Premenstrual Syndrome

an evolutionary perspective on
its causes and treatment

Caroline Doyle, Holly A. Swain Ewald,

and Paul W. Ewald*

ABSTRACT Premenstrual syndrome is a collection of heterogeneous symptoms

that are attributed to hormonal fluctuations and that vary among individuals for un-
known reasons. We propose that much of what is labeled “premenstrual syndrome” is
part of a broader set of infectious illnesses that are exacerbated by cyclic changes in im-
munosuppression, which are induced by cyclic changes in estrogen and progesterone.
This cyclic defense paradigm accords with the literature on cyclic exacerbations of per-
sistent infectious diseases and chronic diseases of uncertain cause. Similar exacerbations
attributable to hormonal contraception implicate hormonal alterations as a cause of
these changes.The precise timing of these cyclic exacerbations depends on the mech-
anisms of pathogenesis and immunological control of particular infectious agents.
Insight into these mechanisms can be obtained by a comparison of timing of menstrual
exacerbations with the timing of exacerbations associated with pregnancy.

REMENSTRUAL SYNDROME (PMS) pertains to symptoms that arise or are ex-

P acerbated during the luteal phase of the menstrual cycle (the interval be-
tween ovulation and the onset of menstruation) and ameliorate after the onset
of menses (Deuster, Adera, and South-Paul 1999; Dickerson, Mazyck, and

Department of Biology, University of Louisville, Louisville, KY 40292.

* Corresponding author.
E-mail: pw.ewald@louisville.edu.

For valuable input, the authors thank C. Corbitt, L. A. Dugatkin, R. A. Goldsby, J. C. Nelson, C. A.
Swain, and A.Toth.

Perspectives in Biology and Medicine, volume 50, number 2 (spring 2007):181–202

© 2007 by The Johns Hopkins University Press

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C . D o y l e , H . A . S w a i n E w a l d , a n d P. W. E w a l d

Hunter 2003). PMS is a diagnosis of exclusion, that is, a collection of states

united by timing of symptoms and unknown etiologies. PMS therefore may be
a catch-all category for exacerbated symptoms of chronic diseases that have not
been sufficiently well characterized for their premenstrual exacerbations to be
recognized. If so, the PMS category may be largely an artifact of the inadequacy
of current knowledge about the true spectrum of chronic diseases, the causes of
chronic diseases, and the reasons why chronic diseases are exacerbated cyclically
in concert with the menstrual cycle.

Heritability and Environmental Influences

We begin by summarizing what is known about the general causes of PMS. A
balanced approach to investigating the causes of chronic illnesses requires that
each of the three major categories of causation—infectious, genetic, and nonin-
fectious environmental—be evaluated both logically and empirically (Cochran,
Ewald, and Cochran 2000; Ewald and Cochran 2000).Twin studies have yielded
only moderate correlations between PMS symptoms and genetic relatedness
(Condon 1993; Kendler et al. 1992;Treloar, Heath, and Martin 2002).These cor-
relations provide a sense of the maximal possible genetic influence rather than a
demonstration of genetic influence, because environmental correlates of genetic
relatedness have not been accounted for. Although the familial studies do not
demonstrate a genetic influence, the large amount of variation that is not expli-
cable by genetic relatedness implicates a major role for environmental influences.
Many noninfectious environmental influences have been suggested, including
tobacco smoke, alcohol, medications, caffeine, and social interactions (Deuster,
Adera, and South-Paul 1999; Rodin 1992). None of these noninfectious envi-
ronmental variables has been shown to be a cause of PMS and most would be
insufficient to account for the global and local distribution of PMS (Deuster,
Adera, and South-Paul 1999; Dickerson, Mazyck, and Hunter 2003; Janiger, Rif-
fenburgh, and Kersh 1972).
Infectious causation has been largely overlooked in studies of PMS. Persistent
infections in particular seem feasible, because immune function varies across the
menstrual cycle.This possibility will be the major focus of the rest of this article.

