Lotta Andréen

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

Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators.

UNLABELLED Certain women experience negative mood symptoms as a result of progesterone during the luteal phase of the menstrual cycle, progestagens in hormonal contraceptives, or the addition of progesterone or progestagens in sequential hormone therapy (HT). This phenomenon is believed to be mediated via the action of the progesterone metabolites on the GABA(A) system, which is the major inhibitory system in the mammalian CNS. The positive modulators of the GABA(A) receptor include allopregnanolone and pregnanolone, both neuroactive metabolites of progesterone, as well as benzodiazepines, barbiturates, and alcohol. Studies on the effect of GABA(A) receptor modulators have shown contradictory results; although human and animal studies have revealed beneficial properties such as anaesthesia, sedation, anticonvulsant effects, and anxiolytic effects, recent reports have also indicated adverse effects such as anxiety, irritability, and aggression. It has actually been suggested that several GABA(A) receptor modulators, including allopregnanolone, have biphasic effects, in that low concentrations increase an adverse, anxiogenic effect whereas higher concentrations decrease this effect and show beneficial, calming properties. The allopregnanolone increase during the luteal phase in fertile women, as well as during the addition of progesterone in HT, has been shown to induce adverse mood in women. The severity of these mood symptoms is related to the allopregnanolone serum concentrations in a manner similar to an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. It has also been shown that progesterone/allopregnanolone treatment in women increases the activity in the amygdala (as measured with functional magnetic resonance imaging) in a similar way to the changes seen during anxiety reactions. However, it is evident that only certain women experience adverse mood during progesterone or GABA(A) receptor modulator treatments. Women with premenstrual dysphoric disorder (PMDD) have severe luteal phase related symptoms; in this phase, they show changes in GABA(A) receptor sensitivity and GABA concentrations that are related to the severity of the condition. These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA(A) receptor. CONCLUSION Progesterone and progestagens induce negative mood, most probably via their GABA(A) receptor active metabolites. In postmenopausal women treated with progesterone and animals treated with allopregnanolone, there is a bimodal association between serum allopregnanolone concentration and adverse mood, resembling an inverted U-shaped curve. In humans, the maximal effective concentration of allopregnanolone for producing negative mood is within the range of physiological luteal phase serum concentrations.

Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone

OBJECTIVE To compare severity of negative mood and physical symptoms between women with different progesterone, allopregnanolone, and pregnanolone plasma concentrations during sequential Hormone Replacement Therapy (HRT) with vaginal progesterone suppositories. DESIGN A randomized, placebo-controlled, double-blind, crossover study. METHOD Postmenopausal women (n=36) with climacteric symptoms were treated with 2mg estradiol daily during three 28-day cycles. Vaginal progesterone suppositories with 400, 800 mg/day or placebo were added sequentially for 14 days per cycle. Daily symptom ratings using a validated rating scale were kept. Blood samples for progesterone, allopregnanolone, and pregnanolone radioimmunoassays were collected during each treatment cycle. RESULTS Women were divided into three groups (low, medium, and high) based on plasma allopregnanolone concentration during progesterone treatment. The concentration of allopregnanolone in the medium group corresponds to the concentration seen during the mid luteal phase of the menstrual cycle. Within women with medium allopregnanolone concentration significantly more negative mood and physical symptoms were rated during progesterone treatment compared to treatment with unopposed estrogen or placebo. Between women significantly more negative mood symptoms were seen during progesterone treatment cycles with medium allopregnanolone concentration compared to cycles with low concentration. Plasma progesterone, allopregnanolone, and pregnanolone concentrations increased with increasing progesterone dose. Progesterone and allopregnanolone plasma concentrations increased 2h after vaginal administration of progesterone at 400 and 800 mg/day. CONCLUSION Vaginal progesterone in sequential HRT causes negative mood, most likely mediated via allopregnanolone.

Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons

Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane Cl(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Tolerance to allopregnanolone with focus on the GABA-A receptor

Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the γ‐amino butyric acid –A (GABA‐A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA‐A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA‐A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA‐A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral‐posteriomedial nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA‐A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA‐A receptors.

