Pharmacotherapy of premenstrual syndromes and premenstrual disphoric disorder: current practices

Review

2002 © Ashley Publications Ltd ISSN 1465-6566 1577

Ashley Publicationswww.ashley-pub.com

1. Introduction

2. Epidemiology and significance

of PMS/PMDD

3. Diagnosis of PMS and PMDD

4. Aetiology of PMS and PMDD:

hypothesised pathophysiology

5. Treatment

6. Conclusion and expert opinion

Monthly Focus: Cardiovascular, Renal, Endocrine & Metabolic

Pharmacotherapy of premenstrual syndromes and premenstrual dysphoric disorder: current practicesMohamed F Mitwally, Linda S Kahn, & Uriel Halbreich†

†SUNY Clinical Center, BB-170, 462 Grider Street, Buffalo, NY 14215, USA

Premenstrual syndromes (PMS) and especially premenstrual dysphoic disorder(PMDD) affect a large segment of the population of women of reproductiveage. Treatment is necessary in ∼ 2 – 10% of women with PMS and PMDDbecause of the degree of impairment and distress experienced. Treatmentmodalities are increasingly based on hypotheses concerning possible underly-ing biological mechanisms: mostly ovulation-related hormonal changes andserotonergic abnormalities. Two treatment modalities distinguish themselvesas highly effective: suppression of ovulation and specific serotonin re-uptakeinhibitor (SSRI) antidepressants. Suppression of ovulation is effective for awide range of PMS, while SSRIs are effective for PMDD with some degree ofefficacy for physical symptoms. The SSRIs are also efficacious when adminis-tered intermittently – only during the luteal phase of the menstrual cycle.

Keywords: GnRH, gonadal hormones, menstrual cycle, PMDD, PMS, SSRI

Expert Opin. Pharmacother. (2002) 3(11):1577-1590

1. Introduction

Premenstrual dysphoric disorder (PMDD) is a cluster of mood symptoms thatimpairs functioning and quality of life of affected women. The term premenstrualsyndromes (PMS) was applied in the 1950s to the physical and psychological symp-toms during the 2 weeks prior to menses with relief after the onset of the menstrualperiod. In the 1990s, the Appendix of the Diagnostic and Statistical Manual forMental Disorders (DSM), 3rd edition (DSM-III) [1], included criteria describinglate luteal phase dysphoric disorder (LLPDD). Later, DSM-IV included criteria forPMDD, a particularly severe form of PMS with an emphasis on the affective symp-toms [2]. In 2000, the American College of Obstetricians and Gynecologists(ACOG) published a Practice Bulletin that included criteria for diagnosis and rec-ommendations for the treatment of clinically significant PMS [3]. Whether diag-nosed as severe PMS or the more recent classification of PMDD, this complexpsychoneuroendocrine disorder is a significant health problem affecting 2 – 10% ofwomen of reproductive age [4-8].

Despite the large numbers of women with periodic repeated symptoms and distress,rigorous scientific examination of purported treatments has occurred only recently.

2. Epidemiology and significance of PMS/PMDD

Over 80% of women of reproductive age may experience emotional and/or physi-cal changes premenstrually [9,10], while 2 – 10% experience severe impairment andmeet criteria for PMDD [6,8]. PMS and PMDD may affect up to 18% of womenof reproductive age who may need treatment to alleviate these symptoms [11].Women are affected irrespective of socioeconomic status, race or cultural

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Pharmacotherapy of premenstrual syndromes and premenstrual dysphoric disorder

1578 Expert Opin. Pharmacother. (2002) 3(11)

background and family clusters are well documented [11].They usually seek medical care mostly by their gynaecolo-gists or general practitioners [4,8,12].

A recent prospective-longitudinal community survey of1488 women aged 14 – 24 reported a baseline 12-monthprevalence of DSM-IV PMDD of 5.8%. Application of thediagnostic exclusion rules with regard to concurrent majordepression and dysthymia decreased the rate only slightly(to 5.3%) [6].

Various risk factors have been suggested for PMS includingovulatory cycles, higher cultural level, greater stress in life(work or study), dysmenorrhoea, and history of depressionsymptoms [13,14].

3. Diagnosis of PMS and PMDD

Although the mood symptoms associated with PMS are simi-lar to PMDD, they are different in one key respect: PMDD isclearly defined and usually much more severe. PMDD shouldbe diagnosed only when mood symptoms seriously impactrelationships and impair functioning at work, home or school.

Diagnostic Criteria for PMDD are delineated in Box 1 andthose for PMS are delineated in Box 2.

According to the appendix of the DSM-IV, a psychiatrist orother physician can diagnose PMDD only if the woman hasfive or more of the symptoms described in Box 1 for most

menstrual cycles and if those symptoms seriously impair herrelationships with others and her ability to be productive atwork, home or school.

Usually for the diagnosis of PMDD a woman needs to keepa mood and symptom diary for at least two months. Some-times it is advisable to keep two separate records: a calendarmarking the days of menstruation and a daily diary of moodand behaviour throughout the entire month. Keeping thesetwo records separate helps prevent incorrectly associatingmood changes with the menstrual cycle. However, in mostcases it is unnecessary.

