Premenstrual Syndrome and Premenstrual Dysphoric Disorder

Number: 0512

Policy

1. Diagnosis and treatment

   Aetna considers the following services and procedures medically necessary for the diagnosis and treatment of pre-menstrual syndrome (PMS) and pre-menstrual dysphoric disorder (PMDD).

   Medically Necessary Procedures/Services:

   1. Assessment:

      • Gynecological consultation
      • Medical evaluation (complete medical history and physical examination)
      • Psychiatric/psychological consultation and testing if the member exhibits mental/nervous symptoms
      • Thyroid function tests (e.g., thyroid stimulating hormone, thyroxine).

   2. Treatment:

      • Bilateral oophorectomy for members with severe symptoms when all medical therapy has either failed or produced unacceptable side effects
      • DiureticsFootnotes for prescription medications ^* such as chlorothiazide (Diuril) and spironolactone (Aldactone) for members with severe edema
      • Gonadotropin-releasing hormone antagonists such as danazol (Danocrine) for members with mastalgia
      • Gonadotropin-releasing hormone agonists such as Lupron (leuprolide acetate) and goserelin (Zoladex) for PMS and PMDD, for women with severe refractory disease who do not respond to or are unable to tolerate selective serotonin reuptake inhibitors (SSRIs) and oral contraceptives
      • Oral contraceptive pillsFootnotes for prescription medications ^* for women who have failed other drug therapies and are candidates for bilateral oophorectomy
      • Selective serotonin re-uptake inhibitorsFootnotes for prescription medications ^* such as fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft).

   Footnotes for prescription medications ^* Note: Medically necessary self-administered prescription medications are usually covered under pharmacy benefit plans.  Coverage of particular drugs within each class may be subjected to formulary restrictions, where applicable.

2. Experimental services

   Aetna considers the following services/procedures experimental and investigational for the diagnosis and treatment of PMS and PMDD because of insufficient evidence in the peer-reviewed literature.

   Ineligible Procedures/Services:

1. Assessment:

   • Evaluation of cortisol awakening response
   • Laboratory tests to detect specific nutrient deficiencies
   • Measurement of plasma leptin
   • Measurement of plasma progesterone
   • Measurement of reproductive hormones
   • Measurement of salivary or serum cortisol
   • Measurement of serum magnesium
   • Measurement of serum trace elements
   • Neuroimaging
   • Pap smears with maturation index
   • Sympathetic skin response for the evaluation of peripheral sudomotor function

2. Treatment:

   • Acupuncture
   • Allopregnanolone antagonists (e.g., sepranolone)
   • Alprazolam (Xanax) and other benzodiazepine anxiolytics
   • Anti-convulsants (e.g., levetiracetam)
   • Acetazolamide (Diamox)
   • Bromocriptine (Parlodel)
   • Clonidine (Catapres)
   • Dietary supplements such as evening primrose oil and magnesium
   • Duloxetine (Cymbalta)
   • Endometrial ablation (see CPB 0091 - Endometrial Ablation)
   • Human chorionic gonadotropin injection
   • Hysterectomy
   • Intravenous magnesium
   • Light therapy
   • Non-benzodiazepine anxiolytics such as buspirone (BuSpar)
   • Non-contraceptive estrogen-containing preparations
   • Progesterone (oral or vaginal suppositories) (see CPB 0510 - Progestins)
   • Progestin-releasing intra-uterine system (e.g., levonorgestrel-releasing intrauterine system)
   • Reflexology
   • Vestibular stimulation
   • Vitamin B6 (pyridoxine)
   • Vitamin E (tocopherol).

Background

Pre-menstrual syndrome (PMS) refers to a set of menstrually related, chronic, cyclical, physical and emotional symptoms occurring in the luteal phase (the second half) of the menstrual cycle.  Symptoms of PMS include breast tenderness, fatigue, cramping, bloating, irritability, aggressiveness, depression, inability to concentrate, food cravings, lethargy, and libido change.  Although the cause of PMS is still unclear, it is thought to involve reproductive hormones, neurotransmitters, and other brain processes.  It is estimated that up to 40 % of women of reproductive age are affected by PMS, with severe impairment occurring in approximately 5 % of these women.  Individuals in the latter group may suffer from pre-menstrual dysphoric disorder (PMDD), a more severe form of PMS.  The key symptoms of PMDD are markedly depressed mood, marked anxiety, marked affective lability, and reduced interest in activities.  In classic PMDD, symptoms occur regularly during the last week of the luteal phase in most menstrual cycles during the preceding 12 months.  Symptoms typically begin to disappear within several days of the onset of menses and are always absent in the week after menses.

Fewer than 50 % of women complaining of PMS have the diagnosis confirmed by rigorous criteria.  One study reported that most women who referred themselves to a PMS clinic met the diagnostic criteria for affective disorders, most commonly major depression or anxiety disorder (Keenan et al, 1992).  Nutrient abnormalities such as deficiencies of manganese, magnesium, B vitamins, vitamin E and linoleic acid have been reported in women with PMS.  Moreover, there are no specific tests to diagnose PMS -- no laboratory tests to detect specific nutrient deficiencies have been demonstrated to be useful.  Measurements of reproductive hormones have not been found to be of value in diagnosing PMS.  There is very little information regarding the use of Pap smears with maturation index for the diagnosis of PMS.  However, since thyroid dysfunction is common among women of reproductive age, thyroid function measures (e.g., thyroid stimulating hormone, thyroxine) may be useful.   Gynecological consultation is appropriate to assess symptoms and to rule out related illnesses such as dysmenorrhea, postpartum status, polycystic ovary disease, and endometriosis.  Psychiatric and psychological consultation and testing are not necessary unless the patient exhibits mental/nervous symptoms.  An accurate diagnosis of PMS can only be made by confirming that symptoms are confined to the luteal phase of the menstrual cycle.  This can be aided by daily symptom charting for at least 2 menstrual cycles (2 periods are studied because of variability between cycles).

