Premenstrual Syndrome and Premenstrual Dysphoric Disorder | Article

This chapter should be cited as follows:
Bixo M, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.418533

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 4

Benign gynecology

Volume Editor: Professor Shilpa Nambiar, Prince Court Medical Centre, Kuala Lumpur, Malaysia

Chapter

Premenstrual Syndrome and Premenstrual Dysphoric Disorder

First published: December 2024

AUTHORS

Marie Bixo

Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden

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INTRODUCTION

Premenstrual syndrome (PMS) is defined as mood symptoms and/or physical symptoms that occur exclusively during the premenstrual (luteal) phase of the menstrual cycle.¹ PMS is common, and mild symptoms are usually regarded as physiological and an effect of normal hormonal fluctuations during the menstrual cycle. More burdensome symptoms that may require treatment are reported by 10–30% of the female population.²^,³^,⁴ PMS is sometimes regarded as a ‘light’ version of the more severe premenstrual dysphoric disorder (PMDD), or a sub-threshold diagnosis. A recently published meta-analysis estimated the prevalence of PMDD as 3.1%,⁵ but variation between countries has been reported.⁶

In contrast to PMS, PMDD is a well-defined condition, typified by cyclical mood symptoms such as irritability, depression, anxiety and mood swings that consistently recur in the luteal phase of the menstrual cycle.¹ Although women with PMDD are not affected during the follicular phase, PMDD seriously affects quality of life.⁷ Research relating to PMDD/PMS has so far been conducted mainly in North America and Europe, but the field is now rapidly expanding globally.⁸ Most of the research done focuses on PMDD, as the diagnosis is more rigorous than PMS and the impact of PMDD is much more serious. This chapter thus mainly focuses on PMDD.

PATHOPHYSIOLOGY

The occurrence of PMDD and PMS symptoms is closely related to the luteal phase of the menstrual cycle, and requires ovulation and subsequent formation of a corpus luteum. Figure 1 shows the hormonal fluctuations during a normal menstrual cycle.⁹ Spontaneous or induced anovulation results in elimination of PMDD symptoms.¹⁰^,¹¹ Thus, hormones produced by the corpus luteum, such as progesterone and some of its metabolites, are suspected to provoke the symptoms. However, the hormonal cycle is not different in women with PMDD compared to those without premenstrual mood symptoms, and relationships with hormone deficiency or excess synthesis have not been found.¹²

Hormonal changes during a normal menstrual cycle. Reproduced from Draper et al.,⁹ under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

Research into the mechanisms behind PMDD has previously revolved around the effect of progesterone. However, treatment with a progesterone receptor antagonist had no clinical effect.¹³ An effect was shown in a trial with a selective progesterone receptor modulator, but this was likely to be due to the high proportion of women in whom ovulation was inhibited.¹⁴ Treatment with micronized progesterone has not proven successful either.¹⁵

The prevailing hypothesis today is that allopregnanolone, an endogenous metabolite of progesterone, is the provoking factor. This is evidenced by the finding that treatment with a 5α‑reductase inhibitor (blocking the key enzyme for synthesis of allopregnanolone) ameliorates PMDD symptoms.¹⁶ Allopregnanolone belongs to a class of steroid hormones called neurosteroids. They are strong positive allosteric modulators of the γ‑aminobutyric acid (GABA_A) receptor in the brain, and, like other GABAergic substances such as benzodiazepines and barbiturates, are sedative and anxiolytic in high concentrations.¹⁷ Allopregnanolone has neuroprotective effects and is important for development of the fetal brain.¹⁸ Peripheral levels of allopregnanolone mirror fluctuations of progesterone across the menstrual cycle and during pregnancy.¹⁹^,²⁰ During pregnancy, allopregnanolone levels seem to be associated with the risk of depression.²¹ As for other GABAergic substances, tolerance to allopregnanolone, and a possible withdrawal effect, have been shown.²² For many years, postpartum depression has been suspected to be an effect of withdrawal from the high levels of hormones to which the pregnant woman is exposed. Allopregnanolone analogs have recently been approved by the US Food and Drug Administration for treatment of postpartum depression under the names brexanolone (for intravenous administration) and zuranolone (for oral administration).²³^,²⁴ There are some indications that women with PMDD are unable to develop a physiological tolerance to allopregnanolone during the luteal phase of the menstrual cycle. This was shown in an experimental study in which women with PMDD and asymptomatic control participants were given allopregnanolone injections in both phases of the menstrual cycle and the effect on saccadic eye velocity was measured.²⁵

