Elena M. Umland, Lara C. Weinstein, and Edward Buchanan
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Describe the underlying etiology and pathophysiology of amenorrhea, menorrhagia, dysmenorrhea, and anovulatory bleeding and how they relate to selection of effective treatment modalities.
2. Describe the clinical presentation of amenorrhea, menorrhagia, dysmenorrhea, and anovulatory bleeding.
3. Recommend appropriate lifestyle and dietary modifications and pharmacotherapeutic interventions for patients with amenorrhea, menorrhagia, dysmenorrhea, and anovulatory bleeding.
4. Identify the desired therapeutic outcomes for patients with amenorrhea, menorrhagia, dysmenorrhea, and anovulatory bleeding.
5. Design a monitoring plan to assess the effectiveness and adverse effects of pharmacotherapy for amenorrhea, menorrhagia, dysmenorrhea, and anovulatory bleeding.
KEY CONCEPTS
Unrecognized pregnancy remains the most common cause of amenorrhea, and a urine pregnancy test should be one of the first steps in the evaluation of this disorder.
For most conditions associated with primary and secondary amenorrhea, estrogen treatment (along with a progestin to minimize the risk of endometrial hyperplasia) is utilized.
Causes of menorrhagia can be divided into systemic disorders and specific uterine abnormalities.
Intrauterine pregnancy, ectopic pregnancy, and miscarriage must be at the top of the differential diagnosis list for any woman presenting with heavy menses.
The reduction in menorrhagia-related blood loss with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and oral contraceptives (OCs) is directly proportional to the amount of pretreatment blood loss.
The most significant mechanism for primary dysmenorrhea is the release of prostanoids and possible eicosanoids in the menstrual fluid; given their impact on inhibiting prostaglandins as well as their ability to provide direct analgesia, NSAIDs are the treatment of choice.
Intrauterine devices (IUDs) are considered therapeutic options in a variety of menstrual-related disorders. Guidelines from the American College of Obstetricians and Gynecologists (ACOG) indicate that any woman (regardless of parity) at low risk of sexually transmitted diseases is a good candidate for IUD use.
Anovulatory bleeding, also referred to as dysfunctional uterine bleeding, is secondary to the effects of unopposed estrogen and does not include bleeding owing to an anatomic lesion of the uterus.
The use of metformin and thiazolidinediones for anovulatory bleeding associated with polycystic ovary syndrome (PCOS) is beneficial for anovulatory bleeding and fertility and also improves glucose tolerance and decreases overall cardiovascular risk.
Problems related to the menstrual cycle are common in women of reproductive age. The issues considered in this chapter are the most frequently encountered menstrual-related difficulties and include amenorrhea, menorrhagia, dysmenorrhea, and dysfunctional uterine bleeding. The need for effective treatments for these disorders stems from their impact on any or all of the following: A reduced quality of life, negative effects on reproductive health, and the potential for long-term detrimental health effects, such as osteoporosis in the case of amenorrhea and cardiovascular disease in the case of polycystic ovary disease.
AMENORRHEA
Amenorrhea is described as either primary or secondary in nature. Primary amenorrhea is the absence of menses by age 16 in the presence of normal secondary sexual development or the absence of menses by age 14 in the absence of normal secondary sexual development. Secondary amenorrhea is the absence of menses for three cycles or 6 months in a previously menstruating woman. However, in clinical practice, there is a significant amount of overlap. The initial evaluation of amenorrhea is often the same regardless of age of onset, except in unusual clinical situations.1
EPIDEMIOLOGY AND ETIOLOGY
Unrecognized pregnancy remains the most common cause of amenorrhea, and a urine pregnancy test should be one of the first steps in the evaluation of this disorder. To help organize an approach to diagnosis and treatment, it is helpful to consider the organs involved in the menstrual cycle, which include the uterus, ovaries, anterior pituitary, and hypothalamus. After pregnancy, the five most common causes of secondary amenorrhea, in descending order of prevalence, include2:
• Hypothalamic suppression (33%)
• Chronic anovulation (28%)
• Hyperprolactinemia (14%)
• Ovarian failure (12%)
• Uterine disorders (7%)
PATHOPHYSIOLOGY
The physiology of the normal menstrual cycle depends on a coordinated system of hormonal interactions involving the hypothalamus, anterior pituitary gland, ovary, and endometrium. Figures 49-1 and 49-2summarize these points. Pulsatile gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus stimulates the anterior pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In the specialized cells of the ovarian follicle, FSH and LH stimulate the release of estradiol. Estradiol stimulates endometrial growth during the follicular phase of the cycle. Following the LH surge and ovulation, the follicle is transformed into the corpus luteum. Progesterone that is secreted by the corpus luteum during the luteal phase of the cycle causes endometrial “organization.” If conception does not occur, the drop in estrogen and progesterone stimulates the shedding of the endometrium.3
Table 49–1 illustrates the pathophysiology of amenorrhea relative to the organ system(s) involved, as well as the related condition(s) that result in amenorrhea. Amenorrhea is also an expected, potential side effect resulting from the use of low-dose oral contraceptives (OCs), extended-cycle OC pill use, or depo medroxyprogesterone acetate (MPA) use.8 Many women may experience delayed return of menses after discontinuation of OCs. Postpill amenorrhea usually is a self-limited condition. Further evaluation for other unrecognized conditions, such as polycystic ovary syndrome (PCOS), should be considered if spontaneous resolution of the amenorrhea does not occur within 3 to 6 months following discontinuation of the OCs.
