The premenstrual syndrome revisited

European Journal of Obstetrics & Gynecology and Reproductive Biology 130 (2007) 4–17 www.elsevier.com/locate/ejogrb

Review

The premenstrual syndrome revisited Daniel M. Campagne a,*, Ghislaine Campagne b a

Department of Personality, Evaluation and Psychological Treatment, Faculty of Psychology, UNED University, Madrid, Spain b Department of Gynaecology, Clı´nica Bella Me´dica, Altea, Spain Received 9 May 2005; received in revised form 20 April 2006; accepted 26 June 2006

Abstract More women – and their families – are affected by the physical and psychological irregularities due to premenstrual symptoms than by any other condition. Up to 90% of women of childbearing age report perceiving one or more symptoms during the days before menstruation, symptoms which can alter their behaviour and wellbeing and which, therefore, can affect their family, social and work circle. However, and notwithstanding this general prevalence, the clinical entity that in a large number of cases results from these symptoms, commonly known as the premenstrual syndrome, still lacks defined and validated contents so that recommendations of treatments backed by adequate experimental and clinical evidence are only slowly appearing. In the present paper, we review recent experimental data as to a possible aetiology of the premenstrual problem. We propose a Premenstrual Profile, i.e. a new register of symptoms, to be used for the differential diagnosis of the three forms of the premenstrual alteration. Finally, we review the evidence-based recommendations from reliable sources as regards the treatment of ‘‘normal’’ and ‘‘abnormal’’ premenstrual symptoms. # 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Premenstrual syndrome; Premenstrual Dysphoric Disorder; Ovarian cycle; Hormones; Luteal phase; Premenstrual Profile; Psychometry

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Premenstrual changes, normal or anomalous . . . . . . . . . . . . . . . . The essential symptom register . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Two full menstrual cycles means how many days? . . . . . . . 2.2. The Premenstrual Profile (D.M. Campagne, G. Campagne) . Evidence-based treatments of premenstrual anomalies . . . . . . . . . 3.1. Oral contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Spironolactone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Primrose oil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Progesterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Hysterectomy and bilateral oophorectomy . . . . . . . . . . . . . 3.6. Calcium, magnesium, Vitamin B6 supplements . . . . . . . . . 3.6.1. Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.2. Dietary habits . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.3. Phytotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Steps to take . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. Psychological treatments . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Corresponding author. E-mail address: [email protected] (D.M. Campagne). 0301-2115/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2006.06.020

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1. Premenstrual changes, normal or anomalous

Table 1 Some premenstrual symptoms

Premenstrual symptoms, those changes in mood, behaviour, physical wellbeing and body shape that appear in the days prior to menstruation are nearly omnipresent in the woman of reproductive age (Fig. 1). More than 200 have been described, and without any risk of exaggeration one can say that nearly all components of the normal functioning of a woman can be affected by the changes related to the phase of her menstrual cycle. These changes are, at times, ‘‘positive’’ and at other times ‘‘negative’’ but in most cases are both positive and negative (Table 1). How the changes are subjectively rated depends, in good measure, on social and even anthropological values that had and have their influence on the way a woman perceives the outer and her inner world. When negative premenstrual symptoms noticeably affect the wellbeing of the woman we talk of a ‘‘premenstrual syndrome’’ but, although it is a common enough term that refers to what seems an easily understood condition, it has as yet no generally accepted definition. Every person is a world in itself, and every woman has her own set of ‘‘normal’’ parameters. We must realize that although clinical diagnostics work with generalised statistical and stereotyped values, there are important differences between the homeostasis – the equilibrium of basic values – of one person and another. The levels of hormones and neuro-active substances, of the hemogram and biochemical values all have an upper and a lower threshold which give rise to innumerable combinations between all possible – still ‘‘normal’’ – variations. Medical science works with a standard model of normalcy but this model refers to a hypothetical entity that definitely does not exist in the real world. This means that the changes we are talking about affect an individual more or less dependent upon her particular homeostasis, not only insofar as her personal upper and lower thresholds go, but also dependent upon what she subjectively experiences as a ‘‘normal’’ variability between them. Moreover, when variations surpass the normal threshold, both in a positive or a negative way, the final effect on her ultimately depends upon her psycholo-

Most frequent negative symptoms

Most frequent positive symptoms

Abdominal distension Anxiety and/or stress Pain and tension in breasts Crying spells Depression

More energy Zest to finish pending matters More efficient at work More interest in things in general Sense of more control over one’s life Socially more able More libido Breast more attractive Younger face More affectionate More relaxed

Fatigue, lack of energy Less libido Unprovoked anger or irritability Problems concentrating Headaches Changes in drinking and eating patterns Oedema in extremities

More self assured

gical resources and the sensitivities or resistances that she may have developed (Table 2). The changes in many aspects of homeostatic functionality during the menstrual cycle vary from individual to individual, to such extent that they result in hundreds of symptoms and perceptions, which in their turn result in thousands of combinations, thus creating a vast personal variability of the cyclical ‘‘normalcy’’. This variability, with its subjectively rated changes, cannot be classified as a pathology or illness but should be considered for what it is: normal effects produced by the ovarian cycle of a woman of reproductive age. In other words, the nature of the premenstrual condition is based upon premenstrual symptoms being the rule. Most women experience them, thus they are ‘‘normal’’. Only in those cases where the symptoms have a decidedly negative influence on the physical, psychological and/or social functioning of a woman, therefore: when in their totality they provoke a reduction or a loss of life quality, can we speak of a premenstrual syndrome. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) contains provisional diagnostic requirements for premenstrual dysphoria that support our view that, only in those cases where this reduction of life quality gets to be a temporary complete psychological functional impairment, the presence of a Premenstrual Dysphoric Disorder (PMDD) – thus distinct from premenstrual syndrome – should be considered, and only can result in a last-resort provisional diagnosis (Table 3). Over the past 70 years, medical and psychological investigation has proposed many different theories as to the aetiology of the premenstrual experience. In the beginning the research concentrated on the obvious intuitive cause, that Table 2 Clinical identities of the premenstrual alteration Normal Abnormal

Fig. 1. Mean menstrual cycle of 28 days. Grey: luteal phase, susceptible to PMS. White: follicular phase, asymptomatic for PMS. Underlined: menstruation of 5  2 days. Italics: days especially susceptible to PMS.