Ozisik and colleagues (2005) examined sympathetic skin response in women with PMS (a disorder known to have many autonomic symptoms) to ascertain if there was sudomotor sympathetic involvement.  The study included 24 subjects with PMS and 20 healthy women (control group). The ages of the women were 22 to 34 years (mean of 25) for the PMS group and 23 to 34 years (mean of 25) for the control group.  The sympathetic skin response was recorded from the palms, soles and genital regions by means of electrical stimuli to the median nerve at the wrist.  The sympathetic skin response was recorded in the follicular phase as well as the late luteal phase of menstruation.  The follicular and late luteal phase sympathetic skin response of the 2 groups were compared.  The amplitudes and latency values of the late luteal and follicular phase sympathetic skin response from the PMS group and the control group were statistically similar.  No differences were found in the latency or amplitude of the sympathetic skin response obtained from the 3 regions of both groups.  The results of this study indicated that at the very least there is no difference between women with PMS and control subjects regarding peripheral sudomotor functions.

Management of patients with PMS/PMDD ranges from conservative approaches to medications, with surgery reserved for the most severe, refractory cases.  Women with PMS without co-morbid conditions should be treated conservatively.  Recommended first-line treatments include a diet low in salt, fat, caffeine, and sugar; restriction of alcohol and tobacco consumption; an aerobic exercise regimen; and stress reduction via changes in lifestyle.  Women with PMDD or PMS, who have failed to adequately respond to 2 to 3 months of first-line treatments, may be prescribed medications.  The most effective medications for PMS and PMDD are selective serotonin reuptake inhibitors such as fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft).  Diuretics such as chlorothiazide (Diuril) and spironolactone (Aldactone) are useful for patients with severe edema.  Gonadotropin-releasing hormone antagonists such as danazol (Danocrine) can be considered for patients with mastalgia.  Although randomized controlled studies have failed to demonstrate the effectiveness of oral contraceptive pills in treating PMS, a small number of women reported improvement of PMDD while on oral contraceptive.  Thus, it may be reasonable to consider oral contraceptive pills for women who have failed other drug therapies and are candidates for bilateral oophorectomy, a last resort for patients with severe symptoms when medical therapy has either failed or has produced unacceptable side effects.

Khine and colleagues (2006) noted that conflicting data exist regarding the presence of magnesium (Mg) deficiency and the therapeutic effectiveness of Mg in patients with PMS or PMDD.  In a randomized controlled trial, these researchers examined Mg retention and mood effects after intravenous Mg infusion in patients with PMDD.  The percentage of Mg retention was determined using 24-hour urinary Mg excretion and the total dose of Mg given intravenously.  In subjects with (n = 17) and without (n = 14) prospectively diagnosed PMDD, several measurements of blood Mg and evaluations of mood were obtained before, immediately after, and the day following an intravenous Mg loading dose (0.1 mM/kg).  A positive mood response was seen under open conditions; as open Mg infusion improved mood, subsequent PMDD patients (n = 10) were randomized in a double-blind, placebo-controlled, cross-over fashion.  Patients (31.5 %) and control subjects (27.5 %) retained comparable mean percentages of Mg.  Neither group differed in measures of mean Mg before, immediately after, or the day following Mg infusion.  Although there was a time effect for all mood measures in the patient group (p < 0.01 for all), there was neither a treatment nor time-by-treatment effect.  The authors concluded that contrary to prior reports, they found no evidence of Mg deficiency in women with PMDD compared with control subjects.  Furthermore, Mg was not superior to placebo in the mitigation of mood symptoms in women with PMDD.

In a pilot study, Mazza and colleagues (2008) examined the effectiveness of duloxetine, a dual serotonin and NE reuptake inhibitor, in the treatment of PMDD.  A total of 55 women were treated with a 60 mg/day dosage of duloxetine for 2 menstrual cycles.  Responses were assessed at first and second treatment cycle.  Outcome measures included a visual analog scale, the Zung Self-rating Scale for Depression, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale and the Clinical Global Impressions Scale.  Fifty patients completed the trial.  All had significant improvement of depression and anxiety and response, defined as a 50 % decrease in daily symptom scores, occurred in 39 (78 %) patients.  The effects of active treatment were marked by the first active cycle of menstruation.  The authors concluded that duloxetine 60 mg/day was effective in reducing PMDD symptoms and generally well-tolerated.  Limitations of the study were open-label design and lack of placebo control.  However, the results appeared to be strong and consistent across measures.  Adverse events (e.g., insomnia, nausea, poor appetite) were low.  The authors stated that further studies are needed to confirm these results.

In a pilot, open-label study, Kayatekin and colleagues (2008) examined the safety and effectiveness of levetiracetam for the treatment of PMDD.  A total of 123 potential patients were prospectively screened to enroll 7 patients into the open-label treatment phase of the study.  Pre-menstrual dysphoric disorder was diagnosed per DSM-IV-TR criteria and 2 consecutive months of prospective ratings of Daily Record of Severity of Problems (DRSP).  The Mini International Neuropsychiatric Interview (MINI) was used to exclude any co-morbid conditions.  Levetiracetam was started at 250 mg qhs at the end of the 1st week of the follicular phase.  Dosage was gradually increased up to 1,500 mg bid as tolerated or clinically effective.  The treatment phase lasted 4 months.  Response to treatment was evaluated by Clinical Global Impression (CGI) and DRSP scores.  Overall, 6 out of 7 patients experienced a considerable decrease in their DRSP scores with levetiracetam, starting from the 1st treatment cycle.  One patient dropped out of the study due to lack of effectiveness after 1 cycle.  Medication was fairly well-tolerated.  Improvements in food cravings and pre-menstrual headaches were also noted as unexpected benefits.  The authors noted that anti-convulsant medications, specifically levetiracetam, could be effective in the treatment of PMDD.  They stated that future double-blind, placebo controlled, randomized studies are needed and should include larger number of patients.