Immunosuppression During the Luteal Phase

We first consider changes in immunological vulnerability to infection during the
menstrual cycle. During the luteal phase of the menstrual cycle, cell-mediated
immunity is suppressed and humoral immunity is enhanced.The shift away from
cell-mediated immunity is probably an evolutionary adaptation to reduce the
chances that the immune system will destroy the developing embryo, which will
be presenting foreign antigens that could otherwise trigger destruction by a pro-

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 Premenstrual Syndrome

cess analogous to rejection of transplanted organs (Faas et al. 2000; Grossman

1985; Scarpellini et al. 1993;Trzonkowski et al. 2001). It also is associated with a
greater reliance by women than men on the cell-mediated arm of immunity and
a concordant difference in vulnerability to different infectious diseases (Garenne
and Lafon 1998). Mechanistically the shift appears to be caused largely by elevated
progesterone during the luteal phase (Clemens, Siiteri, and Stites 1979; Piccinni
et al. 1995). By stimulating production of IL-4 and IL-5 from type 2 helper T cells
(Th2 cells), progesterone promotes development of naïve T cells into Th2 cells
and thus humoral immunity (Trzonkowski et al. 2001; Wang, Campbell, and
Young 1993). By stimulating secretion of IL-4 and IL-10 from Th2 cells, proges-
terone inhibits type 1 helper T cells (Th1 cells; Goldsby et al. 2003, Piccinni et al.
1995). Suppression of Th1 cells reduces the overall production of IL-2 and inter-
feron-g from Th1 cells, and thus inhibits natural killer cells, cytotoxic T lympho-
cytes, Th1 proliferation, and phagocytosis by macrophages (Clemens, Siiteri, and
Stites 1979; Goldsby et al. 2003; Piccinni et al. 1995;White et al. 1997). IL-2 and
interferon-g inhibit humoral immunity by inhibiting Th2 cells; luteal suppression
of IL-2 and interferon-g may therefore also enhance Th2 activity during the
luteal phase. Reductions in Th1 responses are associated with less effective con-
trol of fungi, viruses, and intracellular bacteria (Boncristiano et al. 2003; Kalo-
Klein and Witkin 1991; Ottenhoff et al. 2003; Qiu et al. 2004). Infections by such
pathogens may therefore be exacerbated during the luteal phase.
Estrogen also appears to suppress cell-mediated immunity and inhibit pro-
duction of interferon-g (Salem 2004; Xiao, Liu, and Link 2004).The high estro-
gen levels that characterize the luteal phase may therefore also increase vulnera-
bility to infection by pathogens that are controlled by cell-mediated immunity.
This vulnerability appears to be lessened by a compensating effect of estrogen:
restriction of the nutrient tryptophan (Hrboticky, Leiter, and Anderson 1989;
Xiao, Liu, and Link 2004). Tryptophan restriction can suppress the growth of
viruses, bacteria, fungi, and protozoa (Adams et al. 2004; Bodaghi et al. 1999;
Bozza et al. 2005; Grohmann, Fallarino, and Puccetti 2003).
These immunological changes raise the possibility that PMS symptoms could
be manifestations of persistent infections that are less well controlled, and hence
more strongly symptomatic, during the luteal phase.Three considerations suggest
that such exacerbations should tend to occur during the late luteal (premen-
strual) phase of the menstrual cycle: (1) the cumulative duration of immunosup-
pression increases as the luteal phase progresses; (2) the response of infectious
agents to immunosuppression will inevitably involve a lag; (3) and pathogens that
are controlled by estrogen-induced tryptophan restriction may rebound during
the last few days of the luteal phase, when estrogen (and hence tryptophan
restriction) declines just prior to the decline in progesterone.
The exacerbating effect of luteal immunosuppression on infection may con-
tinue beyond the luteal phase, because restoration of immune competence at the

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onset of menstruation will not control infection instantly. Exacerbation of infec-

tion might even begin just after the onset of menstruation if the exacerbation
results from cell-mediated responses to the elevated presence of the pathogen,
rather than to the pathogen directly. If, for example, Th1-dependent responses
cause autoimmune damage, enhanced autoimmunity would be expected just
after the luteal phase when Th1-dependent immunity is restored. Damage from
inflammation would also be expected at or just after the onset of menstruation,
because inflammatory responses are suppressed during the luteal phase (Clem-
ens, Siiteri, and Stites 1979; Critchley et al. 2001, 2003).
In contrast, pathology caused by the humoral branch of the immune system
(e.g., through antibody complex formation) would be expected during the luteal
phase, because the humoral arm is not suppressed then. If the humoral response
does not control the pathogen effectively, one would expect this exacerbation to
occur increasingly during the luteal phase and during the transition into the
menstrual phase until restoration of cell-mediated immunity again controls the
pathogen.
These considerations suggest that cyclic immunological changes could cause
exacerbations of infection during the luteal and early menstrual phases.The exact
timing of these exacerbations would depend on the effects of luteal immuno-
suppression on control of infection, the pathology due to the immune system
itself, and the effectiveness of tryptophan restriction (or other effects of estrogen)
in controlling infection

