and Dysmenorrhea
Khalid K. Abdul-Razzak , Bayan A. Obeidat , Nehad M. Ayoub , Mudhaffar I. Al-Farras , and Ahmed A. Jaradat
Key Points
• Dysmenorrhea or menstrual pain is one of the most common gynecologic complaints among adolescent and young females.
• Prostaglandin (PG) is the major underlying cause of painful menstruation.
• Management of dysmenorrhea would have an important social infl u- ence for this chronic problem.
• There is a wide range of treatment options available to relief the symp- toms of primary dysmenorrhea, however these approaches showed vari- able effectiveness benefi ts and are troubled by some negative side effects.
• A recent study showed a strong association between intake of dietary calcium and risk of dysmenorrhea.
• When adolescent and young females who experience dysmenorrhea considered dietary calcium approach, the majority of participants docu- mented some improvement in dysmenorrheal symptoms and fewer par- ticipants reported the need for medications for pain relief.
• Therefore, dietary calcium may be considered as a promising nutri- tional therapy for the relief of pain and symptoms associated with menstruation, which can signifi cantly infl uence the quality of life of adolescent girls and young women during the reproductive age.
N. M. Ayoub
Department of Clinical Pharmacy , Jordan University of Science and Technology , Irbid , Jordan
M. I. Al-Farras
Department of Emergency , King Abdulla University Hospital , Irbid , Jordan
A. A. Jaradat
Department of Family and Community Medicine , College of Medicine and Medical Sciences, Arabian Gulf University , Manama , Kingdom of Bahrain
Abbreviations
25(OH)D 25-Hydroxyvitamin D
CAM Complementary and Alternative Medicines
IRB Institutional Review Board
NSAIDs Nonsteroidal anti-infl ammatory drugs OCs Oral contraceptives
PGs Prostaglandins PTH Parathyroid hormone
Introduction
Dysmenorrhea is a Greek word that means painful or diffi cult monthly menstrual fl ow. It is also defi ned as menstrual cramps of uterine origin.
Dysmenorrhea is one of the most common gyne- cologic complaints among adolescent and young females [ 1 , 2 ]. Different types of studies from both developed and developing countries have found a consistently high prevalence of dysmen- orrhea in women of different ages and nationali- ties. Dysmenorrhea is more prevalent in adolescent women. It occurs with an estimated prevalence of up to 97 % of menstruating females [ 3 ].
Dysmenorrhea is commonly subcategorized into two distinct types based on pathophysiology:
primary and secondary. Primary dysmenorrhea is defi ned as painful menses in women with normal pelvic anatomy. It usually begins during adoles- cence, typically in the fi rst few years after men- arche with an age range between 17 and 22 years.
Secondary dysmenorrhea becomes more com- mon as woman ages, many years to decades after menarche and menstrual pain is associated with organic pelvic pathology such as endometriosis, chronic pelvic infl ammatory disease, fi broid tumors, adenomyosis, ovarian cyst, uterine pol- yps, and the use of intrauterine contraceptive devices [ 4 , 5 ].
Risk Factors
The severity of dysmenorrhea is associated with several risk factors including early onset of puberty, long and heavy menstrual fl ow, low body mass index or dieting, stress, depression, anxiety, smoking, obesity, and alcohol consumption.
However, some of the risk factors such as smoking, obesity, and alcohol consumption were not found to be consistently associated with pri- mary dysmenorrhea [ 5 – 8 ].
Symptoms
Dysmenorrhea is characterized by lower abdomi- nal pain that occurs during menstruation, but may start 2 or more days before menstruation and per- sists up to 72 h. The pain may also radiate to the lower back or inner thighs [ 9 , 10 ]. Frequently, pain is associated with several types of symptoms including headache, backache, general weakness, nausea, vomiting, dizziness, sweating, abdominal bloating, loose stool, depression, excitability, and irritability [ 6 , 9 – 11 ].
