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:
* 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.
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.
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: (i) progesterone (oral or vaginal suppositories), (ii) vitamin B6 (pyridoxine) or vitamin E (tocopherol), (iii) dietary supplements such as evening primrose oil or magnesium, (iv) bromocriptine (Parlodel), (v) benzodiazepine anxiolytics such as alprazolam (Xanax), (vi) non-benzodiazepine anxiolytics such as buspirone (BuSpar), (vii) gonadotropin-releasing hormone agonists such as Lupron (leuprolide acetate) and goserelin (Zoladex), (viii) hysterectomy, and (ix) 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: (i) at pre-treatment, (ii) after clonidine treatment, and (iii) 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 pos-tpartum 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 % 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 SSRIs (fluoxetine, sertraline, paroxetine, and venlafaxine), and an OC with a shortened pill-free interval or continuous administration”.
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|Information in the [brackets] below has been added for clarification purposes.  Codes requiring a 7th character are represented by "+":|
|ICD-10 codes will become effective as of October 1, 2015:|
|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|
|84443||Thyroid stimulating hormone (TSH)|
|90791||Psychiatric diagnostic evaluation|
|90792||Psychiatric diagnostic evaluation with medical services|
|96101 - 96103||Psychological testing|
|CPT codes not covered for indications listed in the CPB:|
|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)|
|78270||Vitamin B-12 absorption study (e.g., Schilling teat); without intrinsic factor|
|78271||with intrinsic factor|
|78272||Vitamin B-12 absorption studies combined, with and without intrinsic factor|
|82180||Ascorbic acid (Vitamin C), blood|
|82306||Calcifediol (25-OH Vitamin D-3)|
|82307||Calciferol (Vitamin D)|
|82607||Cyancobalamin (Vitamin B-12)|
|82608||unsaturated binding capacity|
|82652||Dihydroxyvitamin D, 1,25-|
|82725||Fatty acids, nonesterified|
|82726||Very long chain fatty acids|
|82746||Folic acid; serum|
|83001||Gonadotropin; follicle stimulating hormone (FSH)|
|83002||luteinizing hormone (LH)|
|84100||Phosphorus inorganic (phosphate)|
|84207||Pyridoxal phosphate (Vitamin B-6)|
|84252||Riboflavin (Vitamin B-2)|
|84425||Thiamine (Vitamin B-1)|
|84446||Tocopherol alpha (Vitamin E)|
|84591||Vitamin, not otherwise specified|
|+ 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|
|S4993||Contraceptive pills for birth control|
|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|
|J1950||Injection, leuprolide acetate (for depot suspension), per 3.75 mg|
|J3415||Injection, pyridoxine HCl, 100 mg|
|J3475||Injection, magnesium sulphate, per 500 mg|
|J7301||Levonorgestrel-releasing intrauterine contraceptive system, 13.5 mg|
|J7302||Levonorgestrel-releasing intrauterine contraceptive system|
|J7306||Levonorgestril (contraceptive) implant system, including implants and supplies|
|J9202||Goserelin acetate implant, per 3.6 mg|
|J9217||Leuprolide acetate (for depot suspension), 7.5 mg|
|J9218||Leuprolide acetate, per 1 mg|
|J9219||Leuprolide acetate implant, 65 mg|
|S4981||Insertion of levonorgestrel-releasing intrauterine system|
|ICD-10 codes covered if selection criteria are met:|
|N94.3||Premenstrual tension syndrome [PMS] [PMDD]|