Chapter 386: Menstrual Disorders and Pelvic Pain

Menstrual dysfunction can signal an underlying abnormality that may have long-term health consequences. Although frequent or prolonged bleeding usually prompts a woman to seek medical attention, infrequent or absent bleeding may seem less troubling and the patient may not bring it to the attention of the physician. Thus, a focused menstrual history is a critical part of every encounter with a female patient. Pelvic pain is a common complaint that may relate to an abnormality of the reproductive organs but also may be of gastrointestinal, urinary tract, or musculoskeletal origin. Depending on its cause, pelvic pain may require urgent surgical attention. Recent guidelines no longer recommend routine pelvic examination in asymptomatic, average-risk women other than periodic cervical cancer screening. However, pelvic examination is an important part of the evaluation of amenorrhea, abnormal uterine bleeding, and pelvic pain.

DEFINITION AND PREVALENCE

Amenorrhea refers to the absence of menstrual periods. Amenorrhea is classified as primary if menstrual bleeding has never occurred in the absence of hormonal treatment or secondary if menstrual periods cease for 3–6 months. Primary amenorrhea is a rare disorder that occurs in <1% of the female population. However, between 3 and 5% of women experience at least 3 months of secondary amenorrhea in any specific year. There is no evidence that race or ethnicity influences the prevalence of amenorrhea. However, because of the importance of adequate nutrition for normal reproductive function, both the age at menarche and the prevalence of secondary amenorrhea vary significantly in different parts of the world.

Oligomenorrhea is defined as a cycle length >35 days or <10 menses per year. Both the frequency and the amount of vaginal bleeding are irregular in oligomenorrhea, and moliminal symptoms (premenstrual breast tenderness, food cravings, mood lability), suggestive of ovulation, are variably present. Anovulation can also present with intermenstrual intervals <24 days or vaginal bleeding for >7 days. Frequent or heavy irregular bleeding is termed dysfunctional uterine bleeding if anatomic uterine and outflow tract lesions or a bleeding diathesis have been excluded. Oligo- or anovulation are most frequently associated with polycystic ovarian syndrome (PCOS).

Primary Amenorrhea

The absence of menarche (the first menstrual period) by age 16 has been used traditionally to define primary amenorrhea. However, other factors, such as growth, secondary sexual characteristics, and the presence of cyclic pelvic pain, also influence the age at which primary amenorrhea should be investigated. Recent studies suggest that puberty is occurring at an earlier age, particularly in obese girls. However, it is important to note that these data reflect earlier breast development alone with minimal change in the age of menarche. Thus, an evaluation for amenorrhea should be initiated by age 15 or 16 in the presence of normal growth and secondary sexual characteristics; age 13 in the absence of secondary sexual characteristics or if height is less than the third percentile; age 12 or 13 in the presence of breast development and cyclic pelvic pain; or within 2 years of breast development if menarche, has not occurred.

Secondary Amenorrhea or Oligomenorrhea

Irregular cycles are relatively common for up to 3 years after menarche and for 1–2 years before the final menstrual period. In the intervening years, menstrual cycle length is ~28 days, with an intermenstrual interval normally ranging between 25 and 35 days. Cycle-to-cycle variability in an individual woman who is ovulating consistently is generally +/− 2 days. Pregnancy is the most common cause of amenorrhea and should be excluded early in any evaluation of menstrual irregularity. However, many women occasionally miss a single period. Three months of secondary amenorrhea, or 6 months in women with previously irregular cycles, should prompt an evaluation, as should a history of intermenstrual intervals >35 or <21 days or bleeding that persists for >7 days.

DIAGNOSIS

Pregnancy is the most common cause of amenorrhea, and must be excluded in all cases, regardless of patient history. Evaluation of menstrual dysfunction depends on understanding the interrelationships between the four critical components of the reproductive tract: (1) the hypothalamus, (2) the pituitary, (3) the ovaries, and (4) the uterus and outflow tract (Fig. 386-1; Chap. 385). This system is maintained by complex negative and positive feedback loops involving the ovarian steroids (estradiol and progesterone) and peptides (inhibin B and inhibin A) and the hypothalamic (gonadotropin-releasing hormone [GnRH]) and pituitary (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) components of this system (Fig. 386-1).

Disorders of menstrual function can be thought of in two main categories: disorders of the uterus and outflow tract and disorders of ovulation. Many of the conditions that cause primary amenorrhea are congenital but go unrecognized until the time of normal puberty (e.g., genetic, chromosomal, and anatomic abnormalities). All causes of secondary amenorrhea also can cause primary amenorrhea.