In a pilot, single-blind, non-controlled, fixed-dose trial, Ramos and colleagues (2009) examined the effectiveness of duloxetine (a dual reuptake inhibitor of serotonin and NE) in the treatment for women with PMDD.  After 2 cycles for diagnosis confirmation, including a single-blind placebo cycle, 20 women with PMDD were treated continuously for 3 menstrual cycles with 60 mg/day duloxetine.  The primary measure of the efficacy of treatment with duloxetine was the significant reduction in pre-menstrual symptoms demonstrated by the comparison between the mean DRSP scores at baseline to endpoint (p = 0.0002).  Statistically significant symptom reduction was observed in the first treatment cycle and throughout all the treatment phase.  Clinical response, defined as a reduction 50 % of baseline pre-menstrual symptoms, occurred in 65 % of subjects (intention-to-treat population).  Significant improvements were demonstrated by secondary measures, including reduction in self-rated functional impairment (p = 0.01) and improvement in quality of life (p = 0.04).  The main side-effects associated with duloxetine were dry mouth, nausea, drowsiness, insomnia, decreased appetite, decreased libido, and sweating.  Duloxetine was effective and generally well-tolerated in the treatment of PMDD.  Moreover, the authors concluded that further large-scale, double-blind, placebo-controlled studies are needed to evaluate duloxetine as an additional treatment strategy for the management of PMDD.

Deligiannidis and Freeman (2010) noted that complementary and alternative medicine (CAM) therapies are commonly practiced in the United States and are used more frequently among women than men.  These investigators reviewed several CAM treatments for depressive disorders in women, with a focus on major depressive disorder across the reproductive life cycle.  The CAM therapies selected for this review (namely S-adenosyl-L-methionine, omega-3 fatty acids, St John's wort [Hypericum], acupuncture, light therapy, and exercise) were based on their prevalence of use and the availability of randomized, placebo-controlled data.  The authors concluded that further investigation is needed to delineate the role of specific CAM therapies in PMS, PMDD, ante-partum and post-partum depression, lactation, as well as the menopausal transition.

Kim et al (2011) evaluated the current evidence for acupuncture as a treatment for PMS.  A total of 10 databases were searched electronically, and relevant reviews were searched by hand through June 2009.  The review included RCTs of women with PMS; these RCTs compared acupuncture with sham acupuncture, medication, or no treatment.  Study outcomes were presented as mean differences (for continuous data) or risk ratios (RRs) (for dichotomous data) with a 95 % confidence interval (CI).  The risk of bias was assessed using the assessment tool from the Cochrane Handbook.  A total of 10 RCTs were included in this review.  The pooled results demonstrated that acupuncture is superior to all controls (8 trials, pooled RR 1.55, 95 % CI: 1.33 to 1.80, p < 0.00001).  A meta-analysis comparing the effects of acupuncture with different doses of progestin and/or anxiolytics supported the use of acupuncture (4 trials, RR 1.49, 95 % CI: 1.27 to 1.74, p < 0.00001).  In addition, acupuncture significantly improved symptoms when compared with sham acupuncture (2 trials, RR 5.99, 95 % CI: 2.84 to 12.66, p < 0.00001).  No evidence of harm resulting from acupuncture emerged.  Most of the included studies demonstrated a high-risk of bias in terms of random sequence generation, allocation concealment, and blinding.  The authors concluded that although acupuncture seems promising for symptom improvement in women with PMS, important methodological flaws in the included studies weaken the evidence.  They stated that considering the potential of acupuncture, further rigorous studies are needed.

In a Cochrane review, Ford et al (2012) examined if progesterone has been found to be an effective treatment for all or some pre-menstrual symptoms and if adverse events associated with this treatment have been reported.  These investigators searched the Cochrane Menstrual Disorders and Subfertility Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and PsycINFO to February 2011.  They contacted pharmaceutical companies for information about unpublished trials, for the first version of this review.  They included randomized double-blind, placebo-controlled trials of progesterone on women with PMS diagnosed by at least 2 prospective cycles, without current psychiatric disorder.  Two reviewers extracted data independently and decided which trials to include.  From 17 studies, only 2 met inclusion criteria.  Together they had 280 participants aged between 18 and 45 years.  A total of 115 yielded analysable results.  Both studies measured symptom severity using subjective scales.  Differing in design, participants, dose of progesterone and how delivered, the studies could not be combined in meta-analysis.  Adverse events which may or may not have been side effects of the treatment were described as mild.  Both trials had defects.  They intended to exclude women whose symptoms continued after their periods.  When data from ineligible women were excluded from analysis in 1 trial, the other women were found to have benefited more from progesterone than placebo.  The smaller study found no statistically significant difference between oral progesterone, vaginally absorbed progesterone and placebo, but reported outcomes incompletely.  The authors concluded that these trials did not show that progesterone is an effective treatment for PMS nor that it is not.  Neither trial distinguished a subgroup of women who benefited, nor examined claimed success with high doses.