FIGURE 49–1. Summary of the normal menstrual cycle.
FIGURE 49–2. Hormonal fluctuations with the normal menstrual cycle. (From DiPiro JT, Talbert RL, Yee GC, et al., (eds.) Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill, 2008.)
Table 49–1 Pathophysiology of Selected Menstrual Bleeding Disorders
TREATMENT
Desired Outcomes
Therapeutic modalities for amenorrhea are targeted at restoring the normal menstrual cycle. The goals of treatment are to preserve bone density, prevent bone loss, and restore ovulation, thus improving fertility as desired. Amenorrhea resulting from conditions contributing to hypoestrogenism also may affect quality of life via the induction of hot flashes (premature ovarian failure), dyspareunia, and in prepubertal females, lack of secondary sexual characteristics, and absence of menarche.
Nonpharmacologic Therapy
Nonpharmacologic therapy for amenorrhea varies depending on its underlying cause. Amenorrhea secondary to anorexia may respond to weight gain. Such patients would also benefit from psychotherapy. In young women for whom excessive exercise is an underlying cause, a reduction in exercise is recommended.
Clinical Presentation and Diagnosis of Amenorrhea
General
Patients may be concerned about cessation of menses and fertility implications but generally are not in acute distress
Symptoms
• Cessation of menses
• Possible complaints of infertility, vaginal dryness, decreased libido
Signs
• Cessation of menses for longer than 6 months in women with established menstruation, or absence of menses by age 16 in the presence of normal secondary sexual development, or absence of menses by age 14 in the absence of normal secondary sexual development
• Recent significant weight loss or weight gain
• Presence of acne, hirsutism, hair loss, or acanthosis nigricans may suggest androgen excess
Laboratory Tests
• Pregnancy test
• TSH
• Prolactin
• If PCOS is suspected, consider free or total testosterone, 17-hydroxyprogesterone, fasting glucose, and fasting lipid panel
• If premature ovarian failure is suspected, consider FSH and LH measurements
Other Diagnostic Tests
• Progesterone challenge
• Pelvic ultrasound to evaluate for polycystic ovaries
Patient Encounter 1, Part 1
JK is an 18-year-old African American woman who presents to her physician with complaints of no menses for 8 months. She is sexually active and has been with the same male partner for the last 5 months. She is not using any form of contraception. She has recently begun college. In addition, she has been active in cross-country training for the past 4 years.
What menstruation-related disorder does this patient have?
What are the potential etiologies for this condition?
Pharmacologic Therapy
Estrogen/Progestin Replacement Therapy
For most conditions associated with primary or secondary amenorrhea, estrogen treatment (along with a progestin to minimize the risk of endometrial hyperplasia) is utilized. The purpose of estrogen therapy in this patient population is twofold: To reduce the risk of osteoporosis and to improve quality of life.9,10 Table 49–2 identifies a variety of therapeutic options for amenorrhea, including recommended doses. Figure 49–3 illustrates a treatment algorithm for the management of amenorrhea.
Bromocriptine
If hyperprolactinemia is identified as the cause of amenorrhea, the use of bromocriptine, a dopamine agonist, results in a reduction in prolactin concentrations and the resumption of menses.
Amenorrhea related to anovulation resulting from PCOS may respond to the use of agents that reduce insulin resistance. The use of metformin for this purpose will be discussed in the anovulatory bleeding section that follows.
Progesterone
Progestins have long been used to induce withdrawal bleeding in women with secondary amenorrhea. Several factors predict the efficacy of progesterone for this purpose.15 These factors include estrogen concentrations greater than or equal to 35 pg/mL (128 pmol/L) and endometrial thickness (the greater it is, the greater is the amount of withdrawal bleeding).
The efficacy of progestins for secondary amenorrhea also varies depending on the formulation used. For example, progesterone in oil administered intramuscularly results in withdrawal bleeding in 70% of treated patients, whereas oral MPA induces withdrawal bleeding in 95% of treated patients.15 Table 49–2 identifies the types and doses of progesterones used for inducing withdrawal bleeding in women with secondary amenorrhea. Figure 49–3illustrates when to consider the use of progesterone for the treatment of amenorrhea.
For all patients experiencing amenorrhea, owing to the negative impact this has on bone health, it is essential that a diet rich in calcium and vitamin D be followed.
AMENORRHEA IN ADOLESCENTS
Amenorrhea in the adolescent population is of great importance because this is the time in the female life cycle when peak bone mass is achieved. The cause of amenorrhea and appropriate treatment must be identified promptly in this population because hypoestrogenism contributes negatively to bone development. Estrogen replacement, typically via an OC, is important. In addition, ensuring that the patient is receiving adequate amounts of calcium and vitamin D is imperative.
Table 49–2 Therapeutic Agents for Selected Menstrual Disorders
FIGURE 49–3. Treatment algorithm for amenorrhea.