Premenstrual Exacerbation of
Infectious Diseases
If the suppression of cellular immunity during the luteal phase is clinically rele-
vant, infectious diseases that are controlled by cellular immunity should show
exacerbations during the luteal phase. Evidence bearing on this expectation is
summarized in Table 1, which shows that a variety of bacterial, viral, and fungal
infections are exacerbated premenstrually.
The pathogens listed in Table 1 are either known to be controlled by cell-medi-
ated immunity or are suspected of being so controlled. Streptococcus pyogenes,
Chlamydia trachomatis, Porphyromonas gingivalis, Helicobacter pylori, and possibly Pro-
pionibacterium acnes can infect intracellularly (Boncristiano et al. 2003; Hacker and
Heeseman 2002; Lamont et al. 1995; Marouni and Sela 2004; Petersen and
Krogfelt 2003). Accordingly, the infections they cause may become exacerbated
during the luteal phase as a result of the shift from cell-mediated to humoral im-
munity. Chlamydia and Helicobacter are known to be controlled by cell-mediated
immunity (Boncristiano et al. 2003; Qiu et al. 2004). P. acnes stimulates cell-medi-
ated immunity; the tendency for progesterone to trigger acne therefore suggests
that the cell-mediated response is helping to control P. acnes (Burkhart, Burkhart,
and Lehmann 1999; Burton, Cartlidge, and Shuster 1973; Leylek et al. 1997).

184 Perspectives in Biology and Medicine

 Premenstrual Syndrome

Table 1 I NFECTIONS AND I NFECTIOUS D ISEASES E XACERBATED

P REMENSTRUALLY
Pathogen Evidence

Candida albicans Increased proliferation, recurrent vaginitis

Helicobacter pylori Exacerbated peptic ulcers
Porphyromonas gingivalis Exacerbated gingivitis
Propionibacterium acnes Increased pustule density in acne
Streptococcus pyogenes Incidence of scarlet fever
Pulmonary bacteria and viruses Incidence of pneumonia
Cytomegalovirus Increased proliferation from cervix
Human herpes simplex virus-1 Increased number of lesions
Human immunodeficiency virus-1 Increased density of RNA and virions
Hepatitis and coxsackie viruses Incidence of pancreatitis
Hepatitis A virus Incidence of hepatitis

Sources: Andreas 1961; Burton, Cartlidge, and Shuster 1973; Clark 1953; Garcia-Tamayo, Castillo, and Mar-
tinez 1982; Horner et al. 1998; Kalo-Klein and Witkin 1989; McCann and Bonci 2001; Moller et al. 1999;
Mostad et al. 2000; Mysliwska et al. 2000; Reichelderfer et al. 2000; Rosenthal and Landefeld 1990;Yana-
gawa et al. 2004;Yuen et al. 2001; for additional details see Doyle, Swain Ewald, and Ewald n.d.

The luteal-phase exacerbations summarized in Table 1 therefore accord with

the idea that luteal-phase suppression of cell-mediated immunity can cause clin-
ically detectable exacerbation of infection.
Chronic Illnesses of Suspected Infectious Origin
The causes of chronic diseases are still largely uncertain, but infectious agents
are strongly and broadly implicated (Cochran, Ewald, and Cochran 2000).When
these diseases are in fact infectious and are affected by cell-mediated immunity,
the logic of this essay dictates that they should be exacerbated perimenstrually.
A survey of the literature reveals that diseases for which infectious causes are im-
plicated but not yet demonstrated are often exacerbated perimenstrually (Table
2). As is the case with known infectious diseases that are exacerbated perimen-
strually, the candidate causes for these diseases are either known to be controlled
by cellular immunity or strongly stimulate a cellular response.
The autoimmune diseases in Table 2 deserve special attention. A causal role
for C. pneumoniae in multiple sclerosis is supported by the finding of a C. pneu-
moniae–specific peptide that cross-reacts serologically with a portion of myelin
basic protein, which is an autoimmune target in multiple sclerosis.This chlamy-
dial peptide induces a multiple sclerosis–like disease in rats (Lenz et al. 2001).The
exacerbation of multiple sclerosis symptoms during the beginning of the menses
is therefore consistent with reduced suppression of C. pneumoniae during the lu-
teal phase, followed by increased autoimmune pathology after progesterone
declines at the end of the luteal phase. At this time reactivated cellular immunity

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Table 2 C HRONIC D ISEASES E XACERBATED P REMENSTRUALLY