It is important to distinguish symptoms of PMS andPMDD from major depression, anxiety disorders, bulimiaand stress caused by family conflict, domestic violence or sex-ual abuse. Polycystic ovarian syndrome, diabetes, seizure dis-orders, chronic fatigue syndrome, low thyroid hormone levels,anaemia, lupus and some infectious diseases may also producesimilar symptoms [15,16].

4. Aetiology of PMS and PMDD: hypothesised pathophysiology

The aetiology of PMS is likely to be multifactorial involvingdiversified genetic vulnerability, sensitivity to hormonal fluc-tuations, altered brain processes as well as environmental andpsychological inputs. The rate of fluctuation of gonadal

Box 1. DSM-IV diagnostic criteria for PMDD [2].

• 1-year duration of symptoms which are present for the majority of cycles (occur during luteal phase, remit during follicular phase)

• five of the following symptoms (with at least one symptom marked with an asterisk *) must occur during the week before menses and remit within days of menses

• irritability*• affective lability* (sudden

mood swings)• decrease interest in activi-

ties• difficulty concentrating• lack of energy• change in appetite, e.g.,

food cravings

• depressed mood or hope-lessness*

• tension or anxiety*• change in sleep• feeling out of control or

overwhelmed• other physical symp-

toms, e.g., breast tender-ness, bloating

• seriously interferes with work, social activities, relationships

• not an exacerbation of another disorder

• confirmed by prospective daily ratings during at least two consecutive symptomatic cycles

DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edition; PMDD: Premenstrual dysphoric disorder.

Box 2. ACOG diagnostic criteria for PMS [3].

• patient reports ≥ 1 of the following affective and somatic symptoms during the 5 days before menses in each of three prior menstrual cycles:

Affective• depression• angry outbursts• irritability• anxiety• confusion• social withdrawal

Somatic• breast tenderness• abdominal bloating• headache• swelling of extremities

• symptoms relieved within 4 days of menses onset without recurrence until at least cycle day 13

• symptoms present in absence of any pharmacologic ther-apy, hormone ingestion, or drug or alcohol abuse

• symptoms occur reproducibly during two cycles of pro-spective recording

• patient suffers from identifiable dysfunction in social or economic performance

ACOG: American College of Obstetrics and Gynecology; PMS: Premen-strual syndromes.

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Mitwally, Kahn & Halbreich

Expert Opin. Pharmacother. (2002) 3(11) 1579

hormones rather than their absolute levels seem to play animportant role in the aetiology of PMS and PMDD.

Sensitivity to hormonal changes has been shown to have agenetic basis. While as many as 90% of identical twins werefound to be concordant for PMDD, only 44% of dizygotictwins and 31% of sisters who were not twins were concordant[17]. In a population-based twin study [18] and subsequent fol-low-up [19] of 1312 twins, correlations in premenstrual symp-toms were more than twice as high in monozygotic twins as indizygotic twins, with an estimated heredity of 30 – 35%. Cur-rently, researchers are investigating target genes including thegenes that code for serotonin (5-hydroxytryptophan; 5-HT)and γ-aminobutyric acid (GABA) receptors as well as themetabolism of progesterone and other processes related to thehypothalamo-pituitary-gonadal axis.

However, during the last two decades, research has focusedmostly on neurotransmitters, and especially serotonin.

Serotonin is considered to be a major neurotransmittermodulating mood, behaviour, appetite and sexual function. Itis also involved in the regulation of the hypothalamic-pitui-tary adrenal axis and prolactin secretion [20].

Patients suffering from PMS were found to have serotoner-gic dysregulation as manifested by lower luteal phase whole-blood 5-HT levels and abnormal luteal phase response to oraltryptophan loading tests [21,22]. Serotonergic dysfunction inPMS also has been suggested on the basis of findings ofdecreased platelet uptake of serotonin [23], blunted response to5-HT agonists [24] and consistent therapeutic efficacy of selec-tive serotonergic re-uptake inhibitors (SSRIs) in the treatmentof this disorder [25-27].

GABA is another neurotransmitter that is believed to beinvolved in the aetiology of PMS. Plasma GABA levels havebeen reported to be low in some patients with major depres-sive disorder. Women with PMDD and a past history ofmajor depressive disorder were found to have low plasmaGABA levels. In women with PMDD but no past majordepressive disorder, plasma GABA levels decreased from thenon-symptomatic, mid-follicular phase to the symptomatic,late luteal phase. Decreased GABA function may represent acommon biological link between subtypes of depressive andpremenstrual dysphoric disorders [28]. A trait in major depres-sive disorder and a state-dependent decrease in premenstrualdysphoric disorder might imply a possible continuumbetween the two disorders [29].

The consideration of PMS as ovulation-related disorders issupported by the observation that symptoms are reduced oreliminated during pregnancy (when progesterone and oestro-gen concentrations are high but non-cyclical) and are proba-bly absent or substantially reduced during non-ovulatorycycles and after the menopause [30-33].

