Pathophysiology of premenstrual syndrome and premenstrual dysphoric disorder

Abstract

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder are triggered by hormonal events ensuing after ovulation. The symptoms can begin in the early, mid or late luteal phase and are not associated with defined concentrations of any specific gonadal or non-gonadal hormone. Although evidence for a hormonal abnormality has not been established, the symptoms of the premenstrual disorders are related to the production of progesterone by the ovary. The two best-studied and relevant neurotransmitter systems implicated in the genesis of the symptoms are the GABArgic and the serotonergic systems. Metabolites of progesterone formed by the corpus luteum of the ovary and in the brain bind to a neurosteroid-binding site on the membrane of the gamma-aminobutyric acid (GABA) receptor, changing its configuration, rendering it resistant to further activation and finally decreasing central GABA-mediated inhibition. By a similar mechanism, the progestogens in some hormonal contraceptives are also thought to adversely affect the GABAergic system. The lowering of serotonin can give rise to PMS-like symptoms and serotonergic functioning seems to be deficient by some methods of estimating serotonergic activity in the brain; agents that augment serotonin are efficacious and are as effective even if administered only in the luteal phase. However, similar to the affective disorders, PMS is ultimately not likely to be related to the dysregulation of individual neurotransmitters. Brain imaging studies have begun to shed light on the complex brain circuitry underlying affect and behaviour and may help to explicate the intricate neurophysiological foundation of the syndrome.

Keywords

PMS PMDD pathophysiology GABA serotonin

Introduction

This article will review the current understanding of the pathophysiological mechanisms underlying the premenstrual disorders (PMDs). A secondary goal is to provide a neurophysiological foundation upon which to build an understanding of the current treatment regimens for the PMDs. The role of progesterone and neurotransmitters gamma-aminobutyric acid (GABA) and serotonin (5-HT) will be addressed in some detail. Recent brain imaging studies will also be discussed.

How is a PMD defined?

PMDs are comprised of ‘core’ PMD and ‘variants’ of PMDs, according to a consensus conference sponsored by the International Society for the Study of Premenstrual Disorders (ISSPMD).¹

The consensus definition of PMDs does not specify the nature or number of symptoms; only the timing of the symptoms and the presence of functional impairment are relevant. Symptoms must be linked to the luteal phase, beginning sometime after ovulation and ending by the end of the menstrual flow, with a symptom-free interval before the next subsequent ovulation. Core PMD is analogous to the premenstrual syndrome (PMS) as defined by the American College of Obstetricians and Gynecologists (ACOG) and the Royal College of Obstetricians and Gynecologists (RCOG) and may affect as many as 20% of ovulatory women.^2,3 A severe form of core PMD, noted to occur in approximately 5–8% of women, has been defined by the American Psychiatric Association as premenstrual dysphoric disorder (PMDD) and requires five premenstrual symptoms including at least one moderate to severely disabling affective symptom.⁴ In order to diagnose a core PMD, it is imperative that individuals demonstrate prospectively the appropriate timing of symptoms; starting after ovulation and subsequently increasing in conjunction with the rise in serum progesterone during the luteal phase, with a peak, severity of symptoms during the last five premenstrual days, with resolution of symptoms occurring 3–4 days following the onset of menstrual bleeding, and with a period of wellbeing associated with the rise in follicular phase estradiol levels. A ‘variant’ PMD is one in which the symptoms may be related to an exacerbation of an underlying somatic or mood disorder, to exogenous progestogens, to ovarian activity in the absence of ovulation or when cyclic symptoms are present without menses, as in the setting of a prior hysterectomy or endometrial ablation.

Overview of pathophysiology

Role of progesterone

Since the 1980s, the factor responsible for provoking symptoms of PMS has been attributed to the progesterone produced by the corpus luteum.⁵ During anovulatory cycles, when a corpus luteum fails to form, the symptoms of PMS are not observed.⁶ Premenarchal girls, postmenopausal women and those who have undergone bilateral oophorectomy also do not experience PMS. Nevertheless, the role of progesterone in triggering adverse symptomatology is not straightforward. For example, PMS symptoms are absent during pregnancy, in spite of high progesterone and estrogen concentrations. It is unclear how long after conception the typical PMS symptoms that are linked to the luteal phase hormonal complement will diminish.

