Chapter 202 Premenstrual Syndrome
Diagnostic Summary
• Recurrent signs and symptoms that develop during the late luteal phase of the menstrual cycle and disappear by the end of the full flow of menses
• Symptoms typically including decreased energy, tension, irritability, depression, headache, altered sex drive, breast pain, backache, abdominal bloating, and edema of the fingers and ankles
General Considerations
Premenstrual syndrome (PMS) refers to the cyclic constellation of troublesome symptoms that appears during the luteal phase of the menstrual cycle—more so in the late luteal phase—disappear by the end of the full flow of menses, and do not appear during the follicular phase.1 Although some 150 symptoms have been listed as premenstrual, the most common symptoms are as follows (Box 202-1):
PMS is estimated to affect between 30% and 40% of menstruating women; 80% of women experience premenstrual emotional or physical changes but do not have much difficulty. Peak occurrence is among women in their 30s and 40s. In most cases symptoms are relatively mild; however, in about 2.5% to 5% of women symptoms can be severe enough to have a negative impact on their lives, putting home life and work in jeopardy. Severe PMS with depression, irritability, and severe mood swings is referred to as premenstrual dysphoric disorder (PMDD)2 and has a separate diagnostic category in the fourth edition of the American Psychological Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
Although PMS has been a well-defined clinical entity for more than 60 years, some physicians still argue that it really does not exist.3 Therefore, many women suffering from PMS do not receive proper treatment. Until the advent of therapy with selective serotonin reuptake inhibitors (SSRIs), conventional mainstream medicine had not been able to offer women a known cause for PMS, nor has it been able to offer satisfactory interventions. Women were by and large left to self-care or to seek the advice of alternative medicine practitioners.
The etiology of PMS has not yet been fully understood, but endocrine studies have clarified that the premenstrual symptoms are not a result of a simple excess or deficiency of any given hormone.4 Several theories have been proposed to explain the causes of PMS; currently strongest is an interaction between the ovarian steroids and the brain’s neurotransmitters. Genetic predispositions and sociocultural beliefs about menstruation may also influence what women experience. At present, the dominant thinking is that cyclic changes in the ovarian steroids estrogen and progesterone cause changes in many body systems, including brain neurotransmitters, which then have emotional and physical manifestations.5 Therefore, normal ovarian function, and not a true hormonal imbalance, triggers the central nervous system and predisposes a woman to hormone-induced instability.6 We do not currently know why women differ in their sensitivity to the changes in ovarian steroid-induced neurotransmitters. Of the neurotransmitters studied, serotonin is the principal one implicated in the pathogenesis of PMS and PMDD.7,8 Whether PMS and PMDD are related to absolute levels or reduced blood levels of serotonin or to serotonin transport remains unclear.9
Diagnosis and Classification
Therapeutic Considerations
Estrogen Metabolism
In the early 1940s, Morton Biskind observed an apparent relationship between B-vitamin deficiency and PMS.10,11 He postulated that PMS, as well as excessive menstruation and fibrocystic breast disease, was due to an excess in estrogen levels caused by decreased detoxification and elimination in the liver as a result of B-vitamin deficiency. The liver uses various B vitamins to detoxify estrogen and excrete it in the bile.
Cholestasis can be caused by a large number of factors besides estrogen excess (Box 202-2). The presence of cholestasis may be a predisposing factor in PMS, because with cholestasis there is reduced estrogen detoxification and clearance. Hence, a positive feedback scenario is produced. The high incidence of gallstones is a clear indication that many American women suffer from cholestasis.
Again, even though elevated serum estrogen values cannot be confirmed in PMS studies, it is interesting to note that estrogen excess during the luteal phase affects endorphin levels negatively. One study found a direct correlation between an increased estrogen/progesterone ratio and endorphin activity in the brain.12 In essence, when the estrogen/progesterone ratio was increased, there was a decline in endorphin levels. This reduction is significant considering the known ability of endorphins to normalize or improve mood. Other studies have shown that low endorphin levels during the luteal phase are common in women with PMS.13 Endorphins are lowered by stress and raised by exercise. The role of endorphins is discussed further later.
