- 1 Selective serotonin re-uptake inhibitors
- 2 Other antidepressants and anxiolytics
- 3 Prostaglandin inhibitors
- 4 Hormone treatments
- 5 The combined oral contraceptive pill
- 6 Oestrogen therapy, hormone replacement therapy
- 7 Gonadotrophin-releasing hormone agonists (GnRH agonists)
- 8 Danazol (GnRH antagonist)
- 9 Progesterone and progestogens
- 10 Tibolone
- 11 Bromocriptine
- 12 Complementary treatments
- 13 Nutritional supplements
- 14 Surgical treatments
- 15 Related Posts
There are many different medical approaches for premenstrual syndrome although, as for self-help remedies, there is still a scarcity of well-conducted clinical trials. One problem in evaluating the efficacy of drug treatments is that most trials conducted show a very large placebo effect, particularly in the first month of treatment: in one study, 94% of the women in the placebo group showed a significant improvement. Hence any drug trial should be placebo-controlled and ideally crossover, with each phase continuing for at least 3 months. In addition, definitions of premenstrual syndrome vary so widely that it is difficult to generalize from a clinic-based study to sufferers in primary care.
As far as possible, medical treatments should be used when there is a clear indication. Women should be encouraged to think of medical treatment as just one element in the management of premenstrual syndrome. Attention to lifestyle and relationships is still required. The development of healthy habits will enhance any medical effects, especially as drug treatments may not be sustainable or efficacious in long-term use when the disorder is chronic. Most drugs mentioned here have potentially harmful side effects. Any treatment used for premenstrual syndrome must be thought about in terms of its possible hazards in pregnancy and women should be warned about these, particularly with endocrine treatments.
A number of hospitals run out-patient premenstrual syndrome clinics and referral to a specialist clinic can be useful for severe premenstrual syndrome, for complex cases, or when considering one of the more specialized treatments discussed below. Menopause clinics may also see women with premenstrual syndrome; it is useful to check what facilities are available locally. Simply referring women to a gynaecologist may be unhelpful unless the gynaecologist has an interest in premenstrual syndrome and is sympathetic to the problem.
Selective serotonin re-uptake inhibitors
These drugs have had a significant impact on the treatment of depression in recent years. The symptom overlap between depression and premenstrual syndrome has been pointed out and depression itself is often exacerbated premenstrually. Serotonin may play a role in premenstrual syndrome, particularly the affective and mood-related symptoms and therefore Selective serotonin re-uptake inhibitors have been studied for their possible efficacy in this disorder. Fluoxetine has been shown in well-conducted, randomized, double-blind, placebo-controlled trials to be effective in women with both general premenstrual syndrome and premenstrual dysphoric disorder. Women who experience predominantly mood-related and affective symptoms (including tension, irritability, and depressive symptoms) to a severe degree seem to be most helped by Selective serotonin re-uptake inhibitors, but even the physical symptoms are relieved by these drugs. There has now been a systematic review that finds that Selective serotonin re-uptake inhibitors give significant improvement in overall symptoms compared with placebo. This included fluoxetine, sertraline, citalopram, paroxetine, and fluvoxamine. It is likely that the Selective serotonin re-uptake inhibitors will also be suitable for women with premenstrual exacerbation of underlying depression, but there are no studies of this so far.
Recent studies of intermittent (luteal) use of Selective serotonin re-uptake inhibitors suggest that this is also effective. In one trial using citalopram, intermittent doses were more effective than continuous dose or placebo. The improvement in symptoms is immediate, unlike the delay experienced when treating depression. This suggests a different mechanism of action. In general they are well tolerated but side effects can be unpleasant and include headache, nausea, insomnia, anxiety, and sexual dysfunction.
Other antidepressants and anxiolytics
In randomized controlled trials, the serotonergic tricyclic antidepressants clomipramine and nortryptiline were better than placebo for premenstrual syndrome but have significant side effects, which cause problems with adherence. They cause dry mouth, sedation, constipation, dizziness, and blurred vision. Other new non-SSRI antidepressants are under investigation. Lithium is ineffective. Anxiolytics such as alprazolam and buspirone have some positive effects and have been favoured in the USA. randomized controlled trials are mixed, so it remains unclear what role, if any, they should have in treating premenstrual syndrome. In Britain, the fear of tolerance, addiction, and withdrawal problems make them unacceptable to most women and their general practitioners for use in the long term.
Prostaglandin inhibitors are used widely for dysmenorrhoea and two double-blind, controlled trials of naproxen demonstrated relief of physical premenstrual symptoms related to pain but not of mood-related symptoms. Mefenamic acid has also been shown to relieve some premenstrual syndrome symptoms. All randomized controlled trials available show an effect compared with placebo.