Administration of exogenous progesterone or a progestogen can also engender symptoms akin to PMS. Postmenopausal women receiving hormonal therapy consisting of both estrogen and a progestogen may experience PMS-like complaints consisting of negative mood and somatic symptoms. These undesirable effects were investigated and have been attributed to the progestogen.⁷ In addition, PMS-like symptoms often persist even after anovulation has been induced with a hormonal contraceptive, and again it has been hypothesized that the exogenous progestogens are responsible, although the dose of estrogen may also be relevant. There are a number of studies suggesting oral contraceptive pills (OCPs), regardless of the elimination of ovulation, can be associated with ‘PMS-like’ negative affective and physical symptoms such as irritability, depression, anxiety, bloating, fatigue and breast tenderness in a subset of women.⁸

Although compelling evidence points to the role of progesterone in the pathophysiology of PMDs, it appears that the classical progesterone receptor is not involved in this process. This observation is supported by lack of reduction in physical or behavioural manifestation of PMS with administration of the progesterone receptor antagonist, mifepristone.⁹ In addition, numerous studies have been unable to provide evidence for progesterone excess or deficiency in the aetiology of PMDs. In multiple studies, measurement of serum progesterone in women with PMS compared with controls failed to show any significant differences.⁵ Finally, a series of randomized double-blinded placebo-controlled trials (RCTs) failed to show efficacy of progesterone supplementation.¹⁰

Other reproductive hormones, estradiol, testosterone, the adrenal hormones cortisol and dehydroepiandrosterone sulphate and the pituitary and thyroid hormones including prolactin and thyroxin also fail to distinguish women with PMDs from controls. Although in one study, more severe symptoms were found in cycles with higher concentrations of both estradiol and progesterone.¹¹

It appears that women with PMDs are more sensitive to developing negative mood and physical symptoms with the exposure to normal concentrations of ovarian sex steroids. Women with PMS, but not asymptomatic women, had a negative affective response to the administration of physiological doses of exogenous estradiol or progesterone after having achieved a ‘chemical menopause’ by receiving a gonadotrophin-releasing hormone (GnRH) agonist.¹²

The metabolites of progesterone (and corticosterone) have psychoactive properties and have been known for almost a century to produce sedation in animals. These effects are not mediated through the classical progesterone receptor. Given this evidence, researchers have postulated that a metabolite of progesterone may contribute to the generation of the affective and physical symptoms of PMDs through the modulation of a different receptor mechanism.

Gamma amino butyric acid

Temporal onset of PMS begins with ovulation and is likely related to progesterone production. The rising concentration of estradiol in the late follicular phase or a hormonal milieu consisting of estrogen alone fails to produce PMS symptoms. However, progesterone itself did not seem to be specifically the key, leading researchers to investigate the role of the neuroactive metabolites of progesterone that were known to affect mood and behaviour. In the ovary and the brain, progesterone is metabolized to form the potent neuroactive steroids, 3-alpha-hydroxy-5-alpha-pregnane-20-one (allopregnanolone or ALLO) and 3-alpha-hydroxy-5beta-pregnane-20-one (pregnanolone). These metabolites act as positive allosteric modulators of the GABA neurotransmitter system in the brain. The main inhibitory neurotransmitter in the brain, GABA, is a widely distributed neurotransmitter in the central nervous system (CNS) and evidently is an important regulator of stress, anxiety, vigilance, alertness and seizures.¹³

GABA is derived from glutamate, which is synthesized in series of steps by the Krebs cycle, and is then decarboxylated to GABA by the rate-limiting enzyme, glutamic acid decarboxylase, exclusively found in GABAergic neurons. GABA is then stored in vesicles found in the presynpatic terminal of GABAergic neurons. Three subtypes of GABA postsynaptic receptors have been identified: GABA_A, GABA_B and GABA_C receptors. However, it is the GABA_A receptor that is the site of action of endogenous agents such as neuroactive steroids derived from progesterone or synthesized de novo in the CNS, as well as exogenous agents such as progestogens (after metabolism to reduced steroids), benzodiazepines, barbiturates, alcohol and anticonvulsants.¹³

GABA_A receptors are transmembrane protein complexes composed of alpha, beta, delta and gamma subunits that function as ion channels. For example, when GABA binds to the GABA_A receptor it causes a conformational change in the protein complex that results in rapid and transient opening of chloride ion channels. Chloride influx results in hyperpolarization of the membrane and decreases the likelihood of depolarization by excitatory neurotransmitters. This is in contrast to the slow classical genomic effect of cystosolic activation of steroid hormone receptors. Binding of alpha reduced progesterone, corticosterone and testosterone metabolites, barbiturates, benzodiazepines at an allosteric site on the GABA_A receptor results in activation of receptor and increases neuronal inhibition via a direct and rapid mechanism as described above.¹³ Research has shown that ALLO, by binding GABA_A receptors, plays an important physiological modulatory role in changing the sensitivity of GABA_A receptors for GABA.¹³ This modulatory effect is accomplished by altering the subunit composition of the receptor, rending the receptor temporarily insensitive to modulation by neurosteroids.

