Premenstrual symptoms include a constellation of mood, behavioral, and physical indications that occur in a cyclic pattern prior to menstruation and then wane off after the menstrual period in women of reproductive age. Most females have only mild discomfort, and symptoms do not interfere with their personal, social, or professional live; however, 5% to 8% of women have moderate-to-severe symptoms that can cause significant distress and functional impairment.
Although premenstrual symptoms have been recognized for a long time, the diagnostic criteria have been specified only recently. The nomenclature for premenstrual disorders has changed significantly over the years, evolving from "menses moodiness" in the 18th century to "premenstrual tension" in the early part of 19th century to finally "premenstrual syndrome" in the 1950s. While some discomfort prior to menses is quite common, premenstrual syndrome (PMS) includes the subset of women who experience symptoms that are severe enough to impact daily activities and functioning. Late luteal dysphoric disorder (LLDD), now known as premenstrual dysphoric disorder (PMDD), accounts for the most severe form of PMS with the greatest impairment of women’s functioning and perceived quality of life, often prompting them to seek treatment.
Currently, PMDD is listed in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) as a separate entity under Depressive disorders, with the criteria for diagnosis as follows:
Criterion A - At least 5 of the following 11 symptoms (including at least 1 of the first 4 listed) should be present:
Criterion B - symptoms severe enough to interfere significantly with social, occupational, sexual, or scholastic functioning.
Criterion C - symptoms discretely related to the menstrual cycle and must not merely represent an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although the symptoms may be superimposed on those of these disorders).
Criterion D - criteria A, B, and C confirmed by prospective daily ratings during at least 2 consecutive symptomatic menstrual cycles. The diagnosis may be made provisionally before this confirmation.
Women with moderate-to-severe PMS or PMDD experience more quality-of-life detriments, work-productivity losses, and incur greater healthcare costs than women with no or only mild symptoms.
The exact etiology of PMS/PMDD is not known. There are, however, risk factors associated with the development of PMS/PMDD, some of which are well-established while others are speculative.
Proven Risk Factors
Speculative Risk Factor
Premenstrual symptoms can affect all women in reproductive age, ranging from menarche till menopause. Premenstrual symptoms are a common problem for women in the reproductive age group. In the United States, approximately 70% to 90% of women in the reproductive age group complain of at least some premenstrual discomfort. Approximately one-third of these women have symptoms that are bothersome enough to qualify for the diagnosis of PMS. The most severe form of premenstrual symptom complex, PMDD, has been noted in 3% to 8% of these PMS cases.
In a study by Halbreich et al., women in the US have about 481 menstrual cycles during this lifespan. Taking into account the 22 months for two pregnancies and postpartum periods, many women roughly experience 459 cycles during their childbearing years. Also, US women with PMDD experience an average of 6.4 days of severe symptoms per menstrual cycle; this is approximately equivalent to 8 years of debilitating symptoms throughout the menstrual cycle. Examining the numbers leads one to the certainty that PMS or PMDD can cause distress and functional impairment over a significant duration of a woman’s lifetime, making it an important health problem.
Recent evidence from research studies suggests that reproductive hormone release patterns are normal in women with PMS/PMDD, but they have a heightened sensitivity to cyclical variations in levels of reproductive hormones which predisposes them to experience the mood, behavioral, and somatic symptoms.
Role of Sex Steroids
Many scientists have postulated that PMS/PMDD symptoms develop because of a decline of progesterone in the late luteal phase that causes CNS changes in gamma-aminobutyric acid (GABA) and progesterone metabolites that interact with the GABA-A receptor complex. However, there are other sets of scientists who argue against this hypothesis by stating that in many women symptoms can begin at ovulation and early luteal phase before the fall in the level of progesterone. To further corroborate, some studies showed that the hormonal cyclicity was suppressed by treatment with Gonadotropin-releasing hormone and re-exposure to progesterone reproduced symptoms even when the hormone concentrations were stable. Also, if the above theory of decline in the late luteal phase indicating progesterone as the precipitating factor were to be believed then administration of progesterone during this phase would have been an effective treatment which is not.
Allopregnanolone is a metabolite of progesterone, and like progesterone, levels of this metabolite also fluctuate during the menstrual cycle. As mentioned, progesterone metabolites interact with GABA-A receptor complex and allopregnanolone specifically potentiate inhibitory responses to GABA-A receptor agonists. Some studies suggest that women with PMS/PMDD have diminished functional sensitivity of the GABA-A receptor due to deficient allopregnanolone response to stress.
