Introduction

Most women of reproductive age have one or more emotional or physical symptom in the premenstrual phase of the menstrual cycle. The symptoms are mild, but 5–8% have moderate to severe symptoms that are associated with substantial distress or functional impairment. In early medical reports about this issue, clinically significant premenstrual symptoms were named premenstrual tension (PMT)¹ or premenstrual syndrome (PMS).²The WHO International Classification of Diseases (ICD) includes “premenstrual tension syndrome” under the heading “Diseases of the Genitourinary Tract”. However, like PMS and PMT, this description is not useful for the purpose of clinical diagnostics, drug labelling, or research, since it is not defined by specific criteria, and does not specify severity.Manifestations Diagnosis Of Premenstrual Essay.

Diagnosis

In the mid-1980s, a multidisciplinary US National Institutes of Health consensus conference on PMS proposed criteria that were adopted by the Diagnostic and Statistical Manual III (DSM III)³ to define the severe form of this condition. Originally entitled “late luteal phase dysphoric disorder”, it was later renamed “premenstrual dysphoric disorder” (PMDD). The diagnosis of PMDD stipulates (1) the presence of at least five luteal-phase symptoms (panel), at least one of which must be a mood symptom (ie, depressed mood, anxiety or tension, affect lability, or persistent anger and irritability); (2) two cycles of daily charting to confirm the timing of symptoms; and (3) evidence of functional impairment. Finally, symptoms must not be the exacerbation of another psychiatric condition.⁴

A problem with the PMDD diagnosis is that many women with clinically significant premenstrual symptoms do not meet full diagnostic criteria; they might not have a prominent mood symptom or the five different symptoms required as a minimum by DSM IV. The American College of Obstetrics and Gynecology (ACOG) has attempted to rectify this situation by defining moderate to severe PMS; the criteria are the presence of at least one psychological or physical symptom that causes significant impairment and is confirmed by means of prospective ratings.⁵

Despite differences between diagnostic systems, women with clinically significant PMS described in scientific reports usually correspond to those with a diagnosis of PMDD. Accordingly, in this Seminar, we use the term PMS to mean severe variants of premenstrual discomfort such as those that would meet the ACOG and most PMDD criteria. Manifestations Diagnosis Of Premenstrual Essay.t is important to note, however, that some clinicians and researchers question whether all symptoms occurring in the premenstrual phase should be regarded as parts of a single syndrome. This is because although there is general agreement that all symptoms are triggered by fluctuations in sex steroids, and thus abolished when hormonal cyclicity ends, there is no evidence that the symptoms share a common pathophysiological factor, such as an aberration in sex steroid production.

Prevalence

Most studies on the prevalence of premenstrual complaints are based on retrospective reports which, by their nature, can introduce recall bias.^6–12 However, the findings of these studies are consistent with those from the few epidemiological studies that used prospective symptom ratings.^13,14 Findings of prospective and retrospective studies suggest that 5–8% of women with hormonal cycles have moderate to severe symptoms.Manifestations Diagnosis Of Premenstrual Essay.However, some studies suggest that up to 20% of all women of fertile age have premenstrual complaints that could be regarded as clinically relevant.¹⁵

Pattern of symptom expression

The length of symptom expression varies between a few days and 2 weeks (figure 1). Symptoms often worsen substantially 6 days before, and peak at about 2 days before, menses start.^16,17 Anger and irritability are the most severe complaints and start slightly earlier than other symptoms (figure 2).¹⁶ It is not uncommon for symptoms to linger into the next menstrual cycle^16–18 but, by definition, there must be a symptom-free interval before ovulation. Typically, women have the same set of symptoms from one cycle to the next.¹⁹

Several patterns of true or apparent comorbidity can occur in a woman with premenstrual symptoms. First, she might have another psychiatric disorder at another point in her life (lifetime comorbidity). Second, she might have an ongoing psychiatric or general medical condition and concurrent premenstrual symptoms that are not part of the co-occurring disorder (concurrent comorbidity).Manifestations Diagnosis Of Premenstrual Essay.Third, she might have an ongoing psychiatric or general medical condition that becomes worse premenstrually—usually defined as premenstrual exacerbation.^4,20