These compositional alterations of the GABA_A receptor isoforms are postulated to be important in the aetiology of PMDs. Initially a deficiency of these neuroactive steroids was postulated. For example, acute treatment with ALLO has been shown to have anxiolytic, antidepressive and anticonvulsant effects. Similarly, decreased neuroactive steroids have been associated with anxious and depressive behaviour.¹⁴ Reduced progesterone metabolites such as ALLO have been measured in PMS and asymptomatic women in the luteal phase and some but not all studies have shown a deficiency or an association with mood in women with PMS.^15,16

In addition to the importance of concentration of these neuroactive metabolites in determining agonistic effect on GABA_A receptor, the duration of exposure also plays a critical role. For example, whereas acute, very short-term ALLO exposure decreases stress and anxiety, chronic exposure has been shown to produce an anxiety-like reaction.¹⁷ Decreased expression and binding to the GABA_A receptor as well as uncoupling of the receptor from anxiolytic modulators can result in increased anxiety. GABA_A receptor configuration changes after exposure to ALLO in the luteal phase such that GABA_A receptor function and modulation vary throughout the menstrual cycle. Studies completed in rodents have shown that acute and prolonged exposure as well as withdrawal from ALLO attribute to an increased in alpha-4,¹⁷ gamma-2¹⁸ and delta¹⁹ subunit of GABA_A receptors. This GABA_A plasticity subsequently results in temporarily decreased sensitivity to GABA and GABA agonists and enhances anxiety-like behavioural changes.

Although the GABA subunit studies were performed in rats, human studies using saccadic eye velocity as a proxy for GABAergic activity support the postulate that these alterations in GABA_A subunit configuration and GABAergic activity likely contribute to the negative mood symptoms associated with PMS.²⁰ Sundström and Bäckström (1998)²¹ demonstrated that administration of a selective serotonin reuptake inhibitor (SSRI) in the luteal phase to women with PMS increased the saccadic eye velocity to that of control women, suggesting a re-instatement of GABAergic sensitivity by augmenting serotonin.

Serotonin

Serotonin (5-HT, 5-hydroxytryptamine) has been implicated in the modulation of mood, eating, arousal and circadian rhythms. Serotonin depletion through dietary or pharmacological means leads to anxiety and depressive like symptoms.

The role of serotonin in PMS has been supported by various lines of evidence. PMS symptoms overlap symptoms associated with reduction in serotonin transmission.²² These symptoms include depression, mood swings, irritability, self-deprecation, poor impulse control, sleep disturbance, anxiety, aggression, decreased pain threshold, carbohydrate cravings and difficulty in concentrating. In addition, serotonergic function has been shown to be altered during the luteal phase of the menstrual cycle in women with PMS. For example, decreased platelet uptake of serotonin,²³ decreased baseline whole blood serotonin²⁴ and decreased platelet monoamine oxidase (MAO) activity²⁵ have all been shown to occur during the luteal phase of the menstrual cycle. Tryptophan loading tests in women with PMS are abnormal compared with the results for asymptomatic women.

Serotonin metabolism is also modulated in part by ovarian sex steroids. Ovarian sex steroids have also been implicated in serotonin uptake, turnover, binding and transport.²⁵

Finally, administration of drugs augmenting serotonergic neurotransmission is effective for treatment of PMDs. The role of serotonin is further supported by lack of significant improvement of PMS symptoms with antidepressants that only augment norepinephrine and not serotonin. Taken together, the evidence suggests that serotonergic dysregulation may play an important role in symptomatology of PMS and that serotonin in concert with other neurotransmitters such as GABA are important in the pathophysiology underlying the disorder.

5-HT is synthesized in serotonergic neurons. Specifically, the amino acid, tryptophan, is sequentially altered by two enzymes in the CNS. First, tryptophan hydroxylase, the rate-limiting enzyme, produces 5-hydroxytryptophan, then l-aromatic amino acid decarboxylase decarboxylates 5-hydroxytryptophan to 5-HT. 5-HT is then stored in vesicles in the presynaptic terminal, ready to be released upon arrival of nerve impulses. Once 5-HT is released into the synaptic cleft, it is subsequently inactivated primarily by reuptake through the high-affinity presynpatic membrane serotonin transporter (SERT). An important clinical target for therapeutic drugs, SERT, is the site of action of the SSRIs.

Serotonergic activity in the brain is affected by estrogen and progesterone; specifically sex steroids can modify serotonin availability at the neuronal synapses. For example, estrogen has been shown to increase degradation of MAO, enzyme responsible for oxidation of monoamines, and catechol-o-methyl-transferase (COMT), enzyme responsible for degradation of cathecolamines. Estrogen's role in increasing degradation of MAO and COMT results in augmenting action of serotonin in regulating the availability of free tryptophan in the CNS and improving clinical effect of SSRIs. In contrast, progesterone increases MAO activity, therefore decreases 5-HT availability, which may result in depressed mood.

