Premenstrual Syndrome

Oestrogen, testosterone, gestogens, GnRH analogues and hysterectomy and bilateral oophorectomy in the treatment of severe premenstrual syndrome (PMDD).

John Studd, DSc,MD,FRCOG
Professor of Gynaecology
July 2007

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.

REFERENCES

1. Studd, J., Panay N. (2004) Hormones and Depression in Women.
   Climateric. 2004 Dec: 7(4):338-46. Review.
2. 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
3. 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.
4. 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.
5. Cronje, WH., Vashisht, A., Studd, JW. (2004) Hysterectomy and bilateral oophorectomy for severe premenstrual syndrome.
   Hum. Reprod. 2004 Sep;19 (9) 2152-5.

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Hormonal Treatment of Severe Premenstrual Syndrome

Professor John Studd, DSc, MD, FRCOG
Lister Hospital, Chelsea Bridge Road, London SW1W 8RH

Premenstrual syndrome is a common and sometimes severe group of cyclical symptoms with distressing physical and psychological symptoms that can seriously effect a woman's well being. These symptoms follow the hormonal changes (whatever they are-probably progesterone) that occur with and following ovulation. Therefore, these cyclical PMS type symptoms do not occur before puberty, after the menopause, during pregnancy, or after hysterectomy and bilateral salpingo oophorectomy. However, the typical cyclical symptoms do remain after a hysterectomy if the ovaries are conserved. Thus, menstruation is not a necessary feature for this condition and it would be more meaningful if the disorder was called the ovarian cycle syndrome (1).

In spite of frequent usage there is no evidence that progesterone is effective for treatment but there is ample evidence that progestogen makes the condition worse. Proven hormonal therapy for this condition is based upon suppression of ovulation. These are:

1. GnRH treatment over 3-6 months (2). This confirms the diagnosis and removes the symptoms but it is not appropriate for long term therapy without add back oestradiol and progestogen. The progestogen will reproduce the PMS symptoms as these patients are progestogen/progesterone intolerant.
2. Suppression of ovulation by transdermal oestrogens in the dose of 100µg or 200µg of oestradiol patch (3). Such patients also need cyclical progestogen for 7-10 days a month or insertion of a Mirena IUS.
3. Hormonal implants of oestradiol with the addition of testosterone (4) if necessary in the presence of loss of energy, loss of libido and depression. The same protection of the endometrium by progestogen tablets or a Mirena IUS is necessary.
4. Hysterectomy and salpingo oophorectomy with appropriate long term hormonal replacement therapy (5). In those rare patients with bleeding problems or progestogen side effects in spite of the use of a Mirena IUS.

The birth control pill, although it suppresses ovulation, is not usually effective because the progestogen component produces the PMS symptoms for most of the month rather than half of the month.

REFERENCES

1. Studd, J., Panay N. (2004) Hormones and Depression in Women.
   Climateric. 2004 Dec: 7(4):338-46. Review.
2. 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
3. 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.
4. 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.
5. Cronje, WH., Vashisht, A., Studd, JW. (2004) Hysterectomy and bilateral oophorectomy for severe premenstrual syndrome.
   Hum. Reprod. 2004 Sep;19 (9) 2152-5

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Transdermal Estrogens for the Treatment of Premenstrual Syndrome

John Studd, DSc, MD, FRCOG, Professor of Gynaecology.
Wilhelm Cronje, MBChB, Research Fellow Chelsea & Westminster Hospital, London, UK

Introduction

Severe premenstrual syndrome (PMS) is a poorly understood collection of cyclical symptoms, which cause considerable psychological and physical distress. The psychological symptoms of depression, loss of energy, irritability, loss of libido and abnormal behaviour as well as the physical symptoms of headaches, breast discomfort and abdominal bloating may occur for up to 14 days each month. There may also be associated menstrual problems, pelvic pain, menstrual headaches and the woman may only enjoy as few as 7 good days per month. It is obvious that the symptoms mentioned can have a significant impact on the day-to-day functioning of affected women. It is estimated that up to 95% of women have some form of PMS but in about 5% of women of reproductive age they will be affected severely with disruption of their daily activities[1]. Considering these figures it is disturbing that many of the consultations at our specialist PMS clinics start with women saying that for many years they have been told by everyone, including the family physician, that there are no treatments available and that they should simply "live with it". In addition many commonly used treatments only make the symptoms worse.