Estimates for lifetime comorbidity between PMS and other mood disorders range from 30% to 70%.^12,21–23 This prevalence is higher than one would expect, even taking into consideration that mood disorders are common in women (at least 30% of women have a minor or major depressive disorder at some point in their lives); estimates of comorbidity, however, might be inflated because of an overlap in symptoms. It is notable that the risk of developing perimenopausal depression²⁴ and postnatal depression^25,26has been reported to be higher in women who have PMS, leading some to suggest that these different conditions share a vulnerability to changes in gonadal steroid concentrations.

Anxiety disorders also occur at a higher rate in women with PMS.^27,28 Women with PMS, like those with panic disorder (but in contrast to those with other mood disorders), have an increased tendency to panic when exposed to panicogenic agents such as lactate and carbon dioxide, suggesting that panic disorder and PMS share certain pathophysiological mechanisms.^27,28

Aetiology and pathophysiology

Since most women of reproductive age report at least mild premenstrual symptoms, a certain degree of discomfort during the luteal phase should probably be considered physiological rather than pathological. In evolutionary terms,²⁹ luteal mood changes could be remnants of the oestrous cycle-related fluctuations in behaviour shown by lower species with the original purpose of promoting reproduction: sexual receptivity being increased and aggression decreased when oestrogen is high before ovulation.^30–32Although aggression in rodents and other animals might not be entirely equivalent to irritability and anger in human beings, such cycle-related variations in behaviour seem likely to be related to cycle-related variations in behaviour in women.

In this context, one should consider the fact that, historically, repeated pregnancies, lactation, or malnourishment led to extended periods of amenorrhoea, a situation that has changed by advances in nutrition and with our capacity to control reproduction.³³ The result is that women today have much longer periods of cyclic fluctuations of oestrogen and progesterone with associated premenstrual symptoms. ³³

Since the most characteristic feature of PMS is the relation between symptom appearance and menstrual cyclicity, researchers have long suggested that gonadal steroids are involved in the pathophysiology.¹ In line with this notion, symptoms are absent during non-ovulatory cycles,³⁴ abolished by ovariectomy^35–37 or treatment with ovulation inhibitors,^38–41 and reinstated by administration of exogenous hormones.^42–45

How changes in sex steroid production provoke luteal symptoms, however, remains to be understood.Manifestations Diagnosis Of Premenstrual Essay.Many researchers suggest that premenstrual complaints are elicited by the drop in progesterone concentrations in the late luteal phase, and link this to changes in CNS neurotransmitters such as γ-aminobutyric acid (GABA).^46,47 This theory is, however, challenged by the fact that many women have symptoms that start at ovulation and during the early luteal phase—ie, before the fall in progesterone has started.

Moreover, for women in whom the endogenous hormonal cyclicity had been abolished by pretreatment with an agonist of gonadotropin-releasing hormone (GnRH), daily progesterone administration for a month provoked symptoms (with some delay), despite hormone concentrations remaining stable.⁴⁵ Also, if a luteal decrease in progesterone was the precipitating factor, administration of progesterone during this phase would be an effective treatment, which it is not.⁴⁸ The alternative hypothesis, that symptoms are triggered by the preovulatory peak in oestradiol, or by the postovulatory increase in progesterone, or both,^45,49 thus seems more likely. This theory does not explain, however, why symptoms begin with ovulation for some women but late into the luteal phase for others.