Brain neurocircuitry

Neuroimaging studies focusing on hormonally mediated changes across the menstrual cycle and in women with PMDs compared with asymptomatic controls can provide valuable information regarding the underlying neurophysiological abnormalities in PMS and PMDD. For example, an early positron emission tomography (PET) study showed that regional cerebral blood flow in the prefrontal cortex was attenuated by pharmacological ovarian suppression, and this was subsequently normalized with estrogen or progesterone replacement.²⁶ A study employing protein magnetic resonance spectroscopy showed increased cortical GABA concentrations in the luteal phase of women with PMDD when compared with follicular phase; however, healthy subjects showed decreased cortical GABA.²⁷ The authors concluded that abnormal GABA_A receptor functioning could reduce sensitivity to GABA agonists, including neuroactive steroids such as the pregnane metabolites.²⁷ A PET study looking at serotonin-1A receptors showed significantly smaller increment in receptor binding between the follicular and the luteal phase scans in women with PMDD compared with controls.²⁸ In one study using functional magnetic resonance imaging, neural response was evaluated to an emotional Go/No-Go task designed to provoke negative emotion.²⁹ Researchers found that women with PMDD were less able than controls to inhibit incorrect responses to affectively negative words. Control subjects showed more activity during the late luteal phase compared with the follicular phase within the anterior-medial orbitofrontal cortex (OFC) and less activity in the lateral OFC, insula and posterior cingluate cortex. However, PMDD subject showed more activity in the amygdale during the late luteal compared with the follicular phase and less activity in the OFC.²⁹ This was interpreted as diminished impulse control via prefrontal ‘top-down’ modulation of the limbic system. In a more recent study, investigators desired to map functional brain abnormalities associated with negative mood states in PMDD. PET with [18F] fluorodeoxyglucose was used to assess regional cerebral metabolism across the menstrual cycle in women with PMDD and asymptomatic participants. Women with PMDD showed an increase in cerebellar activity from the follicular phase to the late luteal phase and this was correlated with worsening of mood.³⁰ The increased activity was localized primarily to cerebellar regions that have been previously described as the ‘limbic’ cerebellum. The cerebellum is rich in GABA_A receptors containing the delta and alpha subunits and as noted above, animal models suggest women with PMDs may have deficiencies in mechanisms regulating GABA subunits. The increased cerebellar activity could reflect decreased GABA-mediated inhibition during the symptomatic luteal phase.

Understanding the treatment of PMDs based on underlying pathophysiology

In this section, treatment studies will be reviewed only as they pertain to current understanding of the pathophysiology of the PMDs.

Hormonal treatment

A review of symptomatology of PMS highlights a link between rise and fall of sex steroids associated with ovulation and PMS.⁵ As noted above, PMS does not occur during anovulatory cycles or in women who have undergone bilateral oopherectomy. Thus, ovulation suppression is an area of focus for diagnostic and treatment options. Many treatment studies have focused on suppression of ovulation with OCPs, but GnRH agonists (the gonadotrophin inhibitor [danazol]), high doses of transdermal estrogen and bilateral salpingo-oophorectomy (BSO) all have positive evidence as treatment options for prevention of PMS and PMDD.

Combined oral contraceptive pills

Although the combined OCP prevents ovulation, the complex effects of estrogen and progestogens in the CNS is underscored by the fact that few RCTs have shown efficacy for PMDs. A randomized placebo-controlled trial showed that tri-phasic OCPs reduced physical symptoms but not mood symptoms associated with PMS.³¹ A study comparing tri-phasic formulation to monophasic formulation of OCPs concluded that the mono-phasic regimen is less likely to cause adverse mood changes.³² In fact, approximately 16% of women using traditional combined OCPs reported mood deterioration with only 12.3% reporting improvement and 71.4% stating that the combined OCP had no effect at all on mood.³³

Researchers have studied various formulations of OCPs in an effort to find one that would not re-introduce or mimic PMS-like symptoms. Based on the observation that PMS symptoms are linked to the rise and fall of progesterone and estradiol with ovulation and are absent during pregnancy when ovarian sex steroids are constant, one extended active pill OC regimen was subjected to RCTs for PMS and PMDD. In a recent overview of four studies evaluating continuous combined oral contraceptive (COC) use with a specific pill containing levonorgestrel (90 μg) and ethinyl estradiol (20 μg) modest but inconsistent improvements in premenstrual symptoms were noted.³⁴ Continuous COC regimens or progestogen only contraceptives that eliminate ovulation are not well studied but less than optimal efficacy may be due to the physical and mood symptoms associated with the progestogen, the estrogen dose or the break through bleeding.

Since the lack of efficacy of standard COCs in PMDs has been attributed to estrogen dose, progestogen formulation and dosing regimen, novel dosing regimens and progestogens have been studied. In traditional 21/7 oral contraceptive regimens, the seven-day hormone-free interval allows for continued hormonal fluctuation and can be associated with adverse symptoms that can mimic physical symptoms of PMS. The rise and fall of sex steroids can precipitate or worsen PMS symptoms in predisposed individuals. Early studies suggested that the reduction of PMS symptoms could be significant with a shorter pill-free interval.³⁵ Lower dosing of ethinyl estradiol may also be important for preventing PMS-like symptoms. When two COCs with the same progestogen dosing but 25 versus 35 μg of ethinyl estradiol were compared, women taking the lower dosage showed greater improvements in premenstrual mood.

