PMS: What to do about it

If you have read PMS: The Underlying mechanism, you probably know what I think you should do. For those of you who want a quick answer, here it is.

  • Magnesium supplements:  Your daily requirement is about 600mg, and you need half of that from supplements. If you have constipation problem, start with a magnesium based laxative. It may take up to 2 month for the supplement to take full effect. Those who tend to have loose stool, divide the dose into small doses and take it through out the day. Mineral water is also good.
  • Probiotics: Yogurt is one of them. Or if you don't care for yogurt, there are a variety of probiotics supplements on the market. However, it is leafy greens rather than yogurt that promote healthy gut microbes (demonstrated in one of BBC health shows), probably due to the nutrients leafy greens provide. 
  • Progesterone in cream form (10 to 40mg/day): This is especially important if you tend to have diarrhea, menstrual cramps, heavy bleeding, or if you are in transition (over 35yrs old). For the detail of how to apply the cream, see How to use natural progesterone supplementation.
  • Reduce exposure to toxins:  Magnesium and Progesterone will help you cope with toxins, but it is very important not to accumulate more toxins in your body; including heavy metals such as lead and arsenic; and estrogen like substances such as solvents, herbicide, pesticide, Bisphenol A (BPA) in soft plastic such as water bottles and plastic wraps (avoid any food or drink heated or stored directly in such plastics as much as you can. You can smell or taste BPA when it is really bad). 
When it comes to nutritional supplements, it is best to cover all bases, and vitamin B complex is especially important to support your metabolism and brain functions.


PMS: The Underlying mechanism

As I reviewed in PMS: What is it anyway? there are 4 areas of studies that deal with problems associated with  menstrual cycle: Irritable bowel syndrome (IBS), PMS, PMDD, and Catamenial Epilepsy. Here, I will review the underlying mechanism for each and see how related they are.

Underlying mechanism: Catamenial Epilepsy

Seizures are the clinical manifestation of abnormal, excessive excitation and synchronization of a population of cortical neurons. According to a review by Three patterns of catamenial epilepsy. (A G Herzog, P Klein, B J Ransil, 1997), "Estradiol inhibits gamma-aminobutyric acid (GABA) and potentiates glutamatergic transmission. It increases neuronal metabolism and discharge rates. It promotes kindling and animal experimental, as well as clinical seizure occurrence. Progesterone metabolites such as allopregnanolone, in contrast, are potent barbiturate-like ligands at the GABA-chloride ionophore. Progesterone reduces neuronal metabolism and discharge rates, and suppresses kindling, epileptiform discharges, and experimental as well as clinical seizures." The earliest article they cite is dated 1955 (Almqvist R. The rhythm of epileptic attacks and its relationship to the menstrual cycle. Acta Psychiatr Neurol Scand 1955;3O(Suppl 105):l-116).
It is safe to say the role of estradiol and progesterone in epilepsy are well understood and established. It very well explains the observations that seizure frequency decreases when progesterone is high, and increases when progesterone is low and estradiol is high.
In more recent Hormones and Epilepsy, (Mira Katan 2011) reviewed and portrayed more complex picture of hormone actions in brain, but it suggested nothing that contradicts the above understanding. Also NIH-sponsored clinical trial pretty much confirmed the efficacy of progesterone therapy: Neuroendocrine aspects of catamenial epilepsy. (Doodipala Samba Reddy, 2012) reported "Experimental studies have shown that neurosteroids confer greater seizure protection in animal models of catamenial epilepsy, especially without evident tolerance to their actions during chronic therapy. In the recently completed NIH-sponsored, placebo controlled phase 3 clinical trial, Progesterone therapy proved to be beneficial only in women with perimenstrual catamenial epilepsy but not in non-catamenial subjects."

