Premenstrual Syndrome (PMS)
Treatment of PMS or PMDD depends in part on the type and severity of symptoms. Most mild cases of PMS can be treated with lifestyle changes (as described in the Dietary and Lifestyle Considerations section) or over-the-counter drugs to manage physical symptoms (Rapkin 2014), though lifestyle changes are recommended for all patients (Rees 2014). Over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (Advil, Midol) and naproxen (Aleve), are commonly used to treat physical symptoms such as cramping and breast tenderness.
Mefenamic acid (Ponstel), a prescription NSAID commonly prescribed for menstrual pain, is also sometimes used in PMS. A small randomized controlled trial of mefenamic acid found it significantly reduced premenstrual physical symptoms and mood swings (Mira 1986; NLM 2012). Diuretics, such as spironolactone (Aldactone), may be prescribed to treat premenstrual swelling and bloating (Mayo Clinic 2012).
Standard conventional treatment of PMS or PMDD primarily relies on medications that modulate mood; synthetic hormones that interrupt ovulation; referral for cognitive behavioral therapy; or in rare and extremely severe cases, surgical removal of a woman’s ovaries.
Selective serotonin reuptake inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat mood disorders influenced by serotonin, such as anxiety and depression. SSRIs are considered the first-line pharmacologic treatment option for psychological and behavioral symptoms of PMS/PMDD, with improvements observed in 60–80% of women (Marjoribanks 2013). Among women with PMDD who respond to SSRI treatment, there is generally a greater than 50% improvement in symptoms. SSRIs may be effective when taken either continuously, or only during the luteal phase. Currently, fluoxetine (Prozac or Sarafem), sertraline (Zoloft), and paroxetine (Paxil) are the only SSRIs approved by the US Food and Drug Administration (FDA) for the treatment of PMDD (Rapkin 2013).
Side effects of SSRIs are fairly common, with those most frequently reported being nausea, fatigue or weakness, sleepiness, reduced libido, and sweating. These adverse effects have been shown to be dose-related (Marjoribanks 2013). Sexual dysfunction is another relatively common side effect of SSRIs, occurring in 80% of those who take these medications continuously over long periods of time (ARHP 2008). Another potential problem is SSRI discontinuation syndrome, in which patients experience withdrawal symptoms when stopping the medications. These include sensory and gastrointestinal symptoms, dizziness, lethargy, sleep disturbances, and psychological symptoms (Renoir 2013). Gradual withdrawal of SSRI medication appears to prevent some of these problems (Haddad 1998).
Anxiolytic drugs. Anxiolytic drugs are used to treat anxiety. Anxiolytics prescribed for PMS or PMDD include the benzodiazepine alprazolam (Xanax), buspirone (Buspar), and clonidine (Catapres) (Alvero 2014; Rees 2014; Rapkin 2014). Benzodiazepines such as alprazolam have potential to cause significant side effects including physical dependency, as well as withdrawal symptoms upon abrupt discontinuation. Therefore, alprazolam is only used if a patient fails to respond to other treatments, such as SSRI therapy (Freeman 2003).
Suppression of Ovulation
Since PMS/PMDD symptoms are attributed, at least in part, to fluctuations in sex hormones, some treatments work by interrupting ovulation:
Oral contraceptive pills. Oral contraceptive pills (OCPs) that contain a synthetic progesterone-like drug (a progestin) and an estrogen are commonly prescribed to treat symptoms of PMS; however, their effect may depend on the formulation (Rapkin 2012; Lopez 2012; ARHP 2008). Oral contraceptives work by inhibiting ovulation and preventing the changes in hormone levels that occur during the luteal phase (Nevatte 2013). Certain OCPs with 21 days of hormone tablets and 7 days of pills that contain no hormones appear to reduce the physical symptoms of PMS; however, they have limited impact on psychological symptoms (Rapkin 2012). Additionally, some of these OCPs still allow for normal hormonal fluctuations during the hormone-free week, and many women experience PMS-like symptoms during this period (Sulak 2000). Some relatively newer OCPs offer either a continuous hormone dosage without a drug-free interval or a reduced drug-free period, thus reducing the incidence of PMS-like symptoms during the drug-free period (ARHP 2008). An analysis of four studies that evaluated continuous hormone use with levonorgestrel (a progestin) and ethinyl estradiol tablets revealed overall improved symptoms in 30–81% of women (Freeman 2012).