Abnormal

Premenstrual symptoms Premenstrual syndrome, with marked loss of quality of life through physical and psychological impact Premenstrual Dysphoric Disorder, with functional impairment through mood or psychosomatic impact

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D.M. Campagne, G. Campagne / European Journal of Obstetrics & Gynecology and Reproductive Biology 130 (2007) 4–17

of a supposed hormonal imbalance. Then another supposition, that of psychological causal factors was included in the hypothesis in an attempt to explain why some women suffer where others in the same circumstances and with similar hormone levels do not. Adequate trials have not been able to establish any one of the many proposed biological mechanisms as a single cause of either the premenstrual syndrome or the dysphoric disorder thus indicating a multicausal origin of the problem [118]. Some of the proposed theories as to the supposed psychological factors are rather extreme. They relate PMS to neurotic women, to women with affective disorders, or to women with an abnormal personality and are in line with the never proven link between PMS and a mental disorder. That is why renowned gynaecologists, psychiatrists, psychologists and neurologists criticize the very inclusion of the premenstrual dysphoric disorder in the DSM-IV. Were PMDD proven to have a biological origin, it would not classify as a mental disorder. In any case, premenstrual syndrome is different from PMDD, as it compounds necessary biological symptoms with psychological suffering. Endocrine and gynaecological studies on PMS prior to 1983 are generally methodically unsound and heterogeneous for lack of uniform and adequate diagnostic criteria. Psychological studies suffered and suffer from the same inadequacy. Any revision of the premenstrual alteration should disregard the data from methodologically unsound investigation, because citing their conclusions only contributes to confusion. The designs of the investigations after 1983 are not always statistically sound, in which case their results should rather count as probable instead of as confirmed.

The effort of the last 20 years to identify a specific physiopathological mechanism could not establish many differences in hormone levels during the menstrual cycle of women with symptoms and those without. The levels of oestrogen, progesterone, testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactine and sex hormone-binding globulin (SHBG), as well as the increase in presence or levels of substances related to the regulation of fluids, such as aldosterone, were compared [2]. These studies included the circulating levels as well as the secretion patterns during the cycle. No connection whatsoever could be established between PMS and the endogenous metabolites of progesterone, allopregnenolone and pregnenolone [3]. However, the luteal secretion of allopregnenolone is significantly lower in PMS patients, who moreover have progesterone levels that are lower during the entire menstrual cycle [4]. Furthermore, when women with PMS are symptomatic, an abnormal reaction of the hypothalamic–pituitary–adrenal axis (HPA) to progesterone can be measured, in the sense that they do not present the activation of the HPS axis as observed in major depression [5,6]. No changes were detected in magnesium, zinc, vitamin A, vitamin E, thiamine (vitamin B1), nor in pyridoxine (vitamin B6) [7]. Some investigators had suggested relevant changes in endorphins, and that the total of luteal phase symptoms would result from the fall in endogenous opioids (which would point at an auto-addiction and later temporal abstinence), but no others were able to detect these changes in the circulating endorphins of symptomatic patients [8–10]. Although changes do appear in several biological factors, they are not always confined to the luteal phase. Apart from endorphins, these changes include the response to

Table 3 DMS-IV criteria for Premenstrual Dysphoric Disorder [1] Research criteria for Premenstrual Dysphoric Disorder A. In most menstrual cycles during the past year, five (or more) of the following symptoms were present for most of the time during the last week of the luteal phase, began to remit within a few days after the onset of the follicular phase, and were absent in the week postmenses, with at least one of the symptoms being either (1), (2), (3), or (4). (1) Markedly depressed mood, feelings of hopelessness, or self-depreciating thoughts (2) Marked anxiety, tension, feelings of being ‘‘keyed up’’ or ‘‘on edge’’ (3) Marked affective liability (e.g. feeling suddenly sad or tearful or increased sensitivity to rejection) (4) Persistent and marked anger or irritability or increase interpersonal conflicts (5) Decreased interest in usual activities (e.g. work, school, friend, hobbies) (6) Subjective sense of difficulty in concentrating (7) Lethargy, easy fatigability, or marked lack of energy (8) Marked change in appetite, overeating, or specific food cravings (9) Hypersomnia or insomnia (10) A subjective sense of being overwhelmed or out of control (11) Other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, a sensation of ‘‘bloating’’, weight gain B. The disturbance markedly interferes with work or school or with usual social activities and relationships with others (e.g. avoidance of social activities, decreased productivity and efficiency at work or school). C. The disturbance is not merely an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although it may be superimposed on any of these disorders). D. Criteria A–C must be confirmed by prospective daily ratings during at least two consecutive symptomatic cycles. (The diagnosis may be made provisionally prior to this confirmation.) Note: In menstruating females, the luteal phase corresponds to the period between ovulation and the onset of menses and the follicular phase begins with menses. In non-menstruating females (e.g. those who have had a hysterectomy), the timing of luteal and follicular phases may require measurement of circulating reproductive hormones.