The importance of progesterone compared with oestrogen in triggering symptoms is equally unclear. Mood change reported by postmenopausal women taking sequential hormone replacement therapy suggests that progesterone, rather than oestrogen, is responsible for inducing dysphoria;^42,50 moreover, oestrogen exerts an antidepressant effect in women with perimenopausal depression.⁵¹ Of note, the days of the cycle during which symptoms are likely to appear are those in which progesterone dominates over oestrogen. On the other hand, oestradiol has been reported to be as effective as gestagen in provoking PMS-like complaints,⁴⁵ and the oestrogen component of hormone replacement therapy can enhance gestagen-induced dysphoria.⁵² Moreover, luteal administration of oestrogen has been reported to aggravate premenstrual symptoms,⁵³and luteal administration of an oestrogen antagonist reduces premenstrual mastalgia.⁵⁴

Evidence suggests that women with and without PMS do not differ with respect to the production of gonadal steroids,⁵⁵ indicating that PMS might instead be associated with enhanced responsive ness to normal, fluctuating concentrations of these hormones.Manifestations Diagnosis Of Premenstrual Essay.In line with this, administration of exogenous gonadal steroids provoked PMS-like symptoms after pretreatment with an ovulation inhibitor in women with PMS, but not in controls.⁴⁵

Such an enhanced tendency to have disphoria as a reult of the effects of sex steroids on the brain might be heritable, as suggested by twin studies.^56–58 Other possible risk factors for PMS are high body-mass index,⁵⁹ stress,⁷ and traumatic events.⁶⁰

With respect to hormones other than the sex steroids, thyroid indices are reported to be more variable in women with PMS than in controls.^61,62 Moreover, as in anxiety and mood disorders, changes in circadian rhythms have been noted in PMS. Some studies thus suggest that the absolute levels of hormones such as melatonin, cortisol, thyroid-stimulating hormone, and prolactin are not altered but that the timing of their excretion might be aberrant in women with PMS.⁶³

Central neurotransmission in PMS

Since mood and behavioural symptoms are key features of PMS, underlying mechanisms must involve the brain. Indeed, sex steroids easily pass the blood-brain barrier, and sex steroid receptors are abundant in many brain regions that regulate emotions and behaviour, including the amygdala and the hypothalamus.

The brain neurotransmitter serotonin is implicated in the regulation of mood and behaviour, partly because of observations made in preclinical studies, and partly because of the antidepressant and anxiety-reducing effects exerted by serotonin-facilitating drugs in human beings. This notion has also gained support from genetic studies^64,65 and from brain imaging experiments.⁶⁶

The most clear-cut change in rodents exposed to serotonin depletion is an increase in aspects of behaviour that are dependent on sex steroids—ie, aggression and sexual activity, suggesting that a major physiological role for serotonin is to modulate or dampen sex-steroid-driven behaviour.^31,67 Consistent with this, reduced libido is probably the most common side-effect of long-term treatment with serotonin reuptake inhibitors (SRIs).^68,69

Sex steroids have been shown to modulate serotonin transmission in rodents^70–72 and non-human primates,⁷³ indicating that gonadal hormones influence behaviour partly by interacting with serotonergic transmission. Alternatively, serotonin terminals could exert a dampening influence on brain areas, such as the amygdala, that are under a parallel, independent activating influence of sex steroids.  Manifestations Diagnosis Of Premenstrual Essay.

The importance of serotonin for the regulation of mood and aggression, and the probable role of serotonin in modulating sex-steroid-driven behaviour, suggest that serotonin could be involved in the pathophysiology of PMS. Support for this theory is provided by three sources of evidence. First, premenstrual symptoms are effectively dampened not only by SRIs (see below), but also by other serotonin-enhancing treatments, such as serotonin-releasing agents,^74,75 a serotonin precursor,⁷⁶ and a serotonin-receptor agonist.⁷⁷ Second, impairment in serotonergic transmission achieved by a tryptophan-free diet,⁷⁸ or by treatment with a serotonin-receptor antagonist,⁷⁹ provokes symptoms. Third, various indices of serotonergic trans mission are reported to be aberrant in women with PMS.^75,80–89