Newer hormone formulations containing 24-day drospirenone (a progestin) and ethinyl estradiol with only a four-day drug-free interval significantly improve PMDD symptoms and are approved by the FDA to treat PMDD (Lopez 2012; ARHP 2008). It is uncertain if these formulations have any effect in women with less severe symptoms (Lopez 2012).
Potential Risks From Newer Hormone Preparations
Recent studies suggest some of the newer hormone formulations containing the progestin drospirenone, which is often combined with ethinyl estradiol, may increase the risk of life-threatening blood clots known as venous thromboembolism (FDA 2013). Venous thromboembolism includes deep vein thrombosis and pulmonary embolism (Rodriguez 2012). In approximately 6–32% of deep vein thrombosis cases, a clot can travel from the extremities to the lungs, forming a pulmonary embolism. It is estimated that approximately 300 000 people die from pulmonary embolism each year in the United States (Ozaki 2012).
All OCPs are associated with a slightly increased risk of blood clot formation (Tchaikovski 2010; Stegeman 2013). However, some studies have demonstrated that contraceptives containing drospirenone and newer progestogens are associated with up to a 3.3-fold greater risk of venous thromboembolism compared with older formulations (Wu 2013; Parkin 2011; Jick 2011; Tricotel 2014).
The FDA issued a position statement on April 4th, 2012 stating that OCPs containing drospirenone may be associated with a higher risk of blood clot formation than other progestin-containing pills (FDA 2013). It is important for patients to discuss their complete medical history with their physicians to determine if drospirenone-containing OCPs pose any unnecessary risks. Common brand names of drospirenone-containing OCPs are Beyaz, Gianvi, Loryna, Ocella, Safyral, Syeda, Yasmin, Yaz, and Zarah (FDA 2013).
Gonadotropin-releasing hormone agonists. Gonadotropin-releasing hormone (GnRH) agonists interrupt the hormonal cycle and ovulation. This creates a state of medically-induced menopause, which, if continued long-term, carries a risk of osteoporosis and heart disease similar to that of natural menopause. Thus, the use of GnRH agonists for PMS or PMDD is limited to 3–6 month courses, and GnRH agonists are typically only used when other treatments such as SSRIs or OCPs have failed (Rees 2014; Kumar 2014; Magon 2011).
The low levels of circulating sex hormones caused by GnRH agonists can also cause menopausal symptoms such as hot flashes, vaginal dryness, and headaches. To alleviate their undesired effects and allow longer treatment periods, estrogen, progesterone, or both are commonly prescribed as “add back therapy”; however, this can reintroduce symptoms of PMS (Nevatte 2013). To minimize serious complications, hormone replacement therapy is recommended when GnRH treatment lasts longer than six months (Rees 2014; Rapkin 2013). Commonly prescribed GnRH agonists include leuprolide (Eligard, Lupron), buserelin (Suprefact), goserelin (Zoladex), and nafarelin (Synarel) (Freeman 2003).
Estradiol. High doses of estradiol in the form of a patch, gel, or intrauterine implant are sometimes used to suppress ovulation in order to treat PMS/PMDD (Nevatte 2013; Watson 1989; Smith 1995). A side effect of estradiol administration is increased risk of endometrial hyperplasia, which is non-cancerous overgrowth of cells lining the inside of the uterus (CRUK 2014). Endometrial hyperplasia may lead to endometrial cancer in some cases (Goncharenko 2013; Boruban 2008). Bioidentical progesterone may be used to reduce the risk of endometrial hyperplasia in women being treated with transdermal estradiol (PEPI Trial Writing Group 1996).
