Gynecological Disorders - Pharmacotherapy
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This document summarizes several common gynecological disorders: amenorrhea, heavy menstrual bleeding, dysmenorrhea, and polycystic ovarian syndrome (PCOS). It describes the definition, epidemiology, etiology, clinical presentation, diagnostic workup, and treatment approaches for each condition. The disorders covered have a variety of potential causes ranging from structural issues to metabolic/hormonal imbalances. Evaluation involves medical history, physical exam, and targeted lab tests and imaging. Management incorporates lifestyle modifications, medications, and sometimes surgery depending on the underlying pathology.
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Gynecological Disorders - Pharmacotherapy
- 2. AMENORRHEA • Types: 1. Primary amenorrhea 2. Secondary amenorrhea
- 3. Epidemiology • Incidence: – Primary amenorrhea ≤ 0.1%. – Secondary amenorrhea 3-4%.
- 5. CLINICAL PRESENTATION • Symptoms – cessation of menses, infertility, vaginal dryness, or decreased libido. • Signs – Cessation of menses – Recent significant weight loss or weight gain. – Presence of acne, hirsutism, hair loss, or acanthosis nigrans may suggest androgen excess.
- 6. • Labs – Pregnancy test – Serum FSH and LH – Thyroid-stimulating hormone – Prolactin – Tests for PCOS if suspected. • Others – Progesterone challenge. – Pelvic ultrasound. diagnosis
- 7. TREATMENT • Nonpharmacologic Therapy: – Amenorrhea secondary to anorexia weight gain. – Excessive exercise reduction of exercise quantity and intensity. – functional hypothalamic amenorrhea (FHA) Cognitive behavioral therapy
- 10. • Definition: – menstrual blood loss greater than 80 mL per cycle or menstrual bleeding lasting greater than 7 days per cycle.
- 11. Epidemiology • Incidence: – In general: 20% to 30% – von Willebrand disease: 100% – platelet dysfunction: 98%. • 12% to 15% of referrals to gynecologists.
- 12. Etiology • 50% unknown • 20% Bleeding disorders including von Willebrand disease, symptomatic hemophilia, platelet dysfunction, and Factory VII and XI deficiencies • Hypothyroidism • Uterine causes: fibroids (40%), adenomyosis, endometrial polyps and gynecologic cancer.
- 13. CLINICAL PRESENTATION • Symptoms – heavy/prolonged menstrual flow. • Signs • Fatigue, lightheadedness, orthostasis, tachycardia, and pallor
- 14. Laboratory Tests • CBC and ferritin levels • PT, APTT, INR, von Willebrand factor antigen and Factor VIII. • Others: – Pelvic ultrasound – Pelvic MRI – Papanicolaou (Pap) smear – Endometrial biopsy – Hysteroscopy – Sonohysterogram
- 15. Treatment • Nonpharmacologic Therapy – surgical procedures • conservative endometrial ablation • hysterectomy
- 17. DYSMENORRHEA
- 18. Definition • Crampy pelvic pain occurring with or just prior to menses.
- 19. Epidemiology • Prevalence rates: 16% - 90% • Risk factors: – menarche before the age of 12 years, current age less than 30 years, heavy menses, nulliparity, low body mass index, and a history of sexual abuse
- 20. Etiology & pathophysiology • Primary and Secondary dysmenorrhea.
- 21. CLINICAL PRESENTATIOND • Symptoms: – crampy pelvic pain beginning shortly before or at the onset of menses, and lasts from 8 to 72 hours. – Low back pain – Headache – Diarrhea – Fatigue – Nausea and vomiting.
- 22. • Laboratory Tests – Pelvic examination, Gonorrhea, Chlamydia cultures or polymerase chain reaction, wet mount. • Others: – Transvaginal/pelvic ultrasound.
- 23. Nonpharmacologic Therapy 1. Topical heat therapy 2. Exercise 3. low-fat vegetarian diet 4. powdered ginger (250 mg by mouth every 6 hours • If pharmacologic interventions failedtranscutaneous electric nerve stimulation, acupressure, and acupuncture.
