Suppression Of Cyclical Ovarian Function In The Treatment Of Severe Premenstrual Syndrome (Pmdd)
Published November 2007
John Studd, DSc, MD , FRCOG
There are a range of drugs and surgical interventions which are valuable in the hormonal treatment of severe premenstrual syndrome. The logic of using hormones to treat what is essentially an endocrinological disorder needs to be stressed particularly at a time when there is so much effort encouraging the use of SSRIs At the same time the safety of hormones in this age group remains unjustly suspect in spite of the recognised errors in the original WHI study (2)
The syndrome is a collection of cyclical somatic, psychological and behavioural symptoms which occur in the days before a period, .usually vanish with the period only to reoccur after mid-cycle of the next period. These symptoms can last for 14 days and may occur with 5-7 days of painful heavy periods and menstrual migraine. This may allow the woman only about 7 good days a month, or less. (3)
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, loss concentration and generally a loss of self respect (4). Women do complain of a Jekyll & Hyde change in personality which describes perfectly the loss of control of their actions. When these symptoms cause severe depression the condition has been re named, in an unnecessary intervention, Premenstrual Dysphoric Disorder (PMDD) (5)
The fundamental cause whether central or ovarian is unknown, but ultimately the symptoms are produced by hormonal or biochemical changes (whatever they are), which occur following ovulation. It is probably the production of progesterone (6) or one of its metabolites and it is with this reason that woman with PMS are usually progesterone/progestogen intolerant (7). These cyclical symptoms do not occur before puberty, do not occur during pregnancy, and do not occur in the post-menopausal years. They do not occur after hysterectomy and bilateral oophorectomy but do persist after hysterectomy with conservation of the ovaries. In this situation, the cyclical PMS type symptoms without menstruation and the menstrual headaches without menstruation are more correctly referred to as "the ovarian cycle syndrome" (8).
There has been an unproven enthusiasm for the use of progesterone pessaries in the treatment of this condition (9). This is illogical because women with PMS respond badly to progesterone and this luteal phase hormone is probably the essential 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 (10). However it may have a place in protecting the endometrium from oestrogen over stimulation if progestogens produce too many PMS type side effects.
As the ultimate cause of PMS is ovulation, it follows that the logical cure should be suppression of ovulation. This can be achieved by pregnancy, bilateral oophorectomy or waiting for the menopause, but a more straightforward medical therapy should be considered .Danazol which inhibits pituitary gonadotrophins was the first preparations to demonstrate that this was an effective principle of therapy (11) but side effects discourage its frequent use.
There are now many studies showing that GnRH analogues remove the symptoms of PMS by suppressing ovulation and producing a medical menopause. (12) (13) . "Add-back" HRT, will prevent vasomotor symptoms and bone demineralisation (14) The orthodox estrogen/progestogen preparations are useful but the PMS symptoms often recur with the cyclical progestogen component (6). Tibolone seems to be an excellent alternative for "add back" without bleeding or menopausal symptoms (5)
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 100 or 200ugs oestradiol patch twice weekly which has been shown in randomised controlled trial to improve every cluster of symptoms (16). Substantial benefit is almost certain if the diagnosis is correct. A longer term therapy would be a 75mgs estradiol implant inserted every 6 months (17) to which can be added testosterone can be added if loss of energy and libido are a feature..But this would be an inappropriate route in young women who may soon wish to become pregnant. Although there have been no studies of the gel in the equivalent dose of 2 measures once or twice daily it will be as effective as the other transdermal medications They will produce plasma estradiol levels of 500 - 800 pmol/L and abolish ovulation in most cases. However, women should be advised that this must not be used as contraception, as the appropriate population studies have not been performed
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 (18). 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 norgestrol releasing 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.(7)
Although the principle of effective hormone therapy for severe PMS is anovulation it is surprising that the oral contraceptive is often not only unhelpful but may make the symptoms even worse becoming constant rather than cyclical , even worse. This is due to the daily oral progestogen .But there is some evidence that a new gestogen drospirenone with less mineralocorticoid properties found in Yasmin (19) is a useful therapy which also supplies the contraceptive element for these young women.
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 or a 75mg testosterone implant (20) . The testosterone also has in many women a positive effect on depression.