Patient Encounter 1, Part 2
Additional Workup of JK Reveals:
PMH: Seasonal allergic rhinitis
PSH: None
FH: Mother and father are alive and well. She has two younger siblings (ages 12 and 15) who are alive and well
SH: The patient works part-time as a waitress. She has participated in cross-country running throughout high school and now into college. She denies smoking cigarettes or drinking alcohol.
Meds: Loratadine 10 mg daily
Past Gynecologic Hx: Never pregnant and never on contraception; (-) history of abnormal pap smears; (-) history of sexually transmitted infections; (+) history of irregular menses each year during track season
ROS: (-) restrictive eating patterns or self-induced vomiting; (-) galactorrhea, headaches, change in vision; (-) abnormal hair growth; (-) acne
PE:
Gen: Thin appearing African American female, no acute distress
VS: BP 118/62, P 74, RR 16, wt 56 kg (123 lb), ht 5’6” (168 cm),
BMI: 19.9 kg/m2
HEENT: (-) hirsutism
Breasts: (-) galactorrhea
Pelvic: Normal appearance of external genitalia and vagina, cervix without lesions, uterus midposition without masses, adnexa without masses
Labs:
Urine HCG: Negative
TSH: 1.8 μIU/mL (1.8 mIU/L) (within normal limits)
Prolactin: 10 ng/mL (10 mcg/L) (within normal limits)
Progesterone challenge: No withdrawal bleeding
FSH: 7.4 mIU/mL or mU/mL (7.4 U/L) (within normal limits)
LH: 0.4 mIU/mL or mU/mL (0.4 U/L) (within normal limits)
Head MRI: Normal
Given this information what is your assessment of this patient’s condition?
Identify your treatment goals for this patient.
What therapeutic options exist for this patient? Identify those that would be most appropriate.
What monitoring parameters are necessary to employ in assessing efficacy and safety of the therapeutic options?
MENORRHAGIA
The traditional definition of menorrhagia is a menstrual blood loss of more than 80 mL per cycle. This definition has been questioned for several reasons, including difficulty with quantifying menstrual blood loss in clinical practice. Many women are with “heavy menses” but who experience blood loss of less than 80 mL merit consideration for treatment because of problems with containment of flow, unpredictable heavy flow days, and other associated symptoms such as dysmenorrhea.16,17
Epidemiology and Etiology
Rates of menorrhagia in healthy women range from 9% to 14%.4 Causes of menorrhagia can be divided into systemic disorders and specific uterine abnormalities. Intrauterine pregnancy, ectopic pregnancy, and miscarriage, must be at the top of the differential diagnosis list for any woman presenting with heavy menses. In several studies of adolescents with acute menorrhagia, underlying bleeding disorders accounted for 3% to 13% of emergency department visits. von Willebrand s disease has an incidence of 1% in the general population and may present initially as heavy menses in an adolescent.8Hypothyroidism also may be associated with heavy menses. Specific uterine causes of menorrhagia are more common in older childbearing women, and they include fibroids, adenomyosis, endometrial polyps, and gynecologic malignancies.
Clinical Presentation and Diagnosis of Menorrhagia
General
Patient may or may not be in acute distress
Symptoms
Complaints of heavy/prolonged menstrual flow and fatigue and light-headedness in the case of severe blood loss. These symptoms may or may not occur with dysmenorrhea
Signs
Orthostasis, tachycardia, and pallor may be noted, especially in cases of significant acute blood loss
Laboratory Tests
Complete blood count (CBC) and ferritin levels; hemoglobin and hematocrit results may be low
If the history dictates, testing may be done to identify coagulation disorders) as a cause
Other Diagnostic Tests
• Pelvic ultrasound
• Pelvic MRI
• Pap smear
• Endometrial biopsy
• Hysteroscopy
• Sonohysterogram
PATHOPHYSIOLOGY
Table 49–1 illustrates the pathophysiology of menorrhagia relative to the organ system(s) involved, as well as the specific conditions that result in menorrhagia.
TREATMENT
Desired Outcomes
Menorrhagia therapy should focus on reducing menstrual blood flow, improving the patient’s quality of life, and deferring the need for surgical intervention. Table 49–2 identifies the various agents used in the management of menorrhagia. It also includes their dosing and common side effects. Figure 49–4 illustrates how to decide which treatment(s) to use and when.
Nonpharmacologic Therapy
Nonpharmacologic interventions for menorrhagia include surgical interventions that are reserved for patients not responding to pharmacologic treatment. These interventions may vary from conservative endometrial ablation to hysterectomy.18
Pharmacologic Therapy
Nonsteroidal Anti-Inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are firstline treatments for menorrhagia associated with ovulatory cycles.19 They have the advantage of being taken only during menses, and their use is associated with a significant reduction in menstrual blood loss. A 20% to 50% reduction in blood loss has been observed in 75% of treated women.12 In some patients, as much as an 80% reduction has been observed. This reduction is directly proportional to the amount of pretreatment blood loss.12
Combination OCs
The use of OCs is beneficial to women with menorrhagia who do not desire pregnancy. A 43% to 53% reduction in menstrual blood loss has been observed in 68% of patients treated with OCs containing greater than or equal to 35 mcg estradiol for the treatment of menorrhagia.12 As with the use of NSAIDs, the reduction in blood loss is proportional to pretreatment blood loss.