An alternative hypothesis suggests that preovulatory peak in estradiol, postovulatory increase in progesterone, or both trigger symptoms of PMS/PMDD; however, a shortcoming of this theory is its failure to explain why symptoms start with ovulation for some women but in late luteal phase for others. It has also been reported that estrogen is as efficacious as progesterone in provoking PMS-like complaints and the estrogen component of hormone replacement therapy can amplify progesterone-induced dysphoria. Besides, the administration of estrogen in the luteal phase has been reported to provoke premenstrual symptoms and giving estrogen antagonist in the luteal phase decreases premenstrual mastalgia.
Role of Central Neurotransmitters
Serotonin is a central neurotransmitter that is well proven to be involved in mood and behavior regulation. Sex steroids may affect behavior by exerting their effects on serotonergic transmission. Three proofs authenticate this theory. First, premenstrual symptoms are diminished by serotonin reuptake inhibitors (SRIs) and other treatments that boost serotonin levels, like serotonin- releasing agents.. Second, contrary to the first point, a decrease in the serotonergic transmission achieved by a tryptophan-free diet or by treatment with a serotonin-receptor antagonist can give rise to PMS/ PMDD symptoms. Third, women with PMS/PMDD have atypical serotonergic transmission and lower density of serotonin transporter receptors than typical women. In addition, they have a higher level of serotonergic responsiveness in the follicular than in the luteal phase, which is different from that observed in women without PMS/PMDD.
GABA is an inhibitory neurotransmitter, and some imaging studies suggest the possible role of GABA in the pathophysiology of PMS/PMDD based on the fact that some progesterone metabolites interact with GABA A receptor, and that symptomatic women have a different responsiveness of this receptor complex as compared to asymptomatic women. Another noteworthy fact is that GABAergic and serotonergic neurons have meaningful interactions and thus the role of GABA in the pathophysiology of PMS/PMDD is in keeping with the serotonin hypothesis. Additionally, SRIs also strongly influence enzymes involved in creating progesterone metabolites which in turn modulate GABA A receptors.
Glutamate is an excitatory neurotransmitter, and there is a cyclical fluctuation in its levels during the menstrual cycle for all women (symptomatic and asymptomatic), but symptomatic women seem to have an increased sensitivity to these cyclical changes.
Studies have shown that women with PMDD have lower levels of cortisol and beta-endorphins during both the follicular and luteal phases. These observations suggest abnormalities in the hypothalamic-pituitary-gonadal axis in PMDD which is congruent with the findings of HPA-axis dysregulation in mood disorders.
Three Heads of PMDD Symptomatology
Symptom Expression Pattern
The length of time for which the women experience symptoms of PMDD varies from a few days to 2 weeks. For most symptomatic women, symptoms intensify 6 days before and are the most severe 2 days before the menses. Of all the symptoms mentioned, anger and irritability are the most distressing and are experienced slightly before the other symptoms.
As discussed, according to DSM-5, symptoms should be directly related to the menstrual cycle and must not merely represent an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although the symptoms may be superimposed on those of these disorders). Prospective daily ratings must confirm symptoms during at least 2 consecutive symptomatic menstrual cycles. However, a provisional diagnosis may be made before this confirmation.
PMDD Assessment Scales
Treatment modalities for PMDD can be divided into 2 categories:
2. Pharmacological Methods
The symptoms for PMDD can overlap with other psychiatric disorders, most importantly major depression, and it is imperative to rule out another existing disorder before making the diagnosis of PMS/PMDD. The key factor in making the diagnosis is the temporal association of symptoms with the menstrual cycle. Some common differentials include:
Premenstrual dysphoric disorder is a well-recognized, severe form of PMS. It is imperative to establish a precise diagnosis of PMDD that is guided by the DSM-5 criteria. While the diagnosis of PMS is fairly common in females of reproductive age, the referring practitioner plays a pivotal role not only in distinguishing PMDD from PMS but also separating it from other psychiatric disorders like anxiety or depression. A good coordination between the primary physician, gynecologist, and psychiatrist is extremely important in the multidisciplinary management of these patients. Educating the patients about the symptoms and encouraging them to maintain a diary for the accurate record of symptoms should be emphasized by each of treating physicians. It is worthwhile to have a therapist on board too who can help the patients by teaching them various coping skills to deal with the symptoms of anxiety and depression in addition to the medication management.
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