Vitamin and trace element status

in premenstrual syndrome13
MichaelMira, BSc(Med), MB BS, PhD; Peter M Stewart, BSc(Med), MB BS;

andSuzanne FAbraham, PhD

ABSTRACF Nutritional and trace element status as measured by plasma concentrations
ofmagnesium, zinc, retinol (vitamin A), and a-tocopherol (vitamin E) and the activities of red
cell enzymes dependent on thiamin and pyridoxine (vitamin B-6) were determined in 38
women suffering premenstrual syndrome and in 23 control subjects. Blood samples were col-
lected in the premenstruum and in midfollicular phase. Diagnosis ofpremenstrual syndrome
was based on accepted retrospective criteria and on prospective symptom reports collected
over three menstrual cycles. No evidence was found to support the hypothesis that premen-
strual symptoms are caused by absolute or relative nutritional deficiencies. Am J Clin Nuir

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1988;47:636-4 1.

KEY WORDS Premenstrual syndrome, pyridoxine, thiamin, retinol, a-tocopherol, mag-

nesium, zinc

Introduction pothesis is correct one would expect to be able to detect

decreases in activity ofpyndoxal-5-phosphate (P5P)-de-
Over the last 4 y a number of vitamin and mineral pendent enzymes in tissues more accessible than the cen-
supplements have appeared on the Australian market, tral nervous system, such as erythrocyte aspartate amino
purportedly designed to alleviate premenstrual symp- transferase (EAST) (6).
toms. The use of these supplements is based on reports Possible mechanisms of action of other compounds
that women suffering premenstrual tension consume studied that alleviate premenstrual symptoms are un-
more refined sugar, refined carbohydrates, and dairy clear. Abraham (2, 3, 7) provides little theoretical sup-
products and less B-group vitamins, iron, zinc, and mag- port for the hypothesis that Mg and Zn deficiencies may
nesium than do normal women (1). This has led us to occur in premenstrual-symptom sufferers. Red blood
compare the vitamin and mineral status of women who cell Mg levels were reported to be lower in these women
have premenstrual syndrome with control subjects by than in control subjects (3). Vitamin A may affect estro-
biochemical techniques. gen metabolism (8) or thyroid function (9). Vitamin E
The vitamins considered in this study are thiamin, vi- was postulated to effect prostaglandin synthesis (10), but
tamin B-6, vitamin A, and vitamin E. The last three were no evidence was presented to support this hypothesis.
reported by Goei and Abraham (2) to play a possible role There were reports of vitamin A being an effective
in premenstrual-symptom suffering. The plasma levels treatment for premenstrual symptoms (8, 9); these stud-
of Mg and Zn were also investigated because it has been ies were done in the l950s and this potentially toxic treat-
suggested (2, 3) that deficiencies of both these minerals ment seems currently to be out of fashion. One con-
are related to premenstrual symptoms. trolled trial (10) ofadministration of a-tocopherol (vita-
Enzymes which require pyridoxine metabolites for
biological activity include dopa decarboxylase (which
I From the Department ofObstetrics and Gynaecology (MM, SFA),
produces dopamine from /-dopa) and 5-hydroxytrypto-
phan decarboxylase in the serotinin biosynthetic path- University of Sydney, and the Department of Clinical Biochemistry
(PMS), Royal Prince Alfred Hospital, Sydney, Australia.
way (4). Estrogens are hypothesized to reduce the pro-
2 Supported by Warner Lambert International and a scholarship
duction of these neurotransmitters via decreased avail-
from the National Health and Medical Research Council of Australia
ability of coenzyme as a result of increased activity of (MM).
the kynurenine-niacin metabolic pathway of tryptophan 3 Address reprint requests to Dr Michael Mira, Department of Ob-
metabolism, which also requires pyridoxal-5-phosphate, stetrics and Gynaecology, University ofSydney, NSW 2006, Australia.
and by direct inhibition of the action of pyridoxal-5- ReceivedMarch 11, 1987.
phosphate by some estrogen conjugates (5). If this hy- Accepted for publication December 21, 1987.

