Unived PMS Management

Most women of reproductive age have one or more emotional or physical symptom in the premenstrual phase of the menstrual cycle. Mood and behavioural symptoms, including irritability, tension, depressed mood, tearfulness, and mood swings, are the most distressing, but somatic complaints, such as breast tenderness, bloating, and joint and muscle pain can also be problematic[i].

The length of symptom expression varies between a few days and 2 weeks1. Symptoms often worsen substantially 6 days before, and peak at about 2 days before menses start1. Anger and irritability are the most severe complaints and start slightly earlier than other symptoms1

If PMS symptoms are severe and cause problems with work or personal relationships, you may have Primary dysmenorrhea (PDM) or Premenstrual dysphoric disorder (PMDD)

PDM – Primary dysmenorrhea is painful menstrual cramps without any evident pathology to account for them, and it occurs in up to 50% of menstruating females and causes significant disruption in quality of life and absenteeism. Current understanding implicates an excessive or imbalanced amount of prostanoids and possibly eicosanoids released from the endometrium during menstruation. The uterus is induced to contract frequently and dysrhythmically, with increased basal tone and increased active pressure. Uterine hypercontractility, reduced uterine blood flow, and increased peripheral nerve hypersensitivity induce pain.

[i] Kimberly Ann Yonkers et. al., “Premenstrual syndrome”, Lancet. Author manuscript; available in PMC 2011 June 20, NIH Public Access Author Manuscript

There are two types of dysmenorrhoea: primary (of unknown cause) and secondary (when an underlying condition can be identified) [i].

1. Primary dysmenorrhoea refers to recurrent, crampy lower abdominal pain that occurs during menstruation in the absence of other underlying conditions/ disease2.
2. Secondary dysmenorrhoea refers to painful menstruation related to underlying conditions and is more common among women in their forties and fifties2.

[i] Johnston L, BPharm & Jacqueline van Schoor, “Menstrual pain (dysmenorrhoea)” Prof Nurs Today 2014;18(1):13-14. Medpharm

1. Prostaglandins and prostanoids are biosynthesized from arachidonic acid through the COX pathway after production of arachidonic acid from hydrolysis of phospholipids by phospholipase[i].
2. When pregnancy does not occur, progesterone levels decline during the late luteal phase3.
3. This causes labilization of lysosomes and release of their phospholipase enzyme, which then hydrolyzes the cell membrane phospholipids to generate arachidonic acid as well as icosatetraenoic acid3.
4. These compounds then serve as the precursors for the COX and lipoxygenase pathways2.
5. Uterine contraction – Of particular interest and relevance to the pathogenesis of primary dysmenorrhea is the uterine contraction pattern during menstruation when the symptoms of dysmenorrhea occur3. The uterus is taut during contractions or said to have increased “tone.” Rest between contractions requires the uterus to be “soft” when touched or palpated, having a decreased tone. If the uterus is not soft then the tone is increased.

During menstruation in normal women3,

• the uterine basal tone is minimal (less than 10 mm Hg),
• there are 3–4 contractions during each10-minute interval
• with active pressures at the peak of a contraction reaching up to 120 mmHg (comparable to the intrauterine pressure during the second stage of labor with pushing), and
• The contractions are synchronous and rhythmical.

In patients with primary dysmenorrhea, four contraction abnormalities alone or in combination have been reported. These abnormalities lead to poor uterine reperfusion and oxygenation, thus giving rise to pain. They include3;

• elevated basal tone (more than 10 mmhg), which is frequently seen,
• elevated active pressures (more than 120 mmhg, often more than 150–180 mmhg),
• increased number of contractions per 10 minutes (more than 4 or 5), and
• nonrhythmic or incoordinate uterine contractions.

7. Uterine blood flow – In eumenorrheic women the uterine contractions do not affect uterine blood flow. By contrast, the strong and abnormal uterine contractions in dysmenorrheic women reduce uterine blood flow and cause myometrial ischemia, resulting in pain3.

[i] M. Yusoff Dawood, “Primary Dysmenorrhea- Advances in Pathogenesis and Management”, Obstet Gynecol august 2006; VOL. 108, NO. 2 108:428–41

PMS symptoms are different for every woman. You may get physical symptoms, such as bloating or gassiness, or emotional symptoms, such as sadness, or both. Your symptoms may also change throughout your life.