Estrogen Impairs Vitamin B6
The way in which estrogen levels during the luteal phase negatively affect neurotransmitter and endorphin levels may be secondary to impairment of the action of vitamin B6. It is well known that estrogens affect vitamin B6 function negatively. Vitamin B6 levels are typically quite low in depressed patients, especially women taking estrogens (birth control pills or conjugated estrogens [Premarin]).14,15 Vitamin B6 supplementation has been shown to have positive effects on all PMS symptoms, particularly depression, in many women (discussed in greater detail later). This improvement is achieved via a combination of a reduction in midluteal estrogen levels and an increase in midluteal progesterone levels.
Dietary Considerations
Women suffering from PMS typically eat a diet that is even worse than the standard American diet. Abraham16 reports that, compared with symptom-free women, PMS patients consume the following substances:
A diet that is higher in dairy products may also contribute to some PMS symptoms. A survey of 39 women with PMS and 14 women without reported that the women with PMS consumed fivefold more dairy products and threefold more refined sugar than the women without PMS.17 Another study observed that women with PMS also have an increased intake of dietary fat, carbohydrates, and simple sugars and decreased protein intake.18
Food cravings are often also higher in women with PMS; this may in part be due to a decrease in serotonin during the luteal phase in PMS sufferers. Therefore, serotonergic treatments may be helpful in controlling such food cravings.19
Another nutritional factor in PMS is the effect of refined sugars on rapid increases in insulin, which then causes the retention of sodium and subsequent water retention, with swelling in the hands and feet, abdominal bloating, and breast engorgement. Sugar has several detrimental actions in PMS. Eating foods high in simple sugars increases insulin secretion and can be harmful to blood sugar control, especially if the patient is hypoglycemic or diabetic. Sugar, especially combined with caffeine, also has a detrimental effect on PMS and mood (discussed later).20 A high intake of sugar also impairs estrogen metabolism. The evidence is based on the higher frequency of PMS symptoms in women consuming a high-sugar diet and the fact that a high sugar intake is also associated with higher estrogen levels.21 One study found that a low-fat, high-complex-carbohydrate diet alleviated premenstrual breast tenderness.22
C-reactive protein, a marker of inflammation, has been correlated with the severity of both physical and psychological symptoms of PMS.23 A diet that stimulates inflammatory pathways includes sugar, poultry, eggs, cheese, milk, white flour, white rice, and partially hydrogenated oils. Foods that can reduce inflammation include fresh fruits, especially berries, green leafy vegetables, fish, nuts, seeds, turmeric, garlic, and onions.
Vegetarian women have been shown to excrete two to three times more estrogen in their feces and to have 50% lower levels of free estrogen in their blood than omnivores.24,25 These differences are thought to be due to the lower fat and higher fiber intake of the vegetarian women. These dietary differences may also explain the lower incidence of breast cancer, endometriosis, and uterine cancer in vegetarian women. They may also play a role in PMS.
Decreasing the percentage of calories as fat, in particular saturated fat, has dramatic effects on the reduction of circulating estrogen.26,27 In one study, when 17 women switched from the standard American diet (composed of 40% of calories as fat and only 12 g as fiber daily) to a low-fat, high-fiber diet (consisting of 25% of calories as fat and 40 g as fiber daily), there was a 36% reduction in blood estrogen levels, with 16 out of the 17 women demonstrating significant reductions in only 8 to 10 weeks.28
It should be noted that not all nutrition research shows a clear-cut association with PMS. In the Study of Women’s Health Across the Nation, a cross-sectional analysis was conducted of PMS symptoms in a multiethnic sample of 3302 midlife women.29
They sought to determine if the frequency of physical or emotional premenstrual symptoms was associated with dietary intake of phytoestrogens/fiber/fat or calcium, consumption of alcohol or caffeine, cigarette exposure, lack of physical exercise, and race/ethnicity or socioeconomic status. In this study, most dietary factors were not related to PMS. Fat intake was negatively associated with craving and bloating. Fiber intake was positively associated with breast pain. Alcohol intake was negatively associated with anxiety, mood changes, and headaches. Cigarette smoke exposure, whether passive or active, was positively associated with cramps and back pain. Ethnic differences in the reporting of symptoms and comorbidity associations were observed as well.
