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Sexual & Reproductive Health I. HORMONE THERAPY AND MENOPAUSE A. Background of Menopause 1. Definition: Cessation of menstrual periods for 1 year, also known as final menstrual period, loss of ovarian follicular function 2. Average age of menopause is 52 years, but ranges from 40 to 58 yea...

Sexual & Reproductive Health I. HORMONE THERAPY AND MENOPAUSE A. Background of Menopause 1. Definition: Cessation of menstrual periods for 1 year, also known as final menstrual period, loss of ovarian follicular function 2. Average age of menopause is 52 years, but ranges from 40 to 58 years. 3. Common symptoms a. Vasomotor symptoms (hot flashes) i. Most common reason for treatment because they may impact quality of life. Common symptoms include increased skin temperature, nausea, dizziness, headache, palpitations, diaphoresis, and night sweats. ii. May interrupt sleep and cause insomnia iii. Occur in 75%–85% of women, usually within 12–24 months after the last menstrual period. b. Genitourinary syndrome of menopause (GSM): This syndrome includes genital symptoms of dryness, burning, and irritation; urinary symptoms and conditions of dysuria, urgency, and recurrent urinary tract infections (UTIs); and sexual symptoms of pain and dryness (Menopause 2020; 27:976-92). i. Decrease in estrogen and other sex steroids causes thinning of hair in the mons region and shrinkage of the labia minora; vulvovaginal atrophy (VVA) leads to pruritus and pain. ii. Loss of lubrication leads to dyspareunia (pain during sexual intercourse). iii. Vaginal pH changes and becomes more basic (from 4.5−5 to 6−8), creating a favorable environment for bacterial colonization. iv. Thinning of urethra and bladder lining and decreased muscle tone result in recurrent episodes of urinary frequency, urgency with dysuria, and urinary tract infections. B. Treatments 1. Individualization of therapy is essential. The patient’s medical history must be considered, including cancer (specifically breast cancer), cardiovascular disease (CVD), stroke, hypertension, and quality of life with menopausal symptoms. 2.  Hormone therapy (HT) is an all-encompassing term that includes estrogen and progestogen therapy (EPT), estrogen-only therapy (ET), progestogen-only therapy (PT), and estrogen-receptor (ER) agonists or antagonists. (Progestogen is an umbrella term for progesterone [natural] and progestins [synthetic]) a. FDA approved indications for HT: Treatment of moderate to severe vasomotor symptoms, treatment of moderate to severe GSM, prevention of postmenopausal osteoporosis, hypoestrogenism caused by hypogonadism, castration or premature ovarian failure. b. Recommendations for HT i. Menopausal symptom relief (a) Moderate to severe vasomotor symptoms (primary indication) 1. Recommend lowest effective dose. 2. For women younger than 60 or women who are within 10 years of menopause onset without contraindications or at a high risk of CVD or breast cancer, assess the baseline risk of breast cancer and CVD, and consider risk when making a recommendation. (b) Moderate-to-severe GSM 1. Vaginal symptoms – Recommend local ET versus systemic therapy if treating vaginal symptoms only 2. Urinary health – Systemic HT may worsen stress incontinence; local ET therapy may help with overactive bladder (c) Sexual symptoms – HT not recommended for sole treatment of diminished libido ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-552 Sexual & Reproductive Health (d) Osteoporosis – EPT and ET indication for prevention, ↓ osteoporotic fractures, used only when alternative therapies are not appropriate; ER agonists/antagonists may also be used for osteoporosis. See section below. Symptom Assessment Confirm that vasomotor symptoms are adversely affecting sleep, daytime functioning, or quality of life Risk Factor Assessment Confirm abscence of absolute contraindications to HT: Breast or endometrial cancer, CV disease, active liver disease, undiagnosed vaginal bleeding HT Initiation Recommend: Age < 60 yr AND menopause onset within 10 yr AND Low risk of breast cancer and CV disease Consider with caution: Age > 60 yr OR menopause onset > 10 yr OR moderate risk of breast cancer or CV disease Avoid: High risk of breast cancer or CV disease OR age > 60 yr or menopause onset > 10 yr within moderate