Progesterone
Menorrhagia also may be treated with the levonorgestrel-releasing intrauterine devices (IUD). This is a very effective treatment that consistently reduces menstrual flow by 90% or greater.12,20-22 Its use has resulted in the postponement or cancellation of scheduled endometrial resection surgery or hysterectomy. Specifically, 60% of treated patients have been able to avoid hysterectomy.22–24
FIGURE 49–4. Treatment algorithm for menorrhagia.
Progesterone therapy either during the luteal phase of the menstrual cycle or for 21 days starting on day 5 after the onset of menses results in a 32% to 50% reduction in menstrual blood loss.12 Its use has not been shown to be superior to other medical treatments, including NSAIDs.12 In addition, it is not associated with any contraceptive benefit.19
DYSMENORRHEA
Dysmenorrhea is commonly defined as crampy pelvic pain occurring with or just prior to menses. Primary dysmenorrhea implies pain in the setting of normal pelvic anatomy and physiology, whereas secondary dysmenorrhea is associated with underlying pelvic pathology.11
EPIDEMIOLOGY AND ETIOLOGY
Rates of dysmenorrhea range from 20% to 90%.11,25 Dysmenorrhea can be associated with significant interference in attendance at work and school for 15% of women affected by the most severe form.25 Risk factors for dysmenorrhea include young age, heavy menses, and nulliparity.11 Causes of secondary dysmenorrhea may include cervical stenosis, endometriosis, pelvic infections, pelvic congestion syndrome, uterine or cervical polyps, and uterine fibroids.26
Clinical Presentation and Diagnosis of Dysmenorrhea
General
Patient may or may not be in acute distress depending on the level of menstrual pain experienced
Symptoms
Complaints of crampy pelvic pain beginning shortly before or at the onset of menses. Symptoms typically last from 1 to 3 days
Laboratory Tests
• Sexually active females should have a pelvic examination to screen for sexually transmitted diseases
• Gonorrhea, chlamydia cultures or PCR, wet mount
Other Diagnostic Tests
Pelvic ultrasound may be used to identify anatomic abnormalities such as masses/lesions or to detect ovarian cysts and endometriomas
FIGURE 49–5. Treatment algorithm for dysmenorrhea.
PATHOPHYSIOLOGY
The most significant mechanism for primary dysmenorrhea is the release of prostanoids and possibly eicosanoids in the menstrual fluid inducing uterine contractions, reducing uterine blood flow, and causing uterine hypoxia.25Vasopressin-mediated vasoconstriction may also contribute to the resulting symptoms.8,11,25
TREATMENT
Desired Outcomes
The medical management of dysmenorrhea should relieve the related pelvic pain and result in a reduction in lost school and work days. Table 49–2 identifies the agents used in the management of dysmenorrhea, their recommended doses, and their common side effects. Figure 49–5 is a treatment algorithm for the management of dysmenorrhea.
Nonpharmacologic Therapy
Several nonpharmacologic interventions exist for the management of dysmenorrhea. Among these, topical heat therapy, exercise, and following a low-fat vegetarian diet all have been shown to reduce the intensity of the dysmenorrhea.11,14 Dietary changes also may shorten the duration of dysmenorrhea. These interventions require little time and minimal cost and are associated with little risk. Other nonpharmacologic options that may be considered before or, in most cases, after a trial of pharmacologic interventions include the use of transcutaneous electrical nerve stimulation (TENS), acupressure, and acupuncture.11
Pharmacologic Therapy
Nonsteroidal Anti-Inflammatory Drugs
Given their impact on inhibiting prostaglandins as well as their ability to provide direct analgesia, NSAIDs are the treatment of choice for dysmenorrhea. There does not appear to be a difference between agents in efficacy. Choice of one agent over another may be based on cost, convenience, and patient preference.11,25 The most commonly used agents are naproxen and ibuprofen.
It has been suggested that a loading dose (twice the usual single dose) of the NSAID be taken, followed by the usually recommended dose until symptoms resolve.14 An alternate recommendation is to begin the NSAID at the onset of menses or perhaps even the day prior and to continue treatment around the clock instead of waiting until the onset of symptoms. For patients in whom NSAID use is contraindicated, the agents discussed below should be considered. The use of acetaminophen has been proven inferior to the use of NSAIDs for the treatment of this disorder.11
Oral Contraceptives
OCs help to improve dysmenorrhea by inhibiting the proliferation of endometrial tissue. This reduction in tissue translates into a reduction in endometrial-derived prostaglandins that are thought to contribute to the pelvic pain experienced.14,25 A trial of 2 to 3 months of OC dosing is required to establish whether the patient is a responder or a nonresponder. Significant improvements in mild, moderate, and severe dysmenorrhea have been noted with the use of OCs. These agents have other benefits, such as the prevention of pregnancy, improving acne, and reducing ovarian cancer risk. While monophasic formulations may be more efficacious for this indication, the supporting evidence for this is limited.11
Progesterone
The benefit of depo MPA in dysmenorrhea is related to its ability to render most patients amenorrheic within 1 year of use.11 This is an expected side effect. Since the pelvic pain of dysmenorrhea is related to the prostaglandins released during menses, in the setting of amenorrhea, the underlying cause of dysmenorrhea is removed.
Observational data illustrate a reduction in dysmenorrhea from 60% to 29% with the levonorgestrel-releasing IUD after 3 years.11 As observed with depo MPA, this reduction is likely secondary to the increasing incidence of amenorrhea in users of this contraceptive device.