These either attempt to abolish the menstrual cycle or to moderate hormonal fluctuations. Women often arrive at the surgery saying “it must be a hormone imbalance, doctor”. Some informed patients may ask for hormone measurements. Unless the general practitioner feels the woman may be menopausal or suffering from some other complaint such as a thyroid disorder, hormonal measurements are inappropriate. It is important to remember that apart from oral contraception, and the possible use of the progestogen-containing IUCD (intrauterine device) in the future as an adjunct to oestrogen therapy, endocrine therapies cannot be guaranteed to prevent pregnancy.
The combined oral contraceptive pill
Surprisingly few trials have examined the use of COCs for premenstrual syndrome although many women report relief while on the Combined oral contraceptive or first experience premenstrual syndrome after stopping the Combined oral contraceptive. Unfortunately, only randomized controlled trials will separate out the effects of the hormones from the effects of circumstances that lead women to use or cease using COCs. Three randomized controlled trials found no benefit over placebo. One found relief for bloating and breast pain. While some women have experienced an exacerbation of premenstrual symptoms with the Combined oral contraceptive, probably as the result of progestogens, many women, in practice, are helped. In women for whom premenstrual syndrome is exacerbated by anticipation of periods with pain and heavy bleeding, COCs, possibly used continuously for several months, will offer relief. The Combined oral contraceptive does offer the chance to regulate the timing of the cycle and to try another hormonal milieu. Many women need this effective method of contraception anyway. Further research may elucidate which combinations are most likely to be helpful.
Oestrogen therapy, hormone replacement therapy
Evidence from randomized controlled trials suggests that oestrogen relieves premenstrual syndrome. Magos et al. (1986) studied oestradiol implants, which abolished ovulation. There was a significant improvement in severe symptoms. Unfortunately, implants can cause problems with tachyphylaxis, so oestradiol patches were considered. An initial RCT using high doses showed that these were more effective than placebo in relieving most premenstrual syndrome symptoms. More recent work showed that 100 Вµg patches can control symptoms.
In clinical practice it is preferable to start at conventional hormone replacement therapy doses and work up from there until symptoms are controlled. Cyclical progestogen must be used in women who have a uterus. Different progestogens can be tried. Currently, dydrogesterone or medroxyprogesterone acetate look like being the least likely to cause premenstrual syndrome-type symptoms. Progestogen should probably be given for 10 days per month, but for women who find it really hard to tolerate, some gynaecologists working in the field are giving 7 days only. It is now possible to give oestrogen systemically while protecting the endometrium with a progestogen-containing IUCD (intrauterine device). This has the advantage of minimal systemic absorption of progestogen, thereby circumventing the premenstrual syndrome-like side effects. The intrauterine device is licensed for contraception at present but it has great potential for use in premenstrual syndrome. Studies are in progress to evaluate oestradiol patches in conjunction with the levonorgestrel IUCD for premenstrual syndrome.
Side effects of oestrogen include headaches, breast tenderness, bloating, and nausea. Patches may cause skin irritation, and there is a slight increased risk of breast cancer with long-term oestrogen use in menopausal women.
Gonadotrophin-releasing hormone agonists (GnRH agonists)
GnRH agonists have been shown to be more effective than placebo in several well-conducted trials. Ovulation is abolished and a menopausal state follows. Unfortunately, the induction of low oestrogen levels makes them unsuitable for long-term use because of the symptoms of the menopause (sweats and flushes, vaginal dryness) and the risk of osteoporosis. The bone loss caused by low oestrogen has been well documented. These adverse effects can be counteracted by “add-back” therapy with oestrogen and progestogen hormone replacement therapy. So much hormonal manipulation may seem drastic but women with severe premenstrual syndrome find life so intolerable that they will try anything. The best use for GnRH analogues may, however, be in making a definitive diagnosis of premenstrual syndrome in women who are suffering severely but for whom treatment does not appear to be working. Treatment with GnRH analogues is usually initiated in a specialist clinic rather than in general practice.
Danazol (GnRH antagonist)
The advent of oestrogen therapy has relegated danazol very much to the sidelines in premenstrual syndrome treatment. Danazol is an anti-gonadotrophin and in large doses (400 – 800 mg daily) inhibits ovulation, thus alleviating premenstrual syndrome by abolishing the cycle. Most women find this dose intolerable because of side effects such as weight gain, acne, bloating, and hirsutism. In randomized controlled trials it is better than placebo and two trials of intermittent treatment (luteal phase) suggest some effect, particularly for breast pain. It should be prescribed under specialist supervision.
