Perspectives in Biology and Medicine 2007 DoylePremenstrual Syndrome an evolutionary

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181

Caroline Doyle, Holly A. Swain Ewald,

and Paul W. Ewald*

Premenstrual Syndrome

an evolutionary perspective onits causes and treatment

Department of Biology, University of Louisville, Louisville, KY 40292.*Corresponding author.E-mail: [email protected].

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

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.

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

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



182

C. Doyle, H. A. Swain Ewald, and P. W. Ewald

Perspectives in Biology and Medicine

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 berecognized. 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 themenstrual 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 willbe presenting foreign antigens that could otherwise trigger destruction by a pro-



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 (Garenneand 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 hencemore 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


spring 2007 • volume 50, number 2 183



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



Table 1 INFECTIONS AND INFECTIOUS DISEASES EXACERBATED

PREMENSTRUALLY

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 bacter ia 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 virionsHepatitis 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.



186



Table 2 CHRONIC DISEASES EXACERBATED PREMENSTRUALLY

THAT HAVE SUSPECTED INFECTIOUS CAUSES

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-compulsivedisorder Streptococcus pyogenes

Lupus EBV, Toxoplasma gondii

Meniere’s disease CMV, herpes, mumps, and rubella viruses

Treponema pallidumMigraine 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.



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.





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” hypothesisis 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 suggeststhat 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 E2, 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 Witkin1990).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-

188





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 indicatinga 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 morelikely 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 todelayed effects of the growth of a causal pathogen in response to suppression of

cell-mediated immunity. Rather, reduced autoimmunity during the period of





190



Table 3 EXACERBATIONS ASSOCIATED WITH M ENSTRUAL PHASE,

HORMONAL CONTRACEPTION, AN D PREGNANCY

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-compulsivedisorder 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.



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 controlof 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 contraceptivescontaining 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





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 premenstrualperiod.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 aresult 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 clar ified.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 ongenetic 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





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 suggeststhat 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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