Oral contraceptives in premenstrual syndrome: A randomized comparison of triphasic and monophasic preparations

doi:10.1016/0010-7824(92)90006-F

Contraception

Volume 46, Issue 3, September 1992, Pages 253-268

https://doi.org/10.1016/0010-7824(92)90006-F Get rights and content

Abstract

Thirty-seven women with cyclical mood changes, either only in the premenstrual phase (‘pure PMS’) or during the entire cycle with premenstrual aggravation (‘PMA’), were recruited to participate in a randomized study investigating the effect of three different oral contraceptives (OCs) on mood symptoms; 32 out of the 37 women completed the study. The monophasic ethinylestradiol (EE)/desogestrel (DSG) OC was compared, in a single (doctor)-blind cross-over design, with a monophasic and a triphasic levonorgestrel (LNG)-containing combined OC. The women kept a record of their symptoms and complaints by noting daily ratings using a validated visual analogue scale. One pretreatment cycle was followed by four treatment cycles, two cycles on each OC. All OCs had a beneficial effect on the PMS symptoms compared to the pre-treatment period. There were no changes between consecutive cycles. Cyclical symptom changes were noted during all OC treatment.

The monophasic desogestrel pill provoked less changes in mood parameters than the monophasic and triphasic levonorgestrel OCs. However, physical complaints were less frequently reported during the use of the triphasic preparation as compared to the monophasic desogestrel preparation. Women with ‘pure’ PMS (premenstrual syndrome) were more consistent in their reactions on OCs compared to women with PMA.

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Cited by (96)

