> Table of Contents > Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD)
Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD)
Courtney I. Jarvis, PharmD
Allison Hargreaves, MD
image BASICS
DESCRIPTION
  • Premenstrual syndrome (PMS), a complex of physical and emotional symptoms sufficiently severe to interfere with everyday life, occurs cyclically during the luteal phase of menses.
  • Premenstrual dysphoric disorder (PMDD) is a severe form of PMS characterized by severe recurrent depressive and anxiety symptoms, with premenstrual (luteal phase) onset, that remits a few days after the start of menses.
  • PMDD is now included as a full diagnostic category in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).
  • System(s) affected: endocrine/metabolic, nervous, reproductive
EPIDEMIOLOGY
Prevalence
  • Many women have some physical and psychological symptoms before menses (this is not PMS).
  • 30% of menstruating women suffer from PMS; 3-8% of menstruating women have PMDD.
ETIOLOGY AND PATHOPHYSIOLOGY
Not well understood. Leading theories postulate metabolites of progesterone interact with central neurotransmitter receptors (serotonin and &ggr;-aminobutyric acid [GABA]), provoking downstream effects of decreased GABA-mediated inhibition and decreased serotonin levels. Women with PMS/PMDD have similar levels of progesterone but seem to have an increased sensitivity to its metabolites, compared with women without PMS/PMDD.
Genetics
  • Role of genetic predisposition is controversial; however, twin studies do suggest a genetic component.
  • Involvement of gene coding for the serotonergic 5HT1A receptor and allelic variants of the estrogen receptor-&agr; gene (ESR1) is suggested.
RISK FACTORS
  • Age: usually present in late 20s to mid-30s
  • History of mood disorder (major depression, bipolar disorder), anxiety disorder, personality disorder, or substance abuse
  • Family history
  • Low parity
  • Tobacco use
  • Psychosocial stressors/history of trauma
  • High BMI
image DIAGNOSIS
PHYSICAL EXAM
No specific physical exam required; may consider thyroid and pelvic exams if indicated by additional patient symptoms.
DIFFERENTIAL DIAGNOSIS
  • Premenstrual exacerbation of underlying psychiatric disorder
  • Psychiatric disorders (especially bipolar disorder, major depression, anxiety)
  • Thyroid disorders
  • Perimenopause
  • Premenstrual migraine
  • Chronic fatigue syndrome
  • Irritable bowel syndrome (painful symptoms)
  • Seizures
  • Anemia
  • Endometriosis (painful symptoms)
  • Drug/alcohol abuse
DIAGNOSTIC TESTS & INTERPRETATION
  • The repetitive nature of symptoms precludes need for labs if a classic history is present.
  • Consider
    • Hemoglobin to rule out anemia
    • 25-OH vitamin D level to exclude deficiency, although precise relationship of deficiency with the disorder is unclear
    • Serum thyroid-stimulating hormone (TSH) to rule out hypothyroidism
  • Imaging with pelvic ultrasound to diagnose causes of pelvic pain and dysmenorrhea may be needed.
image TREATMENT
GENERAL MEASURES
Although evidence is lacking for aerobic exercise in treating PMS/PMDD, it is often recommended as part of an integrated care plan.
MEDICATION
First Line
  • SSRIs show a small to moderate effect in the treatment of physical, functional, and behavioral symptoms of PMS and PMDD compared to placebo (3)[A]:
    • Both intermittent luteal phase dosing and continuous full-cycle dosing are effective with no clear evidence of difference between modes of administration (3)[A].
    • All SSRIs tested appeared effective (3)[A].
    • SSRIs are effective at low doses. Higher doses have increased effect but are accompanied by increased side effects (3)[A].
  • Fluoxetine (Prozac, Sarafem) 20 mg/day every day or 20 mg/day only during luteal phase, or 90 mg once a week for 2 weeks in luteal phase
  • Sertraline (Zoloft) 50 to 150 mg/day every day or 50 to 150 mg/day only during luteal phase
  • Citalopram (Celexa) 10 to 30 mg/day every day or 10 to 30 mg/day only during luteal phase
  • Adverse effects (number needed to harm [NNH] with moderate-dose SSRI): nausea (NNH = 7), asthenia (NNH = 9), somnolence (NNH = 13), fatigue (NNH = 14), decreased libido (NNH = 14), and sweating (NNH = 14) (3)[A].
