Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:

1. Describe the common symptoms associated with premenstrual disorders.

2. Explain the pathophysiology of premenstrual disorders and the rationale for available treatment strategies.

3. List 2 evidence-based pain management treatments for women with premenstrual disorders.

Pain associated with a woman's menstrual cycle is usually not an isolated symptom. Rather, pain is typically one among many, including bloating, cramping, irritability, negative mood, difficulty concentrating, headaches, and food cravings. Managing pain itself is hard enough, but for some women, multiple symptoms are collectively so disabling that they interfere with normal social and/or physical functioning.

This article describes the pathophysiology of premenstrual disorders and evidence-based treatments to ameliorate symptom severity and improve quality of life.

After completing this CE activity, practitioners who treat pain should be able to better understand these symptoms and recommend evidence-based treatments and management to their patients, to improve their quality of life.

Premenstrual disorders include a constellation of symptoms that begin during the luteal phase of the menstrual cycle (Figure 1) and end with the onset of menstruation.1 At least 90% of women report premenstrual symptoms and approximately 50% of women seek medical care for them.2-4 Ovarian function significantly affects the symptoms of premenstrual syndrome and premenstrual dysphoric disorder as evidenced by the finding that suppression of ovarian hormone secretion consistently attenuates them. However, other demographic, behavioral, and biological factors may also influence symptom severity and duration.5,6 For instance, in women of childbearing age, a high-sensitivity C-reactive protein level over 3 mg/L was significantly positively associated with premenstrual mood symptoms, abdominal cramps/back pain, increased appetite, cravings, weight gain, bloating, and breast pain, but not associated with headaches or number of symptoms.6

Figure 1. Phases of the menstrual cycle. (Licensed under CC-BY 3.0, cnx.org;

Pathophysiology of Premenstrual Disorders

The menstrual cycle occurs in 3 phases: follicular, ovulatory, and luteal (Figure 1). When considering a woman's menstrual cycle, the first day of menses is identified as the first day of the cycle, the onset of the follicular phase. Estrogen levels are low during the onset of menses, and the low estrogen threshold activates the hypothalamus, which in turn, sends a signal to the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These hormones stimulate the growth of several ovarian follicles that contain an egg. As the follicle grows, estrogen levels in circulation rise by cycle day 7, which begins to inhibit the secretion of FSH. When the level of estrogen is sufficiently high, it causes a sudden release of LH, typically around the 13th day of the cycle. Ovulation takes place 28 to 36 hours after the onset of the LH surge and 10 to 12 hours after LH reaches its peak. The follicle changes into the corpus luteum, which begins to release progesterone to keep the uterine lining thick and prepared for the egg to implant if fertilized.7

During the luteal phase, or second half of the cycle, circulating levels of estrogen begin to fall if pregnancy does not result. The endometrium releases prostaglandins that cause contractions of the uterine smooth muscle, leading to menstruation. Within ovulatory cycles, ovarian hormone production varies with weight gain and loss, physical activity, dietary intake, sleep variation, and psychological stress. Ovarian hormone production is also affected by factors such as age, race, and parity. For instance, a descriptive study among 346 naturally cycling women found that ovarian function differed in nulliparous and parous women and was positively associated with the time since last birth.8

Within the milieu of hormones that regulate the menstrual cycle, there is a range of sex corticosteroids in circulation. These corticosteroids easily pass the blood-brain barrier and bind to their receptors in the brain, such as the amygdala and hypothalamus. Both the [gamma]-aminobutyric acid (GABA), or GABAergic, and serotonergic systems have been the most consistently studied neurotransmitter systems involved in premenstrual syndrome and premenstrual dysphoric syndrome.9

From this research, it is known that metabolites of progesterone formed by the corpus luteum of the ovary and in the brain bind to sites on the membrane of GABA receptors, thereby changing its configuration.10 This change results in resistance to further activation and decreases central GABA-mediated inhibition. GABA_A receptors are associated with alterations in affect, mood, and cognition.9 GABA receptors become less sensitive to progesterone metabolites (pregnanolone and allopregnanolone) after exposure to high concentrations, thus providing the cyclical nature of symptoms.

