Chapter 12

Premenstrual Syndrome and Dysphoric Disorders

It is estimated that 80-90% of women develop some premenstrual symptoms, mainly emotional (1), during their reproductive years which indicate imminent start of menstruation. They are usually referred to as premenstrual moliminal symptoms, which can be physical, psychological or behavioural. They cause transient discomfort in the majority of cases, and are relieved by the onset of menstruation. Conversely, 30-40% of these women are significantly affected and need to seek medical advice. A diagnosis of premenstrual syndrome (PMS) is made in these cases. A definition suggested by Magos and Studd for PMS in 1984 (2) was: ‘a condition which manifests with distressing physical, behavioural and psychological symptoms in the absence of organic or underlying psychiatric disease, which regularly recurs during the luteal phase of each menstrual (ovarian) cycle and which disappears or significantly regresses by the end of menstruation’. Traditionally, these patients were considered to have abnormal or excessive reaction to the normal premenstrual withdrawal of oestrogen and progesterone. They almost always have used different remedies including evening primrose for many months, before seeking medical advice. The symptoms may be severe enough to affect quality of life in 2-9% of menstruating women (3). These are mainly in the form of major mood disorders which completely disrupt every day-to-day activity; hence the name premenstrual dysphoric disorder (PMDD) has been introduced. This name replaced the term ‘late luteal phase dysphoric disorder (LLPDD)’ in 1993, on the recommendation of the American Psychiatric Association. Obese women who performed less exercise, and had lower academic achievement were thought to be more at risk. A lower prevalence is usually seen in women who use hormonal contraception (4). The most frequent PMDD symptoms include anger/irritability, anxiety/tension, feeling tired and lethargic, mood swings, feeling sad and depressed, and increased interpersonal conflicts. Such premenstrual problems are not a creation of present day women, as they have been known since the times of Hippocrates who wrote ‘shivering, lassitude and heaviness of the head denote the onset of menstruation’. Most likely with delayed childbirth pattern and smaller family size nowadays, more women are exposed to repeated menstruations than their ancestors who were more likely to be pregnant or breast feeding more frequently at the same age group. Accordingly, they were less exposed to a similar predicament. It is usually forgotten that 5-15% of women have positive changes premenstrually, with improved physical activity and sexuality (5). There are no known criteria to distinguish this group from those who usually suffer premenstrually.

Aetiology of PMS

The range of premenstrual symptoms is wide and includes physical, psychological, and behavioural problems. Headaches, forgetfulness, lack of concentration, insomnia or hypersomnia, fatigue, apathy, hot flushes, irritability, anger, panic attacks, mood swings and loss of self control are common. Other symptoms include clumsiness, being tearful and over sensitive, food cravings, breast tenderness, bloating sensation, swelling, constipation and diarrhoea. It is noticeable that almost >90% of the symptoms are psychological or behavioural, which may be a reflection of some chemical changes in the brain during that period of the cycle.

Two different major endocrine theories have been put forward over the years as possible causes of PMS and PMDD:

• The ovarian hormones theory hypothesised that lack of progesterone or reduced progesterone / oestrogen ratio during the late luteal phase are responsible for these adverse symptoms. This was the basis why progesterone medication has been used for many years and in different forms in an attempt to control these premenstrual symptoms. Evidence from meta-analysis of randomised controlled studies showed that progesterone was not more effective than placebo in this respect, and did not support the use of progesterone in the management of patients with premenstrual syndrome (6)
• The serotonin theory is more plausible, as lower platelets serotonin content and maximum velocity (Vmax) of serotonin uptake by platelets have been shown during the luteal phase in women affected by PMS than a normal control group, as reported by Ashby et al in 1988 (7). The importance of this finding relates to the fact that platelets are believed to be a peripheral model for central serotoninergic neurones, as stated by the same authors. Furthermore, the serotonin theory has been supported by good clinical response after medical treatment with selective serotonin reuptake inhibitors (SSRI) to replenish brain serotonin activity. According to this theory, normal cyclic fluctuation in the level of oestrogen and progesterone triggers brain biochemical changes in susceptible individuals. A relationship has been found between a decline in oestrogen level and altered serotonin brain activity (8). This concept has been supported by the observation that 85% of women with PMS had hot flushes at the same time, compared to 15% of women with no PMS (9, 10). Furthermore, oestrogen therapy has been shown to improve clinical depression by double blind clinical trials in oestrogen deficient patients (11, 12).

