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
      • Laboratory tests to detect specific nutrient deficiencies
      • Measurement of plasma leptin
      • Measurement of reproductive hormones
      • Measurement of salivary or serum cortisol
      • Pap smears with maturation index
      • Sympathetic skin response for the evaluation of peripheral sudomotor function.
    2. Treatment
      • Acupuncture
      • 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.

Several treatment options are not generally recommended for the management of patients with PMS/PMDD:
  1. progesterone (oral or vaginal suppositories),
  2. vitamin B6 (pyridoxine) or vitamin E (tocopherol),
  3. dietary supplements such as evening primrose oil or magnesium,
  4. bromocriptine (Parlodel),
  5. benzodiazepine anxiolytics such as alprazolam (Xanax),
  6. non-benzodiazepine anxiolytics such as buspirone (BuSpar),
  7. gonadotropin-releasing hormone agonists such as Lupron (leuprolide acetate) and goserelin (Zoladex),
  8. hysterectomy, and
  9. endometrial ablation.
In a randomized controlled study, Bunevicius and colleagues (2005) examined the effects of clonidine in comparison with active placebo on pre-menstrual symptoms, mood scores and norepinephrine (NE) concentration, in women with PMDD.  A total of 12 women with prospectively confirmed PMDD were randomly assigned to oral 0.3 mg/day clonidine, as an active treatment, or 10 mg/day loratadine, as an active placebo, for 2 months each using a double-blind, cross-over design.  Norepinephrine concentration, pre-menstrual symptoms ratings and mood scales were measured on 3 occasions:
  1. at pre-treatment,
  2. after clonidine treatment, and
  3. after placebo treatment.
All patients were free of current psychiatric co-morbidity and medication use.  There were no significant differences between clonidine and placebo for mood scales or pre-menstrual symptoms ratings, although clonidine significantly suppressed NE concentration and produced more side effects in comparison with placebo.  These investigators concluded that compared with an active placebo, clonidine demonstrated no beneficial changes in mood and pre-menstrual symptoms in women with PMDD.

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.

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 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

Kiesner and Granger (2016) noted that although decades of research has examined the association between cortisol regulation and PMS/PMDD, no review exists to provide a general set of conclusions from the extant research. In the present review these investigators summarized and interpreted research that has tested for associations between PMS/PMDD and cortisol levels and reactivity (n = 38 original research articles).  Three types of studies were examined:
  1. correlational studies,
  2. environmental-challenge studies, and
  3. pharmacological-challenge studies.
Overall, there was very little evidence that women with and without PMS/PMDD demonstrate systematic and predictable mean-level differences in cortisol, or differences in cortisol response/reactivity to challenges.  Methodological differences in sample size, the types of symptoms used for diagnosis (physical and psychological versus only affective), or the type of cortisol measure used (serum versus salivary), did not account for differences between studies that did and did not find significant effects.  The authors concluded that caution is recommended before accepting the conclusion of null effects, and recommendations are made that more rigorous research be conducted, considering symptom-specificity, within-person analyses, and multiple parameters of cortisol regulation, before final conclusions are drawn.

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.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

58661 Laparoscopy surgical; with removal of adnexal structures (partial or total oophorectomy and /or salpingectomy
58940 Oophorectomy, partial or total, unilateral or bilateral
84436 Thyroxine; total
84439     free
84443 Thyroid stimulating hormone (TSH)
90791 Psychiatric diagnostic evaluation
90792 Psychiatric diagnostic evaluation with medical services
96130 - 96131 Psychological testing evaluation services by physician or other qualified health care professional, including integration of patient data, interpretation of standardized test results and clinical data, clinical decision making, treatment planning and report, and interactive feedback to the patient, family member(s) or caregiver(s), when performed
96136 - 96137 Psychological or neuropsychological test administration and scoring by physician or other qualified health care professional, two or more tests, any method
96138 - 96139 Psychological or neuropsychological test administration and scoring by technician, two or more tests, any method
96146 Psychological or neuropsychological test administration, with single automated, standardized instrument via electronic platform, with automated result only

CPT codes not covered for indications listed in the CPB:

Vestibular stimulation, plasma leptin - no specific code:

