible manner. That seems easier with chronic pain and chronic regional pain syndrome. In the experiments from the 1970s preparations were pre-treated with indomethazine to block the natural production of prostaglandin, and prostaglandins were administered through the perfusate. The resulting effect was then examined. It is only ethical to administer prostaglandin synthesis inhibitors in vivo to volunteers, and then to examine the EFFECT of inhibition non-invasively. Even this has its dilemmas.

located on 11 and 9, respectively; PGF1a and PGF2a have two hydroxyl groups. It is expected that with an excess of oxygen, the hydroxyl group is converted into a ketone group, and with an excess of H+ the ketone group is converted into a hydroxyl group. In an acidic oxygen depleted environment, an increased concentration of H2CO3 and lactic acid can be expected. Therefore many H+ ions. Increased hydrogenase activity is expected when the production of vasoconstrictive prostaglandins increases. An oxygen enriched environment results in more dehydrogenase activity with vasodilatating prostaglandins. It is not logical that oxygen-depleted and oxygen-enriched situations occur simultaneously in the same place in the tissue. Both of them have an effect on blood vessel perfusion, on the oxygenation of the tissue, and thus on the local temperature. This means the research problem of measuring prostaglandin concentrations shifts toward measuring local temperature as parameter of the working effect of the prostaglandins. In vivo this is in fact a variant of the perfusion pressure addressed in the experiments of Manku and Horrobin. Animal experiments are possible with horses, cows and pigs because these animals have short hair and infrared thermography or thermocouples can be applied easily. Ovulation induction in animals is frequently carried out by administering muscular prostaglandins, which means there is sufficient material. The ethical dilemmas are then more limited. This makes it possible to carry out frequent analysis of tissue fluid for variations in concentration of the anticipated regulating prostaglandins from the peripheral of the reflector skin site using the blister technique. The hypothesis is then translated pragmatically in the statement: skin temperature measurements in the organ zone of the uterus and ovaries can determine the switch moments of ovulation, the start of menstruation, and the initiation of the parturition. These moments are affected by prostaglandin syntheses inhibitors. The NULL hypotheses is then: infrared thermography cannot establish any switch moments no matter how much they are affected. Afterword

Potential side effects of the study If prostaglandins affect or even initiate switch moments, then an ovulation can be, probably undesirably, blocked or an anti-contraceptive effect of an IUD cannot be reversed. A cycle can be shortened or lengthened improperly, and the bleeding can be intensified. A birth can be postponed or even induced at an earlier date. Based on the assumption that the concentration of prostaglandins has to be sufficiently high for the switch effects, a synthesis inhibition will have to reduce the switch moments. The most probable outcome would then be that ovulations disappear, the cycle is lengthened, and the bleeding is reduced. The date of parturition would be moved up. The chance of endometritis as a result of IUD as well as the contraceptive effect will be reduced. In comparison to the latter is that the chance of ovulation is also reduced.

The curve obtained is the result of theoretical considerations regarding the local pharmacological activation effects of the prostaglandins mentioned. These considerations are illustrative of the theoretical background of the measurement and regulation system properties of prostaglandins applied to a naturally regulated cycles with fixed activation moments. Based on the same theoretical grounds, the same measurement and regulation system can cause dysregulation on sites of chronic pain resulting in an acute exacerbation such as CRPS. This will be discussed further in a separate article. P.H.E. van der Veen. Heerhugowaard, 2012-04-15 Revised 2015-01-29. Funding Private self-financing – no external funding.

Background of the study technique Disclosure Measurement and regulation switching can only be expected with bell-shaped dosage–effect curves. Indeed, feedback in the form or inhibition will never happen in linear situations. A maximum effect can, however, be achieved by saturating receptors. Negative feedback can only occur through forming prostaglandins that work in opposition. Prostaglandins that work in opposition such as PGE1 and PGF2a differ in the presence or absence of an H+ ion. PGE1 and PGE2 have one hydroxyl and one ketone group