DYSMENORRHEA IN ADOLESCENTS
Dysmenorrhea is very common in adolescent females. Any of the treatment measures discussed earlier for other patients would be appropriate in the adolescent population. While NSAIDs and OCs are among the top choices, use of the levonorgestrel IUD is also an option.22 It had been thought previously that nulliparous females should avoid the use of IUDs secondary to an increased risk of pelvic inflammatory disease (PID) and a subsequent increased risk of infertility. Guidelines from the American College of Obstetricians and Gynecologists (ACOG) state that any woman (regardless of parity) at low risk of sexually transmitted diseases and thus PID is a good candidate for IUD use.22
ANOVULATORY BLEEDING
Anovulatory bleeding is irregular menstrual blood flow from the uterine endometrium that ranges from light spotting to heavy blood flow.5 Anovulatory bleeding, also referred to as dysfunctional uterine bleeding, is secondary to the effects of unopposed estrogen and does not include bleeding owing to an anatomic lesion of the uterus. Anovulatory bleeding includes PCOS, which typically presents with irregular menstrual bleeding, hirsutism, obesity, or infertility.
EPIDEMIOLOGY
Anovulatory bleeding is the most common form of noncyclic uterine bleeding.5 Patients often seek medical care to regulate their menstrual cycle or improve fertility. All women of reproductive age should have a pregnancy test when presenting with irregular menstrual bleeding. Anovulation may be secondary to physiologic or pathologic causes. It is common at menarche and in the perimenopausal period. During adolescence, ovulatory menstrual cycles may not be regular for a year or more after menarche.5 Overall, the frequency of ovulation is related to the time since menarche and the age at menarche.27 In the year following menarche, there may be an immature feedback mechanism in the hypothalamic–pituitary–ovarian (HPO) axis whereby the LH surge needed for ovulation does not occur. During perimenopause, anovulatory cycles may occur owing to a declining quality and quantity of ovarian follicles. As ovarian function declines, estrogen secretion continues and progesterone secretion decreases. Chronic anovulatory cycles and unopposed estrogen secretion lead to endometrial proliferation and increased risk of polyps, endometrial hyperplasia, and carcinoma.
Anovulation also may occur at any time during the reproductive years due to a pathologic cause. The most common causes of nonphysiologic ovulatory dysfunction and their prevalence rates5 are:
• PCOS (70%)
• Hypothalamic amenorrhea (10%)
• Hyperprolactinemia (10%)
• Premature ovarian failure (10%)
PCOS, while responsible for 70% of the cases of ovulatory dysfunction, occurs in approximately 4% of women.28
ETIOLOGY
Anovulation may result from a problem at any level of the HPO axis. In addition to various physiologic life stages such as adolescence, perimenopause, pregnancy, and lactation, other causes of anovulation include:5,27
• Hyperandrogenic anovulation (PCOS, congenital adrenal hyperplasia, androgen-producing tumors)
• Hypothalamic dysfunction (anorexia nervosa, physical or emotional stress)
• Hyperprolactinemia
• Hypothyroidism
• Primary pituitary disease
• Premature ovarian failure
PATHOPHYSIOLOGY
A normal ovulatory cycle consists of follicular development, ovulation, corpus luteum development, and luteolysis. During the cycle, the endometrium undergoes proliferation, secretory change, and desquamation. This cycle is influenced first by the effects of estrogen alone, then by estrogen and progesterone, and culminates with estrogen and progesterone withdrawal. Progesterone stops the growth of the endometrium and stimulates its differentiation. In patients with anovulation, a corpus luteum is not formed, and the ovary does not secrete progesterone. Without progesterone, there is no desquamation or differentiation of the endometrium. Chronic unopposed estrogen causes continuous endometrial proliferation, and the endometrium becomes vascular and fragile, resulting in noncyclic menstrual bleeding. In addition, the endometrium may become hyperplastic and progress to a precancerous state, placing the patient at increased risk of endometrial cancer.6 See Table 49–1 for the pathophysiology of anovulatory bleeding relative to the specific conditions that contribute to it.
Clinical Presentation and Diagnosis of Anovulatory Bleeding
General
May or may not be in acute distress
Symptoms
Irregular, heavy, or prolonged vaginal bleeding, perimenopausal symptoms (hot flashes, etc.)
Signs
Acne, hirsutism, obesity
Laboratory Tests
• If suspect PCOS, consider free or total testosterone, fasting glucose, fasting lipid panel
• If suspect perimenopause, FSH
Other Diagnostic Tests
Pelvic ultrasound to evaluate for polycystic ovaries
Patient Encounter 2, Part 1
TP, a 22-year-old woman, presents to your office for a routine gynecologic examination. She entered menarche at the age of 12. Her last menstrual period was 3 months ago. Her periods are often irregular and occur about every 2 to 3 months. She has had all normal Pap smears in the past and no history of sexually transmitted infections. She is currently in a monogamous relationship with a male partner. She has had four sexual partners. She is not taking OCs and does not routinely use condoms. She has never been pregnant in the past, but she plans to start a family in the near future. As you examine the patient, you note facial and chest acne, increased facial and abdominal hair, and obesity.
