Potential strategies to avoid progestogen-induced premenstrual disorders

Introduction

If we accept the theory that premenstrual syndrome (PMS) is caused by ovulation and subsequent progesterone production in women who have an underlying susceptibility to their own endogenous progesterone and that the patient remains sensitive to any progesterone or progestogen, which is subsequently administered then we can begin to understand and address this problem. ^1–3 It is obvious that when a women has been shown to be sensitive to progestogen-only contraception, combined oral contraception or progestogen treatment for gynaecological disorders to the extent that the treatment cannot be tolerated then we simply have to find an alternative treatment approach.

When this progestogen is cyclical and exactly mimics PMS, be it due to sequential hormone replacement therapy (HRT) or PMS management, it is more difficult. As long as the woman still has her uterus and her endometrium and takes estrogen replacement she will need to take progestogen to prevent endometrial hyperplasia. This remains true even after endometrial ablation.

There are several situations where this may present itself though more often than not the approaches to managing the problem will be similar.

Hormone replacement therapy

Most women taking HRT use a cyclical combined regimen and most of these do well; ⁴ some however develop symptomatic side-effects. ^3,5,6 This is rarely due to the effects of estrogen and more often it relates to the progestogen. This is identifiable by pinpointing the temporal relationship between symptom manifestation and the receiving of the progestogen therapy. For example patients may report symptoms ‘only during the little brown tablet’. Often it is less clear and it may be worth using the daily record of severity of problems (DRSP) chart for clarification – this is the DRSP chart advised for quantifying PMS. ^7,8 Patients on continuous combined HRT or tibolone can develop such symptoms but continuously. Given that with cyclical symptoms we have the flexibility with dose, duration and frequency the range of strategies can be wide as long as we ensure that endometrial protection is maintained.

PMS management using oral contraceptives

While ovulation is clearly suppressed by the use of combined oral contraception (this is its principle contraceptive mode of action) the progestogen content of the pill produces a new progestogen cycle for three weeks out of four and in sensitive women it may give rise to virtually continuous symptoms or certainly ones with a prolonged cyclical component. The usual approach is to swap and change pills, but this is rarely successful. We have seen elsewhere in this issue that this may be addressed by means of newer progestogens such as drospirenone, which are said to be less likely to produce side effects due to anti-aldosterone/anti-androgen effects. ^9,10 In general, though the use of oral contraception has been fairly unhelpful in PMS management given cyclically or continuously as the progestogen element again gives rise to symptoms in progesterone susceptible women.

PMS management – gonadotrophin releasing hormone (GnRH) analogue and add-back

We have seen that one of the most effective ways to treat PMS is by the eradication of ovulation by use of GnRH analogues. ^11,12 These induce a short-term medical menopause and symptoms are thereby eliminated. These drugs are expensive and have all of the consequences of hypo-estrogenic side-effects normally associated with the menopause in particular flushes, mood change, insomnia and osteoporosis. ¹³ In the main this precludes their use for all but short-term therapy. The duration of therapy can be extended by the use of add-back estrogen, which is very effective. ¹⁴ This combination is of course unsafe because of the risks of endometrial proliferation, hyperplasia and cancer and so we must administer progestogen, which ^15,16 as we anticipate, more often than not brings us full circle to the re-stimulation of the original PMS symptoms. ¹⁷ Some of the strategies to deal with this are outlined in the general approach below.

PMS management using estrogen

We have seen in previous sections of the special issue that estrogen has been shown to be effective in managing PMS through the suppression of ovulation. Research trials exist to support the use of patches and implants ^18–20 and the same researchers have suggested the use of appropriate doses of gel and oral tablets, though there is no published evidence to support this. Even though the supportive studies are over 20 years old, continued use in the clinical world reinforces their use and there have certainly been no studies to contradict this view. Even so we are still challenged with the same issues related to the need for progestogen which, while protecting the endometrium, risks re-introduction of the PMS symptoms. Otherwise this is a particularly effective way to manage patients. The approaches which follow attempt to avoid regeneration of PMS and are relevant to all of the above situations, but are particularly relevant to patients receiving otherwise unopposed estrogen for PMS or for HRT. They all involve the use of tailored regimens in that they must adapt to the patients individual requirements and empirically to their individual treatment responses. Such factors as severity of original versus induced symptoms, need for contraception, future family plans, acceptability of bleeding pattern, patient's preferred route of administration, threshold for surgical intervention, willingness to take selective serotonin reuptake inhibitors (SSRIs), acceptance of intrauterine devices, previous treatment response and the existence of other co-morbidities (especially gynaecological) will all influence the chosen method to avoid re-stimulation of symptoms.

Management of progestogen-induced premenstrual disorders

It is clear, then, that avoidance of iatrogenically induced endometrial hyperplasia/cancer at the same time as avoiding the introduction of PMS-like symptoms is the principal challenge in the management of PMS. Non-hormonal approaches to PMS treatment such as SSRIs are by no means effective or acceptable to all women and frequently we must resort to endocrine therapy. For all endocrine strategies we need to balance induced menopause complications, endometrial hyperplasia risk with the difficulties of associated progestogen-induced PMS. The link is very often missed. Most practice in this area depends on clinician experience. We cannot afford to wait for adequate research evidence to be conducted and presented – it probably never will be, and in the meantime we will have to address these issues based on empirical findings, clinical experience, theoretical strategies and a lot of common sense.

Once the diagnosis of a progestogen-induced premenstrual disorder is made then the possibilities for management are multiple. These include:

Avoid progestogen and monitor endometrium;

Avoiding progestogen therapy

There is clearly the option of avoiding administration of progestogen altogether. Unopposed estrogen replacement will eventually give rise to endometrial hyperplasia. Some patients may feel this is a risk worth taking and it may be possible with regular surveillance of the endometrium by endometrial sampling and/or vaginal ultrasound. It is probably not sufficiently safe to accept as a method to be used generally.