T HAT H AVE S USPECTED I NFECTIOUS C AUSES
Disease Suspected pathogens

Appendicitis Various bacteria and fungi

Asthma Rhinovirus, parainfluenza virus, RSV, Chla-
mydia pneumoniae, Hemophilus influenzae,
Mycoplasma pneumoniae,
Bipolar disorder BDV
Chronic fatigue syndrome Mycoplasma species
Coronary events C. pneumoniae, Pophyromonas gingivalis
Crohn’s disease Mycobacterium avium
Diabetes (type 1) Enteroviruses
Diabetes (type 2) HCV
Epilepsy CMV, EBV, HHSV 1, HHV6, Helicobacter
pylori
Fibromyalgia EBV, HCV, Mycoplasma species
Glossitis Fusobacterium nucleatum, H. pylori, Peptostrep-
tococcus micros, Prevotella melaninogenica
Irritable bowel syndrome Shigella, Salmonella, Campylobacter
Juvenile onset obsessive-compulsive
disorder Streptococcus pyogenes
Lupus EBV, Toxoplasma gondii
Meniere’s disease CMV, herpes, mumps, and rubella viruses
Treponema pallidum
Migraine headaches H. pylori
Multiple sclerosis EBV, C. pneumoniae
Osteoporosis HTLV-1, HIV, P. gingivalis
Parkinson’s disease and Parkinsonism Influenza, S. pyogenes
Psychoses BDV, HHSV 2, Influenza, T. gondii
Rheumatoid arthritis CMV, EBV, HBV, HCV, HTLV-1, H. pylori
Tourette’s syndrome S. pyogenes

Abbreviations: BDV=Borna disease virus; CMV=cytomegalovirus; EBV=Epstein-Barr virus: HBV=hepatitis

B virus; HCV=hepatitis C virus; HHSV 1=human herpes simplex virus type 1; HIV=human immunodefi-
ciency virus; HTLV-1=human T-cell lymphoma/leukemia virus type 1; RSV=respiratory syncytial virus.
Sources: Andrews, Ator, and Honrubia 1992; Arnbjörnsson 1982; Belland et al. 2004; Bergemann et al. 2002;
Bode et al. 2001; Bronner 2004; Brook 2002; Brown et al. 2004, 2005; Buka et al. 2001; Buskila 2000; Bus-
kila et al. 1997; Case and Reid 2001; Church et al. 2003; Cook et al. 1998; Dale et al. 2004; Donati et al.
2003; Duncan et al. 1993; Eeg-Olofsson et al. 2004; Fayon et al. 1999; Freymuth et al. 1999; Gall-Troselj
et al. 2001; Garcia, Henshaw, and Krall 2003; Gasbarrini et al. 1998; Hamelin et al. 2003; Harlow et al.
1998; Hatalski, Lewis, and Lipkin 1997; Hendrick, Altshuler, and Burt 1996; Kane, Sable, and Hanauer
1998; Khalili et al. 2004; Ledgerwood, Ewald, and Cochran 2003; Lee and Kanis 1994; Leibenluft 1996;
Lin and Lee 2003; McCann and Bonci 2001; Mehraein et al. 2004; Moon et al. 2004; Munger et al. 2003,
2004; Nasralla, Haier, and Nicolson 1999; Naser et al. 2004; Neal, Hebden, and Spiller 1997; Newman
et al. 2003; Okuda et al. 2004; Ostensen, Rugelsjoen, and Wigers 1997; Pulec 1977; Quinn and Marsden
1986; Rea et al. 1999; Rudge, Kowando, and Drury 1983; Salminen et al. 2004; Schachter, Cartier, and
Borzutzky 2003; Schwabe and Konkol 1992; Seta et al. 2002; Sriram, Mitchell, and Stratton 1998; Stein-
berg and Steinberg 1985; Sumaya et al. 1985; Swedo et al. 1998;Takahashi and Yamada 2001;Tan 2001;
Tanasescu et al. 1999;Terayama et al. 2003;Torrey and Yolken 2003;Williams and Koran 1997;Williams,
Lowery, and Shannon 1987;Wu et al. 2003;Yakova et al. 2005;Yell and Burge 1993; Zentilin et al. 2002;
Zorgdrager and De Keyser 1997; for additional details see Doyle, Swain Ewald, and Ewald 2007.

