Introduction
Premenstrual Syndrome (PMS) can be defined as a pattern of emotional, behavioral, and physical symptoms that occur premen- strually and remit after menses (World Health Organization 1996).
These symptoms typically include minor mood changes such as irritability, tension, or depressed mood, and physical complaints such as breast tenderness, bloating, cramps, or headache. Premen- strual dysphoric disorder (PMDD) denotes PMS with prominent mood symptoms (irritability, tension, dysphoria, or affective lability) severe enough to markedly affect work, social activities, or rela- tionships with others (American Psychiatric Association 1994).
The etiology of PMS and PMDD is still largely unknown, though there is accumulating evidence that these disorders are primarily biological phenomena. For example, investigators have shown the elimination of premenstrual complaints with suppression of ovu- lation (Muse et al. 1984; Schmidt et al. 1998) or surgical menopause (Casper and Hearn 1990; Casson et al. 1990) and an absence of symptoms during nonovulatory cycles (Hammarbäck et al. 1991).
Additionally, there is recent, convincing evidence of the heritability of premenstrual symptoms (Kendler et al. 1998).
The role of the female sex hormones in premenstrual symptoma- tology has long been considered of central importance. That both estrogen and progesterone are important in the manifestation of premenstrual symptoms has been shown in studies of postmen- opausal hormone replacement therapy (Hammarbäck et al. 1985;
Henshaw et al. 1996) and in a recent animal model of PMS (Ho et al. 2001). Women who received estrogen alone did not show any cyclical worsening in mood or physical symptoms (Hammarbäck et al. 1985).
Estrogens and Other Hormones in the Treatment of Premenstrual Syndromes
Leslie Born and Meir Steiner
It was previously thought that premenstrual complaints were induced by hormone deficiency, i.e., a decrease in serum levels of es- tradiol, progesterone, or estradiol and progesterone, in the late luteal phase. Severe PMS or PMDD was regarded as a manifestation of steroid withdrawal. This premise has been challenged by the finding of no differences in the levels or patterns of secretion of progesterone, estradiol, follicle-stimulating hormone, luteinizing hormone, testos- terone-estradiol-binding globulin, dehydroepiandrosterone sulfate, dihydrotestosterone, prolactin or cortisol in women with or without PMS (Rubinow et al. 1988).
By the late 1990s, there was some discussion in the literature as to whether the hormonal changes occurring during the late luteal phase are in fact relevant to the onset of premenstrual symptoms.
One line of thinking posited that premenstrual symptoms begin with the high mid-cycle peak of progesterone and/or estradiol and mani- fest with a delay of a few days or a week, independently of the subse- quent changes in serum hormonal levels (Eriksson et al. 2000a).
Another group examined whether the luteal phase is necessary for the expression of PMS and experimentally showed a follicular phase onset of PMS (Schmidt et al. 1991; Rubinow et al. 1998).
The hypothalamic-pituitary-gonadal axis in women with severe PMS and PMDD is, contrary to previous beliefs, apparently func- tioning normally, with normal estrogen and progesterone levels (Schmidt et al. 1998). The current consensus seems to be that normal ovarian function, rather than simple hormone imbalance, is the cyclic trigger for biochemical events within the central nervous system and other target tissues which unleash premenstrual symp- toms in vulnerable women (Roca et al. 1996). That is, in susceptible women there is an enhanced responsiveness to the interaction of gonadal steroids with neurotransmitters, in particular the seroton- ergic system (Steiner et al. 2002).
In general, two treatment strategies are being used in an attempt to change this interaction. One is the suppression of ovulation, which stops the cyclical hormonal fluctuations. The second – and more current – approach targets correction of possible changes in neuro- transmitter sensitivity by using psychotropic medications, notably serotonin reuptake inhibitors. It is generally recognized that women with PMS or PMDD are likely to be offered one of these two treat- ment pathways, i.e., hormonal or psychopharmacological man- agement, depending on the setting in which they are seen. The focus
of this review is on hormonal treatment strategies, i.e., the use of estrogen and other hormones to treat PMS.