Paradoxically, adverse reactions to positive allosteric modulators (anxiety and irritability) in low concentrations are a well-known phenomenon in a subgroup of the general population.²⁶ In comparison, women with PMDD are prone to adverse reactions to allopregnanolone at peripheral levels comparable to those found in the luteal phase.²⁷ Isoallopregnanolone is another endogenous progesterone metabolite that has the ability to modulate the effect of allopregnanolone on the GABA_A receptor.²⁸ In clinical studies of women with PMDD, isoallopregnanolone reduced mood symptoms when given in injections during the luteal phase.²⁹

Why some women are hypersensitive to endogenous steroid hormones is still not known. Genetic studies have not yielded any conclusive results regarding candidate genes, although there are some indications that PMDD runs in families.³⁰ Imaging studies have shown differences in brain morphology compared with asymptomatic controls.³¹ Also, increased amygdala activation has been observed in functional MRI studies where a paradigm testing emotional regulation was used.³² The GABA_A receptor is a membrane-bound chloride channel consisting of five subunits with a large number of combinations. The subunit composition of the GABA_A receptor determines its pharmacodynamic properties, including sensitivity to neurosteroids.³³ In addition, animal research has shown that the subunit composition appears to depend on endocrine state and hormonal fluctuations.³⁴ There are some indications that the plasticity of the GABA_A receptor is involved in the pathophysiology of PMDD, but this research field is still in its infancy.

PMDD symptomatology and diagnosis

PMDD is classified in DSM‑5 and characterized as a mood disorder,³⁵ but is not regarded as a psychiatric condition. Briefly, DSM‑5 states that five or more symptoms (including at least one of the four core symptoms: irritability, depression, anxiety and mood swings) must be present during the premenstrual week and disappear or sharply decrease until the week after menses. Also, the symptoms must interfere with relationships, social functioning and studies or work performance, or cause significant distress. The full DSM‑5 criteria for PMDD are listed in Box 1.³⁵ Prospective ratings on a validated symptom scale are much more reliable than retrospective anamneses when diagnosing PMDD.³⁶ Another strength of symptom ratings is that, for some women with PMDD/PMS, they may have a therapeutic effect, as they provide a better understanding of the condition and a sense of control. Also, the effect of initiated treatment may be objectively monitored using a validated scale that may also facilitate assessment of possible differential diagnoses. A commonly used scale is the daily rating of severity of problems (DRSP), which is validated and adheres to DSM‑5.³⁶ If this instrument is not available, other scales are also useful as long as they are used prospectively for 1–2 months. The symptom pattern captured by a study in which prospective daily ratings were obtained from women with PMDD and asymptomatic controls with normal menstrual cycles is shown in Figure 2.³⁷

Box 1 Diagnostic criteria for premenstrual dysphoric disorder in DSM‑5.³⁵

In the majority of menstrual cycles, at least five symptoms must be present in the final week before the onset of menses, start to improve within a few days after the onset of menses, and become minimal or absent in the week post-menses
One (or more) of the following symptoms must 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
One (or more) of the following symptoms must additionally be present to reach a total of five symptoms when combined with symptoms from criterion 2 above:
- Decreased interest in usual activities
- 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
The symptoms are associated with clinically significant distress or interference with work, school, usual social activities, or relationships with others
The disturbance is not merely an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, persistent depressive disorder (dysthymia) or a personality disorder (although it may co-occur with any of these disorders)
Criterion 1 should be confirmed by prospective daily ratings during at least two symptomatic cycles (although a provisional diagnosis may be made prior to this confirmation)
The symptoms are not attributable to the physiological effects of a substance (e.g. drug abuse, medication or other treatment) or another medical condition (e.g. hyperthyroidism)

