Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

63. Menstruation-Related Disorders

Elena M. Umland and Jacqueline Klootwyk


KEY CONCEPTS

 Images Unrecognized pregnancy is the most common cause of amenorrhea. A urine pregnancy test should be one of the first steps in evaluating this disorder.

 Images For hypoestrogenic conditions associated with primary and secondary amenorrhea, estrogen (with a progestin) is provided.

 Images Causes of menorrhagia are either systemic disorders or specific uterine abnormalities.

 Images Pregnancy, including intrauterine pregnancy, ectopic pregnancy, and miscarriage, must be at the top of the differential diagnosis for any woman presenting with heavy menses.

 Images The reduction in menorrhagia-related blood loss with use of nonsteroidal antiinflammatory drugs and oral contraceptives is directly proportional to the amount of pretreatment blood loss.

 Images Intrauterine devices (IUDs) are considered therapeutic options in a variety of menstruation-related disorders. Guidelines from the American College of Obstetricians and Gynecologists indicate that both nulliparous and multiparous women at low risk of sexually transmitted diseases are good candidates for IUD use.

 Images Anovulatory bleeding is the standard terminology used to describe bleeding from the uterine endometrium as a result of a dysfunctioning menstrual system, specifically excluding an anatomic lesion of the uterus.

 Images Polycystic ovary syndrome (PCOS) can present as a variety of menstruation disorders, including amenorrhea, menorrhagia, and anovulatory bleeding. Although its definition continues to evolve, it is generally considered a disorder of androgen excess that often includes polycystic ovarian morphology and ovulatory dysfunction.

 Images Metformin and thiazolidinedione use for anovulatory bleeding associated with PCOS is beneficial not only for anovulatory bleeding and fertility but also for improving glucose tolerance and other metabolic parameters that contribute to cardiovascular risk.

 Images The selective serotonin reuptake inhibitors are first-line pharmacologic treatment options for premenstrual dysphoric disorder.


Problems related to the menstrual cycle are exceedingly common in women of reproductive age. This chapter discusses the most frequently encountered menstruation-related difficulties: amenorrhea, menorrhagia, anovulatory bleeding (including polycystic ovary syndrome, PCOS), dysmenorrhea, premenstrual syndrome (PMS), and premenstrual dysphoric disorder (PMDD). The need for effective treatments of these disorders stems from their negative impact on any or all of the following: quality of life, reproductive health, and long-term detrimental health effects, such as increased risk of osteoporosis with amenorrhea and cardiovascular disease with PCOS.

AMENORRHEA

Amenorrhea is described as either primary or secondary in nature. Primary amenorrhea is the absence of menses by age 16 years 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 for 6 months in a previously menstruating woman. There is a significant amount of overlap between the two. The initial evaluation of amenorrhea often is the same, regardless of age of onset, except in unusual clinical situations.1

Epidemiology

Primary amenorrhea occurs in less than 0.1% of the general population. Secondary amenorrhea, in comparison, has an incidence of 0.7% to 5% in the general population and occurs more frequently in women younger than 25 years with a history of menstrual irregularities and in those involved in competitive athletics.2

Etiology

Images Unrecognized pregnancy is the most common cause of amenorrhea. A urine pregnancy test should be one of the first steps in evaluating this disorder. In organizing 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 excluding pregnancy, the most common causes of secondary amenorrhea are hypothalamic suppression, chronic anovulation, hyperprolactinemia, ovarian failure, and uterine disorders.3

Pathophysiology

Each organ in the hypothalamic–pituitary–ovarian–uterine axis is of importance in determining amenorrhea’s etiology and pathophysiology. Beginning with the uterus/outflow tract and progressing caudally will result in a comprehensive differential diagnosis. Table 63-1 lists the pathophysiology of amenorrhea relative to the organ system(s) involved and the specific condition(s) that results in amenorrhea.

TABLE 63-1 Pathophysiology of Selected Menstrual Bleeding Disorders

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Uterus/Outflow Tract

For menstruation to occur, a uterus, functional endometrium, and patent vagina must be present. Several anatomic abnormalities may cause amenorrhea. If primary amenorrhea is the presenting symptom, a congenital anomaly such as imperforate hymen or uterine agenesis may be present and often discovered by physical examination. An acquired condition of the genital tract, such as Asherman’s syndrome or cervical stenosis, is more likely in secondary amenorrhea.

Ovaries

Normal ovarian function is critical for menstruation to occur. The ovaries must respond appropriately to follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by secreting estrogen and progesterone in proper sequence to influence endometrial growth and shedding (Fig. 63-1).

Images

FIGURE 63-1 Hormonal fluctuations with the normal menstrual cycle. (FSH, follicle-stimulating hormone; LH, luteinizing hormone.)

(Courtesy of Hatcher RA, Nelson AL, Zieman M, et al. A Pocket Guide to Managing Contraception. Tiger GA: Bridging the Gap Foundation, 2003;1–146.)

Premature ovarian failure occurs when no viable follicles remain in the ovaries. This is because estrogen production is insufficient to stimulate endometrial growth in the absence of follicles. In a woman younger than 30 years, amenorrhea due to premature ovarian failure may be the result of genetic anomalies.1

The ovaries may play a role in amenorrhea through anovulation. Ovulation is required for the follicle (an estrogen-secreting body) to become a corpus luteum (a progesterone-secreting body). Without ovulation, the proper sequence of estrogen production, progesterone production, and estrogen/progesterone withdrawal will not occur. This can result in amenorrhea. Anovulation can occur secondary to thyroid disease, androgen excess (as in PCOS), or chronic illness.