Other non-endocrine theories have been put forward as well, but they are beyond the remit of this chapter. They included sociocultural, psychosocial, as well as cognitive and learning theories. Suffice to say that they had related most premenstrual symptoms to psychological causes, internal conflicts and previous experiences, which could lead to maladaptive strategies to cope with the onset of menstruation.

A recent breakthrough came with a discovery of genetic predisposition to PMDD in a preliminary report published by Huo et al in 2007 (13). A variant of oestrogen receptor alpha gene, together with a variant form of catechol-o-methyltransferase gene (COMT), were found in women with PMDD. COMT is an enzyme involved with prefrontal lobe activation, which is an important regulator of mood. This genetic finding may explain the familial predisposition to PMDD. About 70% and 36% of the daughters of affected and unaffected women respectively were similarly inflicted with PMDD (14). This discovery does not contradict with the general consensus accepting the serotonin hypothesis as the most credible cause of PMDD. Women with these genetic variants may be more prone to react badly to CNS serotonin deprivation.

All age groups between menarche and the menopause can be affected with PMS or PMDD, though they are more common in the third and fourth decades of life. This can be genuine statistics, but may be a misrepresentation of reality. Younger women especially teenagers may be affected, but their symptoms can be related falsely to unstable teenage hormonal changes and indiscretions. Due to restrictions in medical services, information is lacking regarding the incidence of PMS and PMDD in developing countries. Furthermore, talking about menstruation related issues is a taboo not to be discussed. Most of the research relates to richer societies. Nevertheless, community studies in these richer nations showed no racial differences in the prevalence of PMDD, though some differences were reported in the mode of presentation, and type of symptoms. Food cravings were reported more frequently by black women (15), whereas mood changes and weight gain were more common in white women (16).

It is always important to make sure that the presenting symptoms are not just premenstrual magnification of chronic depression, or some other psychiatric disorder. PMS and PMDD start after ovulation and are relieved after the onset of menstruation. Few women may have different levels of chronic or background psychiatric diseases, which get worse premenstrually. Accordingly, a prospective diagnostic calendar will be more appropriate to help in making the right diagnosis. The patient should document the nature of her symptoms, and rate their severity on daily basis for a period of at least 2 cycles in relation to menstruation. She should also record their effects on her personal wellbeing. This will help in excluding patients with predominantly psychiatric problems including depression, anxiety, panic and bipolar affective disorders being treated in a gynaecology outpatient clinic. It is also important to appreciate that all mild forms of these problems are considered to be risk factors for the development of PMDD. Other predisposing factors include history of sexual abuse and domestic violence. Medical problems which can simulate PMS and PMDD should be sought and excluded. Examples of such diseases include anaemia, thyroid diseases and hyperprolactinaemia. Pelvic endometriosis is another disease which can confound the picture, as it may be associated with migraine headaches and bloating sensation.

Diagnosis of PMDD

It is not unusual for a patient to see many practitioners before her symptoms are taken seriously. There was general acceptance at one time that such symptoms are normal part of menstruation. Retrospective history may not show the exact extent of the problem, or the range of symptoms suffered by the patient, hence the need to keep a prospective calendar as mentioned before.

General history and medical examination can be useful in directing the diagnosis toward a specific medical problem. Weight loss, tremors, sweating, shortness of breath, dry skin and excessive or painful menstruation, premenstrual dyspareunia and dyschezia are helpful symptoms or signs to elicit. They can direct the clinician to such medical conditions as thyroid disease, anaemia and endometriosis just as examples. Maternal or family history of PMDD and history of sexual abuse, infertility, family violence, previous psychiatric diseases, and alcohol abuse are also important to elucidate.