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thyrotropin-releasing hormone (TRH), the secretion of melatonin, the magnesium levels of erythrocytes, the responses of human growth hormone (HGH) and cortisol to tryptophan, the cortisol response to corticotropinereleasing hormone (CRH) and the secretion of free cortisol. The pattern of secretion of cortisol was recently found to show significant differences between women with PMDD and controls [11]. Thyroid function in PMS patients is generally found to be normal and although it is not in about 10% of cases, this rate is comparable to the prevalence of sub-clinical hypothyroidism in the general population [12,13]. A convincing argument against the hypothesis that luteal phase hormonal changes are ‘‘the cause’’ of PMS comes from investigations carried out in 1990 in the National Institute of Mental Health [14]. In these studies a progesterone antagonist, RU486, was used in combination with human chorionic gonadotropin (HCG) or placebo, in order to induce bleeding at different moments of the cycle. The results show that the manipulation of the menstrual cycle had no influence in timing nor in severity of PMS symptoms, therefore, the neuroendocrine and endocrine phenomenons of the luteal phase did not appear to be the cause of the syndrome. However, recent studies suggest that progesterone and progestogens do have influence, because other types of treatments based upon them can have positive results in PMS [15]. Interesting new indications as to the aetiology of the premenstrual alteration are to be found in two recent studies that pursue a line of investigation dating back to the 1970s. In the first of these, experiments with tissue of the animal hippocampus revealed that fluctuations in endogenous steroids, especially progesterone, cause alterations of the kinetics of specific GABA receptors, provoking changes in the excitability both of the hippocampus and of behaviour. The withdrawal of progesterone provokes anxiety and susceptibility to epileptic spells [16]. This bi-modal correlation between progesterone levels and negative mood changes, as well as the possibility of attacks during the luteal phase of the menstrual cycle for women with PMS and catamenial epilepsy, respectively, has been documented before [17]. The new findings seem to identify a ‘‘progesterone withdrawal syndrome’’, the intensity whereof depends upon the presence of the GABAA receptor [117]. With regard to the second study, it is well documented that the effects of oestrogens in the brain depend upon the a and b receptors that are widely present in many neuronal structures. These receptors mediate in emotion, cognition and procreation through the noradrenergic, dopaminergic and serotonergic systems, all strongly implicated in mood disorders. The cause–effect relationship between steroids and oestrogens was studied in human tissue of the hypothalamic paraventricular nucleus. Subjects with mood disorders showed a much higher presence of corticotropineliberating hormone neurons which possess oestrogenreceptors and thus are directly modulated by this substance

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[18]. It was found that the increase in the number of these neurons is due to external factors. Another animal study, practically at the same time, discovered that only the oestrogen b receptors have anxiogenic properties [19]. As a consequence, it could be hypothesised that the mood component of PMS and PMDD could be based upon a neuronal sensibility to changes in oestrogen-levels caused by the menstrual cycle, with direct effects on the HPA axis, and aggravated depending on the relative presence of the GABAA receptor and the density and activity of oestrogen b receptors. Most recent studies show treatments based upon the different theories to have a limited and variable efficacy, which reinforces the argument that we are not dealing with a single but with a multifactorial cause. Another argument that favours this hypothesis can be found in the high placebo response in correctly designed studies. In many cases up to a 50% placebo effect was registered, whilst in other cases it was comparable to treatment. As one of us reasoned before, placebo should not be confounded with ‘‘zero’’ treatment [20]. Where it reaches significant levels, as in this case, placebo treatment should be considered a treatment without identified active substance or therapy, certainly as a treatment in view of its efficacy in an elevated number of cases. What type of treatment should placebo be considered to be? The little we know of the mechanisms through which placebo treatment acts, indicates that its effects are ample, or holistic, or multifactorial. PMS shows an extreme susceptibility to placebo and this points at an important psychosomatic component. The sensitivity to placebo, combined with the influence of social learning and conditioning, underpin the axiom that PMS should be considered to be a biosociopsychomatic syndrome, with relevant biological, psychological and social factors. Most studies continue to encounter the outsized influence of the placebo factor, sometimes up to 80%, which apparently confirms that the main part of the syndrome as perceived is due to those ‘‘other factors’’ [21,22].

2. The essential symptom register A great number of clinical symptoms of PMS have been identified, these being variable and difficult to quantify. The symptoms encompass emotions, sexual sensations, mood states, changes in social behaviour and somatic symptoms. Although a good number of questionnaires have been proposed from different disciplines, finding a reliable and objective means to observe and evaluate the internally perceived symptoms that only are expressed indirectly or tangentially – if at all – in the way of external symptoms or behaviour [23] remains difficult. The considerable possible discrepancy between the data as to cyclical changes that are recorded either retrospectively or prospectively is well documented and recognised, although results at times coincide [24–26]. In consequence, it is

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generally agreed that the register should be prospective in all cases. This requisite is the only generally accepted one, and is reflected as such in the criteria and diagnostic recommendations of the American Psychiatric Association’s DSM-IV, the National Institute of Mental Health (NIMH), the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Family Physicians (AAFP). In general, women use menstruation as a body clock or a time marker, also, easily remembered disagreeable experiences are generally attributed to a recognizable indicator. If our culture conditions women to expect premenstrual symptoms such as liquids retention, pain and emotional reactions, then that is exactly what they will report [24,27]. Is there such a thing as a specific premenstrual syndrome? A definition of PMS should consider that PMS encompasses physiological changes with changes in social behaviour, somatic symptoms and psychological problems, as if a coherent syndrome were present. Part of the problem is that all experimental methods reflect the way the creator of the method conceives PMS and that concept, in turn, is founded upon the cultural and academic baggage of the author [28]. In order to control the effect of the expectations of the investigator it is recommended that the register be a selfadministered one [29–31]. The interpretation of the results of the available studies is complicated because of the already mentioned high incidence of response to placebo. Clinical trials on PMS typically record a 30–35% of placebo responses and up to 80% when the subjects were expecting a positive result. Again, only statistically designed studies should be considered, i.e. double blind, randomised, and with a placebo control group [32]. The more than 30 symptom registers available for PMS and/or PMDD each have their defenders and detractors, but not necessarily result in a reliable basis for diagnosis [25]. As there are, as yet, no uniform diagnostic criteria but only proposed criteria, no symptom register has been technically validated. Very few of the available questionnaires comply with what are considered to be two essential criteria [33]:  The first criterion concerns rigour in data collection. Retrospective data gathering is biased, but prospective gathering may initiate an incontrollable interference of the placebo factor.  The second criterion requires that the application of the psychometric instrument cause only minimal interference with daily clinical practice. The placebo interference we referred to earlier plays a role here too. Questions arise, however, because of the excessive extension of the registers and questionnaires for PMS, which try to comply with the DSM-IV requirement that the register be daily for at least 2 months, and their long lists of symptoms [34,35]. The logistics of ensuring the daily registering of symptoms during a prolonged period of time need modern