Furthermore, hormonal replacement therapy (HRT) withsequential addition of progesterone (replicating to somedegree the normal menstrual cycle) has been reported toinduce PMS-like symptoms in postmenopausal women whohad PMS during reproductive age [34].

Indeed, the strongest support of the involvement of thegonadal hormones in the pathophysiology of PMS is that sup-pression of ovulation and elimination of gonadal hormonefluctuation is often an effective treatment of PMS as evidencedby the success of gonadotropin-releasing hormone (GnRH)agonists in alleviating PMS symptoms (see Section 5.2.1).

Some possible aetiological processes that have been or maybe a basis for treatment are summarised in Table 1.

5. Treatment

Early studies of PMS treatment suffered from many methodo-logical weaknesses. They included subjects with a variety ofdifferent premenstrual symptoms due to differences in theinclusion and exclusion criteria. Earlier studies also sufferedfrom the use of retrospective recall as opposed to prospectivedaily recording to confirm the diagnosis of PMS. A correla-tion of only 50% between retrospective recall and prospectivedaily recording of symptoms was reported [35]. The methodol-ogy employed to rule out underlying or coexisting psychiatricdisorders and the specific rating scales used to record symp-tomatology varied among studies. Moreover, many of theearly studies were not placebo-controlled and the ones inwhich a placebo group was included suffered from a high pla-cebo response rate [36]. Also, many women have a mispercep-tion about the meaning of PMS leading to amplification oftheir premenstrual changes recall, reflecting women’s culturalstereotypes rather than their actual experiences [37].

Because the causes of PMS and PMDD have not been fullyelucidated, numerous treatment modalities have been evalu-ated. There is a wide range of suggested therapies includingnon-pharmacological therapies (e.g., diet, exercise, vitamins,calcium and psychotherapy) and pharmacological interven-tions (e.g., antidepressants, hormones or diuretics). Recently,a herbal supplement well known in Europe has been reportedto relieve the discomfort of PMS.

In the first 50 years since the original description of thesyndrome in 1931 [38], at least 327 different treatment modal-ities for premenstrual syndrome had been tried [39]. Numer-ous others have been tried in the last 20 years. However, someof these interventions have been on the basis of informalobservations, retrospective data collection or inadequatelycontrolled trials.

A wide variety of strategies for PMS have been proposed.For women with mild symptoms, education, supportivecounselling and general self-care measures such as increasedexercise and adoption of a healthy diet might be sufficient.Psychotherapy, coping skills training and relaxation trainingmight also be effective non-pharmacological approaches forrelief of PMS symptoms [40,41]. For women with severe symp-toms, a variety of medications may be helpful. For manywomen, however, neither lifestyle change nor the use ofmedications is an entirely satisfactory approach to the treat-ment of PMS. As PMDD is a periodic condition and treat-ment would likely be required for long periods, adverse

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effects of every approach should be considered, particularlyfor adolescents [42].

5.1 The placebo effect in PMSPlacebo effects are among the most poorly understood issues inmedicine. Their effects positively influence and enhance patientoutcomes, mimic or reverse effects of active drugs and can besuperior to standard treatments for some conditions [43,44].

Placebo effects in the treatment of PMS and PMDD havegenerally been viewed by investigators as troublesome andmasking responses to possible treatments [45]. A recent meta-analysis of controlled treatment trials for PMDD found a pla-cebo response of 6 – 35% [46]. Earlier PMS studies indicatedrates of placebo response as high as 94% [47]. Such high pla-cebo response rates may result in part from differences in sub-ject selection. However, the high rates were found to beconsistent with the estimated power of placebos in naturalclinical settings, where both clinicians and patients expect apositive outcome [48]. Recently, [45] about 20% of PMSpatients randomly assigned to clinical trials after a 3-monthscreening period, were reported to experience sustainedimprovement with placebo medication. The subjects whoimproved for at least 2 months were likely to remainimproved at a level similar to that achieved with drug treat-ment. Although the high rate of placebo response in clinicaltrials of PMS/PMDD is an impediment for assessment of effi-cacy of new active medications, in clinical day to day practicethis is actually an advantage. Many patients may positively

respond to any treatment. However, the clinician should notinfer from success any definite underlying mechanism. It isstill unknown for how long a placebo effect may last.

5.2 Hormonal treatments5.2.1 Suppression of ovulationThere is an obvious link between the appearance ofPMS/PMDD symptoms and the increase and decrease of sexsteroids following ovulation. Cyclic PMS and PMDD symp-toms do not occur premenarchally or in postmenopausalwomen who are not receiving hormone replacement therapyor for the most part during spontaneous anovulatory cycles.Symptoms have also been shown to resolve with pregnancyand with bilateral oophorectomy [49].5.2.1.1 GnRH agonistsOvulation suppression is most often successful for the treat-ment of PMS and PMDD.