  • Contraindications: patients taking monoamine oxidase inhibitors (MAOIs)
  • Precautions
    • Increased risk of suicidal thinking and behavior in children and adolescents with depressive disorders; uncertain if this risk applies to those taking SSRIs for PMDD
    • Bipolar disorder
    • Seizure disorder
    • QTc prolongation (with citalopram)
    • Hepatic dysfunction
    • Renal dysfunction
  • Possible interactions
    • MAOIs
    • Selegiline
    • Pimozide
    • Thioridazine
    • Cimetidine, omeprazole, and QTc prolonging agents (with citalopram)
Second Line
Alternative therapies should be considered if no response to SSRIs:
  • Spironolactone (Aldactone) 50 to 100 mg/day for 7 to 10 days during luteal phase; helpful for fluid retention. Adverse reactions: lethargy, headache, irregular menses, hyperkalemia
  • P.841

  • Oral contraceptive pills (OCPs)
    • OCPs can cause adverse effects similar to PMDD symptoms (4)[B].
    • Extended-cycle use of OCPs (e.g., 12 weeks on and 1 week off) or a shorter placebo interval (e.g., 24 active pills with 4 placebo days [24/4] compared with 21/7 preparations) may be beneficial (4)[B].
    • OCPs containing the progestin drospirenone (structurally similar to spironolactone) may improve physical symptoms and mood changes associated with PMDD (5)[A]. Caution: Risk of venous thromboembolism may be modestly higher than with other OCPs (4)[B].
    • Continuous administration of levonorgestrel/ethinyl estradiol may improve patient symptoms in PMDD (4)[B].
      • Suggested OCP formulations:
        • Ethinyl estradiol 0.02 to 0.03 mg/drospirenone 3 mg (Gianvi/Loryna/Nikki/Ocella/Syeda/Vestura/Yasmin/Yaz Zarah): 1 tablet/day
        • Ethinyl estradiol 0.02 to 0.03 mg/drospirenone 3 mg/levomefolate 0.451 mg (Beyaz/Safyral): 1 tablet/day
        • Levonorgestrel 90 &mgr;g/ethinyl estradiol 20 &mgr;g (Amethyst/Lybrel): 1 tablet/day
  • Anxiolytics
    • Alprazolam (Xanax) 0.25 mg TID-QID only during luteal phase; taper at onset of menses (other benzodiazepines not studied for PMDD). Caution: addictive potential
    • Buspirone (BuSpar) 10 to 30 mg/day divided BID-TID in the luteal phase
  • Ovulation inhibitors
    • Gonadotropin-releasing hormone (GnRH) agonists: leuprolide (Lupron) depot 3.75 mg/month IM
      • Precautions: Menopause-like side effects (e.g., osteoporosis, hot flashes, headaches, muscle aches, vaginal dryness, irritability) limit treatment to 6 months; may be first step if considering bilateral oophorectomy for severe, refractory PMDD
    • Danazol (Danocrine) 300 to 400 mg BID; adverse reactions: androgenic and antiestrogenic effects (e.g., amenorrhea, weight gain, acne, fluid retention, hirsutism, hot flashes, vaginal dryness, emotional lability)
    • Estrogen, transdermal preferred, 100 to 200 &mgr;g:
      • Precautions: increased risk of blood clot, stroke, heart attack, and breast cancer
      • Requires concomitant progesterone add-back therapy to protect against uterine hyperplasia and endometrial cancer
  • Progesterone: insufficient evidence to support use (6)[A]
ISSUES FOR REFERRAL
Referral to psychiatrist may be indicated for mood/anxiety disorders if patient has no symptom-free period.
ADDITIONAL THERAPIES
Cognitive-behavioral therapy (CBT) is theoretically helpful for PMS/PMDD given its application for symptom reduction in other mood disorders, but direct evidence is lacking.
SURGERY/OTHER PROCEDURES
Bilateral oophorectomy, usually with concomitant hysterectomy, is an option for rare, refractory cases with severe, disabling symptoms.
COMPLEMENTARY & ALTERNATIVE MEDICINE
  • Acupuncture demonstrated superiority to progestins, anxiolytics, and sham acupuncture with no evidence of harm (7)[A].