What anovulatory disorder is most likely present?
What signs/symptoms support this conclusion?
What diagnostic tests should be done?
The most common pathologic cause of anovulation is PCOS. It is a syndrome of ovarian dysfunction diagnosed by the presence of two of the following three characteristics: Oligoanovulation or anovulation, clinical or laboratory evidence of hyperandrogenism, and polycystic ovary morphology on ultrasound.29 No gene or environmental substance has been found to cause PCOS.7 However, the observance of familial clustering of cases suggests that genetics plays a role.30 It is thought that insulin resistance, hyperandrogenism, and changes in gonadotropins also influence the development of PCOS.28 The underlying cause for increased androgens is unknown.30
PCOS is associated with a three to seven times increased risk of developing type 2 diabetes.29 Patients diagnosed with PCOS should be screened for impaired glucose tolerance, diabetes, hypertension, and dyslipidemia.28 If any of these conditions are present, there is an increased risk of cardiovascular events.
TREATMENT
Desired Outcomes
In the short term, the desired outcome is to stop acute bleeding. The long-term goals of therapy include preventing future episodes of noncyclic bleeding, decreasing the long-term complications of anovulation (e.g., osteopenia and infertility), and improving overall quality of life.5 Table 49–2 identifies the agents used in the management of anovulatory bleeding, their doses, and common side effects.
Nonpharmacologic Therapy
Nonpharmacologic treatment options for anovulatory bleeding depend on the underlying cause. In a woman of reproductive age with PCOS, weight loss may be beneficial. In women who have completed childbearing or who have failed medical management, endometrial ablation or resection and hysterectomy are surgical options. It is unclear as to which procedure is preferred. Short term, it appears that ablation or resection results in less morbidity and shorter recovery periods.18 However, a significant number of these women eventually undergo hysterectomy in the 5 years that follow.5
Pharmacologic Therapy
Estrogen
Estrogen is the recommended treatment for managing acute bleeding episodes because it promotes endometrial growth and stabilization.5 Further, its use (via OC regimens) has been observed to avert emergency surgical procedures in 95% of treated patients.13 Following its initial use for controlling acute bleeding episodes, it is necessary to continue therapy to prevent future occurrences. The use of OCs fulfills this role.
In addition to controlling acute bleeding, the use of OCs also aids in the prevention of recurrent anovulatory bleeding. They suppress ovarian hormones and adrenal androgen production. They also, indirectly, increase sex hormone-binding globulin (SHBG). This, in turn, binds and reduces circulating androgen. For women with high androgen levels and related signs (e.g., hirsutism), low-dose OCs (less than or equal to 35 mcg ethinyl estradiol) are the treatment of choice.5 In theory, one may consider the use of an OC with a progesterone such as drospirenone that has a larger impact on increasing SHBG and antiandrogenic effects.31 However, to date there is no consensus as to the best OC choice for these women (e.g., those with PCOS).7
Medroxyprogesterone Acetate
Specifically, for women with PCOS, the use of depot and intermittent oral MPA suppresses pituitary gonadotropins and circulating androgens.7 Further, the use of cyclic progesterone may benefit women over age 40 with anovulatory bleeding.5 Similar to the use of OCs, the use of oral MPA has been observed to avert emergency surgical procedures in 100% of patients for acute uterine bleeding justifying immediate medical attention.13
Insulin-Sensitizing Agents
The use of metformin and the thiazolidinediones pioglitazone and rosiglitazone results in improved insulin sensitivity. In patients with PCOS, this is associated with reduced circulating androgen concentrations, increasing ovulation rates, and improving glucose tolerance.7 These improvements can be attributed to the increase in SHBG that occurs via increased insulin sensitivity. These agents are of benefit not only for anovulatory bleeding and fertility but also because they improve glucose tolerance and decrease overall cardiovascular risk.7 If pregnancy is a desired outcome, it is important to note that metformin is a pregnancy category B agent, whereas pioglitazone and rosiglitazone are category C.
Patient Encounter 2, Part 2
PMH: (+) Obesity and acne
FH: Father is living and has hypertension. Mother is living and has diabetes mellitus and hypercholesterolemia. Both parents are obese.
SH: The patient works as a secretary. She lives with her fiancé. She denies any tobacco or recreational drug use. She drinks about five alcoholic beverages per week. She is sedentary
Meds: None
ROS: (+) acne, (+) hirsutism, (-) dysmenorrhea, (-) breast tenderness, (-) vaginal discharge
PE:
VS: BP 128/82, P 80 bpm, RR 18 bpm, wt 123 kg (270 lb), ht 5 ft, 3 in. (160 cm), BMI 47.9 kg/m2
Abd: Obese, soft, nontender, nondistended, (+) bowel sounds, no hepatosplenomegaly
Gyn: Normal external appearance of labia minora and majora, vaginal walls within normal limits, cervix well visualized and without lesions, midposition uterus, no cervical motion tenderness, no adnexal masses palpated
Labs: Urine HCG negative, free testosterone 100 ng/dL (3.47 nmol/L) (elevated), TSH 2.1 μU/mL (2.1 mU/L) (within normal limits), prolactin 9 ng/mL (9 mcg/L) (within normal limits), fasting glucose 120 mg/dL (6.66 mmol/L). Fasting lipid panel: Total cholesterol 181 mg/dL (4.69 mmol/L), HDL cholesterol 58 mg/dL (1.50 mmol/L), triglycerides 65 mg/dL (0.73 mmol/L), LDL cholesterol 110 mg/dL (2.85 mmol/L)
Pelvic Ultrasound: 15 follicles in right ovary, 14 follicles in left ovary, increased ovarian volume of 12 mL
What treatment options are available for this patient?