Another neurotransmitter that has been linked to PMS is the inhibitory aminoacid GABA. This theory gains support from an imaging study,⁹⁰ the fact that some progesterone metabolites interact with GABA A receptor,^46,47 and the observation that women with PMS seem to differ from controls with respect to the responsiveness of this receptor complex.⁹¹ To what extent women with PMS have an abnormal production of GABA-A-modulating progesterone metabolites, however, is a matter of controversy,^92–94 and whether modulation of GABA A activity can relieve symptoms is unclear.⁹⁵Moreover, much of the work implicating GABA in the pathophysiology of PMS is based on the assumption that premenstrual complaints are due to progesterone withdrawal, a notion that has been questioned.Notably, there are important interactions between GABAergic and serotonergic neurons;^96,97 a theory implicating GABA in the pathophysiology of PMS is thus not in conflict with the serotonin hypothesis. Further, several SRIs, which have therapeutic benefit for PMS, also have profound effects on enzymes involved in the production of progesterone metabolites that modulate GABA A receptors.^98,99

Pathophysiology of somatic symptoms

It remains unclear whether premenstrual somatic symptoms—such as breast tenderness, bloating, and joint and muscle pain—result from reduced tolerance to physical discomfort while in a dysphoric mood state, or are caused by changes in hormone-responsive tissues in the periphery. Studies have failed to confirm fluid retention or breast enlargement in women reporting these symptoms;^100,101 moreover, treatment aimed at influencing brain neurotransmission—eg, the SRIs—exerts at least some palliative effect on somatic symptoms. On the other hand, the dopamine D2 receptor agonist, bromocriptine,^102,103 or chasteberry,¹⁰⁴ which lower serum concentrations of prolactin, are effective for the treatment of premenstrual mastalgia, but not for mood symptoms. Likewise, a specific effect on premenstrual mastalgia could be achieved by luteal administration of danazol¹⁰⁵ or an oestrogen-receptor antagonist.⁵⁴

Results of some early studies suggest the involvement of aldosterone¹⁰⁶ or deoxycorticosterone, a progesterone metabolite and aldosterone agonist,^33,106 in the pathophysiology of premenstrual bloating. Given that severe abdominal bloating occurs in the absence of weight gain, any theory related to water retention is, however, called into doubt.Manifestations Diagnosis Of Premenstrual Essay.Many believe that premenstrual headache, migraine, and epilepsy should not be regarded as part of PMS, but as separate conditions. Notably, SRIs have no effect on premenstrual headache. Painful menstrual bleeding (dysmenorrhoea), endometriosis, and menopausal symptoms are often confused with PMS,¹⁰⁷ but they are separate and must be clearly distinguished as such in research and in the clinic environment.

Treatment

Before pharmacological treatment is considered, the medical history of women with presumed PMS should be investigated for conditions such as depression, dysthymic disorder, anxiety disorders, and hypothyroidism. Given the possible links between PMS and sexual abuse, as well as with post-traumatic stress disorder,⁶⁰ a history that assesses the presence of these factors, as well as domestic violence, should be obtained. Some individuals with anxiety and mood disorders, including PMS, attempt to cope with symptoms by using alcohol or illicit drugs, although these substances can provoke or worsen dysphoria and anxiety. Thus, the possible use of such substances should be addressed during the evaluation.

The diagnosis of PMS (according to ACOG criteria) and PMDD requires daily charting of symptoms over two menstrual cycles; various methods have been developed for this purpose, such as the Daily Record of Severity of Problems.¹⁰⁸ A woman with severe symptoms, however, might not be willing to accept the delay in treatment involved with such recording. However, the benefit for the patient and the clinician is that it enables a clear diagnostic distinction between PMS/PMDD on the one hand, and premenstrual exacerbation of an underlying psychiatric disorder, or a condition with no relation to the menstrual cycle, on the other.

Many treatment regimens have been touted as effective for PMS, but few are supported by clinical evidence. Since effective treatments do not necessarily reduce all symptoms equally, assessing improvement using summary scales that evaluate change in many symptoms could obscure a specific effect on a particular symptom. Given that some medications might work better for particular symptoms, treatment should be individualised according to the symptom profile.

