Pre-menstrual Dysphoric Disorder (PMDD) is a severe type of premenstrual syndrome. It is characterised by moderate to severe affective and behavioural symptoms, that occur post ovulation and peak in the luteal phase of the menstrual cycle, becoming minimal or absent at the onset of menstruation[i]. PMDD is believed to affect 3-8%[ii] of women worldwide.
Diagnostic criteria:
In 2022, PMDD was added to the International Classification of Diseases 11th Revision (ICD-11) and placed under the category of gynaecological diseases[iii], however it is also listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) as a separate entity under depressive disorders.
Table 1. DSM-5 Diagnostic criteria for PMDD[iv]
| CORE SYMPTOMS At least 1 of the first 4 core symptoms listed should be present in the week before menses: | 1 or more of the following symptoms must also be present: | |
| Marked affective lability (e.g., mood swings, feeling suddenly sad or tearful, or increased sensitivity to rejection) Marked irritability or anger or increased interpersonal conflicts Markedly depressed mood, feelings of hopelessness, or self-deprecating thoughts Marked anxiety, tension, and/or feelings of being keyed up or on edge | Decreased interest in usual activities (e.g. hobbies, friends) Subjective difficulty in concentration Lethargy, easy fatigability, or marked lack of energy Marked change in appetite; overeating or specific food cravings Hypersomnia or insomnia A sense of being overwhelmed or out of control Physical symptoms such as breast tenderness or swelling; joint or muscle pain, a sensation of “bloating” or weight gain | Symptoms are associated with clinically significant distress, interference with work, school, usual social activities, or relationships with others. Symptoms must not an exacerbation of another disorder e.g. MDD, hypothyroid Should be confirmed by prospective daily ratings during at least 2 symptomatic cycles (although a provisional diagnosis may be made prior to this confirmation |
Pathophysiology:
Hormones such as pregnenolone, progesterone, oestradiol, and corticosterone can be synthesised in the brain where they function as neuro-active steroids (NAS’s)[v]. Here they act on neuron receptors in parts of the brain that influence mood, cognition and behaviour, influencing the release of neurotransmitters (NT’s) such as serotonin, GABA and dopamine[vi]. It is believed that symptoms off PMDD are partially driven by central nervous system sensitivity to normal fluctuations in neuroactive steroid hormones (NASs) and their subsequent action on NT’s[vii].
Allopregnanolone:
A sensitivity to rising levels of progesterone in the luteal phase and its metabolite, allopregnanolone (ALLO) have been implicated in the pathogenesis of PMDD[viii]. In women without PMDD, modulation of the GABA-a receptor by ALLO results in reduced anxiety and mild sedation, however paradoxically women with PMDD show altered GABAA receptor sensitivity to rising levels of ALLO, resulting in the mood and behavioural disturbances such as aggression, anxiety and poor executive function experienced[ix],[x].
Serotonin:
Women with PMDD demonstrate altered serotonergic activity in the luteal phase of the menstrual cycle largely driven by withdrawal of oestrodiol. Oestrodiol is known to increase serotonergic activity via multiple mechanisms including increasing serotonin transporter mRNA particularly in brain areas involved with emotion and behaviour[xi], as well as increasing production of tryptophan hydroxylase, the enzyme responsible for the conversion of tryptophan to serotonin[xii].
AETIOLOGY
Genetics:
Twin studies support a link for genetics increasing susceptibility for development of PMDD. Polymorphisms are observed in many genes, including those coding for[xiii]:
- Serotonergic 5HT1A receptor
- Oestrogen 1 receptor alpha gene (ESR-1)
- ESC/E(Z)[xiv]
Trauma:
Women who have a history of trauma are significantly more likely to experience PMDD than controls. An Australian study observed 83% of women with PMDD had experienced early life trauma, with emotional abuse being the most prevalent[xv]. While the underlying mechanisms are multifaceted, it is suggested to involve dysfunctional HPA-axis activity and subsequent altered neurotransmission[xvi].
Chronic stress:
Women with PMDD demonstrate a maladaptive response to stressors highlighted by a flattened diurnal cortisol slope[xvii] thus suggestive of HPA axis dysfunction; this may explain why they may perceive daily events as more stressful and experience higher arousal of negative feelings in the luteal phase of the cycle. Chronic stress has also been shown to alter the composition of GABA-a receptors reducing tonicity[xviii] which may also partly explain the paradoxical reaction to rising levels of ALLO, and subsequent heighted stress reactivity.
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[i] Tiranini L, Nappi RE. Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome. Fac Rev. 2022 Apr 28;11:11
[ii] Mishra S, Elliott H, Marwaha R. Premenstrual Dysphoric Disorder. 2023 Feb 19. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30335340 https://pubmed.ncbi.nlm.nih.gov/30335340/
[iii] Schroll JB, Lauritsen MP. Premenstrual dysphoric disorder: A controversial new diagnosis. Acta Obstet Gynecol Scand. 2022 101(5):482-483
[iv] Mishra S, Elliott H, Marwaha R. Premenstrual Dysphoric Disorder. 2023 Feb 19. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30335340 https://www.ncbi.nlm.nih.gov/books/NBK532307/
[v] Szpunar MJ, Freeman MP. Investigational Treatment of Depressive Disorders With Neuroactive Steroids: Potential Implications for Premenstrual Dysphoric Disorder. J Clin Psychiatry. 2021 8;82(4):20ac13853
[vi] Hantsoo L, Epperson CN. Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle. Neurobiol Stress.2020 4;12:100213.
[vii] Hantsoo L, Payne JL. Towards understanding the biology of premenstrual dysphoric disorder: From genes to GABA. Neurosci Biobehav Rev. 2023 Apr 12;149:105168
[viii] Carlini SV et al. Management of Premenstrual Dysphoric Disorder: A Scoping Review. Int J Womens Health. 2022 Dec 21;14:1783-1801
[ix] Bäckström T, et al. A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder. Psychoneuroendocrinology. 2021 Nov;133:105426.
[x] Bäckström T, et al. GABAA Receptor-Modulating Steroids in Relation to Women’s Behavioral Health. Curr Psychiatry Rep. 2015 Nov;17(11):92
[xi] Hantsoo L, Epperson CN. Premenstrual Dysphoric Disorder: Epidemiology and Treatment. Curr Psychiatry Rep. 2015 Nov;17(11):87
[xii] Itriyeva K. Premenstrual syndrome and premenstrual dysphoric disorder in adolescents. Curr Probl Pediatr Adolesc Health Care. 2022 May;52(5):101187
[xiii] Hantsoo L, Epperson CN. Premenstrual Dysphoric Disorder: Epidemiology and Treatment. Curr Psychiatry Rep. 2015 Nov;17(11):87
[xiv] Dubey N, et al. The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Mol Psychiatry. 2017 Aug;22(8):1172-1184.
[xv] Kulkarni J, et al. The prevalence of early life trauma in premenstrual dysphoric disorder (PMDD). Psychiatry Res. 2022 Feb;308:114381
[xvi] Girdler SS, et al. Persistent alterations in biological profiles in women with abuse histories: influence of premenstrual dysphoric disorder. Health Psychol. 2007 Mar;26(2):201-13
[xvii] Beddig T, et al. Stress, mood, and cortisol during daily life in women with Premenstrual Dysphoric Disorder (PMDD). Psychoneuroendocrinology. 2019 Nov;109:104372.
[xviii] Jie F, et al. Stress in Regulation of GABA Amygdala System and Relevance to Neuropsychiatric Diseases. Front Neurosci. 2018 Aug 14;12:562