Will this patient have fertility problems in the future?
Table 49–3 Expected Outcome Measures for Selected Menstrual Bleeding Disorders
Although the use of insulin-sensitizing agents may improve fertility, if the goal of treatment is to improve fertility via ovulation induction, then the treatment of choice is combination therapy with an insulin-sensitizing agent such as metformin plus clomiphene citrate.32,33 Treatment with clomiphene citrate 50 mg/day for 5 days can be initiated between days 3 and 5 of the menstrual cycle. This often may occur following the induction of withdrawal bleeding with a progesterone such as MPA at 10 mg/day by mouth for 10 days.
ANOVULATORY BLEEDING IN ADOLESCENTS
Anovulatory cycles are not unusual in the perimenarchal reproductive years. Ovulation typically is established a year or more following menarche. When anovulatory bleeding occurs in this population, it may be excessive. If the bleeding is excessive, the patient should be evaluated for blood dyscrasias. The prevalence of blood dyscrasias, including von Willebrand’s disease and prothrombin deficiency, and the prevalence of idiopathic thrombocytopenia purpura in this population ranges from 5% to 20%.5
Patient Care and Monitoring
1. Assess symptoms to determine if patient-directed therapy is appropriate (e.g., NSAIDs for dysmenorrhea) or whether the patient should be evaluated by a physician (e.g., amenorrhea, menorrhagia, anovulatory bleeding, or premenstrual dysphoric disorder (PMDD). Does the patient have any related complications, such as symptoms of anemia in patients presenting with menorrhagia or complaints of difficulty conceiving in women with amenorrhea or anovulatory bleeding?
2. Review any available diagnostic data, as appropriate, to determine hormonal, reproductive, and pregnancy status.
3. Obtain a thorough history of prescription, nonprescription, and natural drug product use. Determine which treatments have been helpful to the patient in the past.
4. Educate the patient on lifestyle modifications that will improve symptoms and prevent complications.
5. Is the patient taking the appropriate dose of the prescribed medication? If not, why not?
6. Develop a plan to assess effectiveness of the prescribed medication after 1 to 2 months of therapy.
7. Determine if long-term maintenance treatment is necessary.
8. Assess improvement in quality-of-life measures such as physical, psychological, social functioning, and well-being.
9. Evaluate for adverse drug reactions, drug allergies, and drug interactions.
10. Stress the importance of adherence with the therapeutic regimen, including lifestyle modifications. Recommend a therapeutic regimen that is easy for the patient to adhere to.
11. Provide patient education regarding disease state, lifestyle modifications, and drug therapy by noting the following:
• What causes the menstruation-related disorder?
• What are the possible complications of the menstruation-related disorder?
• What lifestyle modifications may help to reduce the risk associated with these complications?
• When and how should patients take their medications?
• What potential adverse effects may occur?
• Which drugs may interact with their therapy?
In the adolescent population, specific blood dyscrasias should be treated. In addition, acute, severe bleeding may be managed with high-dose estrogen. Low-dose OCs (less than or equal to 35 mcg ethinyl estradiol) are the treatment of choice in adolescents with chronic anovulation.5
OUTCOME EVALUATION
Measure the treatment success for the various menstruation-related disorders by the degree to which the care plan (a) relieves or reverses symptoms of the disorder, (b) prevents or reverses the complications of the disorder (e.g., osteoporosis, anemia, and infertility), and (c) minimizes side effects. The return of a regular menstrual cycle with minimal premenstrual symptoms or symptoms of dysmenorrhea should occur. Depending on the desire for conception and subsequent therapy, this cycle may be ovulatory or anovulatory.
Assess the effectiveness of therapy in resuming normal menstrual cycles with minimal related pain after an appropriate treatment interval (1–2 months). Assess improvement in quality-of-life measures such as physical, psychological, and social functioning and well-being. Evaluate the patient for adverse drug reactions, drug allergies, and drug interactions. Table 49–2 illustrates the common side effects that may occur for which monitoring is required. Table 49–3 illustrates the specific expected outcome measures for each of the menstruation-related disorders discussed in this chapter.
Abbreviations Introduced in This chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp/html.
REFERENCES
1. SperoffL, Fritz MA. Clinical Gynecologic Endocrinology and Infertility. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:187–232, 401–463.
2. Reindollar RH, Novak M, Tho SP, McDonough PG. Adult-onset amenorrhea: A study of 262 patients. Am J Obstet Gynecol 1986;155(3):531–543.
3. Barbeiri RL, Ryan KJ. The menstrual cycle. In: Ryan Kistner’s Gynecology and Women’s Health. 7th ed. St. Louis, MO: Mosby, 1999:23–57.
4. Stenchever MA, Droegemueller W, Herbst AL, Mishell DR. Abnormal uterine bleeding: Ovulatory and anovulatory dysfunctional uterine bleeding, management of acute and chronic excessive bleeding. In: Comprehensive Gynecology. 4th ed. St. Louis, MO: Mosby, 2001:1079–1097.
