Treatment of premenstrual syndrome with gonadotropin-releasing hormone agonist in a low dose regimen.

BACKGROUND: GnRH agonists constitute a well-documented treatment for premenstrual syndrome (PMS). However, the hypo-estrogenic state induced by the treatment renders it less suitable for long-term clinical use. The aim of the current study was to investigate the efficacy of a low dose GnRH agonist with respect to its ability to relieve premenstrual symptoms and maintain regular ovulatory cycles. METHODS: The effect of a low dose GnRH agonist (buserelin) on luteal phase symptomatology was evaluated in 27 women with severe premenstrual syndrome. The design was doubleblind, placebo-controlled and cross-over. Patients were randomized to either GnRH-agonist intranasally in a dosage of 100 microg once daily for two months or placebo for two months before the cross-over was made. The primary outcome measure consisted of daily symptom ratings for mood and physical symptoms made by the patients throughout the study. Adverse events and hormone concentrations were assessed at visits every second week. RESULTS: Premenstrual irritability and depression were significantly relieved by low dose GnRH agonist. Positive symptoms such as friendliness and cheerfulness were also improved during the premenstrual week. Likewise physical symptoms of swelling and headache displayed a significant improvement during buserelin treatment, whereas breast tenderness scores were unaffected by the treatment. The low dose GnRH agonist treatment regimen induced anovulation in as much as 56% of patients, but these subjects were significantly older than those women who maintained ovulatory cycles throughout the study. CONCLUSION: GnRH treatment significantly reduced premenstrual depression and irritability. However, low dose GnRH therapy is prone to induce anovulation, particularly with increasing age.

Treatment of premenstrual syndrome by spironolactone: a double-blind, placebo-controlled study.

BACKGROUND: To reevaluate whether spironolactone, a steroid receptor antagonist, is effective in improving premenstrual syndrome (PMS) in a double-blind, placebo-controlled cross over study. METHODS: Thirty-five women with PMS were given one tablet of 100 mg spironolactone or placebo daily from day 14 of the menstrual cycle until the first day of the following menstruation. Two pretreatment cycles were observed for diagnosis in each woman, followed by 6 treatment cycles with spironolactone and placebo applied in either the first or second 3 months. The assessment of symptoms and diagnosis of PMS were based on prospective daily self-ratings made by the women using a validated visual analogue scale. RESULTS: The treatment with spironolactone was associated with an improvement in PMS symptoms compared to placebo as judged by significant decrease in negative mood symptom scores (p < 0.001) and somatic symptom scores (p < 0.001). Of the individual symptoms, spironolactone significantly improved irritability, depression, feeling of swelling, breast tenderness and food craving in comparison to placebo. A lasting effect of spironolactone was observed in women started with spironolactone after cross over to placebo. CONCLUSIONS: Spironolactone appears to be an effective therapy for the negative mood changes and somatic symptoms in PMS.

Premenstrual syndrome--psychiatric or gynaecological disorder?

The premenstrual syndrome (PMS) is a combination of mental and physical symptoms arising in the luteal phase of the menstrual cycle. The symptoms disappear after the onset of menstruation. During the rest of the follicular phase the patient is free from symptoms. The cyclical nature of the symptom variations is characteristic of the syndrome. The lack of a commonly accepted definition and a way to diagnose PMS has led to contradictory results in the search for its aetiology and treatment. The diagnosis of PMS should be based on prospective daily ratings of symptoms and defined criteria of subgroups. In our studies three subgroups can be identified. The "Pure PMS" group with significant cyclical symptoms being worse during the luteal phase and no symptoms during the follicular phase. A "Premenstrual aggravation" group with symptoms always present but with an aggravation premenstrually. A "Non-PMS" group of women who do not suffer from menstrual cycle related symptoms. These three groups show significant differences in the number of patients with an earlier psychiatric history and are different in the extent of neurosis on a personality test. The Pure PMS group had less neurosis and a lower frequency of patients with an earlier psychiatric history. In anovulatory cycles, whether induced or spontaneous, the cyclical nature of symptoms disappeared. This shows the important role that the corpus luteum has in precipitating symptoms in PMS. GnRH-agonists can be used to induce anovulation and this will stop the cyclical changes. Postmenopausal women receiving oestradiol/progestagen sequential treatment develop PMS-like symptoms when progestagen is added to the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous anovulation causing disappearance of cyclical symptoms in women with the premenstrual syndrome.

In the premenstrual syndrome the negative symptoms appear during the luteal phase of the menstrual cycle. Ovulation and the formation of a corpus luteum seem to be of great importance in precipitating the syndrome. In a large group of women with premenstrual syndrome investigated daily with symptom ratings and weekly plasma estradiol and progesterone assays, 8 were found to have one ovulatory and one spontaneously occurring anovulatory menstrual cycle. In both these cycles, the post- and premenstrual phases were compared by testing for recurrence of symptoms. All patients showed a highly significant cyclical worsening of negative premenstrual symptoms during the ovulatory cycles, whereas in the anovulatory cycles the cyclical symptoms disappeared, resulting in relief of the premenstrual syndrome. These results support earlier hypotheses, suggesting that the premenstrual syndrome appears as a result of provoking factors produced by the corpus luteum. This view is in line with earlier therapeutic findings showing that induced anovulation can relieve the premenstrual syndrome.

Progestogen addition during oestrogen replacement therapy--effects on vasomotor symptoms and mood.