186 Perspectives in Biology and Medicine

 Premenstrual Syndrome

may respond to the elevated chlamydial antigen with exacerbated autoimmune

activity against cross-reactive myelin basic proteins.The perimenstrual exacerba-
tion of rheumatoid arthritis symptoms can be explained similarly by reduced
control of a causal pathogen during the luteal phase, followed by increased auto-
immune pathology when declines in progesterone remove the suppression of
cellular immunity again.
The premenstrual exacerbation of systemic lupus erythematosus (SLE)
throughout the luteal phase contrasts with the tendency for multiple sclerosis
and rheumatoid arthritis to be exacerbated only at the end of the luteal phase.
This difference accords with differences in the mechanisms of pathogenesis.
Rheumatoid arthritis and multiple sclerosis are Th1-related autoimmune disor-
ders (Verhoef et al. 1998;Whitacre et al. 1999). Accordingly, the amelioration of
symptoms coincides with the luteal phase decrease in Th1 cytokines. In contrast,
SLE is a Th2-related autoimmune disorder characterized by the pathological for-
mation of antibody complexes, and is exacerbated in the presence of Th2 cyto-
kines (Whitacre, Rheingold, and O’Looney 1999). Accordingly, exacerbations of
SLE occur throughout the luteal phase when humoral immunity and antibody
formation are enhanced.
A full explanation of the cycling of these autoimmune diseases requires an
understanding of the reasons why the immune system is altered to become self-
destructive. If an ongoing infection is to blame, the suppression of cell-mediated
immunity during the luteal phase may be an integral part of the process. In the
case of SLE, the luteal suppression of cell-mediated immunity may increase
pathogen propagation, which in turn increases the antibody production and anti-
body-complex formation. In the case of rheumatoid arthritis and multiple scle-
rosis, increased pathogen propagation may increase the number of infected cells
during most of the luteal phase and hence the intense damage upon reactivation
of autoimmune and inflammatory responses at the end of the luteal phase.
The pathology of atherosclerosis is considered to be largely attributable to in-
flammatory responses (Ridker, Hennehens, and Buring 2000).Accordingly, acute
coronary events, myocardial infarctions, and angina tend to occur within the first
week after the luteal phase (Hamelin et al. 2003; Mukamal et al. 2002).
Anti-Infectives
If PMS results from exacerbation of persistent infections, it may be amelio-
rated by antibiotic treatment.Toth et al. (1988) tested this hypothesis by treating
PMS patients with doxycycline. After one month of treatment, the PMS symp-
toms were reduced significantly in the patients receiving doxycycline, but not in
the placebo group.The placebo group then experienced a similar reduction after
they were started on antibiotics.Amelioration of PMS symptoms persisted for six
months after cessation of antibiotic treatment.

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Endocrinological Hypotheses
Cyclic expression of symptoms in concert with the menstrual cycle has some-
times been explained by hypothesizing direct effects of reproductive hormones
(Case and Reid 1998; Seeman 1996; Tan 2001). This “direct effects” hypothesis
is reasonable for benign effects such as breast enlargement or increased “water
weight,” but it seems intractable as an explanation for incapacitating symptoms
such as severe migraines, because it requires that the brain has evolved to gener-
ate such incapacitating symptoms. Genetic instructions for a brain that suffered
from such negative symptoms would tend to be weeded out by natural selection.
In contrast, the exacerbation-of-infection hypothesis proposes that PMS re-
sults from indirect effects of endocrinological changes on infectious causes of
PMS. The preceding sections deal with the possibility that these indirect effects
arise from immunosuppression, but in at least one case some evidence suggests
that the hormones could affect the pathogens directly. Candida possesses recep-
tors for estrogen and progesterone, which have been shown to be stimulators of
Candida germination, and some studies have shown that estradiol can stimulate
protein synthesis in Candida albicans (Powell, Frey, and Drutz 1983; Sobel 1985).
Progesterone also increases the levels of prostaglandin E 2, which has a stimula-
tory affect on fungal germination, supporting a direct effect of progesterone on
Candida pathogenesis. Other evidence suggests that Candida infections could be
exacerbated indirectly through immune suppression during the luteal phase.
Interferon-g, a Th1 cytokine, suppresses germination (Kalo-Klein and Witkin
1990). The suppression of Th1 immunity during the luteal phase may therefore
exacerbate Candida infections. None of these associations rule out still other
indirect effects of estrogen and progesterone, such as the alteration of the physi-
ology and biochemistry of the vaginal tract in a way that makes it more vulner-
able to Candida.