Estradiol
Estrogen has been considered a major malefactor of PMS for over 60 years (Frank 1931). Yet, studies of estrogen in the treatment of PMS are relatively few. Unlike progesterone, which has been long known to have sedative properties, it was thought that estrogen increased energy (Dhar and Murphy 1991). It is now known that estrogen exerts multiple effects on the central nervous system through neurotransmitter receptor activation in estrogen-responsive neurons, leading to elevated mood, increased activity, and antide- pressant effects (Halbreich and Kahn 2001).
Two factors influence interpretation across studies of estrogen preparations for the treatment of PMS. One is the form of estrogen administration, the other is whether the estrogen is administered alone (unopposed) or combined with a progestin.
Trials of estrogen for the treatment of PMS have included implant, transdermal patch, and oral modes of estrogen delivery. Oral es- trogens are extensively metabolized in the liver (first-pass effect) and circulate primarily as estrone sulfate. This results in limited oral potency. Estrogen drug products administered by nonoral routes are not subject to true first-pass metabolism, but do undergo signifi- cant hepatic uptake, metabolism, and enterohepatic recycling. The transdermal delivery systems provide controlled, sustained near- constant release of effective estradiol, predictable absorption, lack of gastrointestinal adverse effects, and are associated with a slower metabolism to less active estrogens than oral preparations (Scott et al. 1991). Consequently, lower dosages of estradiol need to be given transdermally to achieve therapeutic plasma levels.
Transdermal administration may also render a greater therapeutic benefit for mood compared with oral estrogens, as the former provides minimal fluctuation of plasma estrogen levels and higher levels of estradiol, with a close physiological estrone to estradiol ratio (Halbreich and Kahn 2001). The results of the few studies of estrogen treatment for PMS are consistent with this line of thinking – as are studies of estrogen treatment of menopausal women. A much higher proportion of positive outcomes has been noted for parenteral or
transdermal administration of estrogen, compared with compounds that predominantly yield estrone (Yonkers et al. 2000).
The interpretation of estrogen studies in the treatment of PMS is further complicated by whether the intervention involved addition of continuous or cyclic administration of progestins, or unopposed estrogen. The cyclical addition of a progesterone analogue to estra- diol implants or transdermal estradiol patches to induce endometrial shedding may lead to a relapse of premenstrual-like complaints (Magos et al. 1986; Watson et al. 1989). A combination of estradiol patches and a progesterone-releasing intrauterine device as a treat- ment for premenstrual dysphoria has been proposed, but remains to be evaluated in controlled trials (O’Brien et al. 1995; see chap. 14).
Studies in which women were administered continuous (i.e., during both the follicular and luteal phases) estradiol at doses suffi- cient to suppress ovulation have consistently demonstrated the superiority of estrogen to placebo in the treatment of both physical and psychological symptoms of prospectively diagnosed PMS. This includes transdermal 17β-estradiol (Watson et al. 1989) and Estra- derm TTS (100-µg dose) (Smith and Zamblera 1995), and subcuta- neous estradiol implants (Magos et al. 1986).
A single trial of luteal phase oral conjugated estrogen (Premarin) showed an aggravation, rather than a resolution, of mental or physical premenstrual symptoms in a sample of 11 women (Dhar and Murphy 1990).
In one case, a 100-mg estradiol/ 100-mg testosterone implant with cyclical norethisterone was successfully used to treat recurrent premenstrual depressive symptoms (Crammer 1986). Following treatment, the subject’s elevated plasma cortisol levels returned to normal, and she remained completely well for the next 8 years.
Selective estrogen receptor modulators (SERMs), “compounds that selectively interact with the estrogen receptor to produce targeted tissue-dependent agonist or antagonist effects,” have been indicated for the treatment and/or prevention of breast and endome- trial cancer, osteoporosis, and coronary heart disease (Halbreich and Kahn 2000). In women of reproductive age, there is most likely an antagonistic effect between SERM and estrogen. A greater under- standing, though, of the mechanisms of estrogen effects on the CNS portends the development of a SERM with a sustained estrogen agonist effect on the brain and a possible treatment for PMS.