Thyroid Function
Low thyroid function (hypothyroidism) has been shown to affect a large proportion of women with PMS.30,31 For example, in one study, 51 of 54 subjects with PMS demonstrated low thyroid status compared with 0 of 12 in the control group.30 In another study, 7 of 10 subjects in the PMS group had low thyroid status compared with 0 of 9 in the control group.31 Other studies have also shown hypothyroidism to be only slightly more common in women with PMS than in controls.32,33 Many women with PMS and confirmed hypothyroidism who are given thyroid hormone experience complete relief of symptoms.30 For more information, see Chapter 177.
Stress, Coping Style, and Depression
Study of the interaction of stress/serotonin and PMS has shown that serotonin levels in women with PMS fall after ovulation. Those without PMS had much higher levels of serotonin during the last half of the menstrual cycle. In a holistic/natural medicine approach to PMS, the identification of stressors and stress management should not be overlooked.34 Many women with PMS tend to employ “negative” coping styles,35 examples of which are listed in Box 202-3. It is important to identify the manner in which the patient deals with stress and to counsel her on more positive ways of coping.
There are some important relationships between PMS and depression. Depression is a common feature in many cases of PMS, and PMS symptoms are typically more severe in depressed women.1 The reason appears to be a decrease in the brain level of various neurotransmitters, with serotonin and GABA being the most significant.36,37 The most common class of prescription medications recommended for moderate to severe PMS/PMDD is an SSRI. When they are used for chronic depression, SSRIs must be taken daily. When used for PMS/PMDD, they can be taken just on the days of the month when the symptoms are the most problematic. This would suggest that when used in this way, they are not really increasing neurotransmitter levels but work by altering the neurophysiology and electrical conduction in the brain. Several SSRIs have been used, including fluoxetine, sertraline, and paroxetine. However, various psychotherapy methods have been equally if not more successful in improving the psychological aspects of PMS. In particular, biofeedback and short-term individual counseling (especially cognitive therapy) have documented clinical efficacy.38,39 One of the advantages of cognitive therapy over antidepressant drug therapy in the treatment of PMS is that learning techniques such as cognitive-behavioral coping skills can produce excellent results that are maintained over time.
Exercise
Several studies have shown that women engaged in a regular exercise program do not suffer from PMS nearly as often as sedentary women.40–42 In one of the more thorough studies, mood and physical symptoms during the menstrual cycle were assessed in 97 women who exercised regularly and in a second group of 159 women who did not exercise.40 Mood scores and physical symptoms assessed throughout the menstrual cycle showed significant effects of exercise on negative mood states and physical symptoms. The regular exercisers obtained significantly lower scores for impaired concentration, negative mood, behavior change, and pain.
In another study, 143 women were monitored for 5 days in each of the three phases of their cycles (midcycle, premenstrual, and menstrual).41 The women were 35 competitive athletes, two groups of exercisers (33 high-frequency exercisers and 36 low-frequency exercisers), and 39 sedentary women. The high-frequency exercisers experienced the greater positive mood scores and sedentary women the least. The high-frequency exercisers also reported the least depression and anxiety. The differences were most apparent during the premenstrual and menstrual phases. These results are consistent with the belief that women who exercise frequently (but not competitive athletes) are protected from PMS symptoms. In particular, regular exercise protects against the deterioration of mood before and during menstruation.
These studies provide evidence that women with PMS should partake of the benefits of exercise. Exercise may reduce PMS symptoms by elevating endorphin values, improving glucose tolerance, decreasing catecholamines, and modulating estrogen levels.43
Nutritional Supplements
Vitamin B6
The first use of vitamin B6 in the management of cyclic conditions in women was in the successful treatment of depression caused by birth control pills, as noted in several studies in the early 1970s. These results led researchers to try to determine the effectiveness of vitamin B6 in relieving PMS symptoms. Since 1975 at least a dozen double-blind clinical trials have been performed. Some of these studies have shown no effect, but most of the studies have shown a significant effect on the whole range of PMS symptoms at dosage ranges from 50 to 500 mg/day.44 For example, in one double-blind crossover trial, 84% of the subjects had a lower symptom score during the vitamin B6 treatment period.45 In another double-blind crossover trial, 50 mg/day of vitamin B6 was effective in decreasing premenstrual depression, fatigue, and irritability.46 Although PMS has multiple causes, vitamin B6 supplementation alone appears to benefit most patients.
It is important to note, however, that not all double-blind studies of vitamin B6 have shown a positive effect.44,47 The negative results in some trials may have been caused by many factors, such as the inability of some women to convert vitamin B6 to its active form owing to a deficiency in another nutrient (e.g., vitamin B2 or magnesium) that was not supplemented. These results suggest that supplementing pyridoxine by itself may not produce adequate clinical results for all women suffering from this disorder and that some women may have difficulty converting vitamin B6 into its active form, pyridoxal-5-phosphate. To overcome this conversion difficulty, it may be necessary to use a broader-spectrum nutritional supplement or injectable pyridoxal-5-phosphate.
For most indications, the therapeutic dosage of vitamin B6 is 50 to 100 mg/day. This dose level is generally regarded as safe, even for long-term use. With use of doses greater than 50 mg, it may be important to divide it into 50-mg doses taken throughout the day. A single dose of 100 mg of pyridoxine did not lead to significantly higher pyridoxal-5-phosphate levels in the blood than a 50-mg dose, possibly indicating that a 50-mg oral dose of pyridoxine is about all the liver can handle at once.48
Vitamin B6 is one of the few water-soluble vitamins associated with some toxicity when taken in large doses or in moderate dosages for long periods. One-time doses larger than 2000 mg/day can produce symptoms of nerve toxicity (tingling sensations in the feet, loss of muscle coordination, and degeneration of nerve tissue) in some individuals. Long-term intake of doses larger than 500 mg a day can be toxic if taken for many months or years.49 There are also a few rare reports of toxicity occurring at long-term dosages as low as 150 mg/day.49–51 The toxicity is thought to occur when supplemental pyridoxine overwhelms the liver’s ability to add a phosphate group to produce the active form of vitamin B6 (pyridoxal-5-phosphate). As a result, it is speculated that pyridoxine either is toxic to the nerve cells or actually acts as an antimetabolite by binding to pyridoxal-5-phosphate receptors, thereby creating a relative deficiency of vitamin B6. Another possibility is that minute amounts of contaminants or vitamin B6 analogs may have been introduced during synthesis. Although not a problem at normal doses of vitamin B6, contaminants present in larger doses may block vitamin B6 activation sites. Again, it appears to make sense to limit doses to 50 mg at a time. If more than 50 mg/day is desired, the doses should be spread out throughout the day.
Vitamin B6 has the ability to increase the synthesis of several neurotransmitters in the brain including serotonin, dopamine, norepinephrine, epinephrine, taurine and histamine. There are also extensive interactions between vitamin B6 and magnesium, which work together in many enzyme systems. In fact, another mechanism by which vitamin B6 may improve the symptoms of PMS is by increasing the accumulation of magnesium within body cells.52 Without vitamin B6, magnesium does not get inside the cell.
Magnesium
Magnesium deficiency has been implicated as a causative factor in PMS.53 Red blood cell (RBC) magnesium levels in patients with PMS have been shown to be significantly lower than in normal subjects.16,54 Because magnesium plays such an integral part in normal cell function, magnesium deficiency may account for the wide range of symptoms attributed to PMS. Furthermore, magnesium deficiency and PMS have many common features, and magnesium supplementation has been shown to be an effective treatment of PMS. In one study involving 32 women with PMS, 360 mg of magnesium three times daily was given from midcycle to the onset of menstrual flow.55 Relief of premenstrual mood fluctuations and depression during magnesium treatment was significant.
A recent study designed to improve understanding of the association between magnesium and the menstrual cycle measured plasma, RBC, and mononuclear blood cell (MBC) magnesium concentrations in 26 women with confirmed PMS and in a control group of 19 women during the follicular, ovulatory, early luteal, and late luteal phases of the menstrual cycle.56 Although there were no significant differences in plasma magnesium levels between PMS patients and control subjects and there was no menstrual cycle effect on plasma magnesium, women with PMS had significantly lower RBC magnesium concentrations than those in the control group, which was consistent throughout the menstrual cycle.
The observation of low RBC magnesium concentrations in patients with PMS has now been confirmed by four independent studies. In general, it is thought that women with PMS have a “vulnerability to luteal phase mood state destabilization”56 and that chronic and enduring intracellular magnesium depletion serves as a major predisposing factor for destabilization.
In addition to emotional instability, magnesium deficiency in PMS is characterized by excessive nervous sensitivity with generalized aches and pains and a lower premenstrual pain threshold. One clinical trial of magnesium in PMS showed a reduction of nervousness in 89%, breast tenderness in 96%, and weight gain in 95% of subjects.16 In another double-blind study, high-dose magnesium supplementation (360 mg three times daily) was shown to dramatically relieve PMS-related mood changes.55
Although magnesium has been shown to be effective on its own, even better results may be achieved by combining it with vitamin B6 and other nutrients. Several studies have shown that when PMS patients are given a multivitamin/multimineral supplement containing high doses of magnesium and pyridoxine, they experience a substantial reduction in PMS symptoms.57,58
Magnesium bound to aspartate or one of the Krebs cycle intermediates (malate, succinate, fumarate, or citrate) is preferred to magnesium oxide, gluconate, sulfate, or chloride because of better absorption and fewer side effects (laxative effects).59,60
Calcium
Calcium has emerged as a common nutrient to supplement for PMS. Because calcium regulation and calcium deficiency can actually mimic some PMS symptoms, supplemental calcium has been tested as a treatment. An important multicenter clinical trial was conducted in 479 women who were given either 1200 mg of calcium carbonate or placebo for three menstrual cycles.61 A significantly lower symptom score was observed in the calcium group during the luteal phase of the cycle for both the second and third cycles. By the end of the third cycle, calcium resulted in a 48% reduction in total symptom scores from baseline compared with a 30% reduction in the placebo group. Other studies also show improvements in PMS symptomatology with calcium supplementation (1000 to 1336 mg).62,63 In one of the later studies, calcium and manganese supplementation (1336 and 5.6 mg, respectively) improved mood, concentration, and behavior. In another study, 1000 mg/day improved mood and water retention.62
Zinc
Zinc levels have been shown to be low in women with PMS.64 Zinc is required for proper action of many body hormones, including the sex hormones, as well as in the control of the synthesis and secretion of hormones. In particular, zinc serves as one of the control factors for prolactin secretion.65 When zinc levels are low, prolactin release increases, and high zinc levels inhibit this release. Hence, in high-prolactin states, zinc supplementation is very useful. An effective dose range for zinc supplementation for elevated prolactin levels in women is 30 to 45 mg in the picolinate form.
Vitamin E
Although vitamin E research concerning PMS has focused primarily on breast tenderness, significant reduction of other PMS symptoms has also been demonstrated in double-blind studies.16,66 Nervous tension, headache, fatigue, depression, and insomnia were all significantly reduced. In one double-blind study, patients receiving vitamin E (400 IU/day) demonstrated a 33% reduction in physical symptoms (such as weight gain and breast tenderness), a 38% reduction in anxiety, and a 27% reduction in depression after 3 months of use. In contrast, the placebo group reported only a 14% reduction in physical symptoms. The group taking vitamin E also noted higher energy levels, fewer headaches, and fewer cravings for sweets.
See Chapter 165 for further research on vitamin E and mastalgia.
Essential Fatty Acids
Women with PMS have been shown to exhibit essential fatty acid and prostaglandin abnormalities, the chief abnormality being a decrease in gamma-linolenic acid (GLA).67 GLA is derived from linoleic acid. This conversion requires adequate levels of vitamin B6, magnesium, and zinc, because these nutrients function in delta-6-desaturase, the key enzyme responsible for this conversion. Given that a deficiency of one or more of these nutrients is common in PMS, decreased GLA levels could almost be expected.
Evening primrose, black currant, and borage oils contain GLA, typical levels being 9%, 12%, and 22% respectively. Although these essential fatty acid sources are quite popular, the research on GLA supplements in the treatment of PMS shows no benefit over placebo. In the four double-blind crossover controlled trials of evening primrose oil, this issue may be complicated by a very high response in the placebo group.68,69 One of these studies used 3 g/day and the others used 4 g/day. A meta-analysis of the clinical trials of evening primrose oil concluded that it is of little value in the management of PMS.68
Multiple Vitamin and Mineral Supplements
• Nutritional deficiency is relatively common among women with PMS.
• High-potency multivitamin/multimineral formulations have been shown to have significant benefits in PMS.
The frequency of nutritional supplementation and the calculated intake of select nutrients have been shown to be much lower in patients with PMS than in normal women. Women with PMS have been shown to consume vitamins in their food at levels close to the recommended daily allowance, but compared with women who did not have PMS, their intake levels were only 2.2% as much for thiamin, 2.2% for riboflavin, 16.7% for niacin, 8.7% for pantothenic acid, and 2.7% for pyridoxine.16
Several double-blind studies have shown that patients with PMS who were given a multivitamin/multimineral supplement containing high doses of magnesium and pyridoxine experience reductions (typically at least a 70% reduction) in both premenopausal and postmenstrual symptoms.57,58
L-Trytophan
As discussed earlier in this chapter, decreases in serotonin may be the cause of PMS or at least may exacerbate PMS. Tryptophan is a precursor to serotonin. Studies using L-tryptophan in daily doses of 6 g/day for 17 days from ovulation to day 3 of menses has led to significant reductions in mood swings, insomnia, carbohydrate cravings, tension, irritability, and dysphoria.70,71 As 5-hydroxytryptophan (5-HTP) has shown superior results to tryptophan in depression, it may also prove to be a more effective option for raising serotonin levels in PMS. For more information, see Chapter 98.
Botanical Medicines
Vitex agnus castus (chaste tree)
The chaste tree (V. agnus castus) is native to the Mediterranean, where its berries have long been used for women’s health. Chaste berry extract is probably the single most important herb in the treatment of PMS, not only because of its long tradition and known historical uses but also as a result of modern scientific research. In two surveys of gynecologic practices in Germany, physicians graded chaste berry extract as good or very good in the treatment of PMS. More than 1500 women participated in the studies.72,73 One third of the women experienced complete resolution of their symptoms, and another 57% reported significant improvement.
In a more recent study, a randomized clinical trial compared a chaste tree standardized extract (20-mg tablet standardized for casticin) with placebo in women with PMS.74 One hundred and seventy women with PMS were assigned to take either the chaste tree or a placebo once daily for three consecutive menstrual cycles. Women were asked to rate changes in PMS symptoms, such as irritability, mood changes, anger, headache, breast tenderness, and bloating. At the end of the trial, women taking the chaste tree reported a 52% overall reduction in PMS symptoms, compared with only 24% for those taking placebo. Women taking the chaste tree extract reported significantly greater reductions in irritability, mood changes, anger, headache, and breast tenderness than the women taking the placebo. Bloating was the only symptom that did not change significantly with chaste tree. Another study has looked at the effectiveness of chaste tree extract versus fluoxetine in decreasing PMS symptoms and found the two treatments to have comparable results, with the main difference being that fluoxetine was more effective in treating psychological symptoms and chaste berry was more effective with physical symptoms.75
In more recent research, Chinese women suffering from moderate to severe PMS were studied in a prospective double-blind placebo controlled parallel-group multicenter clinical trial.76 The chaste tree extract contained 4.0 mg of dried ethanolic (70%) extract. The mean total Premenstrual Syndrome Diary (PMSD) score decreased from 29.23 at baseline to 6.41 at the end of the third cycle for the chaste tree group and from 28.14 at baseline to 12.64 at the end of the third cycle for the placebo group. The difference in the PMSD score from baseline to the third cycle was significantly lower in the treatment group than in the placebo group. The Premenstrual Tension Syndrome Self-Rating Scale decreased from 26.17 at baseline to 9.92 for the treatment group and from 27.10 to 14.59 for the placebo group—similar positive results as the PMSD scores.
PMS is also very common in perimenopausal women. A study was undertaken to evaluate the effectiveness of a combination of St. John’s wort and chaste berry in the treatment of PMS-like symptoms in perimenopausal women.77 This clinical trial was conducted over 16 weeks and information rating PMS scores in perimenopausal women who were experiencing irregular menses was collected at 4-week intervals. The daily dose of herbal products given was 3 tablets containing 5400 mg of St. John’s wort standardized to contain 990 mcg hypericins, 9 mg hyperforin, and 18 mg flavonoid glycosides. The daily dose of chaste tree was one tablet of an extract equivalent to 1000 mg of dried fruit. Participants recorded the severity of their PMS symptoms using the Abraham’s Menstrual Symptom Questionnaire. Results for the active treatment group were statistically superior to placebo for total PMS-like symptoms as well as subgroups of PMS depression and PMS food cravings.
Ginkgo biloba
Several compounds and mechanisms of Ginkgo may be involved in physical and psychological benefits for PMS (see Chapter 93). In the first randomized placebo-controlled clinical trial evaluating G. biloba extract (GBE) in PMS, 165 women of reproductive age who had fluid retention, breast tenderness, and vascular congestion were assigned to receive either a GBE of 25% Ginkgo flavone glycosides at 80 mg twice daily or a placebo from day 16 to day 5 of their cycles. Symptom diaries kept by patients and physician evaluation of symptoms demonstrated that G. biloba extract was effective against the congestive symptoms of PMS, particularly breast pain and breast tenderness.78
In a subsequent study, GBE was evaluated using Beck’s Depression Inventory, a daily symptom rating questionnaire containing 19 PMS symptoms according to DSM-IV, and items relative to the inclusion criteria included participants experiencing the symptoms for at least two consecutive cycles before the study and experienced at least 5 of the 19 symptoms for most of the time during the last week before menses. Eighty-five women completed the study. Participants were given 40 mg three times daily of a standardized GBE or a placebo from day 16 of their cycle to day 5 of their next cycle. Overall severity of symptoms in the GBE group was 34.80% before the treatment, which fell to 11.11% after the treatment. In the placebo group, the baseline severity was 34.38%, which dropped to 25.64% after intervention. The severity of the psychological and physical symptoms also declined significantly in both groups, but there was again a significant difference between the two groups, in favor of the GBE.79
Hypericum perforatum
Owing to the influence of St. John’s wort on serotonin (see Chapter 99), it should not be surprising that this herb would be an important botanical in the treatment of PMS, and research has affirmed this. A randomized double-blind placebo-controlled crossover trial of 36 women with regular menstrual cycles and mild PMS was done in which women were randomly assigned to receive St. John’s wort tablets (900 mg/day and standardized to 0.18% hypericin and 3.38% hyperforin) or placebo for two menstrual cycles.80 After a 1-month no treatment cycle, women were crossed over to the opposite group for two additional cycles. Symptoms were rated using the Daily Symptom Report, State Anxiety Inventory, Beck Depression Inventory, Aggression Questionnaire, and Barratt Impulsiveness Scale. Numerous hormones and physiologic markers were also measured in the follicular and luteal phases: follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, prolactin, testosterone, cytokine, interleukins (IL-1B, IL-6, and IL-8), interferon, and tumor necrosis factor alpha.