5. American College of Obstetricians and Gynecologists. Management of anovulatory bleeding. ACOG Practice Bulletin Number 14. Obstet Gynecol 2000(Mar):495–502.
6. Speroff L, Glass RH, Kase NG. Clinical gynecologic endocrinology and infertility. 6th ed. Baltimore, MD: Lippincott Williams & Wilkins, 1999:487–511.
7. American College of Obstetricians and Gynecologists. Polycystic ovary syndrome. ACOG Practice Bulletin Number 41. Obstet Gynecol 2002;100:1389–1402.
8. Adams Hillard PJ, Deitch HR. Menstrual disorders in the college age female. Pediatr Clin N Am 2005;52(1):179–197.
9. Gordon CM, Nelson LM. Amenorrhea and bone health in adolescents and young women. Curr Opin Obstet Gynecol 2003;15:377–384.
10. Pletcher JR, Slap GB. Menstrual disorders—Amenorrhea. Pediatr Clin N Am 1999;46(3):505–518.
11. French L. Dysmenorrhea. Am Fam Physician 2005;71:285–292.
12. Roy SN, Bhattacharya S. Benefits and risks of pharmacological agents used for the treatment of menorrhagia. Drug Safety 2004;27(2):75–90.
13. Munro MG, Mainor N, Basu R, et al. Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: A randomized clinical trial. Obstet Gynecol 2006;108:924–929.
14. Harel Z. A contemporary approach to dysmenorrhea in adolescents. Pediatr Drugs 2002;4(12):797–805.
15. Simon JA. Progestogens in the treatment of secondary amenorrhea. J Reprod Med 1999;44:185–189.
16. Warner PE, Critchley HO, Lumsden MA, et al. Menorrhagia I: Measured blood loss, clinical features, and outcome in women with heavy periods: A survey with follow-up data. Am J Obstet Gynecol 2004;190(5):1216–1223.
17. Warner PE, Critchley HO, Lumsden MA, et al. Menorrhagia II: Is the 80-mL blood loss criterion useful in management of complaint of menorrhagia? Am J Obstet Gynecol 2004;190(5):1224–1229.
18. Dickersin K, Munro MG, Clark M, et al. Hysterectomy compared with endometrial ablation for dysfunctional uterine bleeding: A randomized controlled trial. Obstet Gynecol 2007;110(6):1279–1289.
19. Prentice A. Fortnightly review: Medical management of menorrhagia. BMJ 1999;319(7221):1343–1345.
20. Reid PC, Virtanen-Kari S. Randomized comparative trial of levonorgestrel intrauterine system and mefenamic acid for the treatment of idiopathic menorrhagia: A multiple analysis using total menstrual fluid loss, menstrual blood loss and pictorial blood loss assessment charts. Br J Obstet Gynecol 2005;112:1121–1125.
21. American College of Obstetricians and Gynecologists. Noncontraceptive uses of the levonorgestrel intrauterine system. ACOG Committee Opinion Number 337. Obstet Gynecol 2006(June);107:1479–1482.
22. American College of Obstetricians and Gynecologists. Intrauterine device. ACOG Practice Bulletin No. 59. Obstet Gynecol 2005;105:223–232.
23. Hurskainen R, Paavonen J. Levonorgestrel-releasing intrauterine system in the treatment of heavy menstrual bleeding. Curr Opin Obstet Gynecol 2004;16:487–490.
24. Hurskainen R, Teperi J, Rissanen P, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: Randomized trial 5-year follow-up. JAMA 2004;291(12):1456–1463.
25. Dawood MY. Primary dysmenorrhea: Advances in pathogenesis and management. Obstet Gynecol 2006;108:428–441.
26. Stenchever MA, Droegemueller W, Herbst AL, Mishell DR. Primary and secondary dysmenorrhea and premenstrual syndrome etiology, diagnosis, and management. In: Stenchever MA, ed. Comprehensive Gynecology. 4th ed. St. Louis, MO: Mosby, 2001:1065–1078.
27. American College of Obstetricians and Gynecologists. Menstruation in girls and adolescents: Using the menstrual cycle as a vital sign. ACOG Committee Opinion Number 349. American Academy of Pediatrics; American College of Obstetricians and Gynecologists. Obstet Gynecol 2006(Nov);108:1323–1328.
28. Guzick DS. Polycystic ovary syndrome. Am J Obstet Gynecol 2004;103(1):181–192.
29. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81(1):19–25.
30. Buggs C, Rosenfield, RL. Polycystic ovary syndrome in adolescence. Endocrinol Metab Clin N Am 2005;34:677–705.
31. Mathur R, Levin O, Azziz R. Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome. Ther Clin Risk Manag 2008;4(2):487–492.
32. Creanga AA, Bradley HM, McCormick C, et al. Use of metformin in polycystic ovary syndrome: A meta-analysis. Obstet Gynecol 2008;111(4):959–968.
33. Khorram O, Helliwell JP, Katz S, et al. Two weeks of metformin improves clomiphene citrate-induced ovulation and metabolic profiles in women with polycystic ovary syndrome. Fertil Steril 2006;85(5):1448–1451.