Inger Björn

The Role of Hormones and Hormonal Treatments in Premenstrual Syndrome

Premenstrual syndrome (PMS) is a menstrual cycle-linked condition with both mental and physical symptoms. Most women of fertile age experience cyclical changes but consider them normal and not requiring treatment. Up to 30% of women feel a need for treatment. The aetiology is still unclear, but sex steroids produced by the corpus luteum of the ovary are thought to be symptom provoking, as the cyclicity disappears in anovulatory cycles when a corpus luteum is not formed. Progestogens and progesterone together with estrogen are able to induce similar symptoms as seen in PMS. Symptom severity is sensitive to the dosage of estrogen. The response systems within the brain known to be involved in PMS symptoms are the serotonin and GABA systems. Progesterone metabolites, especially allopregnanolone, are neuroactive, acting via the GABA system in the brain. Allopregnanolone has similar effects as benzodiazepines, barbiturates and alcohol; all these substances are known to induce adverse mood effects at low osages in humans and animals. SSRIs and substances inhibiting ovulation, such as gonadotrophin-releasing hormone (GnRH) agonists, have proven to be effective treatments. To avoid adverse effects when high dosages of GnRH agonists are sed, add-back hormone replacement therapy is recommended. Spironolactone also has a beneficial effect, although not as much as SSRIs and GnRH agonists

Pathogenesis in menstrual cycle-linked CNS disorders.

Abstract: That 3alpha‐hydroxy‐5alpha/beta‐pregnane steroids (GABA steroids) have modulatory effects on the GABA‐A receptor is well known. In behavioral studies in animals high exogenous dosages give concentrations not usually reached in the brain under physiological conditions. Animal and human studies show that GABA‐A receptor‐positive modulators like barbiturates, benzodiazepines, alcohol, and allopregnanolone have a bimodal effect. In pharmacological concentrations they are CNS depressants, anesthetic, antiepileptic, and anxiolytic. In low dosages and concentrations, reached endogenously, they can induce adverse emotional reactions in up to 20% of individuals. GABA steroids can also induce tolerance to themselves and similar substances, and rebound occurs at withdrawal. Menstrual cycle‐linked disorders can be understood by the concept that they are caused by the action of endogenously produced GABA‐steroids through three mechanisms: (a) direct action, (b) tolerance induction, and (c) withdrawal effect. Examples of symptoms and disorders caused by the direct action of GABA steroids are sedation, memory and learning disturbance, clumsiness, increased appetite, worsening of petit mal epilepsy, negative mood as tension, irritability and depression during hormone treatments, and the premenstrual dysphoric disorder (PMDD). A continuous exposure to GABA steroids causes tolerance, and women with PMDD are less sensitive to GABA‐A modulators. A malfunctioning GABA‐A receptor system is related to stress sensitivity, concentration difficulties, loss of impulse control, irritability, anxiety, and depression. An example of withdrawal effect is “catamenial epilepsy,” when seizures increase during menstruation after the withdrawal of GABA steroids. Similar phenomena occur at stress since the adrenals produce GABA steroids during stress.

The impact of different doses of medroxyprogesterone acetate on mood symptoms in sequential hormonal therapy

The aim of this study was to compare adverse mood effects of two different doses of medroxyprogesterone acetate (MPA) during postmenopausal hormone replacement therapy (HRT) in women with and without a history of premenstrual syndrome (PMS). The study was designed as a randomized double-blind cross-over study and included 36 postmenopausal women at three health care areas in northern Sweden. The women received 2 mg estradiol continuously during five 28-day cycles and 10 mg or 20 mg MPA sequentially for 12 days during each cycle. The main outcome measures were mood and physical symptoms noted on a daily rating scale. We found that physical symptoms did not differ between 10 and 20 mg MPA. Both women with a history of PMS and women without responded with more negative mood symptoms with the lower dose of MPA. In women with previous PMS the higher dose of MPA enhanced positive mood symptoms. With respect to mood and physical symptoms, the aim to lower MPA doses in HRT is unwarranted.