Daily ratings of symptoms (means ± SEM) of PMDD during ovulatory menstrual cycles.³⁷ Women with PMDD were compared with asymptomatic controls. Menstruation starts at day 1 and ovulation occurs at around day 14. Reproduced from Psychoneuroendocrinology 26(6): Bixo M, Allard P, Bäckström T, Mjörndal T, Nyberg S, Spigset O, Sundström-Poromaa I. Binding of [³H]paroxetine to serotonin uptake sites and of [³H]lysergic acid diethylamide to 5‑HT_2A receptors in platelets from women with premenstrual dysphoric disorder during gonadotropin releasing hormone treatment, pp. 551–564. Copyright 2001, with pemission from Elsevier.

There is a wide variety when it comes to how PMDD symptoms manifest in terms of the dominating symptoms and duration during the luteal phase, but the intra-individual pattern is usually stable over time.³⁸ Of the core symptoms, irritability and anxiety are more common than depression and mood swings,³⁹ and irritability is unsurprisingly strongly associated with impairment of relationships.³⁸^,⁴⁰ The disease burden of PMDD is substantial: suicide ideation premenstrually is not uncommon,⁴¹ and the risk of disruption of relationships is significantly increased.⁴² Also, comorbidity with psychiatric conditions occurs,⁴³ and previous trauma is an identified risk factor for PMDD.⁴⁴

A larger group of women with cyclical mood symptoms than those fulfilling the DSM‑5 criteria for PMDD seek medical care. Overall, 10–15% of such women may be classified as having PMS and require treatment.²^,⁷ The PMS criteria are defined by the American College of Obstetricians and Gynecologists⁴⁵ as the presence of one or more affective (depression, angry outbursts, irritability, confusion, social withdrawal) or somatic (breast tenderness, abdominal bloating, headache, swelling of extremities) symptoms during a minimum of 5 days premenses in each of three prior menstrual cycles.

These symptoms must be relieved within 4 days from the onset of menses, without recurrence until at least day 13 of the cycle, and must be present in the absence of pharmacological therapy, hormone ingestion or drug or alcohol abuse. The symptoms must occur reproducibly during at least two cycles of prospective recording. The patient must exhibit identifiable dysfunction in social, academic or work performance.

As mentioned above, PMDD is not considered to be a psychiatric condition, although the symptomatology is similar to depression and anxiety disorders, for example. It is important to distinguish PMDD from psychiatric diseases as the latter require specialist care and the treatment strategy differs. However, depressive and anxiety disorders may also have a cyclical symptom pattern with premenstrual aggravation,¹ which sometimes make diagnosis a challenge.

PHARMACOLOGICAL TREATMENT

The first-line treatment for PMDD is an antidepressant; commonly a selective serotonin reuptake inhibitor (SSRI). All SSRIs are equally effective at reducing mood symptoms, especially irritability,⁴⁶ but side-effects are common and are a reason for poor compliance.⁴⁷^,⁴⁸ The most prevalent side-effects are nausea, sleep disturbances and tiredness (usually declining over time), and reduced libido and orgasmic dysfunction (usually persisting).⁴⁷ Side-effects are dose-dependent and vary between individuals for the various SSRIs. Therefore, the lowest effective dose should be prescribed, and, if side-effects occur, changing to another SSRI may be successful. It is recommended that the medication be taken intermittently, i.e. only during the symptomatic premenstrual period. SSRIs have a fast-onset effect on PMDD symptoms compared with treatment of depression, where the effect is usually delayed by several weeks. The mechanism behind the positive effect on PMDD is thus not the same as for psychiatric conditions in general. In addition to minimization of side-effects, this is the reason why an intermittent regimen is preferable. However, for some women, continuous treatment gives a better response,⁴⁷ and thus SSRI treatment should be individualized when it comes to type and regimen to obtain the best result.