solutions. The electronic registry has proved to be efficient and preferred by 70% of users [36]. However, an alternative that would significantly diminish the amount of data consists of registering factors - groups of symptoms - instead of every single one. For this task, the patient will need to be trained in the understanding of the global contents of each factor. Both the physician and the patient need be aware of the fact that the very act of self-registering symptoms during 2 or 3 months can have a considerable therapeutic (‘‘placebo’’) effect of just going through the routine [37]. Completing a daily symptom register helps to reduce PMS or PMDD [38]. As PMS symptoms co-occur with mood disorders, with a significant overlap that can make the distinction hard to establish clinically, diagnostic differential algorithms should be applied as early as possible.

2.1. Two full menstrual cycles means how many days? The shared basic characteristics of PMS and PMDD are: 1. cyclic symptoms; 2. severity of symptoms is relative and individual. As a consequence, DSM-IV requires that the cyclic nature be determined by way of a register during two menstrual cycles, and the NIMH proposes a criterion of an increase of at least 30% in symptom intensity. In order to collect data for PMS or PMDD during two menstrual cycles, however, a 2 months’ register is not sufficient: it should cover at least 2 months and 3 days. This is because the register must start on the first day of the cycle, being the only hard reference available of the menstrual cycle. The first day of the cycle is the first day of bleeding, thus the days of menstruation of the first registered cycle do not provide any premenstrual information, which only can appear with the next luteal phase. For this reason, one needs the days of menstruation of the second cycle to complete the first ‘‘premenstrual data cycle’’. Finally, at the end of the second month one needs to register the date of at least the first 3 days of menstruation of the third month in order to complete this second cycle. This important difference between the ovarian cycle and the cycle we need for a premenstrual register is not taken into consideration by the DMS-IV or by existing questionnaires. They are structured to register two ovarian months but not two complete premenstrual cycles. The fact that the registering of symptoms must start with the first day of bleeding even though the statistical relevance of the register does not begin until the start of the luteal phase, offers – apart from a base line – the possibility to train and let the patient get used to the routine of the daily register, without any early possible mistakes negatively affecting the definite data.

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2.2. The Premenstrual Profile (D.M. Campagne, G. Campagne) The Premenstrual Profile (Fig. 2) was developed in 2004 as a theoretical psychometric model. The value of a psychometric method such as a questionnaire or a register of symptoms is conditioned by the specific diagnostic criteria, as validated and accepted by the relevant medical discipline. In the case of the premenstrual syndrome there are no such criteria available, just suggestions, indications and proposals. In this case, moreover, the questionnaire should help to discover any apparent but false continuity in symptomatology and serve to establish the clinical distinction between common premenstrual symptoms, a premenstrual syndrome, and the premenstrual dysphoric disorder. The gradual development of questionnaires since the 1960s revealed ‘‘factors’’, groups of symptoms with the same class of manifestations. The investigation since Moos started with eight factors that were reduced to four on the basis of later studies and, finally, following Steiner and the psychometric validation offered there [39], the Premenstrual Profile considers three provisional first order factors, defined as: Factor I: Negative Mood—Includes symptoms of DSMIV categories for PMDD, nos. 1–7 and 10. Comprises: markedly depressed mood, feelings of hopelessness or self-depreciating thoughts; marked anxiety, tension, feeling of being ‘‘keyed up’’ or ‘‘on edge’’; marked affective lability (e.g. feeling suddenly sad or

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tearful or increased sensitivity to rejection); persistent and marked anger or irritability or increased interpersonal conflicts; decreased interest in usual activities (e.g. work, school, friends, hobbies); subjective sense of difficulty in concentrating; lethargy, easy fatigability, or marked lack of energy; a subjective change of being overwhelmed or out of control Factor II: Pain and Discomfort—Includes symptoms of DSM-IV categories for PMDD, nos. 8, 9, 11 (in part). Comprises: marked change in appetite, overeating, or specific food cravings; hypersomnia or insomnia; other physical symptoms, such as breast tenderness, headaches, joint or muscle pain, stomach/abdomen pain, backache. Factor III: Bloating—Includes symptoms of DSM-IV category for PMDD, no. 11 (in part). Comprises: breast swelling; a sensation of ‘‘bloating’’; oedema; weight gain. Traditional questionnaires aspire at collecting the amount of data necessary to arrive at a diagnosis by surpassing a calculated threshold but a psychometric profile such as ours is designed to collect the data needed for a well-based screening. The utility of profiles has been established in other situations where the physician does not dispose of validated diagnostic instruments, for instance, as to suicide risk due to mood alterations during pregnancy [40]. In the present case, the

Fig. 2. Example of the Premenstrual Profile. For a 28 day-menstrual cycle—with a diagnosis of PMDD. Note: The self-register form should admit cycles of up to 40 days.