In addition to fluctuations in GABA receptor activity, lowering of serotonin can give rise to premenstrual syndrome-like symptoms, and women with premenstrual disorders have been shown to have serotonin transmission abnormalities as a result of few transporter receptors.11

Although less studied, immune system involvement influences follicular recruitment, ovulation, implantation, and endometrial repair.12,13 Inflammatory cytokines, interleukin(IL)-1[beta], IL-6, and tumor necrosis factor-[alpha], and C-reactive protein increase during ovulation and are highest during menstruation, although the magnitude of cyclic changes differs between women.14 Psychosocial factors, including stress appraisal, have been associated with symptoms of premenstrual syndrome, suggesting that targeting stress-related coping skills may improve symptoms.15-17

Additional underlying pathology may also be present in women suffering from premenstrual disorders, including endometriosis, uterine fibroids, or adenomyosis.

Endometriosis is an estrogen-dependent inflammatory condition in which endometrial tissue grows on other pelvic organs, such as the ovaries or fallopian tubes.18 Approximately 10% of women of reproductive age have endometriosis, and although the extent of endometriosis has no relationship with the degree of pain, it can have significant negative psychosocial and economic impact on affected women and their families.

Endometriosis typically causes noncyclic general pelvic pain that is accompanied by dyspareunia and dyschezia.18,19 For women with comorbid premenstrual disorder and endometriosis, the typical cyclic pattern of premenstrual disorder may not be as obvious because of the overlapping general pelvic pain associated with endometriosis. Therefore, whenever a noncyclic pattern is identified, endometriosis should be high on the differential diagnosis list.

Endometriosis is usually treated with hormonal contraceptives, gonadotropin-releasing hormone agonists and antagonists, progestin therapy, and/or aromatase inhibitors, whereas laparoscopic surgery is used to remove lesions for severe cases.

Uterine fibroids, or leiomyomas, are noncancerous growths of the uterus that range in size from undetectable to bulky masses.19 They are often identified incidentally during a pelvic examination. Depending on the size, location, and number of fibroids, some women experience no symptoms, whereas others have heavy menstrual bleeding, pelvic pressure or pain, and/or difficulty emptying the bladder. Symptoms of premenstrual disorder along with abnormally heavy bleeding should alert the clinician to the possibility of fibroids, the presence of which can be confirmed by ultrasound.

Adenomyosis is a condition in which the endometrial tissue grows into the muscle wall of the uterus. However, the tissue continues to go through cyclic thickening, breakdown, and sloughing during menstruation, leading to an enlarged uterus with often painful and heavy periods.19,20 The characteristic pain during menstruation is described as knifelike pelvic pain, and it can be associated with chronic pelvic pain. As the tissue growth depends on levels of circulating estrogen, hormonal treatment is usually indicated, with consideration of hysterectomy for severe cases.20

Diagnostic Criteria of Premenstrual Disorders

In women of reproductive age, premenstrual symptoms are highly prevalent and range from relatively mild to severely disabling.21 Core characteristics of premenstrual disorders include that:

* Symptoms occur in ovulatory cycles and may be somatic and/or psychological;

* Symptoms are absent after menstruation and before ovulation, and then recur in the luteal phase; and

* Symptoms cause significant impairment.22

Premenstrual syndrome and premenstrual dysphoric disorder meet the core criteria of premenstrual disorders. Variants of premenstrual disorders include:

* Premenstrual exacerbation, in which underlying somatic or psychological symptoms significantly worsen before menstruation;

* Premenstrual disorder due to nonovulatory ovarian activity;

* Progestogen-induced premenstrual disorder; and

* Premenstrual disorder with absence of menstruation.22

Premenstrual syndrome is different from the normal somatic and psychological premenstrual symptoms experienced by most women, owing to the significant negative impact of this syndrome on level of distress and daily functioning.22 The current definition of clinically significant premenstrual syndrome by the American College of Obstetricians and Gynecologists includes at least 1 affective or physical symptom associated with "economic or social dysfunction" that occurs during the 5 days before onset of menses and with the symptom(s) being present in at least 3 consecutive cycles of menstruation.23