The exact cause is uncertain but fundamentally it is due to the hormonal or biochemical changes, whatever they are, and the resulting complex interaction between ovarian steroids and neuro-endocrinological factors that occur with ovulation. This combination produces these varied symptoms in women who are somehow vulnerable to changes in their normal hormone levels. These cyclical chemical changes, probably due to progesterone or one of its metabolites, produce the cyclical symptoms of PMS.

History

This condition is mentioned in the fourth century BC by Hippocrates but became a medical epidemic in the nineteenth century. Victorian physicians were aware of menstrual madness, hysteria, chlorosis, ovarian mania, as well as the commonplace neurasthenia. In the 1870's Maudsley[2] , the most distinguished psychiatrist of the time, wrote " . . . The monthly activity of the ovaries which marks the advent of puberty in women has a notable effect upon the mind and body; wherefore it may become an important cause of mental and physical derangement . . ." This was somehow recognised, rightly or wrongly, to be due to the ovaries and bilateral oophorecotomy - Battey's operation[3] - was performed in tens of thousands of women in North America and Britain. Longo[4] , in his brilliant essay on the decline of Battey's operation, posed the question whether it worked. Of course they had no knowledge of osteoporosis and the devastation of long-term oestrogen deficiency, therefore, on balance the operation was not helpful long-term but probably did, as was claimed, cure the "menstrual/ovarian madness". The essential logic of this operation was to remove cyclical ovarian function but happily this can now effectively be achieved by simpler medical therapy. Only in 1931 was the phrase 'premenstrual tension' introduced by Frank [5], who described 15 women with the typical symptoms of PMS as we know it. Greene and Dalton extended the definition to 'premenstrual syndrome' in 1953[6] , recognising the wider range of symptoms.

Oestrogens

PMS does not occur if there is no ovarian function [7]. Obviously it does not occur before puberty or after the menopause or after oophorectomy. It also does not occur during pregnancy. However, it is important to realise that hysterectomy with conservation of the ovaries does not often cure PMS[8] as patients are left with the usual cyclical symptoms and cyclical headaches. This condition, best-called "the ovarian cycle syndrome"[9]is usually not recognised to be hormonal in aetiology, as there is no reference point of menstruation.

A medical Battey's operation can be achieved by the use of GnRH analogues and Leather et al [10] have demonstrated that three months of Zoladex therapy cures all of the symptom groups of PMS. The women do, of course, have hot flushes and sweats but these are usually far preferable to the cyclical depression, irritability and headaches. The long-term risk of Zoladex therapy is bone demineralisation but the same group showed that add-back with a product containing 2 mgs of oestradiol valerate and cyclical levonorgestrel (Nuvelle, Schering Health) maintain the bone density at both the spine and the hip [11]. Most of the PMS symptoms remain improved with this "add-back" but bloating, tension and irritability recur - probably due to the cyclical progestogen. In a Scandinavian study Sundstrom and colleagues used low-dose GnRH analogues (100 µg buserelin) with good results on the symptoms of PMS, but the treatment still caused anovulation in as much as 56% of patients[12]. Danazol is another method to treat PMS by inhibiting pituitary gonadotrophins, but it has side-effects including androgenic and virilising effects. When used in the luteal phase only [13] it only relieved mastalgia and not the general symptoms of PMS even though side-effects were minimal.

Greenblatt et al showed the effects of an anovulatory dose of oestrogen implants for the use of contraception [14] and the first study for its use in PMS was by Magos et al [15] using 100 mg oestradiol implants, which was a dose shown to inhibit ovulation by previous ultrasound and day 21 progesterone studies. This showed a huge improvement with placebo implants but the improvements of every symptom cluster is greater in the active oestradiol group (Figure 1). In addition the placebo effect waned after a few months with continued response to oestradiol. These patients, of course, were also given 7-13 days of oral progestogen per month to prevent endometrial hyperplasia and irregular bleeding [16]. Subsequently a placebo-controlled trial of cyclical norethisterone in hysterectomised women reproduced the typical symptoms of PMS [17]. We believe that cyclical oral progestogen in the oestrogen primed woman is the model for PMS. It is also significant that progestogen intolerance is one of the principal reasons why older, post-menopausal women stop taking HRT [18]. It is common for progestogens to cause PMS-like symptoms (Figure 2) [19], in the same way endogenous cyclical progesterone is the probable cause of premenstrual syndrome.