Neuroactive steroids and central nervous system disorders.

Steroid hormones are vital for the cell life and affect a number of neuroendocrine and behavioral functions. In contrast to their endocrine actions, certain steroids have been shown to rapidly alter brain excitability and to produce behavioral effects within seconds to minutes. In this article we direct attention to this issue of neuroactive steroids by outlining several aspects of current interest in the field of steroid research. Recent advances in the neurobiology of neuroactive are described along with the impact of advances on drug design for central nervous system (CNS) disorders provoked by neuroactive steriods. The theme was selected in association with the clinical aspects and therapeutical potentials of the neuroactive steroids in CNS disorders. A wide range of topics relating to the neuroactive steroids are outlined, including steroid concentrations in the brain, premenstrual syndrome, estrogen and Alzheimers disease, side effects of oral contraceptives, mental disorder in menopause, hormone replacement therapy, Catamenial epilepsy, and neuractive steroids in epilepsy treatment.

Compliance to antidepressant drug therapy for treatment of premenstrual syndrome

Serotonin reuptake inhibitors (SSRIs) have today become the first-line treatment of premenstrual dysphoric disorder (PMDD). However, the actual success rate of these agents in clinical practice also depends on factors such as adequate dosing, duration of therapy and patient compliance. The aim of the current study was to investigate compliance and reasons for discontinuing tricyclic antidepressant (TCA) or SSRI treatment which had been prescribed for premenstrual syndrome. All women who were given an SSRI or TCA prescription for premenstrual symptoms at three gynecologic practices between January 1994 and December 1997 received a written questionnaire. In all, 202 women received the questionnaire, of whom 84.2% replied. Thirteen per cent never started TCA or SSRI treatment and 54% continued the therapy for more than 6 months. Reasons for discontinuing SSRI or TCA were negative side-effects (43%), other reasons (29%), a wish to deal with the problems ‘naturally’ (23%), fear of dependence (19%), not wanting to take these drugs (20%) and a desire to find out if the premenstrual symptoms had ended (18%). The main reason for poor compliance was negative side-effects, most often sexual dysfunction. The results of this study suggest that the future challenge in this area for gynecologists will be to ensure adequate education of patients and adequate monitoring of the initial phase of treatment.

Patients with psychiatric disorders in gynecologic practice--a three year follow-up.

Objective. Patients with depressive disorders are commonly encountered in gynecologic practice. The prevalence rates for depressive disorders have been reported to vary between 10 and 40% among patients consulting their gynecologist. The purpose of the current study was to study health care utilization by patients with a psychiatric disorder in the gynecologic setting during a three-year period after the initial diagnosis of depression and/or anxiety. Study design. In 1998 all scheduled and walk-in patients, at two gynecologic centers in northern Sweden during one month, were screened for prevalence of depression and anxiety disorders using the PRIME-MD system. Medical records for the period 16 December 1998 to 31 December 2001 have been reviewed. Results. Patients diagnosed with any anxiety disorder made significantly more appointments to the gynecologist and were acutely hospitalized more often than control subjects. Both patients with any depressive or any anxiety diagnosis made significantly more visits to health care personnel other than the gynecologist and they received counseling by phone and/or letter significantly more often than patients in the control group. Furthermore, patients with depressive and/or anxiety diagnosis were also referred to other medical specialists more often than controls. Conclusion. The present study has indicated that gynecologic patients with depression and anxiety over a three-year follow-up period have an increased health care utilization with more frequent consultations and more frequent referrals.