Physical symptoms of PMS can include:

• Swollen or tender breasts
• Constipation or diarrhea
• Bloating or a gassy feeling
• Cramping
• Headache, backache or abdominal pain
• Skin problems
• Water retention
• Swelling of extremities or muscle stiffness.
• Nausea

Behavioural symptoms of PMS can include:

• Fatigue
• Dizziness
• Insomnia
• Food and alcohol cravings
• Overeating
• Clumsiness
• Excessive sleep
• Difficulty in concentrating

Psychological symptoms of PMS can include:

• Irritability or hostile behavior
• Restlessness
• Trouble with concentration or memory
• Tension or anxiety
• Depression, feelings of sadness, or crying spells
• Feeling of isolation
• Mood swings
• Less interest in sex

NSAIDs are considered first-line treatment in the management of dysmenorrhoea. Nonsteroidal anti-inflammatory drugs NSAIDs provide analgesia by inhibiting prostaglandin synthesis and reducing the volume of menstrual flow. There is some evidence that combined oral contraceptives are effective in the management of menstrual pain.

Adverse effects of NSAIDs include gastrointestinal symptoms, central nervous system symptoms, nephrotoxic and hepatotoxic effects, hematologic abnormalities, bronchospasm, fluid retention, and edema, but with a 3-day regimen used in primary dysmenorrheics who are usually young and healthy, adverse effects are infrequent, well tolerated, and usually confined to gastrointestinal symptoms such as nausea, indigestion, heart burn, and vomiting.

Antidepressants or Serotonin reuptake inhibitors (SRIs) SRIs reduce both mood symptoms and somatic complaints, and they also improve quality of life and social functioning2

Oral contraceptives (estrogen and progestin) reduce menstrual fluid volume and prostaglandins to within, or even below, normal range, with concomitant clinical relief during that cycle. The relief and the reduction in prostaglandins are confined only to that particular cycle, with no carry-over effect after stopping the OCP. Drugs that prevent ovulation, such as hormonal contraceptives, may lessen physical symptoms. However, not all may relieve the mood symptoms of PMS.

Diuretics (“water pills”) are drugs that help reduce fluid buildup. Your health care provider can prescribe a diuretic if water retention is a major symptom for you.

More often than not all these above mentioned medications have a negative impact on the body. Also it should be noted that these medicines have a specific actions and one drug alone will not be enough for complete relief from PMS. If any healthy regularly menstruating woman is to consider any of these as a constant for every monthly cycle, she is more likely to experience a side effect of these drugs. Periods are natural and they are not meant to be uncomfortable and if unfortunately they are one should only resort to nature for treatment.

Unived’s PMS Management is one such product that is made with natural ingredients along with vitamin D3 & B6, Magnesium and Iron that will help relieve both psychological as well as physical symptoms of PMS without disturbing your reproductive health so you can have a comfortable menstrual cycle.

Curcumin: Changes of prostaglandins and neurotransmitters levels are known to perform major role in the pathophysiology of PMS. Prostaglandins mostly result in outbreak of physical symptoms and neurotransmitters mainly have responsibility in incidence of mood and behavioral symptoms during PMS[i]

• Studies have shown curcumin reduces prostaglandins synthesis through inhibition of cyclooxygenase-2 (COX-2) enzyme4.
• In the curcumin group physical, behavioral and mood scores after intervention reduced significantly than before intervention4.
• Collectively, after intervention total PMS score in curcumin group significantly decreased from 102.06 ± 39.64 to 42.47 ± 16.37 (P < 0.0001), whereas this score after intervention in placebo group had not significant differences with before intervention4.
• The antidepressant-like effects of curcumin is related to the serotonergic system, maybe due to interactions of curcumin with serotonin receptors and increase in serotonin concentration in brain4.
• In addition to neurotransmitters, cyclooxygenase-2enzyme (COX-2) that is responsible for the production of prostaglandin E2 (involved in some physical problems, such as pain, swelling, inflammation and fever) is known to play a major role in the pathophysiology of PMS. Curcumin have shown that it can down-regulate gene expression of COX-2 enzyme and thereby inhibit prostaglandin synthesis4.
• Altered luteal BDNF levels in women with PMS might play a role in a set of psychological and somatic symptoms of the PMS[ii]

KSM-66® Organic Ashwagandha Extract: manufactured using a water-based extraction process, without the use of any alcohol or chemical solvents, based on the principles of Green Chemistry. It has the most extensive set of research studies and clinical trials; 22 studies – 11 published studies, 6 additional studies completed and in peer review and 5 ongoing studies.  KSM-66® is organic & vegan ashwagandha root extract, which features the highest percentage of withanolides derived from roots alone (5% by HPLC) and its safety and effectiveness are supported by clinical and preclinical studies.