Leminen et al (2012) examined the effect of hysterectomy or levonorgestrel-releasing intra-uterine system (LNG-IUS) on pre-menstrual symptoms in women treated for menorrhagia.  A cohort of 236 women, aged 35 to 49 years (mean of 43 years) referred for menorrhagia between 1994 and 1997 were included in this analysis.  Women were not diagnosed with PMS.  Women were randomized to treatment by hysterectomy (n = 117) or LNG-IUS (n = 119).  Analyses were performed using the intention-to-treat and actual treatment principles.  Women using estrogen therapy and women who underwent bilateral salpingo-oophorectomy were excluded from the analyses.  Main outcome measures included the occurrence of pre-menstrual symptoms evaluated by questionnaires at baseline and at follow-up visits 6 and 12 months after the treatment and 5 years after the randomization.  Pre-menstrual symptoms decreased significantly in both groups by 6 months (p ≤ 0.028) without significant differences between the groups, except that in the LNG-IUS group the decrease of breast tenderness was seen first by 12 months (p = 0.048).  Even though 42 % of the women assigned to treatment with LNG-IUS were hysterectomized during the follow-up period, the results of intention-to-treat and actual treatment analyses were comparable.  The authors concluded that both hysterectomy and LNG-IUS seem to alleviate pre-menstrual symptoms of women treated for menorrhagia, while the effect of these treatments on PMS remains unsettled.

Sani et al (2014) noted that the treatment of PMDD is far from satisfactory, as there is a high proportion of patients who do not respond to conventional treatment.  The anti-diuretic sulfonamide, acetazolamide, inhibits carbonic anhydrase and potentiates GABAergic transmission; the latter is putatively involved in PMDD.  These researchers therefore tried acetazolamide in a series of women with intractable PMDD.  They described a series of 8 women diagnosed with DSM-IV-TR PMDD, 5 of whom had co-morbidity with a mood disorder and 1 with an anxiety disorder, who were resistant to treatment and responded with symptom disappearance after being added-on 125 mg/day acetazolamide for 7 to 10 days prior to menses each month.  Patients were free from pre-menstrual symptoms at the 12-month follow-up.  The authors suggested that acetazolamide may be used to improve symptoms of PMDD in cases not responding to other treatments.  These preliminary findings need to be validated by well-designed studies.

An UpToDate review on “Treatment of premenstrual syndrome and premenstrual dysphoric disorder” (Casper and Yonkers, 2015) states that “In women with severe symptoms who have not responded to or cannot tolerate SSRIs or OCs, we suggest GnRH agonist with estrogen-progestin addback therapy. However, GnRH agonists should not be considered until the patient has first tried selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine, sertraline, paroxetine, and venlafaxine), and an OC with a shortened pill-free interval or continuous administration”.

Sepede and colleagues (2016) reviewed the original articles pertaining to the treatment of PMDD in adult women free of any current or previous psychiatric co-morbidity.  These investigators searched PubMed to identify published studies on PMDD, including RCTs, open-label trials, and case series or case reports involving adult women with no history of co-morbid mental conditions.  The search was conducted in April 2015.  These researchers found 55 studies that met their inclusion criteria, 49 of them focused on pharmacological/chemical agents and the remaining 6 on non-pharmacological interventions.  The authors concluded that based on the results of their qualitative synthesis, the best therapeutic option in the treatment of adult PMDD patients free of other mental disorders are SSRI anti-depressants (especially paroxetine and fluoxetine) and low doses of oral estro-progestins.  Other interventions (e.g., cognitive behavioral therapy, food supplements, herbal medicines, and light therapy) showed promising effects, but other investigations are needed to confirm their effectiveness.

Measurement of Salivary or Serum Cortisol

Non-Contraceptive Estrogen-Containing Preparations

In a Cochrane review, Naheed and colleagues (2017) examined the safety and effectiveness of non-contraceptive estrogen-containing (NCEC) preparations in the management of PMS.  On March 14, 2016, these investigators searched the following databases: the Cochrane Gynecology and Fertility Group (CGF) Specialized Register; Cochrane Central Register of Studies (CRSO); MEDLINE; Embase; PsycINFO; CINAHL; ClinicalTrials.gov; metaRegister of Controlled trials (mRCT); and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal.  In addition, they checked the reference lists of articles retrieved.  These researchers included published and unpublished randomized placebo or active controlled trials on the effectiveness of the use of NCEC preparations in the management of PMS in women of reproductive age with PMS diagnosed by at least 2 prospective cycles without current psychiatric disorder.  Two review authors independently selected studies, assessed risk of bias, extracted data on PMS and adverse effects and entered data into Review Manager 5 software.  Where possible, intention-to-treat or modified intention-to-treat analysis was used.  Studies were pooled using a fixed-effect model, analyzing cross-over trials as parallel trials.  Standardized mean differences (SMDs) with 95 % CIs were calculated for PMS scores.  Risk ratios with 95 % CIs were calculated for dichotomous outcomes.  The overall quality of the evidence was assessed using the GRADE working group methods.  The search resulted in 524 potentially relevant articles; 5 eligible RCTs were identified (305 women).  Trials using oral tablets, transdermal patches and implants were identified.  No trial used gels; 1 small cross-over trial (11 women, effective sample size 22 women considering cross-over trials) compared oral luteal-phase estrogen versus placebo. Data were very low quality and unsuitable for analysis, but study authors reported that the intervention was ineffective and might aggravate the symptoms of PMS.  They also reported that there were no adverse events (AEs); 3 studies compared continuous estrogen with progestogen versus placebo (with or without progestogen).  These trials were of reasonable quality, although with a high risk of attrition bias and an unclear risk of bias due to potential carry-over effects in 2 cross-over trials.  Continuous estrogen had a small-to-moderate positive effect on global symptom scores (SMD -0.34, 95 % CI: -0.59 to -0.10, p = 0.005, 3 RCTs, 158 women, effective sample size 267 women, I² = 63 %, very low quality evidence).  The evidence was too imprecise to determine if the groups differed in withdrawal rates due to AEs (RR 0.64, 95 % CI: 0.26 to 1.58, p = 0.33, 3 RCTs, 196 women, effective sample size 284 women, I² = 0 %, very low quality evidence).  Similarly, the evidence was very imprecise in measures of specific AEs, with large uncertainties around the true value of the RR.  None of the studies reported on long-term risks such as endometrial cancer or breast cancer.  One study compared patch dosage (100 versus 200 µg estrogen, with progestogen in both arms) and had a high risk of performance bias, detection bias and attrition bias.  The study did not find evidence that dosage affects global symptoms, but there was much uncertainty around the effect estimate (SMD -1.55, 95 % CI: -8.88 to 5.78, p = 0.68, 1 RCT, 98 women, very low quality evidence).  The evidence on rates of withdrawal for AEs was too imprecise to draw any conclusions (RR 0.70, 95 % CI: 0.34 to 1.46, p = 0.34, 1 RCT, 107 women, low-quality evidence).  However, it appeared that the 100-µg dose might be associated with a lower overall risk of AEs attributed to estrogen (RR 0.51, 95 % Cl: 0.26 to 0.99, p = 0.05, 1 RCT, 107 women, very low quality evidence) with a large uncertainty around the effect estimate.  The overall quality of the evidence for all comparisons was very low, mainly due to risk of bias (specifically attrition), imprecision, and statistical and clinical heterogeneity.