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Premenstrual Profile can be defined as a prospective daily selfregister of the menstrual cycle with the objectives to: 1. Determine the cyclic nature of the three primary factors most commonly related to the premenstrual syndrome. 2. Objectively evaluate the subjective perception of these three factors. Subjective experiences are converted into objective data by a psychometric instrument such as a questionnaire. The Premenstrual Profile requires the patient to register daily her overall perception of the group of symptoms in each one of the three factors, as well as to indicate if the symptoms are extreme or bad enough to prevent her from performing her daily tasks. The resulting objective data are then tested with the ‘‘substantial increase’’ criterion of the NIMH (and others like Rubinow and Steiner), that asks for a 30 to 50% increase of the perceived symptoms in the luteal phase and their subsequent comparable decrease once the follicular phase commences. The Premenstrual Profile is meant to gather data over at least two menstrual cycles plus 1 week so that it will reflect the subjective changes in the three groups of symptoms during two ‘‘premenstrual cycles’’ that is, two entire luteal phases and their returns to the follicular phase. The Premenstrual Profile has been provisionally validated in a mixed nationality sample N = 20. Validation in English Instructions: see Table 7 is pending.

3. Evidence-based treatments of premenstrual anomalies Every physiological theory about the aetiology of PMS has resulted in proposals for treatment. According to a 1997 revision, the relevant studies did not come up with any specific benefit superior to placebo of the following therapeutic modalities [41]:        

oral contraceptives; vitamin B6; bromocriptine; monoamine oxidase inhibitors; synthetic progestagens; spironolactone; primrose oil; progesterone.

The apparently negative results of the studies do not necessarily imply that these substances do not produce any therapeutic effect, just that the placebo effect can be as high as the medical effect of the treatment [42]. The therapeutic recommendations as commented hereafter are examples of the difficult duality between presently available inconclusive experimental data and the possibilities derived from clinical data.

3.1. Oral contraceptives The ACOG recommends the use of oral contraceptives to treat premenstrual problems, though studies have only shown certain specific effects that, however, remain without a clear scientific explanation. Numerous studies question the efficacy of oral contraceptives as a treatment for PMS [43], especially insofar as mood symptoms go [44] but newer multicentre studies with modern low-dose contraceptives (desogestrel, levonorgestrel, drospirenone) affirm that some reduce dysmenorrhea and PMS in general, whilst others have a positive effect on a wide range of physical effects [45–47]. 3.2. Spironolactone Many theoreticians and also clinicians recommend spironolactone, a diuretic with antiandrogenic and antimineralocorticoid properties, on the grounds of it being an antagonist of steroid receptors and to specifically treat oedema as a principal symptom. Several double blind studies, controlled with placebo, did not manage to demonstrate a clinical impact nor elimination of the oedema superior to placebo [48,49]. However, some later studies do reveal a moderate positive effect [50]. 3.3. Primrose oil It has been theorised that patients with PMS suffer from a deficiency in the metabolism of fatty acids and treatment with primrose oil was recommended. This oil contains linoleic and gamma linoleic acids, which are precursors of prostaglandin E. Various double blind studies with control group, could not show primrose oil to be superior to placebo [51–55]. 3.4. Progesterone Following the recommendations of the recently disappeared Dalton, progesterone injections or vaginal suppositories were widely recommended in the past [56]. The first four studies that did not corroborate positive effects with this treatment were criticised on the grounds of sample size and progesterone dosage [57–60]. Well-designed studies found that neither progesterone nor placebo improved symptoms [61–63]. A single study with just 23 highly motivated women reported beneficial results from progesterone treatment, although the major effect was limited to the first month of treatment [64]. 3.5. Hysterectomy and bilateral oophorectomy Although it is true that no single organic cause of premenstrual problems has been found, there certainly are clear indications of several causes, organic ones amongst them. No necessary causes could be defined.

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The syndrome basically only affects women with ovarian functionality intact, so both surgical and chemical oophorectomy present, through gonadotropin suppression, a solution for severe PMS. Not all women with PMS or PMDD will want to exchange their premenstrual problems for an induced premature menopause, however. The positive response to medical and surgical hysterectomy and bilateral oophorectomy in women nonresponders to medical treatment is lasting [63,65–72]. In general, the response to ovarian suppression with a GnRH agonist suggests that PMS symptoms represent an abnormal reaction to normal changes in hormone levels [71]. 3.6. Calcium, magnesium, Vitamin B6 supplements In a randomised, placebo controlled study, a daily calcium supplement (1200 mg) was associated with a reduction of 48% in the symptoms ratings, whereas in the placebo group the reduction was 30% [72]. Later studies confirmed these results and the positive effects [73]. A daily magnesium supplement (200 mg) may improve fluid retention and mood but not PMDD [74], and a daily supplement with a reduced quantity (50 mg) of vitamin B6 did reduce PMS, notably so from the second month [75]. 3.6.1. Antidepressants Serotonin regulates behaviour and mood. Some studies indicate that women with premenstrual problems present low serotonin levels during the whole cycle and as a result could be vulnerable to dysphoric mood states as in PMS or PMDD. Other data seem to indicate that serotonin levels may be affected during the premenstrual period. Randomised, double blind and placebo-controlled studies show positive results in up to 60% of subjects with the antidepressants fluoxetine, comipramine, sertraline, citalopram, paroxetine and – to a lesser degree – with the anxiolytic alprazolam, both in physical and affective symptoms [63,76–82]. Non-serotonergic antidepressants such as maprotiline and desipramine did not produce the same results [83]. Fluoxetine produced results in 2–3 months, and a dosage of 20 mg is as effective as higher doses, whilst reducing the side effects [76,77,81,82,84]. In a fair percentage of cases an intermittent treatment limited to the premenstrual phase may be sufficient and could even be more effective than a continuous administration [85–87]. The beneficial effects of the SSRIs – though not in all cases – suggest the existence of a serotonergic imbalance related to the cyclic changes in gonadal steroids [88]. However, SSRIs only slowly modulate serotonin levels, so it remains unclear how intermittent treatment can be effective. Although serotonergic effects seem stronger than the noradrenergic ones [80], norepinephrine in plasma does not show cyclicity in PMS women, whilst being clearly cyclic, with maximums during ovulation and the initial luteal phase, in women without PMS. Norepinephrine levels showed a negative correlation with mood changes and