Magnesium connection
Another well established understanding of epilepsy is low magnesium model of seizure. As reviewed in Surface charge impact in low-magnesium model of seizure in rat hippocampus. (Dmytro Isaev, Gleb Ivanchick, Volodymyr Khmyz, Elena Isaeva, Alina Savrasova, Oleg Krishtal, Gregory L. Holmes, Oleksandr Maximyuk. J Neurophysiol. 2012), "The low Mg2+ model of epilepsy was developed several decades ago, and since that time has been widely used as a model to test antiepileptic drugs. This model of epilepsy has clinical relevance as Mg2+ deficits can increase seizure susceptibility to proconvulsant stimuli or even cause seizures in humans. There is also an evidence that Mg2+ concentration in serum and cerebrospinal fluid is lower in patients with generalized tonic-clonic seizures. In addition, intravenously injected Mg2+ has an anticonvulsant effect in animal models of epilepsy and is used to treat seizures, particularly in women with eclampsia."
According to Serum ionized magnesium and calcium levels in adult patients with seizures (R Sinert, S Zehtabchi, S Desai, P Peacock, B T Altura, B M Altura, 2007) "Seizure patients had a significantly lower mean Mg2+, but not total serum Mg and a significantly higher Ca2+/Mg2+ ratio than that in controls....Magnesium is a potential modulator of seizure activity because of its ability to antagonize the excitatory calcium influx through the N-methyl-D-aspartate (NMDA) receptor. We hypothesize that serum ionized levels of calcium (Ca2+) and magnesium (Mg2+) would be altered significantly during certain types of seizures."
According to a review Can magnesium supplementation reduce seizures in people with epilepsy? A hypothesis. (Yuen AW, Sander JW, Epilepsy Res. 2012), "There are case reports of seizures being controlled with magnesium supplementation in people with specific conditions, and recently in an open randomized trial, children with infantile spasms responded better to adrenocorticotropic hormone (ACTH) plus magnesium than to ACTH alone."
As Ray Peat (Ph.D.) emphasized in his booklet Progesterone in Orthomolecular Medicine (1993), many of the biological effects of estrogen and progesterone are reflection of their roles in promoting intracellular calcium ions (Ca2+) and magnesium ions (Mg2+) respectively, and progesterone's role as a rapid acting calcium blocker.
One thing that is known to happen when progesterone starts to secrete after ovulation is a slight rise in body temperature, indicating an increase in the basal metabolic rate and oxygen consumption, which requires higher magnesium ions involved in more than 300 biochemical processes.
What this means is that from the day after ovulation to a few days before menstruation, progesterone is secreted and it helps intracellular use of magnesium, and if magnesium intake is not adequate, circulating available magnesium depletes more and more until progesterone secretion stops, at which point, the body looses progesterone's help to boost intracellular Mg under the worst Mg deficiency. That is probably why Catamenial Epilepsy or PMS in general is most severe during the days when progesterone is dropping (premenstrual days) rather than at the peak of progesterone or at ovulation when estradiol/progesterone ratio is at the worst, which you may expect if progesterone or estrogen dominance is the direct cause of PMS or the epilepsy. After a while the body's Mg requirement goes down and circulating available magnesium level recovers, and the symptoms disappear. If there is a severe Mg deficiency, however, even with progesterone's help, your body may struggle with Mg deficiency a lot longer. When looking at PMS this way, it makes sense for both progesterone and magnesium supplementation during this period can help reduce the severity of the symptoms or make it disappear all together.
Magnesium levels and menstrual cycle 
Sex steroid hormones modulate serum ionized magnesium and calcium levels throughout the menstrual cycle in women. (O Muneyvirci-Delale, V L Nacharaju, B M Altura, B T Altura, 1998) measured the serum concentrations of the sex steroid hormones with respect to the concentrations of the biologically active fractions of magnesium and calcium during the different phases of the menstrual cycle for healthy reproductive age women. In each woman, there was a comparatively high ionized Mg level coincident with the early follicular phase, a statistically significant decrease in ionized Mg around the time of ovulation, a significant decrease in ionized and total Mg when the serum progesterone concentration peaked, and a significant increase in the serum Ca2+/Mg2+ ratio at both the ovulatory and luteal phases. They concluded "The changes in serum concentrations of these important physiologically active cations, in the range at which they occur, can affect such entities as the vasculature, synaptic transmission, and excitation-secretion coupling and thus can produce the well-known premenstrual syndromes during the luteal phase in women who are somewhat deficient in Mg or in those who have an unusually increased Ca2+/Mg2+ ratio."
Interestingly, Premenstrual increase of intracellular magnesium levels in women with ovulatory, asymptomatic menstrual cycles. (F Facchinetti, P Borella, M Valentini, L Fioroni, A R Genazzani,1988) did not find fluctuation in the circulating magnesium in the plasma, but they have shown intracellular Mg levels measured in lymphocytes and polymorphonucleated cells increase toward the end of progesterone secreting period compared with the other periods of the cycle, which is consistent with the role of progesterone to promote intracellular Mg. Perhaps, it is important to keep circulating magnesium in the plasma steady at an adequate level to avoid PMS, as this study seems to suggest.