Newer oral contraceptive regimens with longer active pill administration and novel progestogens can result in improved PMS symptoms. A regimen involving 24 active pills and four placebo days, combined with a progestogen with a longer half-life and a lower estradiol dose, results in more complete suppression of folliculogenesis and endogenous estradiol.³⁵ The OCP containing 20 μ of ethinyl estradiol and 3 mg of the progestogen drospirenone, in a regimen containing 24 active followed by four inactive pills (24/4 regimen), has proven to be effective in the treatment of PMDD in two prospective RCTs.^35,36 On the basis of these two trials, this COC received US Food and Drug Administration (FDA) approval for the indication of PMDD in those who desire hormonal contraception. The progestogen drospirenone is not derived from 19-nortestosterone but is an analogue of spironolactone and has antiandrogenic and antimineralocorticoid properties that may contribute to its efficacy for PMDD.

The adverse mood effects of OCPs may be related to the progestogens used in OCPs that are derivative of testosterone (19-nortestosterone). In addition, physical side-effects of OCPs including bloating and breast tenderness are in part attributed to water retention and probably related to the estrogenic component of the OCPs, possibly mediated by the renin angiotensin system. The formulation of OCPs that contain drospirenone and lower ethinyl estradiol (20 μg), consisting of 24 active pills followed by four placebo pills, have been proposed to counteract the effect of progesterone induced symptoms. In addition, OCPs with drospirenone, instead of 19-nortestosterone derived progestogens may ameliorate water retention, bloating, weight gain and breast tenderness.

GnRH analogues

A GnRH analogue is a synthetic peptide that interacts with a GnRH receptor and subsequently elicits release of follicle-stimulating hormone and leutinizing hormone from the anterior pituitary. After the initial surge of production of ovarian steroid production, it then suppresses ovarian steroid production and therefore results in a ‘medical menopause’ with its associated relief of symptoms of PMS. Several randomized controlled trials have demonstrated the efficacy of GnRH analogues in relieving symptoms of PMS.³⁷

GnRH analogues have also been proposed to differentiate symptoms of PMS or PMDD from the premenstrual exacerbation of an underlying affective disorder.¹ However, one study reported that some women who appeared to have pure PMS continue to have symptoms after GnRH exposure.³⁸ Although these women had structured clinical interviews and prospectively documented symptoms consistent with PMS, they did manifest more rapidly cycling mood symptoms throughout the premenstrual phase and therefore may have had an underlying affective disorder and not pure PMS. However, this study highlights some of the gaps in our knowledge of the role of sex steroids in the disorder.

In managing PMDs with GnRH analogues it is important to keep in mind that the ensuing hypo-estrogenic state can result in several unfavourable side-effects such as depression, anxiety, irritability, vasomotor symptoms, vaginal dryness, insomnia, headache and muscle aches, and that long-term use can result in osteoporosis and increased risk of cardiovascular disease. ‘Add-back’ treatment with estrogen can mitigate all of the above side-effects and decrease the risks but unopposed estrogen is contraindicated for extended periods of time due to the risks of endometrial hyperplasia and carcinoma. A combination of estrogen and low dose of a progestogen or tibolone, a synthetic anabolic steroid, have been shown to decrease adverse effects of GnRH without reducing efficacy. However, ‘add-back’ hormones can contribute to mood symptoms in women with severe PMS³⁸ and it is the progestogen that is most poorly tolerated. A meta-analysis on effects of tibolone has shown that it is less likely to re-introduce premenstrual symptoms when compared with cyclical estrogen and progestogen.³⁷ The lowest systemic exposure to an endometrial protective progestogen is afforded by the levonorgestrel containing intrauterine device.

Progestogens

A systematic review of RCTs using progesterone or progestogens (norethisterone, medroxyprogesterone acetate, levonorgestrel) during the luteal phase or continuously have shown that their use is ineffective in treatment of PMS and often re-stimulates the symptoms.³⁹ Progestogen-induced premenstrual disorders are now well recognized as the direct consequence of progestogen administration.⁴⁰ As mentioned above, a plausible explanation for ineffectiveness of progesterone in treatment of PMS is that progesterone metabolites via modulation of the GABA_A receptor are responsible for reinstating the symptoms of PMS even if ovulation has been eliminated with the progestogen. For many years progesterone and progestogens have been the only preparations available that are specifically licensed in the UK for managing premenstrual syndrome. This arose from the very enthusiastic non-evidence-based claims by Katharina Dalton and surprisingly this licence and their prescription have continued despite robust negative evidence for their efficacy and scientific research that fails to demonstrate any evidence of progesterone deficiency in affected women. This contrasts greatly with the situation in the US where only evidence-based licensing has occurred (SSRIs and drospirenone OCs).⁴¹

Hysterectomy and BSO

Endometrial ablation or hysterectomy does not eliminate symptoms of PMS, as the primary result of these treatments is the elimination of menstruation and preservation of ovarian function. In order to eliminate ovarian function, women may desire to proceed with bilateral oophorectomy. This approach has been shown to be effective in women with severe PMS.⁴² If BSO is being considered as a treatment modality for severe and debilitating symptoms of PMS, it may be beneficial to consider a trial of GnRH agonist first to establish the relative contributions of endocrine-related pathology as the aetiology of symptoms versus underlying psychiatric or psychosocial causes of PMS. After BSO, it is important to replace estrogen until the age of natural menopause in order to prevent the complications of premature menopause outlined above. It is important to perform a hysterectomy at the time of BSO in order to allow women to receive unopposed estrogen replacement and to avoid recurrent progestogen-induced premenstrual symptoms with the combination hormonal replacement.