• Serum cortisol levels: a statistically significant (p<0.05) decrease of 22.2% was observed in serum cortisol (a stress hormone) levels as a result of KSM-66 Ashwagandha supplementation, significant when compared to the placebo[iii]^,[iv].
• Ashwagandha is seen as a GABA-mimetic that reduces over-excitation of neurons, thereby producing calmness, reducing stress and increasing focus, mental well-being and self-control6^,7.
• Treatment with Ashwagandha can be helpful in limiting stress-associated weight gain in humans6^,7
• Study suggests that a high-concentration full-spectrum Ashwagandha root extract safely and effectively improves an individual’s resistance towards stress and thereby improves self-assessed quality of life[v].
• A study demonstrated that Withania somnifera downregulate the expression of key genes (ALOX5AP, DPEP2, LTC4S) involved biosynthesis of leukotrienes A, B, C, D and E, resulting in inhibition of leukotriene signaling pathway[vi].

L-theanine: L-Theanine is a unique non-proteinic amino acid that has been reported with predominant therapeutic values present almost exclusively in the tea plant (Camellia sinensis).

• The relaxing effects of tea consumption have been known for decades; however, the modern neuropharmacological science has demonstrated that an active constituent of tea, called L-theanine (gamma glutamylethylamide) has modulatory effects on the brain state[vii].
• It has been shown to regulate oscillatory brain activities in humans with an ability to pass through the blood–brain barrier during cognitive task execution and electroencephalographic (EEG) transcriptions and is believed to cause a relaxation effect10.
• L-theanine has been proposed as a neuroprotective and cognitive-enhancing agent[viii].
• Peripherally and centrally administered L-theanine has been reported to act on the brain, to modulate monoamine levels in the central nervous system, and glutamate and glycine neurotransmissions11.
• In the brain L-theanine increases serotonin production[ix]
• Regardless of the mechanism, theanine increases alpha-brain wave activity, a sign of induced relaxation12.

VITAMINS

Vitamin D3: Recent studies showed efforts on the possibility of vitamin D in treating dysmenorrheal. The association between pain severity and vitamin D level is inversely correlated

• The possible mechanism for vitamin D in the treatment of dysmenorrhea is the anti-inflammatory effects mediated by reduced cytokines such as interleukin 6 and tumor necrosis factor and by decreasing the release of Prostaglandins[x].
• The other clinical trial found that vitamin D supplementation could improve dysmenorrhea and reduce the need for using NSAIDs in patients with dysmenorrhea and vitamin D deficiency13.
• The treatment group showed a significant difference in pain severity after they received vitamin D supplements in comparison with the control group who remained on their usual analgesics regimen with no significant difference in pain severity13.
• By using independent sample t-test, at the end of the trial there was a significant increase in vitamin D level in the treatment group (80.2 ± 14.3 SD) compared to (30.1 ± 13.4 SD) at baseline13.
• It has been found that 45.5% of women in the vitamin D group stopped analgesics in the follow-up visit and 64% of women stopped analgesics at the end of the study13.
• Pain length during menstruation is measured by days. It was found that 9 women (82%) out of 11 women from the vitamin D group reported pain length of more than two days at baseline while the number decreased to only 2 women (18.2%) at the end of the study. In the control group, 6 (54.5%) women remained suffering from pain for more than two days in comparison to 8 (73%) at baseline13.
• Pain severity indicated by VAS was reduced from almost8 at baseline to about 3.5 at the end of the study13.

Vitamin B6: Vitamin B6 is a versatile vitamin that’s involved in more than 100 enzyme reactions. It not only helps produce neurotransmitters, it also performs other important tasks like regulating how hormones work, bolstering immune functions, and playing a pivotal role in metabolism. B6 also keeps homocysteine levels in check; without it, too much homocysteine would cause inflammation.