Associations with Hormonal Contraceptives

and Pregnancy
Evidence from women using hormonal contraceptives may provide an inde-
pendent test of the proposed effects of reproductive hormones on perimenstrual
symptoms of illness. Specifically, if the changes in illness during the menstrual
cycle result from changes in estrogen and progesterone, use of hormonal contra-
ceptives should alter diseases in ways that are analogous to the changes that occur
during the menstrual cycle. Approximately one-half to two-thirds of women
who begin using oral contraceptives discontinue using them within the first
year, mainly because of side effects (Berenson et al. 1997; Rosenberg and Waugh
1998). Many of these side effects are similar to symptoms of PMS, suggesting that
oral contraceptives may exacerbate the same underlying processes that are exac-
erbated in PMS. If these effects result from endocrinological influences on infec-
tion, effects of oral contraceptives on infectious diseases should mirror the peri-

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 Premenstrual Syndrome

menstrual exacerbations of infectious diseases. Table 3 shows that this is gener-

ally the case.
Exacerbations of illnesses during and after pregnancy provide another means
of evaluating the causes of the perimenstrual exacerbations. High levels of estro-
gen and progesterone and a concomitant shift from cellular immunity to hu-
moral immunity persist throughout pregnancy (Al-Shammri et al. 2004). Pro-
gesterone falls to luteal phase levels within a day after childbirth, and to pre-
ovulatory levels after several days; estrogen falls to pre-ovulatory levels by the
third day (Greenspan and Gardner 2004). Immuno-competence returns within
three weeks (Elenkov et al. 2001). Tryptophan restriction occurs throughout
pregnancy mirroring the restriction during the luteal phase of the menstrual
cycle (Shröcksnadel et al. 1996).Within a few days after birth, tryptophan restric-
tion ends, except among women with postpartum depression, perhaps indicating
a connection between postpartum depression and infection (Maes et al. 2002).
Because the duration of pregnancy is far longer than the duration of the luteal
phase, the timing of exacerbations and ameliorations of infections and illnesses
during pregnancy may clarify the mechanisms by which immune suppression
alters illness during the menstrual cycle. For example, if declines in progesterone
and estrogen cause perimenstrual changes in manifestations of illness by causing
changes in autoimmunity or by relaxation of tryptophan restriction, analogous
changes are expected after birth.
Many illnesses are altered by hormonal contraceptives as well as during preg-
nancy and the post-partum period (see Table 3, columns 1 and 3). These effects
are generally consistent with the fluctuations in illness that occur during men-
strual cycles (Table 3, column 2). The major exceptions generally involve con-
flicting results from studies of hormonal contraceptives (e.g., asthma) and stud-
ies with small sample sizes (e.g., Tourette’s syndrome). Conflicting findings may
result from the artificial nature of grouping diseases of different causes when the
cause is uncertain; asthma, for example, may be a heterogeneous category that
includes illness caused by a variety of pathogens. The importance of small sam-
ple size is illustrated by the development of evidence pertaining to appendicitis:
Arnbjörnsson (1984) found that oral contraceptive users were significantly more
likely to have gangrenous or perforated appendices, even though no trend was
found in a previous study that was based on less than half the sample size (95
versus 253 patients) (Arnbjörnsson 1982).
As was the case with exacerbations during the menstrual cycle, exacerbations
of diseases with immunological pathologies deserve special attention. Multiple
sclerosis, for example, is ameliorated during pregnancy and then becomes exac-
erbated during the postpartum period for up to three months (Poser et al. 1979).
The amelioration of multiple sclerosis throughout pregnancy indicates that its
analogous amelioration during the luteal phase is not attributable simply to
delayed effects of the growth of a causal pathogen in response to suppression of
cell-mediated immunity. Rather, reduced autoimmunity during the period of

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Table 3 E XACERBATIONS A SSOCIATED WITH M ENSTRUAL P HASE ,

H ORMONAL C ONTRACEPTION, AND P REGNANCY
Menstrual Hormonal
Pathogen or disease phase contraception Pregnancy

Candida albicans P E E
Chlamydia trachomatis P E
Neisseria gonnorrheae E
Prevotella species E E
HIV-1 P E
HPV E
Varicella zoster virus E
Acne P E*
Appendicitis P E
Asthma P E,0,A E
Bipolar disorder A
Cardiovascular events M E
Gingivitis P E E
Juvenile onset obsessive-compulsive
disorder P E E,pp
Epilepsy P E,0
Fibromyalgia P E E
Inflammatory bowel disease P E E,pp
Lupus P E E
Meniere’s disease P E E
Migraine headaches P E,0,A 0,pp
Multiple sclerosis P A pp
Osteoporosis P E* E
Pancreatitis P E E
Peptic ulcers P E
Psychoses P,M uncertain pp
Rheumatoid arthritis P pp
Tourette’s syndrome P 0