Imaging techniques are not useful, and there are no confirmatory endocrine tests pathognomonic of the condition. Nevertheless, blood tests will be necessary to exclude medical conditions such as anaemia, thyroid disease and hyperprolactinaemia. Furthermore, serum progesterone level estimations in women who had a hysterectomy can be used to relate the patients’ symptoms to their ovarian cycle. Transvaginal ultrasound scanning may show a corpus luteum. Frequently, thorough medical history and a charted calendar of symptoms may prove to be more diagnostic in this respect. The most important symptoms are irritability, anxiety, anger and depression. According to the American Psychiatric Association, the presence of 5 or more of the following symptoms is necessary to make a diagnosis of PMDD (17), after ruling out other possible causes. Furthermore, symptoms should be severe enough to affect the quality of life, and at least one of the first four symptoms should be included in a 2-months prospective study:

1. Marked depressed mood;
2. Marked anxiety;
3. Marked affective lability;
4. Persistent and marked anger;
5. Decreased interest in usual activities;
6. Lethargy;
7. Marked change in appetite;
8. Hypersomnia or insomnia;
9. Sense of being overwhelmed or out of control;
10. Physical symptoms.

Treatment

Treatment of patients with PMS and PMDD should start with the recognition of the problem itself by the doctors involved. Patients do not need to see many practitioners before their problems can be addressed. PMS and PMDD are not imaginary problems in the heads of the inflicted patients. In most cases these patients had different medications for many months if not years, while waiting to find proper medical attention.

Patients should be encouraged to change their lifestyle. This should involve changes in eating habits, as small and frequent meals can reduce the risk of  mood swings. It has been shown that intracellular uptake of glucose can be impaired during the premenstrual period (18). More physical activity, especially aerobic exercising reduces stress and has temporary favourable effect on mild cases. All these attempts are less likely to be effective in moderate or severe cases. Historical advice given to these patients included reduction of caffeine intake and smoking to reduce irritability and insomnia. Increased consumption of salt and sugars to satisfy premenstrual cravings can result in bloating sensation and rapid weight gain (19). Accordingly, these items should be avoided and high fibre food used instead.

Definitive medical treatment

All medical problems, mentioned before, which may be contributing to the patients’ sufferings should be treated effectively. Excessive menstrual bleeding and dysmenorrhoea should be addressed as well, as they add to the patients’ sufferings. Endometriosis is one problem which can demoralise these patients. Waiting in expectation for premenstrual and menstrual pain may have a negative impact on the patient’s morale in anticipation of her periods. Changes in most dimensions of quality of life were significantly associated with pain as reported by Cox et al in 2007 (20). They also found that role limitation due to emotional problems and mental health were associated with pain during sexual intercourse and bladder and bowel function. Furthermore, the repeated sense of disappointment of having a period by an infertile woman who is keen to conceive should be taken into consideration. This is especially so with the undue family pressure endured by women in certain circumstances, and after repeated unsuccessful infertility treatment attempts. The role of counsellors in such cases is very important, and patients should be encouraged to see one, despite the common reluctance shown by many patients.

There is enough evidence to treat patients with PMDD with one of the many selective serotonin reuptake inhibitors (SSRIs) available. They have direct effect by improving the brain serotonin deficiency. Few patients may not be agreeable to use antidepressants, because of the stigma attached to them. Fluoxetine is the most widely used SSRI for PMDD, in a dose of 20 mg/day. It can be used continuously during the whole month to start with, before being restricted to the symptomatic luteal phase of the cycle. This later luteal phase regimen can be effective for many women as a primary protocol from the start of medication (21). Fluoxetine has been found to be more effective in patients suffering mainly from premenstrual depression and fatigue. Patients suffering from irritability, anxiety and insomnia are better treated with sertraline. It is evident that SSRIs are not equally effective in all aspects of PMDD. Accordingly, changing the brand with another one is indicated if a patient does not respond to the initial medication. The only tricyclic antidepressant with any benefit in the treatment of PMDD is clomipramine, because of its potent serotoninergic activity. An important side effect of SSRIs is loss of libido, which can be a problem for a patient already suffering from PMDD. This can worsen what is remaining of her marital relationship. An alternative line of management should be pursued in these cases, and for patients not agreeable to use antidepressants.