• The results indicated that combination of Mg and vitamin B6 was more effective than Mg and placebo on decreasing the PMS symptoms. They reported that vitamin B6 decrease the severity of the symptoms more effectively16.
• Significant improvement of global symptoms only for vitamin B­6 over placebo[xi]
• Vitamin B­6 was significantly better than placebo in relieving overall premenstrual symptoms and in relieving depression associated with premenstrual syndrome[xii].
• Pyridoxine is believed to affect brain monoamine metabolism specifically by an alteration in the metabolism of tryptophan. It is suggested that depression may be a consequence of a decrease in the metabolism of tryptophan to 5-hydroxytryptamine (5HT) and that imbalances in the levels of steroid hormones may cause a relative deficiency of pyridoxine, the necessary co-factor in this pathway15.
• The results strongly suggest that pyrixodine, even in a dose as low as 50 mg per day, has a statistically significant beneficial effect on emotional type symptoms (depression, irritability and tiredness) during the premenstrual period in women with the premenstrual syndrome; there was an approximate halving of these symptoms in drug months compared with placebo months15.
• Researchers have proposed that a deficiency in a specific type of prostaglandin – the PgE1, may worsen PMS. Many nutrients are important for the synthesis of PgE1, vitamin B6 is one.

MINERALS

Magnesium: Abraham was the first one who proposed magnesium deficiency as the underlying causes as well as the aggravation factor of the PMS symptoms[xiii]. He believed that the relief of the symptoms after administration of Mg results from the relaxing effect of Mg in controlling the neuromuscular stimulations. The Mg level of erythrocytes and leukocytes of women with PMS is lower than that in the women without the syndrome16

• As can be observed in the results, the combination of Mg plus vitamin B6 is more effective that Mg and placebo in lowering the mean score of the PMS symptoms (p<0.05)16
• Considering the changes in the mean score of the PMS symptoms after the intervention, it was demonstrated that the mean score significantly decreased in the magnesium plus vitamin B6 group and the magnesium group but not in the placebo16.
• To simplify the comparison of effectiveness of each treatment, 30 symptoms were recorded into five sub-groups, according to the Abraham’s classification, the subgroups of symptoms and the mean score of Mg+B6, Mg and placebo were as follows respectively: depression (-31.26, -17.3, -13.33), anxiety (-22.16, -12.14, 0.00) craving (-20.76, -23.04, -14.09), water retention (-23.33, -15.39, -5.2) and somatic sub-groups (-18.09, -12.73, -2.5)16.
• The combination of Mg and vitamin B6 showed the highest effectiveness in relieving the PMS symptoms.
• Magnesium calms the nervous system and reduces the activity of the hypothalamic-pituitary-adrenal (HPA) axis (2). The result is less anxiety, less cortisol, and a better capacity to cope with stress. Reduced stress can, in turn, have positive effects on your menstrual cycle and health.
• It works by relaxing the smooth muscle of the uterus and by reducing the prostaglandins that cause period pain. Magnesium helps decrease overall stress resulting in quality night’s sleep.

Iron: Unexplained fatigue can be caused by iron deficiency. The effects of iron deficiency on fatigue can be explained by decreased activity of iron dependent enzymes; for example, those affecting the metabolism of neurotransmitters that enhance neurophysiologic changes.

• Treatment of iron deficiency with either supplementation or a high iron diet results in improved mental health and decreased fatigue among women of childbearing age[xiv].
• The mean score on the Current and Past Psychological Scale for fatigue decreased by 47.7% in the iron group and by 28.8% in the placebo group (difference –18.9%, 95% CI–34.5 to –3.2; p = 0.02)[xv].
• Compared with placebo, iron supplementation increased hemoglobin (0.32 g/dL; p = 0.002) and ferritin (11.4 μg/L; p < 0.001)18.
• Intention-to-treat analysis showed that patients receiving the iron supplement had a 3.5 point improvement in their fatigue score; thus, patients who received iron reported a 47.7% decrease in fatigue18.
• Iron also had significant effects on the global fatigue index from the Multidimensional Assessment of Fatigue Scale (p =0.03) and its severity index (p = 0.03)18.

[i] Samira Khayat et. al., “Curcumin attenuates severity ofpremenstrual syndrome symptoms:A randomized, double-blind,placebo-controlled trial”, Complementary Therapies in Medicine (2015) 23, 318—324 Elsevier Ltd

[ii] Hamed Fanaei, et. al., “Effect of curcumin on serum brain-derived neurotrophic factor levels in women with premenstrual syndrome: A randomized, double-blind, placebo-controlled trial”, Neuropeptides (2015), http://dx.doi.org/10.1016/j.npep.2015.11.003

[iii] ‘Ksm-66® ashwagandha / scientific studies: highly bioavailable, clinically effective, sustainably produced.’ www.ashwagandhaadvantage.com

[iv] Dnyanraj Choudhary, et. al., ‘Body Weight Management in Adults Under Chronic Stress Through Treatment With Ashwagandha Root Extract: A Double-Blind, Randomized, Placebo-Controlled Trial’ Journal of Evidence-Based Complementary & Alternative Medicine 2017, Vol. 22(1).