Estradiol

Placebo-controlled studies have indicated the therapeutic effect of ovulation suppression by increasing plasma estradiol levels in improving symptoms of PMS. For example, percutaneous estradiol has been shown to prevent ovulation and in addition improve PMS symptoms.⁴³ Specifically, high-dose transdermal estradiol (200 μg) via the patch has been shown to prevent ovulation and reduce symptoms of PMS.⁴³ Unopposed estrogen may lead to endometrial hyperplasia and cancer but studies have shown that oral progesterone may worsen symptoms of PMS. An alternative to orally administered progestogen is use of levonorgestrel releasing intrauterine system, which circumvents issues associated with oral progestogen by having a local effect on the endometrium with minimal serum levels.

SSRIs and serotonin norepinephrine reuptake inhibitors

Numerous double-blind placebo-controlled trials have shown efficacy of serotonergic pharmacological agents for treatment of severe forms of PMS and PMDD with an on average response rate of approximately 60% in effectively controlling PMS symptoms compared with placebo.⁴⁴ ACOG currently recommends treatment with SSRIs as the drug of choice for severe PMS/PMDD. Specifically fluoxetine and sertraline have been shown to be effective in treatment of both the affective and the physical symptoms of PMDD, with improvement of quality of life and psychosocial functioning.⁴⁵ Meta-analyses of placebo-controlled trials have demonstrated that either continuous use or luteal phase use of SSRIs and serotonin norepinephrine reuptake inhibitors are effective in reducing symptoms.⁴⁶ The fact that treatment during luteal phase has been shown to be effective for fluoxetine, citalopram, sertraline and clomipramine underscores the contention that serotonergic dysregulation in PMDs may be confined to the luteal phase for fluoxetine, citalopram, sertraline and clomipramine.

Research on other CNS-acting drugs for treatment of PMS has not shown to be very effective compared with serotonergic antidepressants. As noted above, augmenting noradrenergic activity alone has not been shown to be effective in treatment of PMDD. For example, trials comparing fluoxetine to bupropion,⁴⁷ sertraline to desipramine⁴⁸ and paroxetine to maprotiline⁴⁹ have shown that augmenting noradrenergic activity alone is not effective.

The exact mechanism of action of SSRIs in ameliorating symptoms of PMS is unknown; however, researchers have partially contributed this effectiveness by increasing the CNS serotonergic activity. An additional possible mechanism of action involves ALLO. GABA has been shown to regulate the activity of 5-HT neurons through ALLO modulation of GABA_A-mediated inhibition. SSRIs have been shown to augment the reactions involved in the formation of ALLO. In one study, l-tryptophan, a precursor of serotonin that crosses the blood–brain-barrier, was administered and ALLO and pregnenolone concentrations were assessed. After l-typtophan challenge, the circulating ALLO concentrations were significantly increased in both controls and women with PMS during the luteal phase of the menstrual cycle.⁵⁰ The relationship between serotonergic activity and brain neurosteroids such as ALLO may partially explain the benefit of treatment with SSRIs in women with PMS. Efficacy data on GABA agonists such as benzodiazepine and alprazolam are conflicting. Agents that bind GABA_A receptors may not be effective for the same reason that progesterone is not useful. No other GABAergic agents have been studied and there are no GABA subunit specific pharmaceuticals currently available.

Calcium

The ovarian steroids influence calcium, magnesium and vitamin D metabolism. Specifically, estrogen plays a role in regulation of calcium metabolism, intestinal absorption and parathyroid gene expression and secretion, resulting in fluctuation across the menstrual cycle. Hypocalcaemia has been associated with many affective disturbances that are similar to the symptoms of PMS. Some evidence indicates that women with PMS have underlying calcium dysregulation with a secondary hyperparathyroidism and vitamin D deficiency. In two controlled trials, calcium carbonate 1200 mg/day in divided doses has been shown to decrease PMS symptoms.⁵¹ Ghanbari et al. (2009)⁵² showed that calcium, 500 mg twice daily, reduced fatigability, changes in appetite and depression in women with PMS.