Disorders of the Uterus or Outflow Tract

Abnormalities of the uterus and outflow tract typically present as primary amenorrhea. In patients with normal pubertal development and a blind vagina, the differential diagnosis includes obstruction by a transverse vaginal septum or imperforate hymen; müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome), which can be caused by mutations in the WNT4 gene; and androgen insensitivity syndrome (AIS), which is an X-linked recessive disorder that accounts for ~10% of all cases of primary amenorrhea (Chap. 384). Patients with AIS have a 46,XY karyotype, but because of the lack of androgen receptor responsiveness, those with complete AIS lack features of androgenization and have female external genitalia. The absence of pubic and axillary hair distinguishes them clinically from patients with müllerian agenesis, as does a testosterone level in the male range. The rare patient with 5α reductase type 2 enzyme deficiency has a similar presentation, but undergoes virilization at the time of puberty. Asherman’s syndrome presents as secondary amenorrhea or hypomenorrhea and results from partial or complete obliteration of the uterine cavity by adhesions that prevent normal growth and shedding of the endometrium. Curettage performed for pregnancy complications accounts for >90% of cases; genital tuberculosis is an important cause in regions where it is endemic.

TREATMENT

Disorders of Ovulation

Once uterus and outflow tract abnormalities have been excluded, other causes of amenorrhea involve disorders of ovulation. The differential diagnosis is based on the results of initial tests, including a pregnancy test, an FSH level (to determine whether the cause is likely to be ovarian or central), and assessment of hyperandrogenism (Fig. 386-2).

HYPOGONADOTROPIC HYPOGONADISM

Low estrogen levels in combination with normal or low levels of LH and FSH are seen with anatomic, genetic, or functional abnormalities that interfere with hypothalamic GnRH secretion or normal pituitary responsiveness to GnRH. Although relatively uncommon, tumors and infiltrative diseases should be considered in the differential diagnosis of hypogonadotropic hypogonadism (Chap. 373). These disorders may present with primary or secondary amenorrhea. They may occur in association with other features suggestive of hypothalamic or pituitary dysfunction, such as short stature, diabetes insipidus, galactorrhea, and headache. Hypogonadotropic hypogonadism also may be seen after cranial irradiation. In the postpartum period, amenorrhea occurs normally in association with breast feeding, but may also be caused by pituitary necrosis (Sheehan’s syndrome) or lymphocytic hypophysitis. Because reproductive dysfunction is commonly associated with hyperprolactinemia from neuroanatomic lesions or medications, prolactin should be measured in all patients with hypogonadotropic hypogonadism (Chap. 373).

Isolated hypogonadotropic hypogonadism (IHH) occurs in women, although it is three times more common in men. IHH generally presents with primary amenorrhea, although 50% have some degree of breast development, and ~10% report one to two menses. IHH is associated with anosmia in half of women (termed Kallmann’s syndrome). Genetic causes of IHH have been identified in ~50% of patients (Chaps. 384 and 385).

Functional hypothalamic amenorrhea (HA) is a diagnosis of exclusion of other causes of hypogonadotropic hypogonadism including chronic diseases (type 1 diabetes, celiac disease, hyperthyroidism, Cushing Syndrome) and use of opioids, glucocorticoids or psychotropic medications that increase prolactin levels. Functional HA is most commonly associated with conditions causing a mismatch between energy expenditure and energy intake and/or significant stress. Variants in genes associated with IHH may increase susceptibility to these environmental inputs, accounting in part for the clinical variability in this disorder. Metabolic and stress signaling is transduced to the reproductive axis, at least in part, through leptin signaling from the periphery and via hypothalamic kisspeptin control of GnRH. The diagnosis of HA generally can be made on the basis of a careful history, a physical examination, and the demonstration of low levels of gonadotropins and normal prolactin levels. Eating disorders and chronic disease must be specifically excluded. An atypical history, headache, signs of other hypothalamic dysfunction, or hyperprolactinemia, even if mild, necessitates cranial magnetic resonance imaging (MRI) to exclude a neuroanatomic cause. Up to 10% of women with HA may have some features of PCOS (increased ovarian volume, higher anti-mullerian hormone [AMH] levels, and slightly elevated androgen levels).

HYPERGONADOTROPIC HYPOGONADISM

Ovarian failure is considered premature when it occurs in women <40 years old and accounts for ~10% of secondary amenorrhea. Primary ovarian insufficiency (POI) has replaced the terms premature menopause and premature ovarian failure in recognition of the continuum of impaired ovarian function encompassed by this disorder. Ovarian insufficiency is associated with the loss of negative-feedback restraint on the hypothalamus and pituitary, resulting in increased FSH and LH levels. FSH is a better marker of ovarian failure because of loss of negative feedback effects of both estradiol and the inhibins and because its levels are less variable than those of LH. AMH levels will also be low in patients with POI, but are more frequently used in management of infertility. As with natural menopause, POI may wax and wane, and serial measurements may be necessary to establish the diagnosis.