636 Am J C/in Nuir 1988;47:636-4l. Printed in USA. © 1988 American Society for Clinical Nutrition
 VITAMINS AND TRACE ELEMENTS IN PMS 637

mm E) to premenstrual symptom sufferers showed a TABLE 1

significant improvement in breast symptoms in the pre- Description of subjects
menstrual phase.
Premenstrual Control
In summary a number oftheories have been proposed sufferers subjects
to suggest that vitamins and minerals play a role in pre- (n=38) (n=23)
menstrual symptom suffering. In 198 1 Reid and Yen
( 1 1) stated acceptance
“. . . of any vitamin deficiency Mean SD Mean SD p
theory for PMS must await further clarification of the Age (y) 32.7 5.4 30.4 4.7 NS*
role of vitamins in hormone metabolism in humans, PercentSBWt 99.9 15.9 98.8 13.4 NS
demonstration of a vitamin deficiency in affected Parity 1.8 1.5 0.9 1.2 <0.01
patients when compared to control subjects, and the ver- Gravidity 2.5 1.8 1.2 1.3 <0.005
ification of the efficacy of vitamin therapy in large con- Age at
trolled, double blind trials.” The study reported here in- menarche (y) 1 2.7 1 .6 12.8 1 .4 NS
vestigates vitamin and mineral status of premenstrual- Duration of
symptoms 7.6 5.3 NAf NA NA
symptom sufferers by use ofbiochemical techniques.
* NS: not significant at p = 0.05

Subjects and methods t Standard body weight from reference 17.

f NA: not applicable for control subjects.
Subjects
mize hemolysis. Subjects were seated for 20 mm before vene-

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Premenstrual symptom sufferers, all of whom were seeking
treatment for their symptoms, were referred to the study by section and blood was collected at the same time ofday in both
family doctors or gynecologists. These women fulfilled criteria cycle phases. An interview was conducted at the time of blood
modified from those ofSteiner et al (12). Control subjects who collection to confirm that subjects had taken no medication or
reported minimal or no change in symptoms during the men- nutritional supplements for 2 mo before the sampling and a
strual cycle were sought from the same sources. All subjects systems review was carried out to ensure that none of the sub-
fulfilled the following criteria: 1) aged 20-45 y; 2) no history of jects had experienced a recent acute illness.
psychiatric illness, defined as a condition requiring more than Blood was collected into plastic tubes, immediately centri-
two visits to a psychiatrist, or of treatment with therapeutic fuged, and divided into aliquots for assay. Plasma progesterone
doses of psychotropic medication other than for premenstrual concentration was determined to ensure that the cycle during
symptoms; 3) no significant medical conditions from history which the luteal phase sample was collected was ovulatory. In
or on medical examination and no significant abnormalities on all cycles studied luteal phase progesterone concentration cx-
hematological or biochemical screening (including liver func- ceeded 20 nmol/L.
tion tests and plasma creatinine estimations); 4) no evidence of Plasma Mg and Zn concentrations were determined using
gynecological disease with specific reference to conditions an inductively coupled plasma quantifier (13). The activity of
likely to influence attitudes toward menstruation, for example, EAST was determined before and after addition ofP5P accord-
recurrent herpes genitalis, severe dysmenorrhea, or menorrha- ing to the method of Williams (6) and the percent activation
gia; 5) menstrual cycle lengths of23-35 d; 6) adequate, nonhor- was calculated. Erythrocyte transketolase (ETKA) activity be-
monal contraceptive practices continued for duration of the fore and after the addition of thiamin diphosphate (TPP) was
study; 7) not breast-feeding at time of study; and 8) prepared measured by the method of Williams (6) and the percent acti-
to remain medication- and nutritional supplement-free for 2 vation was determined. Plasma concentrations of retinol and
mo before collection ofblood for biochemical analysis. a-tocopherol were determined using high-performance liquid
All subjects gave informed consent. This study was approved chromatography (14, 15).
by the Ethics Committee ofthe University of Sydney.
Data analysis
Subjects were asked to complete daily a series of question-
naires about a number of commonly reported premenstrual The parametric distribution ofthe data was confirmed. Data
symptoms. A summary factor was derived that reduces 22 pay- were analyzed by paired I tests and two-sample I tests as appro-
chological symptoms to one summary factor (general mood priate.
factor) (unpublished observations). The general-mood-factor Data were analyzed accordingto the classification of subjects
scores were used to classify subjects from their prospective re- upon study entrance, subgroups ofpremenstrual sufferers pro-
ports because control subjects have frequently shown premen- spectively shown to have significantly cyclic general-mood-
strual increases in physical symptom factors. factor scores, and control subjects confirmed not to have sig-
nificantly cyclic general-mood-factor scores. Subjects were
Methods considered to have significantly cyclic factor scores ifa one-way
analysis of variance (16) showed a significant (p < 0.05) effect
Blood was collected on two occasions, the first - 5 d before
of time during the menstrual cycle on factor scores and if the
the expected onset of menses and the second 6 d after the
onset of menses. These times were chosen because results of a
factor scores were highest (indicating greatest severity) in the
pilot study indicated that symptoms were maximal at the time luteal phase.
ofthe luteal phase blood collection and because it was thought
that day six would be a hormonally stable time midway be- Results
tween fall in progesterone and preovulatory estradiol increase.
Blood was collected from a large antecubital vein (usually The characterization ofthe subjects taking part in this
the basilic) using a 19-gauge blood-collecting needle to mini- study is given in Table 1. Premenstrual-symptom
638 MIRA ET AL

‘S..