Pathogenesis of Primary Dysmenorrhea
The pathogenesis of primary dysmenorrhea is not fully understood. Current evidence suggests that prostaglandins (PGs) are the major underlying cause of painful menstruation [ 12 ]. Evidence that support this theory is the presence of high level of prostaglandins PGF2 and PGE2 in menstrual fl uid that correlate with symptoms of dysmenor- rhea [ 13 ]. PGs are potent compounds that induce a wide range of physiologic and pathologic responses. PGs are synthesized mainly from ara- chidonic acid, a C20:4 omega-6 fatty acid which Keywords
Dysmenorrheal • Dietary factors • Lifestyle modifi cation • Calcium • Dairy products
55
is found in membrane phospholipids. Before the start of menstruation and after the drop in proges- terone level, arachidonic acid is released from cellular membrane phospholipids by phospholi- pase A2 for the synthesis of prostaglandins (PGs) in the uterus, which leads to constriction of arte- rioles, and reduction in uterine blood fl ow and pain level [ 14 , 15 ].
Treatment of Dysmenorrhea
A wide range of treatment options for primary dysmenorrhea are available [ 16 ]. Virtually all treatment options are directed toward correction of the risk factors or the etiology that produced dysmenorrhea with minimal side effects.
However, these approaches showed variable ben- efi ts in the management of menstrual pain.
Nonsteroidal Anti-infl ammatory Drugs
Nonsteroidal anti-infl ammatory drugs (NSAIDs) are the most common pharmacologic treatment for primary dysmenorrhea [ 10 , 17 ]. Several ran- domized controlled trials demonstrated the superiority of NSAIDs in treating of primary dysmenorrhea compared with placebo but no superiority was established among different NSAIDs in the treatment options of dysmenor- rhea [ 15 , 18 ]. However, despite the considerable effi cacy of NSAIDs, not all adolescents with dysmenorrhea respond to NSAIDs. For many women, NSAID therapies offer inadequate treatment with a failure rate of 10–25 % [ 19 ].
This failure was attributed to different media- tors or causes that have been implicated to either the pathogenesis of primary dysmenorrhea or the secondary causes of dysmenorrhea [ 1 , 20 ].
Moreover, some women have intolerable side effects to current therapies such as gastric upset and even infertility [ 21 ]. Simple analgesics such as paracetamol and aspirin can be considered for pain relief in women when other treat- ments are contraindicated or intolerable [ 1 ].
NSAIDs affect the physiological mechanisms
behind menstrual pain, inhibiting prostaglandin production through reducing the activity of the cyclooxygenase pathway, which is the rate- limiting factor in the conversion of arachidonic acid to PGs [ 1 ].
Oral Contraceptive Pills
Treatment of dysmenorrhea also includes a well- accepted, off-label use of oral contraceptives (OCs) [ 6 , 22 ]. Results from multiple studies indi- cate that low-dose oral contraceptive pills can effectively reduce the incidence and severity of pain and symptoms associated with primary dys- menorrhea [ 23 ]. A recent randomized controlled study demonstrated a signifi cant improvement of primary dysmenorrhea and its associated symp- toms in response to combined low-dose oral con- traceptives ethinyl estradiol and norethisterone (IKH-01) treatment [ 24 ].
Reduced menstrual pain severity was attrib- uted to reduction in uterine contractions and vol- ume of menstrual fl ow through suppression of PG synthesis [ 25 ]. However, some women prefer not to use OCs because of side effects or cultural reasons. Adverse effects of combined OCs including headache, nausea, and weight gain have been reported [ 24 ].
Complementary and Alternative Medicines
A number of alternative therapies have been stud- ied for the treatment of dysmenorrhea and have been reported to be effective in relieving men- strual cramps. However, some reports have small number of participates and only short-term follow- ups, and sometimes are limited to only one trial.
Herbal Medicine
Complementary and Alternative Medicines (CAM) research has focused on the possible benefi cial effects of herbal preparations. The most widely studied formulations are the traditional Chinese herbal preparations. Chinese herbal preparations
5 Reproduction, Pregnancy, and Women: Diet Quality and Dysmenorrhea
are found to be effective for the treatment of dys- menorrhea with minimal side effects [ 26 ]. The effectiveness of Chinese herbals in dysmenorrhea therapies could be related to several mechanisms including decrease of PG levels, modulating nitric oxide, elevation of plasma beta-endorphin levels, blocking of calcium- channels, and improvement of microcirculation [ 26 ].