GnRH agonists (GnRH-a) induce a state of hypogonado-tropic hypogonadism by downregulating pituitary GnRHreceptors. These drugs are administered in the treatment ofvarious gynaecological pathologies, which are dependant onsex hormones, such as uterine leiomyomatosis, endometriosisand PMS. The original randomised trial confirming the bene-fit of GnRH agonist therapy in women with severe PMS waspublished by Muse et al. [50]. This was confirmed by quite anumber of studies [51-59].

The GnRH agonists that were also studied as treatment forPMS included depot leuprolide acetate (Leupron™, TAP) at

Table 1. Aetiological factors of PMS and PMDD and pharmacological strategies.

Aetiological factor Relevant treatment

1. Neurotransmission disorders:Serotonergic deficiency and dysfunction:• lower luteal phase of whole blood serotonin• decreased platelet uptake of serotonin• blunted response to 5-HT

SSRIs, especially intermittent-luteal

GABA dysregulation Benzodiazepines

2. Gonadal hormone dysfunctionA. PMS are not reported during the premenarchal and

postmenopause period

B. Symptoms are absent during: • anovulatory cycles• menopause• after oophorectomy

C. Steady gonadal hormone levels e.g.:• continuous estrogen administration• during menopause• GnRH agonist treatment are associated with improved PMS-like symptoms

D. Sequential HRT with progesterone is associated with PMS-like symptoms

Ovulation suppression• GnRH agonists• continuous oestrogen• oral contraceptive pills• Danazol

3. Fluid retention symptoms: Diuretics

5-HT: 5-Hydroxytryptophan (serotonin); GABA: γ-Aminobutyric acid; GnRH: Gonadotropin-releasing hormone; HRT: Hormone replacement therapy; PMDD: Premenstrual dysphoric disorder; PMS: Premenstrual syndromes; SSRI: Selective serotonin re-uptake inhibitor.

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a dose of 3.75 – 7.5 mg [51,52] and goserelin (Zoladex™,Astrazeneca) 3.6 mg [53,54]. GnRH agonists have been admin-istered every 4 weeks. Buserelin (Suprefact™, Aventis) isanother GnRH agonist that has been tried on a daily basisintranasally as 900 µg/day [55]. A more recent trial found thata low-dose regimen of 100 µg/day given intranasally may alsobe effective [56].

However, not all studies involving the use of GnRH-a forPMS have been positive. Some studies found that dysphoriamay be less responsive to GnRH-a treatment [51,58,59]. Moreo-ver, long duration of treatment with GnRH-a seems to beimportant to achieve a proper response – as short-term treat-ment was found to be less effective in severe PMS [60]. The var-iable duration of treatment needed to achieve adequatepituitary downregulation and ovulation suppression wouldexplain, at least in part, the discrepancy in some of the reportsconcerning the PMS response to GnRH-a.

Most patients with PMS report complete resolution ofsymptoms during therapy with GnRH-a [50,51,56-60]. However,treatment needs to be continued for long periods as PMS andPMDD symptoms usually return soon after discontinuation oftreatment. Unfortunately, GnRH-a administration is fre-quently associated with adverse effects secondary to the contin-uous status of hypo-oestrogenism – ‘medical menopause’.These adverse effects include climacteric-like apparent symp-toms, such as hot flushes, vaginal dryness and reduction oflibido. However, the most notable adverse effect with long-term use is a decrease in bone mineral density (BMD) andbone loss that is almost inevitable after 6 months of GnRH-atreatment. For this reason, it is not advisable to use GnRH-atreatment for over 6 months [61].

HRT add-back during treatment with GnRH-a may preventbone loss and other symptoms of oestrogen deficiency withoutreactivating the underlying pathologic process, if administeredin an appropriate dosage and schedule. Several studies haveevaluated ‘add-back’ oestrogen-progestin supplementation inpatients treated with GnRH-a and found this therapy effectivein treating PMS symptoms [52,61-65].

However, Schmidt et al. [66] and Leather et al. [53] did notconfirm the add-back results. In a group of 10 women withPMS who were given leuprolide plus estradiol or progesterone,there was a significant recurrence of symptoms [66], whereaswomen without PMS had no symptoms with add-back.

A novel add-back regimen that consisted of low doseinterrupted pulsed progestogen with continuous oestrogenHRT has been evaluated [67,68] and shown to prevent boneloss and hypo-oestrogenic symptoms in long-term GnRH-adownregulated patients with severe PMS as well as patientswith endometriosis.5.2.1.2 Oral contraceptive pillsAs explained above, ovulation suppression has been reported tobe effective for the treatment of PMS and PMDD, thereforeoral contraceptive pills (OCPs) should be an effective therapyfor PMS and PMDD. Moreover, there are other known bene-fits including prevention of bone loss, and decreased risk for

ovarian and endometrial cancer, anaemia, abnormal uterinebleeding, uterine myomata, endometriosis and pelvic inflam-matory disease. However, the main limitation regarding theuse of OCPs for PMS and PMDD is that many OCPs havebeen found to be associated with PMS-like adverse effects suchas breast tenderness, headache, bloating and depression.Therefore, it is important to identify an oral contraceptive pillformulation that has minimal ‘PMS-like’ adverse effects.