risk of breast cancer CV disease Figure 1. Risk Assessment for Initiating Hormone Therapy CV = cardiovascular; HT = hormone therapy Adapted from: Shifren JL, Crandall CJ, Manson JE. Menopausal hormone therapy. JAMA 2019;321:2458-9. ii. Risk assessment (J Clin Endocrinol Metab 2015;100:3975-4011) (a) For women with a high risk of venous thromboembolism (VTE) Nonoral route at lowest effective dose is recommended (if not contraindicated). (b) For women with a high risk or history of breast cancer: Nonhormonal treatment is recommended for symptom relief. (c) For women with a high risk of CVD (known myocardial infarction [MI], cerebrovascular disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes mellitus, chronic kidney disease, and 10-year CVD risk greater than 10%): Nonhormonal treatment is recommended for symptom relief. (d) For women with a moderate risk of CVD: Transdermal estradiol with appropriate use of progestogen (individualized) is recommended. c. Benefits and risks of estrogen and progestogens i. Benefits of estrogen (a)  Relieves genitourinary atrophy (b) Relieves vasomotor instability ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-553 Sexual & Reproductive Health (c) Osteoporosis: Reduction in hip fractures by 25%; reduction in vertebral fractures by 50%. Estrogen reduces the rate of bone resorption but does not reverse bone loss. (d) May help improve sleep by decreasing hot flashes ii. Risks of estrogen (a) Adverse effects: Bloating, headache, breast tenderness (5%–10%) (b) Endometrial cancer: Risk increases with unopposed estrogen use in women with an intact uterus. (1) Cancer risk increases 8-fold for 10–20 years of estrogen use. (2) Not recommended for use in women with a history of endometrial cancer. Women with early stage, low-risk endometrial cancers (grade 1 and 2 endometrioid subtypes with negative estrogen and progesterone receptors) who used HT may have similar recurrence and death rates but overall recommendation is to avoid HT use in women with endometrial cancer, especially advanced stages (Menopause 2017;24:1-26). (3) A progestogen is recommended in all women with an intact uterus using estrogen (JAMA 1996;275:370-5, Menopause 2017;24:1-26). (c) Breast cancer with unopposed estrogen: Uncertain (1) The Women’s Health Initiative (WHI) showed no increased risk and a nonsignificant decrease in risk in women who use estrogen for an average of 7.2 years. May increase relative risk among women who take estrogen for longer than 5 years, though some studies have not shown this risk (Menopause 2017;24:1-26). (2) Not recommended for use in women with a history of breast cancer (Menopause 2017;24:1-26). (3) Risk seems to increase with the addition of the progestogen and be related to the length of use. The risk is small and decreases after discontinuation of use. (d) CHD: Possible increased risk of cardiovascular outcomes; not recommended for coronary protection at any age. (e) Gallbladder effects: oral estrogen may increase risk of gallbladder disease (gallstones, cholecystitis, cholecystectomy). Risk is slightly lower with medroxyprogesterone acetate in combination with estrogen (Menopause 2017;24:1-26). iii. Benefits of progestogen: (a) Decreased risk of estrogen-induced irregular bleeding (b) Decreased risk of endometrial hyperplasia and carcinoma iv. Risks of progestogen (a) Adverse effects: Bloating, weight gain, irritability, depression (dose related) (b) Unpredictable endometrial bleeding with continuous estrogen/progestin during first 8–12 months (30%–50%) v. Selected outcomes related to EPT and ET (a) Cardiovascular outcomes with conjugated estrogens and medroxyprogesterone acetate (JAMA 1998;280:605-13) (1) A longer duration of use leads to a greater decrease in relative hazards in nonfatal MI and CHD death; however, there was an increased risk of VTE and gallbladder disease. (2) Conclusions of study: HT was not appropriate to initiate for secondary prevention of CHD, but for women already using HT, long-term use might result in a decrease in CHD. (3) A follow-up study suggested that older women with CHD who used HT for longer than 6.8 years had a higher risk of VTE and biliary tract surgery (JAMA 2002;288:58-66). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-554 Sexual & Reproductive Health (b) Other findings related to cardiovascular outcomes from various trials (1) Venous thromboembolism (A) Observational studies indicated increased risk. (B)  A randomized controlled trial, the WHI (JAMA 2002;288:321-33), found increased risk in the EPT arm (18 additional VTEs per 10,000 women per year of EPT) and in the estrogen only therapy (ET) arm (7 additional VTEs per 10,000 women per year of ET). (C) In WHI, when EPT and ET were initiated in women 50–59 years of age, the risk of VTE was lower in this age group (11 additional VTEs per 10,000 women per year of EPT and 4 additional VTEs per 10,000 women per year of ET). (2) Stroke (A) Both EPT and ET showed an increased risk of stroke (8 additional strokes per 10,000 women per year of EPT and 11 additional strokes per 10,000 women per year of ET). (B) Women 50–59 years of age had no significant increase in stroke with EPT in the WHI, but in the ET group alone, risk doubled. Nurses’ Health Study showed similar results (Cochrane Database Syst Rev 2015;3:CD002229). (3) Coronary heart disease (A) Observational studies indicated therapy may decrease CHD risk, but most women were younger than 55 and had entered menopause within the past 2–3 years. (B) Randomized controlled trials indicated an increased risk of CHD, but women had an average age of 63–64 years and had entered menopause about 10 years earlier. When adjusted for age, the estrogen-only arm of the WHI trial matches observational data, indicating a lower risk of CHD in younger patients. (C) Data show women who begin HT within 10 years of entering menopause may have a lower risk of CHD, whereas older women (more than 10 years from the onset of menopause) may have a higher risk of CHD. (D) Coronary artery calcium, a marker associated with atheromatous plaque burden and CHD risk, has been decreased in some observational studies. In the WHI study, estrogen-only arm participants had lower concentrations of coronary artery calcium after 7 years of treatment. (E)  Subclinical atherosclerosis, measured as carotid intima-media thickness, is reduced in women who started estrogen therapy with or without a progestogen less than 6 years past the time of menopause compared with placebo. This was not true in women who started hormone therapy 10 years or more after menopause onset (N Engl J Med 2016;374:1221-31). (F) WHI findings (JAMA 2002;288:321-33). The WHI trial included conjugated estrogens and medroxyprogesterone acetate in healthy women 50–79 years of age for primary prevention of CHD. Controversy exists because the average age of women was older; thus, increases in breast cancer or CVD could be caused by age (Table 1). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-555 Sexual & Reproductive Health Table 1. Summary of WHI Outcomes for EPT Use Risk or Benefit Relative Risk Absolute Risk Each Year Blood clots Dementiaa 2.11, or 111% ↑ 18 more cases in 10,000 women 2.05, or 105% ↑ 1.41, or 41% ↑ 1.29, or 29% ↑ 1.26, or 26% ↑ 0.66, or 33% ↓ 0.63, or 37% ↓ 23 more cases in 10,000 women > 65 8 more cases in 10,000 women 7 more cases in 10,000 women 8 more cases in 10,000 women 5 fewer cases in 10,000 women 6 fewer cases in 10,000 women Strokes Heart attacks Breast cancer Hip fractures Colon cancer Women’s Health Initiative Memory Study. EPT = estrogen and progestogen therapy; WHI = Women’s Health Initiative. a (c) Further information suggests increased risk of ovarian cancer (data conflicting); longterm use greater than 5 years may increase risk, particularly in estrogen-only therapy; overall risk of occurrence considered rare, according to WHI data (JAMA 2009;302:298305). A more recent meta-analysis showed that hormone therapy, regardless of type or regimen, was associated with an increased risk of ovarian cancer (Menopause 2016;4:41724, Menopause 2017;24:1-26). (d) Lung cancer may be increased in older women with a history of smoking (Lancet 2009;374:1243-51); some data are conflicting. Seems to be more associated with EPT use than with ET use. (e)  Cumulative 18-year follow-up on WHI trials of conjugated equine estrogens (0.625 mg/day) and medroxyprogesterone acetate (2.5mg/day) used for a median of 5.6 years or conjugated equine estrogens alone for a median of 7.2 years showed no difference in all-cause and cause-specific mortality risk (JAMA 2017;318:927-38). vi. Formulations (a) Oral: Used for vasomotor symptoms, also covers GSM if concomitant. (b) Transdermal: For women who are intolerant of oral preparations, used for vasomotor symptoms, also covers GSM if concomitant; consider as first-line for women with moderate risk of CVD if estrogen is needed. (c) Vaginal and local preparations: For women with GSM. In general, topical treatment is sufficient and should be tried before oral preparations for patients experiencing no other symptoms. vii. Hormone regimens (a) Therapy duration: Lowest dose for least amount of time. Check after 3 months to 1 year, and try to discontinue if asymptomatic; if symptoms recur, treat for an additional 3 months; best to limit treatment to less than 5 years. (b) Unopposed estrogen (1) Women with a uterus must use estrogen in combination with progestogen; use of estrogen alone in women with a uterus causes endometrial hypertrophy and increases the risk of endometrial cancer (JAMA 1996;275:370-5). (2) Estrogen taken daily without interruption is suggested for women with a hysterectomy. (A) Transdermal estradiol patches can be used in women who are intolerant of oral preparations or want nondaily administration ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-556 Sexual & Reproductive Health (c) Estrogen plus cyclic progestogen (1) Continuous estrogen daily (2) Cyclic progestogen such as medroxyprogesterone acetate 5−10 mg/day for 10–14 days/month (3) Similar to female cycle, with a withdrawal bleed each cycle (d) Estrogen plus continuous progestogen (1) Continuous estrogen daily (2) Continuous progestogen such as medroxyprogesterone acetate 1.5–2.5 mg/day without interruption (3) Irregular menstrual cycle for the first 8–12 months of therapy, leading to amenorrhea (e) Intermittent (1) Continuous estrogen daily (2) Three days on progestogen, 3 days off (3) Seldom used viii. Monitoring criteria (a) Monthly: Breast self-examination (b) Annually: Breast examination by provider, mammography, pelvic examination (c) Evaluation of potentially abnormal vaginal bleeding (1) Unopposed estrogen: Any episode of vaginal bleeding unless the woman has had a health assessment deemed normal in the past 6 months (2) Estrogen plus cyclic progestogen: If bleeding occurs other than at the time of expected withdrawal bleeding (3) Estrogen plus continuous progestogen: If bleeding is heavier than normal, is prolonged (longer than 10 days at a time), is frequent (more often than monthly), or persists for more than 10 months after beginning therapy ix. Products and dosing (Tables 2, 3, 4, 5, and 6) Table 2. Oral Estrogen Products Brand Name Generic Name Strengths (mg) Estrace Femtrace Menest Premarin, Cenestin, Enjuvia 17β-Estradiol Estradiol acetate Esterified estrogens Conjugated estrogens 0.5, 1, 2 0.45, 0.9, 1.8 0.3, 0.625, 1.25 0.3, 0.45, 0.625, 0.9, 1.25 ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-557 Sexual & Reproductive Health Table 3. Vaginal Estrogen Products Formulation Vaginal creams Brand Name Estrace Generic Name and Strength Micronized estradiol (0.1 mg/g) Premarin Conjugated estrogens (0.625 mg/g) Vaginal rings Estring Femring Vaginal tablet Vagifem, Yuvafem Imvexxy 17β-Estradiol (2-mg ring that delivers 7.5 mcg/day) Estradiol acetate (0.05 or 0.1 mg/day) Estradiol hemihydrate (10 mcg/day) Estradiol inserts (4 or 10 mcg) Dose Initial: 2–4 g/day for 1–2 wk; then gradually reduced to half the initial dose for 1–2 wk, followed by maintenance of 1 g/day applied vaginally one to three times weekly Atrophic vaginitis: Use 0.5–2 g/day applied vaginally for 21 days and then 7 days off; may also use twice-weekly regimen of 0.5 g intravaginally for dyspareunia 1 ring every 3 mo inserted vaginally 1 vaginal tablet once daily for 2 wk; then 1 tablet twice weekly 1 vaginal insert daily for 2 wk; then 1 vaginal insert twice weekly Table 4. Transdermal Estrogen Products Brand Name Formulation Estrogen Provided (mg/day) Alora 0.025, 0.05, 0.075, 0.1 1 patch twice weekly 17β-Estradiol matrix patch Climara Minivelle Vivelle-Dot, Dotti Menostar Lyllana Estraderm Divigel 0.1% Elestrin 0.06% EstroGel 0.06% Evamist 17β-Estradiol transdermal gel 17β-Estradiol transdermal spray 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 0.025, 0.0375, 0.05, 0.075, 0.1 0.025, 0.0375, 0.05, 0.075, 0.1 0.014 0.025, 0.0375, 0.05, 0.075, 0.1 0.05, 0.1 Unknown 0.52 (0.0125 absorbed), 1.04 (0.0375 absorbed) 0.75 (0.035 absorbed) Dose Unique Traits and Counseling Points Rotate sites of application to avoid irritation for all patches 1 patch weekly 1 patch twice weekly 1 patch twice weekly 1 patch weekly 1 patch twice weekly 1 patch twice weekly 0.25, 0.5, 0.75, or 1 g of gel 0.25, 0.5, 0.75, or 1 g of gel 0.25, 0.5, 0.75, or 1 g of gel 1.53 (0.021 absorbed) Initial 1 spray/day (1.53 mg) increasing to 2 or 3 sprays/day Minivelle should be placed on dry skin below umbilicus on abdomen or buttocks Menostar is lowest-dose transdermal patch available; indicated only for prevention of postmenopausal osteoporosis Apply Divigel to one leg daily, alternate sites daily Apply Divigel to one leg daily, alternate sites daily Apply Divigel to one leg daily, alternate sites daily 1 spray on forearm daily, can increase to 2 or 3 sprays on forearm daily ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-558 Sexual & Reproductive Health Table 5. Combination Products Brand Name Activella, Amabelz, Mimvey, Lopreeza Angeliq Generic Name 17β-Estradiol/ norethindrone acetate 17β-Estradiol/ drospirenone Climara Pro 17β-Estradiol/ levonorgestrel CombiPatch 17β-Estradiol/ norethindrone acetate Bijuva 17β-Estradiol/ progesterone Jinteli, Fyavolv Ethinyl estradiol/ norethindrone acetate Prefest 17β-Estradiol/ norgestimate Premphase Conjugated estrogens/ medroxyprogesterone acetate Prempro Conjugated estrogens/ medroxyprogesterone acetate Hormone Strengths 0.5 mg estrogen, 0.1 mg norethindrone (Mimvey unavailable at 0.5/0.1 mg strength); 1 mg estrogen, 0.5 mg norethindrone Dose 1 tablet daily 1 mg estrogen, 0.5 mg drospirenone; 0.5 mg estrogen, 0.25 mg drospirenone 0.045 mg estrogen, 0.015 mg levonorgestrel 1 tablet daily 1 patch weekly 0.05 mg estrogen, 0.14 mg norethindrone 0.05 mg estrogen, 0.25 mg norethindrone 1 mg estrogen, 100 mg progesterone 1 patch twice weekly 1 capsule every evening with food 0.0025 mg estrogen, 0.5 mg progestogen (Fyavolv) 1 tablet daily 0.005 mg estrogen, 1 mg norethindrone 1 mg estrogen, 0.09 mg norgestimate 3 days of estrogen tablets only, 3 days of estrogen and progestogen 0.625 mg estrogen, 5 mg medroxyprogesterone 0.625 mg/day for 14 days; then 0.625 mg and 5 mg/day for 14 days 0.3 mg estrogen, 1.5 mg medroxyprogesterone; 1 tablet daily 0.45 mg estrogen, 1.5 mg medroxyprogesterone; 0.625 mg estrogen, 2.5 mg medroxyprogesterone Table 6. Progestogen Products Brand Name Generic Name Dosage Strengths and Formulation Crinone 4%, 8% Progesterone gel Endometrin Prometrium Provera Progesterone vaginal suppository Micronized progesterone in peanut oil Medroxyprogesterone acetate 45-mg vaginal applicator vaginally, 90-mg vaginal applicator vaginally 100 mg vaginal suppository 100- and 200-mg oral capsules 2.5-, 5-, and 10-mg oral tablets d. Selective estrogen receptor modulators, also known as estrogen receptor agonist/antagonists, indicated for use in menopause symptoms. Benefits include provision of endometrial protection in patients with a uterus, without the need for a progestogen. i. Ospemifene 60-mg oral tablets (Osphena): 1 tablet orally daily (a) Indicated for the treatment of moderate to severe dyspareunia or vaginal dryness caused by vulvar and vaginal atrophy of menopause. (b) Agonist on endometrial lining affects uterine endometrium; it is recommended that women with a uterus add a progestin to any agent with estrogenic properties, although clinical studies with ospemifene alone did not find an increased risk of endometrial hyperplasia. No studies are available evaluating the use of ospemifene with a progestin. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-559 Sexual & Reproductive Health (c) Adverse reactions (greater than 1%) (1) Hot flashes (2) Muscle cramps (3) Vaginal discharge (4) Hyperhidrosis (d) Contraindications similar to those of estrogen (e.g., history of estrogen-dependent cancer, undiagnosed vaginal bleeding) (1) Pregnancy, nursing, pediatrics (2) History of VTE (3) Severe hepatic impairment (Child-Pugh class C) (e) Drug interactions (1) Rifampin decreases ospemifene exposure by 59%. Avoid concomitant use. (2) Fluconazole increases ospemifene concentrations 2.7-fold and should not be used concomitantly; ketoconazole increases ospemifene 1.4-fold. (3) Highly protein bound, about 99%; may affect other medications that are protein bound. (4) Should not be given with estrogen products, including other selective estrogen receptor modulators. ii. Conjugated estrogens 0.45 mg plus bazedoxifene 20 mg oral tablets (Duavee); 1 tablet orally daily (see Osteoporosis section in text that follows for more information) (a) Indicated for treatment of moderate to severe vasomotor symptoms and prevention of osteoporosis in patients with a uterus. (b) Selective estrogen receptor modulator used instead of a progestin (c) May increase risk of DVT; should not be used in women with a history of blood clots; has contraindications similar to those of estrogen. (d) Common adverse effects: Muscle spasms; nausea and vomiting; throat, neck, or upper abdominal pain; and indigestion e. Prasterone vaginal insert (Intrarosa) i. Indicated for the treatment of moderate to severe dyspareunia due to vulvar and vaginal atrophy resulting from menopause. ii. Inactive endogenous steroid that is converted into androgens and/or estrogens. Mechanism of action is not fully understood. iii. Administration: Prasterone 6.5 mg placed vaginally once at bedtime iv. Should not be used in women with current or past history of breast cancer; contraindicated in women with undiagnosed genital bleeding. v. Common adverse effects: Vaginal discharge and abnormal pap smear vi. May be stored in refrigerator or at room temperature. f. Other hormone products i. Bioidentical hormones: May still have adverse effects similar to those of conjugated/esterified estrogens and synthetic progestins. ii. Androgens: Testosterone may help with sexual dysfunction but not vasomotor symptoms; not approved for use. iii. Phytoestrogens (see text that follows for soy isoflavones): Act similarly to estrogen and carry similar contraindications. iv. Megestrol (progestogen; see earlier section on progestogens) 3. Serotonin reuptake inhibitors: Best for vasomotor symptoms in high-risk women for whom HT is not recommended. a. Paroxetine 7.5 mg orally once daily (Brisdelle; only selective serotonin reuptake inhibitor with indication for vasomotor symptoms) b. Venlafaxine 75 mg orally once daily ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-560 Sexual & Reproductive Health c. Fluoxetine 20 mg orally once daily d. Paroxetine 20 mg orally once daily e. Sertraline 100 mg orally once daily f. Escitalopram 10–20 mg orally once daily g. Citalopram 10–20 mg orally once daily h. Desvenlafaxine 100–150 mg orally once daily 4. Natural products: Some data for effectiveness (no FDA indication) a. Soy isoflavones: May still have adverse effects similar to those of conjugated estrogens. b. Evening primrose oil: No solid evidence for use. c. Black cohosh: Some effectiveness for vasomotor symptoms; reports of liver toxicity. 5. Others: Used for vasomotor symptoms (no FDA indication) (Int J Womens Health 2012;4:305-19) a. Clonidine b. Gabapentin c. Pregabalin d. Acupuncture e. Hypnosis f. Lifestyle changes Patient Case Questions 1 and 2 pertain to the following case: E.L. is a 50-year-old woman with hot flashes and vaginal irritation. She has tried exercise, diet, and antidepressants to help relieve her hot flashes but has been unsuccessful. She is otherwise healthy with no history of cancer and no surgical procedures. She states that her hot flashes are interfering with her daily activities and wants to try HT. 1. When counseling E.L. on the use of HT and explaining the WHI trial, which has been proven to be statistically significant with conjugated estrogen and medroxyprogesterone acetate? A. Increased risk of VTE B. Decreased risk of stroke C. Decreased risk of MI D. Increased risk of fractures 2. Which treatment is best to recommend to E.L.? A. Estrogen patch 0.025 mg (17β-estradiol); change patch twice weekly. B. Prasterone 6.5 mg vaginal inserts; insert vaginally once daily. C. Conjugated estrogen 0.3 mg/medroxyprogesterone acetate 1.5 mg; take 1 tablet daily. D. Ospemifene 60 mg; take 1 tablet daily. II. OSTEOPOROSIS A. World Health Organization (WHO) Definitions Based on T-scores (T-score indicates that for every standard deviation [SD] below the mean young adult bone mineral density [BMD], fracture risk increases 2-fold) 1. Normal = BMD within 1 SD of the young adult mean. 2. Low bone mass (osteopenia) = BMD 1–2.5 SD below the young adult mean (often seen as T-score between -1 and -2.5). 