Dysmenorrhea in Adolescents and Young Adults: Etiology and Management

Abstract

Dysmenorrhea is the most common gynecologic complaint among adolescent and young adult females. Dysmenorrhea in adolescents and young adults is usually primary (functional), and is associated with normal ovulatory cycles and with no pelvic pathology. In approximately 10% of adolescents and young adults with severe dysmenorrhea symptoms, pelvic abnormalities such as endometriosis or uterine anomalies may be found. Potent prostaglandins and potent leukotrienes play an important role in generating dysmenorrhea symptoms. Nonsteroidal anti-inflammatory drugs (NSAID) are the most common pharmacologic treatment for dysmenorrhea. Adolescents and young adults with symptoms that do not respond to treatment with NSAIDs for 3 menstrual periods should be offered combined estrogen/progestin oral contraceptive pills for 3 menstrual cycles. Adolescents and young adults with dysmenorrhea who do not respond to this treatment should be evaluated for secondary causes of dysmenorrhea. The care provider's role is to explain about pathophysiology of dysmenorrhea to every adolescent and young adult female, address any concern that the patient has about her menstrual period, and review effective treatment options for dysmenorrhea with the patient.

Introduction

Menarche, the onset of menstrual periods, marks an important point in life for the female adolescent, as it symbolizes the entrance into womanhood. In 1997, Herman-Giddens and colleagues examined pubertal development and age of menarche of young girls seen in pediatric practices throughout the United States.¹ The majority of girls were Caucasian (90.4%) and 9.6% were African-American. Mean age of breast development was 8.87 years in African-American girls and 9.96 years in Caucasian girls. Mean menarchal age was 12.2 years in African American girls and 12.9 years in Caucasian girls. These findings revealed that young girls begin the pubertal process earlier than previously reported.² The findings also indicated that the age of menarche in the USA has remained stable among Caucasian girls and has slightly decreased among African American girls over the past 40 years.

In adult women, most of the cycles are ovulatory and regular, lasting between 21 and 35 days. During the first half of the cycle (follicular phase) pulsatile GnRH secretion from the hypothalamus stimulates secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. FSH and LH stimulate development of a dominant follicle in the ovaries. The estrogen produced by the ovaries is capable of exerting a positive stimulatory feedback on LH release, leading to LH surge around day 14 of the cycle. Ovulation occurs approximately 12 hours after the LH surge. If ovulation has occurred, progesterone is secreted from the corpus luteum during the second half of the cycle (luteal phase) with a peak around 8 days after the LH surge. While the luteal phase is constant and lasts 14 days, the number of days required for follicular growth and maturation in the follicular phase may vary, leading to slight variability in cycle length among women. Regression of the corpus luteum results in a decrease of both progesterone and estrogen, triggering a synchronous sloughing of the endometrial lining (menstruation). The average blood loss during the menstrual period is 40 mL, with a normal range between 25 and 69 mL.³ Most of the blood loss occurs during the first few days of the menstrual period, which generally lasts from 2 to 7 days.

In adolescents, the positive stimulatory feedback mechanism of estrogen on LH does not mature, and the LH surge does not occur, until 2–5 years after menarche. As a consequence, 50–80% of the cycles are anovulatory and irregular during the first 2 years after menarche, and approximately 10–20% of cycles remain anovulatory up to 5 years after menarche. The length of the interval between the onset of menses and the establishment of ovulatory cycles is associated with the age of menarche, with earlier menarche correlating with a shorter interval.⁴ The eventual attainment of ovulatory cycles by the teenagers leads to normal, repetitive menstrual bleeding. While dysmenorrhea (menstrual cramps and other menstruation-associated symptoms) is less common during the first 2–3 years after menarche, when most of the menstrual cycles are anovulatory, it becomes more prevalent during mid and late adolescence, with the establishment of ovulatory menstrual cycles.⁵

