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PMS is a common condition but still poorly managed in many cases ­ Dr Nick Panay

examines the evidence base behind the wealth of different treatments now available

Premenstrual syndrome (PMS) can be the cause of considerable morbidity and at times even mortality. PMS is defined as distressing physical, behavioural and psychological symptoms, not due to organic disease, which regularly recur during the same phase of each menstrual (ovarian) cycle and disappear or significantly regress during the remainder of the cycle. Typical psychological symptoms include depression, anxiety, irritability and loss of confidence. Physical symptoms include bloating and mastalgia.

Many women experience minor physical and emotional changes before a period, but for about 5 per cent the symptoms are so severe that they lead to a breakdown in relationships and interfere with normal everyday activities.

Crucial to the management of PMS is the need to make the correct diagnosis. This can only be accurately established by the prospective logging of symptoms by the patient, ideally over two cycles. A symptom questionnaire, such as the one on NAPS website www.pms.org.uk, is the best way to diagnose PMS. Patients should continue filling in the questionnaires after treatment has started to give an objective indication of response to therapy.

Look at lifestyle first

Before medical treatments are started, lifestyle changes should be optimised. There is little doubt that reduction of stress, for instance, is a great help in ameliorating symptoms.

Dietary measures such as avoidance of carbohydrate binges and limitation of alcohol and caffeine intake is often beneficial. But while these lifestyle changes can help many women, in cases of moderate to severe PMS it is important that medical therapy is instituted sooner rather than later to avoid unnecessary suffering.

Main medical treatments

The two chief evidence-based medical treatments of moderate to severe PMS are:

·ovulation suppression

·selective serotonin reuptake inhibitors.

Although the underlying cause of severe PMS remains unknown, cyclical ovarian activity appears to be an important factor.

So a logical treatment for severe PMS is to suppress ovulation and thus suppress the cyclical endocrine/biochemical changes which cause the distressing symptoms. A number of drugs are capable of performing this function, but they are not without their own side-effects which may influence efficacy or the duration for which they may be given.

Few treatments for PMS are licensed, but from a medicolegal point of view sufficient evidence exists for a GP with an interest in women's health to safely prescribe Yasmin, transdermal oestradiol and SSRIs.

The combined oral contraceptive pill

Although able to suppress ovulation, and used commonly to improve PMS symptoms, the combined pill (COC) was initially not shown to be of benefit in randomised prospective trials. This is probably because it was used with a pill-free week and because the daily progestogen in the second-generation pills caused PMS-type symptoms of its own accord.

Yasmin, a new type of combined pill, contains an anti-mineralocorticoid and anti-androgenic progestogen, drospirenone. This is showing considerable promise in the treatment of severe PMS as it is devoid of progestogenic side-effects and has a mild diuretic and anti-androgenic effect.

There is now both observational and small randomised trial data supporting its efficacy1. If the COC is used to treat severe PMS, pill packets should be used back to back (bicycling/tricycling or continuously) and a break only introduced if erratic bleeding occurs.

Transdermal oestradiol

An ovulation suppressant treatment of proven efficacy in a placebo-controlled trials which appears suitable for long-term usage is continuous 17?-oestradiol combined with cyclical progestogen.

In one of the first studies, 200µg oestradiol patches were tested against placebo in a crossover trial and found to be highly effective. Both the physical and psychological symptoms of PMS were reduced by an average of 60 per cent. The standard dose is now 100µg which produces physiological mid follicular oestradiol levels2.

Selective serotin reuptake inhibitors

Studies have shown that the serotonin uptake and content of platelets is significantly lower in the premenstrual phase in patients diagnosed with PMS compared with controls. There is now considerable evidence for the beneficial effects of serotonin reuptake inhibitors in treating PMS.

Initial studies with fluoxetine showed it to be efficacious compared with placebo for treating premenstrual dysphoric disorder (PMDD) ­ the American Psychiatric Association's definition of severe PMS. One of these studies led to the licensing of Prozac 20mg/day for the treatment of PMDD. Although the product licence has recently been withdrawn there is sufficient data to entirely justify the use of fluoxetine for PMS.