The authors found very low quality evidence to support the effectiveness of continuous estrogen (transdermal patches or subcutaneous implants) plus progestogen, with a small-to-moderate effect size.  They found very low quality evidence from a study based on 11 women to suggest that luteal-phase oral unopposed estrogen is probably ineffective and possibly detrimental for controlling the symptoms of PMS.  A comparison between 200-µg and 100-µg doses of continuous estrogen was inconclusive with regard to effectiveness, but suggested that the lower dose was less likely to cause side effects.  Uncertainty remains regarding safety, as the identified studies were too small to provide definite answers.  Moreover, no included trial addressed adverse effects that might occur beyond the typical trial duration of 2 to 8 months.

Vestibular Stimulation

In an experimental study, Johny and colleagues (2017) examined the effectiveness of vestibular stimulation in the management of PMS.  A total of 20 subjects of aged 18 to 30 years were recruited for this study.  Conventional swing was used to administer vestibular stimulation.  Variables were recorded before and after vestibular stimulation and compared.  Depression and stress scores were significantly decreased after 2 months of intervention.  Anxiety scores decreased followed by vestibular stimulation.  However, it was no statistically significant.  Serum cortisol levels significantly decreased after 2 months of intervention.  WHOQOL-BREF-transformed scores were not significantly changed followed by the intervention.  However, psychological domain score (T2) and social relationships domain score (T3) were increased followed by intervention.  Systolic blood pressure was significantly decreased after 2 months of intervention.  No significant change was observed in diastolic pressure and pulse rate.  Pain score was significantly decreased after 2 months of intervention.  Mini mental status examination (MMSE) scores and spatial and verbal memory score were significantly improved followed by intervention.  The authors concluded that the findings of this study provided preliminary evidence for implementing vestibular stimulation for management of PMS as a non-pharmacological therapy.  They recommended further well-controlled, detailed studies in this area with higher sample size.

Measurement of Plasma Leptin

Nicolau and colleagues (2017) noted that PMS is characterized by physical and psychological symptoms in the luteal phase.  Leptin can influence PMS as it acts on the hypothalamic-pituitary-gonadal axis.  These investigators evaluated data regarding the profile of plasma leptin in women with PMS.  They performed a search of databases using both descriptors.  A total of 3 studies (n = 181) were identified; 2 of these studies found higher leptin levels in women with PMS.  Conflicting results were found regarding the leptin levels in the luteal phase and the correlation between leptin, estradiol, and progesterone levels.  The authors concluded that leptin could have a role in the pathophysiology of PMS and indicate degree of severity of PMS.  Moreover, they stated that future studies on the role of leptin in PMS are needed

Cognitive Behavioral therapy

In a review on PMS and PMDD, Hofmeister and Bodden (2016) stated that SSRIs are 1st-line treatments.  They can be used continuously or only during the luteal phase.  Oral contraceptives and calcium supplements may also be used.  There is insufficient evidence to recommend treatment with vitamin D, herbal remedies, or acupuncture, but there are data to suggest benefit from cognitive behavior therapy (CBT).  On the other hand, in a general overview on treatment strategies for PMDD (Andrade, 2016), CBT is not mentioned as a therapeutic option.

In a RCT, Ussher and Perz (2017) examined the efficacy of couple-based CBT for premenstrual disorders (PMDs), in comparison to one-to-one CBT and a wait-list control.  Triangulation of quantitative and qualitative outcome measures evaluated changes pre-post intervention.  A total of 83 women were randomly allocated across 3 conditions, with 63 completing post-intervention measures, a retention rate of 76 %.  Repeated measures analysis of variance found a significant time by group interaction identifying that women in the 2 CBT conditions reported lower total premenstrual symptoms, emotional reactivity/mood, and premenstrual distress, in comparison to the wait list control.  Significantly higher active behavioral coping post-intervention was found in the couple condition than in the one-to-one and wait-list control groups.  Qualitative analysis provided insight into the subjective experience of PMDs and participation in the intervention study.  Across groups, women reported increased awareness and understanding of premenstrual change post-intervention.  A larger proportion of women in the CBT conditions reported reduction in intensity and frequency of negative premenstrual emotional reactivity, increased communication and help-seeking, increased understanding and acceptance of embodied change, and the development of coping skills, post-intervention.  Increased partner understanding and improved relationship post-intervention was reported by a greater proportion of participants in the CBT conditions, most markedly in the couple condition.  The authors concluded that these findings suggested that one-to-one and couple CBT interventions can significantly reduce women's premenstrual symptomatology and distress, and improve premenstrual coping.  They stated that couple-based CBT interventions may have a greater positive impact upon behavioral coping and perceptions of relationship context and support suggesting that CBT should be available for women reporting moderate-severe PMDs, with couple-based CBT offering additional benefits to a one-to-one modality.