Abbreviations: A=amelioration; E=exacerbation during pregnancy or hormonal contraception; E*=exacer-

bation associated with progesterone; M=exacerbation during menstruation; P=exacerbation in premen-
strual phase; pp=exacerbation postpartum; 0=studies in which neither exacerbation nor amelioration was
found during pregnancy or hormonal contraception.
Sources: Abramowitz et al. 2003; Alstead 2002; Anbjörnsson 1984; Angelini 2002; Burkman 2001; Case and
Reid 1998, 2001; Clark 1953; Corrao et al. 1998; Couturier et al. 2003; Derimanov and Oppenheimer
1998; Dzoljic et al. 2002; Fajardo 1981; Grimes 1999; Haggarty et al. 2003; Jensen, Liljemark, and Bloom-
quist 1981; Krueger, McQuarrie, and Swinyer 1977; Lange et al. 2001; Leylek et al. 1997; Liu 1982; Louve
et al. 1989; MacGregor et al. 1990; McCann and Bonci 2001; Moore and Black 2005; Murphy et al. 2005;
Nelson and Steinberg 1987; Ostensen, Rugelsjoen, and Wigers 1997; Paffenbarger 1964; Pearson et al.
2004; Poser et al. 1979; Pugh et al. 1963; Rasgon et al. 2003; Sances et al. 2003; Schiefer 1997; Scholes
et al. 2002; Schwabe and Konkol 1992; Sinnathuray 1988; Spinillo et al. 1995;Tan 2001; Uchide et al.
1997;Vessey and Painter 2001;Vessey, Painter, and Yeates 2002;Wagner 1996;Wang et al. 2004;Yell and
Burge 1993;Ylitalo et al. 1999; for additional details see Doyle, Swain Ewald, and Ewald 2007.

190 Perspectives in Biology and Medicine

 Premenstrual Syndrome

hormone-induced immunosuppression may ameliorate multiple sclerosis, which

then becomes exacerbated upon the return of a partially effective cellular im-
mune response as the levels of suppressive hormones decline prior to the menses
and after parturition. Alternatively, both patterns could be explained by control
of causal pathogens through estrogen-induced tryptophan restriction, which
diminishes as estrogen declines prior to menstruation and after parturition. A
similar argument applies to rheumatoid arthritis. Lupus, in contrast, is exacer-
bated among oral contraceptive users and pregnant women (Nelson and Stein-
berg 1987;Yell and Burge 1993).This exacerbation is consistent with the pathol-
ogy induced by antibody complex formation and exacerbation of lupus broadly
during the luteal phase.
A tripling in cardiovascular events (venous thromboembolism, stroke, and
myocardial infarction) has been reported in women using oral contraceptives
containing higher levels of estrogen, and a seven-fold increase has been reported
for the newer progestins (Burkman 2001). The timing of the cardiovascular
events may help distinguish whether these associations are due to hormonal
effects on infection, as opposed to direct effects of reproductive hormones. If the
hormones themselves were directly causing the pathology, one would not expect
the cardiovascular events to occur during the first week of each cycle, when
women are taking pills that do not contain the hormones. If the hormones were
indirectly causing the pathology through immune suppression during the luteal
phase, followed by enhanced inflammation during the menstrual phase, one
would expect a preponderance of cardiovascular events just after the luteal phase,
when suppression of the inflammatory response ends. This association is ex-
pected from the exacerbation of cardiovascular events during the menstrual
cycle, because these exacerbations tend to occur during menstruation (Hamelin
et al. 2003; Mukamal et al. 2002).
The general consistency of the exacerbations found during the luteal phase,
hormonal contraception, and pregnancy (Table 3) lends credence to the hypoth-
esis that hormonal changes are causally involved in the symptoms that recur dur-
ing the menstrual cycle, and that these changes often involve exacerbations of
infections. The literature on hormonal contraception, however, provides rela-
tively little evidence to assess directly the hormonal effects on manifestations of
persistent infection.