Conclusions regarding the treatment of PMS and PMDDwith oral contraceptives are limited by lack of adequatenumber of placebo-controlled trials (For a comprehensivereview, see [69]). A randomised placebo-controlled trial foundthat a triphasic OCP reduced physical symptoms but notmood abnormalities of PMS [70]. In another study comparinga triphasic to a monophasic OCP, monophasic OCP wasfound less likely to cause adverse mood changes [71]. Sulaksuggested that studies are needed to determine whether con-tinuous OCP intake for long periods of 3 months or longermay help to ameliorate the symptoms associated with PMSand PMDD [72] while still maintain safety.

The major trend in the formulation of oral contraceptivesover the last 40 years has been a reduction in the doses of bothoestrogen and progestin components and more recently, chem-ical alterations of the progestins to provide less androgeniccompounds. Estradiol (ethinyl estradiol) doses have decreasedfrom 100 µg to 20 – 30 µg. The dose of the progestin compo-nent has also decreased. All but one currently prescribed OCPstill contain a progestin derived from 19-nortestosterone.

5.2.2 OestrogenSeveral controlled studies have reported the efficacy of oes-trogen as treatment of severe PMS [47,73,74], albeit inconsist-ently [75]. The methodology used by the investigators variedin several ways. Various doses [75] and routes of oestrogenadministration (i.e., implants [47], transdermal [73,74] and oralpreparations), were used. The length of treatment periodvaried, e.g., both follicular and luteal phases of the menstrualcycle [47] or luteal phase only [75]. However, findings fromstudies in which women were administered oestrogen duringboth the follicular and luteal phases at doses sufficient tosuppress ovulation consistently demonstrated the superiorityof oestrogen to placebo in the treatment of both the physicaland psychological symptoms of prospectively diagnosedPMS. The suppression of ovulation seems to be a key factorin the efficacy of high-dose oestrogen therapy as is the casewith other drugs, such as GNRH-a and danazol (Dano-crine™, Sanofi-Synthelabo) [76]. Unfortunately, each ofthese treatment modalities is associated with significant sideeffects that limit their utility. Transdermal oestrogen is morepractical than oestrogen implants with respect to administra-tion and ability to discontinue treatment. Women using anyroute of administration of high-dose oestrogen must becycled with progesterone because of the proliferative effectsof oestrogen on the endometrium. About 30% of patientsmay develop hyperplasia within 3 months of unopposed

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therapy [77]. However, addition of progesterone is associatedwith a partial return of symptoms in some cases.

5.2.3 DanazolDanazol is a synthetic, attenuated anabolic steroid(17-α-pregn-4-en-20-in[2,3D]isoxazol-17-ol) used for treat-ment of endometriosis, fibrocystic breast disease [78,79] and forprevention of angioedemic attacks in patients with hereditaryC1-esterase inhibitor deficiency [80].

In doses of 200 mg/day, danazol reduces mood and somaticsymptoms of PMS, especially migraine and mastaglia, but alsodepressive symptoms [81-83]. Danazol seems to be effective pri-marily if anovulation is induced [82]. Contraception is manda-tory when prescribing danazol in low dose (200 mg) becauseovulation and pregnancy can result and this compound mayresult in virilisation of the foetus. At higher doses of600 – 800 mg/day usually required to suppress ovulation, dan-azol is associated with side effects such as weight gain, moodchanges, fluid retention and acne. The significant side effectsand the need for a reliable contraceptive method in addition tothe increased cost of treatment prevented danazole from beinga popular treatment approach for PMS and PMDD.

5.2.4 Other hormonal interventions5.2.4.1 Thyroid hormonesThyroid axis abnormalities have been suggested to contributeto PMS [84]. However, thyroid axis dysfunction could not beconfirmed by most groups [85-88]. It is still unclear if a subgroupof women with PMS do have relative hypothyroidism becauseall studies examined the mean of the entire group of women.However, unless clinically highly suspicious, as with hypothy-roidism-associated depression, we do not believe that thyroidfunction tests are routinely needed for women with PMS.5.2.4.2 BromocriptineThe therapeutic influence of dopaminegic agonists includ-ing bromocriptine may result from both their influence onthe dopaminegic system and their ensuing prolactin-decreas-ing activity. This issue still calls for clarification. The use ofbromocriptine has been initially suggested for treatment ofPMS due to the report of increased levels of prolactin (PRL)in these women [89]. It may be effective only for the relief ofbreast complaints associated with PMS. Swelling and minordiscomfort lasting 1 – 4 days premenstrually is considered‘normal’ [90]; however, many women have moderate-to-severe cyclic mastalgia lasting 5 – 14 days or more eachmonth, sometimes severe enough to interfere with usualactivities and it may be associated with high use of mam-mography among young women [91]. However, clinical andresearch literature focusing solely on cyclic mastalgia rarelyincludes full assessment of PMS; thus the relationship ofsevere cyclic mastalgia to other premenstrual symptom clus-ters has not been fully clarified [91,92]. In a recent prospectiverandomised trial, lisuride maleate, a dopamine agonist, hasbeen reported to be useful for the symptomatic treatment ofpremenstrual mastalgia [93].

