John Studd, DSc,MD,FRCOG
Professor of Gynaecology
There is a range of drugs important in the hormonal treatment of severe premenstrual syndrome. (PMDD). The syndrome is a collection of cyclical somatic, psychological and behavioural symptoms which occur in the days before a period usually vanish with the periods only to reoccur after mid-cycle of the next period. These symptoms can last for 14 days and may occur with 5-7 day painful heavy periods and menstrual migraine. This may allow the woman only about 7 good days a month.
These somatic symptoms consist essentially of breast pain, abdominal bloating and headaches but the more distressing symptoms are those of irrational sometimes violent behaviour, depression, loss of energy loss of libido, and loss of self respect. Women do complain of a Jekyll & Hyde change in personality which describes perfectly the loss of control of their actions.
The causes are unknown, but ultimately it is produced by hormonal changes (whatever they are), which occur following ovulation. It is probably the production of progesterone or one of its metabolites and it is with this reason that woman with PMS are progesterone/progestogen intolerant. These cyclical symptoms do not occur before puberty, do not occur during pregnancy, and do not occur in the post-menopausal years. The symptoms do not occur after hysterectomy and bilateral oophorectomy but do occur after hysterectomy with conservation of the ovaries. In this situation, the cyclical PMS type symptoms without menstruation and the menstrual headaches without menstruation should be called "The ovarian cycle syndrome".
There has been an unproven enthusiasm for the use of progesterone pessaries in the treatment of this condition. This is illogical because women with PMS respond badly to progesterone and it is probably the cause of the condition. There are now more than 10 good scientific trials to show that progesterone is not helpful for the treatment of PMS. However it may have a place as discussed below in protecting the endometrium from over stimulation.
As the ultimate cause of PMS is ovulation, it follows that the logical cure should be suppression of ovulation. Certainly this achieved by pregnancy, surgery or waiting for the menopause, but a more straightforward medical therapy should be considered.
There are now many studies showing that GnRH analogues remove the symptoms of PMS by suppressing ovulation and producing a medical menopause. An injection of Gonapeptyl, every month is ideal and 'add-back' HRT, will prevent vasomotor symptoms and bone demineralisation. The orthodox estrogen/progestogen preparations are useful but the PMS symptoms may recur with the cyclical progestogen. Livial seems to be an excellent alternative without bleeding or progestogenic side effects.
Ovulation can also be suppressed by moderately high dose transdermal oestrogens in the form of oestradiol patches or oestradiol gel. Appropriate doses would be a 200ugs oestradiol patch or 2 or 3 doses of oestrogel twice daily. Woman may occasionally feel a little worse in the first two weeks on this high dose, like an early pregnancy, but should be advised to continue as substantial benefit is almost certain if the diagnosis is correct. A longer term therapy would be a 75mgs estradiol implant inserted every 6 months. This like the patches and the gel will produce plasma estradiol levels of about 600pmol/L and abolish ovulation in most cases. However, women should be advised that this will not be used as contraception, as the appropriate tests have not yet been carried out.
Cyclical progestogen is necessary but if this produces problems because of progestin intolerance, a shorter duration of 7 days rather than the orthodox 12 days should be used. This duration is adequate to prevent endometrial hyperplasia. It is recommended that the progestin is taken for the first 7 days of each calendar month with withdrawal bleed occurring on about day 10 of each calendar month. Alternatively the weaker preparation closer to a natural progesterone uterogestin should be used for 7 - 10 days each month. This is the only place for natural progesterone in the treatment of PMS.
If the problems of progestogen intolerance or irregular bleeding remain, the use of a Mirena IUS is of great benefit as it is a local intra-uterine application of progestogen will produce endometrial atrophy and amenorrhea without (usually) any systemic absorption that may produce symptomatic side effects.
Many women with PMS also suffer loss of libido, loss of energy as well as the major problem of depression. These two symptoms will often respond to the transdermal estrogens and elimination of the cycles but occasionally they persist. If so, it is helpful to add testosterone with its undoubted effect upon libido. This can be by testosterone gel, (unlicensed in women) testosterone patches which will be licensed in February 2007 or a 75mg testosterone implant. The testosterone also has in many women a positive effect on depression.
PMS is an endocrine disorder and should be treated by logical hormonal therapy and not in the first instance by anti-depressants or other psychiatric therapy. Although most psychiatrists would view SSRIs as the first line of treatment, these drugs do cause dependency, weight gain and loss of libido and should be the last resort in patients who have failed hormone therapy.
There will remain a small group of women who have tried estradiol patches implants and gel, and have tried various combination of oral or intra-cavity progestogen for whom still have unacceptable symptoms. These were often keen to have a hysterectomy with removal of ovaries, and there is no doubt that this is a very effective treatment for a small number of women who have problems with medical therapy.
- Studd, J., Panay N. (2004) Hormones and Depression in Women.
Climateric. 2004 Dec: 7(4):338-46. Review.
- Leather A.T., Studd J.W.W., Watson N.R. Holland E.F.N. (1999)
The treatment of severe premenstrual syndrome with goserelin with and without 'add-back' estrogen therapy: a placebo controlled study.
Glynecol Endocrinol 13:48-55
- Watson N.R., Studd. J.W.W. Savvas M., Garnett T., Baber R.J. (1989).
Treatment of severe pre-menstrual syndrome with oestradiol patches and cyclical oral noresthisterone.
Lancet ii: 730-734.
- Magos, A.L., Brincat, M., Studd, J.W.W. (1986)
Treatment of the Premenstrual Syndrome by Subcutaneous Oestradiol Implants and Cyclical Oral Noresthisterone: Placebo Controlled Study.
B.M.J. 292, 1629-33.
- Cronje, WH., Vashisht, A., Studd, JW. (2004) Hysterectomy and bilateral oophorectomy for severe premenstrual syndrome.
Hum. Reprod. 2004 Sep;19 (9) 2152-5.