The authors stated that his study had several drawbacks.  First, the rate of attrition post-intervention resulted in a small sample size.  Second, the absence of daily diary ratings throughout the study, which would have allowed for measurement of ongoing change. Third, while partners were included in the couple condition, no evaluation of the perspectives of partners across conditions was included.  This would strengthen the design of future couple interventions for PMDs, allowing for evaluation of the impact of intervention on partners, and possible changes in their perspective on women’s PMDs.  Lastly, the majority of women who took part in this study were in heterosexual relationships.  However, the one-to-one intervention used in the study has been found to be efficacious with women who are single and in lesbian relationships in previous research, suggesting it has efficacy beyond women in a heterosexual couple.

Reid and Soares (2018) stated that most ovulatory women experience premenstrual symptoms (PMS, molimina) that indicate impending menstruation and are of little clinical relevance because they do not affect quality of life (QOL).  A few women, however, experience significant physical and/or psychological symptoms before menstruation that, if left untreated, would result in deterioration in functioning and relationships.  The precise etiology remains elusive, although new theories are gaining support in pre-clinical and early clinical trials.  Refined diagnostic criteria allow better discrimination of this condition from other psychiatric diagnoses and the selection of symptom appropriate therapies that afford relief for most women.  Pharmacotherapies (particularly SNRIs) represent the 1st-line treatment for PMDD and severe, mood-related PMS.  Continuous combined oral contraceptives have limited evidence for usefulness in PMDD, whereas medical ovarian suppression is often recommended for patients who fail to respond or cannot tolerate 1st-line treatments (e.g., SSRIs).  The use of CBT is promising, but it remains limited by sparse data and restricted access to trained professionals.

Furthermore, an UpToDate review on “Treatment of premenstrual syndrome and premenstrual dysphoric disorder” (Casper and Yonkers, 2018) does not mention cognitive behavioral therapy as a therapeutic option.

Acupuncture

Armour and colleagues (2018) stated that acupuncture has a history of traditional use in China for women's health conditions including PMS, but its effectiveness for this condition remains unclear.  Ina Cochrane review, these investigators evaluated safety and effectiveness of acupuncture or acupressure for women with PMS or PMDD.  The authors concluded that the limited available evidence suggested that acupuncture and acupressure may improve both physical and psychological symptoms of PMS when compared to a sham control.  There was insufficient evidence to determine whether there was a difference between the groups in rates of AEs.  There was no evidence comparing acupuncture or acupressure versus current International Society for Premenstrual Disorders (ISPMD) recommended treatments for PMS such as selective serotonin reuptake inhibitors (SSRIs).  These researchers stated that further research is needed, using validated outcome measures for PMS, adequate blinding and suitable comparator groups reflecting current best practice.

Plasma Progesterone and Premenstrual Dysphoric Disorder

Di Florio and colleagues (2018) stated that the molecular mechanisms underpinning the progesterone-triggering mood symptoms in women with PMDD are unknown.  Cell metabolism is a potential source of variability.  Very little is known about the effect of progesterone sensitivity on the metabolome.  These researchers characterized the effects of progesterone on the global metabolic profile and examined the differences between women with PMDD and controls.  Plasma was obtained from 12 women with prospectively confirmed PMDD and 25 controls under 2 hormonal conditions: gonadal suppression induced by leuprolide acetate (3.75 mg IM monthly); and add-back phase with leuprolide and progesterone (200 mg twice-daily by vaginal suppository).  The global metabolic profile was obtained using liquid and gas chromatography followed by mass spectrometry.  Differences between groups and time-points were tested using repeated measures analysis of variance.  The false discovery rate was calculated to account for multiple testing.  Amino acids and their derivatives represented 78 % (28/36) of the known compounds that were found in significantly lower plasma concentrations after progesterone administration than during gonadal suppression.  The concentration of tyrosine was nominally significantly decreased after progesterone add-back in controls, but not in cases (p = 0.02).  The authors concluded that plasma levels of some amino acids were decreased in response to progesterone.  These researchers stated that albeit preliminary, evidence further suggested that progesterone has a different effect on the metabolic profiles of women with PMDD compared to controls.  They stated that further research is needed to replicate these findings in a larger sample and to identify the unknown compounds, especially those differentially expressed.

Serum Magnesium and Premenstrual Syndrome

Moslehi and colleagues (2019) noted that a number of studies have examined the association between serum Mg and PMS in different population, but the findings have been inconclusive.  In a systematic review and meta-analysis, these investigators reviewed available observational studies to elucidate the overall relationship between Mg and PMS.  PubMed, Cochrane's library, ScienceDirect, Scopus, Google Scholar, and ISI web of science databases were searched for all available literature until January 2019 for studies evaluating the association between Mg and PMS.  The Newcastle-Ottawa Quality Assessment Scale was used to evaluate the quality of observational studies.  A total of 13 studies out of 196 met our inclusion criteria and were included in this study.  There were no associations between serum Mg and PMS (weighed mean difference [WMD] - 0.04; 95 % CI: - 0.14 to 0.06; p = 0.46) during follicular or serum/erythrocyte Mg (WMD - 0.37; 95 % CI: - 1.01 to 0.27; p = 0.25)/(WMD - 0.04; 95 % CI: - 0.10 to 0.03; p = 0.26) and during luteal phase except for the sub-group of studies done outside of the U.S. in which recent association became significant and means that serum Mg was lower in PMS subjects.  The authors concluded that although this study did not show any significant association between serum/erythrocyte Mg and PMS except for serum Mg in luteal phase in the sub-group of studies done outside of the U.S., heterogeneity between studies should be taken into accounts when interpreting these findings.  Moreover, these researchers stated that additional well-designed clinical trials are needed to develop firm conclusions on the efficacy of Mg on PMS.