35.1

31.1
I
I

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I
1
t I
25.1
I’ I I
4,
/
‘I
I “
I /1
t ‘1
I
,

14 28 14 + 28 ‘‘ 14 28
blood blood
collection collection

FIG 1 . General mood factor scores of premenstrual-symptom sufferers (unbroken line) and control subjects
(broken line) during three menstrual cycles. Menstrual flow commences at day 1 and ovulation occurs at day 15.

sufferers were ofsignificantly higher gravidity and parity cal assays performed on the samples collected in the fol-
and had suffered symptoms an average of7.6 y. Twenty- licular phase. The only significant difference between the
six premenstrual-symptom sufferers reported that they premenstrual-symptom sufferers and the control sub-
had been previously treated with pyridoxine. The sub- jects was in the plasma concentration ofa-tocopherol (p
groups selected on the basis of presence or absence of < 0.05). No differences were detected in the activity of
significantly cyclic mood-factor scores were much red blood cell enzymes or in the plasma concentrations
smaller than the original groups. This was partly due to ofretinol, Zn, or Mg.
subjects not having three ovulatory cycles of descriptive Table 3 shows the results ofthe biochemical assays on
data collected. Thirty-two ofthe 38 premenstrual suffer- the samples collected in the luteal phase for all subjects.
ers from whom blood was collected at appropriate times No significant differences were detected. The difference
in the cycle also completed three ovulatory cycles of in plasma levels ofa-tocopherol approached significance
the descriptive study, but 20 of these women did not (p = 0.09), with the levels in the premenstrual-symptom
have significantly cyclic mood-factor scores. Twelve sufferers tending to be higher than those in the control
premenstrual-symptom sufferers who were confirmed as subjects.
having significantly cyclic mood-factor scores were stud- The effect ofcycle phase on the biochemical variables
ied as were 22 control subjects who were found not to investigated was determined using paired t tests. No sig-
have significantly cyclic mood factor scores. The charac- nificant differences were found for any ofthe variables in
teristics of these subgroups did not differ significantly either group. There was a nonsignificant trend for the
from those ofthe primary groups described above. activity of ETKA with and without the addition of TPP
Figure 1 shows the average general-mood-factor score to decrease in the luteal phase (p < 0. 10) within the
over the menstrual cycle for premenstrual-symptom premenstrual-symptom sufferers but not in the control
sufferers and control subjects. The times ofblood collec- group. There was no variation in the activation after ad-
tion are indicated. dition of TPP, nor was there evidence of any cyclic
Table 2 shows the results for all subjects of biochemi- change in any indices related to pyridoxine.
 VITAMINS AND TRACE ELEMENTS IN PMS 639

To determine ifa relative deficiency ofany ofthe com- TABLE 3

pounds investigated occurs in the luteal phase, change Results ofbiochemical assays in the luteal phase
in plasma levels or red cell enzyme activities between
Premenstrual Control
luteal and follicular phases was compared between the
sufferers subjects
premenstrual-symptom sufferers and the control group (n=38) (n=23)
by means of a two-sample test. The only
t significant
difference in the amount of change between the luteal Mean SD Mean SD p
and the follicular phase was in ETKA activity after addi- Magnesium
tion ofTPP (p 0.05).
< There was a nonsignificant trend (mmol/L) 0.79 0.07 0.80 0.07 NS*
(p = 0.08) for the activity of ETKA also to be different. Zinc
The activities tended to decrease in the luteal phase for (jmol/L) 12.0 2.3 12.1 1.7 NS
premenstrual-symptom sufferers and to increase in the Retinol
luteal phase for the control subjects. There was no (mol/L) 1.78 0.40 1.68 0.37 NS
difference in the change in percent activation. a-tocopherol

Table 4 shows the results of biochemical assays of (zmol/L) 17.8 3.8 16.2 3.2 NS
ETKA
samples collected in the follicular phase for the
(U) 0.74 0.28 0.63 0.29 NS
premenstrual-symptom sufferers who showed signifi-
(pkat/gHb) 1.86 0.71 1.59 0.73 NS
cantly cyclic general-mood-factor scores and for control
ETKA + TPP
subjects who showed no significant variation in general- (U) 0.85 0.29 0.72 0.28 NS
mood-factor scores. No significant differences were (pkat/gHb) 2.15 0.73 1.82 0.71 NS