There is now a wealth of data from other randomised controlled trials for the treatment of severe PMS with most types of SSRIs. What is of great interest is that randomised studies have shown that half cycle SSRI treatment is as efficacious as continuous administration5.

The importance of this is that patients are less likely to develop dependence on this regimen, benefit is immediate and patients are more likely to accept the treatment as it can be regarded as different to the regimens used for psychiatric disorders.

One of the optimum regimens for treatment-resistant PMS is half cycle citalopram, 20mg per day from day 15 to day 28 of the cycle. This appears to be effective even in women whose previous SSRI treatment has failed6.

Other suppression treatments

Depo progestogens/ Cerazette

Depo-Provera, Implanon and Cerazette all have ovulation suppressant activity. But cyclical symptoms can be replaced by continuous low-grade symptoms due to the PMS-like side-effects of synthetic progestogens. Data regarding efficacy is therefore either absent or contradictory.

Progestogen intolerance

Oestradiol treatment for PMS requires the use of oral progestogens, eg norethisterone or dydrogesterone, to prevent endometrial hyperplasia. However, the side-effects from progestogens often lead to a reduction in efficacy and treatment discontinuation.

Progestogen intolerance can be reduced using less androgenic progestogens and/or a shorter duration of progestogen. However, an improvement in treatment efficacy using less oral progestogen must be balanced with the risks of endometrial hyperplasia. The hormone released by the levonorgestrel intrauterine system Mirena acts locally to produce endometrial atrophy, with minimal systemic progestogenic side-effects3.

Suppression in secondary care

Danazol

Cycle suppression may be achieved using danazol, an androgenic steroid. A study demonstrated benefit for several symptoms, but due to masculinising side-effects, especially at higher doses, it is not commonly used.

GnRH analogues

Gonadotrophin releasing hormone analogue usage results in cycle suppression and elimination of premenstrual symptoms. But because symptoms return with ovarian function, therapy would have to be continued indefinitely; this is precluded by significant trabecular bone loss which can occur with only six months of therapy.

The use of GnRH analogues with add-back HRT or tibolone, however, is a useful option4 both to prevent vasomotor symptoms and bone loss; bone mineral density should be monitored in women using analogues for more than six months.

Hysterectomy

Total abdominal hysterectomy and bilateral salpingo-oophorectomy is the ultimate form of ovulation suppression and the only true cure for PMS as this removes the ovarian cycle completely. The procedure is only rarely performed for this indication, as a lesser alternative can usually be found.

Preoperative GnRH analogues are a useful test of whether hysterectomy/oophorectomy will be successful in treating symptoms. It is essential that adequate hormone therapy is given (including consideration of testosterone replacement) to prevent simply replacing one set of symptoms with another.

Women who have had a hysterectomy with ovarian conservation often continue to have cyclical symptoms in the absence of menstruation.

The way forward

Alternative options for treating PMS, such as agnus castus, red clover and St John's wort, are showing promising results in studies. The data on natural progesterone remains controversial, although many women appear to derive benefit. Progestogens should not be used as they are very good at reproducing the symptoms of PMS.

The more established therapies are the combined third-generation pills (especially Yasmin), transdermal oestradiol, SSRIs and the GnRH analogues.

Hysterectomy with bilateral salpingo-oophorectomy and adequate HRT remains an option for the severely afflicted woman whose family is complete and has not responded fully to the other therapies7.

Nick Panay is chair of the National Association for Premenstrual Syndrome; director of the Menopause and PMS Centre; consultant obstetrician and gynaecologist, Queen Charlotte's and Chelsea Hospital, Hammersmith Hospitals NHS Trust

Does evening primrose

oil work for PMS?

The active ingredient contained in evening primrose has one of the highest sources of gamma-linolenic acid.