Pituitary Gland

The anterior pituitary gland secretes FSH and LH in sequential fashion in response to hypothalamic stimulation and a complex ovarian feedback mechanism. Normal secretion of FSH and LH is altered by several endocrinologic and iatrogenic conditions, including thyroid disease, hyperprolactinemia, and dopaminergic drug administration.

Hypothalamus

The hypothalamus secretes cyclic gonadotropin-releasing hormone (GnRH), which causes the pituitary to produce FSH and LH. Disrupting this cyclic process will interrupt the hormonal cascade that results in normal menstruation. Anorexia nervosa, bulimia, intense exercise, and stress may cause hypothalamic amenorrhea.

TREATMENT

The treatment options for amenorrhea are as varied as its causes.

Desired Outcome

Therapeutic modalities for amenorrhea should ensure the occurrence of normal puberty and restore the menstrual cycle. Treatment goals include bone density preservation, bone loss prevention, and ovulation restoration, improving fertility as desired. Amenorrhea from hypoestrogenism may affect quality of life via hot flash induction (premature ovarian failure), dyspareunia, and, in prepubertal females, lack of secondary sexual characteristics and absence of menarche. Treatment is targeted at reversing these effects.


CLINICAL PRESENTATION Amenorrhea

General

    • Although patients may be concerned about cessation of menses and implications for fertility, patients are generally not in acute distress

Symptoms

    • Patients will note cessation of menses

    • Patients may complain of infertility, vaginal dryness, or decreased libido

Signs

    • Cessation of menses for more than 6 months in women with established menstruation, 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 nigrans may suggest androgen excess

Laboratory Tests

    • Pregnancy test

    • Thyroid-stimulating hormone

    • Prolactin

    • If PCOS is suspected, consider free or total testosterone, 17-hydroxyprogesterone, fasting glucose, fasting lipid panel

    • If suspect premature ovarian failure, consider FSH and LH

Other Diagnostic Tests

    • Progesterone challenge

    • Pelvic ultrasound to evaluate for polycystic ovaries

General Approach to Treatment

The overall success of any intervention to treat amenorrhea depends on proper identification of the disorder’s underlying cause(s). Once the cause is identified, the appropriate intervention(s) can be made. For patients experiencing amenorrhea secondary to hypoestrogenic states, a diet rich in calcium and vitamin D is essential to minimize negative impact on bone health.

Nonpharmacologic Therapy

Nonpharmacologic therapy for amenorrhea varies depending upon the underlying cause. Amenorrhea secondary to anorexia may respond to weight gain. In young women for whom excessive exercise is an underlying cause, reduction of exercise quantity and intensity are important.

Pharmacologic Therapy

Images For hypoestrogenic conditions associated with primary or secondary amenorrhea, estrogen (with a progestin) is provided. It can be administered as an oral contraceptive (OC), conjugated equine estrogen, or estradiol patch. Estrogen therapy in this patient population reduces osteoporosis risk7 and improves quality of life. Table 63-2 lists therapeutic agents for amenorrhea treatment, including recommended doses. Figure 63-2 illustrates a treatment algorithm for management of amenorrhea.

TABLE 63-2 Therapeutic Agents for Selected Menstrual Disorders

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Images

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FIGURE 63-2 Treatment algorithm for amenorrhea. aRegardless of cause, adequate calcium and vitamin D intake must be ensured. (OC, oral contraceptive; PCOS, polycystic ovary syndrome.)

When hyperprolactinemia is the cause of amenorrhea, dopamine agonists such as bromocriptine aid in reducing prolactin concentrations and the resumption of menses. Bromocriptine normalizes prolactin levels in 90% of affected women, and fertility is restored in 80% of treated women.10

Amenorrhea related to PCOS-induced anovulation may respond to agents that reduce insulin resistance. Metformin and the thiazolidinediones for this purpose are discussed in the “Anovulatory bleeding” section.

Progestins induce withdrawal bleeding in women with secondary amenorrhea. Several factors predict progesterone’s efficacy for this purpose.9 These factors include estrogen concentrations greater than or equal to 35 pg/mL (128 pmol/L) and endometrial thickness (greater initial thickness resulting in more withdrawal bleeding).

Progestin efficacy for secondary amenorrhea varies by formulation used. Progesterone in oil administered intramuscularly results in withdrawal bleeding in 70% of treated patients, whereas oral medroxyprogesterone acetate (MPA) induces withdrawal bleeding in 95% of treated patients.9 Table 63-2 identifies the types and doses of progestins used for secondary amenorrhea treatment. Figure 63-2illustrates when to consider progestin use for amenorrhea treatment.

Special Populations

Amenorrhea in the adolescent population is of concern because this is the developmental time when peak bone mass is achieved. The cause of amenorrhea, whether primary or secondary, must be promptly identified in this population, as amenorrhea and its related hypoestrogenism negatively affect bone development. In addition to treating or eliminating amenorrhea’s underlying cause, ensuring that the patient is receiving adequate amounts of calcium and vitamin D is imperative. Estrogen replacement, typically via an OC, is important.

Drug Class Information

Table 63-3 identifies the significant pharmacologic properties requiring monitoring of the agents used for amenorrhea management.

TABLE 63-3 Pharmacologic Properties and Monitoring Parameters for Agents Used in the Management of Menstrual Disorders

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Images

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Evaluation of Therapeutic Outcomes

Table 63-3 lists the expected outcomes and specific monitoring parameters for treatment modalities used in amenorrhea management.