Once the diagnosis of POI has been established, further evaluation is indicated because of other health problems that may be associated with POI. Although POI is most commonly of unknown cause, it also occurs in association with a variety of chromosomal abnormalities (most often Turner’s syndrome), autoimmune polyglandular failure syndromes, and other rare disorders. Radiotherapy and chemotherapy may reduce ovarian reserve, with effects on both the oocytes and the supporting granulosa cells. New approaches, including ovarian preservation, are being developed to support long-term fertility choices in women of reproductive age prior to oncologic treatment. The recognition that early ovarian failure occurs in premutation carriers of the fragile X syndrome is important because of the increased risk of severe mental retardation in male children with FMR1 mutations. Thus, follow-up testing should include a karyotype in all POI patients, serum anti-cortical and 21-hydroxylase antibodies (specific but not sensitive for subsequent adrenal insufficiency), thyroid function and thyroid peroxidase antibodies, FMR1 premutation screening, and assessment of bone mineral density. Ovarian biopsy is of no diagnostic or prognostic value. Although the number of genetic causes POI is increasing, routine testing for mutations other than FMR1 is currently not recommended.

Hypergonadotropic hypogonadism occurs rarely in other disorders, such as mutations in the FSH or LH receptors. Aromatase deficiency and 17α-hydroxylase deficiency are associated with decreased estrogen and elevated gonadotropins and with hyperandrogenism and hypertension, respectively. Gonadotropin-secreting tumors in women of reproductive age generally present with high, rather than low, estrogen levels and cause ovarian hyperstimulation or dysfunctional bleeding.

TREATMENT

POLYCYSTIC OVARIAN SYNDROME

PCOS is diagnosed based on a combination of clinical or biochemical evidence of hyperandrogenism, amenorrhea or oligomenorrhea, and the ultrasound appearance of polycystic ovaries. Approximately half of patients with PCOS are obese, and abnormalities in insulin dynamics are common, as is metabolic syndrome. Symptoms generally begin shortly after menarche and are slowly progressive. Lean oligo-ovulatory patients with PCOS generally have high LH levels in the presence of normal to low levels of FSH and estradiol, although these may be suppressed by undernutrition or stress. The LH/FSH ratio is less pronounced in obese patients in whom insulin resistance is a more prominent feature.

TREATMENT

The mechanisms that cause pelvic pain are similar to those that cause abdominal pain (Chap. 12) and include inflammation of the parietal peritoneum, obstruction of hollow viscera, vascular disturbances, and pain originating in the abdominal wall. Pelvic pain may reflect pelvic disease per se but also may reflect extrapelvic disorders that refer pain to the pelvis. In up to 60% of cases, pelvic pain can be attributed to gastrointestinal problems, including appendicitis, cholecystitis, infections, intestinal obstruction, diverticulitis, and inflammatory bowel disease. Urinary tract and musculoskeletal disorders are also common causes of pelvic pain.

APPROACH TO THE PATIENT

ACUTE PELVIC PAIN

Pelvic inflammatory disease (PID) most commonly presents with bilateral lower abdominal pain. It is generally of recent onset and is exacerbated by intercourse or jarring movements. Fever is present in about half of these patients; abnormal uterine bleeding occurs in about one-third. New vaginal discharge, urethritis, and chills may be present but are less specific signs. With public health efforts to control sexually transmitted diseases, the rate and severity of PID have declined in the United States and Europe; however, this is not the case in the developing world. Subclinical PID with its attendant risks of infertility and ectopic pregnancy remains a significant problem worldwide. Public health and professional organizations recommend annual testing for C. trachomatis in all sexually active women <25 and both C. trachomatis and N. gonorrhea in all women at increased risk. Adnexal pathology can present acutely and may be due to rupture, bleeding or torsion of cysts, or, much less commonly, the fallopian tubes. Neoplasms of the ovary or fallopian tube are much less common causes. Fever may be present with ovarian torsion. Ectopic pregnancy is associated with right- or left-sided lower abdominal pain, with clinical signs generally appearing 6–8 weeks after the last normal menstrual period. Vaginal bleeding occurs in ~50% of cases. Orthostatic signs and fever may be present. Risk factors include the presence of known tubal disease, previous ectopic pregnancies, a history of infertility, diethylstilbestrol (DES) exposure of the mother in utero, or a history of pelvic infections. Rupture of the fallopian tube remains a life-threatening emergency; the incidence depends on access to care but is ~18% in developed countries. Threatened abortion may also present with amenorrhea, abdominal pain, and vaginal bleeding. Although more common than ectopic pregnancy, it is rarely associated with systemic signs. Uterine pathology includes endometritis and, less frequently, degenerating leiomyomas (fibroids). Endometritis often is associated with vaginal bleeding and systemic signs of infection. It occurs in the setting of sexually transmitted infections, uterine instrumentation, or postpartum infection.

A sensitive pregnancy test, complete blood count with differential, urinalysis, tests for chlamydial and gonococcal infections, and abdominal ultrasound aid in making the diagnosis and directing further management.

TREATMENT

TREATMENT

TREATMENT