It's been well known that modern diet is deficient of magnesium (Dietary magnesium intake in a national sample of US adults. Earl S Ford, Ali H Mokdad 2003), and magnesium supplementation can improve a wide range of poor health conditions and vulnerabilities. In 1988, R J Elin (Clinical Pathology Department, National Institutes of Health, Bethesda, Maryland) reviewed the importance of magnesium and the consequences of a chronic latent magnesium deficiency in the US in Magnesium metabolism in health anddisease as follows:
A large segment of the U.S. population may have an inadequate intake of magnesium and may have a chronic latent magnesium deficiency that has been linked to atherosclerosis, myocardial infarction, hypertension, cancer, kidney stones, premenstrual syndrome, and psychiatric disorders.
It's been more than 20 years since, and 40 years since Seelig and Durlach, in the early sixties, based on long-term balance studies of intake and excretion of magnesium, recommended a daily magnesium intake of 6 mg/kg/day (Seelig, M.S: The requirement of magnesium by the normal adult. Summary and analysis of published data. Am J Clin Nutr 14(6), 342-390 (1964)). Yet, this knowledge is by no means shared or promoted in general public nor among clinicians, while the evidence is mounting: magnesium supplements will prevent cardiovascular diseases better than cholesterol lowering statin drugs and blood thinning aspirin, reduces inflammation, and improves emergency room survival rates (The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review. Laurent Dubé, Jean-Claude Granry. 2003), for example.