MENORRHAGIA

Menorrhagia is the term used to describe heavy menstrual blood loss (greater than 80 mL per cycle) or prolonged menstrual bleeding (menses for greater than 7 days).1,4 This definition has been questioned because of several factors, including difficulty quantifying menstrual loss in clinical practice. Additionally, many women with “heavy menses” but blood loss less than 80 mL merit treatment consideration because of flow containment issues, unpredictably heavy flow days, or other associated symptoms.28,32,33

Epidemiology

Menorrhagia rates in healthy women range from 9% to 14%.4 In women with coagulation disorders such as von Willebrand’s disease or platelet dysfunction, the rates of menorrhagia are as high as 100% and 98%, respectively.6,33

Etiology

Images Causes of menorrhagia are either systemic disorders or specific uterine abnormalities. Images Pregnancy, including 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 room presentations. For example, von Willebrand’s disease has an incidence of 1% in the general population;34 its prevalence in women with menorrhagia may be as high as 20%.35 Menorrhagia initially may present as heavy menses in the adolescent.34 Hypothyroidism also may be associated with heavy menses. Specific uterine causes of menorrhagia are more common in older childbearing women and include fibroids, adenomyosis, endometrial polyps, and gynecologic malignancies.


CLINICAL PRESENTATION Menorrhagia

General

    • Patients may or may not be in acute distress

Symptoms

    • Patients may complain of heavy/prolonged menstrual flow. They also may have signs of fatigue and lightheadedness in cases 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 and ferritin levels; hemoglobin and hematocrit results may be low

    • If the history dictates, testing may be performed to identify coagulation disorder(s) as a cause

Other Diagnostic Tests

    • Pelvic ultrasound

    • Pelvic magnetic resonance imaging

    • Papanicolaou (Pap) smear

    • Endometrial biopsy

    • Hysteroscopy

    • Sonohysterogram

Pathophysiology

Table 63-1 lists the pathophysiology of menorrhagia relative to the organ system(s) involved and the specific conditions that result in menorrhagia.

TREATMENT

Initial treatment choice for menorrhagia is influenced by whether or not the woman desires to become pregnant.

Desired Outcome

Menorrhagia therapy should reduce menstrual blood flow, improve the patient’s quality of life, and defer the need for surgical intervention. Table 63-2 lists the agents and their recommended dosing for menorrhagia management. Figure 63-3 presents an algorithm for menorrhagia treatment.

Images

FIGURE 63-3 Treatment algorithm for menorrhagia. (IUD, intrauterine device; NSAIDs, nonsteroidal antiinflammatory drugs; OC, oral contraceptive.)

General Approach to Treatment

Several treatment options exist for menorrhagia. Initial and subsequent treatment options should be thoughtfully chosen in an effort to avoid surgery.

Nonpharmacologic Therapy

Nonpharmacologic interventions for menorrhagia include surgical procedures that are generally reserved for patients not responding to pharmacologic treatment. These interventions vary from conservative endometrial ablation to hysterectomy.36

Pharmacologic Therapy

Among the agents used to treat menorrhagia, the nonsteroidal antiinflammatory drugs (NSAIDs) have the advantage of administration only during menses. NSAID use is associated with a 20% to 50% reduction in blood loss in 75% of treated women.13,32 In some patients, as much as an 80% reduction in blood loss has been observed.13

For women desiring to avoid pregnancy, OC use is beneficial for menorrhagia and should be considered. A 40% to 50% reduction in menstrual blood loss has been observed in patients treated with cyclic combined OCs.37 ImagesThe reduction in menorrhagia-related blood loss with use of NSAIDs and OCs is directly proportional to the amount of pretreatment blood loss.13

Another menorrhagia treatment option is the levonorgestrel-releasing intrauterine device (IUD). This is a very effective treatment to reduce menstrual flow.38 In particular, a 79% to 97% reduction in blood loss has been observed with its use.38 Its use has also resulted in postponing or cancelling scheduled endometrial ablation surgery or hysterectomy. Sixty percent of treated patients avoided hysterectomy when employing this treatment option,39 and its therapeutic efficacy is similar to endometrial ablation up to 2 years following treatment.18

Progesterone therapy either during the luteal phase of the menstrual cycle or for 21 days, starting on day 5 after onset of menses, results in a 32% to 50% reduction in menstrual blood loss.13 However, progesterone use is not superior to other medical treatments, including the NSAIDs.13

Tranexamic acid was recently approved in the United States for primary menorrhagia treatment. Its use is associated with a significant 26% to 60% reduction in menstrual blood loss.40

Drug Treatments of First Choice

For women who have menorrhagia associated with ovulatory cycles and do not desire hormonal therapy and/or contraception, NSAIDs during menses is a reasonable choice in the absence of any contraindications or GI illnesses such as peptic ulcer disease or gastroesophageal reflux disease. This choice is convenient (only taken during menses) and comparatively inexpensive. For women desiring contraception, it is reasonable to start with either an OC or the levonorgestrel-releasing IUD. Either choice is acceptable for both nulligravid and multiparous women who desire a long-term reversible form of contraception.37,38 Given cost-effectiveness data, the levonorgestrel-releasing IUD is the best first-line choice for women desiring contraception.41 Clinical trial data illustrate a higher failure rate with the OCs (62.5%) compared to the levonorgestrel-releasing IUD (34%) as the primary treatment method.41