[v] Krutika J, et. al., “Studies of Ashwagandha (Withania somnifera Dunal)”, International Journal of Pharmaceutical & Biological Archives 2016

[vi] Alexander Panossian,et. al., “Effects of anti-inflammatory and adaptogenic herbal extracts on gene expression of eicosanoids signaling pathways in isolated brain cells”, 2019 The Authors. Published by Elsevier GmbH.

[vii] Akiko higashiyama, et. al., “Effects of L-theanine on attention and reaction time response”, Journal of functional foods 3 (2011) 171–178, 2011 elsevier ltd.

[viii] Shinsuke Hidese, et. al., “Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial”, Nutrients 2019, 11, 2362

[ix] “Monograph: L-Theanine”, Alternative Medicine Review. Volume 10, Number 2, 2005

[x] Alshaigi Lama et. al., “Vitamin D Supplements as Adjunctive Therapy with Analgesics for Primary Dysmenorrhea: A Randomized Clinical Trial”, Int J Reprod Med Gynecol. 2019;5(1): 004-014.

[xi] Katrina M Wyatt, et. al., “Efficacy of vitamin B­6 in the treatment of premenstrual syndrome: systematic review”, BMJ VOLUME 318 22 MAY 1999

[xii]Helen Doll et. al., “Pyridoxine (vitamin B6) and the premenstrual syndrome: a randomized crossover trial”, Journal of the Royal College of General Practitioners, 1989, 39,

364-368.

[xiii] Nahid Fathizadeh, et. al., “Evaluating the effect of magnesium and magnesium plus vitamin B6 supplement on the severity of premenstrual syndrome”, IJNMR 2010; 15(Special Issue): 401-405

[xiv] Amanda J. Patterson, et. al., “Dietary and Supplement Treatment of Iron Deficiency Results in Improvements in General Health and Fatigue in Australian Women of Childbearing Age”, Journal of the American College of Nutrition, Vol. 20, No. 4, 337–342 (2001)

[xv] Paul Vaucher DiO, et. al., “Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial”, CMAJ, August 7, 2012, 184(11)

Curcumin: curcumin by augmenting levels of neurotransmitters improved mood and behavioral symptoms of PMS and through inhibition of COX-2 enzyme (prostaglandin E2 synthesis) attenuated physical symptoms of menstruation cycle. It also works as an anti-depressant by increasing serotonin concentration.

KSM-66® Organic Ashwagandha Extract: it helps to maintain stress hormone levels and reduces over-excitation of neurons, thereby producing calmness, reducing stress and increasing focus, mental well-being and self-control. It also works as an anti-inflammatory ingredient that may help with reduction of pain.

L-theanine: is a neuroprotective and cognitive-enhancing agent. It increases serotonin production and increases alpha-brain wave activity, a sign of induced relaxation.

Vitamin D3: features plant-based vitamin D3 as cholecalciferol from Lichen. The possible mechanism for vitamin D in the treatment of PMS is its anti-inflammatory effects and reduction of the release of prostaglandins, which helps reduce the severity of menstrual pain.

Vitamin B6: Vitamin B6 is a cofactor in neurotransmitter biosynthesis. B6 has the unique ability to increase amounts of the neurotransmitters serotonin in the brain. It reduces severity of PMS symptoms by helping with the synthesis of the good prostaglandins.

Magnesium: Magnesium helps sooth and tone the smooth muscles of the uterus, easing cramps over time. By decreasing levels of prostaglandins, magnesium may lessen cramps. Magnesium helps decrease overall stress resulting in quality night’s sleep. This makes a huge difference when it comes to hormone regulation and mood.

Iron: it increases hemoglobin levels which then elevates the blood flow and oxygen transfer to the uterus, thus indirectly helping relieve pain and reduces fatigue almost by 48%. With adequate hemoglobin and iron level there is enough oxygen transfer to tissues thus it helps to reduce fatigue and breathlessness.