Dysmenorrhea is the most common gynecologic complaint and the leading cause of recurrent short-term school or work absenteeism among female adolescents and young adults.⁵ Despite the high prevalence of dysmenorrhea in adolescents and young adults, many girls either do not seek medical advice or are under-treated. In one study, a majority (98%) of adolescents used nonpharmacologic methods such as heat, rest, or distraction to treat dysmenorrhea, with perceived effectiveness of 40% or less.⁶ In other studies from different populations, 30–70% of girls reported at least occasionally self-medicating with over-the-counter (OTC) pain medications.7, 8, 9 However, 57% of those who self-medicated with OTC preparations used sub-therapeutic doses.⁹ Only 54% of adolescents knew that certain medications could relieve menstrual cramps,⁸ and 27% of girls were unable to recognize any of three non-steroidal anti-inflammatory drugs (NSAID) listed as possible treatments for dysmenorrhea.¹⁰

While lower abdominal cramping is the most common dysmenorrhea symptom, many adolescents suffer from other menstruation-associated symptoms, such as headaches and vomiting (Fig. 1). Symptoms typically accompany the start of menstrual flow or occur within a few hours before or after onset, and last for the first 24–48 hours. Severity of dysmenorrhea symptoms positively correlates with early menarche and with increased duration and amount of menstrual flow.7, 11 Low fish consumption correlated with dysmenorrhea severity in two studies.11, 12 In addition, cigarette smoking may increase duration of dysmenorrhea, presumably because of nicotine induced vasoconstriction.¹³ Premenstrual symptoms, which are more common starting in the third decade of life, are less common in adolescent girls and are often alleviated by adequate treatment of dysmenorrhea.

The majority of dysmenorrhea in adolescents and young adults is primary (or functional), is associated with a normal ovulatory cycle and with no pelvic pathology, and has a clear physiologic etiology.5, 14 After ovulation there is a buildup of fatty acids in the phospholipids of the cell membranes. The high intake of omega-6 fatty acids in the western diet results in a predominance of the omega-6 fatty acids in the cell wall phospholipids.¹⁵ After the onset of progesterone withdrawal before menstruation, these omega-6 fatty acids, particularly arachidonic acid, are released, and a cascade of prostaglandins (PG) and leukotrienes (LT) is initiated in the uterus (Fig. 2). The inflammatory response, which is mediated by these PG and LT, produces both cramps and systemic symptoms such as nausea, vomiting, bloating, and headaches. In particular, the prostaglandin F2α, cyclooxygenase (COX) metabolite of arachidonic acid, causes potent vasoconstriction and myometrial contractions, leading to ischemia and pain.¹⁴

Chan and Hill measured PGF2α activity in menstrual fluid from tampons and found that PG activity was twice as high in the dysmenorrheic as in the eumenorrheic women.¹⁶ Similar findings were reported by Rees et al.¹⁷ Lundstrom and Green examined endometrial specimens taken from both dysmenorrheic and eumenorrheic women during the menstrual period and found that women with dysmenorrhea receiving no medication had endometrial PGF2α levels four times higher than the eumenorrheic women on the first day of the menstrual period.¹⁸ While the PG pathway has been extensively investigated in dysmenorrhea, there is a paucity of data regarding the LT pathway. Previous studies have shown that human uterine tissue has the capacity to synthesize and metabolize LT,¹⁹ and LT receptors have been detected in uterine tissue.²⁰ Rees et al found that the highest LT values were present in uterine tissue obtained (during hysterectomy) from adult women with a complaint of dysmenorrhea.¹⁹ Nigam et al found a close correlation between menstrual flow LT-C₄/D₄ levels and the severity of dysmenorrhea symptoms in adult women with primary dysmenorrhea.²¹ In a preliminary study, we found an increase in urinary LT-E₄ in adolescent girls with dysmenorrhea,²² further indicating a possible involvement of these potent vasoconstrictors and inflammatory mediators in generating symptoms of dysmenorrhea in adolescents.

Secondary dysmenorrhea refers to painful menstruation associated with pelvic abnormalities, which may be seen in about 10% of adolescents and young adults with dysmenorrhea. Secondary dysmenorrhea is more likely to be associated with chronic pelvic pain, midcycle pain, dyspareunia, and metrorrhagia.

