Int Assoc Premenstrual Disease 2022-10

Evidence-Based Management of Premenstrual Disorders (PMDs) page 1

Evidence-Based Management of Premenstrual Disorders (PMDs)

Note: this guide is intended primarily as a resource for health care providers. If you are a patient, we recommend you also check out our treatment
options page designed for patients at iapmd.org/treatment-options.

Premenstrual disorders such as premenstrual dysphoric disorder (PMDD) and premenstrual exacerbation (PME) of psychiatric disorders are complex
to diagnose and treat. Below, we provide guidelines to help health care providers educate and treat their patients effectively.

Assessment and Diagnosis of PMDs: Ultimately, each patient with premenstrual symptoms is unique, and deserves a compassionate health care
provider who will work with them to find an effective treatment--or set of treatments-- for their unique needs. Given that PME often predicts poor
response to first-line PMDD treatments (see below), prospective diagnosis using two months of daily symptom ratings is recommended to
differentiate between PMDD (symptoms present only premenstrually), PME (symptoms always present but worsened premenstrually), and
non-cyclical symptoms. Daily ratings can also be continued in the context of treatment in order to evaluate effectiveness over time. A daily symptom
rating form can be downloaded at https://iapmd.org/provider-resources. Standardized scoring of these daily ratings to determine diagnosis can be
accomplished using the C-PASS scoring system available at https://iapmd.org/c-pass. Please note that it is possible to have both PMDD (five
symptoms that are present only in the luteal phase) and also PME of other underlying disorders.

Treatment of PMDs: Since this is a relatively new area of medical science, the number of randomized controlled trials for PMDs remain relatively
small. However, several treatments have been found to be effective, and more are currently under investigation. Below, we outline what the scientific
evidence indicates about how the average p erson with a premenstrual disorder (typically PMDD-- PME is less well-studied) will respond to various
treatments. Many patients utilizing IAPMD services have already tried many of the treatments below with no relief, whereas others have tried none.
The purpose of this page is not to provide a “one-size-fits-all” recommendation for the treatment of premenstrual disorders; rather, it is to help those
seeking information about effective treatments by reviewing the best evidence about general efficacy and safety of each treatment in those with
premenstrual disorders.

Please visit iapmd.org for more information and resources.

This guide was prepared by the IAPMD Clinical Advisory Board, under the direction of Dr. Tory Eisenlohr-Moul.

© 2020 International Association for Premenstrual Disorders www.iapmd.org | updated November 4th, 2020


Treatments with Strong Scientific Evidence for Efficacy and Safety in PMDD

Important Note: Because nearly all clinical trials in this area have focused on PMDD, the tables below are organized according to effectiveness and
safety of treatments for PMDD; however, please note accompanying information about possible efficacy in PME of psychiatric disorders.

Treatment Efficacy in PMDD Efficacy in PME Side Effects and Safety Mechanism of Action
Selective Serotonin Reuptake Strong evidence of efficacy for Untested for PME of psychiatric Well tolerated, generally few side Normalizes altered
Inhibitors (SSRIs) PMDD in many trials1. Response disorders, but is a rational effects. Most common side effect premenstrual serotonin
rates in randomized controlled treatment choice for PME of leading to discontinuation is function in PMDD4, alters
- fluoxetine 20mg (“Prozac”) trials are around 60-75%1. Beats disorders for which SSRIs are the sexual dysfunction. metabolism of progesterone5
- sertraline 50-150mg (“Zoloft”) placebo very quickly, often after first-line treatment (i.e.,
- paroxetine 20-30mg (“Paxil”) one day2. More effective for depression and anxiety).
- citalopram 20-30mg (“Celexa”) psychological symptoms than for
- escitalopram 10-20mg (“Lexapro”) physical symptoms3.

Dosing Schedule:
Symptom-Onset, Luteal, or
Continuous
Drospirenone-containing oral Evidence of efficacy for PMDD One study shows no benefit for Well tolerated, generally few side Prevention of ovulation and
contraceptive pill with from two randomized controlled PME of depressive disorders effects. related hormone flux in PMDD
shortened hormone-free trials6,7. Usually effective in first when given as an adjunctive
interval month of treatment. Response treatment to SSRI8. Risk of blood clot and
rates were 48% and 61%. Effects estrogen-dependent cancers
- drospirenone 3mg/ may be smaller than SSRIs. should be considered based on
ethinylestradiol .02mg daily (e.g., individual risk profiles.
“Yaz”)
Some individuals do not tolerate
Dosing: 24-4 or continuous progestins and develop chronic
dosing (i.e., shortened or symptoms similar to PMDD;
eliminated hormone-free progestin treatment should be
interval) discontinued in these patients9.