Use of combined oral contraceptives may be a good alternative, especially for women requesting contraception, and combinations with anti-androgenic progestogens such as drospirenone are usually more effective at ameliorating symptoms of PMS and PMDD.⁴⁹ Continuous use, without the monthly break for bleeding, is recommended. In theory, a combined oral contraceptive would be an obvious treatment for PMDD as it effectively inhibits ovulation. The problem is that some women with PMDD are extremely sensitive to exogenous hormones also, and thus respond with mental side-effects on combined oral contraceptives.¹² So far, there is no evidence that use of progestogen-only pills for contraception has any effect on symptoms of PMDD or PMS.

Spironolactone may ameliorate both depressed mood and somatic symptoms,⁵⁰ and may be an option for women with PMS.

In severe cases of PMDD, treatment with an injectable gonadotropin-releasing hormone (GnRH) analog, which effectively downregulates the hypothalamus–pituitary–gonad axis, is the only solution. To counteract hypoestrogenic effects, e.g. reduced bone density and cardiovascular disease, it is necessary to add low doses of estradiol and progestogen, which sometimes trigger hormonal side-effects.⁵¹ This treatment is usually available exclusively within specialist care, and is usually offered instead of oophorectomy. Combinations of a GnRH antagonist and estrogen/progestogen add-back therapy for oral administration are now on the market for other indications,⁵² and may be a future alternative for PMDD also.

ALTERNATIVE NON-PHARMACOLOGICAL TREATMENTS

For women who are unwilling to use pharmaceutical compounds or hormonal treatments (or who are unable to do so due to side-effects), the best evidenced alternative treatment is cognitive behavioral therapy.⁵³ A recommendation to try cognitive behavioral therapy as a first-line treatment for PMS has recently been issued by the American College of Obstetricians and Gynecologists.⁴⁵

A moderate effect on premenstrual physical and mental symptoms has been shown in studies of acupuncture and herbal compounds with Vitex agnus-castus, but the studies are small and of low quality.⁵⁴^,⁵⁵

Many substances such as vitamins, minerals and various herbal compounds are marketed today for their effect on premenstrual mood symptoms, without any scientific evidence. Instead, there are risks of adverse effects on liver function, for example.⁵⁶

Progesterone treatment is still recommended by some, although solid evidence exists that it is not superior to use of placebo.¹⁵ The research field today revolves around neurosteroids and modulators of the GABA_A receptor, but no such pharmacological treatments have so far been developed.

PRACTICE RECOMMENDATIONS

A PMDD diagnosis should be based on prospective symptom ratings for 1–2 months, preferably using a validated scale such as the daily rating of severity of problems (DRSP).
Treatment with an SSRI intermittently is recommended for PMDD as the first-line treatment.
Women with PMDD or PMS who require contraception should be offered a combined oral contraceptive with an anti-androgenic progestogen in a continuous regimen.
For women with severe PMDD, a GnRH analog and add-back with estrogen/progestogen could be tried.
Cognitive behavioral therapy is the only recommended non-pharmaceutical alternative for PMS.

GUIDELINES

International guidelines for the management of PMDD and PMS:

Management of Premenstrual Disorders. ACOG Clinical Practice Guideline No. 7, 2023. Obstet Gynecol. 2023 : 142(6):1516–1533. doi: 10.1097/AOG.0000000000005426.
Premenstrual Syndrome and Dysphoric Disorder. BMJ Best Practice, 2024. https://bestpractice.bmj.com/topics/en-gb/419.
Management of Premenstrual Syndrome. RCOG Green-top Guideline No. 48, 2017. BJOG. 124(3):e73–e105. doi: 10.1111/1471-0528.14260

CONFLICTS OF INTEREST

M.B. is a scientific advisor for Asarina Pharma.

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