0111T Long-chain (C20-22) omega-3 fatty acids in red blood cell (RBC) membrane
58150 - 58210, 58260 - 58294 Hysterectomy (open)
58353 Endometrial ablation, thermal, without hysteroscopic guidance
58356 Endometrial cryoablation with ultrasonic guidance, including endometrial curettage, when performed
58541 - 58544 Laparoscopy, surgical, supracervical hysterectomy
58550 - 58554 Laparoscopy, surgical, with vaginal hysterectomy
58563 Hysteroscopy, surgical; with endometrial ablation (e.g., endometrial resection, electrosurgical ablation, thermoablation)
82180 Ascorbic acid (Vitamin C), blood
82306 Calcifediol (25-OH Vitamin D-3)
82307 Calciferol (Vitamin D)
82310 Calcium; total
82530 Cortisol; free
82533 Cortisol; total
82607 Cyancobalamin (Vitamin B-12)
82608     unsaturated binding capacity
82652 Dihydroxyvitamin D, 1,25-
82670 Estradiol
82671 Estrogens; fractionated
82672     total
82677 Estriol
82679 Estrone
82725 Fatty acids, nonesterified
82726 Very long chain fatty acids
82746 Folic acid; serum
82747     RBC
83001 Gonadotropin; follicle stimulating hormone (FSH)
83002     luteinizing hormone (LH)
83540 Iron
83735 Magnesium
84100 Phosphorus inorganic (phosphate)
84105     urine
84207 Pyridoxal phosphate (Vitamin B-6)
84252 Riboflavin (Vitamin B-2)
84255 Selenium
84425 Thiamine (Vitamin B-1)
84446 Tocopherol alpha (Vitamin E)
84590 Vitamin A
84591 Vitamin, not otherwise specified
84597 Vitamin K
84630 Zinc
+ 88155 Cytopathology, slides, cervical or vaginal, definitive hormonal evaluation (e.g., maturation index, karyopyknotic index, estrogenic index) (List separately in addition to code(s) for other technical and interpretation services)
95923 Testing of autonomic nervous system function; sudomotor, including one or more of the following: quantitative sudomotor axon reflex test (QSART), silastic sweat imprint, thermoregulatory sweat test, and changes in sympathetic skin potential
96900 Actinotherapy (ultraviolet light)
97810 - 97814 Acupuncture

Other CPT codes related to the CPB:

58570 - 58573 Laparoscopy, surgical, with total hysterectomy

HCPCS codes covered if selection criteria are met:

J1205 Injection, chlorothiazide sodium, per 500 mg
J1950 Injection, leuprolide acetate (for depot suspension), per 3.75 mg
J9202 Goserelin acetate implant, per 3.6 mg
J9217 - J9219 Leuprolide acetate
S4993 Contraceptive pills for birth control
S9560 Home injectable therapy; hormonal therapy (e.g.; leuprolide, goserelin), including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem

HCPCS codes not covered for indications listed in the CPB:

A4633 Replacement bulb/lamp for ultraviolet light therapy system, each
E0691 Ultraviolet light therapy system panel, includes bulbs/lamps, timer and eye protection; treatment area 2 sq feet or less
E0692 Ultraviolet light therapy system panel, includes bulbs/lamps, timer and eye protection; 4 ft panel
E0693 Ultraviolet light therapy system panel, includes bulbs/lamps, timer and eye protection; 6 ft panel
E0694 Ultraviolet multidirectional light therapy system in 6 ft cabinet, includes bulbs/lamps, timer and eye protection
J0725 Injection, chorionic gonadotropin, per 1000 USP units
J0735 Injection, clonidine HCl, 1 mg
J1120 Injection, acetazolamide sodium, up to 500 mg
J3415 Injection, pyridoxine HCl, 100 mg
J3475 Injection, magnesium sulphate, per 500 mg
J7296 Levonorgestrel-releasing intrauterine contraceptive system (Kyleena), 19.5 mg
J7297 Levonorgestrel-releasing intrauterine contraceptive system, 52 mg, 3 year duration
J7298 Levonorgestrel-releasing intrauterine contraceptive system, 52 mg, 5 year duration
J7301 Levonorgestrel-releasing intrauterine contraceptive system, 13.5 mg
J7306 Levonorgestril (contraceptive) implant system, including implants and supplies
S4981 Insertion of levonorgestrel-releasing intrauterine system

ICD-10 codes covered if selection criteria are met:

N94.3 Premenstrual tension syndrome [PMS] [PMDD]

The above policy is based on the following references:

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