Treatments with Strong Scientific Evidence for Efficacy and Safety in PMDD, Continued

GnRH analogues Many trials12 demonstrate Two studies show no benefit for Menopausal symptoms. Requires Suppression of ovulation and
effectiveness for severe PMDD. PME of depressive disorders11,12. hormone replacement to prevent related hormone flux
Dosing: Monthly outpatient bone loss.
injections Typically reserved for those who However, no evidence is
have failed to respond to both SSRI available regarding effectiveness
- leuprolide 3.75mg monthly and OCs. when long-term hormone
injection (“Lupron”) addback is provided (see below).
- goserelin 3.6mg monthly injection Not effective when ovulation is not
(“Zoladex”) suppressed10 Note: I f PME (e.g., of depression)
is comorbid with other
symptoms (e.g., anxiety,
irritability) that DO show a
PMDD-like confinement to the
luteal phase, treatment may still
be indicated for PMDD.
GnRH analogues + Stable Many trials12 demonstrate Untested for PME of depressive In two studies, the first month of Suppression of ovulation and
Hormone Addback effectiveness for severe PMDD. disorders, but represents a stable oral estrogen + vaginal related hormone flux
rational option to trial for progesterone addback caused a
- transdermal estradiol addback Typically reserved for those who treatment-resistant patients. resurgence of PMDD symptoms,
(“Climara”) have failed to respond to both SSRI but symptoms remitted after 1
- progestogen addback for and OCs. Note: I f PME (e.g., of depression) month13. Patients should be
endometrial protection is comorbid with other informed of possible short-term
(“Prometrium”) symptoms (e.g., anxiety, symptom flare and appropriate
irritability) that DO show a supports should be provided.
PMDD-like confinement to the
luteal phase, treatment may be
indicated for PMDD.



Treatments with Strong Scientific Evidence for Efficacy and Safety in PMDD, Continued

Total hysterectomy with Studies17,18 indicate that THBSO is Untested, but a rational A very routine and safe Complete cessation of ovarian
bilateral effective for those patients who treatment choice for a patient gynecologic procedure, but still activity and related hormone flux
salpingo-oophorectomy improve during GnRH agonist who has improved during GnRH major abdominal surgery with
(THBSO) trial. agonist trial. risks (including bleeding,
infection, and death). Risk
- removal of both ovaries is If patient does not tolerate GnRH If patient does not tolerate GnRH increases with other medical
required analogues (and therefore cannot analogues (and therefore cannot conditions (heart, lung, liver, or
- removal of uterus is indicated to get a “fair GnRH trial”), THBSO get a “fair GnRH trial”), THBSO kidney disease, obesity, diabetes,
eliminate need for progestin may still be indicated given may still be indicated given history of prior surgery).
addback post-surgery evidence of severe cyclicity. evidence of severe cyclicity. Permanent. Requires hormone
replacement to prevent bone
loss.
Cognitive-Behavioral Therapies CBT is an important tool for Untested for PME of psychiatric Well tolerated, generally few side Reduction in neurobiological
Dosing: Weekly sessions with a reducing functional disorders but is a rational effects when provided by a stress responses, improved
qualified therapist with impairment19,20 in PMDD. treatment choice given the qualified professional. coping and relationships
appropriate training in CBT and widespread effectiveness of CBT
DBT. DBT is effective for preventing for psychiatric disorders.
suicidal behaviors14, a common
-C ognitive Behavioral Therapy outcome in severe cases of
(CBT) PMDD.
-D ialectical Behavior Therapy
(DBT)

Close attention should be paid to
the quality of the therapy being
provided; providers not engaging
in skills training or providing
behavioral homework
assignments to patients should
be replaced with providers more
adherent to CBT principles.



Treatments with Limited but Promising Scientific Evidence for Efficacy and Safety in PMDD

5-alpha reductase inhibitors One study shows improvement Untested for PME of psychiatric Causes birth defects if Prevents formation of (and flux
in PMDD symptoms with disorders. Given evidence of conception occurs while on the in) neurosteroid metabolites of
- dutasteride 2.5mg/day (“Avodart”) dutasteride15; dosage must be reduced biosynthesis of drug; a period of washout is progesterone15
high enough to inhibit formation GABAergic neurosteroids (e.g., needed prior to pregnancy to
Note: finasteride is untested in of allopregnanolone. allopregnanolone) in chronic avoid birth defects.
clinical trials but is sometimes used depressive and anxiety
in clinical practice due to its disorders16,17, this medication is Patients should be monitored
shorter half-life, which may reduce not recommended for PME of closely for side effects since no
risk of birth defects in the event of psychiatric disorders as it may long-term trials exist in PMDD. In
pregnancy further exacerbate neurosteroid other populations, these
deficits. medications can cause
depression.
Available primarily in USA
Ovulation Suppression using There have been two positive Not tested. Increased risk of blood clots, Suppression of ovulation and
Transdermal Estradiol + trials18,19. increased breast cancer risk, and related hormone flux19
Cyclical Progestogen increased endometrial
May represent alternative to OCs thickening/cancer risk can occur
.1mg Transdermal E2 Patch (twice for those who cannot tolerate in at-risk women, particularly
weekly; “Vivelle”) + norethisterone synthetic progestins i f with inadequate progestogen
1mg/day, 10 days per cycle18 anovulation can be achieved at opposition.
safe doses.
Alternative Progestogen for
Endometrial Protection: More work is needed to
determine the safety and efficacy
- levonorgestrel-containing IUD of various doses.
(“Mirena”)