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 are 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 (21) (22).It should not be condemned as "radical" or un necessary as more than 95% of women are very satisfied 4 years after surgery in these carefully selected cases (21) With the loss of their ovarian hormones from the pre menopausal ovary they will need long term replacement of testosterone as well as oestradiol (23) (24)
PMS is a neuroendocrine disorder and should be treated by logical hormonal therapy and not in the first instance by anti-depressants or other psychiatric therapy (25) 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 reserved for patients who have failed the more logical hormone therapy ablating the cyclical hormonal changes of ovulation which produce the cyclical symptoms of severe PMS. Another reason why psychiatrists avoid hormone therapy is one of unfamiliarity of usage particularly with type of estrogen or progestogen, dose, route of administration and side effects of mastalgia and uterine bleeding .(25)
Even if the role of estrogens in treatment of PMS is accepted there is still anxiety about safety. In fact there is no evidence that estrogens are unsafe in this age group as the later WHI studies report a decrease in CVD and overall mortality.(2) (26) This is of vital importance as PMS becomes worse and less cyclical with age blending with the worst depression in the years of the menopausal transition . Schmidt and colleagues (27) and others (3) have shown that peri-menopausal depression also responds to transdermal estrogens and that these women have a more frequent past history of PMS. Thus the two conditions are closely related occurring in the same psychiatrically vulnerable women and should benefit from the appropriate hormone therapy (3) (27) (28)
1. Steiner M Romano Babcock S et al The efficacy of fluoxetine in improving symptoms associated with premenstrual dystrophic disorder BJOG 2001 108 462-468
2. Studd J Second thoughts on the WHI study :the effect of age on the safety of HRT Climacteric (2004) 4 412-414
3. Studd, J., Panay N. (2004) Hormones and Depression in Women.
Climacteric. 2004 7:338-46.
4. Reid R Premenstrual Syndrome N Eng J Med 1991 324 1208-1210
5. Panay N Green Top Guideline for Premenstrual Syndrome for Health Professionals 2007 RCOG Press London
6. Magos AL Brincat M et al The effect of noresthisterone in postmenopausal; women on oestrogen therapy : A model for the aetiology of premenstrual syndrome (1986) Br J Obstet and Gynaecol 93 1290-6
7. Panay N Studd J Progestogen intolerance with hormone replacement therapy in post menopausal women Hum Reprod.1997 3 159-171
8. Studd J Prophylactic oophorectomy B J Obstet Gynaecol 1989 96 506-9
9. Dalton K Trial of progesterone suppositories in the treatment of premenstrual syndrome (1987) Am J Obstet and Gynecol 156 155-6
10. Wyatt K Dimmock P Jones P Obrai m O'Brien S 2005 Efficacy of progesterone and progestogen in the management of premenstrual syndrome BMJ 2001 323 1-8
11. Watts JF Butt WR Logan Edwards R A clinical trial using danazol for the treatment of premenstrual tension 1987 Br J Obstet and Gynaecol. 94 30-34
12. 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.
Gynecol Endocrinol 13:48-55
13. West CP Hillier H Ovarian suppression with goserelin in management of severe Premenstrual Syndrome (1994) Hum Reprod 6 1058-63
14. Leather A Studd J Watson NR Holland E F The prevention of bone loss in young women treated with GnRH analogues and add back estrogen therapy Obstet Gynecol (1993) 81 104-107
15. Di Carlo C Palomba S Nappi C Use of leuprolide plus tibolone in the treatment of severe premenstrual syndrome Fertil Steril 2001 75 380-4
16. 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.
17. 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.
18. Paterson M E L Wade Evans T Sturdee D Thom M Studd JWW Endometrial disease after treatment with oestrogens and progestogens in the climacteric Brit Med J (1980) 280 822-824
19. Perlstein TB Backmann GA Zacur HA Yonkers KA Treatment of PMDD with a new drospirenone containing oral contraceptive Contraception 2005 72 414-4321
20. Davis SR Burger HG The rational for physiological testosterone replacement in women Clin Endocrinol Metab 1998 12 391-405
21. Cronje, WH., Vashisht, A., Studd, JW. Hysterectomy and bilateral oophorectomy for severe premenstrual syndrome.
Hum. Reprod. 2004 Sep;19 (9) 2152-5
22. Casper RF Hearn MT The effect of hysterectomy and bilateral oophorectomy on women with severe premenstrual syndrome 1990 Am J Obstet Gynecol 162 105-109
23. Sherwin BB Gelfand M M Sex steroids and affect in the surgical menopause. a double blind cross over study Psychoneuroendocrinology 1985 10 325-335
24. Studd JWW Does retention of ovaries influence survival after hysterectomy: prophylactic oophorectomy? Climacteric 2006 9 164-166
25. Studd JWW Why are estrogens rarely used for the treatment of depression in women? Gynecol Endocrinol 2007 23 63-64
26. Rousseau JE Prentice RL Manson JE et al Post menopausal hormone therapy and risk of cardiovascular disease by age and years since menopause JAMA 2007 297 1465-77
27. Schmidt PJ Rubinow DR Reproductive ageing , sex steroids and depression 2006 J Brit Men Soc 12 178-85
28. North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society.Menopause. 2007 14(2):168-82.
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