Alternative Drug Treatments

Given their side effects, reduced efficacy compared to the first-line agents, and/or cost, use of oral progesterone and depot MPA should be reserved. Tranexamic acid is another treatment option. In comparison to luteal phase oral progesterone, tranexamic acid results in a significantly greater reduction in menstrual blood loss and greater relief of patient-reported symptoms.13 Its use has been associated with a significant improvement in quality of life and high patient satisfaction following three cycles of use.19,42

Special Populations

Although historically it was believed that IUD use should be avoided in nulliparous women, Images guidelines from the American College of Obstetricians and Gynecologists (ACOG) indicate that both nulliparous and multiparous women at low risk of sexually transmitted diseases are good candidates for IUD use.38 Therefore, any of the treatments discussed are options in any female presenting with menorrhagia. Dosage adjustment for tranexamic acid is recommended for reduced renal function. Women with serum creatinine between 1.4 and 2.8 mg/dL (124 and 248 μmol/L) should receive only 1,300 mg by mouth twice daily; women with serum creatinine between 2.9 and 5.7 mg/dL (256 and 504 μmol/L) should receive 1,300 mg by mouth once daily; those with serum creatinine above 5.7 mg/dL (504 μmol/L) should receive 650 mg by mouth once daily.

Drug Class Information

Table 63-3 identifies the significant pharmacologic properties that require monitoring for the agents used to manage menorrhagia.

Evaluation of Therapeutic Outcomes

Table 63-3 illustrates the expected outcomes and specific monitoring parameters for the treatment modalities used in menorrhagia management.

ANOVULATORY BLEEDING

Images Anovulatory bleeding is the standard terminology used to describe bleeding from the uterine endometrium as a result of a dysfunctioning menstrual system, specifically excluding an anatomic lesion of the uterus.1,29Anovulatory bleeding is also referred to as dysfunctional or irregular uterine bleeding.

Epidemiology

Anovulatory bleeding is the most common form of noncyclic uterine bleeding.4 The most common cause is PCOS, for which the prevalence rates range from 6% to 8%.4345 In fact, PCOS is the most common endocrine abnormality among U.S. women of reproductive age.45 Images PCOS can present as a variety of menstruation disorders, including amenorrhea, menorrhagia, and/or anovulatory bleeding. Although its exact definition continues to evolve, it is a disorder of androgen excess that often includes polycystic ovarian morphology and ovulatory dysfunction. It is a significant risk factor for the metabolic syndrome, type 2 diabetes, dyslipidemia, hypertension, and possibly cardiovascular disease.21,46,47 PCOS is a common cause of ovulation dysfunction in adult women.21 Other common causes in adult women include hyperprolactinemia, hypothalamic amenorrhea, also known as hypogonadotropichypogonadism, premature ovarian failure, and thyroid dysfunction.1,29

Etiology

When considering the etiology of anovulatory bleeding, the patient’s age must be considered. All patients presenting with abnormal bleeding should be evaluated for pregnancy. Most adolescents will experience physiologic anovulatory cycles in the first few years following menarche because their hypothalamic–pituitary–gonadal axis is still maturing. However, if an adolescent has not developed regular menstrual cycles within 5 years of menarche, further evaluation for the cause, such as PCOS, should be considered.48 Anovulatory cycles may “unmask” an underlying bleeding disorder. When irregular menses is associated with significant bleeding, an inherited bleeding disorder should be a considered cause, especially in adolescence.6,29 Women experiencing anovulation in their reproductive years should be evaluated for pathologic causes, including PCOS, thyroid dysfunction, hyperprolactinemia, primary pituitary disease, premature ovarian failure, hypothalamic dysfunction, disordered eating, adrenal disease, and androgen-producing tumors. Women in their perimenopausal years may experience “physiologic” anovulatory cycles because of intermittently declining estrogen levels. Regardless of age, evaluation for endometrial hyperplasia and/or endometrial cancer should be considered when a woman experiences excessive bleeding with anovulatory cycles. When considering the etiology of anovulation, it is common for several conditions to coexist (e.g., PCOS and hypothyroidism), each contributing to the woman’s constellation of symptoms. All common etiologies should be considered when beginning to evaluate anovulation.1

Pathophysiology

Normal menstrual cycles occur through a complex interaction of the hypothalamus, pituitary gland, ovaries, and endometrium (Fig. 63-1). In an ovulatory cycle, the ovary produces a mature, estrogen-secreting follicle in response to FSH release from the pituitary. The endometrium proliferates under the influence of this estrogen production. At a critical level of estrogen concentration, the pituitary responds by producing an “LH surge,” which creates a cascade of ovarian events, culminating in ovulation. Upon oocyte release, the follicle becomes a progesterone-producing corpus luteum. The endometrium “organizes” into secretory endometrium in the presence of adequate progesterone. If conception and implantation do not occur, corpus luteum involution causes a decline in estrogen and progesterone leading to predictable, organized menstrual flow as the endometrium sloughs.

If ovulation does not occur, progesterone is not produced, and the endometrium will continue to proliferate in an “unorganized” fashion under the influence of continued estrogen production. Eventually the endometrium will become so thick that it can no longer be supported by continued estrogen production. This results in unorganized, sporadic sloughing of the endometrium, characteristic of the unpredictable and heavy bleeding of anovulation. Anovulation has several etiologies. In adolescence, hypothalamic–pituitary axis immaturity contributes to the absence of the LH surge required for ovulation. In the anorexic patient, the hypothalamus loses much of its pulsatile GnRH release, leading to low levels of FSH and LH, enough for estrogen production but not enough to induce ovulation.

TREATMENT

Optimizing anovulatory bleeding therapy depends on accurate identification of the disorder’s cause(s). The treatment options for anovulatory bleeding are wide and varied.