Bioidentical Hormones and PMS
Some evidence suggests that hormonal imbalance may contribute to PMS symptoms (Studd 2011). Since sex hormones exert broad influence throughout the body, a relative excess or deficiency of one or more hormones may give rise to a wide spectrum of symptoms, such as those associated with PMS. Thus, ensuring hormonal balance may ease PMS symptoms for some women (Steiner 2003; Studd 2011). Diligent use of bioidentical hormone replacement therapy is a natural way to accomplish this.
Bioidentical hormones are hormones that have the identical chemical structure as hormones produced by the human body. These include hormones approved by the FDA for treatment of menopausal symptoms, or hormones sold over-the-counter or compounded by a compounding pharmacy. Bioidentical estrogens include estriol, estradiol, and estrone. Bioidentical progesterones include oral micronized progesterone and progesterones sold over-the-counter or compounded in the form of gels and creams (Files 2011; Fugh-Berman 2007; Marsden 2010). FDA-approved bioidentical hormones have also been used to treat PMS and PMDD (Fugh-Berman 2007; Files 2011).
Achieving hormonal balance through the use of bioidentical hormones may require different protocols for different women, since each woman’s body may not respond exactly the same way to specific hormone levels. A reasonable approach is for a woman who experiences bothersome PMS symptoms to undergo hormone blood testing about seven days before the cycle starts, which corresponds to day 21 of a typical 28 day cycle. (Day number 1 is the day that bleeding begins). This will allow an innovative physician to discern the levels of hormones in the woman’s body during her luteal phase, when PMS symptoms occur. If, for example, a woman is found to have a low level of progesterone relative to her level of estrogen, then her progesterone levels can be bolstered using transdermal bioidentical micronized progesterone. If this results in waning of the woman’s symptoms, the woman could then work with her doctor to continue progesterone therapy and follow up with a blood test on the 21st day of her next menstrual cycle to monitor the impact of the bioidentical progesterone on her hormone levels and PMS symptoms. Likewise, a similar approach could be undertaken with bioidentical estradiol, or possibly even testosterone, depending on blood test results.
This approach is difficult to study in organized clinical trials involving many women, because each woman may require a different dose of bioidentical hormones or different hormones altogether. Unfortunately, this means that published scientific evidence in favor of treating PMS with bioidentical hormone therapy has been slow to accumulate. However, some evidence has been published. For example, a randomized controlled trial showed that oral bioidentical progesterone therapy resulted in an improvement in mood and some physical symptoms of PMS after one and two months of treatment (Dennerstein 1985; Fugh-Berman 2007). Also, several integrative physicians have reported clinical success using bioidentical hormones (Hudson 2013).
Women interested in learning more about bioidentical hormones can refer to the Life Extension magazine article Bioidentical Hormones: Why are They Still Controversial? and to the Female Hormone Restoration protocol.
Cognitive Behavioral Therapy
Cognitive behavioral therapy (CBT) may be an effective treatment for the psychological and behavioral symptoms of PMS (Busse 2009). CBT is commonly used to treat mood disorders, anxiety, and depression (Duckworth 2012). A review of randomized, controlled trials found that CBT significantly reduced anxiety and depression, with possible benefit for behavioral changes, in women with PMS (Busse 2009).
For women with severe PMDD that does not respond to any other treatment, bilateral oophorectomy (surgical removal of the ovaries) with or without hysterectomy (surgical removal of the uterus) may be considered (Rapkin 2014; Rees 2014). Bilateral oophorectomy removes PMDD hormone-related symptomatology; however, due to the highly invasive nature of this procedure, it should only be considered when all other treatment options have failed (Alvero 2014). Removal of the ovaries induces menopause by eliminating the source of most sex steroid hormones (Cunningham 2009; AMS 2013).