Summary and future directions

Our conceptualization of the aetiology of the PMDS incorporates available knowledge regarding the effects of exposure to the rise and fall of estrogen and in particular, progesterone on neurotransmitters such as GABA and serotonin. However, current understanding of the neurobiological substrates of mood and behaviour are still in their infancy. Additional research is clearly needed to understand the complex effects of the menstrual cycle on the brain in asymptomatic women and those with premenstrual mood and other somatic disorders. Most mood, autoimmune and pain disorders are exacerbated in the luteal phase. Future research will continue to shed light on the myriad influences of ovarian sex steroids on the functioning of the central nervous system in health and disease.

Competing interests

None declared.

References

O'Brien

, Bäckström

, Brown

, Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus. Arch Womens Ment Health 2011;14:13–21

ACOG practice bulletin No. 15: Premenstrual syndrome. Int J Gynecol Obstet 2000:1–9

Royal College of Obstetricians and Gynecologists. Premenstrual Syndrome. Management. Green-Top Guidelines 48. RCOG Press, 2007. See www.rcog.org.uk/guidelines (last accessed 1 April 2012)

Premenstrual dysphoric disorder. In: Diagnostic and Statistical Manual of Mental Disorders. 4th edn. American Psychiatric Press. 2000:771–4

Bäckström

, Sanders

, Leask

, Davidson

, Warner

, Bancroft

. Mood, sexuality, hormones and the menstrual cycle. II. Hormone levels and their relationship to premenstrual syndrome. Psychosom Med 1983;45:503–7

Hammarbäck

, Ekholm

, Bäckström

. Spontaneous anovulation causing disappearance of cyclical symptoms in women with the premenstrual syndrome. Acta Endocrinol 1991;125:132–7

Andreen

, Sundström-Poromaa

, Bixo

, Andersson

, Nyberg

, Bäckström

. Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone. Psychoneuroendocrinology 2005;30:212–24

Oinonen

, Mazmanian

. To what extent do oral contraceptives influence mood and affect? J Affect Disord 2002;70:229–40

Chan

, Mortola

, Wood

, Yen

. Persistence of premenstrual syndrome during low-dose administration of the progesterone antagonist RU 486. Obsret Gynecol 1994;84:1001–5

10.

Sampson

. Premenstrual syndrome: a double-blind controlled trial of progesterone and placebo. Br J Psychiatry 1979;135:209–15

11.

Hammarbäck

, Damber

, Bäckström

. Relationship between symptom severity and hormone changes in patients with premenstrual syndrome. J Clin Endocrinol Metab 1989;68:125–30

12.

Schmidt

, Nieman

, Danaceau

, Adams

, Rubinow

. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med 1998;338:209–16

13.

Rupprecht

. Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 2003;28:139–68

14.

Uzunova

, Sheline

, Davis

, Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA 1998;95:3239–44

15.

Rapkin

, Morgan

, Goldman

, Brann

, Simone

, Mehesh

. Progesterone metabolite allopregnanolone in women with premenstrual syndrome. Obstet Gynecol 1997;90:709–14

16.

Wang

, Bäckström

, Sundström

, Neuroactive steroids and central nervous system disorders. Int Rev Neurobiol 2001;46:421–59

17.

Smith

, Gong

, Li

, Withdrawal from 3alpha-OH-5alpha-pregnan-20-One using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor alpha4 subunit in association with increased anxiety. J Neurosci 1998:18:5257–84

18.

Follesa

, Porcu

, Sogliano

, Changes in GABAA receptor gamma 2 subunit gene expression induced by long-term administration of oral contraceptives in rats. Neuropharmacology 2002;42:325–36

19.

Maguire

, Stell

, Rafizadeh

, Mody

. Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 2005;8:797–804

20.

Sundström

, Smith

, Gulinello

. GABA receptors, progesterone and premenstrual dysphoric disorder. Arch Womens Ment Health 2003;6:23–41

21.

Sundström

, Bäckström

. Citalopram increases pregnanolone sensitivity in patients with premenstrual syndrome: an open trial. Psychoneuroendocrinology 1998;23:73–88

22.

Rapkin

. The role of serotonin in premenstrual syndrome. Clin Obstet Gynecol 1992;35:629–36

23.

Ashby

, Carr

, Cook

, Steptoe

, Franks

. Alteration of platelet serotonergic mechanisms and monoamine oxidase activity in premenstrual syndrome. Biol Psychiatry 1988;24:225–33

24.

Rapkin

, Edelmuth

, Chang

, Reading

, McGuire

, Su

. Whole-blood serotonin in premenstrual syndrome. Obstet Gynecol 1987b;70:533–7

25.

Biegon

, McEwen

. Modulation by estradiol of serotonin receptors in brain. J Neurosci 1982;2:199–205

26.

Berman

, Schmidt

, Rubinow

, Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. Proc Natl Acad Sci USA 1997;94:8836–41

27.

Epperson

, Haga

, Mason

, Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study. Arch Gen Psychiatry 2002;59:851–8

28.

Jovanovic

, Cerin

, Karlsson

, Lundber

, Halldin

, Nordström

. A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria. Psychiatry Res 2006;148:185–93

29.