The criteria for diagnosis of premenstrual dysphoric disorder provide thresholds on symptom timing, symptom constellations, and severity.24 During a diagnostic workup, it is important to exclude other medical conditions, such as major depressive disorder, anxiety or panic disorder, personality disorder, or hyperthyroidism, as these conditions require additional targeted treatment. In addition, because associations have been found between premenstrual disorders and sexual abuse and posttraumatic stress disorder, the practitioner should obtain a full history from the patient.25 Recommendations to collect daily symptom rating during at least 3 symptom cycles can be useful, although a provisional diagnosis may be made before confirmation with the scores.26 To diagnose a premenstrual syndrome, the practitioner should be able to determine that the patient experiences a clear, symptom-free interval between the end of menstruation and approximate time of ovulation.22

Symptom timing for diagnosis of premenstrual dysphoric disorder includes having 5 or more symptoms during the final week before the onset of menses, which improve at the time of menses onset or a few days after, with minimal or absent symptoms in the week postmenses. Symptoms must be present from 2 major categories (Table 1).

Table 1. Diagnosis of Premenstrual Dysphoric Disorder: Symptoms

Symptoms also must be associated with clinically significant distress or interference with work, school, usual social activities, or relationships with others. The Daily Record of Severity of Problems is a validated instrument that can be used to track symptoms and associated levels of severity and impairment by the patient.27 This can be used by the clinician to determine symptom patterns and criteria for diagnosis.

Treatment of Premenstrual Disorders

Typical premenstrual symptoms are usually well managed with over-the-counter analgesics, especially nonsteroidal anti-inflammatory drugs, a well-balanced diet with regular intake of fresh fruit and vegetables, and regular exercise-at least 150 minutes of moderate-to-intense physical activity per week. Lifestyle behavioral changes that follow these recommendations can be encouraged for women during symptom tracking, but are often insufficient for improving symptoms in patients with premenstrual disorders. Women on contraceptive therapy may still continue to have premenstrual symptoms, but not usually at the diagnostic threshold criteria of premenstrual disorder.

A stepwise approach is often used, starting with nonpharmacological treatments, antidepressants, hormonal medications, and surgical options if indicated.9

Data from the 2012 National Australian Longitudinal Study of Women's Health were used to investigate the use of complementary and alternative interventions among women suffering with cyclic perimenstrual pain. Compared with women who had infrequent premenstrual symptoms, women with premenstrual syndrome were more likely to consult with an osteopath, massage therapist, naturopath/herbalist, or other alternative health practitioners and to have used all forms of complementary and alternative therapies.28 Therefore, asking the patient what types of complementary or alternative strategies have been attempted and their effectiveness may be helpful in guiding the next steps.

The effectiveness of a 12-week yoga intervention on premenstrual symptoms was investigated in a pre-/poststudy with 64 women, of which a majority (91%) reported menstrual pain during their menstrual period.29 After the yoga intervention, subjects reported decreased use of analgesics during menstruation (P < 0.029) and decreased effect of moderate or severe menstrual pain on work (P = 0.001). The yoga intervention was associated with an improvement in physical function, bodily pain, and decreased abdominal swelling, breast tenderness, abdominal cramps, and cold sweats.

Although other complementary and alternative therapies can be used to improve general health, the effectiveness of these interventions has not been scientifically validated. Cognitive-behavioral therapy has been shown to be effective for mild premenstrual syndrome, with results being comparable to fluoxetine.30 Although the rate of improvement may not be as rapid as pharmacotherapy, successful cognitive-behavioral therapy may avoid the need for long-term supplement or medication use.

Supplements of calcium, vitamin B₆, and vitamin E have been examined in women with premenstrual syndrome.31 At least 1 study has demonstrated that calcium supplement (600 mg twice daily) effectively decreases negative mood and somatic symptoms. However, only marginal improvements were seen with vitamin B₆ and vitamin E.32,33 The extract of the agnus castus fruit (Vitex agnus castus), or chasteberry, was found to improve premenstrual symptoms in 52% of participants, although it was a small study sample.34 A randomized controlled trial demonstrated that chasteberry was as effective as fluoxetine in symptom treatment.35 In the study, 42 women who met criteria for premenstrual dysphoric disorder were randomized to 8 weeks of treatment with either chasteberry or fluoxetine, and both response rates and adverse outcomes were similar. However, there were no sexual side effects reported in the chasteberry group.