Despite the fact that PMDD is related to ovulatory cycles, blocking ovulation with oral contraceptive pills may not cause significant relieve of symptoms in all cases (22, 23). There is even increased incidence of headaches, pelvic pain, bloating sensation and breast tenderness during the hormone free intervals, compared to the 21 days while the pill has been taken (24). This negative effect was attributed to the progestogen fraction of the pill, irrespective of it chemical type. In fact one community based study published by Joffe et al in 2003 (25) reported mood deterioration in 16.3% of women who took the pill. Previous history of depression was found to be the only significant predictor of this effect in this study (odds ratio, 2.0; 95% CI, 1.1-3.8). Shortening the hormone free period can be of benefit in many cases, as well as using extended or continuous contraceptive regimens. Contraceptive pills with the progestogen fraction changed to drospirenone, which is a mild diuretic, have been shown to be effective with both the physical and psychological symptoms (26, 27). Accordingly, they can be used as the first line of treatment by willing patients, and those who are seeking contraception as well. Drospirenone also has antimineralocorticoid effect, and can counteract oestrogen induced aldosterone production. This can potentially reduce water retention and weight gain. A further option is to insert a mirena system, and to use transdermal oestradiol patches or gel continuously. The mirena system liberates 20 µg of levonorgestrel daily into the uterine cavity, and protects the endometrium against the sustained effect of continuous oestradiol medication. It has secondary beneficial effects by reducing menstrual blood loss and improving dysmenorrhoea, and accordingly the patient’s morale.

Vitamin B6 (pyridoxine) is another medication which has been used for many years for the treatment of PMS. Conclusions from published randomised placebo controlled trials were limited by the low quality of most of those trials (28), but in daily doses of 100 mg it is likely to relieve symptoms related to PMS and premenstrual depression. Nevertheless, it can lead to peripheral neuropathy, and patients should be advised to stop taking it, if they had any peripheral tingling sensation or numbness. The routine use of diuretics in the management of patients with PMDD or PMS is not indicated. Loss of salt and water stimulates several hormonal systems to compensate for the changes in sodium and water balance. This includes the renin-angiotensin-aldosterone system, vasopressin secretion, and the sympathetic nervous system which may have important clinical implications (29). Rebound fluid retention and weight gain may occur when medication is stopped. The only exception for a useful diuretic is spironolactone which has been shown to affect both mood swings and physical signs related to PMS or PMDD (30, 31). This effect was thought to be related to the steroidal structure of the spironolactone molecule rather than its diuretic effect (26, 27). This explains the beneficial effect of oral contraceptive pills containing drospirenone which is a derivative of spironolactone. Yasmin (Bayer plc) is one pill with 30 mg ethinyloestradiol and 3 mg drospirenone.

There is also a place for gonadotrophins releasing hormone (GnRH) analogues in downregulation of the pituitary gonadotrophs, and reducing the production of gonadotrophins, mainly LH. This leads to anovulation, and a hypoestrogenic state. Prolonged use of such medication is not recommended, because of its effect on reducing bone mineralization. When needed for more than 3-6 months, an add-on medication is necessary to sustain normal oestrogenisation. This can be offered in the form of continuous oestrogen and progestogen medication, or in the form of livial (Schering-Plough) which is made of oestrogen, progestogen and androgens. Another disadvantage of this medication is the expensive cost of repeated GnRH injections, but it can be used for a short period of time to give another medication, used in parallel, ample time to take effect.

Treatment of specific types of symptoms

It is not unusual for women to present with one or two specific premenstrual problems in repeated months. Dealing with such patients is occasionally difficult, but success is very rewarding. It is usually easier to monitor and rank symptoms when dealing with one or two problems than in patients presenting with vague unrelated symptoms. In most cases, relapse can occur if medication is suspended. Occasionally, patients may be symptomatic during few months only for no obvious reasons. The most common of these problems are premenstrual breast pain, premenstrual migraine headaches, severe anxiety and insomnia, panic attacks, and severe bloating sensation.

The help of a fellow psychiatrist may be needed for patients presenting with anxiety, depression or panic attacks as they may be part of genuine psychiatric problems not revealed during the gynaecological clinic interview, or by the symptoms chart filled by the patient. Different medications other than SSRIs are available, and the patient may need to stay on one or more of them for a long period of time, rather than just premenstrually. Buspiron hydrochloride is a useful drug in cases of anxiety, especially for patients who developed sexual dysfunction on SSRIs medication (32). It acts on 5-HT_1A receptors, and it usually takes a couple of weeks before response to treatment is noticed.