Available primarily in the UK
Quetiapine (luteal phase; One small trial20 demonstrated Not tested. Generally safe and well tolerated, Unknown
adjunct to SSRI) benefit as an adjunctive but potential for serious and
treatment to SSRI. life-threatening side effects.
- 25mg quetiapine/day during the
luteal phase (“Seroquel”)



Treatments with Limited but Promising Scientific Evidence for Efficacy and Safety in PMDD, Continued

Isoallopregnanolone injections Two clinical trials have tested One study demonstrates no Initial study shows few side Blocks paradoxical effects of
(“Sepranolone”) sepranolone against placebo in benefit for PME of psychiatric effects21; however, primary progesterone-derived
PMDD. In the first randomized disorders.21 clinical trials are still underway neurosteroids (e.g.,
Varying; dosages in development controlled trial, sepranolone and could reveal important allopregnanolone) at GABA-A
showed effectiveness for long-term side effects. receptor in PMDD
NOT YET AVAILABLE PMDD.21 However, sepranolone
failed to beat placebo in the
second trial, which may have
been due to a very large and
persistent placebo response.



Treatments with No Evidence, Mixed Evidence, or Negative Evidence for Efficacy in PMDD

Treatment Efficacy in PMDD Efficacy in PME Side Effects and Safety Proposed Mechanism of Action
Lifestyle Changes A healthy lifestyle improves Not studied. N/A N/A

general mental and physical
- Improved diet health. However, only low-quality
- Increased exercise evidence is available linking
- Reduced caffeine intake these outcomes to premenstrual
- Reduced alcohol intake symptoms, and findings are
mixed22,23. May be more
appropriate for mild
premenstrual symptoms than for
PMDD.
Vitamin and mineral Mixed evidence25,27. May be more Not tested. Supplements are readily N/A
supplements appropriate for mild available, but also poorly
premenstrual symptoms than for regulated in the United States.
PMDD. Risk of overdose or toxicity. Very
safe if taken in consultation with
Some evidence that calcium, a provider.
magnesium, Vit D, and Vit B6
supplements may improve
premenstrual symptoms.
Levonorgestrel-containing Four studies24 show inconsistent Not tested. Risk of blood clot and Prevention of ovulation
continuous oral contraceptive effects in PMDD, with some estrogen-dependent cancers
pill demonstrating benefit and should be considered based on
others not. individual risk profiles.
- levonorgestrel .09mg + .02mg
ethinylestradiol daily with no Some individuals do not tolerate
pill-free interval (“Lybrel”) oral contraceptives and develop
chronic or cyclical symptoms
similar to PMDD9;
progestin-containing
medications should be
discontinued for these patients.



Treatments with No Evidence, Mixed Evidence, or Negative Evidence for Efficacy in PMDD, Continued

Combined EE + progestin Not yet tested, but is known to Not tested. Risk of blood clot and Efficacy not yet established
vaginal ring contraceptive ring consistently suppress ovulation27 estrogen-dependent cancers
(“Nuvaring”) and may be a rational treatment Given the lack of efficacy of other should be considered based on
given efficacy of other ovulation-inhibiting agents in individual risk profiles.
ovulation-suppression agents in PME of depression, a beneficial
PMDD; however, patient should effect is not necessarily Can be easily removed by
be monitored for expected. patient.
progestin-induced mood
symptoms.
Levonorgestrel-containing No evidence available, but not a No evidence, but not a rational May have adverse effects on N/A; not expected to be effective
Intrauterine Device ( IUD: rational treatment given that treatment given that they do physiological stress responses25;
“Mirena”, “Skyla”) they do NOT consistently NOT consistently suppress many women discontinue due to
suppress ovulation ovulation depressive symptoms26.