Progesterone and progestogens
Many women are still being prescribed progesterone for premenstrual syndrome because Katerina Dalton has advocated it. Her books make interesting reading and she has done much to publicize the plight of women with premenstrual syndrome. However, results of well-conducted trials of progesterone (usually in the form of pessaries or suppositories) have been disappointing. A systematic review of 14 randomized controlled trials using progesterone against placebo and other treatments found no improvement in overall symptoms. For example, a double-blind crossover study of 168 women showed no difference between progesterone in a dose of 400 mg or 800 mg daily from day 16 to day 28 of the cycle and placebo. Adverse effects include abdominal pain, headache, dizziness, dysmenorrhoea, and excessive bleeding.
Although dydrogesterone has also been used in premenstrual syndrome, results of placebo-controlled trials are conflicting. Three out of seven randomized controlled trials found improvement using dydrogesterone, four showed no effect. Some women experience premenstrual syndrome-like symptoms when taking progestogen as part of hormone replacement therapy. Thus progesterone and progestogens have little place in the treatment of premenstrual syndrome at present.
Two small randomized controlled trials show some evidence of benefit. One trial compared tibolone with placebo and the other with a vitamin supplement. No significant adverse effects were noted.
None of the 14 randomized controlled trials showed any effect on overall symptoms but it does relieve breast tenderness. Bromocriptine has many side effects and thus is no longer used for premenstrual syndrome.
Women have sought help for premenstrual syndrome from various complementary or alternative practitioners including acupuncturists, homeopaths, and herbalists. There is little systematic evidence for such treatments, but many offer considerable psychotherapeutic support alongside specific techniques. Some encourage lifestyle improvements as outlined above, though perhaps with a different rationale. The placebo response is likely to be large, but until such treatments are subject to controlled trials, the extent of treatment efficacy is unknown. There are some treatments that have been researched, usually in the realm of dietary supplements, that can be evaluated in conventional ways. These include pyridoxine, magnesium and calcium, evening primrose oil, vitex agnus castus fruit and chiropractic therapy. It should be remembered that some complementary treatments have significant adverse effects and risks, especially herbal remedies. Some Chinese herbal treatments and some dietary supplements contain potent substances that are not covered by the usual legal safeguards for pharmaceuticals. Women who are trying to conceive may not be made aware of the possible teratogenic effects of these substances.
Pyridoxine (vitamin B6)
Trials of vitamin B6 have been of poor quality. A systematic review found no high quality randomized controlled trials and three further randomized controlled trials gave conflicting results. Wyatt noted that none of the trials met the criteria for inclusion in a systematic review, so it remains an unevaluated treatment, but the trend from the existing studies suggest that the limited evidence is positive.
Whatever the evidence, it is usually the first treatment that women try as it is freely available without prescription. High doses (>200 mg/day) should be avoided because of the risk of peripheral neuropathy.
Oil of evening primrose
One systematic review conducted some time ago found eight randomized controlled trials of oil of evening primrose for premenstrual syndrome. The numbers involved in the studies and size of the effect were small. Therefore, there continues to be insufficient evidence for its use for general symptoms of premenstrual syndrome except for premenstrual breast tenderness for which the product is licensed in the UK.
Magnesium, manganese, and calcium have been investigated in controlled trials for their usefulness in premenstrual syndrome. Results have been so mixed that it is hard to draw any conclusions from them.
Vitex agnus castus extract
This plant extract is used by herbalists for control of premenstrual symptoms. A recent RCT has suggested that it is indeed effective in relieving a range of premenstrual syndrome symptoms. It was well tolerated.
One RCT has compared chiropractic therapy with placebo therapy and found benefit. However, there was a crossover and women who had placebo first got no better with subsequent chiropractic therapy.
Oophorectomy and hysterectomy
For women with extremely severe premenstrual syndrome, perhaps particularly for those who also have menstrual problems, oophorectomy and hysterectomy with subsequent oestrogen replacement therapy will result in a cure for premenstrual syndrome. Randomized controlled trials confirm this and show a reduction in symptoms even with hysterectomy alone, though some women continue to experience the symptoms as ovulation continues. However, women and their general practitioners must make an informed decision about this, as it is a major step. The risks are those of a major operation and fertility is lost. Its use is rare and general practitioners may be mediators between women and gynaecologists to ensure that the best decision is made for a particular woman. No evidence is available for other surgical procedures such as laparoscopic oophorectomy or endometrial ablation.