Vasomotor symptoms and mood changes were followed in 2 groups of post-menopausal women receiving cyclic replacement therapy with 3 mg/day of percutaneous oestradiol-17 beta alone or in sequential combination (days 11-21) with lynestrenol 5 mg/day. During 6 mth of therapy, daily symptom ratings were performed using a visual analogue scale technique. Serum levels of oestradiol were similar in both groups but sequential oestrogen/progestogen treatment was more efficient in suppressing vasomotor symptoms and serum gonadotropins. However, all negative mood symptoms were also more pronounced in this group. Progestogen addition may enhance the therapeutic effect on hot flushes and sweats but, at least in individual women cause unfavourable effects on mental status, mood and well-being.

Relationship between symptom severity and hormone changes in women with premenstrual syndrome.

The relationship between symptoms and plasma hormone levels was investigated during 2 consecutive cycles in 18 women with the premenstrual tension syndrome (PMS). The women were asked to provide daily symptom ratings using a previously described and tested rating scale, and blood samples were taken daily during the luteal phase and most of the follicular phase for plasma estradiol, progesterone, FSH, and LH measurements. The symptom scores during the premenstrual phase were compared within each woman and between cycles with higher luteal phase and cycles with lower luteal phase plasma estradiol, progesterone, FSH, and LH concentrations. The results indicated that higher adverse premenstrual scores occurred in cycles with high luteal phase plasma estradiol and progesterone concentrations. In particular, a high luteal phase plasma estradiol concentration was related to higher premenstrual scores for adverse symptoms and lower scores for positive mood symptoms. The women experienced more severe PMS in cycles with high luteal phase plasma estradiol and progesterone levels. The results contradict the hypothesis that progesterone deficiency plays a part in the etiology of PMS.

A demographic study in subgroups of women seeking help for premenstrual syndrome.

Eighty-two consecutive cases of women who sought help for premenstrual syndrome (PMS) at the PMS clinic, University Hospital of Umeå, Sweden were studied. The presence of PMS was diagnosed by prospective daily rating of symptoms. The women also completed a modified Moos menstrual distress questionnaire (MDQ)- and an Eysenck Personality Inventory (EPI). Two patients were excluded because of poor daily ratings. The remaining 80 women were divided after the diagnostic procedure into three groups: group I with pure PMS, group II called the premenstrual aggravation group and group III where cyclicity of symptoms could not be ascertained. Several demographic factors concerning marital status, education, employment, and previous medical, psychiatric and PMS history were studied, as well as menstrual problems per se. No significant differences between the three subgroups were found in the analysis of the demographic factors. The only difference was that the pure PMS group contained a significantly smaller number of patients with pathologically high scores for neuroticism in the EPI, together with a smaller number of patients with a psychiatric history.

Induced anovulation as treatment of premenstrual tension syndrome. A double-blind cross-over study with GnRH-agonist versus placebo.

A treatment with the GnRH-agonist, buserelin, was given intranasally in a dosage of 400 micrograms once daily, to induce anovulation in 26 women with premenstrual tension syndrome; 23 patients completed the study course. The design was double-blind and cross-over. Daily symptom ratings were made for two pretreatment, diagnostic cycles and continued for up to six cycles or 6 months. The rating scale used was an earlier described visual analogue scale. Blood samples for estradiol and progesterone radio-immunoassay were taken once weekly throughout the study. Results show beneficial effects of both placebo and GnRH-agonist, compared with the pretreatment situation. The GnRH-agonist was, however, significantly better than placebo. At the end of the treatment periods the patients while still taking placebo, still showed cyclical symptom changes, whereas during the GnRH-agonist treatment the cyclical changes had disappeared. The results indicate that a factor from the corpus luteum must be involved in the etiology of cyclical mood changes. The results also show that inhibition of ovulation by mean of GnRH-agonists is one possible way to treat premenstrual tension syndrome.

Ovarian steroid hormones. Effects on mood, behaviour and brain excitability.

Estradiol and progesterone both accumulate in the brain. Specific cytosol receptors are present in certain CNS regions. Estradiol increases but progesterone decreases the brain's excitability. The effects can be mediated via monoamine systems or a change in monoamine metabolizing enzymes, but other mechanisms are possible. The combination of estradiol and progesterone seem to provoke a negative mood change in certain sensitive women. Estradiol and progesterone singly seem not to have these negative effects on mood, but perhaps positive effects instead.

Cyclical mood changes as in the premenstrual tension syndrome during sequential estrogen-progestagen postmenopausal replacement therapy.

The etiology of the cyclical mood changes seen in the premenstrual syndrome is still unknown. A close relation to the luteal phase has been shown. One of the differences between the follicular and the luteal phase is the higher plasma progesterone concentration during the luteal phase. The present investigation has been conducted to study the effect of exogenously administered estrogen/gestagen sequential postmenopausal replacement therapy on mood and physical signs. Twenty-two women requiring postmenopausal estrogen treatment were recruited and divided into two groups. Eleven women were given estradiol treatment only (Oestrogel creme 3 mg percutaneously/day) for 21 days with a subsequent break of 7 days. The other 11 women were in addition given progestagen (Lynestrenol, Orgametril 5 mg/day) during the last 11 days of treatment. The women were asked to keep a daily record of their mood, using a visual analogue scale earlier tested in women with premenstrual syndrome. They also kept a record of physical signs and sexual feelings. The records were kept for between one and 6 months. The group with estrogen treatment only did not show any cyclical worsening in mood or physical signs during the treatment. The women who in the latter stage of the estrogen treatment cycle also received progestagen, showed significant cyclicity in both moods and physical signs, with a maximum symptom degree during the final days of gestagen treatment. The negative mood change started 1-3 days after the progestagen was added to the treatment. The results suggest that progestagens are involved in the provocation of cyclical symptom changes seen in the premenstrual syndrome.