Desired Outcome

Control of excessive bleeding in the short-term is paramount. Longer-term goals of therapy include restoring the natural cycle of orderly endometrial growth and shedding,29,49 decreasing anovulation complications (e.g., osteopenia, infertility), and improving overall quality of life. Table 63-2 identifies the agents used to manage anovulatory bleeding and their recommended doses.

General Approach to Treatment

Although the appropriate primary treatment choice for anovulatory bleeding depends on the accurate diagnosis of its cause and identification of desired outcomes, additional treatment may be necessary to manage other signs and symptoms. Treatment to resolve anovulatory bleeding should be initiated and any underlying menorrhagia should be managed.

Nonpharmacologic Therapy

Nonpharmacologic treatment options for anovulatory bleeding depend on the underlying cause. In a woman of reproductive age with PCOS, moderate weight loss of 2% to 5% may result in improved menstrual regularity and ovulatory function, reduced hirsutism, increased insulin sensitivity, and improved response to fertility treatments.21 In women who have completed childbearing or who have not responded to medical management, endometrial ablation or resection and hysterectomy are surgical options. Procedure choice involves shared decision making with the patient. In the short term, ablation results in less morbidity and shorter recovery periods. However, a significant number of women eventually undergo hysterectomy in the subsequent 5 years.29

Pharmacologic Therapy

Estrogen is the recommended treatment for managing acute severe bleeding episodes because it promotes endometrial stabilization.49 Following its initial use to control acute bleeding episodes, therapy continuation may be necessary to prevent future occurrences. OC use fulfills this role and contributes to predictable menstrual cycles.

OCs prevent recurrent anovulatory bleeding by providing a progestin and suppressing ovarian hormones and adrenal androgen production. They also, indirectly, increase sex hormone-binding globulin (SHBG). SHBG binds androgens and reduces their circulating free concentrations. For women with high androgen levels and its related signs such as hirsutism (e.g., those with PCOS) OCs containing less than or equal to 35 mcg of ethinyl estradiol and a progesterone that exhibits minimal androgenic side effects (e.g., norgestimate and desogestrel) or with antiandrogenic effects (e.g., drospirenone) may be desirable.20


CLINICAL PRESENTATION Anovulatory Bleeding

General

    • Patients may or may not be in acute distress

Symptoms

    • Irregular, heavy, or prolonged vaginal bleeding, perimenopausal symptoms (hot flashes, nights sweats, vaginal dryness)

Signs

    • Acne, hirsutism, obesity

Laboratory Tests

    • If PCOS is suspected, consider free or total testosterone, fasting glucose, fasting lipid panel

    • If perimenopause is suspected, measure FSH

    • Thyroid-stimulating hormone

Other Diagnostic Tests

    • If the patient is older than 35 years, endometrial biopsy

    • Pelvic ultrasound to evaluate for polycystic ovaries

    • If perimenopause is suspected, measure FSH


Clinical Controversy…

OCs containing antiandrogenic progesterones are very effective for managing the acne and hirsutism that accompany PCOS; they also suppress ovarian androgen production and increase sex hormone-binding globulin, thus reducing free testosterone concentrations. Controversy regarding their use in PCOS exists secondary to their potential adverse effects on insulin resistance, glucose tolerance, vascular reactivity, and coagulability.20 An increase in high-sensitivity C-reactive protein (a predictor of cardiovascular disease) and an increase in homocysteine levels (indicating an increased risk of cardiovascular disease) have been observed with the use of such OCs.50 Another trial found a reduction in brachial artery flow-mediated dilatation and an increase in carotid intima-media thickness, both indicators of endothelial dysfunction, following therapy with OCs containing ethinyl estradiol and cyproterone acetate.51Additional, longer-term clinical trials will clarify whether the benefits of these agents outweigh the risks. It has been suggested that cardiovascular risk calculators be employed as an adjunct to guidelines suggesting the use of OCs in this patient population.52

In women with contraindication(s) to estrogen or in whom the side effects are unacceptable, progesterone-only products are an option. They should be strongly considered for women experiencing menorrhagia associated with anovulatory bleeding.53 In women with PCOS, depot and intermittent oral MPA provide endometrial protection through endometrial shedding.5 If pregnancy is not a desired outcome of treatment, another progesterone option is placement of a levonorgestrel-containing IUD.29,53

Metformin and the thiazolidinediones, including pioglitazone and rosiglitazone, improve insulin sensitivity. In patients with PCOS, this contributes to reduced circulating androgen concentrations, increased ovulation rates,5,54,55and improved glucose tolerance.5,21 These improvements occur due to the SHBG increase that occurs via increased insulin sensitivity. Images Metformin and thiazolidinedione use for anovulatory bleeding associated with PCOS is beneficial not only for anovulatory bleeding and fertility but also for improving glucose tolerance and other metabolic parameters that contribute to cardiovascular risk.5,21,56 For women desiring pregnancy, metformin is pregnancy category B, and pioglitazone and rosiglitazone are category C.


Clinical Controversy…

The overall role of metformin in treating PCOS and its duration of therapy remain controversial. For ovulation induction, data show that metformin is highly effective in both clomiphene citrate-resistant patients and patients using it as initial therapy.54,55 Its use throughout pregnancy has been associated with a reduction in early pregnancy loss rates.57 The presence of dyslipidemia and hyperinsulinemia increases the long-term risk for developing cardiovascular disease in PCOS patients. Current research indicates that metformin should be considered to reduce cardiovascular risk in these women.56 More research is needed to definitively identify the role(s) of metformin in PCOS, particularly as it relates to ovulation induction.