- 25. polycystic ovarian syndrome (PCOS) • major features: menstrual dysfunction, anovulation, and signs of hyperandrogenism.
- 26. Etiology • abnormalities in the metabolism of androgens and estrogen and in the control of androgen production.
- 27. Labs • HDL, cholesterol, and triglycerides. • Hyperinsulinemia • High androgens level • Low or normal FSH levels • Elevated LH levels • The LH-to-FSH ratio >3
- 28. Clinical presentation • Menstrual disorders • Hyperandrogenisim • Hirsutism • Infertility • Obesity and metabolic syndrome • Diabetes • Sleep apnea
- 29. Diagnosis criteria • At least 2 of the following 3 criteria – Oligo-ovulation or anovulation – Clinical/biochemical evidence of hyperandrogenism – Polycystic ovaries on ultrasonograms (>12 small antral follicles in an ovary)
- 30. Treatment • Non-pharmacological treatment: – weight reduction – increased exercise – dietary modifications.
- 31. Pharmacological treatment: -For menstrual abnormalities and hirsutism/acne, hormonal contraceptives are first-line treatment. – For infertility, clomiphene is first-line treatment. – If symptoms such as hirsutism are not sufficiently alleviated, an androgen-blocking agent may be added.
- 32. • For metabolic/glycemic abnormalities and for improving menstrual irregularities, metformin is beneficial. • Metformin is of limited or no benefit for managing hirsutism, acne, or infertility.
- 33. Surgery • Electrocautery • laser drilling • multiple biopsy
Editor's Notes
- Primary amenorrhea: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: the absence of menses for 6 months in a previously menstruating woman
- Secondary amenorrhea: more frequently in women younger than 25 years with a history of menstrual irregularities and in those involved in competitive athletics.
- Etiology: While a urine pregnancy test should be one of the first steps in evaluating amenorrhea, the majority of primary amenorrhea cases can be attributed to either anomalies of the gonads or outflow tract or anomalies of the hypothalamic–pituitary axis.1 Similarly, greater than 50% of secondary amenorrhea cases are due to the impact of disturbances of the hypothalamic–pituitary–adrenal axis or the hypothalamic–pituitary–ovarian axis.3 Specifically, hypothalamic suppression, chronic anovulation, hyperprolactinemia, ovarian failure, and uterine disorders.4 Therefore, 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. Patho: Uterus/Outflow Tract For menstruation to occur, a uterus, functional endometrium, and patent vagina must be present. Several anatomic abnormalities may cause amenorrhea.1 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 the proper sequence to influence endometrial growth and shedding 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. 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. Further, recent research has confirmed the role of leptin insufficiency in causing hypogonadotropic hypogonadism leading to hypothalamic amenorrhea.
- 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.
- Progesterone challenge to confirm functional anatomy and adequate estrogenization. Pelvic ultrasound to evaluate for polycystic ovaries, presence/absence of uterus, and/or structural abnormalities of the reproductive tract organs.
- General Approach to Treatment ++The overall success of any intervention to treat amenorrhea depends on proper identification of the disorder’s underlying cause(s) Nonpharmacologic Therapy: ++Depends on the underlying cause.
- ++For patients experiencing amenorrhea secondary to hypoestrogenic states, a diet rich in calcium and vitamin D is essential to minimize any negative impact on bone health. +++When hyperprolactinemia is the cause of amenorrhea, dopamine agonists such as bromocriptine and cabergoline aid in reducing prolactin concentrations and the resumption of menses. Bromocriptine normalizes prolactin levels in 58% of affected women while cabergoline has the same effect in 85%.16 ++Amenorrhea related to PCOS-induced anovulation may respond to agents that reduce insulin resistance. Metformin for this purpose is discussed in the “abnormal uterine bleeding” section. ++Progestins induce withdrawal bleeding in women with secondary amenorrhea, and several factors predict progesterone’s efficacy for this purpose.14 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.14 Table 80-2 identifies the types and doses of progestins used for secondary amenorrhea treatment. Figure 80-2 illustrates when to consider progestin use for amenorrhea treatment. Special Populations ++Amenorrhea in the adolescent population is of concern because developmentally this is the time when peak bone mass is achieved. The cause of amenorrhea, whether primary or secondary, must be promptly identified, 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.