Our group still uses oestradiol implants, often with the addition of testosterone for loss of energy and loss of libido, in our PMS clinics but we have reduced the oestradiol dose, never starting with 100 mgs but we will insert pellets of oestradiol 50 mgs or 75 mgs with 100 mgs of testosterone. These women must have endometrial protection by oral progestogen or a Mirena (Schering Healthcare) levonorgestrel-releasing intra-uterine system (LNG IUS). These women with PMS respond well to oestrogens but are often intolerant to progestogens and it is therefore common-place for us to reduce the orthodox 13 day course of progestogen to 10 or 7 days starting, for convenience, on the first day of every calendar month. Thus, the menstrual cycle is reset. The Mirena IUS could also play a vital role in preventing PMS-like symptoms as it performs its role of protecting the endometrium without systemic absorption. In a recent study [20]we have shown a 50% decrease in hysterectomies in our practice (Figure 3) since the introduction of the Mirena IUS in 1995. With its profound effect on menorrhagia and the possibility of less progestogenic side-effects, Mirena looks a very promising component of PMS treatment in the future.

Hormone implants are not licensed in all countries and are unsuitable for women who may wish to easily discontinue treatment in order to become pregnant. Oestradiol patches are an alternative and our original double-blind cross-over study used 200 mcgs of oestradiol patch twice weekly [21]. This produced plasma oestradiol levels of 800 pmol/l and suppressed luteal phase progesterone and ovulation. Once again this treatment was better than placebo in every symptom cluster of PMS. Figure 4 shows the initial response to placebo and active treatment, as well as the respective effects after 3 month cross-over. When active treatment was substituted by placebo there was deterioration in response, whereas there was continued improvement when placebo was replaced by active treatment. Subsequently an uncontrolled observational study from our PMS clinic indicated that PMS sufferers could have the same response to 100 mcg patches with fewer symptoms of breast discomfort and bloating with less anxiety about high dose oestrogen therapy [22](Figure 5).

The original studies outlined in this paper are all scientifically valid placebo-controlled trials showing a considerable improvement in PMS symptoms with oestrogens. Although this treatment is used by most gynaecologists in the United Kingdom, its value has not been exploited by psychiatrists anywhere in the world. We believe that the benefit of this therapy in severe PMS is due to its inhibition of ovulation but there is probably also a central mental tonic effect. Klaiber et al [23]using very high doses of Premarin showed this and our other psycho-endocrine studies of climacteric depression and post-natal depression have shown the benefit of high dose transdermal oestrogens for these conditions[24].

In general terms there is an excess of depression in women than men and this depression occurs at times of hormonal flux beginning with puberty[25]. It also characteristically occurs as post-natal depression, premenstrual depression and climacteric depression - the triad of hormone responsive mood disorders[26]. Premenstrual depression is the most common of these disorders and when severe can be treated effectively by transdermal oestrogens together with the appropriate endometrial protection with oral or intra-uterine progestogen.

Ultimately there are some women who, after treatment with oestrogens and Mirena coils will prefer to have a hysterectomy in order to remove all cycles with a virtual guarantee of improvement of symptoms. This should not be seen as a failure or even treatment of last resort as it does carry many other advantages[19].

It is important that these women who have had a hysterectomy and bilateral salpingo-oophorectomy have effective replacement therapy, ideally with replacement of the ovarian androgens. Implants of oestradiol 50 mgs and testosterone 100 mgs are an ideal route and combination of hormones for this long-term therapy post-hysterectomy with a continuation rate of 90% at 10 years[19].

REFERENCES

1. O'Brien PMS. Helping women with premenstrual syndrome. Br Med J 1993;307:1471-75.
2. Maudsley H. Sex in mind and education. Fortnightly Review 1874.
3. Battey R. Battey's operation - its matured results. Transactions of the Georgia Medical Association 1873.
4. Longo LD. The rise and fall of Battey's operation: a fashion in surgery. Bull Hist Med 1979;53:244-67.
5. Frank RT. The hormonal basis of premenstrual tension. Arch Neurol Psychiat 1931;26:1053-7.
6. Greene R and Dalton K. The premenstrual syndrome. Br Med J 1953;I:1007-14.
7. Studd JWW. Premenstrual tension syndrome. Br Med J 1979;I:410.
8. Backstrom T, Boyle H, Baird DT. Persistence of symptoms of premenstrual tension in hysterectomized women. Br J Obstet Gynaecol 1981;88:530-6.
9. Studd JWW. Prophylactic oophorectomy at hysterectomy. Br J Obstet Gynaecol 1989;96:506-9.
10. Leather AT, Studd JWW, Watson NR, Holland EFN. The treatment of severe premenstrual syndrome with goserelin with and without "add-back" estrogen therapy: a placebo-controlled study. Gynecol Endocrinol 1999;13:48-55.
11. Holland EF, Leather AT, Studd JW, Garnett TJ. The effect of a new sequential oestradiol valerate and levonorgestrel preparation on the bone mineral density of postmenopausal women. Br J Obstet Gynaecol 1993;100:966-7.
12. Sundstrom I, Nyberg S, Bixo M, Hammarback S, Backstrom T. Treatment of premenstrual syndrome with gonadotropin-releasing hormone agonist in a low dose regimen. Acta Obstet Gynecol Scand 1999;78:891-9.
13. O'Brien PM, Abukhalil IE. Randomized controlled trial of the management of premenstrual syndrome and premenstrual mastalgia using luteal phase-only danazol. Am J Obstet Gynecol 1999;180:18-23.
14. Greenblatt RB, Asch RH, Mahesh VB, Bryner JR. Implantation of pure crystalline pellets of estradiol for conception control. Am J Obstet Gynecol 1977;127:520-7.
15. Magos AL, Brincat M, Studd JWW. Treatment of the premenstrual syndrome by subcutaneous oestradiol implants and cyclical oral norethisterone: placebo controlled study. Br Med J 1986;292:1629-33.
16. Studd JWW, Thom MH. Oestrogens and endometrial cancer. In: Studd JWW (Ed). Progress in obstetrics and gynaecology. Vol. 1. Edinburgh: Churchill Livingstone 1981:182-98.
17. Magos AL, Brewster E, Singh R, O'Dowd T, Brincat M, Studd JWW. The effects of norethisterone in postmenopausal women on oestrogen replacement therapy: a model for the premenstrual syndrome. Br J Obstet Gynaecol 1986;93:1290-6.
18. Bjorn I, Backstrom T. Drug related negative side-effects is a common reason for poor compliance in hormone replacement therapy. Maturitas 1999;32:77-86.
19. Watson NR, Studd JWW. Use of oestrogen in treatment of the premenstrual syndrome: a comparison of the routes of administration. Contemp Rev Obstet Gynaecol 1990;2:117-23
20. Studd JWW, Domoney C, Khastgir G. The place of hysterectomy in the treatment of menstrual disorders. In: Disorders of the menstrual cycle (RCOG Press) 2000;29:313-23.
21. Watson NR, Studd JWW, Savvas M, Garnett T, Baber RJ. Treatment of severe pre-menstrual syndrome with oestradiol patches and cyclical oral norethisterone. Lancet 1989;ii:730-734.
22. Smith RNJ, Studd JWW, Zamblera D, Holland EFN. A randomised comparison over 8 months of 100 mcgs and 200 mcgs twice weekly doses of transdermal oestradiol in the treatment of severe premenstrual syndome. Br J Obstet Gynaecol 1995;102:475-484.
23. Klaiber EL, Broverman DM, Vogel W, Kobayashi Y. Estrogen therapy for severe persistent depressions in women. Arch Gen Psychiatry 1979;36:550-9. 23
24. Gregoire AJP, Kumar R, Everitt B, Henderson A, Studd JWW. Transdermal oestrogen for treatment of severe postnatal depression. Lancet 1996;347:930-933.
25. Montgomery JC, Brincat M, Tapp A, Appleby L, Versi E, Fenwick PBC, Studd JWW. Effect of oestrogen and testosterone implants on psychological disorders in the climacteric. Lancet 1987;I:297-9. 25
26. Panay N, Studd JWW. The psychotherapeutic effect of oestrogens. Gynecol Endocrinol 1998;12:353-363.