An Integrated Perspective on PMS

PMS is often attributed to quirky hormonal effects or psychosomatic illness, in
contrast with “true” illnesses, which are characterized by accepted etiologic
agents—genes, germs, or noninfectious environmental factors (Rodin 1992).This
article, however, offers a more integrated perspective on PMS. Immunological
processes that suppress or exacerbate infectious diseases vary over the menstrual

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C . D o y l e , H . A . S w a i n E w a l d , a n d P. W. E w a l d

cycle. Persistent infections are exacerbated in concert with these immunological

changes, as are manifestations of diseases for which infectious causes are impli-
cated. For these diseases the accepted or suspected pathogens tend to be con-
trolled by cell-mediated immunity, which is suppressed during the premenstrual
period. This immune suppression may exacerbate infectious diseases in different
ways depending on the pathological mechanism of the infectious disease. When
the pathological mechanisms results from immunological activity, exacerbation
occurs at a time when the incriminated branch of the immune system is activated
by the infection. In lupus, for example, the pathology results from antibody com-
plex formation, and exacerbation occurs broadly over the luteal phase when
humoral immunity is active. In the case of cardiovascular events that are associ-
ated with inflammatory processes, the exacerbation peaks during the week after
the onset of menstruation, when inflammatory responses may be heightened as a
result of both the end of the cyclic suppression of inflammation and an increased
presence of pathogens that may have proliferated during the luteal phase.
The consistency between effects of hormonal contraception and menstrual
changes in hormone levels (Table 3) helps to ground these arguments.This con-
sistency implicates the change in hormones as the initial trigger of the chain of
causation, rather than simply being a correlate of cyclic symptomatic changes.
The consistency between menstrual changes and changes associated with
pregnancy provides a different kind of check. By comparing effects of immuno-
logical alterations over a nine-month period to those over a two-week period,
the mechanism of immunological effects on infection can be clarified. For exam-
ple, the amelioration of multiple sclerosis until the end of the luteal phase can-
not be attributed simply to a lag in the growth of a causative microorganism in
response to suppressed cell-mediated immunity.
It is not parsimonious to conclude that incapacitating manifestations of PMS
and the great diversity of illnesses categorized under other labels would be exac-
erbated perimenstrually by direct effects of estrogen and progesterone. Such an
explanation ignores the suppression of cellular immunity by these hormones, and
the fact that infections are known to cause these diseases or are strongly suspected
of causing them. We have found no evidence implicating hormonal effects on
genetic diseases or diseases caused by noninfectious environmental factors, unless
the pathology of these diseases is known or is suspected to involve infection, as is
the case with cystic fibrosis.The known cyclic changes in the spectrum of diseases
and pathogens are therefore well explained by effects of these immunological
changes, but not by direct effects of the hormones themselves.
This argument does not, however, exclude the possibility that reproductive
hormones may sometimes have cyclic effects on PMS symptoms that are not
attributable to infection. This possibility is most applicable to PMS manifesta-
tions that are pervasive and not incapacitating. Examples include breast enlarge-
ment, edema, insomnia, food cravings, body aches, irritability, nervousness, and

192 Perspectives in Biology and Medicine

 Premenstrual Syndrome

emotional tension. But when manifestations such as incapacitating pain interfere

with the ability of an individual to function, one must consider how a genetic
predisposition to such a handicap would withstand the culling effects of natural
selection. This argument is particularly applicable to severe manifestations of
PMS, because severe manifestations are present only in a portion of the popula-
tion, which indicates that severe manifestations are not a necessary consequence
of the hormonal fluctuations.
This consideration of perimenstrual exacerbation of suspected and known
infectious diseases provides a framework for integrating PMS with the broader
study of chronic disease. Because PMS is a diagnosis of exclusion, we can expect
that the causes of PMS will be a grab-bag mix of a variety of different illness-
producing processes.The pervasive perimenstrual exacerbations of more discrete
categories of illnesses and the linkage of these illnesses with infection suggests
that PMS may also be a collection of symptoms often caused by a heterogeneous
mix of poorly understood infections; moreover, this body of evidence suggests
that the concept of PMS may be an artifact of the inadequate knowledge about
true categories of disease and the effects of immune suppression on their expres-
sion. For example, depression is one of the most common symptoms of PMS. If
a woman has been diagnosed with bipolar disorder, an exacerbation of depres-
sion would be considered an exacerbation of bipolar disorder, but if she has not
been diagnosed as bipolar, premenstrual depression would be considered a man-
ifestation of PMS.A variety of infections could contribute to depression by aug-
menting estrogen-induced tryptophan restriction, which in turn may reduce the
synthesis of the neurotransmitter serotonin. Lowered levels of serotonin have
been strongly implicated in depression (Kandel, Schwartz, and Jessell 2000).
Besides offering a more cohesive picture of perimenstrual alterations of well-
ness, this cycling defense model of PMS provides a basis for future work by
emphasizing the need to assess whether the individual manifestations of PMS are
associated with exacerbations of infectious processes. If so, treatment of the in-
fections with anti-infectives might be an effective way of controlling PMS symp-
toms and the cellular pathology that accompanies them.

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