- This definition has been questioned because of difficulty quantifying menstrual loss in clinical practice. Additionally, many women with “heavy menses” but whose blood loss is less than 80 mL merit treatment consideration because of flow containment issues, unpredictably heavy flow days, or other associated symptoms.19,37 More recently, diagnosis has also been considered based upon the impact of HMB on quality of life and social, professional, familial or sexual roles.
- R/O: Pregnancy, including intrauterine pregnancy, ectopic pregnancy, and miscarriage Uterine causes of HMB are more common in older childbearing women
- CBC and ferritin levels; hemoglobin and hematocrit results may be low. PT, APTT, INR, von Willebrand factor antigen and Factor VIII. To R/O coagulation disorders Papanicolaou (Pap) smear for cervical CA Hysteroscopy : polyps, fibroids, abnormal growth Sonohysterogram: special kind of US (use fluid more detailed)
- +Several treatment options exist for HMB. Initial and subsequent treatment options should be thoughtfully chosen in an effort to avoid surgery. ++surgical procedures that are generally reserved for patients not responding to pharmacologic treatment. These interventions vary from conservative endometrial ablation to hysterectomy
- ++(NSAIDs) have the advantage of administration only during menses and are associated with a 10% to 51% reduction in blood loss34 For women desiring to avoid pregnancy, hormonal contraception (HC) use is beneficial for HMB and should be considered as a 40% to 50% reduction in menstrual blood loss has been observed with cyclic combined HCs ++The best studied HC option for HMB, and the only OC approved by the FDA for the indication of HMB is the four-phasic formulation containing estradiol valerate and dienogest. +++Another HMB treatment option is the levonorgestrel-releasing intrauterine system (LNG-IUS). This is the most effective treatment to reduce menstrual flow.23,34,40 In particular, a 79% to 97% reduction in blood loss has been observed with its use,40 and its use has also resulted in postponing or cancelling scheduled endometrial ablation surgery or hysterectomy. Among women using this treatment option, only 9% eventually opted for surgery.34 Further, its therapeutic efficacy is similar to endometrial ablation up to 2 years following treatment +++Cyclic progesterone therapy for 21 days, starting on day 5 after onset of menses, results in a 37% to 87% reduction in menstrual blood loss.28 While progesterone use provides no benefit in efficacy over other medical treatments,28 its use may be considered in women with contraindications to estrogen.34 ++Tranexamic acid was recently approved in the United States for primary HMB treatment. Its use is associated with a significant 34% to 60% reduction in menstrual blood loss.28,41 Compared to many of the other options, its use may be preferable among women desiring pregnancy or in whom hormonal therapy may not be appropriate. +++Clinical trial data illustrate a higher failure rate with the OCs (32%) compared to the LNG-IUS (11%) as the primary treatment method.28 When compared to other conventional medical therapies used for HMB, the levonorgestrel intrauterine system is associated with a 61% lower discontinuation rate and 82% fewer treatment failures. +++Alternative Drug Treatments For women who have HMB 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. 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 which has been associated with a significant improvement in quality of life and high patient satisfaction following three cycles of use. ++Special Populations Although historically it was believed that IUD use should be avoided in nulliparous women, 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.40 Therefore, any of the treatments discussed (including the LNG IUS) are options in any female presenting with HMB. +++++++++++++++++++Dosage adjustment of tranexamic acid SCr 1.4 - 2.8 mg/dL: 1,300 mg PO BID SCr 2.9 - 5.7 mg/dL: 1,300 mg PO QD SCr >5.7 mg/dL 650 mg PO QD
- its presence may be associated with significant interference in work and school attendance. In addition, significant reductions in quality of life and lower overall life satisfaction and contentment ratings have been observed in women with dysmenorrhea compared to controls.