Progesterone
Progesterone is perhaps the most widely known, albeit polemical treatment for PMS. The rationale for progesterone therapy has been the ostensible relationship between PMS symptoms and cyclic changes in plasma progesterone levels and the presumed low levels of progesterone in women with PMS (Dalton 1990). Until the early 1990s, progesterone pessaries or suppositories were among the most widely prescribed treatments for PMS in North America and the United Kingdom (Wyatt et al. 2001).
Yet, there is neither consistent evidence that plasma progesterone, allopregnanolone, or pregnanolone levels are altered in women with PMS (Rubinow et al. 1988; Schmidt et al. 1994; Wang et al. 1996;
Bicikova et al. 1998; Monteleone et al. 2000; Girdler et al. 2001; Free- man et al. 2002) nor any indication that progesterone or progesterone receptors are mediators of PMS (Chan et al. 1994). Notwithstanding, there is recent evidence to suggest progesterone and the neuro- steroids may have an important role in the pathogenesis of these dis- orders (Epperson et al. 1999; 2002; Sundstrom-Poromaa et al. 2002).
Progesterone may have anxiolytic properties through the action of its metabolites at the GABA-A receptors by binding to the GABA receptor complex at or near the barbituate binding site (Majewska 1992). This had led some investigators to suggest that there may be subgroup of women who might benefit from progesterone (Rapkin et al. 1997; Freeman et al. 1995) and may help to explain the clinical satisfaction in some women with PMS who were treated with pro- gesterone.
A recent meta-analysis of 10 placebo-controlled trials investi- gating the efficacy of progesterone for the treatment of premenstrual symptoms has unequivocally shown that progesterone is no more beneficial than placebo for the treatment of PMS (Wyatt et al. 2001).
Only one study of 23 women found that oral micronized progesterone (at a dose of 3 × 100 mg/day) was superior to placebo for premenstrual mood symptoms (Dennerstein et al. 1985). The most commonly reported side effects for oral micronized progesterone were fatigue or sedation and dizziness (Wyatt et al. 2001). The (slight) efficaciousness and side effects of oral micronized progesterone may be due to a higher concentration of progesterone metabolites, in particular pregnanolone with its notable anxiolytic and hypnotic properties (Freeman et al. 1993).
There are two case reports on the successful use of natural proges- terone organogel for treatment of premenstrual dysphoria in adoles- cents, administered in a 25-mg bid dose to the dorsal hand during the late luteal phase (Schaller et al. 2000). Organogel is a matrix for the transdermal transport of drugs (Willimann et al. 1992).
The utility of several progestins in the treatment of premenstrual mood symptoms has also been tested, and although the results are not as consistent as those of the trials using progesterone, they are generally negative (Wyatt 2001). The progestin most commonly evaluated was dydrogesterone: the results of two prospective pla- cebo-controlled studies showed no significant difference between placebo and dydrogesterone in the rating of premenstrual symptoms (Williams et al. 1983; Dennerstein et al. 1986). Taken together, the results of several open trials suggested some relief for somatic symptoms; yet interpretation of some of these findings is hindered by the lack of a prospective diagnosis for PMS (Wyatt 2001).
Some, but not all, studies with medroxyprogesterone suggest that this compound may be somewhat better than progesterone or dy- drogesterone for premenstrual depression or other psychological symptoms and breast discomfort (Jordheim 1972; West 1990; Helberg et al. 1991). Again, it should be noted that in two trials there was no prospective diagnosis of PMS (Jordheim 1972; Helberg et al. 1991).
West noted breakthrough bleeding in about three-fourths of the cycles treated with medroxyprogesterone.
Two placebo-controlled trials of norethisterone in the treatment of PMS reported significant improvement for breast symptoms only (Ylöstalo et al. 1981; West 1990).