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headache [89]. Thus selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) probably have a different effect on PMS than SSRIs. As an SSRI-alternative for patients with gastric problems, hypericum extract (St. John’s Wort) has been proposed. In an n = 1 study it proved effective [90]. Although the FDA approved fluoxetine for PMDD in 2002, the European Commission in June 2003 established that this condition has not been included in the International Classification of Diseases (ICD) and that in the DSM-IV it appears as a provisional diagnosis for investigative purposes only. The Commission made the manufacturer of Prozac, one of the commercial names of fluoxetine, eliminate the indication of PMDD from the prospectus. The FDA is under pressure to take the same measure [94]. Nevertheless, in 2005 it approved another SSRI for PMDD, paroxetine (Paxil Controlled Release). Apart from SSRIs, limited beneficial effects have been attributed to buspirone and to alprazolam [63,91–93]. Tryptophan reduces symptoms more than placebo, but its use is limited for safety reasons. Lithium did not show any effect. 3.6.2. Dietary habits It has been shown that changes in the habitual diet can have a certain effect on specific symptoms. These effects have a biological basis: - A possible deficiency in circulating serotonin levels could be compensated by increasing tryptophan presence through increased ingestion of carbohydrates or other foods high in tryptophan, resulting in a reduction of mood symptoms. - A reduction in intake of refined sugars and salts will reduce liquid retention. - A reduction in intake of methylxanthines (coffee, tea, coke, chocolate) will reduce breast discomfort [95]. - Soy isoflavones act on oestrogen and may reduce cramps and oedema [96].

3.6.3. Phytotherapy The efficacy of phytotherapeutic treatment of the premenstrual alteration with Vitex agnus castus is well proven and reported in Evidence Based Mental Health [98]. A recent study revealed a significant negative correlation between soy isoflavones intake and perimenstrual symptoms [119]. Schellenberg found that treatment once daily with 20 mg of extract of agnus castus fruit, or chaste berry, reduced irritability, mood changes, rage, headache and breast swelling by 50% or more [97]. The extract works as a dopaminic agonist, inhibiting prolactine release and probably increasing the secretion of oestroegens. The plant contains flavonoids that bind to benzodiazepine receptors, and presents antidepressant and anxiolytic properties similar to oestrogens and progesterone. Their levels decline during the premenstrual

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period, this decline being associated with premenstrual dysphoria. A comparative, prospective, double blind study with fluoxetine and agnus castus fruit showed a comparable efficacy (fluoxetine 68.4% and agnus castus 57.9%), although fluoxetine had more effect on psychological symptoms and agnus castus reduced physical symptoms more [99]. 3.7. Steps to take In 2000, the American College of Obstetricians and Gynecologists (ACOG), on the basis of the then available evidence, published a set of recommendations that, interestingly, favour those treatments that are not backed up by sufficient scientific evidence but were apparently considered preferable to other available options. The recommendations are divided into three groups, according to the level of scientific support at present, to conclude with the three steps with which to structure clinical practice that, according to the ACOG, should start with the simpler treatments. These recommendations are, in effect, a ‘‘consensual clinical intuition’’, only in part supported by evidence-proven facts. 3.8. Psychological treatments PMS is to be considered a sociopsychosomatic condition, correlated with a biological cyclicity. Its treatment should, therefore, not remain limited to medical treatment of the physiological and/or mood symptoms but should adequately cover the treatment of all implicated factors. Recent references on the syndrome insist that the physician try

and get the patient to consider premenstrual symptoms with less negativity, convincing him this way to apply a type of ‘‘light’’ therapy, even when his primary concern remains with medication or surgery. When it is clear that psychological and social components represent decisive influences, then psychological and social treatments should occupy a foremost place both in investigation and in clinical practice, not in ‘‘light’’ versions but in a professional and validated form [100,101]. Keye and Trunnell, some 20 years ago, combined what has been known for a long time in a biopsychosocial model of the premenstrual syndrome, with a specific way of evaluating women with PMS on the basis of six factors. Although their model does not quite fit in with the premenstrual alteration, what has been accepted is their conclusion that, in a majority of cases, it is not sufficient to prescribe a drug, to change habits or reduce stress but that a proper multidisciplinary therapy should be applied [102,103]. The importance of what has been identified as ‘‘social pathways to premenstrual symptoms’’ was analyzed in a study published in 1995, in which three perimenstrual symptom patterns were identified. With the aid of a health diary women’s symptoms across the menstrual cycle were classified as low severity symptom (LS), premenstrual symptom (PMS) or premenstrual magnification (PMM). Stepwise discriminant function analysis indicated that stressful life context, menstrual socialisation and expectations about symptoms related to menstruation differentiated women with an LS from those with a PMS or PMM symptom pattern. In addition, presence and intensity of depressed mood differentiated the three groups [104]. In the