A scoping review of hormonal clinical trials in menstrual cycle-related brain disorders: Studies in premenstrual mood disorder, menstrual migraine, and catamenial epilepsy
2023, Frontiers in Neuroendocrinology
Cyclic variations in hormones during the normal menstrual cycle underlie multiple central nervous system (CNS)-linked disorders, including premenstrual mood disorder (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite this foundational mechanistic link, these three fields operate independently of each other. In this scoping review (N = 85 studies), we survey existing human research studies in PMD, MM, and CE to outline the exogenous experimental hormone manipulation trials conducted in these fields. We examine a broad range of literature across these disorders in order to summarize existing diagnostic practices and research methods, highlight gaps in the experimental human literature, and elucidate future research opportunities within each field. While no individual treatment or study design can fit every disease, there is immense overlap in study design and established neuroendocrine-based hormone sensitivity among the menstrual cycle-related disorders PMD, MM, and CE.
Background. The menstrual cycle can be a biological trigger of symptoms in certain brain disorders, leading to specific, menstrual cycle-linked phenomena such as premenstrual mood disorders (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite the overlap in chronicity and hormonal provocation, these fields have historically operated independently, without any systematic communication about methods or mechanisms.
Objective. Online databases were used to identify articles published between 1950 and 2021 that studied hormonal manipulations in reproductive-aged females with either PMD, MM, or CE. We selected N = 85 studies that met the following criteria: 1) included a study population of females with natural menstrual cycles (e.g., not perimenopausal, pregnant, or using hormonal medications that were not the primary study variable); 2) involved an exogenous hormone manipulation; 3) involved a repeated measurement across at least two cycle phases as the primary outcome variable.
Charting methods. After exporting online database query results, authors extracted sample size, clinical diagnosis of sample population, study design, experimental hormone manipulation, cyclical outcome measure, and results from each trial. Charting was completed manually, with two authors reviewing each trial.
Results. Exogenous hormone manipulations have been tested as treatment options for PMD (N = 56 trials) more frequently than MM (N = 21) or CE (N = 8). Combined oral contraceptive (COC) trials, specifically those containing drospirenone as the progestin, are a well-studied area with promising results for treating both PMDD and MM. We found no trials of COCs in CE. Many trials test ovulation suppression using gonadotropin-releasing hormone agonists (GnRHa), and a meta-analysis supports their efficacy in PMD; GnRHa have been tested in two MM-related trials, and one CE open-label case series. Finally, we found that non-contraceptive hormone manipulations, including but not limited to short-term transdermal estradiol, progesterone supplementation, and progesterone antagonism, have been used across all three disorders.
Conclusions. Research in PMD, MM, and CE commonly have overlapping study design and research methods, and similar effects of some interventions suggest the possibility of overlapping mechanisms contributing to their cyclical symptom presentation. Our scoping review is the first to summarize existing clinical trials in these three brain disorders, specifically focusing on hormonal treatment trials. We find that PMD has a stronger body of literature for ovulation-suppressing COC and GnRHa trials; the field of MM consists of extensive estrogen-based studies; and current consensus in CE focuses on progesterone supplementation during the luteal phase, with limited estrogen manipulations due to concerns about seizure provocation. We argue that researchers in any of these respective disciplines would benefit from greater communication regarding methods for assessment, diagnosis, subtyping, and experimental manipulation. With this scoping review, we hope to increase collaboration and communication among researchers to ultimately improve diagnosis and treatment for menstrual-cycle-linked brain disorders.
Progesterone – Friend or foe?
2020, Frontiers in Neuroendocrinology
Citation Excerpt :
In particular, low-dose CHCs containing anti-androgenic progestogens have been proven useful in women with PMDD (Lopez et al., 2012; Kim et al., 2015), but also see (Eisenlohr-Moul et al., 2017)). Trials investigating CHCs with androgenic progestogens, on the other hand, have been less successful (Freeman et al., 2012; Backstrom et al., 1992). A potential explanation for the discrepancy between clinical reports and the aforementioned RCTs could be that while women with PMDD experience symptom relief in the luteal phase, they respond negatively to progestogens at other phases of the cycle (Lundin et al., 2017).
Estradiol is the “prototypic” sex hormone of women. Yet, women have another sex hormone, which is often disregarded: Progesterone. The goal of this article is to provide a comprehensive review on progesterone, and its metabolite allopregnanolone, emphasizing three key areas: biological properties, main functions, and effects on mood in women. Recent years of intensive research on progesterone and allopregnanolone have paved the way for new treatment of postpartum depression. However, treatment for premenstrual syndrome and premenstrual dysphoric disorder as well as contraception that women can use without risking mental health problems are still needed. As far as progesterone is concerned, we might be dealing with a two-edged sword: while its metabolite allopregnanolone has been proven useful for treatment of PPD, it may trigger negative symptoms in women with PMS and PMDD. Overall, our current knowledge on the beneficial and harmful effects of progesterone is limited and further research is imperative.
Mood and physical symptoms improve in women with severe cyclical changes by taking an oral contraceptive containing 250-mcg norgestimate and 35-mcg ethinyl estradiol
2013, Contraception
Citation Excerpt :
This indicates that in a subgroup of women, a progestagen and estradiol, together and alone, seem to induce mood symptoms and that different types of progestagens affect mood differently [4]. A monophasic combination seems to induce less negative symptoms than a triphasic combination with less hormonal fluctuation over cycle, leading to a more mood-stabilizing effect [4,15]. Data have been contradictory regarding the effect of oral contraceptive treatment on mood, but in healthy women with no underlying mood disorder, most of the reports indicate a benefit [6,16].
The purpose of this study was to investigate how women without and with different severity of premenstrual symptoms react to treatment with a combined oral contraceptive containing 250-mcg norgestimate/35-mcg ethinyl estradiol (EE). Focus was placed on mood and physical symptoms.