If the treatment goal is improved fertility via ovulation induction, clomiphene citrate is an option. Treatment with 50 mg/day for 5 days can be initiated between menstrual cycle days 3 and 5. This often occurs after inducing withdrawal bleeding with a progesterone such as MPA 10 mg daily orally for 10 days. If ovulation does not occur with this dose of clomiphene, a dose of 100 mg/day is warranted. In rare instances, it may be increased by 50 mg increments up to 250 mg/day.

Drug Treatments of First Choice

As with many menstruation-related disorders, there is not one universal treatment option of first choice for anovulatory bleeding. Rather, the treatment(s) chosen depends on accurate etiologic diagnosis as well as identification of the desired treatment outcome(s).

OCs are the first-choice treatment in women with anovulatory bleeding who do not desire pregnancy.22 The use of OCs containing ethinyl estradiol and a progesterone with minimal androgenic or antiandrogenic effects is effective for cycle control and minimizing the androgenic signs and symptoms of PCOS.20,47,49

Relative to anovulation in women with PCOS, insulin-sensitizing agents including metformin and the thiazolidinediones improve ovulatory frequency and metabolic parameters. Clomiphene use may further assist in achieving ovulation induction.

More recent data support even further metformin’s use compared to clomiphene for ovulation induction.54,55 Metformin for ovulation induction54 as well as its use throughout pregnancy57 in women with PCOS has been associated with reduced miscarriage rates in this patient population.

Special Populations

Anovulatory cycles are fairly common in the perimenarchal reproductive years. Ovulation typically is established 1 year or more following menarche. Anovulatory bleeding occurring in this population may be excessive. If excessive bleeding occurs, the patient should be evaluated for bleeding disorders. The prevalence of bleeding disorders, including von Willebrand’s disease, prothrombin deficiency, and idiopathic thrombocytopenia purpura, in this population ranges from 5% to 24%.6

If identified, the specific bleeding disorders should be treated. Acute severe bleeding can be managed with high-dose estrogen. OCs containing less than or equal to 35 mcg of ethinyl estradiol is a first-line treatment in adolescents with chronic anovulation.49

Drug Class Information

Table 63-3 identifies the significant pharmacologic properties that require monitoring for the agents used to treat anovulatory bleeding.

Personalized Pharmacotherapy

While not typically an issue among the relatively young population of patients treated with metformin for PCOS, one must be cognizant of the risk of lactic acidosis in metformin users with renal impairment. As such, this drug should be avoided in women with serum creatinine >1.4 mg/dL (124 μmol/L).

Evaluation of Therapeutic Outcomes

Table 63-3 lists the expected outcomes and specific monitoring parameters for the treatment modalities used to manage anovulatory bleeding.

DYSMENORRHEA

Dysmenorrhea is one of the most commonly encountered gynecologic complaints. It is 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. Secondary dysmenorrhea is associated with underlying pelvic pathology.14


CLINICAL PRESENTATION Dysmenorrhea

General

    • Patients may or may not be in acute distress, depending on the level of menstrual pain experienced

Symptoms

    • Patients complain of crampy pelvic pain beginning shortly before or at the onset of menses. Symptoms typically last from 1 to 3 days

Laboratory Tests

    • Pelvic examination should be performed to screen for sexually transmitted diseases as a cause of the pain in sexually active females

    • Gonorrhea, Chlamydia cultures or polymerase chain reaction, wet mount

Other Diagnostic Tests

    • Pelvic ultrasound can be used to identify potential anatomic abnormalities such as masses/lesions or to detect ovarian cysts and endometriomas

Epidemiology

Dysmenorrhea prevalence rates range from 16% to 90%.30,31 Its presence may be associated with significant interference in work and school attendance. Risk factors include young age, heavy menses, nulliparity, early menarche, and cigarette smoking.9,11

Etiology

For most patients, dysmenorrhea is associated with normal ovulatory cycles and normal pelvic anatomy. This is referred to as primary, or functional, dysmenorrhea. However, in approximately 10% of the adolescents and young adults presenting with painful menses, an underlying anatomic or physiologic cause exists.11

Pathophysiology

The most significant mechanism for primary dysmenorrhea is the release of prostaglandins and leukotrienes into the menstrual fluid, initiating an inflammatory response and possibly vasopressin-mediated vasoconstriction.9,11,34Causes of secondary dysmenorrhea include cervical stenosis, endometriosis, pelvic infections, pelvic congestion syndrome, uterine or cervical polyps, uterine fibroids, genital outflow tract obstructions, and pelvic adhesions.11,31Pregnancy and miscarriage must be considered in new onset dysmenorrhea.

TREATMENT

Initial treatment choice is influenced by whether or not the woman desires pregnancy. Nonpharmacologic options have been studied and observed to be as effective as some existing pharmacologic options.

Desired Outcome

Medical management of dysmenorrhea should relieve the pelvic pain and result in reducing lost school and work days. Table 63-2 identifies the agents used to manage dysmenorrhea and their recommended doses. Figure 63-4 shows a treatment algorithm for dysmenorrhea management.

Images

FIGURE 63-4 Treatment algorithm for dysmenorrhea. (IUD, intrauterine device; MPA, medroxyprogesterone acetate; NSAIDs, nonsteroidal antiinflammatory drugs; OC, oral contraceptive.)