Effects of Roux-en-Y gastric bypass surgery on eating behaviour and allopregnanolone levels in obese women with polycystic ovary syndrome

Abstract Polycystic ovary syndrome (PCOS) is associated with abnormal eating habits. We examined whether surgical treatment affected allopregnanolone levels and eating behaviour in nine women with PCOS who qualified for Rou-en-Y gastric bypass surgery. Blood samples were obtained to measure sex-hormone-binding globulin, total testosterone, progesterone, and allopregnanolone, and eating behaviour was evaluated using the Three-Factor Eating Questionnaire before surgery and at 6 and 12 months after surgery. Body mass index and total testosterone levels decreased, and progesterone and sex-hormone-binding globulin levels increased after bariatric surgery compared with pre-surgical values. In patients with anovulatory menstrual cycles, both the serum allopregnanolone level and the allopregnanolone/progesterone ratio were unchanged after surgery. The patients had high uncontrolled and emotional eating scores, and low cognitive restraint scores before surgery, and these scores had improved significantly at 6 and 12 months after surgery. The presurgical allopregnanolone levels were significantly correlated with uncontrolled eating. In conclusion, these results suggest that allopregnanolone appear to be part of the mechanism underlying the abnormal eating behaviour of obese PCOS patients by causing the loss of control over food intake. Roux-en-Y gastric bypass surgery can improve eating behaviour and clinical symptoms, and may facilitate weight loss in obese women with PCOS.

Treatment of premenstrual dysphoric disorder with the GABA(A) receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial

CONTEXT Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABAA receptor. This endogenous steroid may induce negative mood in sensitive women when present in serum levels comparable to the premenstrual phase. Its endogenous isomer, isoallopregnanolone, has been shown to antagonize allopregnanolone effects in experimental animal and human models. OBJECTIVE The objective was to test whether inhibition of allopregnanolone by treatment with the GABAA modulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase could reduce symptoms of the premenstrual dysphoric disorder (PMDD). The pharmacokinetic parameters of UC1010 when given as a subcutaneous injection were measured in healthy women prior to the study in women with PMDD. DESIGN This was an explorative randomized, double-blind, placebo-controlled study. SETTING Swedish multicentre study with 10 centers. PARTICIPANTS Participants were 26 healthy women in a pharmacokinetic phase I study part, and 126 women with PMDD in a phase II study part. Diagnosis followed the criteria for PMDD in DSM-5 using Daily Record of Severity of Problems (DRSP) and Endicotts algorithm. INTERVENTION Subjects were randomized to treatment with UC1010 (10 or 16mg) subcutaneously every second day during the luteal phase or placebo during one menstrual cycle. OUTCOME MEASURES The primary outcome measure was the sum of all 21 items in DRSP (Total DRSP score). Secondary outcomes were Negative mood score i.e. the ratings of the 4 key symptoms in PMDD (anger/irritability, depression, anxiety and lability) and impairment (impact on daily life). RESULTS 26 healthy women completed the pharmacokinetic phase I study and the dosing in the following trial was adjusted according to the results. 106 of the 126 women completed the phase II study. Within this group, a significant treatment effect with UC1010 compared to placebo was obtained for the Total DRSP score (p=0.041) and borderline significance (p=0.051) for the sum of Negative mood score. Nineteen participants however showed symptoms during the follicular phase that might be signs of an underlying other conditions, and 27 participants had not received the medication as intended during the symptomatic phase. Hence, to secure that the significant result described above was not due to chance, a post hoc sub-group analysis was performed, including only women with pure PMDD who completed the trial as intended (n=60). In this group UC1010 reduced Total DRSP scores by 75% compared with 47% following placebo; the effect size 0.7 (p=0.006), and for sum of Negative mood score (p=0.003) and impairment (p=0.010) with the effect size 0.6. No severe adverse events were reported during the treatment and safety parameters (vital signs and blood chemistry) remained normal during the study. CONCLUSIONS This explorative study indicates promising results for UC1010 as a potential treatment for PMDD. The effect size was comparable to that of SSRIs and drospirenone containing oral contraceptives. UC1010 was well tolerated and deemed safe.

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.