Serum Trace Elements and Premenstrual syndrome

Bahrami and colleagues (2019) noted that PMS, primary dysmenorrhea (PD), and irritable bowel syndrome (IBS) are common complaints in women of reproductive age.  Trace element status may be associated with the development of these disorders but the current data are unclear.  In a cross-sectional study, these researchers examined the relationship between serum and dietary copper and zinc with some common physical and psychosomatic conditions among young females.  This trial comprised 448 adolescent girls who were classified into 4 groups: individuals with PMS (n = 67), PD (n = 161), both PMS and PD (n = 146), and normal (n = 74); IBS was diagnosed according to the Rome III questionnaire.  Flame atomic absorption (Varian AA240FS) was used to measure serum zinc and copper.  Food intake of micronutrients was estimated using a 3-day dietary record.  There was a significant difference in the frequency of IBS across the 4 corresponding groups as the percentage of subjects.  The prevalence of IBS was significantly higher in the PD group [PMS (13.6 %), PD (19.9 %), both PMS and PD (17.4 %) and normal (8.1 %); p < 0.05].  There was no significant differences between the mean values for serum and dietary intake of zinc and copper among 4 groups (p > 0.05); although, the mean dietary zinc intake was significantly lower in subjects with IBS (6.7 ± 2.8 mg/day) versus those without IBS (7.9 ± 3.1 mg/ day, p = 0.032).  The authors concluded that girls with IBS were found to have significantly higher rates of gynecological symptoms, including PD and PMS.  The lower dietary intake of zinc in subjects with IBS indicated a need for greater attention towards dietary patterns in these individuals.  The role of serum trace elements in the development of PMS need to be further investigated.

Reflexology

Ernst (2009) assessed the evidence on the effectiveness of reflexology for treating any medical condition.  A total of 6 electronic databases were searched from their inception to February 2009 to identify all relevant randomized controlled trials (RCTs).  No language restrictions were applied.  Randomized controlled trials of reflexology delivered by trained reflexologists to patients with specific medical conditions were selected.  Condition studied, study design and controls, primary outcome measures, follow-up, and main results were extracted.  A total of 18 RCTs met all the inclusion criteria.  These studies examined a range of conditions: anovulation, asthma, back pain, dementia, diabetes, cancer, foot edema in pregnancy, headache, irritable bowel syndrome, menopause, multiple sclerosis, the post-operative state and PMS.  There were more than 1 study for asthma, the post-operative state, cancer palliation and multiple sclerosis; 5 RCTs yielded positive results.  Methodological quality was evaluated using the Jadad scale.  The methodological quality was often poor, and sample sizes were generally low.  Most higher-quality trials did not generate positive findings.  The authors concluded that the best evidence available to date does not demonstrate convincingly that reflexology is an effective treatment for any medical condition.

In a systematic review and meta-analysis, Hasanpour and colleagues (2019) examined the effect of reflexology on PMS.  This study was conducted by searching in 8 electronic data-bases including PubMed, Embase, Cochrane Library, Web of Science, ProQuest, Scopus, Google Scholar, and SID until December 28, 2018.  In this regard, interventional studies, which examined the impact of reflexology on women with PMS, were included.  These studies were published during 1993 to 2018.  The Cochrane Collaboration's Risk of Bias Tool was used to assess the quality of studies.  Meta-analysis was performed by the help of CMA 2 software.  A total of 9 out of 407 studies remained after screening, and quantitative and quantitative analyses were performed on them.  The total number of research samples was 475.  The mean treatment time with reflexology was 40.55 mins per session that was performed in 6 to 10 sessions of treatment in 66.67 % of studies.  According to the meta-analysis and based on the random effects model, the reflexology could decrease the severity of PMS in the intervention group compared to the control group (SMD = - 2.717, 95 % CI: - 3.722 to - 1.712).  Meta-regression results indicated that the duration of intervention sessions (β = - 0.1124, 95 % CI: - 0.142 to - 0.084, p < 0.001) had a significant impact on the severity of PMS.  Reflexology could also significantly affect somatic (SMD = - 1.142, 95 % CI: - 1.481 to - 0.803) and psychological (SMD = - 1.380, 95 % CI: - 2.082 to - 0.677) symptoms arising from PMS.  The authors concluded that in general, results of the present study indicated that the reflexology could relieve PMS symptoms, so that overall scores, somatic and psychological symptoms of PMS decreased by applying the reflexology intervention.  Furthermore, an increase in the length of reflexology time in each session increased its efficiency.  Reflexology can be used as an effective intervention in a patient care program by nurses and its efficiency can be enhanced by increasing intervention time in each reflexology treatment session.  These researchers stated that a logical step towards the future clinical trials is to compare reflexology interventions with other complementary and alternative therapies in order to provide a systematic review and meta-analysis study in this regard.

The authors stated that a drawback of this study was the low number of studies that directly measured and reported somatic symptoms as outcomes; thus, the performance of applied statistical tests was somewhat affected to examine the publication bias in the studies.  Another drawback was the publication bias in studies that examined the impact of reflexology on overall score of PMS.  In this regard, adjusted effect size was measured by applying the trim and fill method.  Another drawback of this study was the poor and incomplete report of studies in study design and subjects’ age.  In some studies, these investigators received more detailed information by emailing authors.