Dietary Factors
A variety of nutrients have been the focus of number of researches that examined the possible benefi cial effects in management of primary dys- menorrhea including vitamin B1 (thiamine), vita- min B3 (niacin), vitamin B6 (pyridoxine), vitamin E, fi sh oil supplement, calcium, and magnesium.
Vitamin B1 and B6
In a single study, supplementation of 100 mg of vitamin B1 daily for 3 months to 556 Indian ado- lescent girls with moderate to very severe dys- menorrhea was shown to be an effective therapy.
The majority of participants (87 %) reported no menstrual pain as compared to placebo [ 27 ].
Some evidence also exists for the benefi t of 100 mg/day supplementation of vitamin B6 taken with or without magnesium in management of dysmenorrhea. However, magnesium can have adverse effects such as constipation.
Vitamin E
Three trials have demonstrated the effectiveness of vitamin E in relieving menstrual pain of pri- mary dysmenorrhea.
In the fi rst trial, 100 adolescent girls who suf- fered from primary dysmenorrhea received sup- plements of 500 IU/day vitamin E (about 333 mg) 2 days before the onset of menses and continued through the fi rst 3 days of menstruation for 2 months. Vitamin E supplementation signifi - cantly improved menstrual pain as compared to placebo [ 28 ]. Also the intake of 500 mg vitamin E 10 days before the menses and continued until the fourth day of menses for 3 months was reported to improve menstrual pain as compared to placebo (68 % vs. 18 %) [ 29 ]. Similar result was obtained in another randomized controlled
trial when vitamin E (200 U/day) was administered 2 days before the menses and continued through the fi rst 3 days of menses for 3 months [ 30 ].
In this trial, participants also reported reduced blood loss.
Fish Oil
The protective effect of fi sh oil on dysmenorrhea is supported by several crossover design clinical tri- als. In the fi rst trial, 42 girls who experience dys- menorrhea were placed into two groups of 21 each.
One group received 6 g of fi sh oil (1,080 mg EPA, 720 mg DHA, and 1.5 mg vitamin E) daily for 2 months followed by a placebo for an additional 2 months, while the second group received placebo for the fi rst 2 months followed by fi sh oil for 2 more months. The results show marked reduc- tion in symptoms of dysmenorrhea due to fi sh oil treatment [ 31 ]. In the second trial, 36 girls aged 18–22 were randomly allocated into two groups.
The treated group received 15 mL of fi sh oil per day for 3 months while the control group received placebo. In that trial, fi sh oil was proven to be more effective for relief of menstrual pain than placebo [ 32 ]. In another double blind, randomized, placebo- controlled trial, 78 Danish women who experience dysmenorrhea [ 33 ] supplemented with 2.5 g/day fi sh oil with or without vitamin B12, seal oil (5 g/
day), or placebo for three menstrual cycles. Women taking fi sh oil plus B12 reported a signifi cant reduction in the intensity of menstrual pain and some associated symptoms.
The benefi cial effect of fi sh oil is apparently due to its content of omega-3 fatty acids (eicosa- pentaenoic acid and decosahexaenoic acid).
Several mechanisms have been proposed for the anti-infl ammatory effect of omega-3 fatty acids including fi rst: fewer PGs are made from omega-3 fatty acids, second: omega-3 can inhibit the formation of arachidonic acid from C18 fatty acids at the level of δ6 desaturase enzyme, third:
binding of omega-3 fatty acids to cyclooxygen- ase reduces the conversion of omega-6 to PGs, and fourth: PGs derived from omega-3 fatty acids are less potent than those formed from the omega-6 fatty acids [ 34 ]. Therefore, high omega-3 intake is expected to be associated with
57
milder menstrual pain. Adverse effects of fi sh oil have been reported, including stomach upset, slight nausea and bad taste, and acne.
Lifestyle Modifi cation
Few studies have examined the effect of lifestyle modifi cation with respect to ameliorating symp- toms of dysmenorrhea, including low-fat vege- tarian diet [ 35 ] and exercise [ 36 ]. Low-fat vegetarian diet was reported to be associated with reduction in dysmenorrhea duration and intensity as compared with baseline in a crossover design which involved 33 women for two menstrual cycles. The effect was attributed to diet infl u- ences on estrogen activity. A low-fat vegetarian diet was associated with increased serum sex hormone-binding globulin concentration, which inactivates estrogens. Estrogen and progesterone stimulate the endometrium, which is the source of the PGs which induce ischemia and uterine muscle contraction [ 37 ].