- Primary dysmenorrhea implies pain in the setting of normal pelvic anatomy and physiology.56 Secondary dysmenorrhea is associated with underlying pelvic pathology.5 secondary dysmenorrhea associated with pelvic pathology should be suspected in women over 30 years of age without a history of dysmenorrhea +++primary dysmenorrhea: Release of prostaglandins and leukotrienes into the menstrual fluid, initiating an inflammatory response and possibly vasopressin-mediated vasoconstriction. secondary dysmenorrhea causes: endometriosis, current or history of pelvic inflammatory disease, uterine fibroids, and adenomyosis leiomyomata.
- ++Pelvic examination should be performed to screen for sexually transmitted diseases and/or pelvic inflammatory disease as a cause of the pain in sexually active females. +++Transvaginal/pelvic ultrasound can be used to identify potential anatomic abnormalities such as masses/lesions or to detect ovarian cysts and endometriomas.
- 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.57,58,60 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.60,61 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. Recent data is suggestive of the benefits of powdered ginger (250 mg by mouth every 6 hours) in significantly reducing the pain associated with dysmenorrhea when begun at the onset of menses.62,63 Nonpharmacologic options that are reserved for use following a failed trial of pharmacologic interventions include transcutaneous electric nerve stimulation, acupressure, and acupuncture.
- ----Treatment choice is influenced by the desire for contraception, the patient’s level of sexual activity, potential for adverse effects, and cost. ----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.19,20 Choice of one agent over another may be based on cost, convenience, and patient preference. 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.58 Acetaminophen is inferior to NSAID in treatment of this disorder.58 If an NSAID or celecoxib use is contraindicated or not desired, hormonal agents should be considered. +++Hormonal contraceptives improve dysmenorrhea by inhibiting endometrial tissue proliferation which reduces endometrial-derived prostaglandins that cause the pelvic pain.8,58 Significant improvements in mild, moderate, and severe dysmenorrhea have been noted with HCs. 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. ++++Long-acting progesterones, such as depot MPA and the LNG-IUS, can be considered for dysmenorrhea treatment. Their efficacy is secondary to their ability to render most patients amenorrheic within 6 to 12 months of use.8,58 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. +++++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.
- Symptoms occur as a result of high androgens level
- High serum concentrations of androgenic hormones, such as testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S), may be encountered in these patients. However, individual variation is considerable, and a particular patient might have normal androgen levels. ++Mean platelet volume (MPV) is a marker associated with adverse cardiovascular events, and women with newly diagnosed PCOS appear to have significantly elevated MPV levels.
- . Menstrual disorders Some women have oligomenorrhea (ie, menstrual bleeding that occurs at intervals of 35 days to 6 months, with < 9 menstrual periods per year) or secondary amenorrhea (an absence of menstruation for 6 months). . Hyperandrogenism clinically manifests as excess terminal body hair in a male distribution pattern. Hair is commonly seen on the upper lip, on the chin, around the nipples, and along the linea alba of the lower abdomen. Some patients have acne and/or male-pattern hair loss (androgenic alopecia). Other signs of hyperandrogenism (eg, clitoromegaly, increased muscle mass, voice deepening) are more characteristic of an extreme form of PCOS termed hyperthecosis. . Infertility A subset of women with PCOS is infertile. Most women with PCOS ovulate intermittently. Conception may take longer than in other women, or women with PCOS may have fewer children than they had planned. In addition, the rate of miscarriage is also higher in affected women
- This diet emphasizes increased fiber; decreased refined carbohydrates, trans fats, and saturated fats; and increased omega-3 and omega-9 fatty acids.
- ++++clomiphene citrate as first-line therapy to stimulate ovulation when fertility is desired. [2, 3, 5] An alternative first line therapy to stimulate ovulation is letrozole. [54] Second-line therapy, when clomiphene citrate fails to lead to pregnancy, is either exogenous gonadotropins or laparoscopic ovarian surgery ++++++++Women who do not wish to become pregnant can be effectively treated for hirsutism with oral contraceptives. [77] Oral contraceptives slow hair growth in 60-100% of women with hyperandrogenemia. Therapy can be started with a preparation that has a low dose of estrogen and a nonandrogenic progestin. Preparations that have norgestrel and levonorgestrel should be avoided because of their androgenic activity
- , have been used with the goal of creating focal areas of damage in the ovarian cortex and stroma