Underlying mechanism: Constipation

There are various factors that influence the bowel habits and most of them can be altered independent of menstrual cycle such as water, fiber, magnesium, prostaglandins, microbiota of colon (bad v.s. good microbes), stress, physical activities, etc. although they may be inter-related in various ways with menstrual cycle as in the case of magnesium level as reviewed above.  
Association between dietary fiber, water and magnesium intake and functional constipation among young Japanese women. 2007 by K Murakami, S Sasaki, H Okubo, Y Takahashi, Y Hosoi, M Itabashi reported "Low intakes of water from foods and magnesium are independently associated with an increasing prevalence of functional constipation among a population whose dietary fiber intake is relatively low." Yet for many, menstrual cycle seems the most dominant factor. Relationships between symptoms, menstrual cycle and orocaecal transit in normal and constipated women. (G K Turnbull, D G Thompson, S Day, J Martin, E Walker, J E Lennard-Jones 1989) reported "... patients noted variation in constipation during the menstrual cycle, in all cases this comprised an improvement in symptoms just before or during menstruation." That certainly was my case.
Progesterone receptor types
When menstrual cycle is involved, the first place researches look is the hormones, in this case progesterone. One of the factors making the hormone research complicated is the involvement of multiple receptor types of each hormone. The function of a hormone is not determined by the hormone itself. It is dependent on the receptor types expressed at the cell. For progesterone, there are receptor type A (PRA) and B (PRB), and when PRA is dominating in tissue cells, progesterone does not work (Mg intake, for example). Uterine contraction necessary for labor is initiated by increase of PRA (Nuclear progesterone receptors in the human pregnancy myometrium: evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-A., Merlino, et. al., 2007). In intestines, when PRA is low relative to PRB, intestines become less active, resulting in constipation. In other words, the uterine contraction required for labor as well as colon movement depends on the progesterone receptor A to block progesterone action, and this is true for many other smooth muscle cells (Broad tissue expression of membrane progesterone receptor Alpha in normal mice. Shaojin You, Lian Zuo, Vijay Varma 2010).
A group of researchers lead by Jose Behar, (Rhode Island Hospital and Warren Alpert Medical School at Brown University), have been pursuing this subject and have demonstrated that progesterone affects the colon muscle of constipation sufferers far more than that of normal control subjects due to overexpression of PRB. They also demonstrated that normal colon cells exposed to extremely high level of progesterone for 6 hours become abnormal in terms of progesterone receptor. However, the fact remains that not everyone get constipated during progesterone is secreted. The incidence of constipation during pregnancy is only approximately 25% despite high serum progesterone levels. In other words, exposure to high level of progesterone alone is not enough to cause constipation in naturally occurring conditions. Something else is involved to cause the over expression of progesterone receptor B and/or under expression of PRA (Overexpression of progesterone receptor B increases sensitivity of human colon muscle cells to progesterone. Ling Cheng, Victor Pricolo, Piero Biancani, Jose Behar 2008; Progesterone receptors and serotonin levels in colon epithelial cells from females with slow transit constipation. M Guarino, L Cheng, M Cicala, V Ripetti, P Biancani, J Behar 2011).
To make some observations from my personal experience, there seems some switching mechanism to turn on normal colon movement as well as labor. Every month, I could feel that switching 2 days before the flow started, and that was a big relief. I felt my entire body was going back to normal. Sometime, I also noticed one time release of distinctive fragrant odder in urine, which accompanied at that very moment. Interestingly, it did continue even after my surgical menopause for years, indicating it did not originate from ovaries or uterus.
Role of prostaglandins (they promote inflammation and pain. Pain medicines, like Aspirin, inhibit enzymes such as COX-1 and COX-2 that are necessary to make prostaglandins.) and their receptor types in colon movement is also known. There are variety of prostaglandins and most of them (e.g. PGF2α and PGE2) promote contraction of smooth muscles (blood vessels, digestive tract, uterus, etc.). One exception is PGE2 in combination with the receptor EP2 that relaxes intestines, while PGE2 with receptor EP1 promotes contraction of smooth muscles of intestines as well as uterus (Characterization of the EP receptor types that mediate longitudinal smooth muscle contraction of human colon, mouse colon and mouse ileum. S E Fairbrother, J E Smith, R A Borman, H M Cox. 2011). So far, I have not seen IBS studies that checked the receptor type along with PGE2, while PGE2 have been blamed for both constipation and diarrhea. Another interesting research direction on PGE2 is that with receptor type EP3 in brain, it may cause  mental symptoms of PMS (Prostaglandins and premenstrual syndrome. N Koshikawa, T Tatsunuma, K Furuya, K Seki 1992; [The mechanism of prostaglandin effects on GABAa receptor at molecular level.]  Sugimoto 2009).