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noted in any of the indices measured. The mean a-to- Percentactivation 17 12 18 12 NS
copherol level was again higher in premenstrual-symp- EAST
tom sufferers but did not reach significance (p = 0.07). (U) 5.0 1.3 4.9 1.2 NS
Results ofbiochemical assays on samples collected in the (pkat/g Hb) 12.6 3.28 12.4 3.03 NS
luteal phase from these subjects are shown in Table 5. EAST + P5P
Again no significant differences were detected. Compari- (U) 8.0 1.9 7.3 1.7 NS
(pkat/g Hb) 20.2 4.80 18.4 4.29 NS
Percent activation 63 34 52 27 NS
TABLE 2
* NS: not significant atp = 0.05.
Results ofbiochemical assays in the follicular phase

Premenstrual Control
sufferers subjects
son of results from follicular and luteal phases showed
(n=38) (n=23)
no cyclic effect on any of the indices measured within
Mean SD Mean SD p either ofthe subgroups. There were no significant differ-
ences between the subgroups in the changes in analyte
Magnesium
concentrations or in activities between follicular and lu-
(mmol/L) 0.80 0.07 0.80 0.06 NS*
teal phases.
Zinc
A selection bias may have affected the entry of subjects
(tmol/L) 1 1.5 2.0 12.1 1.6 NS
Retinol to this study. Because pyridoxine is commonly used as a
(imol/L) 1.74 0.38 1.69 0.41 NS treatment for premenstrual symptoms, women who re-
a-tocopherol sponded to this vitamin may have chosen not to enter a
(mol/L) 18.8 3.3 16.7 3.3 <0.05 study of other medications. To overcome this potential
ETKAt bias a subgroup of 23 premenstrual-symptom sufferers
(U) 0.64 0.24 0.70 0.26 NS who either had not received pyridoxine treatment or who
(pkat/g Hb) 1.62 0.6 1 1.77 0.66 NS had reported a beneficial effect ofthe vitamin were stud-
ETKA + TPP
ied. No significant differences in indices related to pyri-
(U) 0.73 0.27 0.82 0.27 NS
doxine were found between the luteal and follicular
(pkat/g Hb) 1.84 0.68 2.07 0.68 NS
Percent activation 16 12 20 13 NS
phases in this group nor were there any differences be-
EAST tween this group and the control subjects in either
(U) 4.84 1.0 4.77 1.3 NS the follicular or the luteal phase. There were no signifi-
(pkat/g Hb) 12.2 2.52 12. 1 3.28 NS cant differences between control and premenstrual-
EAST + P5P symptom-sufferer subgroups in the amount of change
(U) 7.42 1.60 7.43 1.54 NS between the follicular and luteal phases. Eight women
(pkat/gHb) 18.7 4.04 18.7 3.89 NS in the premenstrual-symptom-sufferer subgroup showed
Percent activation 55 27 61 34 NS significant cyclic mood factor scores. No differences in
*N5: not significant atp = 0.05. measures of pyridoxine deficiency were found for these
t ETKA, erythrocyte transketolase; TPP, thiamin diphosphate; women between the follicular and the luteal phases or
EAST, erythrocyte aspartateaminotransferase; P5P, pyridoxal-5-phos- between this group and the confirmed noncyclic control
phate. U = mol.min.gHb. subjects in either cycle phase.
640 MIRAETAL

TABLE 4 phase. This finding supported by the results reported

Results ofbiochemical assays in the follicular phase, cyclic vs here.
noncyclic subjects There are no reports in the literature of biochemical
indices of pyridoxine or thiamin status or of plasma Zn,
Cyclic Noncyclic
premenstrual control retinol, or a-tocopherol levels in premenstrual-symptom
sufferers subjects sufferers. This is surprising in view ofthe interest in pyri-
(n=12) (n=22) doxine as a treatment for premenstrual symptoms and
the publication in 1973 ofthe detailed and well-designed
Mean SD Mean SD p
study ofAdams et al (4) on the effects ofpyridoxine sup-
Magnesium plementation in women taking the oral contraceptive
(mmol/L) 0.78 0.05 0.80 0.06 NS* pill who had clinical evidence of depression and bio-
Zinc chemical evidence ofpyridoxine deficiency. Adams et al
(Mmol/L) 1 1.8 1.5 12.0 1.6 NS found that activation of erythrocyte aspartate transami-
Retinol nase correlated well with other indices ofpyridoxine de-
(mol/L) 1.66 0.32 1.70 0.41 NS ficiency. We found no significant differences between the
a-tocopherol premenstrual-symptom sufferers and control subjects in
(Mmol/L) 18.8 2.9 16.6 3.3 NS
the activation of EAST with P5P nor were any differ-
ETKA
(U) 0.74 0.33 0.70 0.26 NS
ences detected between cycle phases despite rigorous mi-
(pkat/g Hb) I .86 0.83 1.77 0.66 NS tial entry criteria, a prolonged medication-free interval
ETKA + TPP before testing, and the selection ofa subgroup of women