In terms of estrogen alone at the higher doses used for ovulation suppression in PMS treatment this is presumably even less safe.

Change progestogen

Much has been written concerning changing the type of progestogen, but very little of this has been based on any more than opinion, theory or experience. It is well-known that 19-nortestosterone derived progestogens produce PMS-like side-effects, ²¹ but evidence confirming the use of alternative progestogens has been sparse and every gynaecologist treating PMS will have seen patients who do equally badly with the alternatives including pure progesterone preparations (oral tablets, pessaries and creams) and with other synthetic progestogens. Contraceptives and HRT preparations containing drosperinone, which is anti-aldosterone/anti-androgenic, have been proposed; however, the logic of this should be questioned as there is no consistent scientific evidence to demonstrate abnormal levels of androgens or aldosterone in PMS. Limited studies have actually led to the licensing of drospirenone-containing oral contraceptives in the USA for women who have premenstrual dysphoric disorder (PMDD) and require contraception. No evidence has been published on drospirenone-containing HRT preparations in relation to PMS symptoms either as HRT or as add-back therapy during GnRH treatment.

Continuous combined treatment

There has long been a view that PMS is directly related to cyclicity of progesterone/progestogen particularly as symptoms disappear during the high levels of non-cyclical progesterone achieved in pregnancy. But it is likely such cyclicity is probably not necessary for generation of symptoms since continuous symptoms both physical (bloatedness) and mood change (depression) have been described with all manner of progestogen contraception and other progestogen therapy. However, there is no reason why continuous oral contraceptive or HRT therapy should not be explored in an individual patient. ²²

Reduction in dose, duration and frequency

Whether reductions in dose, duration and frequency of administration of the progestogen has been the subject of well conducted research studies is doubtful. It would seem common sense to try such an approach and this is seen as a positive strategy in clinical practice. It is always important to ensure that endometrial protection is adequate and should there be any doubt endometrial surveillance must be considered.

Increase estrogen during progestogen phase

There have been one or two anecdotal reports of using additional estrogen during the progestogen administration phase in order to antagonize the progestogenic effects. These are no more than suggestions from individual clinicians and have not been the subject of any research study and certainly there are no relevant publications.

Prescription of SSRIs during progestogen therapy

The use of SSRIs for the management of PMS and PMDD ²³ is well-established and they are highly effective. ²⁴ Given the proposed method of action namely the synaptic interaction between sex steroid and serotonergic mechanisms ^25,26 it would not be surprising if similar mechanisms operate at the same level with progestogens. Thus in the same way that continuous and luteal phase SSRIs are effective in PMS/PMDD, co-administration of these drugs continuously or at the same time as the progestogen should theoretically be effective. No such trials have been undertaken, and thus this regimen has only been tried to a limited extent in clinical practice. It would seem a good avenue for future study.

Intrauterine progestogen

For many years it was hoped that either a hormone with no central nervous system or peripheral effects would be synthesized, specific only to those receptors in the endometrium or a progestogen could be devised that delivered progestogen directly to the endometrium and not peripherally. While it is likely that research work continues on the former, the second of these has now been with us for some time in the form of the levonorgestrel intrauterine system (IUS). Very high doses of levonorgestrel are presented to the endometrium. There is very good published evidence to demonstrate the efficacy of the levonorgestrel IUS in preventing endometrial hyperplasia. ²⁷ It is also well-established that estrogen reliably suppresses ovulation and eliminates PMS symptoms. Well-conducted studies have yet to be published confirming the efficacy of this estrogen/IUS combination, though it is widely used. A small group of women with a levonorgestrel IUS find even the low levels of levonorgestrel accumulated in the blood, intolerable.

Removal of uterus

Surgical removal of the endometrium avoids the need for progestogen and the patient's management can be conducted with estrogen unhindered. Ablation is not sufficient as pockets of endometrium usually persist and they would remain a focus for endometrial proliferation and subsequent cancer. Only by removing the uterus can we be sure that all endometrium has been removed. If this is being done the next choice is whether the ovaries are also removed. If they are removed, that places the woman into a premature surgical menopause with the requirement for estrogen until the age of the natural menopause. Without estrogen replacement there is increased risk of heart disease and osteoporosis. ²⁸ If the ovaries are conserved then symptoms will persist and she will continue to require estrogen at doses sufficient to suppress ovulation, which will be higher than that required simply for replacement. The removal of uterus and ovaries is the best guarantee of success. Once the endometrium is removed, the requirement for progestogen is eliminated permanently and the patient needs only to receive replacement doses of estrogen.

While this is quite an invasive approach to treatment, it is the only method that currently exists to allow long term unopposed estrogen when other strategies have failed. ^29–31 Because it is such an invasive measure, prior testing with a GnRH analogue is advised and in depth counselling recommended.

Conclusion

There is little real evidence for most strategies to avoid progestogen-induced PMS though a reasonable amount of advice has been written based on anecdotal evidence. Further research into alternative methods of using estrogen, progestogen and SSRIs may provide us with more evidence to support these strategies. ³² Avoidance of endometrial cancer while avoiding regeneration of PMS-like symptoms is one of the principal challenges in managing premenstrual disorders. The development of a selective progesterone receptor modulator that has anti-proliferative action on the endometrium, but without effects on the central nervous system is the Holy Grail for PMS and its management.

Competing interests

Professor O'Brien has received support for travel, lecturing, consensus meetings, as well as, research grants related to premenstrual disorders and heavy menstrual bleeding from Bayer Schering Pharma.