Magnesium connection
Here again we need to remember the role of magnesium, the fact that various magnesium salts have been used as very effective laxative. Magnesium hydroxide: new insights into the mechanism of its laxative effect and the potential involvement of prostaglandin E2. by M Donowitz, R P Rood (1992) reported how effective Magnesium hydroxide is as laxative:
(a) increased number of bowel movements
(b) increased percentage of stool water
(c) increased stool volume
(d) increased stool Mg2+
(e) increased total stool 24-h prostaglandin E2 (PGE2) in a dose dependent manner
With this results, they thought that magnesium's laxative effect may have something to do with the prostaglandin E2 (PGE2) increase.
Water inside colon/stool can be increased either by retaining water inside colon blocking absorption, or by moving water out of blood vessel into inside intestinal tube. In general, there are two types of laxatives, osmotic and stimulant. Magnesium salts are osmotic laxative that alter the osmotic pressure inside intestinal tube by its own electrochemical property in favor of increasing water inside colon. A stimulant laxative such as Senna, on the other hand, stimulates/irritate colon wall to induce biochemical reactions at intestinal mucosa or nerve endings to retain more water and/or stimulate peristaltic action of intestines (see Laxative in Wikipedia).
The osmotic pressure theory of magnesium laxative tells that the higher concentration of magnesium ions in colon relative to colon wall and blood vessel surface tissues would result in more water in colon. Furthermore, magnesium absorbed by the tissues increases intracellular Mg+ which increases aquaporin-3 that aid in water transport, from the blood to inside colon, in this case. Aquaporins (AQPs) are membrane channels that transport water within the human body, and AQP3 is predominantly expressed in colon to transport water between blood vessel in colon wall and inside colon (The elucidation of the function and the expression control mechanism of aquaporin-3 in the colon. Ikarashi N. 2013).
How about PGE2 that seems to increase with Magnesium laxatives as reviewed above? There are many conditions that lead to PGE2 increase, and stimulant laxative is one of them and menstruation is another which increases both PGE2 and PGF2a in uterus right next to colon, and causes reduced blood circulation in the area and more frequent bowel movements.  
Interestingly, The elucidation of the function and the expression control mechanism of aquaporin-3 in the colon. (Ikarashi N. 2013) reported that bisacodyl, which is classified as a stimulant laxative, increases PGE2, which in turn decreases the expression level of AQP3 in the mucosal epithelial cells of the intestines, reducing water absorption, eventually leading to the development of diarrhea.
To put these observations together with the menstrual cycle dependency of constipation, the following picture emerges: If there is a magnesium deficiency (it's common), since progesterone promotes Mg absorption to increase intracellular Mg, leaving less inside colon resulting in altered osmotic pressure, while increased Aquaporin-3 facilitates water absorption as well. The result is harder stool and constipation. Also it is conceivable that magnesium deficiency may be a cause of increased progesterone receptor type B, which might be designed to make progesterone work harder to compensate for the magnesium deficiency, to the extent the colon movement is slowed. 

Effects of Microbiota of Intestines 
It is a popular notion that eating probiotics such as yogurt promote good bowel habits, and bad microbiota of intestines such as yeast infection can lead to poor health. Today, researchers are finding out all sorts of health problems, including obesity and mental health, are associated or caused by some bad microbiota of intestines (yeast = Candida albicans is one of them). Magnesium deficiency is one of the results and a cause of yeast infection (Normocalcemic tetany and candidiasis. L Galland 1985). Inflammation and prostaglandins are also affected by bad microbiota of intestines.
[Predominance of constipationin subjects with hydrogen-consuming intestinal flora].  (Dima et. al. 2012) reported "IBS patients with low hydrogen production on lactulose breath test were 6 times more frequently constipated.

Interestingly, according to The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota (L. Crouzet, et. al. 2013), sensitivity to colonic distension of IBS patients can be transferred to rats by the fecal microbiota (more sulfate-reducing bacteria and Enterobacteriaceae and less bifidobacteria).

Whatever the cause, constipation itself has a certain negative health consequences such as depression and anxiety, not to mention the negative health consequences of magnesium deficiency and internally generated toxins staying longer inside the body. It is best to take care of it early with laxatives (preferably magnesium based) when necessary.

So, constipation implies more or less normal hormonal balance with magnesium deficiency, it looks like. A menstrual cycle without progesterone (therefore estrogen dominance) on the other hand, does the opposite promoting diarrhea according to my experience.
Man's IBS is primarily diarrhea, and it has a lot to do with testosterone (Androgens Induce Nongenomic Stimulation of Colonic Contractile Activity through Induction of Calcium Sensitization and Phosphorylation of LC20 and CPI-17. María C González-Montelongo, Raquel Marín, Tomás Gómez, Jorge Marrero-Alonso, Mario Díaz. 2010).

Underlying mechanism: PMS

Magnesium deficiency + estrogen dominance
I have seen various approaches to PMS. To lay out my conclusion up front, I arrived at the magnesium deficiency + estrogen dominance theory of PMS. As I reviewed above in Catamenial epilepsy and Irritable Bowel Syndrome/constipation sections, magnesium deficit plays a major role whether there is hormonal imbalance or not, and it exacerbates hormonal imbalance, if it exists, or it can cause hormonal imbalance.
Abraham (Nutritional factors in the etiology of the premenstrual tension syndromes. G E Abraham 1983) was the first one who proposed magnesium deficiency as the underlying causes as well as the aggravation factor of the PMS symptoms, and demonstrated the efficacy of a nutritional supplement program emphasizing magnesium and vitamin B6 in early 1980's. More recently, the efficacy of magnesium + B6 in reducing PMS symptoms was replicated by researchers in Iran (Evaluating the effect of magnesium and magnesium plus vitamin B6 supplement on the severity of premenstrual syndrome. Fathizadeh N, Ebrahimi E, Valiani M, Tavakoli N, Yar MH. 2010), and in Italy (Pilot study of the efficacy and safety of a modified-release magnesium 250 mg tablet (Sincromag) for the treatment of premenstrual syndrome. 2007). The efficacy of Magnesium supplementation has been also demonstrated with menstrual migraine (Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Headache. 1991) and premenstrual symptoms of fluid retention (Magnesium supplementation alleviates premenstrual symptoms of fluid retention. Walker AF, De Souza MC, Vickers MF, Abeyasekera S, Collins ML, Trinca LA. J Womens Health. 1998).

Use of progesterone goes back even farther. By 1977, Katharina Dalton, a British doctor, has written The Premenstrual Syndrome and Progesterone Therapy based on her success with natural progesterone. Progesterone in Orthomolecular Medicine by Raymond Peat (Ph.D.) published in 1993 explained PMS as part of estrogen dominance syndrome, where estrogen / progesterone balance is lost due to too much estrogen, too little progesterone or both. He also pointed out that many of the progesterone's biological effects are derived from its role in increasing intracellular Magnesium ions as well as zinc and oxygen and reducing intracellular water. 
Effects of hormones on PMS have been studied by measuring PMS severity, estradiol and progesterone levels throughout the cycle. It has also been studied by adding or blocking estradiol and/or progesterone. They have consistently shown high estrogen level overall or during premenstrual days relates to worse PMS symptoms even with normal or seemingly a higher than normal level of progesterone (clearly, it is estradiol/progesterone ratio that matters). They have also shown early drop or a lower level of progesterone in premenstrual days correlates with worse PMS symptoms.
Correlations between progesterone, oestradiol and aldosterone levels in the premenstrual syndrome. M R Munday, M G Brush, R W Taylor 1981 (All the PMS patients were apparently ovulatory but the pooled progesterone values from days --9 to --5 premenstrually were significantly lower than the control values. The oestradiol levels in the PMS patients were higher than in control subjects over the last 4 days of the cycle. )
Luteal-phase estradiol relates to symptom severity in patients with premenstrual syndrome. L Seippel, T Bäckström 1998 (High estradiol or high estradiol + low luteal progesterone =PMS)
Lack of effect of induced menses on symptoms in women with premenstrual syndrome. P J Schmidt, L K Nieman, G N Grover, K L Muller, G R Merriam, D R Rubinow 1991 (PMS does occur even when luteal phase is cut short by 1 week using progesterone antagonist. Indicating it is the early drop of progesterone that has something to do with PMS, rather than progesterone itself.)
Relationship between symptom severity and hormone changes in women with premenstrual syndrome. S Hammarbäck, J E Damber, T Bäckström 1989 (In particular, a high luteal phase plasma estradiol concentration was related to higher premenstrual scores for adverse symptoms and lower scores for positive mood symptoms.)
Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20-one. M Wang, L Seippel, R H Purdy, T Bãckström 1996 (A significantly higher level of E2 and a lower level of P were observed in PMS patients. More negative symptoms occurred in cycles with higher luteal phase E2, Pe, and PS concentrations, whereas higher luteal phase 5 alpha-DHP and 5 alpha-THP concentrations were associated with improved symptom ratings in PMS patients.)
Reproductive hormonal changes and catamenial pattern in adolescent females with epilepsy. Hamed A El-Khayat, Nancy A Soliman, Hoda Y Tomoum, Maher A Omran, Amany S El-Wakad, Rania H Shatla 2008 (Of female patients with epilepsy with lower FSH and P levels and higher E/P ratio, a total of 31% of patients showed catamenial pattern of seizures that was significantly related to P withdrawal.)

When you look at the history of PMS research, many have struggled trying to make sense starting with a very simple minded line of thinking: If it happens when progesterone is secreted, progesterone must be causing it. From this, many doctors are convinced that progesterone is the culprit and they try to stop ovulation by surgically or chemically inducing menopause so that no progesterone secretion occurs. For those doctors, it is unthinkable to use progesterone to alleviate PMS. Those researchers and doctors apparently did not examine the fact closely enough to see it happens when progesterone starts to drop, to say nothing about the poor out come of trading PMS with menopausal symptoms and the associated health risks. Realizing that, some researcher thought it must be a progesterone withdrawal symptoms. It, however, cannot explain those cases that occur right after ovulation when estrogen is high and progesterone is barely starting to secrete. That can be explained by estrogen dominance. Now if you look at the estradiol and progesterone ratio, you would realize that during the first half of the cycle (from the start of the menstruation to ovulation) there is no progesterone secretion, and estrogen slowly rises and surges right before ovulation. In other words, there is an extreme estrogen dominance right before ovulation, yet that is the time most women feel the best, no PMS.
To explain this pattern, you need to look at magnesium deficiency in relation with estrogen / progesterone patterns as I have discussed earlier. If there is a magnesium deficiency, progesterone can still help by increasing intracellular magnesium, but it further depletes the circulating magnesium, and a drop of progesterone level means a drop of intracellular magnesium, at the moment circulating magnesium is depleted, therefore magnesium supplementation is also effective. In addition, as I reviewed in the Constipation section, magnesium deficiency + progesterone can lead to constipation, another complication factor of PMS.

Underlying mechanism: PMDD

Endotoxin and heavy metal toxicities have been considered in the context of bad PMS cases (Calcium, magnesium, and other elements in the red blood cells and hair of normals and patients with premenstrual syndrome. Raymond J Shamberger 2003; Nutritional factors in the etiology of the premenstrual tension syndromes. G E Abraham 1983; Cigarette smoking and the development of premenstrual syndrome. Elizabeth R Bertone-Johnson, Susan E Hankinson, Susan R Johnson, Joann E Manson 2008). Since progesterone is an important hormone used to protect the body against all sorts of toxins according to Progesterone in Orthomolecular Medicine (Raymond Peat, 1993), presence of toxins at high level would put higher demands on progesterone. This is an area where more research is needed considering the highly polluted environment we live in today. Why haven't researchers paid enough attention to these leads? The answer may lie in the politics of research funding/promotion (see this Moyers Moment (2001), and The Toxic Politics of Science).

Effects of Microbiota of Intestines

Another source of toxin is the bad bugs in your intestines. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part II - contemporary contextual research. (Bested, et. al., 2010) reviewed endotoxins such as  lipopolysaccharide endotoxin (LPS) from disease causing bacteria and D-lactic acid from carbohydrate fermentation, and pointed out that they can cause mood disturbances, anxiety, aggression, impaired memory, and fatigue. Furthermore, they also pointed out that a deficiency of magnesium and zinc reduces the healthy diversity of gut microbiota and increases the systemic endotoxin burden.
So, it goes like this: After ovulation (high estrogen = high Ca2+/Mg2+), body temperature rises slightly (this probably favors the bad bugs), progesterone secretes (helps intracellular magnesium to increase to counteract high Ca2+), less magnesium left in intestines (another factor to favor the bad bugs as well as constipation)endotoxin starts to increase (you starts to feel bad), circulating magnesium starts to deplete (your body start to struggle with magnesium deficiency), progesterone starts to drop (now your cells cannot get enough magnesium at all and Ca2+/Mg2+ gets high). It keeps getting worse until the body temperature drops, constipation goes a way, new cycle starts with menstruation, and things calm down with low hormonal activities (both estrogen and progesterone) and less active endotoxin producing microbes, and circulating magnesium level recovers.