Copper IUD ( “Paragard”) No evidence available, but not a No evidence, but not a rational Heavy periods N/A; not expected to be effective
rational treatment given its treatment given its inability to
inability to suppress ovulation suppress ovulation
Danazol ( “Danocrine”) Not effective for emotional Not tested. Not recommended Common side effects include Efficacy not yet established
PMDD symptoms when given side effect profile. acne, weight gain, hirsutism and
considering the whole cycle22,27. deepening of the voice; some
changes may be irreversible. May
cause birth defects.
Benzodiazepines Mixed evidence, with Not tested for PME. Not High risk of addiction and abuse; Sedation
well-controlled studies showing indicated for those with marked tolerance often develops.
- alprazolam (“Xanax”) either no benefit14,15 or some impulsivity or family/personal Withdrawal can be
benefit16. Tolerance and reduced history of drug abuse. Not life-threatening.
efficacy expected with long-term recommended as daily or
use. Not indicated for those with long-term therapy for any patient
marked impulsivity or due to risk of tolerance and
family/personal history of drug abuse.
abuse. Not indicated for daily or
long-term use.



Treatments with No Evidence, Mixed Evidence, or Negative Evidence for Efficacy in PMDD, Continued

Oral micronized progesterone9 Several studies show that this is Not tested in PME. Progestins can trigger mood N/A, not effective
or progestins20 only

ineffective, and is likely to symptoms, particularly acutely21
worsen symptoms in the first
- usually given in the luteal phase month11.
only

Recommended Reading:

- Up-to-Date Guidelines for Management of Premenstrual Syndrome and PMDD10
- Royal College of Obstetrics and Gynecology Guidelines for the Management of Premenstrual Syndrome11
- International Society for Premenstrual Disorders Consensus Guidelines29

Citations

1. Halbreich, U. Selective Serotonin Reuptake Inhibitors and Initial Oral Contraceptives for the Treatment of PMDD: Effective But Not Enough. C
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3, 566–572 (2014).
2. Steinberg, E. M., Cardoso, G. M. P., Martinez, P. E., Rubinow, D. R. & Schmidt, P. J. RAPID RESPONSE TO FLUOXETINE IN WOMEN WITH PREMENSTRUAL DYSPHORIC DISORDER. D
epress.
Anxiety 2
9, 531–540 (2012).
3. Freeman, E. W., Sammel, M. D., Lin, H., Rickels, K. & Sondheimer, S. J. Clinical Subtypes of Premenstrual Syndrome and Responses to Sertraline Treatment. O
bstet. Gynecol. 1
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4. Roca, C. A. e
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5. Lovick, T. SSRIs and the female brain–potential for utilizing steroid-stimulating properties to treat menstrual cycle-linked dysphorias. J
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8. Peters, W., Freeman, M. P., Kim, S., Cohen, L. S. & Joffe, H. Treatment of Premenstrual Breakthrough of Depression With Adjunctive Oral Contraceptive Pills Compared With Placebo. J
. Clin.
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9. Gingnell, M. et al. Oral contraceptive use changes brain activity and mood in women with previous negative affect on the pill—A double-blinded, placebo-controlled randomized trial of a
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10. Bancroft, J., Boyle, H., Warner, P. & Fraser, H. M. The use of an LHRH agonist, buserelin, in the long-term management of premenstrual syndromes. C
lin. Endocrinol. (Oxf.) 2
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11. Freeman, E. W., Sondheimer, S. J. & Rickels, K. Gonadotropin-releasing hormone agonist in the treatment of premenstrual symptoms with and without ongoing dysphoria: a controlled study.
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18. Treatment of severe premenstrual syndrome with oestradiol patches and cyclical oral norethisterone. - PubMed - NCBI. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2570971.
(Accessed: 7th January 2019)
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International Journal of Obstetrics & Gynaecology - Wiley Online Library. Available at:
https://obgyn-onlinelibrary-wiley-com.proxy.cc.uic.edu/doi/full/10.1111/j.1471-0528.1995.tb11321.x. (Accessed: 7th January 2019)
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oyal College of Obstetricians & Gynaecologists Available at:
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23. Casper, R. F. & Yonkers, K. A. Treatment of premenstrual syndrome and premenstrual dysphoric disorder.
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29. Fourth consensus of the International Society for Premenstrual Disorders (ISPMD): auditable standards for diagnosis and management of premenstrual disorder | SpringerLink. Available at:
https://link.springer.com/article/10.1007/s00737-016-0631-7. (Accessed: 7th January 2019)

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Evidence-Based Management of Premenstrual Disorders (PMDs) page 1

Evidence-Based Management of Premenstrual Disorders (PMDs)

Lifestyle Changes A healthy lifestyle improves Not studied. N/A N/A

levonorgestrel-containing combined oral contraceptive. P

(Accessed: 7th January 2019)

https://obgyn-onlinelibrary-wiley-com.proxy.cc.uic.edu/doi/full/10.1111/j.1471-0528.1995.tb11321.x. (Accessed: 7th January 2019)

22. Premenstrual Syndrome, Management (Green-top Guideline No. 48). R

https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg48/. (Accessed: 20th July 2018)

28. Management of Premenstrual Syndrome. B

https://link.springer.com/article/10.1007/s00737-016-0631-7. (Accessed: 7th January 2019)

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