Endometriosis is the most common cause of secondary dysmenorrhea in adolescents and young adults. It is defined as the presence and growth of uterine glands and stroma outside the uterine cavity. The majority of endometriosis implants are located in the pelvis, with the ovaries being the most common site. Other common endometriosis sites include the pelvic peritoneum, anterior and posterior cul-de-sac, uterosacral ligaments, pelvic lymph nodes, cervix, uterus, vagina, vulva, rectosigmoid colon, and appendix. Rare sites of implantation include the umbilicus, surgical scars, bladder, kidneys, lungs, and extremities. The incidence of endometriosis in adolescents has been reported to be between 45% and 70% in a referral population presenting with chronic pelvic pain.²³ The youngest reported patient to have biopsy-proven endometriosis was 10 years of age.²⁴ The 6.9% incidence of endometriosis in first-degree relatives of women with the disease compared with the 1% incidence in a control population, implies a possible polygenic multifactorial model of inheritance.²⁵

The most widely accepted theory about the development of endometriosis is the Sampson's theory of retrograde menstruation. Deficient cell-mediated immunity with impaired clearing of endometriotic cells from aberrant locations has also been implicated. Other theories of origin include the Meyer's theory of multipotential cells undergoing metaplasia, and the Halban's theory of hematogenous and lymphatic dissemination of endometrial cells. Abnormal local hormonal activity and potent inflammatory mediators are also involved in the pathophysiology of endometriosis.

Endometriosis is an estrogen-dependent disorder. Immunohistochemical studies have located estrogen receptor expression and increased expression of aromatase in epithelial and stromal cells of endometriotic tissues and peritoneum.26, 27 Thus, while aromatase activity is not detectable in normal endometrium, it is expressed inappropriately in endometriosis, leading to a rise in local biosynthesis of estrogen. This acquisition of steroidogenic capacity may permit the ectopic endometrial tissues to survive despite the lack of ovarian steroids during menstruation. In addition, aberrant expression of cytokines such as interleukin-1 and tumor necrosis factor-alpha may influence the establishment and proliferation of these ectopic endometrial implants.²⁸ Immunohistochemical studies have shown that the COX-2 expression is upregulated in endometriotic lesions,²⁹ and this increase in COX-2 is most likely secondary to the increase in estrogen.³⁰ The increased COX activity results in production of PG such as PG E₂, which, in turn, is a potent inducer of aromatase expression and activity in endometriotic stromal cells.³¹ Another abnormality that contributes to the rise of estrogen in endometriosis is a deficient 17beta-hydroxysteroid dehydrogenase (17β-HSD) type 2 expression which impairs the inactivation of estradiol to estrone.³² This 17β-HSD type 2 deficiency may also be viewed as a defective action of progesterone, which fails to induce this enzyme in endometriotic tissue. Thus, the positive feedback loop in endometriosis consists of high local level of estrogen, which induces transcription of COX-2 and synthesis of PG E₂, resulting in further expression and activity of aromatase, and further increase in estrogen (Fig. 3). The accumulation of estrogen and PG results in a potent inflammatory process and pelvic pain.

The severity of pain from endometriosis involves several factors. These include the location of the lesion, depth of invasion, and stretching or scarring of tissue. In particular, women with deep implants tend to have more active disease and more severe pain.³³ However, the presence of symptoms does not always predict the extent of endometriosis.³⁴

In the adolescent age group the distinct possibility of a mullerian anomaly must also be considered. The patient may have a didelphic uterus with unilateral obstruction resulting in pelvic pain that may or may not be cyclic. In particular, an early age of presentation of endometriosis is often associated with a genital outflow obstruction. In one study by Goldstein et al, congenital anomalies of the reproductive tract were noted in 11% of teenagers with endometriosis.³⁵ Adhesions, pelvic inflammatory disease, abscess, ectopic pregnancy, miscarriage, ovarian cyst, and, rarely, ovarian neoplasm are also included in the differential diagnosis of secondary dysmenorrhea.