5.2.4.3 ProgesteroneProgesterone has long been advocated as treatment for severepremenstrual symptoms [94] and has been both the mostwidely known and the most controversial PMS treatment. Inthe early 1990’s it accounted for about two-thirds of prescrip-tions for PMS [95]. The rationale for progesterone therapy hasbeen the apparent relationship between PMS symptoms andcyclic changes in plasma progesterone levels and the presumedlow levels of progesterone in women with PMS.

Because the most severe symptoms occur in the late lutealphase, at the time of declining progesterone concentrations,early therapeutic interventions applying progesterone supple-mentation without suppression of ovulation have been tried.However, there is still no evidence of a consistent hormonalaberration in PMS and progesterone levels are not consistentlyaltered in women with PMS [96-98]. Moreover, double-blindplacebo-controlled trials of progesterone supplementation forthe treatment of PMS have not demonstrated efficacy [98-105].

A small preliminary study found that oral micronised pro-gesterone was effective for symptoms of swelling, water reten-tion and hot flushes [106]. It was speculated that the increase inthe levels of pituitary gonadotropins during the later part ofthe menstrual cycle, secondary to the decline in the sex hor-mones secreted by the degenerating corpus luteum, might beresponsible for hot flushes in women with PMS. The admin-istration of progesterone may result in amelioration of the hotflushes possibly through a suppressive effect on pituitarygonadotropin production. However, hot flushes are quite rarein women of reproductive age with or without PMS and puta-tive premenstrual increase in luteinising hormone-follicle-stimulating hormone (LH-FSH) is also questionable. Theenthusiastic clinical satisfaction in many women with PMSwho were treated with progesterone cannot be completely dis-missed. Although progesterone may have dysphoric and anx-iogenic properties, some of its metabolites are anxiolytic byacting as GABAA receptor agonists [107]. There may be a sub-group of women who might benefit from progesterone. Thatsubgroup has not yet been identified.

Furthermore, a recent meta-analysis [108] of 10 publishedrandomised, placebo-controlled trials of progesterone therapy(531 women) and 4 trials of progestogen therapy(378 women), found an odds ratio of only 1.07 (1.03 – 1.11)showing a statistically, but not clinically, significant improve-ment for women taking progestogens. The authors con-cluded that the evidence from these meta-analyses did notsupport the use of progesterone or progestogens in the man-agement of PMS [108].

5.3 Oophorectory (ovariectomy)Bilateral oophorectomy (with hysterectomy) was reported to behighly effective as treatment for PMS [49,109]. These reportsconfirm the importance of suppression or elimination of ovula-tion in the treatment of PMS/PMDD. However, this approachwhich is actually a surgical castration is extreme and irreversi-ble. The same results may be achieved with GnRH analogues.

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5.4 Selective serotonin re-uptake inhibitorsAccumulating neurobiological research on PMS and PMDDsuggests abnormalities in serotonergic neurotransmission[110-112]. Dysregulation in serotonergic functioning in womenwith PMS is similar to that associated with mood disorders, anx-iety disorders as well as symptoms of impulsiveness, anger andirritability [113]. Thus, medications that increase serotonergicneurotransmission were clearly demonstrated to be effective astreatment for PMS and especially for PMDD. To date, severaldouble-blind, placebo-controlled studies [25,114-116] and severalopen trials [117-119] demonstrated the efficacy of the continuousadministration of 20 – 60 mg/day of fluoxetine (Prozac™,Sarafem) as a treatment for PMS and PMDD, and this was thefirst medication approved by the FDA with a specific indicationfor PMDD. This was followed by FDA approval of sertraline(Zoloft™, Pfizer) for PMDD. The efficacy of sertraline50 – 100 mg/day was clearly demonstrated as a continuoustreatment. Other SSRIs that have been reported to be effectivefor treatment of PMDD are paroxetine (Paxil™, GlaxoSmith-Kline) and citalopram (Celexa™, Forest Pharmaceuticals) [26].

Due to the rapid onset of improvement or response to con-tinuous treatment with both sertraline and fluoxetine, therewere several preliminary studies demonstrating the efficacy ofintermittent luteal phase treatment of PMDD [120-124]. Thiswas confirmed by two large scale studies showing the efficacyof sertraline [125] as well as fluoxetine [126] administered foronly 14 days at each luteal phase and discontinued with thebeginning of menses. An attempt to further shorten the treat-ment period only to the actual symptomatic period failed[127]. Recently, it has been reported that long-acting, slow-release 90 mg fluoxetine was effective when given intermit-tently orally once a week at 14 and 7 days prior to menses butnot when given only once 7 days prior to menses [127].