Three selective serotonin reuptake inhibitors (SSRIs) have FDA-approved indications for the treatment of premenstrual dysphoric disorder: fluoxetine 20 to 60 mg/d; sertraline 50 to 150 mg/d; and oaroxetine 20 to 30 mg/d. A 2013 Cochrane review assessing SSRIs for premenstrual syndrome and premenstrual dysphoric disorder concluded that these drugs decreased symptoms more effectively than placebo when taken during the luteal phase or continuously. Therefore, SSRIs are often recommended as first-line therapy.36

Continuous dosing is usually reserved for patients with concomitant mood disorder, erratic cycles, difficulty remembering cyclical dosing, or side effects when rapidly starting/stopping the medication. As an alternative to continuous dosing, patients may do well on intermittent dosing in which treatment is initiated at ovulation and the medication is ceased 1 to 2 days after the start of menstruation.31 Therapy during the luteal phase, or semi-intermittent dosing, uses a low dose of an SSRI with increased dosing during the luteal phase. The most flexible dosing schedule is symptom-onset dosing, in which treatment is initiated when symptoms begin and continued until the onset of menses. These options provide women with the ability to tailor treatment according to their symptom patterns.

Oral contraceptives have been used to treat symptoms of premenstrual disorder, and a 2008 Cochrane review found that those containing drospirenone alleviated symptoms more significantly than placebo.37 The oral contraceptive with drospirenone 3 mg and ethinyl estradiol 20 [mu]g was evaluated in a double-blind, randomized, placebo-controlled, crossover design. The authors found the patients to have significant improvement in somatic and mood symptoms taking this oral contraceptive, compared with placebo.38

With the concern for increased risk of venous thromboembolism, the use of oral contraceptives has been questioned. However, a large study demonstrated no conferral of increased risk. In the study, 85,000 new users of oral contraceptives (with drospirenone for 24 or 21 days and those containing other progestins) were evaluated in a prospective, controlled, cohort study. Overall, no cohort was associated with higher risk for venous thromboembolism or serious adverse outcome.39 Although this study provides some reassurance, it is highly recommended that providers obtain a detailed medical and family history, perform a risk assessment, and provide the full range of options and risks versus benefits before initiating treatment.

Gonadotropin-releasing hormone agonists and antagonists are used to create an artificial menopause by blocking the production of ovarian-stimulating hormones.31 The low estrogen levels prevent menstruation. However, women may need to be maintained on a low dose of estrogen and progestin along with the gonadotropin-releasing hormone agonists and antagonists to reduce side effects, including bone loss, hot flashes, and vaginal dryness.

Bilateral salpingoophorectomy (BSO) with or without hysterectomy to remove the ovaries and cease the menstrual cycle is a treatment only considered after trialing available medical therapies. Significant improvement with BSO has been shown for women who have not improved with traditional treatments, although the sample size is small.40

Women who decide to undergo BSO should be prescribed estrogen replacement (with a progestin if the uterus is retained) to maintain cardiac and bone health.

Conclusion

Premenstrual disorders can significantly affect the lives of women of reproductive age, negatively influencing their social and physical functioning. The pathophysiology of premenstrual disorders involves cyclic secretion of sex hormones with dysregulation of neurotransmitters, mainly GABA and serotonin, with some evidence that inflammation plays a role in symptom frequency, severity, and duration. Diagnostic workup of premenstrual disorder should consider other medical or psychiatric conditions while tracking symptoms over at least 3 menstrual cycles for confirmation. Treatment of premenstrual disorders is typically performed in a stepwise fashion, although the use of SSRIs is considered to be a first-line therapy. Although other therapeutic options are available, there is limited evidence on their effectiveness. Surgical options should only be discussed after trialing the range of options available.

References