Protopopescu

, Tuescher

, Pan

, Toward a functional neuroanatomy of premenstrual dysphoric disorder. J affect Disord 2008;108:87–94

30.

Rapkin

, Berman

, Mandelkern

, Silverman

DHS

, Morgan

, London

. Neuroimaging evidence of cerebellar involvement in premenstrual dysphoric disorder. Biol Psychiatry 2011;69:374–80

31.

Graham

, Sherwin

. A prospective treatment study of premenstrual symptoms using a triphasic oral contraceptive. J Psychosom Res 1992;36:257–66

32.

Bäckström

, Hansson-Malmström

, Lindhe

, Cavalli-Björkman

, Nordenström

. Oral contraceptives in premenstrual syndrome: a randomized comparison of triphasic and monophasic preparations. Contraception 1992;46:253–68

33.

Joffee

, Cohen

, Harlow

. Impact of oral contraceptive pill use on premenstrual mood: predictors of improvement and deterioration. Am J Obstet Gynecol 2003;189:1523–30

34.

Freeman

, Halbreich

, Grubb

, An overview of four studies of a continuous oral contraceptive (levonorgestrel 90 mcg/ethinylestradiol 20 mcg) on premenstrual dysphoric disorder and premenstrual syndrome. Contraception 2011 Dec 5;Epub ahead of print.

35.

Pearlstein

, Bachmann

, Zacur

, Yonkers

. Treatment of premenstrual dysphoric disorder with a new drospirenone-containing oral contraceptive formulation. Contraception 2005;72:414–21

36.

Yonkers

, Brown

, Pearlstein

, Foegh

, Sampson-Landers

, Rapkin

. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dyphoric disorder. Obstet Gynecol 2005;106:492–501

37.

Wyatt

, Dimmock

, Ismail

, Jones

, O'Brien

PMS

. The effectiveness of GnRHa with and without ‘add-back’ therapy in treating premenstrual syndrome: a meta-analysis. BJOG 2004;111:585–93

38.

Pincus

, Alam

, Rubinow

, Bhuvaneswar

, Schmidt

. Predicting response to leuprolide of women with premenstrual dysphoric disorder by daily mood rating dynamics. J Psychiatr Res 2011;45:386–94

39.

Ford

, Lethaby

, Roberts

, Mol

. Progesterone for premenstrual syndrome. Chochrane Database Syst Rev 2009;2:CD003415

40.

Baker

, O'Brien

PMS

. Potential strategies to avoid progestogen-induced premenstrual disorders. Menopause International 2012;18:71–74

41.

Wyatt

, Dimmock

, Jones

, O'Brien

PMS

. A systematic review to assess the efficacy of progesterone and progestogens in the treatment of premenstrual syndrome. BMJ 2001;323:776–80

42.

Cronje

, Vashisht

, Studd

. Hysterectomy and bilateral oophorectomy for severe premenstrual syndrome. Hum Reprod 2004;19:2152–5

43.

Watson

, Studd

, Savvas

, Garnett

, Baber

. Treatment of severe premenstrual syndrome with oestradiol patches and cyclical oral norethisterone. Lancet 1989;2:730–2

44.

Dimmock

, Wyatt

, Jones

, O'Brien

. Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: a systematic review. Lancet 2000;356:1131–6

45.

Pearlstein

, Halbreich

, Batzar

, Psychosocial functioning in women with premenstrual dysphoric disorder before and after treatment with Sertraline or placebo. J Clin Psychiatry 2000;61:101–9

46.

Rapkin

, Winer

. The pharmacologic management of premenstrual dysphoric disorder. Expert Opin Pharmacother 2008;9:429–45

47.

Pearlstein

, Stone

, Lund

, Scheft

, Zlotnick

, Brown

. Comparison of fluoxetine, bupropion, and placebo in the treatment of premenstrual dysphoric disorder. J Clin Psychopharmacol 1997;17:261–6

48.

Freeman

, Rickels

, Sondheimer

, Wittmaack

. Sertraline versus desipramine in the treatment of premenstrual syndrome: an open-label trial. J Clin Psychiatry 1996;57:7–11

49.

Eriksson

, Hedberg

, Andersch

, Sundblad

. The serotonin reuptake inhibitor paroxetine is superior to the noradrenaline reuptake inhibitor maprotiline in the treatment of premenstrual syndrome. Neuropsychopharmacology 1995;12:167–76

50.

Rasgon

, Serra

, Biggio

, Neuroactive steroid-serotonergic interaction: responses to an intravenous L-tryptophan challenge in women with premenstrual syndrome. Eur J Endocrinol 2001;145:25–33

51.

Thys-Jacobs

, Starkey

, Bernstein

, Tian

. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol 1998;179:444–52

52.

Ghanbari

, Haghollahi

, Shariat

, Foroshani

, Ashrafi

. Effects of calcium supplement therapy in women with premenstrual syndrome. Taiwan J Obstet Gynecol 2009;48:124–9