Even though SSRIs are currently considered to be the mosteffective treatment for PMDD and some claim that they arealso effective for physical premenstrual symptoms [128], itshould be considered that, as is the case for treatment of otherdepressions, they are efficacious in ≤ 60% of patients. Almost40% of women with PMDD would not respond. Further-more because PMS and PMDD are periodic conditions thatrequire treatment for long periods, the adverse effects of SSRIsshould be considered, particularly for adolescents. Insomnia,gastrointestinal disturbances and fatigue were the most com-monly reported short-term adverse effects associated withSSRI use [26]. In addition, sexual dysfunction, (reduced libidoand anorgasmia), weight gain and gradual loss of effectivenesshave been document with long-term SSRI use.

Other serotonergic antidepressants such as clomipramineand nefazodone have been documented as effective treatmentfor PMS and PMDD [120,129,130].

Noradrenergic agonist antidepressants are probably notefficacious as treatment for PMS/PMDD [128]. Eriksson et al.[131], reported the significant superiority of paroxetine (anSSRI) over maprotiline (a selective noradrenaline re-uptakeinhibitor [NARI]), which suggests that PMS respond better

to SSRIs than to antidepressants with a noradrenergic profile.However, one study found that nortriptyline, an NARI, wasan efficacious treatment for PMS [132].

5.5 AnxiolyticsThe anxiolytic alprazolam which is a short acting benzodi-azepine with antidepressant properties, has been reported tobe effective in the management of PMS and PMDD at a doseof 0.25 – 0.5 mg t.i.d. administered during the late lutealphase of the menstrual cycle [107,133,134]. Another anxiolytic,Buspirone, a 5-HT agonist, has also been reported to be moreeffective than placebo [135]. However, because anxiolytics areassociated with a higher rate of undesirable side effects, suchas sedation and, in the case of alprazolam and other benzodi-azepines, have addictive potential, the use of these medica-tions for long-term management of PMS and PMDD maynot be advisable, though withdrawal effects were not reported.

5.6 β-Blockersβ-Blockers including propranolol and atenolol have been usedfor PMS and PMDD and may be particularly useful inpatients whose symptoms are seasonal. Such treatment wasbased on experience with seasonal affective disorder, which isbelieved to respond to propranolol based on its effect on mela-tonin secretion. However, in a study of 11 patients with PMS,there was no significant improvement in mood followingtreatment with atenolol versus placebo [136,137]. The role ofβ-blockers in treatment of PMS and PMDD is still unclear.

5.7 DiureticsThe use of diuretics in the management of PMS has beenpractised for at least 50 years. Diuretics have been advocatedbecause of reports of fluid retention symptoms during theluteal phase of the menstrual cycle. There is no conclusive evi-dence that thiazide diuretics are beneficial in treating PMS.However, the antialdosterone, spironolactone is believed bysome to be the only diuretic that may be of specific benefit forwomen with PMS [42]. Moreover, the chronic use of thiazidesplaces the patient at risk for hypokalaemia, secondary aldos-teronism and cyclic oedema [42]. Three randomised trials[138-140] reported positive results, including improvement ofphysical symptoms such as sense of weight gain and some-times breast tenderness, also when spironolactone was givenonly intermittently during the luteal phase.

5.8 Non-steroidal anti-inflammatory drugsThe NSAIDs mefenamic acid and naproxen, administeredduring the luteal phase have been studied in small placebo-controlled randomised trials [141-143] and were reported to sig-nificantly reduce both physical (headache, fatigue, other pain)and mood (tension, irritability, mood swings) symptoms ascompared with placebo. Medication was given ∼ 1 weekbefore the onset of menses and continued through the firstfew days of bleeding so as to have an impact on dysmenor-rhoea as well. Additional studies are needed.

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5.9 LithiumSince its introduction into psychiatry > 40 years ago, lithiumtreatment has been widely used for prevention of bipolar dis-orders. Several studies have investigated the use of lithium forpremenstrual tension without consistent positive results. Fur-thermore, lithium may cause adverse effects and is not favour-ably viewed for PMS/PMDD [144-147].

5.10 Non-pharmacological interventionsComplementary/alternative therapies have recently becomemore popular and more acceptable. Surveys of women in theUS [148] and UK [149] found that those with PMS had tried arange of complementary/alternative therapies including diet,yoga, massage, exercise, faith healing, hypnosis, Chineseherbs, acupuncture, chiropractic, meditation, homeopathyand vitamins/supplements. Unfortunately, none have beenadequately evaluated. At most they may be considered aspromising until well conducted double-blind studies con-firm their efficacy. Diet, nutritional supplements and exer-cise have also been studied for PMS and PMDD, albeit, in alimited number of investigations. A carbohydrate-rich bev-erage was suggested to help relieve premenstrual symptoms[150]. Aerobic exercise was suggested to help the physicalsymptoms of PMS [151,152]. Calcium carbonate 1200 mg/dayin divided doses has been found in a large controlled study,as well as a small preliminary one, to reduce PMS symptoms[153]. Magnesium supplementation was found to be effectivefor the treatment of PMS in one placebo-controlled trial[154]. Vitamin E, at doses of 400 units/day, may be mini-mally effective for PMS [155]. Vitamin B6, 50 – 100 mg/day,may be effective for PMS based on meta-analysis ofinconsistent data [156].