Serotonin reuptake inhibitors (SRIs)

Many clinical trials evaluating the efficacy of an SRI for the management of PMS/PMDD have shown benefit,¹⁰⁹ the response rate usually being 60–90% for active treatment versus 30–40% for placebo.¹¹⁰ SRIs that have been shown effective are the serotonergic tricyclic antidepressant clomipramine,^111,112 the selective SRIs citalopram,¹¹³ escitalopram,¹¹⁴ fluoxetine,^115–120 paroxetine,^121–125 and sertraline,^126–130 and the serotonin and noradrenaline reuptake inhibitor venlafaxine (table).^131,132SRIs reduce both mood symptoms and somatic complaints, and they also improve quality of life and social functioning.^122,140,141 Many believe that SRIs should be regarded as first-line treatment in PMS patients with severe mood symptoms.^{142,143. Manifestations Diagnosis Of Premenstrual Essay.}

SRIs are more effective for PMS than are anti-depressants that predominantly affect noradrenergic transmission,^115,121,133 implying that the effect of SRIs in PMS is not merely an antidepressant effect. This notion is also supported by the fact that the beneficial effect of SRIs for PMS begins rapidly, whereas the antidepressant effect is slow in onset. The fast onset of action in PMS renders intermittent treatment, from midcycle to menses, a feasible alternative to continuous therapy.^{112,113,119,120,125,127,128,134,144} Data suggest that even briefer periods of active treatment are more effective than placebo.^124,145

Clinical experience suggests that most but not all women with PMS prefer intermittent treatment to continuous. SRIs administered intermittently, however, seem less effective for somatic symptoms than for mood symptoms,^{119,120,125,146} and less effective for somatic symptoms than is continuous treatment.¹²⁵

Side-effects of SRIs are usually mild. Manifestations Diagnosis Of Premenstrual Essay.ausea is very common during the first days of treatment, but vanishes after a few days. It usually does not reappear, even when the treatment is intermittent.¹²⁵ Reduced libido and anorgasmia are not uncommon, and often persist for the duration of treatment,⁶⁹ but are not present during the drug-free intervals of intermittent treatment. SRIs are not addictive, but many individuals experience discontinuation symptoms when they stop medication abruptly.¹⁶ When SRIs are used intermittently, discontinuation symptoms are seldom a problem, suggesting that 2 weeks is too short an exposure period to elicit withdrawal symptoms.^113,117,124

SRIs are approved for PMDD in the USA, Canada, and Australia, but not in Europe. The lack of a European consensus on diagnostic criteria and terminology for PMS/PMDD probably accounts in part for the fact that the European Agency for the Evaluation of Medicinal Products (EMEA) withdrew the existing licence for fluoxetine in four European countries (including the UK). They argued that there is no sharp borderline between mild PMS and PMDD, and that approval of an SRI for PMDD might lead to unwarranted medication in mild cases. Additionally, they said, PMDD is a condition that could go on for years, and that long-term trials would be needed to assess long-term tolerability. However, these same arguments could be, but have not been, applied to other long-lasting conditions—such as generalised anxiety disorder, social phobia, and dysthymic disorder—for which SRIs are approved in Europe and for which it is equally true that there is no sharp borderline between mild and severe variants.

Other psychoactive drugs

Other CNS-acting drugs tested for use in PMS do not seem to be particularly effective. Whereas lithium¹⁴⁷ and non-serotonergic antidepressants^121,133,148 have been completely ineffective, the serotonergic 5HT1-A agonist buspirone^77,149 exerts weak beneficial effects. For the high-affinity benzodiazepine, alprazolam, efficacy data are conflicting;^95,150–152 alprazolam can, however, be a helpful adjunctive treatment for women who identify premenstrual insomnia or overwhelming anxiety as important symptoms. Treatment with alprazolam should be monitored carefully because of the risk of dependence, particularly if the individual has a history of substance abuse. Manifestations Diagnosis Of Premenstrual Essay.