General Approach to Treatment

A variety of effective treatment options for dysmenorrhea are available, including nonhormonal and hormonal pharmacologic options and noninvasive nonpharmacologic options. Treatment choice is influenced by the desire for contraception, the patient’s level of sexual activity, potential for adverse effects, and cost.

Nonpharmacologic Therapy

Several nonpharmacologic interventions are used for managing dysmenorrhea. Among these, topical heat therapy, exercise, and a low-fat vegetarian diet have been shown to reduce dysmenorrhea intensity.11,12,14,30 Dietary changes may shorten dysmenorrhea duration. Topical heat application via an abdominal patch is as effective as 400 mg of ibuprofen dosed three times daily.58 Because topical heat, exercise, and dietary changes do not impart systemic effects, they are associated with little to no risk compared to the pharmacologic options. Nonpharmacologic options that are reserved for use following a failed trial of pharmacologic interventions include transcutaneous electric nerve stimulation, acupressure, and acupuncture.14,30

Pharmacologic Therapy

Given the role of prostaglandins in dysmenorrhea pathophysiology, NSAIDs are the initial treatment of choice. These agents do not differ in efficacy. The most commonly used agents are naproxen and ibuprofen.

All NSAIDs have a propensity for causing GI distress and ulceration; their administration with food or milk minimizes these effects. In women who have a history of NSAID-induced gastric effects, the use of celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor, is an alternative.11,15 Choice of one agent over another may be based on cost, convenience, and patient preference.14 Some research suggests that NSAID therapy should begin at the onset of menses or perhaps even the day before and continued around the clock instead of waiting until symptom onset. The data substantiating this are weak.30 If an NSAID or celecoxib use is contraindicated or not desired, hormonal agents should be considered. Acetaminophen is inferior to NSAID in treatment of this disorder.14,30

OCs improve dysmenorrhea by inhibiting endometrial tissue proliferation which reduces endometrial-derived prostaglandins that cause the pelvic pain.11,12,30 Significant improvements in mild, moderate, and severe dysmenorrhea have been noted with OCs. Evidence supporting monophasic versus multiphase OC regimens, however, is lacking. And while the use of extended-cycle OCs would be desirable for this purpose, data illustrating their superiority over traditional monthly OCs do not currently exist.

Depot MPA can be considered for dysmenorrhea treatment. Its efficacy is secondary to its ability to render most patients amenorrheic within 6 to 12 months of use.14,30 Because 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.

Another progesterone product used for dysmenorrhea management is the levonorgestrel-releasing IUD. Observational data indicate its ability to reduce dysmenorrhea from 60% to 29% after 3 years of use.11,14As observed with depot MPA, this reduction likely is secondary to its effect in reducing menstrual flow.

Drug Treatments of First Choice

Several factors influence the choice of first-line treatment for dysmenorrhea. If contraception is desired, then a hormonal option may be considered taking into account cost, adherence issues, and side effects. If contraception is not desired, then NSAID use would be desirable from cost and convenience standpoints. If NSAIDs are not tolerated, celecoxib could be recommended. In patients for whom OCs, NSAIDs, or celecoxib is not an option, topical heat should be considered.

Special Populations

Dysmenorrhea is common in adolescent females. The treatment measures used for adult patients are also appropriate for adolescents. Although NSAIDs, topical heat, and OCs are among the top choices, use of the levonorgestrel IUD is also an option.38

Drug Class Information

Table 63-3 identifies the significant pharmacologic properties requiring monitoring for the agents used to treat dysmenorrhea.

Evaluation of Therapeutic Outcomes

Table 63-3 lists the expected outcomes and specific monitoring parameters for the treatment modalities used in the management of dysmenorrhea.


CLINICAL PRESENTATION PMDD

A summary of the American Psychiatric Association’s criteria for PMDD is as follows1,62:

    • Symptoms are temporally associated with the last week of the luteal phase and remit with onset of menses

    • At least five of the following symptoms are present: markedly depressed mood, marked anxiety, marked affective lability, marked anger or irritability, decreased interest in activities, fatigue, difficulty concentrating, changes in appetite, sleep disturbance, feelings of being overwhelmed, and physical symptoms, such as breast tenderness or bloating

    • One of the symptoms must be markedly depressed mood, anxiety, irritability, or affective lability

    • Symptoms interfere significantly with work and/or social relationships

    • Symptoms are not an exacerbation of another underlying psychiatric disorder

    • The criteria are confirmed prospectively by daily ratings over two menstrual cycles

PREMENSTRUAL SYNDROME AND PREMENSTRUAL DYSPHORIC DISORDER

PMS is a constellation of symptoms including mild mood disturbances and physical symptoms occurring prior to menses and resolving with menses initiation. It is distinct from PMDD.

Epidemiology

Up to 75% of menstruating women experience PMS symptoms.59 However, a spectrum of premenstrual mood disturbances exists, and PMDD is the most severe. Approximately 3% to 8% of women have PMDD.5961

Etiology and Pathophysiology

PMDD is a complex psychiatric disorder with multiple biological, psychological, and sociocultural determinants.62 Although cyclic hormonal changes are in some way related to PMS and PMDD, the association is neither linear nor simple. When ovulation is suppressed medically or surgically, symptoms improve. Some evidence suggests that PMS and PMDD symptoms are related to low levels of the centrally active progesterone metabolite allopregnanolone in the luteal phase and/or lower cortical γ-aminobutyric acid levels in the follicular phase.62 A number of studies suggest a link between PMS and PMDD and low serotonin levels.62 Despite similar affective symptoms, hypothalamic–pituitary–adrenal (HPA) axis function in PMS and PMDD is distinct from that seen in major depressive disorder. Specifically, women with PMS show a decrease in stimulated HPA axis response, whereas this response is increased in women with major depressive disorder.63 Although several cross-cultural studies suggest that PMS physical symptoms are consistent across cultures, the negative affective symptoms are part of the negative “menstrual socialization” in western culture.1,62

TREATMENT

Women experiencing PMS and PMDD symptoms miss significantly more work and school than do controls. They also report significant impairment of their ability to participate in social activities and hobbies and in their relationships with others.61 Given this, the need for effective treatment modalities is clear.

