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Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD)
Courtney I. Jarvis, PharmD
Allison Hargreaves, MD
image BASICS
  • 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
  • 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.
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.
  • 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.
  • 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
No specific physical exam required; may consider thyroid and pelvic exams if indicated by additional patient symptoms.
  • 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
  • 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.
Although evidence is lacking for aerobic exercise in treating PMS/PMDD, it is often recommended as part of an integrated care plan.
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]
Referral to psychiatrist may be indicated for mood/anxiety disorders if patient has no symptom-free period.
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.
Bilateral oophorectomy, usually with concomitant hysterectomy, is an option for rare, refractory cases with severe, disabling symptoms.
  • 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
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
  • Reduce consumption of salt, sugar, caffeine, dairy products, and alcohol (anecdotal reports).
  • Eat small, frequent portions of food high in complex carbohydrates (limited data).
  • 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.
  • Many patients can have their symptoms adequately controlled. PMS disappears at menopause.
  • PMS can continue after hysterectomy, if ovaries are left in place.
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
  • 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.
N94.3 Premenstrual tension syndrome
Clinical Pearls
  • 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.