This essential fatty acid is found in many areas of the body, including breast milk and the brain, and is the active part of polyunsaturated fats. Evening primrose is thought to replace essential fatty acids that are decreased in women predisposed to premenstrual syndrome.

However, the two most well-controlled studies have failed to show any beneficial effects for evening primrose oil (EPO). Because the trials were relatively small, modest effects cannot be excluded.

On current evidence EPO is of little value in the management of severe premenstrual syndrome.

The only proven benefit for EPO is for the specific symptom of cyclical mastalgia. The recommended dosage is 1,500mg twice a day and it needs to be used for at least two cycles before a benefit is seen.

It is available over the counter but cannot now be prescribed on the NHS, making it prohibitively expensive for many women who have previously derived significant benefit for cyclical mastalgia.

Evidence on alternative PMS treatments

Agnus castus

One randomised placebo-controlled study has shown that agnus castus is an effective treatment for women with PMS. The effects were confirmed by the women's self-assessment and by the investigators' evaluation. Tolerability of agnus castus was good. Patient acceptance was high and side-effects were few and mild.

Red clover

Data exists on the follicular phase of the ovarian cycle being lengthened by red clover isoflavones. This, coupled with benefits for menopausal symptoms, has led to further research on the use of this product in the treatment of PMS in both pre- and perimenopausal women. Data is expected in the next year from the author's unit.

Vitamin B6

In a recent meta-analysis insufficient data was available to give a recommendation for using vitamin B6 in the treatment of PMS. Therefore, there is no rationale for giving daily doses of vitamin B6 in excess of 100mg, especially following the recommendation from the Department of Health and the Medicine Control Agency in 1999 to restrict the dose of vitamin B6 available generally to 10mg and to limit the dose sold by a pharmacist to less than 50mg.

St John's wort

Extensive trial data exists for St John's wort as an antidepressant. In a small pilot study in women with severe PMS, treatment resulted in a significant improvement of symptoms. Tolerance and compliance with the treatment was good. However, the absence of a placebo group in this trial limited the evaluation of the extent of the effectiveness of St John's wort.

Light mask

One study showed significant improvements for women with severe PMS during treatment with bright white light from a face mask. The mechanism of action of light therapy in severe PMS is unknown and further data is required. Some investigations have linked severe PMS to disturbance in circadian rhythms and hence light therapy may act by correcting abnormal circadian rhythm.

Progesterone and progestogen

A recent meta-analysis showed no significant benefit for the treatment of severe premenstrual syndrome with progestogens and progesterone. This is not surprising. Synthetic progestogens actually have PMS-like side-effects! Natural progesterone could actually have some benefits as it can have an anxiolytic effect and act as a mild diuretic. However, of the few underpowered studies conducted only one has shown benefit and better data is needed.

References

1 Freeman EW et al. PMS/PMDD Research Group. Evaluation of a unique oral contraceptive in the treatment of premenstrual dysphoric disorder. J Wom Health Gend Based Med 2001;10:561-9

2 Smith RNJ et al. A randomised comparison over eight months of 100µg and 200µg twice-weekly doses of transdermal oestradiol in the treatment of severe premenstrual syndrome.

Br J Obstet Gynaecol 1995;102:475-84

3 Panay N, Studd J. Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Hum Reprod Update 1997;3:159-71

4 Di Carlo C et al. Use of leuprolide acetate plus tibolone in the treatment of severe premenstrual syndrome. Fertil Steril 2001;75:380-4

5 Full- or half-cycle treatment of severe premenstrual syndrome with a serotonergic antidepressant.

Freeman E et al. J Clin Psychopharmacol 1999;19:3-8

6 Freeman EW et al. Citalopram in PMS patients with prior SSRI treatment failure: a preliminary study.

J Women's Health Gend Based Med 2002;11(5) 459-64

7 Ng.et al. Management of severe premenstrual syndrome. The Year in Obstetrics & Gynaecology Eds.

Barter J, Hampton N. 2002; Part III

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