Adverse mood effects during postmenopausal hormone treatment in relation to personality traits

Objective When postmenopausal women are treated with sequential hormone therapy (HT), cyclical mood swings similar to symptoms seen in the premenstrual dysphoric disorder (PMDD) are described. Women with a history of premenstrual symptoms (PMS) seem to respond differently to the addition of a progestin to estrogen than women without previous PMS. This study aimed to investigate personality traits and daily mood symptoms in women with a history of PMS and women without, while treated with estrogen and sequential progestin. Methods A total of 106 women, who participated in clinical trials designed to evaluate mood and physical responses to sequential estrogen and progestin therapy, filled out the Karolinska Personality Scale (KSP) form, before entering the studies. The treatment consisted of 2 mg estradiol valerate continuously, with an addition of 10 mg medroxyprogesterone acetate (MPA) during the last 12 days of the 28-day cycle. Subjects kept daily symptom ratings using a validated symptom scale during these two treatment cycles, and these were used for the analyses. The study-groups were stratified for a history of PMS or not, appearance of progestin-induced adverse mood effects or not, and symptom cyclicity or not. Results There was a significant co-variation between the women who reported the highest negative mood scores during the addition of progestin to estrogen and a history of PMS. Women with PMS history reported different personality characteristics as having higher scores of anxiety symptoms of muscular tension, feeling more indirect aggression and lack of impulse control, and being less satisfied with their lives or childhood, compared to women without a PMS history. Women who reported the most intense negative mood symptoms during the progestin phase reported more somatic anxiety, an aim to avoid monotony, a lower satisfaction with life or childhood, and higher scores of indirect aggression and irritability. Conclusions Women with a history of PMS and women with a high anxiety-related personality might respond with adverse mood effects to a combination of estrogen and sequential progestin and therefore a thorough evaluation should be made, at the consultation for hormone therapy, of mood benefits or disadvantages before initiation of treatment and there should be a close follow-up after.

The role of progesterone and GABA in PMS/PMDD

The relationship between the luteal phase of the menstrual cycle and symptom development in premenstrual dysphoric disorder/premenstrual syndrome (PMDD/ PMS) is self-evident. Symptoms starts after ovulation and then increase in parallel with the rise in serum progesterone during the luteal phase. The symptom severity reaches a peak during the last five premenstrual days or the first day of menstruation. Thereafter, the symptoms decline and disappear 3–4 days after the onset of menstrual bleeding. During the postmenstrual phase there is a period of well-being, closely following estrogen production, to the estradiol peak. This suggests that there is a symptom-provoking factor produced by the corpus luteum of the ovary.1 This is further supported by the fact that in anovulatory cycles, spontaneous or induced, when a corpus luteum is not formed, no symptom cyclicity occurs.2–4

Neuroactive Steroids in Brain and Relevance to Mood

Depression and anxiety often affect women in relation to reproductive events like menarche, premenstrual periods, post-partum and perimenopause. A prominent example of the interaction between mood, neuroactive-steroids and the GABA system is premenstrual dysphoric disorder (PMDD). Severe premenstrual negative mood symptoms occur in 3–8% of women. Sex and stress hormones are metabolized to neuroactive steroids with effects on brain function as positive modulators of the GABA A receptor (called GABA-steroids) similar to benzodiazepines, barbiturates and alcohol. One example of a neuroactive sex steroid is allopregnanolone, and other GABA-steroids, are produced within the brain, by the adrenals at stress and from the ovary during the menstrual cycle. Animal and human studies show that benzodiazepines, barbiturates, alcohol and allopregnanolone have a bimodal effect on behavior. In high dosages or concentrations the positive GABA A receptor modulators are CNS depressants, anesthetic, and anxiolytic, whereas in certain sensitive individuals low concentrations instead of being anxiolytic cause severe anxiety, irritability, aggressiveness and depressive mood in 3–6% of individuals, and moderate symptoms in up to 30%. Low concentrations of GABA-steroids are found endogenously during the luteal phase and induce adverse emotional reactions. In women with PMDD/ PMS this paradoxical effect of neuroactive steroids seems to provoke negative mood symptoms as tension, irritability and depression. The mechanism behind the effect is called disinhibition that acts together with tolerance development by GABA A receptor active substances. Effective treatments are inhibition of ovarian steroid production or changing the CNS response to neuroactive steroids.