Oral Contraceptives
Oral contraceptives (OCs) suppress ovulation while maintaining menstruation through periodic steroid withdrawal. OCs typically contain a combination of ethinylestradiol and a progestin. Premen- strual symptoms have been prospectively documented in women taking oral contraceptives (Bancroft and Rennie 1993; Marriott and Faragher 1986; Sveindóttir and Bäckström 2000; Freeman et al.
2001a).
Years ago, there was a common perception that OCs caused mood disorders. A recent review of the literature, however, has found
limited support for OC-induced mood deterioration (Yonkers et al.
2000). The extent to which OCs alleviate, precipitate, or exacerbate premenstrual mood and behavior symptoms remains unresolved (Kahn and Halbreich 2001). The use of oral contraceptives in reducing PMS symptoms has been somewhat controversial, with clinical trials few in number.
The more recent findings are, at best, suggestive of some benefit, mostly for the physical symptoms such as increased appetite, cravings, and acne (Freeman et al. 2001b). One group (Graham and Sherwin 1992; 1993) found OCs to be effective in treating breast pain and bloating, but to be no more beneficial than placebo in reducing premenstrual mood symptoms. Another group (Walker and Bancroft 1990) found breast tenderness to be the only symptom showing a clear difference between OC users and nonusers, with monophasic OC users experiencing less discomfort than triphasic users or OC nonusers. Bancroft and Rennie (1993) found that in comparison to nonusers, OC users (monophasic or triphasic) experienced signifi- cantly less improvement in negative mood, in particular irritability.
Some investigators, on the other hand, have reported OCs to be an effective option for treatment of PMS mood symptoms (Roy-Byrne et al. 1984; Bäckström et al. 1992). Although both monophasic and triphasic preparations have been shown to be beneficial, women taking combined preparations report less severe premenstrual negative moods than those taking triphasic preparations (Bancroft et al. 1987; Bäckström et al. 1992; Bancroft and Rennie 1993). In one study, a monophasic desogestrel pill was more effective in reducing negative mood changes than monophasic or triphasic levonorgestrel pills, while the triphasic preparation was more effective in relieving physical symptoms (Bäckström et al. 1992).
Androgens
The influence of androgens on behavior and mood in women is gaining attention. Androgen excess in women has been suggested to be associated with depression, irritability, and compulsive behavior (Eriksson et al. 2000b). Many researchers regard irritability as the cardinal symptom of PMDD (Steiner et al. 1980; Endicott et al. 1999).
Ovarian production of androstendione, the major ovarian androgen, is influenced by luteinizing hormone and, hence, fluctuates during
the menstrual cycle, with higher levels in the luteal than in the folli- cular phase. While there are mixed reports on (abnormal or normal) serum levels of testosterone and premenstrual complaints (Eriksson et al. 2000b), a strong correlation between irritability and free testos- terone levels has been found in a group of women diagnosed with PMDD (Steiner et al. 1997).
Several studies of spironolactone, a testosterone (and aldosterone) antagonist, have reported a significant reduction in premenstrual psychological and physical symptoms compared with placebo (O’Brien et al. 1979; Burnet et al. 1991; Hellberg et al. 1991; Wang et al. 1995). The beneficial effect of spironolactone may at least partly be due to the antiandrogenic properties of the drug (Burnet et al. 1991;
Hellberg et al. 1991). One group noted, however, that a significant difference in androgen levels from follicular to the luteal phases may be an important determinant of response to spironolactone therapy in the treatment of PMS (Burnet et al. 1991).
Women who received an oral contraceptive with a spironolactone- like progestin and antiandrogenic properties for the treatment of PMDD showed, after three cycles of use, only a slight improvement in psychological symptoms compared with a placebo group (Freeman et al. 2001b).