Dietary Habits and Primary Dysmenorrhea
Although the prevalence and severity of dysmen- orrhea in adolescents and young females are high, many girls either do not ask for medical advice or are undertreated [ 17 ]. The severity of dysmenorrheal pain varies among different females; however, it could be severe enough to cause a substantial negative impact on women’s daily activities. Pain may inconvenience a woman during holidays, social activities, or sometimes when high performance is required.
Chronic recurrent pain of dysmenorrhea leads to high rate of school or work absences as well as limits their class concentration, which affects their academic performance [ 12 , 38 ]. Besides the negative impact on the society, dysmenor- rhea causes signifi cant cost to the health care system and imposes signifi cant socioeconomic consequences [ 39 ].
Although there is a wide range of treatment options available to relief dysmenorrheal pain,
these approaches showed variable benefi ts in the management of menstrual pain. Therefore, fi nd- ing an effective and safe nonpharmacologic inter- vention for management of dysmenorrhea would have an important social infl uence on females.
Knowledge of benefi cial food-related practices can provide better inexpensive nonpharmacologic alternative treatment for primary dysmenorrhea. It can also limit several negative side effects of the current pharmacological treatments. In addition, it will contribute positively to the general health of adolescent girls and young women.
Few studies had examined the relationship between dietary habits and menstrual pain.
Higher intake of fruit, eggs, and animal and fi sh products was found to correlate with milder menstrual pain [ 34 , 40 ]. The protective effect of fruit and eggs was attributed to their calcium and magnesium contents. However, the role of cal- cium in the treatment of primary dysmenorrhea was subjected to controversial results. A study with a relatively small sample size (only ten women) conducted by Penland et al. [ 41 ] found that increased dietary intake of calcium (587 or 1,336 mg/day) and magnesium (1.0 or 5.6 mg/
day) reduced menstrual pain and improved some psychological symptoms. In contrast, Di Cintio et al. [ 42 ] reported no clear relationship between the intake of 50 various food items (grains, veg- etables, fruits, meat, poultry and fi sh, milk and milk products, and oil) and risk of dysmenorrhea with the exception of cheese and eggs consump- tion, which showed a little positive association.
The fi nding of Di Cintio et al. does not support previous suggestions that calcium [ 41 ] and even omega-3 fatty acids [ 34 , 40 ] intake reduces risk for dysmenorrhea.
The effectiveness of magnesium in the treat- ment of primary dysmenorrhea has been also eval- uated in three small randomized controlled trials [ 43 – 45 ]. The results suggest that magnesium supplementation is effective in treatment of dys- menorrhea. The appropriate dose of magnesium for treatment of dysmenorrhea is not clear due to different magnesium dose and formulation used in different trials. The improvement of dysmenorrhea symptoms was attributed to reduction in the PGF2α level and to direct muscle relaxant and vasodilatory
5 Reproduction, Pregnancy, and Women: Diet Quality and Dysmenorrhea
effect of magnesium [ 43 ]. However, treatment with magnesium reported to be either free of side effect [ 43 , 44 ] or associated with intestinal discomfort and other minor adverse effects [ 45 ].
Although the available data provides little direct scientifi c evidence to the relationship between dietary habits and risk factor for dys- menorrhea, consistent observations indicate the presence of an association between frequency of dietary calcium intake and the risk of dysmenor- rhea. A study by Abdul-Razzak et al. [ 10 ] showed the possible relationship between daily dairy products intake and risk of dysmenorrhea and other associated symptoms among university female students. A detailed description of fi eld data collection can be found elsewhere. In this study, a strong correlation between dairy prod-
ucts intake and dysmenorrhea and its associated symptoms among participants was found. A sig- nifi cantly lower percentage of female students expressing dysmenorrhea were observed when their intakes of dairy products were three or four servings per day as compared to female who took none (Table 5.1 ). Similar infl uence pattern of dairy products on most dysmenorrhea-associated symptoms was also observed as symptoms fre- quency was analyzed against the number of daily serving of dairy products (Table 5.2 ). On the other hand the severity of primary dysmenorrhea decreased with increasing the number of daily dairy products intake (Fig. 5.1 ).