Desired Outcome

PMS and PMDD interventions should alleviate the presenting symptoms and subsequently improve quality of life. Table 63-2 lists the various agents used in the managing PMS and PMDD and their recommended dosing.

General Approach to Treatment

A treatment modality that is minimally invasive or without systemic effects is desired for initial therapy. Key to the successful choice of pharmacologic therapy for PMS and PMDD is having the patient chart her specific symptoms for at least 2 months.

Nonpharmacologic Therapy

Lifestyle interventions should be started and followed for 2 months while the patient charts her symptoms. Although these interventions lack significant supporting clinical trial data, anecdotal reports of efficacy exist. Some lifestyle changes for women with mild-to-moderate premenstrual symptoms include minimizing intake of caffeine, refined sugar, and sodium and increasing exercise.22,59,64 Vitamin and mineral supplements, such as vitamin B6 (50–100 mg daily) and calcium carbonate (1,200 mg daily), may help reduce the physical symptoms associated with PMS.22,60 A clinical trial review concludes that the following options lack efficacy and safety data and should not be recommended: herbal medicines, homeopathic remedies, dietary supplements, relaxation, massage therapy, reflexology, chiropractic treatments, and biofeedback.65,66

Pharmacologic Therapy

If symptoms persist after 2 months of symptom charting and lifestyle modifications, pharmacologic therapy for PMDD management is warranted. Over the past decade, the selective serotonin reuptake inhibitors (SSRIs) have been studied significantly for this disorder.24,6769 Studies have revealed very positive results relative to most symptoms associated with PMDD. Other agents that have been studied and are alternatives include the selective serotonin–norepinephrine reuptake inhibitor venlafaxine, as well as OCs, tricyclic antidepressants, and GnRH agonists.

Drug Treatments of First Choice

Images The first-line pharmacologic treatment options for PMDD are the SSRIs.22,59 Among this class of agents, data support the use of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. Whether to dose these agents continuously or only during the luteal phase67 and the optimal duration of treatment70 are still not evident. The use of paroxetine, in particular, may be questioned, as this agent has been associated with an increased risk of congenital abnormalities when taken during the first trimester of pregnancy.22 Paroxetine is pregnancy category D; its use should be avoided in women of childbearing age who do not use a reliable form of contraception.


Clinical Controversy…

Current evidence supports SSRIs as first-line PMDD treatment, either dosed continuously or during the luteal phase alone. Some evidence suggests that SSRI dosing at symptom onset also may be effective.71The bulk of studies include women over age 18 and with treatment durations not longer than 3 to 6 months.59 Contrary to the excitement surrounding luteal phase dosing, a meta-analysis found in favor of the continuous dosing regimen for efficacy.69Relapse rates appear to be higher with shorter-duration treatment (4 months vs. 12 months).70 The most effective dosing strategy67 (continuous, luteal phase, or symptom onset), most efficacious treatments in the adolescent versus perimenopausal populations, and the optimal treatment duration70 are not evident at this time and warrant further investigation.

The SSRIs are efficacious in more than half of the treated patients compared to less than 30% of those receiving placebo.22,68,71 A meta-analysis reports 50% or greater symptom reduction with SSRI treatment compared to baseline.69 Improvement often occurs during the first cycle of use.22

Alternative Drug Treatments

The serotonin–norepinephrine reuptake inhibitor (SNRI), venlafaxine, has been studied dosed on a continuous daily basis22,72 and dosed during the luteal phase only.73 Both regimens resulted in significant symptom improvement (compared to placebo) in more than 60% of treated women.

The use of a monophasic OC containing 20 mcg of ethinyl estradiol and 3 mg of drospirenone, a progesterone with antiandrogenic effects, improves premenstrual symptoms in women with PMDD.23 The continuous cycle OC regimen delivering 90 mcg of levonorgestrel and 20 mcg of ethinyl estradiol daily has also been studied in controlled trials resulting in a 30% to 59% improvement in symptoms.74 As with the SSRI and SNRI agents, optimal treatment duration is unknown, and superiority of one OC relative to another OC has not been established.

If treatment with the above options is unsuccessful, hormonal treatment with a GnRH agonist, such as leuprolide, can be considered.22 Leuprolide improves premenstrual emotional symptoms as well as some physical symptoms, such as bloating and breast tenderness. However, its cost, the need for intramuscular administration, and its hypoestrogenism side effects (e.g., vaginal dryness, hot flashes, and bone demineralization) severely limit its use.

Drug Class Information

Table 63-3 lists the significant pharmacologic properties that require monitoring for the agents used to treat PMDD.

Personalized Pharmacotherapy

It is important that concomitant drug therapy of women prescribed any of the SSRIs or venlafaxine be evaluated closely for pharmacokinetic drug–drug interactions given the interface of these drugs with cytochrome P450 isoenzyme systems.

Evaluation of Therapeutic Outcomes

Table 63-3 lists the expected outcomes and specific monitoring parameters for the treatment modalities used in PMDD management.

ABBREVIATIONS

Images

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