Dietary modifications and supplements as well as lifestylemodifications and specific psychotherapies are not the focusof the current review. None have been definitively confirmedas efficacious by themselves. However, reduction of salt, sugar,alcohol and caffeine consumption as well as some other die-tary modifications are general well-being enhancers. The sameapplies to exercise and increased social support and positivechanges in the environment.

Because of the possible importance of cognitive alterationsin the aetiology of PMS symptoms [157], several cognitive ther-apy modalities have been applied as treatment [40,41]. Some ofthem may be effective, but this still needs to be confirmed.

5.11 Herbal Treatments:As recently as 2001, an extensive review of the literature [158]

concluded that none of the trials of herbal medicines producedconvincing evidence of any effectiveness. One of the moststudied and administered potential remedies was primrose oil.It has been believed that women with PMS are deficient inγ-linoleic acid, an essential substrate for prostaglandin biosyn-thesis. Primrose oil, which is derived from the seeds of theprimrose plant, is rich in γ-linoleic acid and thus may be ofbenefit to women with PMS [159]. It has been widely used in

UK for women with PMS at a dose of 500 mg t.i.d. during theluteal phase [160] but, at best, marginal benefit for primrose oilwas found [159] and the authors concluded that this therapy ismost likely not beneficial.

5.11.1 ChasteberryThe fruits of Vitex agnus castus (the chaste tree) contain a mix-ture of iridoids and flavonoids, and compounds similar instructure to the sex hormones have been isolated from theleaves and flowers [161]. The effects of agnus castus have beendescribed as similar to those of the corpus luteum [162,163]. Themechanism of action may also be related to modulation ofstress-induced prolactin secretion via dopamine, withoutdirectly affecting luteinising hormone or follicle stimulatinghormone [164,165]. The plant has been used traditionally todecrease libido in monks and increase the wellbeing of meno-pausal women as well as to relieve the symptoms of premen-strual syndrome, although systematic evaluation of its efficacyis relatively recent [164,166]. Three randomised double-blindplacebo-controlled trials suggested that it may be effective inrelieving PMS symptoms [167-169].

6. Conclusion and expert opinion

PMS and PMDD are very prevalent among women ofreproductive age. When they cause impairment and/or dis-tress, pharmacological treatment is warranted, available andquite effective.

Prior to initiation of pharmacological-hormonal treatment,general well-being should be enhanced. This includesimproved self-care, exercise and other lifestyle changes,attempts at improvement of environmental and social sup-port, dietary changes, multivitamins (including vitamin B6 inlow dosages), calcium carbonate, relaxation training and otherstress reduction measures. If available and affordable, cogni-tive therapy may be applied. For any woman, proper educa-tion and information should be provided.

These non-specific measures may be applied while thewoman prospectively monitors her symptoms on a dailybasis. In many mild-to-moderate cases, they are sufficient.However, for women with severe PMS/PMDD, two classesof treatment are effective. First, physiological elimination ofthe trigger – suppression of ovulation. This may be achievedby GnRH analogues and preferably by selected monophasicoestrogen-progestin contraceptives. It may also be achievedby high levels of oestrogen, preferably estradiol transdermalpatches. However, suppression of ovulation with GnRH ago-nists is often time-limited because they cannot be used safelyon a long-term basis. It should be emphasised that in the US,none of these treatments are FDA approved for PMS indica-tions. Second, the FDA did approve two symptomatic treat-ments for PMDD: fluoxetine and sertraline. These two SSRIantidepressants are effective when given continuouslythroughout the menstrual cycle. They are equally effectivewhen administered intermittently – only during the luteal

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phase of the menstrual cycle. Similar efficacy is projected forother SSRIs or SSRI + NARIs or other combined-actionpreparations. Recently, the use of fluoxetine as two singledoses spaced 1 week apart during the luteal phase has beenreported to be effective.

There are several widely publicised treatment modalitiesthat were not reported to be effective. Foremost among themis progesterone. The same applies to thyroid hormones and

lithium. The efficacy of these medications for a small sub-group of women with PMS is still a possibility.

Despite the enthusiasm for SSRIs, it should be emphasisedthat they have been reported to be effective in only 60% ofwomen with PMDD. This may be due to the diversity ofpremenstrual syndromes. Innovative approaches to treat the40% of women who are non-responders to SSRIs still needto be developed.

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Affiliation:Mohamed F. Mitwally, MD2, Linda S. Kahn, PhD3 & Uriel Halbreich, MD†1,2,3

†Author for correspondence1Director of Biobehavioural Research, SUNY Clinical Center, BB-170, 462 Grider Street, Buffalo, NY 14215, USA2Department of Gynecology and Obstetrics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14215, USA3Biobehavioural Program, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Biobehavioral Program, 462 Grider Street, Buffalo, New York, NY 14215, USA

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Pharmacotherapy of premenstrual syndromes and premenstrual disphoric disorder: current practices

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