Premenstrual mastalgia

It has been estimated that about 70% of women affected with PMS present with premenstrual mastalgia as their main symptom. Breast examination usually reveals no abnormality, except for extreme tenderness. The inflicted patient may not be able to wear her usual brassier. Different studies showed no specific endocrine derangement to account for this presentation, including prolactin estimations. Similarly, different medications have been tried with different effects including tocopherol (vitamin E), evening primrose, bromocripine and danazol. Despite its popularity as a prime medication for this specific problem, evening primrose has generally not shown significant beneficial effects on PMS or PMDD symptoms in controlled clinical trials (33). A useful drug in this respect is danazol which can be used in a small daily dose of 50-100 mg during the luteal phase of the cycle. It should be avoided in women with hyperandrogenic tendency, but it showed no detrimental effect in normal women. Similarly, bromocripine proved to be useful in treating premenstrual mastalgia. Paradoxically, luteal phase medication in a dose of 1.25 mg twice daily proved to be more effective in the management of breast pain than a similar dose given continuously (34).

Premenstrual migraine

Premenstrual migraine headaches may be the only problem a woman presents with. It is occasionally seen in women taking different brands of oral contraceptive pills. Stopping the pill may or may not resolve the problem, and the patient may get disheartened in persistent cases. Ultimately, she will have MRI and other investigations to exclude brain or other intracranial pathologies. It is not unusual for migraine headache to be a manifestation of oestrogen withdrawal in many women. Nevertheless, the initial treatment should be similar to that provided for migraine occurring at other times during the cycle. This should include lifestyle modifications, and use of appropriate therapy to reduce the attack symptoms, its duration and disability (35). Eventually a time contingent therapeutic trial of oestrogen therapy during the luteal phase and menstruation time can relieve the headache in many women (36-38). Continuous, but not cyclic, use of combined oral contraceptives reduces the hormonal fluctuations during the cycle, and can reduce menstrual migraine attacks frequency. This medication has extra hormonal effects by acting on associated comorbidities like dysmenorrhoea, menorrhagia and endometriosis. A study by Ferrero et al in 2004 (39) showed that women with endometriosis were twice at risk of having migraine headaches, and at a younger age than a control group (38.3% vs. 15.1% respectively). In a different study, Tietjen et al (40) looked at women with migraine as the primary study group, and reported higher prevalence of endometriosis than in non headache controls. Furthermore, they showed that women with endometriosis and migraine had more frequent disabling attacks of migraine than women with migraine but no endometriosis. Additionally they had more menorrhagia, dysmenorrhoea and infertility than other patients with migraine only and normal controls. Nonsteroidal anti inflammatory drugs can be used when oestrogen medication is contraindicated, and can also help with any coexistent dysmenorrhoea. Acute attacks may be better controlled by a tryptamine based drug, including sumatriptan and rizatriptan. They can abort an attack within 30-90 minutes in the majority of patients, but recurrence of the migraine even within the same day is a possibility. They act by binding to 5-HT₁ receptors in cranial blood vessels and nerve terminals; hence causing vasoconstriction and reduce pain. For safety reasons, they should not be used at the same time with SSRIs. Together they can cause the serotonin syndrome (serotonin toxicity). Patients may present with nausea, diarrhoea, headache, sweating, muscle twitching, tachycardia, high blood pressure, hyperthermia, tremors, hyperreflexia, mental confusion, hallucinations, and might end up in coma (41). The main treatment strategy in such cases is to stop all serotoninergic medication, and the syndrome will resolve spontaneously. In more severe cases supportive care should be provided to the patient as necessary, depending on her symptoms and signs.

Summary

Premenstrual dysphoric disorders are disabling medical problems which can affect the quality of life of up to 9% of menstruating women. They also increase the risk of major depressive disorders and postpartum depression. They are an important cause of family disruption, and should be taken seriously. Patients should be followed prospectively with a symptoms chart for two months, to make a detailed and proper diagnosis. Normally the symptoms are present only during the second half of the cycle, and disappear after the onset of menstruation. Patients with symptoms spilling into the follicular phase suffer from other psychiatric conditions, which should be managed within that context. Different medications are available for different symptoms, and supportive counselling should be offered when necessary. Patients should also be encouraged to change their life style in relation to healthy dieting, more exercise, and to avoid smoking, caffeine intake, pure sugars and salt. There is no evidence that most of the alternative therapies taken by many patients have any benefit more than a placebo effect. It is important not to neglect the effects of the comorbidities associated with PMDD, and patients should be treated within a total multidisciplinary management plan.

References