  • Some data support the use of the following (8)[A]:
    • Calcium: 600 mg BID
    • Vitamin B6: 50 to 100 mg/day
    • Chasteberry (Vitex agnus-castus): 4 mg/day of extract containing 6% of agnuside (or 20 to 40 mg/day of fruit extract)
    • Omega-3 fatty acids 2 g/day
  • Data insufficient regarding the following (8)[A]:
    • Magnesium: 200 to 400 mg/day
    • Vitamin D: 2,000 IU/day
    • Vitamin E: 400 IU/day
    • Manganese: 1.8 mg/day
    • St. John's wort: 900 mg/day
    • Soy: 68 mg/day isoflavones
    • Ginkgo: 160 to 320 mg/day
    • Saffron: 30 mg/day
  • Evidence supporting efficacy and/or safety of herbal products is lacking; the following products/interventions have not been found useful for PMS/PMDD, although not all studies are of high quality and able to eliminate possibility of benefit completely (8)[A]:
    • Evening primrose oil
    • Black currant oil
    • Black cohosh
    • Wild yam root
    • Dong quai
    • Kava kava
    • Light-based therapy
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Increased risk of suicidal thinking and behavior in children and adolescents with depressive disorders on initiation of SSRIs; uncertain if this risk applies to those taking SSRIs for PMDD
DIET
  • Reduce consumption of salt, sugar, caffeine, dairy products, and alcohol (anecdotal reports).
  • Eat small, frequent portions of food high in complex carbohydrates (limited data).
PATIENT EDUCATION
  • Counsel patients to eat a balanced diet rich in calcium, vitamin D, and omega-3 fatty acids and low in saturated fat and caffeine.
  • Counsel women that they are not “crazy.” PMDD is a real disorder with a physiologic basis.
  • Although incompletely understood, successful treatment is often possible.
PROGNOSIS
  • Many patients can have their symptoms adequately controlled. PMS disappears at menopause.
  • PMS can continue after hysterectomy, if ovaries are left in place.
REFERENCES
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.
2. Borenstein JE, Dean BB, Yonkers KA, et al. Using the daily record of severity of problems as a screening instrument for premenstrual syndrome. Obstet Gynecol. 2007;109(5):1068-1075.
3. Marjoribanks J, Brown J, O'Brien PM, et al. Selective serotonin reuptake inhibitors for premenstrual syndrome. Cochrane Database Syst Rev. 2013;(6):CD001396.
4. Freeman EW, Halbreich U, Grubb GS, et al. An overview of four studies of a continuous oral contraceptive (levonorgestrel 90 mcg/ethinyl estradiol 20 mcg) on premenstrual dysphoric disorder and premenstrual syndrome. Contraception. 2012; 85(5):437-445.
5. Lopez LM, Kaptein AA, Helmerhorst FM. Oral contraceptives containing drospirenone for premenstrual syndrome. Cochrane Database Syst Rev. 2012;(2):CD006586.
6. Ford O, Lethaby A, Roberts H, et al. Progesterone for premenstrual syndrome. Cochrane Database Syst Rev. 2012;(3):CD003415.
7. Kim SY, Park HJ, Lee H, et al. Acupuncture for premenstrual syndrome: a systematic review and meta-analysis of randomised controlled trials. BJOG. 2011;118(8):899-915.
8. Whelan AM, Jurgens TM, Naylor H. Herbs, vitamins and minerals in the treatment of premenstrual syndrome: a systematic review. Can J Clin Pharmacol. 2009;16(3):e407-e429.
Additional Reading
&NA;
  • Biggs WS, Demuth RH. Premenstrual syndrome and premenstrual dysphoric disorder. Am Fam Physician. 2011;84(8):918-924.
  • Nevatte T, O'Brien PM, Bäckström T, et al. ISPMD consensus on the management of premenstrual disorders. Arch Womens Ment Health. 2013;16(4): 279-291.
  • Rapkin AJ, Akopians AL. Pathophysiology of premenstrual syndrome and premenstrual dysphoric disorder. Menopause Int. 2012;18(2):52-59.
Codes
&NA;
ICD10
N94.3 Premenstrual tension syndrome
Clinical Pearls
&NA;
  • Have the patient keep a daily log of her symptoms and menses. Symptoms beginning in the week before menses and abating before the end of menses, occurring over at least 2 months, and sufficiently severe to interfere with daily functioning are diagnostic of PMS.
  • The difference between PMS and PMDD is that PMDD is a severe form of PMS characterized by recurrent depressive and anxiety symptoms with luteal phase onset, sufficiently severe to disrupt social and occupational functioning. These symptoms remit a few days after the onset of menses.
  • PMDD is not the same as more generalized depressive/anxiety disorders. PMDD-associated symptoms of depression and anxiety begin to resolve within the first few days of menses.
  • Treatment only during the luteal phase is likely as effective as continuous-cycle treatment with SSRIs but has fewer adverse effects.