In a prospective, open, uncontrolled observational study, 19 women who were diagnosed with PMS completed a daily symptom rating questionnaire for one menstrual cycle and underwent a screening interview with physicians. The participants then took St. John’s wort tablets (300 mg St John’s wort standardized to 900 mcg of hypericin) for two complete menstrual cycles.81 Symptoms were rated daily by means of the Hospital Anxiety and Depression scale and modified Social Adjustment Scale, which were administered at baseline and after each of the two cycles. The degree of improvement in overall PMS scores between the beginning of the study and the end was 51%, with more than two thirds of the women having at least a 50% decrease in the severity of symptoms. The mood subscale showed the most improvement (57%); the symptoms with the greatest reductions in scores were crying (92%), depression (85%), confusion (75%), feeling out of control (72%), nervous tension (71%), anxiety (69%), and insomnia (69%).
Saffron (Crocus sativus L.)
Saffron has been previously shown to have an antidepressant effect in women with mild to moderate depression through a serotonergic mechanism, so it is not surprising that it would be beneficial in PMS. A double-blind placebo-controlled trial was done to study whether saffron could be used to relieve PMS symptoms. Fifty women of reproductive age with regular menstrual cycles and PMS symptoms for at least the last 6 months were randomly assigned to receive 15 mg of saffron twice daily or placebo twice daily for four full menstrual cycles.82 The Daily Symptom Report and the Hamilton Depression Rating Scale were used to evaluate the response. According the Daily Symptom Report, 19 of the 25 women in the saffron group responded with at least a 50% reduction in severity of symptoms versus only 2 of 25 in the placebo group (P <0.0001). A significant difference between the saffron and placebo groups occurred between the third and fourth cycles and was statistically significant by the end of the study (P <0.0001). According to the Hamilton Depression Rating Scale, 15 of 25 women in the saffron group responded to treatment versus only 1 of 25 in the placebo group. (P <0.0001). Again, a significant difference was seen between the third and fourth cycles, with a statistically significant difference by the end of the study (P <0.0001).
Bioidentical Progesterone Therapy
Bioidentical progesterone, also called natural progesterone, is a white crystalline powder most often made by extracting diosgenin from Mexican wild yam and then converting this in a manufacturing laboratory into a progesterone molecule that is biochemically identical to the body’s own progesterone. It is not wild yam, nor should it be considered an herbal product. What makes natural progesterone “natural” is not so much that it is made from plant material but rather that it is identical to the progesterone hormone produce in a woman’s ovaries. Conventional medical practitioners have historically used a synthetic version, called progestin, which is found in birth control pills as a hormonal treatment for PMS. This has largely been replaced by using select antidepressants for their effect on serotonin levels. Although bioidentical progesterone has been studied in controlled clinical trials for the treatment of PMS, efforts to consistently demonstrate the superiority of progesterone therapy over placebo have failed (possibly because there is a significant placebo response in PMS).83–88 The studies showing positive effects have used dosages of 200 to 400 mg twice daily as a vaginal or rectal suppository from 14 days before the expected onset of menstruation until the onset of vaginal bleeding.87,88 Transdermal creams of natural progesterone generally sold in natural foods/nutrition stores have been a popular self-treatment for PMS. These products vary greatly from an herbal wild yam cream only to wild yam cream with bioidentical progesterone added, up to 20 mg per ¼ tsp. Side effects are few and tend to be generally mild, but they may occur in 4% to 5% of individuals using transdermal creams that include 20 mg of USP progesterone per one quarter teaspoon. In one of the later double-blind studies that did show a positive effect for progesterone therapy (400 mg twice a day by vaginal or rectal administration), adverse events were reported by 51% of patients in the progesterone group compared with 43% in the placebo group.88 Irregularity of menstruation, vaginal itching, and headache were reported more frequently by the women taking the progesterone.
Therapeutic Approach
1. Evaluate PMS symptoms by having the patient complete a questionnaire.
2. Rule out psychiatric or other medical conditions.
3. Have the patient adopt the following dietary recommendations for PMS:
4. The patient may also benefit from the guidelines for nutritional supplementation given below.
5. Select the appropriate herbal support.
6. Establish a program for stress reduction and recommend regular exercise.
7. If, after at least three complete periods, the patient is not experiencing a significant improvement or complete resolution of symptoms, additional causative factors should be sought, as detailed above, or change made to the treatment program.
Nutritional Supplements
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