Evaluation of Cortisol Awakening Response for the Diagnosis of Premenstrual Syndrome (PMS) / Premenstrual Dysphoric Disorder (PMDD)

Hou and colleagues (2019) stated that previous studies have revealed stress-induced dysregulation of hypothalamic-pituitary-adrenal (HPA) axis in women with PMS; however, the findings regarding the relationship between HPA axis dysregulation and PMS are mixed.  Therefore, it is necessary to examine the basal activity of the HPA axis in women with PMS instead of only assessing a certain stressor.  These researchers assessed the relationship between the cortisol awakening response (CAR) and PMS.  A total of 32 women with PMS (mean age of 22.47 ± 2.20 years) and 36 healthy controls (mean age of 22.28 ± 2.43 years) were included in this study.  Saliva samples of subjects were collected successively at 0, 30, 45, and 60 mins after awakening to assess CAR during each of 2 phases of the menstrual cycle (the mid-follicular phase and the late luteal phase).  The findings showed a significantly attenuated CAR in women with PMS compared with the healthy controls, especially at 45 and 60 mins after awakening, regardless of the menstrual cycle phases.  In addition, there was a significant negative correlation between PMS severity as measured by PMS scale and AUCi (i.e., the area under the curve with respect to increase) in the mid-follicular phase.  The authors concluded that these findings suggested that an attenuated CAR activity profile may be an important risk factor for the development of PMS.

Neuroimaging for the Diagnosis of PMS / PMDD

Liu and associates (2019) noted that PMS is a menstrual cycle-related disorder.  Although the precise pathophysiology is not fully understood, it is increasingly believed that the central nervous system(CNS) plays a vital role in the development of PMS.  These researchers examined specific functional connectivity between the thalamus and cerebral cortex.  Resting-state functional magnetic resonance imaging (fMRI) data were obtained from 20 PMS patients and 21 healthy controls (HCs).  Seed-based functional connectivity between the thalamus and 6 cortical regions of interest, including the pre-frontal cortex (PFC), posterior parietal cortex, somatosensory cortex, motor cortex/supplementary motor area, temporal and occipital lobe, was adopted to identify specific thalamo-cortical connectivity in the 2 groups.  Correlation analysis was then used to examine relationships between the neuroimaging findings and clinical symptoms.  Activity in distinct cortical regions correlated with specific sub-regions of the thalamus in the 2 groups.  Comparison between groups exhibited decreased PFC-thalamic connectivity and increased posterior parietal-thalamic connectivity in the PMS patients.  Within the PMS group, the DRSP score negatively correlated with the PFC-thalamic connectivity.  The authors concluded that these findings may provide preliminary evidence for abnormal thalamo-cortical connectivity in PMS patients and may contribute to a better understanding of the pathophysiology of PMS.

Dubol and colleagues (2020) noted that endocrine organizational and activational influences on cognitive and affective circuits are likely critical to the development of PMDD.  These investigators carried out an overview of the anatomical and functional neural characterization of this disorder by means of neuroimaging correlates, identified from 18 publications (n = 361 subjects).  While white matter integrity remains uninvestigated, greater cerebellar grey matter volume and metabolism were observed in patients with PMDD, along with altered serotonergic and GABAergic neurotransmission.  Differential cortico-limbic activation in response to emotional stimuli distinguishes the PMDD brain, namely enhanced amygdalar and diminished fronto-cortical function.  Thus far, the emotional distress and dysregulation linked to PMDD appeared to be defined by structural, chemical and functional brain signatures; however, their characterization remains sparsely studied and somewhat inconsistent.  The authors concluded that clear and well-replicated neurobiological features of PMDD are needed to promote timely diagnoses and inform development of prevention and treatment strategies.

Furthermore, an UpToDate review on “Clinical manifestations and diagnosis of premenstrual syndrome and premenstrual dysphoric disorder” (Yonkers and Casper, 2020) does not mention neuroimaging as a management option.

Allopregnanolone Antagonists (e.g., Sepranolone) for the Treatment of PMS / PMDD

Carlini and Deligiannidis (2020) stated that the emergence of evidence implicating allopregnanolone in the etiology of PMDD has led to novel drug development.  A phase-II clinical trial in a sample of women with PMDD of sepranolone, an allopregnanolone antagonist, conducted over the length of 1 menstrual cycle demonstrated that patients receiving the active compound had significant reduction in symptoms compared to placebo as measured by the total score of the DRSP.  Sepranolone was dosed as a 10-mg or 16-mg subcutaneous injection standardized to 0.4 ml every other day during the luteal phase for a total of 5 injections, with the 1st injection occurring at ovulation.  In addition to the primary outcome of reduction in DRSP total score, secondary outcomes of reduction in DRSP negative mood score (a subscale composed of the sum of depression, anxiety, lability, and anger/irritability items) and reduction in a functional impairment score were also compared between groups.  Marginally significant reductions in functional impairment (p = 0.091) and DRSP negative mood score (p = 0.051) were found in the active treatment group compared to placebo.  Furthermore, there was no significant difference in frequency of AEs between groups, with the most common AE being injection site reaction, leading the study authors to conclude that the findings of this study suggested a favorable safety profile compared to the established treatment protocols with SSRIs and oral contraceptives.

Furthermore, an UpToDate review on “Treatment of premenstrual syndrome and premenstrual dysphoric disorder” (Casper and Yonkers, 2020) does not mention allopregnanolone antagonist / sepranolone as a management / therapeutic option.

The above policy is based on the following references: