Therapeutics II.pdf

‫لجنة عمداء ل ات الص دلة‬ ‫لجنة توح د منهاج مادة )‪(Therapeutics II‬‬ ‫‪Therapeutics II‬‬ ‫المرحلة الخامسة‬ ‫‪2024‬‬ ‫‪1‬‬  ‫ل ل ات الص دلة للعام الدرا‬ ‫تم اعداد ومراجعة هذا المنهج الموحد لﻼمتحان التق‬ ‫‪.‬‬ ‫التدر س والعمل اﻻ اد‬ ‫لديهم خ ة...

‫لجنة عمداء ل ات الص دلة‬ ‫لجنة توح د منهاج مادة )‪(Therapeutics II‬‬ ‫‪Therapeutics II‬‬ ‫المرحلة الخامسة‬ ‫‪2024‬‬ ‫‪1‬‬  ‫ل ل ات الص دلة للعام الدرا‬ ‫تم اعداد ومراجعة هذا المنهج الموحد لﻼمتحان التق‬ ‫‪.‬‬ ‫التدر س والعمل اﻻ اد‬ ‫لديهم خ ة كب ة‬ ‫‪ 2024-2023‬من ق ل اساتذة متخصص‬ ‫جمع المعلومات وحرصوا ع ترت بها وتنظ مها لتكون‬ ‫لقد ذل اﻻساتذة قصارى جهودهم‬ ‫ط قهم ا‬ ‫طلب نا اﻻعزاء ‪..‬نأمل من طلب نا اﻻعزاء اﻻستفادة منه‬ ‫واضحة س ة ع‬ ‫النجاح والتفوق ‪ ،‬وﷲ الموفق‬ ‫‪2‬‬  Adrenal Gland Disorders INTRODUCTION  Hyperfunction of the adrenal glands involves excess production of the adrenal hormones cortisol (resulting in Cushing syndrome) or aldosterone (resulting in hyperaldosteronism).  Adrenal gland hypofunction is associated with primary (Addison disease) or secondary adrenal insufficiency. CUSHING SYNDROME: PATHOPHYSIOLOGY  Cushing syndrome results from effects of supraphysiologic glucocorticoid concentrations originating from either exogenous administration or endogenous overproduction by the adrenal gland (adrenocorticotropic hormone [ACTH] dependent) or by abnormal adrenocortical tissues (ACTH independent).  ACTH dependent Cushing syndrome (80%of all Cushing syndrome cases) is usually caused by overproduction of ACTH by the pituitary gland, causing bilateral adrenal hyperplasia. Pituitary adenomas account for about 85% of these cases (Cushing disease). Ectopic ACTH secreting tumors and nonneoplastic corticotropin hypersecretion cause the remaining 20% of ACTH dependent cases.  Ectopic ACTH syndrome refers to excessive ACTH production resulting from an endocrine or nonendocrine tumor, usually of the pancreas, thyroid, or lung (eg, small cell lung cancer).  ACTH-independent Cushing syndrome is usually caused by adrenal adenomas and carcinomas. CLINICAL PRESENTATION  The most common findings in Cushing syndrome are central obesity and facial rounding (90% of patients). Peripheral obesity and fat accumulation occur in 50% of patients. Fat accumulation in the dorsocervical area (buffalo hump) is nonspecific, but increased supraclavicular fat pads are more specific for Cushing syndrome. Patients are often described as having moon facies and a buffalo hump.  Other findings may include myopathy or muscular weakness, abdominal striae, hypertension, glucose intolerance, psychiatric changes, gonadal dysfunction, facial plethora (reddish complexion), and amenorrhea and hirsutism in women.  Up to 60% of patients develop Cushing induced osteoporosis; about 40% present with back pain, and 20% progress to spinal compression fractures. 3 DIAGNOSIS  Hypercortisolism can be established with one or more of the following tests: 24 hour urinary free cortisol (UFC), midnight plasma cortisol, late night (11 PM) salivary cortisol, and/or low dose dexamethasone suppression test (DST).  Other tests to determine etiology are plasma ACTH; adrenal vein catheterization; metyrapone stimulation test; adrenal, chest, or abdominal computed tomography (CT); corticotropin releasing hormone (CRH) stimulation test; inferior petrosal sinus sampling; and pituitary magnetic resonance imaging (MRI).  Adrenal nodules and masses are identified using high resolution CT scanning or MRI. TREATMENT  Goals of Treatment: Limit morbidity and mortality and return the patient to a normal functional state by removing the source of hypercortisolism while minimizing pituitary or adrenal deficiencies.  Treatment plans in Cushing syndrome based on etiology: Table1: Treatment Options in Cushing Syndrome Based on Etiology Etiology Nondrug Drug Name Dosing Initial Dose Usual Range Maximum Ectopic Surgery, chemotherapy, Metyrapone 1–2 g/day, 6 g/day Metyrapone ACTH divided syndrome irradiation 250-mg 250-mg capsules every 4–6 hours capsules Ketoconazole 200–1200 1600 mg/day Ketoconazole 200-mg tablets divided four 200-mg tablets mg/day, divided Pituitary dependent Surgery, Mitotane 500- 0.5–1 g/day, 1–4 g daily, 12 g/day irradiation mgtablets increased with food to decrease GI by 0.5–1 g/day effects every 1–4 weeks Metyrapone See above See above See above Mifepristone 300 mg once 600–1200 1200 mg/day 300-mg tablets daily,increased by 300mg/day every mg/day or 20 2–4 mg/kg/day Cabergoline 0.5- 0.5 mg once 0.5–7 mg once 7 mg/week mg tablets weekly weekly Pasireotide 0.3-, 0.6–0.9 mg twice 0.3–0.9 mg twice 1.8 mg/day 0.6-, and 0.9- daily daily mg/mLsolution Adrenal adenoma Surgery, Ketoconazole See above See above See above postoperative replacement Adrenal carcinoma Surgery Mitotane See above See above See above a 4 Nonpharmacologic Therapy  Treatment of choice for both ACTH dependent and ACTH independent Cushing syndrome is surgical resection of offending tumors.  Transsphenoidal resection of the pituitary tumor is the treatment of choice for Cushing disease. Radiotherapy may be preferred for tumors invading the dura or cavernous sinus and provides clinical improvement in ∼50% of patients within 3– 5 years but increases the risk for pituitary dependent hormone deficiencies (hypopituitarism  Laparoscopic adrenalectomy is often preferred for unilateral adrenal adenomas or when transsphenoidal surgery and pituitary radiotherapy have failed or cannot be used. Pharmacologic Therapy  Pharmacotherapy is generally used as second line treatment in patients who are not surgical candidates and may also be used preoperatively or as adjunctive therapy in postoperative patients awaiting response Rarely, monotherapy is used as a palliative treatment when surgery is not indicated. Steroidogenesis Inhibitors Metyrapone inhibits 11 β hydroxylase, thereby inhibiting cortisol synthesis. After administration, a sudden decrease in cortisol concentration prompts a compensatory rise in plasma ACTH levels. With cortisol synthesis blocked, adrenal steroidogenesis shunts toward androgen production, resulting in androgenic side effects such as acne and hirsutism. Inhibition of aldosterone synthesis can result in natriuresis and blood pressure changes. Nausea, vomiting, vertigo, headache, dizziness, abdominal discomfort, and allergic rash have been reported after oral administration. Ketoconazole inhibits cytochrome P 450 enzymes, including 11 β hydroxylase and 17 α hydroxylase. It is effective in lowering serum cortisol levels after several weeks of therapy. It also has antiandrogenic activity, which may be beneficial in women but can cause gynecomastia and hypogonadism in men. The most common adverse effects are reversible elevation of hepatic transaminases, GI discomfort, and dermatologic reactions. Because of the risk of severe hepatotoxicity, monitoring should include liver function tests at baseline followed by weekly monitoring of serum ALT throughout therapy. Ketoconazole may be used concomitantly with metyrapone to achieve synergistic reduction in cortisol levels; in addition, ketoconazole’s antiandrogenic actions may offset the androgenic potential of metyrapone. Etomidate is an imidazole derivative similar to ketoconazole that inhibits 11 β hydroxylase and may have other mechanisms. Because it is only available in a parenteral formulation, use is limited to patients with acute hypercortisolemia requiring emergency treatment or in preparation for surgery. Frequent monitoring of serum cortisol is advised to prevent hypocortisolemia. Side effects include sedation, injection site pain, hypotension, myoclonus, nausea, and vomiting. 5 Osilodrostat (Itsurisa) prevents cortisol synthesis via inhibition of 11β hydroxylase and is indicated for patients with Cushing disease who are either not candidates for surgery or in whom symptoms persist after surgery. Osilodrostat is available as an oral tablet taken twice daily, with or without food. Hypokalemia and hypomagnesemia should be corrected prior to use, and an ECG should be obtained at baseline and again one week after treatment initiation to monitor possible QTc prolongation. Adverse effects are similar to other 11β hydroxylase inhibitors, including hypocortisolism, QTc prolongation, nausea, and headache. Adrenolytic Agents Mitotane is a cytotoxic drug that inhibits the 11hydroxylation of 11-deoxycortisol and 11desoxycorticosterone in the adrenal cortex, reducing synthesis of cortisol and corticosterone. Similar to ketoconazole, mitotane takes weeks to months to exert beneficial effects. Sustained cortisol suppression occurs in most patients and may persist after drug discontinuation in up to one third of patients. Mitotane degenerates’ cells within the zona fasciculata and reticularis, resulting in atrophy of the adrenal cortex; the zona glomerulosa is minimally affected during acute therapy but can be damaged during long term treatment. Mitotane can cause significant neurologic and GI side effects, and patients shouldbe monitored carefully or hospitalized when initiating therapy. Nausea and diarrhea are common at doses greater than 2 g/day and can be avoided by gradually increasing the dose and/or administering it with food. Lethargy, somnolence, and other CNS effects are also common. Reversible hypercholesterolemia and prolonged bleeding times can occur. Neuromodulators of ACTH Release Pituitary secretion of ACTH is normally mediated by neurotransmitters such as serotonin, γ aminobutyric acid (GABA), acetylcholine, and catecholamines. Although ACTH secreting pituitary tumors (Cushing disease) self-regulate ACTH production to some degree, these neurotransmitters can still promote pituitary ACTH production. Consequently, agents that target these transmitters have been proposed for treatment of Cushing disease, including cyproheptadine, bromocriptine, cabergoline, valproic acid, octreotide, lanreotide, pasireotide, rosiglitazone, and tretinoin. With the exception of pasireotide, none of these drugs have demonstrated consistent clinical efficacy for treating Cushing disease. Cyproheptadine, a nonselective serotonin receptor antagonist and anticholinergic drug, can decrease ACTH secretion in some patients with Cushing disease. However, side effects such as sedation and weight gain significantly limit its use. Pasireotide (Signifor) is a somatostatin analog that binds and activates somatostatin receptors, thereby inhibiting ACTH secretion, leading to decreased cortisol secretion. It is approved for treatment of adults with Cushing disease for whom pituitary surgery is not an option or has not been curative. Side effects include nausea, diarrhea, cholelithiasis, increased hepatic transaminases, hyperglycemia, sinus bradycardia, and QT prolongation. 6 Glucocorticoid Receptor Blocking Agents Mifepristone (Korlym) is a progesterone and glucocorticoid receptor antagonist that inhibits dexamethasone suppression and increases endogenous cortisol and ACTH levels in normal subjects. Evidence suggests that mifepristone is highly effective in reversing the manifestations of hypercortisolism (hyperglycemia, hypertension, and weight gain). It is FDA approved for treatment of endogenous Cushing syndrome in patients who have type 2 diabetes or glucose intolerance and who are not eligible for, or have had poor response to, surgery. Common adverse effects include fatigue, nausea, headache, arthralgia, peripheral edema, endometrial hyperplasia, and hypokalemia. EVALUATION OF THERAPEUTIC OUTCOMES Close monitoring of 24-hour UFC and serum cortisol is essential to identify adrenal insufficiency in patients with Cushing syndrome. Monitor steroid secretion with all drug therapy (except mifepristone) and give corticosteroid replacement if needed. HYPERALDOSTERONISM: PATHOPHYSIOLOGY  Hyperaldosteronism involves excess aldosterone secretion and is categorized as either primary (stimulus arising from within the adrenal gland) or secondary (stimulus from extra adrenal etiologies).  Primary hyperaldosteronism (PA) is usually caused by bilateral adrenal hyperplasia and aldosterone producing adenoma (Conn syndrome). Rare causes include unilateral (primary) adrenal hyperplasia, adrenal cortex carcinoma, renin responsive adrenocortical adenoma, and three forms of familial hyperaldosteronism (FH): Type I (glucocorticoid remediable aldosteronism); Type II (familial occurrence of adenoma or hyperplasia type II); and Type III.  Secondary hyperaldosteronism results from excessive stimulation of the zona glomerulosa by an extra adrenal factor, usually the renin– angiotensin system. Elevated aldosterone secretion can result from excessive potassium intake, oral contraceptives, pregnancy, and menses. Heart failure, cirrhosis, renal artery stenosis, and Bartter syndrome also can lead to elevated aldosterone concentrations. CLINICAL PRESENTATION  Patients may complain of muscle weakness, fatigue, paresthesias, headache, polydipsia, and nocturnal polyuria.  Signs may include hypertension, tetany/paralysis, and olydipsia/nocturnal polyuria.  A plasma aldosterone concentration to plasma renin activity (PAC to PRA) ratio or aldosterone to renin ratio (ARR) >30 ng/dL per ng/(mL·h) (830 pmol/L per mcg/(L·h) and a PAC >15 ng/dL (420 pmol/L) is suggestive of PA. Other laboratory findings include suppressed renin activity, elevated plasma aldosterone, hypernatremia (>142 mEq/L), hypokalemia, hypomagnesemia, elevated serum bicarbonate (>31 mEq/L), and glucose intolerance. 7 DIAGNOSIS  Initial diagnosis is made by screening patients with suspected PA. Any patient with a blood pressure >150/100 mm Hg measured on three separate days, and those meeting the criteria for treatment resistant hypertension should be screened. Additional patients at risk for PA include those with diuretic induced hypokalemia, hypertension and adrenal incidentaloma, hypertension and sleep apnea, hypertension and a family history of early onset hypertension or cerebrovascular accident at an age 39.4°C [103°F]), tachycardia, tachypnea, dehydration, delirium, coma, nausea, vomiting, and diarrhea. Precipitating factors include infection, trauma, surgery, radioactive iodine (RAI) treatment, and withdrawal from antithyroid drugs. DIAGNOSIS  Elevated 24 hour radioactive iodine uptake (RAIU) indicates true hyperthyroidism: the patient’s thyroid gland is overproducing T4, T3, or both (normal RAIU 10%–30%). A low RAIU indicates that excess thyroid hormone is not a consequence of thyroid gland hyperfunction but is likely caused by thyroiditis, struma ovarii, follicular cancer, or exogenous thyroid hormone ingestion.  In thyrotoxic Graves’ disease, there is an increase in the overall hormone production rate with a disproportionate increase in T3 relative to T4 (Table 1). Saturation of TBG is increased due to elevated serum levels of T4and T3, which is reflected in elevated T3resin uptake. As a result, concentrations of free T4, free T3, and the free T4 and T3 indices are increased to an even greater extent than the measured serum total T4 and T3concentrations. The TSH level is undetectable due to negative feedback by elevated levels of thyroid hormone at the pituitary. In patients with symptomatic disease, measurement of serum free T4, total T4, total T3, and TSH will confirm the diagnosis of thyrotoxicosis. If the patient is not pregnant or lactating, an increased 24 hour RAIU indicates that the thyroid gland is inappropriately using iodine to produce more thyroid hormone when the patient is thyrotoxic. 14   For toxic adenomas, because there may be isolated elevation of serum T3 with autonomously functioning nodules, a T3 level must be measured to rule out T3toxicosis if the T4level is normal. If autonomous function is suspected but the TSH is normal, the diagnosis can be confirmed by failure of the autonomous nodule to decrease iodine uptake during exogenous T3administration sufficient to suppress TSH.  In multinodular goiters, a thyroid scan shows patchy areas of autonomously functioning thyroid tissue.  TSH induced hyperthyroidism is diagnosed by evidence of peripheral hypermetabolism, diffuse thyroid gland enlargement, elevated free thyroid hormone levels, and elevated serum immunoreactive TSH concentrations. Because the pituitary gland is extremely sensitive to even minimal elevations of free T4, a “normal” or elevated TSH level in any thyrotoxic patient indicates inappropriate production of TSH.  TSH secreting pituitary adenomas are diagnosed by demonstrating lack of TSH response to TRH stimulation, inappropriate TSH levels, elevated TSH α subunit levels, and radiologic imaging.  In subacute thyroiditis, thyroid function tests typically run a triphasic course in this self-limited disease. Initially, serum T4 levels are elevated due to release of preformed thyroid hormone. The 24 hour RAIU during this time is 20 years or with vascular disease should not use CHCs. 64 Dyslipidemia  Generally, synthetic progestins decrease high density lipoprotein (HDL) and increase low density lipoprotein (LDL). Estrogens decrease LDL but increase HDL and may moderately increase triglycerides. Most low dose CHCs have no significant impact on HDL, LDL, triglycerides, or total cholesterol.  The mechanism for the increased cardiovascular disease in CHC users is believed to be thromboembolic and thrombotic changes, not atherosclerosis.  CHCs use in individuals with dyslipidemia as a single cardiovascular risk factor is generally acceptable. An alternative method of contraception is recommended in individuals with dyslipidemia and other cardiovascular risk factors. Thromboembolism  The risk of venous thromboembolism (VTE) in individuals using combined oral contraceptives (COCs) is three times that of nonusers, but is less than the risk of thromboembolic events during pregnancy.  Estrogens increase hepatic production of factors involved in the coagulation cascade. Risk for thromboembolic events is increased in those with underlying hypercoagulable states or with acquired conditions (eg, obesity, pregnancy, immobility, trauma, surgery, and certain malignancies) that predispose to coagulation abnormalities.  COCs containing the newer progestins (eg, drospirenone, desogestrel, norgestimate) carry a slightly increased risk of thrombosis compared to other progestins due to unknown mechanisms.  The transdermal patch and vaginal ring provide continuous higher exposure to estrogen and have an increased thromboembolic risk.  For individuals at increased risk of thromboembolism (older than 35 years, obesity, smoking, personal or family history of venous thrombosis, prolonged immobilization), consider low dose oral estrogen contraceptives containing older progestins or progestin only methods. Obesity  COCs have lower efficacy in obesity, and low dose COCs may be especially problematic. IUDs, implants, and DMPA have very low failure rates, and progestin only contraceptives are considered safe in obese individuals.  Obese individuals have increased VTE risk, and progestin only contraception may be better for those over 35 years. Migraine Headache  CHCs may decrease or increase migraine frequency.  C HCs may be considered for healthy, nonsmoking individuals (less than 35 years old) with migraines without aura. Discuss continued use of CHC risks and benefits with individuals developing migraines without aura.  individuals of any age who have migraine with aura should not use CHCs due to the risk of stroke. individuals who develop migraines with aura while receiving CHCs should discontinue their use and consider a progestin only option 65 Breast Cancer  There is a small increase in the relative risk of having breast cancer while CHCs are taken and for up to 10 years following discontinuation.  For individuals over the age of 40 or those with elevated breast cancer risk due to family history or other factors, alternatives may be considered.  The choice to use CHCs should not be influenced by the presence of benign breast disease or a family history of breast cancer. For individuals with either BRCA1 or BRCA2 mutation, CHC use is controversial, and individuals with a current or past history of breast cancer should not use CHCs. Systemic Lupus Erythematosus (SLE)  COCs with less than 50 mcg EE do not increase the risk of flare in those with stable SLE and without antiphospholipid/anticardiolipin antibodies.  CHCs and progestin only products should be avoided in individuals with SLE and antiphospholipid antibodies or vascular complications. The copper IUD may be the best.  For those with SLE without antiphospholipid antibodies or vascular complications, progestin only contraceptives or the copper IUD may be an alternative.  A copper IUD and DMPA injection should be avoided in those with SLE and severe thrombocytopenia. Postpartum  In the first 21 days postpartum (when the risk of thrombosis is higher), estrogen containing hormonal contraceptives should be avoided due to increased VTE risk. Progestin only methods should be used if contraception is necessary.  CHC should be avoided in the first 42 days postpartum in individuals with VTE risk factors and for 30 days for those without VTE risk factors who are breastfeeding. Medication Interactions  Tell patients to use an alternative method of contraception if a possible medication interaction may compromise OC efficacy.  There is a small interaction risk with antimicrobials, and additional nonhormonal contraceptives should be considered, especially when receiving an antimicrobial for more than 2 months.  Rifampin reduces the efficacy of CHCs. Additional nonhormonal contraception should be used for at least 7−28 days after rifampin therapy.  Phenobarbital, carbamazepine, and phenytoin potentially reduce the efficacy of CHCs, and many anticonvulsants are known teratogens. IUDs, injectable medroxyprogesterone, or nonhormonal options should be used instead.  CHCs may decrease the efficacy of lamotrigine and increase seizure risk.  Certain antiretroviral therapies and St. John’s Wort may decrease the efficacy of CHCs.  Monitor potassium in patients taking drospirenone and concomitant medications that increase potassium levels or those taking strong CYP3A4 inhibitors. 66 Return of Fertility After Discontinuation  There is no evidence that hormonal contraception use decreases subsequent fertility and there is no greater chance of miscarriage or a birth defect in the first month after discontinuation Emergency Contraception (EC).  EC is used to prevent unintended pregnancy after unprotected or inadequately protected sexual intercourse.  FDA approved progestin only and progesterone receptor modulator products are recommended as first line EC options. They will not disrupt the fertilized egg if implantation has already occurred.  Progestin only EC formulations containing one 1.5 mg tablet of levonorgestrel are available without a prescription in the United States. They may be less effective in individuals weighing greater than 75 kg.  Ulipristal (Ella) is a prescription selective progesterone receptor modulator. It is taken as a single dose of 30 mg within 120 hours (5 days) of unprotected intercourse. It is considered noninferior to levonorgestrel containing ECs and is not recommended in breastfeeding individuals.  Common adverse medication effects of EC include nausea, vomiting, and irregular bleeding.  Insertion of a copper IUD or prescribing higher doses of CHCs (Yuzpe method) are other EC options.  EC should be given within 72 hours (3 days) of unprotected intercourse, but the sooner it is taken, the greater the efficacy. There is some evidence that it may be effective for up to 5 days after unprotected intercourse, but in this situation ulipristal or a copper IUD may be a better option.  Backup nonhormonal contraceptive methods should be used after EC for at least 7 days. Pregnancy Termination  Medications used in early pregnancy (≤70 days) termination include mifepristone and misoprostol. Misoprostol can be used alone or more effectively in combination with mifepristone.  The FDA has approved mifepristone 200 mg orally on day 1 and then misoprostol 800 mcg buccally 24–48 hours after the mifepristone dose. This regimen has a 98% efficacy in pregnancies up to 49 days.  Mifepristone binds progesterone receptors to block progesterone, resulting in cervical softening and an increase in prostaglandin sensitivity, leading to contraction stimulation. Mifepristone is usually administered orally, and prescribing is limited to trained prescribers who also dispense the medication. It is contraindicated in patients with bleeding disorders or those on anticoagulants. It is a major substrate for CYP3A4, so medication interactionsneed to be considered.  Misoprostol is a prostaglandin 1 analog that has good absorption when given vagibnuacllcya,lly, or sublingually resulting in cervical ripening and contractions. Oral administration is not recommended. 67 ✔ Adverse medication effects of misoprostol include stomach upset, diarrhea, headache, dizziness, and fever. Mifepristone has a boxed warning regarding infection and excessive bleeding may occur and could be a sign of incomplete termination or other complications and needs prompt medical attention. EVALUATION OF THERAPEUTIC OUTCOMES  Monitor blood pressure annually in all CHC users.  Monitor glucose levels closely when CHCs are started or stopped in individuals with a histofyglucose intolerance or diabetes mellitus.  Contraceptive users should have an annual exam that may include cytologic screening, andpelvic and breast examination. Regularly evaluate for problems that may relate to the CHCs (eg, breakthrough bleeding, amenorrhea, weight gain, and acne). These screenings do not hae to occur before prescribing hormonal contraceptives.  Monitor Nexplanon users annually for menstrual cycle disturbances, weight gain, local inflammation or infection at the implant site, acne, breast tenderness, headaches, and hair loss  Evaluate individuals using DMPA every 3 months for weight gain, menstrual cycle disturbances and fractures.  Monitor IUD users at 1 to 3 month intervals for proper IUD positioning, changes in menstrual bleeding patterns, and upper genital tract infection.  Clinicians should monitor and when indicated screen for HIV and STIs. Counsel about healthy sexual practices, including the use of condoms to prevent transmission of STIs when necessary. 68  Hormone Replacement Therapy INTRODUCTION Perimenopause begins with the onset of menstrual irregularity and ends 12 months after the last menstrual period, which marks the beginning of menopause. Menopause is the permanent cessation of menses caused by the loss of ovarian follicular activity. Females spend about 40% of their lives in postmenopause. PATHOPHYSIOLOGY  The hypothalamic−pituitary−ovarian axis controls reproductive physiology. Follicle stimulating hormone (FSH) and luteinizing hormone (LH), produced by the pituitary in response to gonadotropin releasing hormone from the hypothalamus, regulate ovarian function.  Gonadotropins are also influenced by negative feedback from the sex steroids estradiol (produced by the dominant follicle) and progesterone (produced by the corpus luteum). Other sex steroids are androgens, primarily testosterone and androstenedione, secreted by the ovarian stroma.  As females age, circulating FSH progressively rises, and ovarian (inhibin-B) and anti-Mullerian hormone decline. In menopause, there is a 10-to-15-fold increase in circulating FSH, a 4-to-5- fold increase in LH, and a greater than 90% decrease in circulating estradiol concentrations. CLINICAL PRESENTATION  Vasomotor symptoms (hot flushes and night sweats), sleep disturbances, depression, anxiety, poor concentration and memory, vaginal dryness and dyspareunia, headache, sexual dysfunction, and arthralgia. Individuals of different races/ethnicity experience vasomotor symptoms differently.  Signs include urogenital atrophy in menopause and dysfunctional uterine bleeding in perimenopause. Additionally, loss of estrogen production results in metabolic changes; increase in central abdominal fat; and effects on lipids, vascular function, and bone metabolism. DIAGNOSIS  Menopause is determined retrospectively after 12 consecutive months of amenorrhea. FSH on day 2 or 3 of the menstrual cycle greater than 10−12 IU/L indicates diminished ovarian reserve.  The diagnosis should include a comprehensive medical history and physical examination, complete blood count, and measurement of serum FSH. Altered thyroid function and pregnancy must be excluded. TREATMENT The goals are to relieve symptoms, improve quality of life, and minimize medication adverse effects. NONPHARMACOLOGIC THERAPY  Mild vasomotor and/or vaginal symptoms can often be alleviated by lowering the room temperature; decreasing intake of caffeine, spicy foods, and hot beverages; smoking cessation; exercise; and a healthy diet.  Mild vulvovaginal symptoms may be adequately managed with nonhormonal lubricants and moisturizers. 69 PHARMACOLOGIC THERAPY  FDA approved indications and contraindications for menopausal hormone therapy (MHT) are shown in Table 1.  The decision to use MHT and the type of formulation used must be individualized based on several factors, including personal preference, age, menopause onset, the severity of menopausal symptoms, and MHT associated risks.  MHT remains the most effective treatment for moderate and severe vasomotor symptoms, impaired sleep quality, and vulvovaginal symptoms of menopause.  When urogenital symptoms, such as vaginal dryness and dyspareunia, are the only menopausal complaint, intravaginal estrogen cream, tablet, or ring should be considered before oral therapy.  Intravaginal estrogen minimizes systemic absorption and is more effective for vaginal symptoms than oral therapy. Intravaginal estrogen reduces the risk of recurrent urinary tract infections and may improve urge incontinence and overactive bladder.  Ospemifene, a selective estrogen receptor modulator, is another option.  MHT is the most effective treatment for moderate to severe vasomotor symptoms, and impaired sleep quality. Estrogen only therapy may decrease heart disease and all-cause mortality in 50- to 59-year-old females with a history of hysterectomy.  MHT is effective and appropriate for prevention of osteoporosis related fractures in recently menopausal individuals at risk.  In patients with an intact uterus, MHT consists of an estrogen plus a progestogen or estrogen agonist/antagonist (e.g. bazedoxifene).  In patients who have undergone hysterectomy, estrogen therapy is given unopposed by a progestogen. Concomitant progestogen therapy is unnecessary when low dose vaginal estrogen is used.  Individuals with vasomotor symptoms taking MHT have better mental health and fewer depressive symptoms compared with those receiving placebo, but MHT may worsen the quality of life in individuals without vasomotor symptoms. Table 1: FDA Approved Indications and Contraindications for Menopausal Hormone Therapy with Estrogens and Progestins Indications For systemic use Treatment of moderate to severe vasomotor symptoms (ie, moderate to severe hot flashes) For intravaginal use Treatment of moderate to severe symptoms of vulvar and vaginal atrophy (low (ie, moderate to severe vaginal dryness, dyspareunia, and atrophic vaginitis) systemic exposure) Contraindications Absolute  Undiagnosed abnormal genital bleeding contraindications  Known, suspected, or history of cancer of the breast  Known or suspected estrogen or progesterone dependent neoplasia  Active deep vein thrombosis, pulmonary embolism, or a history of these conditions  Active or recent (eg, within the past year) arterial thromboembolic disease (eg, stroke, myocardial infarction) 70   Liver dysfunction or disease Relative  Elevated blood pressure contraindications  Hypertriglyceridemia  Impaired liver function and past history of cholestatic jaundice  Hypothyroidism  Fluid retention  Severe hypocalcemia  Ovarian cancer  Exacerbation of endometriosis  Exacerbation of asthma, diabetes mellitus, migraine, systemic lupus erythematosus, epilepsy, porphyria, and  hepatic hemangioma Estrogens  The oral and transdermal routes are used most frequently and are considered equally effective.  Conjugated equine estrogens are composed of estrone sulfate (50%–60%) and other estrogens such as equilin and 17α-dihydroequilin.  Estradiol is the predominant and most active form of endogenous estrogens. Given orally, it is metabolized by the intestinal mucosa and liver, and resultant estrone concentrations are three to six times those of estradiol.  Ethinyl estradiol is a semisynthetic estrogen that has similar activity following oral or parenteral administration.  Nonoral estrogens, including transdermal, intranasal, and vaginal products, to avoid first pass metabolism and result in a more physiologic estradiol : estrone ratio. Transdermal estrogen is also less likely to increase sex hormone–binding globulin, triglycerides, blood pressure, or C- reactive protein levels. Transdermal dosage forms may also have a lower risk for deep vein thrombosis, stroke, and myocardial infarction.  Variability in absorption is common with percutaneous preparations (ie, gels, creams, and emulsions).  Vaginal creams, tablets, and rings are used for treatment of urogenital atrophy. Most tablets and rings provide local estrogen, but Femring is designed to achieve systemic estrogen concentrations and is indicated for moderate to severe vasomotor symptoms.  New evidence indicates that lower doses of estrogens are effective in controlling postmenopausal symptoms and reducing bone loss. Topical gels, creams, and sprays are also available in low doses. The lowest effective dose should be used. ✓ Adverse effects of estrogen include nausea, headache, breast tenderness, and heavy bleeding. More serious adverse effects include increased risk for stroke, venous thromboembolism (VTE), and gallbladder disease. Transdermal estrogen is less likely to cause breast tenderness, gallbladder disease, and deep vein thrombosis. ✓ Risk of VTE and stroke increases with oral MHT containing estrogen, but the absolute risk is low below 60 years of age. Transdermal MHT and low dose oral estrogen therapy appear to have a lower risk of VTE and stroke compared to standard dose oral estrogen regimens. ✓ MHT is contraindicated in individuals with a personal history of breast cancer. The risk of MHT related 71 breast cancer appears to be associated with the addition of progestogen to estrogen after 3 years of combined use. ✓ Combined oral MHT does not increase endometrial cancer risk compared with placebo, but estrogen alone given to individuals with an intact uterus significantly increases uterine cancer risk. ✓ Postmenopausal individuals 65 years or older taking estrogen plus progestogen therapy had twice the rate of dementia, including Alzheimer disease, than those taking placebo. Combined therapy did not prevent mild cognitive impairment. The estrogen alone arm showed similar findings. Progestogens In individuals who have not undergone hysterectomy, a progestogen or tissue selective estrogen complex (estrogen/bazedoxifene) should be added for endometrial protection. Medroxyprogesterone acetate, Micronized progesterone and Norethindrone acetate are progestogens approved for menopausal symptom treatment. ✓ Adverse effects of progestogens include irritability, headache, mood swings, fluid retention, and sleep disturbance. Methods of administration include the following:  Cyclic (Sequential) estrogen progestogen results in scheduled vaginal withdrawal bleeding in approximately 80%–90% of patients. The progestogen is administered 12−14 days of the 28day cycle.  Continuous combined estrogen progestogen causes endometrial atrophy but prevents monthly bleeding, which is preferable, although it may initially cause unpredictable spotting or bleeding. Use of conjugated estrogens (0.625 mg/day) plus medroxyprogesterone acetate (2.5 mg/day) lead to a decreased risk of endometrial cancer.  Intermittent combined estrogen progestogen (continuous pulsed) consists of 3 days of estrogen therapy alone, followed by 3 days of combined estrogen and progestogen, repeated without interruption. It causes fewer adverse effects than regimens with higher progestogen doses and lowers the incidence of uterine bleeding. Compounded Bioidentical Hormone Therapy (CBHT)  CBHTs are hormone therapy formulations custom prepared (ie, compounded) for individual patients, often involving the use of measuring and monitoring hormone levels in blood and/or other body fluids such as saliva.  Hormones commonly used in CBHT include estrone, estradiol, estriol, progesterone, testosterone, DHEA, and thyroid hormone. Bioidentical hormones appear to carry the same risks as traditional hormone therapy products. Use is only recommended only when there is a medical need for an unusual dosing regimen or ingredients or when patients have allergies to FDA approved therapies. Estrogen Alternatives for the Treatment of Hot Flashes  Some clinicians consider selective serotonin reuptake inhibitors (eg, paroxetine, fluoxetine, citalopram, escitalopram) or serotonin norepinephrine reuptake inhibitors (eg, venlafaxine and desvenlafaxine) to be first line agents. 72   Clonidine can be effective, but adverse effects are often problematic (eg, sedation, dry mouth, hypotension). Gabapentin has beneficial effects for reducing the frequency and severity of vasomotor symptoms but adverse effects may limit dosing. It may be a reasonable option for those with disrupted sleep and hot flashes when administered in the evening. Androgens  Testosterone use is controversial, but use with or without estrogen, may improve the quality of the sexual experience in postmenopausal individuals.  Absolute contraindications to androgen therapy include pregnancy or lactation and known or suspected androgen dependent neoplasia.  Adverse effects include virilization, fluid retention, and adverse lipoprotein lipid effects, which are more likely with oral administration. Evidence on the efficacy and safety of testosterone in females is lacking.  Dehydroepiandrosterone (DHEA) is a precursor hormone in the synthesis of estrone, estradiol, and testosterone. Intravaginal DHEA (Prasterone) has FDA approval for the treatment of moderate to severe dyspareunia. Selective Estrogen Receptor Modulators (SERMs)  SERMs are nonsteroidal compounds that act as estrogen agonists in some tissues such as bone and as estrogen antagonists in other tissues such as breast through high affinity binding to the estrogen receptor.  Tamoxifen is an antagonist in breast tissue and an agonist on the bone and endometrium.  Raloxifene is approved for prevention and treatment of postmenopausal osteoporosis and reduction in risk of invasive breast cancer.  The third generation SERM, bazedoxifene, is used in conjunction with conjugated estrogen, and is FDA approved for moderate to severe vasomotor symptoms and prevention of osteoporosis.  Ospemifene is approved for dyspareunia from menopausal vulvar and vaginal atrophy. It has a boxed warning for increased risk of endometrial cancer in patients with a uterus who use ospemifene without a progestogen to reduce endometrial hyperplasia. ✓ Depending on tissue selectively, the SERMs are associated with hot flashes and leg cramps. They can also increase the risk of VTE and stroke similar to oral estrogen, but the degree of risk is agent specific. Additional adverse effects of bazedoxifene include muscle spasms, nausea, diarrhea, dyspepsia, upper abdominal pain, oropharyngeal pain, dizziness, and neck pain. Complementary and Alternative Agents  Phytoestrogens are plant compounds with estrogen like biologic activity and relatively weak estrogen receptor binding properties, resulting in physiologic effects in humans.  Although clarity regarding, dosing, biological activity, safety, and efficacy is needed before they can be considered as an alternative to MHT.  Other herbals and alternative treatments that may be used include black cohosh, dong quai, red clover leaf (contains phytoestrogens), and ginseng. EVALUATION OF THERAPEUTIC OUTCOMES  In order to adequately assess treatment effect, individuals should be encouraged to continue their MHT regimen for at least 1 month with dosages being modified to balance adverse effects and efficacy. Those receiving MHT should be seen annually for monitoring. 73  Menstruation Related Disorders Introduction Menstrual cycle disorders are common amongst women of reproductive age. The most common include dysmenorrhea, amenorrhea, anovulatory bleeding, and heavy menstrual bleeding. Menstruation-related disorders can negatively affect quality of life (QOL), reproductive health, and productivity and may also lead to long-term health consequences. As menstruation begins to cease, the perimenopause and menopause phases begin. During this time, irregular menses, vaginal dryness, dyspareunia, hot flashes, and mood swings may occur. Dysmenorrhea Dysmenorrhea is pelvic pain, generally described as painful cramping, occurring during or just prior to menstruation. Primary dysmenorrhea occurs with normal pelvic anatomy and physiology, whereas secondary dysmenorrhea is associated with underlying pelvic pathology. Epidemiology and Etiology Dysmenorrhea is the most commonly reported menstrual complaint, with over 50% of menstruating women reporting pain for at least 1 or 2 days each month. Of adolescents with dysmenorrhea, up to 12% report missing work or school each month due to pain. Risk factors include irregular or heavy menses, age less than 30, menarche prior to age 12, body mass index less than 20 kg/m2, history of sterilization or sexual abuse, and smoking. Causes of secondary dysmenorrhea may include endometriosis, pelvic inflammatory disease (PID), uterine or cervical polyps, and uterine fibroids. Pathophysiology In primary dysmenorrhea, elevated arachidonic acid levels in the menstrual fluid lead to increased concentrations of prostaglandins and leukotrienes in the uterus. This induces uterine contractions, stimulates pain fibers, reduces uterine blood flow, and causes uterine hypoxia. Treatment ▶ Desired Outcomes: Desired treatment outcomes (Figure 50–1) are reduction of pelvic pain, improved QOL, and fewer missed days from school and work. ▶ Nonpharmacologic Therapy: Dysmenorrhea intensity has shown to be decreased by exercise, applying topical heat therapy, acupuncture, and consuming a low-fat vegetarian diet. ▶ Pharmacologic Therapy: 1. Nonsteroidal Anti-inflammatory Drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs) are first- line therapy for dysmenorrhea and are effective in up to 80% of patients. NSAIDs inhibit prostaglandin production, exert analgesic properties, decrease uterine contractions, and reduce menstrual blood flow. Choice of agent is based on effectiveness, tolerability, and patient preference, with the most commonly utilized agents being naproxen and ibuprofen. Of note, aspirin is not recommended as it is not potent enough in usual dosages. NSAID treatment should begin 1 to 2 days prior to menses, or at dysmenorrhea onset, and continued for 2 to 3 days or until pain resolves. A loading dose (twice the usual single dose) is recommended, followed by the usual recommended dose. For patients with limited response or with contraindications to NSAID therapy, combination hormonal contraceptives (CHCs) should be considered. 2. Combination Hormonal Contraceptives: CHCs improve dysmenorrhea by decreasing 74  endometrial lining and inhibiting ovulation, which decreases the formation of prostaglandins and leukotrienes contributing to menstrual pain. Precisely, 2 to 3 months of therapy are often required to achieve full effects, and can take up to 6 months.4 Both cyclic(28-day) and extended cycle (91- day) therapies have been used effectively. Continuous CHC may provide more rapid pain relief when compared to cyclic therapy; however, both effects are similar when evaluated at 6 months. For dysmenorrhea secondary to endometriosis, CHCs, specifically extended cycle regimens, are considered first-line. If no response with any agent occurs after 3 to 6 months, the patient should be reevaluated. 3. Progestin-Only Hormonal Contraceptives: Long-acting progestins are often utilized for dysmenorrhea treatment and work by reducing or eliminating menses over 6 to 12 months of use, thus eliminating prostaglandin release. Three long-acting reversible contraceptive agents are available: depot medroxyprogesterone acetate (MPA), etonogestrel implant, and levonorgestrel- releasing intrauterine device (IUD). Observational data showed that women with active dysmenorrhea symptoms who used a levonorgestrel-releasing IUD saw a reduction in their symptoms from 60% to 29% after 3 years of therapy. Dysmenorrhea in Adolescents: Dysmenorrhea is the most common gynecologic complaint amongst female adolescents, reported in 60% to 90%, and the most common reason for missed school or work. NSAIDs are the preferred initial treatment in adolescents, followed by hormonal treatment. Adolescents with symptoms unresponsive to NSAID therapy for three menstrual periods should be offered CHC, which can also provide effective contraception if desired. If symptoms do not improve within 3 to 6 months of NSAIDs and CHC, it is important to assess for medication adherence. If adherence is confirmed and patient still not experiencing symptom relief, further evaluation through laparoscopy is indicated. Since adolescence is a critical period for bone mineral density (BMD) accrual, and prolonged use of depot MPA may lead to significant loss of BMD that may not be completely reversible, other agents are considered first line. 75  Amenorrhea Amenorrhea is the absence of menses over a 90-day period and can be primary or secondary. Primary amenorrhea is the failure to reach menarche by age 15, in women who have never menstruated. Secondary amenorrhea is the cessation of menses for 3 months in a previously regular menstruating woman or 6 months in a previously irregular menstruating woman. Epidemiology and Etiology: Unrecognized pregnancy can be a common cause of amenorrhea; therefore, a urine pregnancy test should be one of the first steps in evaluating amenorrhea. There are three main causes of amenorrhea: anatomical causes including pregnancy and uterine structural abnormalities, endocrine or hormone imbalances leading to chronic amenorrhea, and ovarian insufficiency or failure. Primary amenorrhea is often caused by chromosomal irregularities resulting in primary ovarian insufficiency or anatomic abnormalities. Causes of secondary amenorrhea include polycystic ovary syndrome (PCOS), hypothalamic suppression, thyroid disorders, hyperprolactinemia, or primary ovarian insufficiency. Additional causes include undernutrition, anorexia, and excessive exercise. Pathophysiology Normal menstrual cycle physiology depends on hormonal interactions involving the hypothalamus, anterior pituitary gland, ovary, and endometrium. Amenorrhea is a potential side effect from using low-dose or extended oral CHCs, MPA, or levonorgestrel-releasing IUD. Many women experience delayed return of menses after discontinuing hormonal contraception. If resolution of amenorrhea does not occur within 3 to 6 months after discontinuing contraception, evaluation for other conditions should be considered (eg, PCOS). Treatment ▶ Desired Outcomes: Treatment goals include ensuring normal puberty is occurring, restoring the normal menstrual cycle, preserving bone density, preventing bone loss, improving QOL, reduction of associated symptoms, and restoring ovulation, thus improving fertility. ▶ Nonpharmacologic Therapy Nonpharmacologic therapy depends on the underlying cause. Amenorrhea secondary to undernutrition or anorexia may respond to weight gain and psychotherapy.11 If excessive exercise is the cause, exercise reduction is recommended.11 Women with functional hypothalamic amenorrhea should undergo a reasonable trial of psychological (such as cognitive behavior therapy), nutritional, and/or exercise intervention prior to starting pharmacologic therapy ▶ Pharmacologic Therapy 1. Estrogen/Progestin Replacement Therapy: For most conditions associated with primary or secondary amenorrhea, estrogen supplementation with either an oral contraceptive, conjugated equine estrogen (CEE), or estradiol patch has historically been recommended. However, CHC and synthetic estrogen are no longer recommended as first-line agents for patients with functional hypothalamic amenorrhea. The 2017 Endocrine Society Clinical Practice Guideline for functional hypothalamic amenorrhea recommends patients trial nonpharmacological therapy first (with psychological and nutritional interventions), and then start a short-term transdermal estrogen with cyclic oral progestins. 2. Dopamine Agonists: When hyperprolactinemia is the cause of amenorrhea, dopamine agonists are preferred. Dopamine agonists restore normal prolactin levels, resolve amenorrhea, and restore ovulation in 80% to 90% of women. Bromocriptine and cabergoline are the most commonly studied agents, with cabergoline being more effective in resolving amenorrhea. 3. Progestins: Progestins induce withdrawal 76bleeding in women with secondary amenorrhea.  Withdrawal bleeding occurs with intramuscularly injected progesterone and oral MPA in 70% and 95% of patients, respectively. The usual dose of oral MPA is 10 mg orally once daily for 7 to 10 days. 4. Insulin-Sensitizing Agents: PCOS-induced amenorrhea may respond well to insulin sensitizing agents. Using metformin for this purpose is discussed in the anovulatory bleeding section. All patients experiencing amenorrhea should follow a diet rich in calcium and vitamin D to support bone health. Supplemental calcium and vitamin D (1200 mg/800 IU/day) should be recommended for patients with inadequate dietary consumption.11 Figure 50–3 illustrates treatment recommendations for amenorrhea. Amenorrhea in Adolescents Optimal treatment of adolescents diagnosed with amenorrhea, especially primary ovarian insufficiency, includes careful consideration to both the physical and emotional needs of a young patient receiving this diagnosis. It may be difficult to process the emotions to understand the immediate and long-term impacts of amenorrhea diagnosis on long-term fertility. Patients may need higher doses of estrogen than menopausal women in order to ensure adequate replacement and optimal bone health. For patients with absent or incomplete breast development, estrogen therapy should be started and increased slowly before adding progesterone in order to allow for breast development and prevent tubular breast development. Once puberty is complete, the goal becomes maintaining normal ovarian functioning levels of estradiol. Estradiol 100 mcg daily is recommended, either by transdermal, oral, or occasionally transvaginal administration may be considered. Cyclic progesterone should be added for 10 to 12 days each month to help protect against endometrial hyperplasia and endometrial cancer. Oral contraceptives often contain higher doses of estrogen than what is needed and are no longer recommended as first-line therapy. Anovulatory bleeding Anovulatory uterine bleeding is irregular menstrual bleeding from the endometrium ranging from light spotting to heavy blood flow.18 It includes menstrual bleeding that occurs outside of the normal cyclic bleeding. This bleeding occurs due to the effects of unopposed estrogen. Of 77  note, it does not include bleeding due to uterine anatomic lesions.18 Many women pursue medical care to regulate menstrual cycles or improve fertility. Epidemiology and Etiology Anovulatory uterine bleeding is the most common form of noncyclic uterine bleeding. PCOS is the most common cause, occurring in 8% to 13% of women. Anovulation results from dysfunction at any level of the hypothalamic–pituitary–ovarian axis which can be due to physiologic life stages such as adolescence, perimenopause, pregnancy, and lactation or pathologic causes. Anovulation may also occur at any time during the reproductive years due to a pathologic cause. The most common causes of nonphysiologic ovulatory dysfunction are PCOS, hypothalamic amenorrhea, hyperprolactinemia, and premature ovarian failure Pathophysiology In anovulation, a corpus luteum does not develop, and the ovary fails to secrete progesterone. This causes the endometrium to continue proliferation under the influence of unopposed estrogen, and eventually it becomes thick, vascular, and fragile. The clinical result is unpredictable, heavy, noncyclic bleeding, as sporadic sloughing of the endometrium begins to occur. Treatment ▶ Desired Outcomes The desired outcomes are to stop acute bleeding, restore natural cycle of endometrial growth and shedding, decrease long-term complications of anovulation (eg, osteopenia and infertility), and improve QOL. ▶ Nonpharmacologic Therapy Nonpharmacologic treatment options depend on the underlying cause. For women with PCOS, weight loss of 5% to 10% may help improve menstrual regularity, decrease hirsutism, improve insulin sensitivity, and increase response to fertility treatments. In women who have completed childbearing or who have failed medical management, endometrial ablation or resection, and hysterectomy are considered surgical options. ▶ Pharmacologic Therapy 1. Estrogen: Estrogen is the recommended treatment for managing acute bleeding episodes because it promotes endometrial growth and stabilization. CHCs are useful for cycle regulation, helping to provide a more predictable menstrual cycle. For women with PCOS, CHCs also suppress ovarian hormones and adrenal androgen production, and oral agents also indirectly increase sex hormone-binding globulin. This, in turn, binds and reduces circulating androgen. Women with high androgen levels or signs of hyperandrogenism (eg, hirsutism, acne) are recommended to start low-dose CHCs (35 mcg or less ethinyl estradiol) and a progesterone with minimal androgenic side effects (eg, norgestimate and desogestrel) or antiandrogenic effects (eg, drospirenone). 2. Progestins: Women who experience side effects or have contraindication(s) to estrogen, or who have abnormal uterine bleeding due to anovulatory bleeding, should consider progesterone-only products. For women with PCOS, depot and intermittent oral MPA suppress pituitary gonadotropins and circulating androgens, leading to endometrial shedding. If contraception is desired, placement of a levonorgestrel-releasing IUD is an option. 3. Estrogen Modulators: Women with anovulatory bleeding from PCOS who are pursuing pregnancy should be seen by a fertility specialist. Women may be treated with letrozole or clomiphene citrate for ovulation induction under specialist care. 78 4. Insulin-Sensitizing Agents: Metformin improves insulin sensitivity, reduces circulating androgen concentrations, and improves ovulation rates and should be considered for women with PCOS for management of metabolic features. Notably, metformin may increase spontaneous ovulation, and contraception should be used in women with PCOS who do not desire pregnancy. Anovulatory Bleeding in Adolescents Anovulation is the most common cause of non-cyclic uterine bleeding in adolescents. Anovulatory bleeding in teenagers can become excessive, persistent, and require medications to treat. The differential diagnosis is similar to adults and should include evaluation for blood dyscrasias. Patients should also be evaluated for PCOS by assessing for signs of hyperandrogenism, including acne and hirsutism. 79  Cancer chemotherapy & treatment Cancer (neoplasm, tumor, or malignancy) is a group of diseases (more than 100 disease characterized by uncontrolled cellular growth, tissue infiltration, and spread of abnormal cells (can't carry out normal physiological functions). Cancer Prevention  Most cancers are not curable in advanced stages.  Both lifestyle modifications and chemoprevention agents may significantly reduce the risk of developing cancer.  The Food and Drug Administration (FDA) has approved vaccines that can help prevent cancer. Available vaccines include those that prevent infection with human papillomavirus (HPV), responsible for cancers of the cervix, vulva, vagina, and anus and a vaccine that prevents hepatitis B viral infections, which can cause liver cancer.  Additionally, medications, such as the selective estrogen receptor modulator (SERM) tamoxifen reduces the risk of breast cancer in premenopausal women, while raloxifene and the aromatase inhibitor (AI) exemestane reduce breast cancer in high-risk postmenopausal women. Because of possible long-term complications (eg, an increased risk of endometrial cancer with the use of tamoxifen) benefits versus risks needs to be weighed when making a recommendation.  Smoking cessation is associated with a gradual decrease in the risk of cancer (e.g., lung, pharynx, mouth and esophageous), but more than 5 years is needed before a major decline in risk is detected.  Proper sun protection, including minimizing sun exposure, using sunscreens with a sun protection factor (SPF≥15) on exposed areas, wearing protective clothing and sunglasses, avoiding tanning beds and sun lamps, can help in preventing the risk of skin cancer. CARCINOGENESIS  Carcinogenesis is the process by which normal cells are transformed into cancer cells.  The exact cause of cancer remains unknown and is probably very diverse. It is thought that cancer develops from a single cell in which the normal mechanisms for control of growth and proliferation are altered.  Evidence indicates that there are 4 stages in the cancer development process. 1. The first step, initiation, occurs when a carcinogenic substance encounters a normal cell to produce genetic damage and results in a mutated cell. 2. The environment is altered by carcinogens or other factors to favor the growth of the mutated cell over the normal cell during promotion. (reversible process) 3. Third, transformation (or conversion) occurs when the mutated cell becomes malignant 4. Finally, progression occurs when cell proliferation takes over and the tumor spreads or develops metastases  There are two major classes of genes involved in carcinogenesis, oncogenes and mutation of tumor suppressor genes (eg. p53 gene). A. Protooncogens are normal genes present in cells that converted by carcinogenic substances (eg. Smoking or radiation) into oncogene. B. Tumor suppressor genes are normal genes which have protective effects against oncogenes. They inhibit inappropriate cellular growth and proliferation. 80  Carcinogenic substances 1. Chemicals, such as aniline and benzene, are associated with the development of bladder cancer and leukemia, respectively. 2. Environmental factors, such as excessive sun exposure, can result in skin cancer, and smoking is widely known as a cause of lung cancer. 3. Viruses, including HPV, Epstein-Barr virus, and hepatitis B virus, have been linked to cervical cancers, lymphomas, and liver cancers, respectively. 4. Anticancer agents such as the alkylating agents (eg, melphalan), anthracyclines (eg, doxorubicin), and epipodophyllotoxins (eg, etoposide) can cause secondary malignancies (eg, leukemias) years after therapy has been completed. Note: The patient’s age, gender, family history, diet, and chronic irritation or inflammation may be considered to be promoters of carcinogenesis. Metastases  A metastasis is a growth of the same cancer cell found at some distance from the primary tumor site. The presence of metastasis at diagnosis usually is associated with a poorer prognosis than the patient with no known metastatic disease. Usually, once distant metastases have occurred, the cancer is considered incurable.  Cancers spread usually by two pathways: hematogenous (through the bloodstream) or through the lymphatics (drainage through adjacent lymph nodes).  The usual metastatic sites for solid tumors are the brain, bone, lung, and liver. PATHOPHYSIOLOGY Tumor Origin  Tumors may arise from the 4 basic tissue types: epithelial (carcinoma), connective (ie, muscle, bone, & cartilage) (called sarcoma), lymphoid, or nerve tissue.  Adenocarcinomas arise from glandular tissue (eg. Lung, breast, colon, …).  Malignancies of the bone marrow or lymphoid tissue, such as leukemias or lymphomas, are named differently.  The suffix -oma is added to the name of the cell type if the tumor cells are benign (eg. Lipoma).  Precancerous cells have cellular changes that are abnormal but not yet malignant and may be described as hyperplastic or dysplastic. Tumor Characteristics  Tumors are either benign or malignant.  Benign tumors often are encapsulated, localized, and indolent; they seldom metastasize; and they rarely recur once removed.  Malignant tumors are invasive and spread to other locations even if the primary tumor is removed. The cells no longer perform their usual functions, and their cellular architecture changes (anaplasia). TREATMENT Desired Outcome  Chemotherapy may be given to cure cancers, or it may be given to help control the symptoms of an incurable cancer (also known as palliation).  Palliative care consists of pharmacologic and nonpharmacologic treatments and is most effective when initiated at the time of other treatments, improving quality of life. 81  Treatment of cancer  The three primary treatment modalities of cancer are surgery, radiation, and pharmacologic therapy. Non pharmacological therapy of cancer  Surgery is useful to gain tissue for diagnosis of cancer and for treatment, especially those cancers with limited disease. However, when cancer is widespread, surgery may play little or no role, but radiation therapy localized to specific areas may palliate symptoms.  Radiation plays a key role not only in the treatment and possible cure of cancer but also in palliative therapy.  Together, surgery and radiation therapy may provide local control of symptoms of the disease. Pharmacological therapy of cancer  Adjuvant therapy: Systemic therapies that administered after surgery (surgery can remove all macroscopic but not all microscopic disease) to destroy microscopic malignant cells. The goals of adjuvant chemotherapy are to decrease the recurrence by eliminating microscopic malignant cells of the cancer and to prolong survival.  Neoadjuvant chemotherapy: Chemotherapy that is given before surgical resection of the tumor to decrease the tumor burden to be removed and make the surgery easier to perform because the tumor has shrunk away from vital organs or vessels. Dosing of Chemotherapy  Chemotherapeutic agents typically have a very narrow therapeutic index.  The doses of chemotherapy must be given at a frequency that allows the patient to recover from the toxicity of the chemotherapy; each period of chemotherapy dosing is referred to as a cycle.  Each cycle of chemotherapy may have the same dosages; the dosages may be modified based on toxicity; or a chemotherapy regimen may alternate from one set of drugs given during the first, third, and fifth cycles to another set of different drugs given during the second, fourth, and sixth cycles.  The dose density of chemotherapy refers to shortening of the period between cycles of chemotherapy. Administration of dose-dense chemotherapy regimens often used when goal of therapy is cure and it requires the use of colony-stimulating factors (eg, filgrastim or granulocyte– colony stimulating factor [G-CSF]) to be administered to shorten neutropenia duration & severity.  When a chemotherapy regimen is used as palliation (to control symptoms), the dosages of chemotherapy may be decreased based on toxicity or the interval between cycles may be lengthened to maintain quality of life.  Factors that affect chemotherapy selection and dosing are age, concurrent disease states (e.g., Renal failure, heart disease), and performance status (assessed through specific scales). Combination Chemotherapy  The principles of using combination therapy are to use: 1. Agents with different pharmacologic actions 2. Agents with different organ toxicities (e.g., Anthracyclines (eg, doxorubicin) have the potential to cause cardiac toxicity; Microtubule- targeting agents (eg, vincristine) are associated with various forms of neurotoxicity; Alkylating agents (eg, melphalan) are associated with secondary malignancies. 3. Agents that are active against the tumor and ideally synergistic when used together 4. Agents that do not result in significant drug interactions.  When two or more agents are used together, the risk of development of resistance may be lessened, but toxicity may be increased. 82 The most commonly used anticancer agents Class Drugs General comment Antimetabolites Pyrimidine analogues like fluorouracil All can cause Myelosuppression Purine Analogues like mercaptopurine Folate Antagonists like Methotrexate Vinca Alkaloids Vincristine, vinblastine, and Used mainly in hematological vinorelbine malignancies The dose-limiting toxicity of vincristine is neurotoxicity while for vinorelbine and vinblastine is myelosuppression. Taxanes Paclitaxel, Docetaxel, and Cabazitaxel. They have activity in several solid tumors. Mainly cause myelosupression Anthracyclines Daunorubicin, doxorubicin, idarubicin, They can cause cardiac toxicity. and epirubicin Alkylating agents Nitrogen mustard like Cause hemorrhagic cystitis Cyclophosphamide & ifosfamide Nitrosoureas like carmustine and Can cause myelosupression and lumstine used in brain tumors Platinum compounds like Cisplatin, Cisplatin is highly emetogenic carboplatin, and oxaliplatin (higher than carboplatin and oxaliplatin). There is risk of nephrotoxicity, Ototoxicity and electrolyte abnormalities. Antibiotics Bleomycin Pulmonary toxicity Monoclonal Like almetuzumab, obintuzumab, Hypersensitivity reactions antibodies rituximab, etc Checkpoint CTLA-4 inhibitors like ipilimumab They act by promoting activation inhibitors PD-1 and PD-L1 inhibitors like and proliferation of T cells to pembrolizumab, durvalumab, induce tumor infiltration and atezolizumab,etc regression. Used in many solid and hematological cancers Tyrosine kinase BCR-ABL inhibitors like imatinib, Used mainly for CML inhibitors dasatinib, ponatinib, etc BRAF inhibitors like Dabrafenib, They most often are used to treat Vemurafenib, etc melanoma and also some colon cancers with BRAF mutations Anaplastic Lymphoma Kinase (ALK) Mainly used in small cell lung Inhibitors (Alectinib, Brigatinib, cancer Ceritinib, Crizotinib, and Lorlatinib) B-cell Lymphoma 2 (Bcl-2) Inhibitor Used in mainly CLL (Venetoclax (Venetoclax) and Bruton’s Tyrosine may be effective in AML) Kinase (BTK) Inhibitors (Ibrutinib, Acalabrutinib, & Zanubrutinib) 83  Leukemia Acute leukemia  The acute leukemias are hematologic malignancies of bone marrow precursors characterized by excessive production of immature hematopoietic cells.  This proliferation of “blast” cells eventually replaces normal bone marrow and leads to the failure of normal hematopoiesis (Resulting in anemia, neutropenia, and thrombocytopenia) and the appearance in peripheral blood as well as infiltration of other organs including the liver, spleen, bone, skin, lymph nodes, testis, and central nervous system (CNS). Types of acute leukemia Acute leukemias are classified according to their cell of origin. 1. Acute lymphocytic leukemia (ALL) arises from the lymphoid precursors. 2. Acute nonlymphocytic leukemia (ANLL) or acute myelogenous leukemia (AML) arises from the myeloid or megakaryocytic precursors. Epidemiology  Leukemia is a relatively uncommon disease. In the pediatric population, leukemia is a common cancer.  ALL accounts for 75% to 80% of all cases of childhood leukemia.  The average age of diagnosis for AML is about 65 years and is a result of an increasing incidence of AML with age. Etiology  The cause of acute leukemias is unknown; multiple influences related to genetics, socioeconomics, infection, environment (e.g. chemicals, pesticides, and radiation), hematopoietic development, and chance may play a role.  Alkylating agents, such as ifosfamide and cyclophosphamide, and topoisomerase inhibitors, such as etoposide, are linked to an increased risk of AML and myelodysplastic syndrome (MDS). Diagnosis of acute leukemia  Immunophenotyping by flow cytometry has taken on an increasingly important role in the diagnosis of leukemia.  Immunophenotyping is a test used to identify cells on the basis of the types of markers or antigens present on the cell's surface, nucleus, or cytoplasm.  Flow cytometry is the preferred method for leukemic lineage as well as prognostic assignment. Prognostic Factors  Patients with leukemia are categorized based on clinical and biological features that mirror their risk of relapse.  Risk assessment is an important factor in the selection of treatment (minimized overtreatment or undertreatment).  Age, WBC, leukemic cell-surface markers, DNA content, and specific cytogenetic abnormalities predict response to therapy and are used to assign risk and associated treatment.  On the basis of these prognostic variables, patients are assigned to standard-, high-, or very- high- risk groups that determine the aggressiveness of treatment.  For ALL patients: Minimal residual disease (MRD) is a quantitative assessment (By PCR) of subclinical remnant of leukemic burden remaining at the end of the initial phase of treatment (induction) when a patient may appear to be in a complete morphologic remission. This measure has become one of the strongest predictors of outcome for patients with acute leukemia. The elimination of MRD is a principal objective of postinduction leukemia therapy. MRD is an important indicator of disease recurrence 84  Clinical Presentation of acute leukemia  Typically, patients with acute leukemia have non-specific symptoms (fatigue, pallor and fever) with no obvious distress for 1 to 3 months before presentation.  Patients with acute leukemia may present with malaise and weakness (due to anemia); bleeding due to thrombocytopenia; fever and high susceptibility to infection (due to neutropenia), bone pain (due to leukemic infiltration) and weight loss.  Lymphoadenopathy is common seen in ALL patients.  Chloromas (localized leukemic deposits named after their color) may be seen, especially in the periorbital regions and as skin infiltrates in AML patients. Gum hypertrophy is indicative of AML M4 and M5 subtypes.  Potassium and phosphorus often are elevated. Uric acid is increased in approximately 50% of patients secondary to rapid cellular turnover. Treatment Desired outcomes  The primary objective in treating patients with acute leukemia is to achieve a continuous complete remission (CCR).  Remission is defined as the absence of all clinical evidence of leukemia with the restoration of normal hematopoiesis.  For both ALL and AML, remission induction is achieved with the use of myelosuppressive chemotherapy. Failure to achieve remission in the first 7 to 14 days of therapy is highly predictive of later disease recurrence. This again represents the growing importance of MRD in prognosis and treatment. Non pharmacological treatment of acute leukemia  Cancer survivors are at greater risk for developing second malignancies, cardiovascular disease, diabetes, and osteoporosis than those in the general population. Thus, it is important to provide supportive care and counseling related to nutrition, smoking cessation, and exercise as a part of their active treatment. Pharmacologic Therapy: ALL The treatment for ALL consists of five main elements: 1. Initial therapy is called induction (sometimes called remission induction) which aim to induce a remission, a state in which there is no identifiable leukemic cells in the bone marrow or peripheral blood with light microscopy. Current induction therapy for ALL typically consists of vincristine, L- asparaginase, and a steroid (prednisone or dexamethasone). An anthracycline is added for higher risk patients (e.g. adults). Dexamethasone often replaces prednisone because of its longer half- life and better CNS penetration. 2. CNS-directed treatment, 3. Post remission therapies include: A. Intensive postremission consolidation regimens (for 1 month) to reduce the burden of residual leukemic cells B. Reinduction (Interim maintenance for 2 months and delayed intensification by repetition of initial induction therapy given 3 months after remission): followed by C. A prolonged maintenance phase to further eliminate leukemic cells and produce an enduring continuous complete remission (CCR). Maintenance 85 chemotherapy is a combination of oral  methotrexate and 6- mercaptopurine. The total duration of treatment is 2 to 3 years Note: Improved outcome is associated with increasing 6-mercaptopurine doses to the limits of individual tolerance based on absolute neutrophil count (ANC). CNS Prophylaxis  Leukemic invasion of the CNS is an almost universal event in patients. Thus, all patients with ALL and AML leukemia receive intrathecal (IT) chemotherapy.  CNS prophylaxis relies on IT chemotherapy (eg, methotrexate, cytarabine, and corticosteroids), systemic chemotherapy with dexamethasone and high-dose methotrexate, and craniospinal irradiation (XRT) in selected high-risk patients (T-cell ALL). Relapsed ALL  Relapse is the recurrence of leukemic cells at any site after remission has been achieved.  Bone marrow relapse is the major form of treatment failure in 15% to 20% of patients with ALL. Most relapses have the same immunophenotype and cytogenetic changes seen of the original disease. Extramedullary sites of relapse include the CNS and the testicles  Site of relapse and the length of the first remission are important predictors of second remission and overall survival (OS).  Treatment strategies for relapsed ALL include chemotherapy or allogeneic hematopoietic stem cell transplant (allo-HSCT).  Clofarabine has shown considerable activity in refractory acute leukemias.  Blinatumomab, a monoclonal antibody that targets CD19, was approved for Ph negative relapsed or refractory ALL.  Inotuzumab ozogamicin (anti CD-22) is also used in relapsed and refractory B-ALL.  Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that has been shown to induce durable remissions in patients with relapsed and refractory B-cell ALL.  Nelarabine is used in patients with relapsed or refractory T-lineage ALL. Outcome evaluation  Failure to obtain morphologic bone marrow remission by day 28 is a very adverse prognostic sign and dictates further induction treatment.  For those who have a morphologic remission, quantification of MRD has become an increasingly important prognostic factor. Levels of residual less than 0.01% appear to be associated with better outcome. Treatment of AML Treatment of AML is divided into two phases: 1. Induction (to achieve remission): consists of a combination of cytarabine, and daunorubicin. Adding gemtuzumab ozogamicin to induction therapy for older patients improved relapsed rates and OS. 2. Consolidation (postremission) to further enhance remission with more cytoreduction and prevent relapse. Mainly through the use of 2-4 cycles of high-dose cytarabine Note: Midostaurin, an oral multi- target kinase inhibitor, was recently approved by the FDA for treatment of Fms-like tyrosine kinase 3(FLT3) positive AML 86  Allogeneic Hematopoietic Stem Cell Transplantation  Hematopoietic stem cell transplantation (HSCT) is the most effective treatment for AML. Its promising benefit must be weighed against the potential risk of transplantation related sequelae. Patients who do not have an HLA-matched sibling proceed to postremission therapy with chemotherapy alone.  The role of HSCT, particularly whether it should be performed during the first CR or reserved for second remission, remains the most controversial issue in pediatric AML. In certain institutions, HSCT is often reserved for patients that are considered high risk. CNS therapy  Patients with CNS disease at diagnosis can be cured with IT therapy. In most cases, IT cytarabine with or without methotrexate and systemic high-dose cytarabine provide effective treatment. Relapsed AML  Even though there is no standard therapy for relapse, most studies have shown that high-dose cytarabine-containing regimens have considerable activity in obtaining a second remission.  Cytarabine has been used in combination with mitoxantrone, etoposide, fludarabine, 2- chlorodeoxyadenosine, and clofarabine.  For patients unable to tolerate intensive chemotherapy, low dose cytarabine and the hypomethylating agent, azacitidine, are also options for relapsed disease.  Venetoclax in combination with either decitabine or azacitidine is also an alternative in the relapsed setting.  Gilteritinib is an FLT3 inhibitor approved for AML patients with an FLT3- ITD mutation in relapsed setting.  Enasidenib is an oral inhibitor of mutant IDH2 proteins and is approved for use in patients with relapsed AML who harbor IDH2 mutations. Similarly, ivosidenib is an IDH1 inhibitor that is approved for use in relapsed AML patients with an IDH1 mutation.  After a patient has achieved a second remission with conventional chemotherapy, allo-HSCT is the therapy of choice. Complications of Treatment 1. Tumor Lysis Syndrome  Tumor lysis syndrome (TLS) is an oncologic emergency that is characterized by metabolic abnormalities resulting from the death of blast cells and the release of large amounts of purines, pyrimidines, and intracellular potassium and phosphorus.  Measures to prevent TLS include aggressive hydration to increase urine output, and allopurinol to reduce uric acid production. Rasipuricase is indicated in some cases. Infection  Anfection is a primary cause of death in acute leukemia patients. Both the disease and aggressive chemotherapy cause severe myelosuppression, placing the patient at risk for sepsis.  Because the progression of infection in neutropenic patients can be rapid, empirical antibiotic therapy (usually 4th generation cephalosporins) is started whenever a fever is documented. 2. Secondary malignancy: discussed later 87  Supportive care  Platelet transfusions are a common tool to prevent hemorrhage. Patients with uncomplicated thrombocytopenia can be transfused when the platelet count falls below 10 × 103/mm3. Patients who are either highly febrile or actively bleeding may require transfusions at higher levels.  Red blood cell transfusions generally are not necessary for a hemoglobin concentration greater than 8 g/dL.  The use of CSFs (G-CSF most commonly) generally is limited to those chemotherapy regimens that place the patient at highest risk for prolonged neutropenia. Chronic leukemias  The two most common forms are chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL).  The slower progression of the disease contrasts it from acute leukemia, with the survival of chronic leukemia often lasting several years without treatment. Clinical course of CML  It is a triphasic disease based on % of myeloblasts in peripheral blood or bone marrow: 1. Initial chronic phase 2. Accelerated phase (disease is progressing with worsening symptoms), 3. Blast crisis which resembles acute leukemia, immediate aggressive treatment is required Epidemiology and etiology of CML  The incidence of CML increases with age, with the median age of diagnosis being 65 years.  The etiology cannot be determined, but high doses of ionizing radiation and exposure to solvents such as benzene are recognized risk factors. Ph Chromosome  The Philadelphia chromosome (Ph) results from a translocation between chromosomes 9 and 22, leaving a shortened chromosome 22.  The Ph results in the formation of an abnormal fusion gene (translocation of genetic material) between the chromosome 22 (breakpoint cluster region-BCR gene) and chromosome 9 (the Abelson proto-oncogene-ABL gene), which encodes an overly active tyrosine kinase. The loss of control of tyrosine kinase activity causes abnormal cellular proliferation and inhibition of apoptosis.  Molecular tools such as quantitative reverse transcriptase-polymerase chain reaction (Q-PCR) and fluorescence in situ hybridization (FISH) are used in the detection and monitoring of BCR-ABL transcripts found in CML Clinical Presentation of CML  ~50% are asymptomatic at diagnosis.  Symptoms may include fatigue, fever, bleeding, and weight loss.  Organomegaly consisting of splenomegaly and hepatomegaly occur in chronic leukemia.  Lab data: Anemia and Leukocytosis (WBC count > 100 × 103/mm3). 88  Treatment of CML Desired Outcome  The primary goal in the treatment of CML is to achieve long-term disease control with TKI therapy and possibly treatment-free remission (TFR).  A deep, long-lasting molecular response (BCR-ABL 100 × 103/mm3), especially lymphocytosis (absolute lymph count > 5 × 103/mm3). Hypogammaglobulinemia, and thrombocytopenia. Prognostic factors of CLL  Increasingly, biological markers of the disease such as deletions of chromosome 17p (del(17p)) and 11q (del(11q)) and mutational status of immunoglobulin heavy chain variable region gene (IgVH) are being used to predict the likely clinical course. Patients with del(17p) or TP53 mutations tend to have a poor response to therapy. TREATMENT Desired Outcomes  Because the current treatments for CLL are not curative, reduction in tumor burden and improvement in disease symptoms are reasonable end points, particularly in older patients.  A complete response (CR) to therapy can be defined as a resolution of lymphadenopathy and organomegaly, normalization of peripheral blood counts, and elimination of lymphoblasts in the bone marrow. Non pharmacological treatment  Asymptomatic early stage CLL (especially elderly people) can be observed (watch and wait) without treatment until evidence of disease progression.  Allogeneic HSCT remains an option for younger patients with aggressive disease who have failed prior therapies. 91  Pharmacological treatment  The NCCN guidelines provide recommendations on first-line and subsequent CLL therapies based on mutational status, age, and whether comorbidities are present.  Oral small molecule inhibitor therapy (eg, ibrutinib, venetoclax) has established a pivotal role in the front-line treatment of symptomatic CLL. This has minimized the use of traditional chemotherapy-based regimens (eg, purine analogs and alkylating agents).  Monoclonal antibodies targeting CD20 antigen may also be incorporated into front-line therapy. Treatment options of CLL A. Cytotoxic chemotherapy B. Small-Molecule Inhibitors (new novel oral therapies) C. Monoclonal antibodies Cytotoxic chemotherapy  NCCN still recommends fludarabine, cyclophosphamide, and rituximab (FCR) as the preferred regimen for younger (< 65 years old) patients with IgVH- mutated CLL. The aggressive use of FCR may offer a potential cure for these select patients.  Fludarabine is associated with myelosuppression and prolonged immunosuppression.  Clinicians should consider antibacterial and antiviral prophylaxis for Pneumocystis and varicella zoster when using fludarabine- based therapy. 92  Monoclonal antibodies  Anti-CD20 monoclonal antibodies are widely used in the treatment of CLL. They include Rituximab, which has been largely replaced by the next- generation monoclonal antibodies, obinutuzumab, and ofatumumab.  Obinutuzumab is different than the other anti-CD20 monoclonal antibodies, having a higher binding affinity to the CD20 epitope and causing direct cell death.  The anti-CD20 monoclonal antibodies are often used in combination with targeted therapy or chemotherapy. They are less frequently used as a monotherapy. The selection and combination of the monoclonal antibody depends on clinical studies.  The most common side effects for monoclonal antibodies include infusion reactions consisting of fever, chills, hypotension, nausea, vomiting, and headache. Premedication with diphenhydramine and acetaminophen is recommended to minimize infusion reactions.  Reactivation of hepatitis B virus (HBV) is also a concern for patients on anti- CD20 therapy. Prophylactic hepatitis B antiviral therapy or treatment with entecavir may be warranted. Small-Molecule Inhibitors  An understanding of the B-cell receptor signaling pathways of CLL has led to the approval of oral targeted therapies. Many of these therapies have improved the median overall survival of CLL. 1. BTK inhibitors: BTK is an essential enzyme in the B-cell receptor pathway, they include: A. Ibrutinib: may be used as first-line therapy for all patients (used as monotherapy), including patients with del(17p), regardless of age. An increased risk of atrial fibrillation has been also associated with ibrutinib. B. Acalabrutinib is a second-generation BTK inhibitor. It has a higher BTK selectivity than ibrutinib which has led to promising results. The indications are similar to ibrutinib with acalabrutinib being used with or without obinutuzumab for first-line therapy of CLL and in relapsed and refractory CLL. 2. Oral Phosphatidylinositol-3-kinase (PI3-K) inhibitors include Idelalisib and duvelisib. A. Idelalisib targets phosphatidylinositol-3-kinase (PI3-K). Idelalisib has been studied as monotherapy as well as combination therapy with rituximab. B. Both idelalisib and duvelisib may be used for patients with relapsed/refractory CLL. Boxs warnings for idelalisib and duvelisib include hepatotoxicity, for idelalisib and colitis, infestion, cutaneous reactions and pneumonitis for duvelisib. Patients should receive Pneumocystis pneumonia prophylaxis and CMV antiviral prophylaxis should also be considered to prevent CML infection and reactivation. 3. Venetoclax (Venclexta) is a small molecular inhibitor that targets B-cell lymphoma 2 (BCL-2) protein and may be used as first line therapy or for patients with relapsed/refractory CLL. Adverse effects for venetoclax include tumor lysis syndrome and prolonged neutropenia (may require growth factor support). Venetoclax is used in combination with anti-CD20 monoclonal antibodies. 93  Breast Cancer INTRODUCTION Breast cancer is a malignancy originating from breast tissue. Disease confined to a localized breast lesion is referred to as early, primary, localized, or curable. Disease detected clinically or radiologically in sites distant from the breast is referred to as advanced or metastatic breast cancer (MBC), which is incurable. EPIDEMIOLOGY  Two variables most strongly associated with the occurrence of breast cancer arebiological sex and age. Additional risk factors include endocrine factors (eg, menarche before age 11, age 55, or later for natural menopause, nulliparity, late age at first birth, and hormone replacement therapy), genetic factors (eg, personal and family history, mutations of tumor suppressor genes [BRCA1 and BRCA2]), and environmental and lifestyle factors (eg, radiation exposure, tobacco use, and alcohol consumption).  Breast cancer cells often spread undetected by contiguity, lymph channels, and through the blood early in the course of the disease, resulting in metastatic disease after local therapy. The most common metastatic sites are lymph nodes, skin, bone, liver, lungs, and brain. PREVENTION OF BREAST CANCER  Risk reduction strategies include prophylactic mastectomy, oophorectomy, and pharmacologic agents.  Agents available for pharmacologic risk reduction include selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). The SERMs, tamoxifen and raloxifene taken for 5 years, reduce the risk of invasive and noninvasive breast cancer by about 50% in women at high risk for developing the disease. Tamoxifen increased the incidence of endometrial cancer and both agents increased thromboembolic events.  A similar reduction in the risk of contralateral primary breast cancers in high risk, postmenopausal individuals was demonstrated with the AIs, exemestane and anastrozole.  Clinical guidelines recommend the use of SERMs or AIs for risk reduction in postmenopausal women at high risk. CLINICAL PRESENTATION  A painless, palpable lump is the initial sign of breast cancer in most women. The typical malignant mass is solitary, unilateral, solid, hard, irregular, and nonmobile. Nipple changes are less commonly seen. More advanced cases present with prominent skin edema, redness, warmth, and induration.  Symptoms of