There are no conflicts of interest whatsoever. References [1] Hansen K, Schliack H. Segmentale Innervation Ihre bedeutung für klinik und praxis. 2nd ed. Stuttgart: Thieme; 1962. [2] Horrobin DF, Manku MS. Roles of prostaglandins suggested by the prostaglandin agonist/antagonist actions of local anaesthetic, anti-arrythmic,

P.H.E. van der Veen / Medical Hypotheses 84 (2015) 557–569

[3]

[4]

[5] [6] [7] [8] [9]

[10] [11]

[12]

[13] [14]

[15] [16] [17] [18] [19] [20] [21] [22]

anti-malarial, tricyclic antidepressant and methyl xanthine compounds: Effects on membranes and on nucleic acid function. Med Hypoth 1977;3(2):74. Horrobin DF, Manku MS. Roles of prostaglandins suggested by the prostaglandin agonist/antagonist actions of local anaesthetic, anti-arrythmic, anti-malarial, tricyclic antidepressant and methyl xanthine compounds: Effects on membranes and on nucleic acid function. Med Hypoth 1977;3(2):75. Horrobin DF, Manku MS. Roles of prostaglandins suggested by the prostaglandin agonist/antagonist actions of local anaesthetic, anti-arrythmic, anti-malarial, tricyclic antidepressant and methyl xanthine compounds: effects on membranes and on nucleic acid function. Med Hypoth 1977;3(2):71–86. Lewis GP. Pharmacology of prostaglandins. Pharmaceutisch Weekblad 1980;115:648–54. Maier R. Biochemistry of prostaglandins. Pharmaceutisch Weekblad 1980;115:642–7. Pischinger A. Das System der Grundregulation. 5th ed. Heidelberg: Haug Verlag; 1975. 55–58. Dosch P. Lehrbuch der Neuraltherapie nach Huneke. 6th ed. Heidelberg: Haug Verlag; 1976. 22–26. Clark, K, Myatt, L, Glob. libr. women’s med., (ISSN: 1756-2228) 2008; 2. http:// dx.doi.org/10.3843/GLOWM.10314. Available from http://www.glowm.com/ section_view/heading/Prostaglandins%20and%20the%20Reproductive%20Cycle/ item/313. Costa G, Pasquale RD, Abate F. e.a. Effetti di alcune prostaglandine sui livelli plasmatici di prolattina nel ratto. Boll Soc Ital Biol Sper 1979;15:1485–91. Costa G, Trovato A, Abate F. e.a. Ruolo del sistema prostaglandinico nel controllo monoaminergico della liberazione di prolattina nel ratto 1979;15: 1492–7. Costa G, Frisina N, Forestieri AM. ea. Effetti inhibitori dell’indometacina sulla liberazione di prolattina indotta con peptidi oppioidi. Boll Soc Ital Biol Sper 1979;23:2425–30. Merkus JMWM, Sorge van AA. Prostaglandines in de gynaecologie en obstetrie. Pharmaceutisch Weekblad 1980;115:668–76. Perrin DG. Studies on the effects of some prostaglandins and luteinizing hormone releasing hormone on luteinizing hormone levels in the female rabbit and rhesus monkey. Dissertation Abstr Intern B 1980;40(9):4153. Ufer J. Hormoontherapie in de gynaecologie: grondslagen en praktisch toepassing. Library of congress catalog nr 72–171799. 1973; 4 ed: fig 20–24. Brenninkmeyer VJ. Prostaglandines en de longen. Pharmaceutisch Weekblad 1980;115:679–82. Brouwers JRBJ, Bakker JH. Prostaglandines bloedstolling en vaatziekten. Pharmaceutisch Weekblad 1980;115:655–9. Harting JW. Prostaglandines en het maag-darmkanaal. Pharmaceutisch weekblad 1980;115:660–4. Moore WW. Endocrinology of reproduction. In: Selkurt F, editor. Physiology. Boston: Little, Brown and Company; 1963. p. 704-11. Brown & Barker. Basic Endocrinology. 2 ed. Oxford: Blackwell Scientific Publications. 1966; 8–9,39–46. Warberg J, Larsen E. Effect of 7 oxa-13-prostynoic acid on prostaglandin induced LH release in male rats. Acta Physiol Scand 1980;108(2):25. Bernheim HA, Gilbert TM, Stitt JT. Prostaglandin E levels in third ventricular cerebrospinal fluid of rabbits during fever and changes in body temperature. J Physiol 1980;301:69–78.

569

[23] Dascombe MJ, Milton AS. Study on the possible entry of bacterial endotoxin and prostaglandin E2 into the central nervous system from the blood. Brit J Pharmacol 1979;66(4):565–72. [24] Komaroni I. Effect of prostaglandinE1 on oxygen consumption and colonic temperature in the neonatal guinea pig. Acta Physiol Acad Scie Hüng 1978;52(2):230. [25] Szekely M. Endotoxin fever in the newborn kitten: the role of prostaglandins and monoamines. Acta Physiol Acad Scie Hüng 1979;54(3):265–76. [26] Tse J, Coceani F. Does 15-hydroxy prostaglandindehydrogenase contribute to prostaglandin inactivation in brain. Prostaglandins 1979;17(1):71–7. [27] Karppanen H, Siren AL. Eskeli Kaivosoja A. Central cardiovascular and thermal effects of prostaglandin F2a in rats. Prostaglandins 1979;17(3):385–94. [28] Lin MT, Chandra A, Sun R. The catecholamine mechanisms of prostaglandin E1 induced hypothermia in rats. J Pharm Pharmacol 1980 Jul;32(7):489–92. [29] Ufer J. Hormoontherapie in de gynaecologie: grondslagen en praktisch toepassing. Library of congress catalog nr 72–171799. 1973; 4 ed: 65–66. [30] Bastiaanse Bouwdijk, Berge MA, Ten BS, Holmer M, Plate WP, De Rom FMP, et al. Leerboek der vrouwenziekten. Amsterdam: Scheltema en Holkema; 1965. pp. 514. [31] Stachenfeld NS, Silva C, Keefe DL. Estrogen modifies the temperature effects of progesterone. J Appl Physiol 2000;88:1643–9. [32] Isometrik. own work. Available from [Internet]. http://en.wikipedia.org/wiki/ Ovulation. licensed under: http://commons.wikimedia.org/wiki/File: MenstrualCycle2_en.svg. [33] Carr BR, Wilson JD. Disorders of the ovary and female reproductive tract. In: Braunwald E, Isselbacher KJ, Petersdorf RG, et al., editors. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 1987. p. 1818–37. [34] Grimshaw A. The Endocrine Cycle and the Physiology of the Menstrual Cycle. [Internet] 2014. Available from [Internet]. http://lakecharlesobgyn.com/ Complete/231-Endocrinology-Menstrual-Cycle.aspx. [35] Häggström M. Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle. Wikiversity J Med, 20018762 2014;1(1). http://dx.doi.org/10.15347/wjm/ 2014.001. Own work. Available from: [Internet]. http://en.wikipedia.org/ wiki/Menstrual_cycle. [36] Patwardhan VV, Lanthier A. Concentration of prostaglandins PGE and PGF, estrone, estradiol and progesterone in human corpora lutea. Prostaglandins 1980 december;20(6):963–9. [37] Manku MS, Mtabaji JP, Horrobin DF. Effects of prostaglandins on baseline pressure and responses to noradrenaline in a perfused rat mesenteric artery preparation: PGE1 as an antagonist of PGE2. Prostaglandins 1977 april;13(4):701–9. [38] van derVeen PHE, Martens EP. Viscerocutaneous reflexes with abdominal wall pain: a study conducted in 1981 on pregnant women from a general practice. Thermol Int .2013;23(2):56–63. [39] Arendt-Nielsen L, Schipper KP, Dimcevski G, Sumikura H, Krarup AL, Giamberardino MA, et al. Viscero-somatic reflexes in referred pain areas evoked by capsaicin stimulation of the human gut. Eur J Pain 2008;12(5):544–51. [40] Oosterbaan RJ. Agricultural Waterlogging, Soil Salinity, Field Irrigation, Plant Growth, Subsurface Drainage, Groundwater Modelling, Surface Runoff, Land Reclamation, and other Crop Production and Water Management. 2014. [Internet]: Available from: http://www.waterlog.info.