Table 4 Major recommendations of the American College of Obstetricians and Gynecologists (ACOG) [100] The following recommendations are based on good and consistent scientific evidence (Level A) Women in whom premenstrual syndrome (PMS) has been diagnosed should meet standard diagnostic criteria and should have the timing of their symptoms confirmed using a prospective symptom calendar. Risk factors such as increased imposed stress and specific personality profiles are not helpful in differentiating women with PMS from those without PMS. The selective serotonin reuptake inhibitors (SSRIs), particularly fluoxetine and sertraline, have been shown to be effective in treating PMS. The bulk of scientific evidence does not support the usefulness of natural progesterone or primrose oil in the treatment of PMS. The following recommendations are based on limited or inconsistent scientific evidence (Level B) The use of gonadotropin-releasing hormone (GnRH) agonists and surgical oophorectomy has been shown to be effective in PMS. However, the side effects of GnRH agonists and oophorectomy limit their usefulness in most patients. Treatment with the anxiolytic alprazolam is effective in some patients. Its side effects limit its use as a first-line approach. Carbohydrate-rich foods and beverages may improve mood symptoms and food cravings in women with PMS and are a reasonable first-line approach in many patients. Calcium supplements have been shown to be effective in treatment of PMS. Magnesium, Vitamin B6, and Vitamin E may have minimal effectiveness in the treatment of PMS. Oral contraceptives may improve physical symptoms of PMS. The following recommendations are based primarily on consensus and expert opinion (Level C) Supportive therapy is central to the management of all PMS patients. Aerobic exercise can be recommended to PMS patients. As an overall clinical approach, treatments should be employed in increasing orders of complexity. Using this principle, in most cases, the therapies should be used in the following order Step 1. Supportive therapy, complex carbohydrate diet, aerobic exercise, nutritional supplements (calcium, magnesium, Vitamin E), spironolactone Step 2. The SSRIs (fluoxetine or sertraline as the initial choice); for women who do not respond, consider an anxiolytic for specific symptoms Step 3. Hormonal ovulation suppression (oral contraceptives or GnRH agonists)

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same year, a small Spanish study found that an informative talk on menstruation had a lasting positive effect on PMS [105]. Trait and state anxiety are positively correlated with the premenstrual alteration. Stress levels increase during the premenstrual phase in most women, with or without PMS [106]. A study showed women with social problem-solving abilities and problem orientation to have lower levels of premenstrual and menstrual pain, whilst women who feel not in control report high levels of premenstrual and menstrual discomfort [107]. Self-diagnosis of PMS has a negative effect on behaviour and mood [108,109]. All this demonstrates the well-known fact that stress predisposes to and augments the perception of negative inputs. Therefore, improving social and personal evaluation and attitude may help to reduce the perception of symptoms but never eliminating them until the biological component has been reduced as well. No biopsychosocial model of the premenstrual symptom may be able to explain the origin of the problem but may explain the way the subjective experience is perceived and the factors that play a role there. Biological alterations may not reach abnormal thresholds but could dislodge the organism from its homeostatic platform. This creates a basis for this symptomatology in those persons who do not have the necessary means to absorb this ‘‘unsettling’’, either due to a lack of adequate biochemical reactions or of sufficient psychological abilities. This way biological, psychological and social factors interact as regards the genesis and maintenance of a premenstrual problem. Our model accepts that the problem has a real biological basis (the homeostatic failure) and does not exclusively ascribe the symptoms to social or psychological aspects. The proposal rejects the apparent continuity from PMS to PMDD, and considers PMDD to be a specific mood disorder related to the premenstrual period, whilst PMS is regarded as a cyclic biological unbalance with sociopsychosomatic components. As a result, the model does not accept the proposed theories as to PMS implying a ‘‘behavioural problem’’, as its biological manifestations can be all too real. Exclusively in those cases where a mood disorder, according to the DSMIV diagnostic criteria is present, can we justifiably speak of a ‘‘mental disorder’’. PMS may contain an important psychological factor but this does not mean that during the late luteal phase a woman would see her cognitive faculties affected. Some theories seem to suggest this, but studies failed to prove diminished cognitive performance despite subjective feelings of inadequacy or reduced mental agility [110]. Women with PMS present a significantly more depressed mood than controls. This may lead to exaggerated reports of inadequacy. Premenstrual women may at times feel inadequate without being so and may consider themselves more sad or emotional than they really are. The prospective data of a large study (n = 2447) established that they do not cry more during the premenstrual period, although their retrospective opinions did say so [111].

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Table 5 Summary of management guidelines [116] All women with PMS or PMDD Non-pharmacological treatment: education, supportive therapy, rest, exercise, dietary modifications Symptom diary to identify times to implement treatment and to monitor improvement of symptoms Treatment of specific physical symptoms Bloating: spironolactone Headaches: non-prescription analgesic such as acetaminophen/ paracetamol, ibuprofen, or naproxen sodium Fatigue and insomnia: instruction on good sleep hygiene and caffeine restriction Breast tenderness: Vitamin E, evening primrose oil, luteal-phase spironolactone, or danazol Treatment of psychological symptoms For symptoms of PMDD, continuous or intermittent therapy with an SSRI Treatment failure Hormonal therapy to manipulate menstrual cycle

Treatment of the psychological factor in PMS with cognitive-behavioural therapy (CBT) proved to be effective compared with the usually prescribed drugs [112]. A study of the John Radcliffe Hospital of Oxford showed that cognitive therapy resulted in near total remission of psychological and somatic symptoms in the medium term [113]. CBT proved equally effective as fluoxetine at 6 months, and more effective at 12 months [114,115]. More controlled studies are needed to define and verify the efficacy of cognitive-behavioural therapies. Authoritative voices from the American Academy of Family Physicians (AAFP) and the American College of Obstetrics and Gynecologists (ACOG), as shown in Tables 4 and 5, consider that, initially, all patients with PMS should be offered non-pharmacologic treatments, including sociopsychologic therapies such as patient-education, supportive therapy and behavioural changes [116]. However, there is still no consensus as to the definition of PMS and its diagnostical criteria and neither have treatment recommendations been adapted to the available evidence (Table 6). Table 6 Evidence-based efficacy of non-pharmacologic treatments Considerable benefits with positive and relatively solid evidence Vitex castus (plant extract) Cognitive therapy Calcium Possible benefits with contradictory, insufficient or preliminary evidence Primrose oil Potassium gluconate Magnesium Vitamin B6 Vitamin E Food or drinks rich in carbohydrates Reduce or avoid refined sugar, alcohol, caffeine, fat Efficacy for mood symptoms and depressive states with considerable evidence St. John’s Wort (hypericin)

