There have been many theories of premenstrual syndrome etiology. Progesterone deficiency and water retention were popular, but have been largely discredited. Factors other than differences in the levels of individual hormones must be important. Interactions with other endocrine, neuroendocrine or biochemical systems may operate, or differences in receptor status may be relevant.

Ovulation, suppression of ovulation and premenstrual syndrome

premenstrual syndrome does not exist before puberty, during pregnancy or in the untreated postmenopause. It disappears during gonadotropin-releasing hormone (GnRH) therapy and after bilateral oophorectomy. Therefore, ovulation seems to be the trigger for premenstrual syndrome.

For many gynecological problems, ovulation is suppressed by GnRH analogs, danazol, estradiol, progestogen or removal of the ovaries. In the following paragraphs, the effects of these interventions on the course of premenstrual syndrome are discussed.

GnRH analogs

Suppression of ovulation using injected depot GnRH analogs is highly effective. Unfortunately, discontinuation of therapy results in the return of symptoms, and the long-term effect of such combinations is untested. Therefore, GnRH analogs are mainly used as a diagnostic test for premenstrual syndrome, to exclude an underlying physical or psychological problem. While this test has been shown scientifically to eliminate premenstrual syndrome symptoms, it has not been used in the preoperative test scenario in any scientific way.

Danazol

There is good evidence to show that danazol in doses that suppress ovulation is effective for many premenstrual syndrome symptoms, particularly for cyclical mastalgia. Unfortunately, this drug has limited use in the long term because of its androgenic side-effects, particularly those on the lipid profile. Studies have attempted to reduce these adverse effects by using a lower dose (200 mg/day) during the luteal phase of the cycle; a positive effect is seen for breast symptoms only and no others. Probably the persistence of ovulation in the latter method of administration is the reason for the inadequate therapeutic effect.

Estrogen

There is good evidence showing that ovulation suppression with estradiol implants or patches (100 and 200 mg) effectively treats premenstrual syndrome.

However, estrogen alone incurs the risk of endometrial hyperplasia, and, as discussed below, administration of progestogens can restimulate premenstrual syndrome symptoms. This can be avoided by administering the progestogen via the intrauterine route (levonorgestrel intrauterine system (IUS) when systemic levels are low, and thus central nervous system (CNS) stimulation is very unlikely. Data relating to this approach have yet to be published.

Bilateral oophorectomy

Randomized trials of oophorectomy are probably not ethical, and although the procedure is the only curative treatment, it can only rarely be justified. However, it is worth considering if there is an indication for hysterectomy when the patient with extremely severe premenstrual syndrome has to make the decision to conserve or lose her ovaries. The patient must make this well-documented choice after appropriate counselling and informed consent. Undertaking a ‘GnRH test’ may help this decision.

Progesterone, progestogens and premenstrual syndrome

Because of the previous popularity of the progesterone deficiency theory, progesterone pessaries and progestogens are the most commonly prescribed preparations for premenstrual syndrome in the UK and USA. This is surprising, as there is no evidence to support their continued use; meta- analysis of randomized clinical trials shows them to be no more effective than placebo.

Smith and colleagues studied the symptomatology of progesterone intolerance. The commonest symptoms of progesterone intolerance were bloating, mastalgia, mood swings, fatigue, depression, irritability, skin disorders, weight gain and anxiety. The similarity of these symptoms to those of premenstrual syndrome lends support to the theory that progesterone is most probably the trigger hormone for the generation of premenstrual syndrome. However, no differences have been identified in hormone levels following ovulation in women suffering with premenstrual syndrome, compared with asymptomatic controls. Therefore, it seems that women develop premenstrual syndrome because they are hypersensitive to their normal endogenous levels of progesterone produced after ovulation. The concept that women who are hypersensitive to natural progesterone are also hypersensitive to synthetic progestogens is discussed below in more detail.

Neurotransmitters and premenstrual syndrome

The role of serotonin in depression has been extended to premenstrual syndrome research. Low serotonin levels in red cells and platelets have been demonstrated in premenstrual syndrome patients. This serotonin deficiency seems to enhance sensitivity to progesterone. Selective serotonin reuptake inhibitors (SSRIs) have been shown to be an extremely efficacious treatment for severe premenstrual syndrome/premenstrual dysphoric disorder. A recent meta-analysis of 15 trials showed an overall odds ratio of 6.91 in favor of SSRIs. Common adverse effects were headache, nervousness, insomnia, drowsiness/ fatigue, sexual dysfunction and gastrointestinal disturbances. Unlike anxiolytics and non-SSRI antidepressants they do not cause dependence. Fluoxetine (Prozac ®) is now licensed for premenstrual dysphoric disorder. Most of the above trials used continuous dosing regimens, but targeted luteal-phase regimens may offer minimal side-effects while maintaining efficacy.

Other neurotransmitters may have relevance to premenstrual syndrome, for example γ-aminobutyric acid (GABA), dopamine and acetylcholine, although research data are less convincing for these in comparison with serotonin. There are relatively new data suggesting that lack of allopregnanolone (a progesterone metabolite which acts as a neurotransmitter and has GABA-ergic activity) may be involved. However, confirmatory data are awaited.

Based on the above observations, a plausible etiological theory, which allows some understanding of the proposed treatment methods for premenstrual syndrome, is as follows. Ovulation is the trigger through the release of progesterone into the circulation. However, there is no hormone excess or deficiency. Women with premenstrual syndrome are thought to be hypersensitive to their own, normal progesterone levels. This progesterone hypersensitivity seems to be secondary to a dysfunctional serotoninergic system.

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