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(U) 0.85 0.34 0.83 0.27 NS who showed a statistically significant increase in negative
(pkat/gHb) 2.15 0.86 2.10 0.68 NS mood in the luteal phase. Further subgrouping by select-
Percentactivation 18 11 21 13 NS ing women who had never received pyridoxine treat-
EAST ment and those who reported a beneficial effect still
(U) 4.82 0.80 4.85 1.27 NS failed to show any differences from control subjects. It is
(pkat/gHb) 12.2 2.02 12.3 3.21 NS
possible that pyridoxine effects in the red cell may not
EAST + P5P
(U) 7.16 1.39 7.55 1.46 NS
(pkat/gHb) 18.1 3.51 19.1 3.69 NS
Percent activation 50 31 61 34 NS TABLES
Results ofbiochemical assays in the luteal phase, cyclic vs noncyclic
* NS: not significant at p = 0.05.
subjects

Cyclic Noncyclic
premenstrual control
Discussion suffererers subjects
(n=l2) (n=22)
The study reported here is the first systematic investi-
gation of biochemical indices of nutritional status in Mean SD Mean SD p
premenstrual-symptom sufferers and control subjects. Magnesium
Nutritional supplements have been widely promoted as (mmol/L) 0.8 1 0.08 0.80 0.07 NS*
a treatment for premenstrual symptoms but scientific Zinc
support for their use has been lacking. This study sug- (mol/L) 1 2.7 3.0 1 2. 1 1 .8 NS
gests that the effect oftreatment (ifany) with pyridoxine, Retinol
thiamin, retinol, a-tocopherol, Mg, or Zn, is pharmaco- (imo1/L) I .68 0.36 1 .70 0.38 NS
logical rather than correction ofa deficiency state. a-tocopherol
The control subjects and premenstrual-symptom (,mol/L) 18.0 4.1 16.1 3.2 NS
ETKA
sufferers were adequately matched on a number of de-
(U) 0.78 0.40 0.64 0.29 NS
scriptive indices. The criterion applied for significantly
(pkat/gHb) 1.97 1.01 1.62 0.73 NS
cyclic general mood factor scores was rigorous. Figure 1 ETKA + TPP
shows that subjects not classified as having significantly (U) 0.90 0.43 0.73 0.28 NS
cyclic general-mood-factor scores did show an increase (pkat/g Hb) 2.27 1 .09 1 .84 0.7 1 NS
in scores in the premenstruum although this increase did Percent activation 20 16 18 14 NS
not reach significance for individuals. Although the total EAST
number of women in this group is small these subjects (U) 4.9 1.5 4.8 1.2 NS
would be expected to show nutritional deficiencies if (pkat/gHb) 12.4 3.79 12.1 3.03 NS
EAST + P5P
these deficiencies are related to premenstrual-symptom
(U) 7.9 1.5 7.3 1.7 NS
suffering.
(pkat/gHb) 20.0 3.79 18.4 4.29 NS
Abraham and Lubran (3) found no difference in
Percent activation 67 34 52 28 NS
plasma Mg concentrations between premenstrual-
symptom sufferers and control subjects in the midluteal * NS: not significant at p = 0.05.
 VITAMINS AND TRACE ELEMENTS IN PMS 641

parallel effects in the central nervous system. The study The results of this study do not support a nutritional
of Adams et a! (4) suggests that this is not the case be- etiology for premenstrual syndrome. B
cause subjects with evidence of depression and pyridox-
The Department of Biochemistry, Royal Prince Alfred Hospital,
inc deficiency, most ofwhom had P5P activation values
outside two standard deviations from the control mean, performed the assays that are reported in this study.
responded to treatment with pyridoxine.
Our finding that there is no biochemical evidence for References
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ers contrasts with double-blind studies that show a bene- with PMT. J AppI Nutr l982;34:4-l 1.
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MM. Serum and red cell magnesium levels
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