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4. Conclusion The ovarian cycle of the woman of reproductive age affects several physiological, hormonal and neurological parameters thus producing a diverse premenstrual symptomatology with no single specific cause. The resulting clinical problems can notably reduce the quality of life or impede the woman’s functionality during several days before menstruation. One of their causes could be found in the cyclic changes in hormone levels, but others have been

identified, amongst them a special sensitivity to the (partial) withdrawal of hormonal or neurosteroid substances related to cyclic changes. Moreover, perceived symptom severity depends upon the psychological abilities of each person and, therefore, upon a subjective valuation. The two ‘‘abnormal’’ clinical entities of premenstrual changes are the premenstrual syndrome and the premenstrual dysphoric disorder. For PMS a necessary requisite is the presence of biologic symptoms as well as possibly mood symptoms, whilst PMDD needs the prevailing presence of

Table 7 Patient and physician instructions for the premenstrual profile Patient instructions - Each factor that this register measures refers to a group of related symptoms and sensations. Read the contents of each factor several times to become familiar with their overall meaning. - The register commences with the first day of your menstrual cycle, i.e. the first day of bleeding. - Everyday, approximately at midday, mark in the corresponding boxes the intensity with which you perceive the contents of each factor. Mark ‘‘0’’ when you are symptom-free, ‘‘1’’ when the symptoms are slight, ‘‘2’’ when they are of medium or moderate intensity and ‘‘3’’ when they are strong and make you suffer. - Once you are familiar with the contents of each factor it will not be necessary to continue to contemplate their details. Just mark the intensity of the overall contents of each factor, as represented by their names: ‘‘Negative Mood’’, ‘‘Discomfort’’, and ‘‘Bloating’’. - If you perceive the symptoms of any factor with an intensity such that you cannot function normally, in other words, you cannot do your normal tasks or activities (well), then circle the mark to signal this functional disability, for instance when it was strong and more over incapacitating: - Keep registering for at least 2 menstrual cycles plus the following week. The three factors are: (1) Negative mood Comprises: markedly depressed mood, feelings of hopelessness, or self-depreciating thoughts; marked anxiety, tension, feeling of being ‘‘keyed up’’ or ‘‘on edge’’; marked affective lability (e.g. feeling suddenly sad or tearful or increased sensitivity to rejection); persistent and marked anger or irritability or increased interpersonal conflicts; decreased interest in usual activities (e.g. work, school, friends, hobbies); subjective sense of difficulty in concentrating; lethargy, easy fatigability, or marked lack of energy; a subjective change of being overwhelmed or out of control (2) Discomfort Comprises: marked change in appetite, overeating, or specific food cravings; hypersomnia or insomnia; other physical symptoms, such as breast tenderness, headaches, joint or muscle pain, stomach/abdomen pain, backache (3) Bloating Comprises: breast swelling; a sensation of ‘‘bloating’’; oedema; weight gain Instructions for the Physician Have the patient read aloud the contents of the three factors and emphasize that the register aims at reflecting the daily overall change of each factor. She should not try to make a meticulous calculation by parts, but simply ask herself: ‘‘How much discomfort?’’ and mark the total impression. The same goes for each of the three factors. Clearly explain the difference between noting some discomfort and having it prevent you from doing the normal daily tasks and activities. When the total symptoms of a certain factor are so intense that normal activities become difficult or impossible, she should circle the daily mark to call attention to it. to signal: ‘‘strong discomfort’’ (or negative mood, or bloating) and I am disfunctional. Thus, the first time this happens she should mark If the next day she feels the same and is still dysfunctional, she should continue registering the same mark until she feels functional again when she should omit the attention circle. Explaining the Premenstrual Profile will take 5–7 min. Results and Diagnosis (A) The premenstrual period may manifest itself from day 13 of the cycle onwards, although in the majority of cases it commences in the 7 days before bleeding. The Profile considers the 7 days prior to bleeding to be the premenstrual period. (B) The first 7 days of the first menstrual cycle are a training period for the patient to get familiar with the register routine and these ratings are not considered. (C) After completion of the entire registration period of 2 months and one week, the average rating per day of both follicular periods (days 1 to 13) is compared with the average rating per day of both luteal periods (days 13 until the end of cycle). A luteal points average that surpasses the follicular points average with 50% of more, should be considered an indication of either Premenstrual Syndrome or Premenstrual Dysphoric Disorder. (D) A follicular points average of 1 or over, or circled marks to indicate days of dysfunctionality, should be considered indication of pathology or disorder, other than PMS or PMDD, and a differential diagnosis is required. (E) During days 22–28 of the cycle: An average daily rating of 3 is indicative of PMS. One or two circled ratings are indicative of PMS. (F) Three or more days with circled ratings are indicative of PMDD, to be confirmed with a validated questionnaire for depression and anxiety.

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mood symptoms. The first produces a considerable reduction in the perceived quality of life whilst the second necessarily causes dysfunctionality during at least a number of days. In many other aspects they may share characteristics. It is important that the clinical distinction between these ‘‘abnormalities’’ be established in order to avoid that, without proper justification, the stigma of ‘‘mental disorder’’ or ‘‘anomalous behaviour’’ be projected upon the woman with premenstrual syndrome. It is moreover of utmost important that it is established by means of differential diagnostics, that the symptoms do not result from other causes, such as exacerbated underlying psychiatric or physical disorders. To this purpose the use of a daily premenstrual symptom register during at least two complete premenstrual cycles, is essential. Lastly, further investigation is necessary as to the effects of pharmaceuticals, phytotherapies, psychological therapies and other treatments that have proven efficacy. With the results, a multifactor and multidiscipline algorithm for the clinical treatment of the premenstrual alteration can be validated.

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