Ovulation Suppressants
Research has shown that gonadotropin-releasing hormone (GnRH) agonists can reversibly suppress the menstrual cycle, and this is often called medical ovariectomy or medical menopause. GnRH agonists have proven to be very successful in relieving mostly physical symptoms in clinical trials. Intranasal buserelin (Hammarbäck and Bäckström 1988; Hussain et al. 1992) or intramuscular leuprolide (Mezrow et al. 1994; Brown et al. 1994; Freeman et al. 1997; Di Carlo et al. 2001) are the most appropriate GnRH treatments for clinical use.
Unfortunately, the long-term use of GnRH agonists is limited by the occurrence of side effects that mimic menopause and the potential for hypoestrogenism and osteoporosis. Preliminary evi- dence suggests that “add-back” therapy with estrogen and proge- sterone replacement therapy may prevent some of these side effects (Leather et al. 1993; Mezrow et al. 1994). A recent pilot study of five
patients with severe PMS who received depot leuprolide with add- back therapy showed stable bone mineral density more than 36 months later (Mitwally et al. 2002). Notwithstanding, two groups have found a reduced clinical response of GnRH analogue therapy with the addition of estrogen and progesterone (Leather et al. 1999, Schmidt et al. 1998).
Tibolone (a synthetic add-back compound with estrogenic, andro- genic and progestogenic properties) in combination with a GnRH agonist has been proven to provide long-term medical treatment for women suffering from premenstrual physical and psychological symptoms (Di Carlo et al. 2001). Treatment with tibolone alone has also proved to be effective in reducing mood and somatic PMS symptoms (Taskin et al. 1998).
Danazol, a gonadotropin inhibitor (known as Danocrine and Cyclomen), has also been effective in clinical trials (Sarno et al. 1987;
Hahn et al. 1995; O’Brien and Abukhalil 1999) and in the treatment of premenstrual mastalgia (O’Brien and Abukhalil 1999). Some common side effects with the use of danazol, however, include decrease in breast size, irregular menstrual periods, weight gain, redness of skin, and nervousness.
Summary and Recommendations
To date, no single intervention has proven to be equally effective in treating all women with PMS or PMDD. The optimal treatment plan begins with lifestyle modifications, followed by pharmacotherapy.
Most, but not all studies, suggest the symptoms of PMS are effec- tively reduced by inhibition of ovulation. However, for the long-term management of PMS, all of these strategies are somewhat proble- matic concerning tolerability and adverse health effects. First line therapy is still low-dose selective serotonin reuptake inhibitors, which have demonstrated efficacy with minimal side effects (Dimmock et al. 2000; Born and Steiner 2001).
The average age of onset of severe PMS or PMDD is around 26 years. Further evidence suggests that symptoms gradually worsen over time and most likely recur when treatment is halted (Endicott et al. 1999). Thus, therapeutic goals must be set to ensure maximal safety and efficacy for the patient.
Modification of the menstrual cycle should be considered only after all other treatment options have failed (Eriksson et al. 2002).
The adverse effects associated with ovulation suppression (in partic- ular, the GnRH agonists, estrogen, and danazol) are serious enough to question use of these methods as first-line treatments for severe PMS or PMDD. Moreover, the utility of a treatment that is advised for up to 6 months only, for example, GnRH agonists, is questionable as PMS and PMDD symptoms will persist until the menopause.
Some authors have suggested use of a GnRH agonist as a temporary strategy to assist with decision-making for the most appropriate therapeutic option (e.g., Lyall et al. 1999).
Symptom charting will help to track efficacy, symptom response to dosing changes, symptoms on termination of therapy, and real versus perceived side effects. Investigators have yet to reach a consensus on how to define efficacy. Clinically, the easiest way to define efficacy is by the reduction of luteal symptoms, i.e., the luteal symptoms remit significantly, or the follicular to luteal difference is less than 30% (Born and Steiner 2001).
For women reporting premenstrual somatic complaints but not psychological symptoms, hormonal intervention may be of limited value. However, further studies are warranted to clarify the explicit role of various forms of hormonal treatment for the management of PMS and PMDD.
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