This open, prospective study evaluated 24 women using norgestimate/EE for three cycles in a 21/7 regimen. Symptoms and bleeding pattern were captured by daily ratings on the Cyclicity Diagnoser scale.
Women with severe premenstrual mood symptoms improved in summarized negative mood (p<.001) and summarized positive mood (p<.05), as well as in swelling (p<.05) and effect on daily life (p<.05). Women with no or mild or moderate symptoms did not show any significant improvement or deterioration in any symptom after 3 months of treatment.
Norgestimate 250 mcg/EE 35 mcg significantly improved premenstrual summarized negative mood symptoms during 3 treatment months compared to pretreatment in women with severe premenstrual symptoms, together with improvement in positive symptoms, swelling and effect on daily life.
Luteal phase dysphoric disorder and premenstrual syndrome
2009, Quaderni Italiani di Psichiatria
La sindrome premestruale (PMS) comprende un’ampia varietà di sintomi ciclici e ricorrenti di natura fisica, emozionale, comportamentale e cognitiva che insorgono durante la fase luteale del ciclo mestruale e che vanno in remissione rapidamente con l’inizio della mestruazione. La non univocità degli strumenti diagnostici ha portato negli anni a conclusioni differenti sul piano epidemiologico, eziopatogenetico e clinico. Il disturbo disforico della fase luteale (PMDD) è la forma più severa e debilitante di disordine premestruale che si verifica nel 3-8% dei casi e che comprende sempre almeno un sintomo della serie disforica. Talvolta, rappresenta un’esacerbazione premestruale di un disturbo della serie depressiva/ansiosa.
PMS/PMDD rappresentano un modello del compromesso psiconeuroendocrino ciclico che i sistemi adattativi femminili mettono in atto mensilmente in risposta alle fisiologiche fluttuazioni degli steroidi ovarici. La complessità della sindrome sembra ricondursi alla peculiare soglia di vulnerabilità di ciascuna donna, modulata nell’arco della vita fertile da numerosi fattori non soltanto di natura biologica, ma anche di origine psicosociale. Da ciò derivano, pertanto, la poliedricità sintomatologica, la mancanza di marcatori biochimici e il non sempre agevole approccio terapeutico, che può beneficiare di associazioni estroprogestiniche con azione contraccettiva.
Premenstrual Syndrome (PMS) comprises a wide variety of cyclical and recurrent symptoms, including physical, emotional, behavioral and cognitive symptoms that occur during the luteal phase of the menstrual cycle and rapidly resolve with the onset of menstrual bleeding. The lack of a clear diagnostic framework has brought to different epidemiological, etiopathogenetic and clinical conclusions over the years. Premenstrual Dysphoric Disorder (PMDD) is the most severe and disabling form of premenstrual disorder and occurs in 3–8% of cases, including always at least a dysphoric symptom. In some cases, it represents the premenstrual exacerbation of depression/anxiety symptomatology.
PMS/PMDD represent a model of the cyclical psychoneuroendocrine compromise deriving from women's adaptive responses which fluctuate monthly in response to periodic sexual hormone variations throughout the menstrual cycle. The complexity of the syndrome is likely to be related to the peculiar threshold of vulnerability of each woman which is modulated during the reproductive life span by several biological and even psychosocial factors. That being so, symptoms are extremely diverse, no biochemical markers are evident and therapeutic management is not always easy. Estro-progestin preparations for hormonal contraception may represent a suitable treatment strategy.
Prevalence of psychiatric disorders and premenstrual dysphoric symptoms in patients with experience of adverse mood during treatment with combined oral contraceptives
2009, Contraception
Negative mood symptoms remain one of the major reasons for discontinuation of combined oral contraceptive pills (COCs). The primary aim of this study was to compare the prevalence of mood and anxiety disorders in women with different experience of COCs.
Thirty women currently on COCs with no report of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects, 33 women who had discontinued COC use due to adverse mood effects and 27 women who had discontinued COC use for reasons other than adverse mood symptoms were included. Ongoing psychiatric disorders were evaluated by a structured psychiatric interview and prevalence rates of premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) were assessed by daily prospective ratings on the Cyclicity Diagnoser scale.
Women with ongoing or past experience of COC-induced adverse mood, more often suffered from mood disorders than women with no reports of adverse mood while on COC. The prevalence of prospectively defined PMS or PMDD did not differ between prior users with positive or negative experience. Women who had discontinued COC use due to adverse mood symptoms more often had had a legal abortion in the past.
Women with ongoing or past self-reported adverse mood effects from COCs had a significantly increased prevalence of mood disorders.
The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: Implications for diagnosis and treatment
2008, Epilepsy and Behavior
Despite our understanding of hormonal influences on central nervous system (CNS) function, there is still much to learn about the pathogenesis of menstrual cycle-linked disorders. A growing literature suggests that the influence of sex steroids on neurological and psychiatric disorders is in part mediated by an aberrant CNS response to neuroactive steroids. Although sex steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO) influence numerous neurotransmitter systems, it is their potent effect on the brain’s primary inhibitory and excitatory neurotransmitters γ-aminobutyric acid (GABA) and glutamate that links the study of premenstrual dysphoric disorder (PMDD) and catamenial epilepsy (CE). After providing an overview of these menstrual cycle-linked disorders, this article focuses on the preclinical and clinical research investigating the role of estradiol and progesterone (via ALLO) in the etiology of PMDD and CE. Through exploration of the phenomenological and neurobiological overlap between CE and PMDD, we aim to highlight areas for future research and development of treatments for menstrual cycle-linked neuropsychiatric disorders.

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Oral contraceptives in premenstrual syndrome: A randomized comparison of triphasic and monophasic preparations

Abstract

J Psychosom Res

Mood changes and menstrual symptoms with different gestagen/estrogen combinations. A double-blind comparison with placebo

Acta Psychiat Scand

Mood, sexuality, hormones and the menstrual cycle. I. Changes in mood and physical state: description of subjects and methods

Psychosom Med

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

Acta Obstet Gynaecol Scand

Premenstrual complaints, I. Prevalence of premenstrual symptoms in a Swedish urban population

J Psychosom Obstet Gynaec

The effects of oral contraceptives on mood and sexuality: comparison of triphasic and combined preparations

J Psychosom Obstet Gynaecol