This study appears to elucidate the relation- ship between dietary intake of dairy products and the risk of dysmenorrhea.
Table 5.2 The association between intake of daily dairy servings and dysmenorrhea-associated symptoms
Symptom
Total number of daily servings ( n %)
0 1 2 3 4
Nausea and vomiting 7(26.92) 5(19.23) 8(30.77) 3(11.54) 3(11.54)
Sweat 13(35.14) 10(27.03) 8(21.62) 4(10.81)* 2(5.41)
Abdominal bloating 32(32.32) 24(24.24) 23(23.23) 10(10.10)** 10(10.10)
Stool 17(34.00) 16(32.00) 12(24.00) 4(8.00)*** 1(2.00)
Dizziness 17(37.78) 9(20.00) 11(24.44) 3(6.67)**** 5(11.11)
Others 7(26.92) 5(19.23) 7(26.92) 2(7.69) 5(19.23)
Cited from ref. [ 10 ] with permission from John Wiley & Sons Ltd.
Signifi cant reduction in dysmenorrhea-associated symptom was found in participants who took three compared with participants who took no daily servings of dairy products
n number of students expressing the symptom * P value = 0.009
**P value = 0.000 *** P value = 0.001 **** P value = 0.000
Table 5.1 Dysmenorrhea in relation to daily intake of dairy products
Parameter
Total number of dairy servings/day
0 1 2 3 4
Number (%) of female students who experience dysmenorrheic pain (total number = 111)
36(32.4) 26(23.4) 26(23.4) 11(9.9)* 12(10.8)**
Number of female students who experience no dysmenorrheic pain (total number = 16)
1(6.3) 3(18.7) 7(43.8) 4(25) 1(6.3)
Total number 37 29 33 15 13
There was signifi cant reduction in dysmenorrheic pain in participants who took three daily servings ( * P value = 0.000) or four daily servings (** P value = 0.000) of dairy products compared to participants who took none. Cited from ref.
[ 10 ] with permission from John Wiley & Sons Ltd.
59
Dietary Calcium Is a Promising Nutritional Therapy for Primary Dysmenorrhea
In another study 35 participants of those who were involved in a previous study [ 10 ] and expe- rienced dysmenorrhea and their daily intake of dairy products was none were asked to take three daily servings of dairy products, 7–10 days before the onset of menstruation. To evaluate the overall improvement in dysmenorrhea after including dairy products in the diet, participants were requested to fi ll out another questionnaire to assess any changes in the usual pattern of their menstruation, if any improvement to pain or the other symptoms that are usually associated with menstruation were noticed, and if daily activities were continued as usual with less or without need to administer medications or herbs.
The overall improvement in dysmenorrheal pain and associated symptoms after considering the dairy products therapy were evaluated as
“excellent, very good, good, and slight.” After considering dietary calcium management, 83 % of participates had documented some degree of
improvement regarding their menstrual pain.
About 11 % of participants reported an excellent response to the dietary approach with complete resolution of pain, while 26 %, 44 %, and 19 % of students have reported very good, good, and slight improvement, respectively. Students also reported improvement of some symptoms associated with dysmenorrhea in different degrees (11 % for nau- sea and vomiting, 14 % for sweating, 31 % for abdominal bloating, 9 % for loose stools, and 23 % for dizziness). Interestingly and after con- sidering the dietary calcium approach, fewer par- ticipants had reported the need for medications to relieve pain associated with dysmenorrhea (46 % vs. 68.57 %, P = 0.047). Additionally, lower per- centage of participating students continued to report a negative impact of dysmenorrhea on their daily activities (46 % vs. 74.3 %, P = 0.01).
The fi nding of this single cohort study clearly elucidated that dietary calcium is a promising nutritional therapy for the relief of pain and symptoms associated with menstruation, thus can signifi cantly infl uence the quality of life of ado- lescent girls and young women. Besides calcium
Fig. 5.1 The relationship between daily intake of dairy serving and pain severity. Cited from ref. [ 10 ] with permission from John Wiley & Sons Ltd. * P = 0.028, ** P = 0.002
5 Reproduction, Pregnancy, and Women: Diet Quality and Dysmenorrhea