3. Osteoporosis = BMD at least 2.5 SD below the young adult mean (often seen as T-score less than –2.5). 4. Severe or established osteoporosis = BMD 2.5 SD below the young adult mean (often seen as T-score less than -2.5) with a fragility fracture ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-561 Sexual & Reproductive Health B. Guidelines were updated by the North American Menopause Society (NAMS) in 2021 and by the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) in 2020 (Table 7). Additional guidelines that influence osteoporosis care include the 2019 Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society (ES) Clinical Guideline and Osteoporosis in Men and the American College of Physicians 2017 Clinical Guideline. Table 7. 2020 AACE/ACE Criteria for Diagnosis of Osteoporosis in Postmenopausal Women T-score -2.5 or below (lumbar spine, femoral neck, total proximal femur, or 1/3 radius) Low-trauma spine or hip fracture (regardless of bone mineral density) T-score between -1.0 and -2.5 and a fragility fracture (proximal humerus, pelvis, distal forearm) T-score between -1.0 and -2.5 and high FRAX fracture probability FRAX = Fracture Risk Assessment Tool. 1. Risk factors for osteoporotic fractures a. Female sex b. White race c. Poor nutrition, long-term low-calorie intake d. Early menopause (before age 40-45 years) or prolonged premenopausal amenorrhea e. Estrogen deficiency f. Drugs: glucocorticoids, heparin, anticonvulsants, excessive levothyroxine, gonadotropin-releasing hormone (GnRH) agonists, lithium, cancer drugs, proton pump inhibitors, sodium glucose-like transporter-2 inhibitors, selective serotonin-reuptake inhibitors g. Low body mass index (BMI) or low weight h. Family history of osteoporosis i. Low calcium and vitamin D intake j. Sedentary lifestyle, decreased mobility k. Cigarette smoking l. Chronic alcohol use m. Dementia n. Impaired eyesight despite adequate correction o. Previous fractures p. History of falls q. Type 1 and Type 2 diabetes r. Inflammatory bowel disease s. Chronic liver disease 2. Recommendations a. Avoid smoking and consume only moderate amounts of alcohol. b. Regular weight-bearing and muscle-strengthening exercise. c. Adequate intake of calcium (at least 1000 mg/day) and vitamin D (800–1000 international units/ day) according to the National Osteoporosis Foundation (NOF), or 600 international units/day for those younger than 70 years and 800 international units/day for 70 years or older according to the Institute of Medicine (IOM). d. Assessment i. Dual-energy x-ray absorptiometry (DXA): Gold standard, measures hip or lumbar spine BMD ii. Quantitative computed tomography (QCT): Measures volumetric BMD of lumbar spine iii. Peripheral DXA (pDXA) and peripheral QCT (pQCT): Not appropriate for monitoring ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-562 Sexual & Reproductive Health iv. Vertebral imaging: Used to identify vertebral fractures because they are often asymptomatic (a) All women 70 years or older and men 80 years or older with BMD T-score of –1.0 or less at spine, total hip, or femoral neck (b) Women 65–69 years and men 70–79 years if BMD T-score is –1.5 or less at spine, total hip, or femoral neck (c) Postmenopausal women or men 50 and older with the following risk factors: (1) Low-trauma fracture as an adult (age 50) (2) Historical height loss of 1.5 inches (4 cm) or more (since peak in adulthood) (3) Prospective height loss of 0.8 inches (2 cm) or more (measured at medical assessments) (4) Recent or ongoing long-term glucocorticoid treatment (d) Follow-up needed only if new back pain or further height loss is documented v. Clinical screening tools (a) Fracture Risk Assessment Tool (FRAX) score items (www.sheffield.ac.uk/FRAX/tool.jsp) (1) Used to estimate fracture risk (2) Most useful to estimate for patients with low BMD of hip (3) Recommended for postmenopausal women and men 50 years or older (4) Useful to determine whether patients with low bone mass (osteopenia) need pharmacologic treatment (5) Not validated for patients on drug therapy for osteoporosis (6) No data to show benefit in fracture reduction based on use for treatment decisions. (b) Other screening tools (1) Simple Calculated Osteoporosis Risk Estimation (SCORE) (2) Osteoporosis Risk Assessment Instrument (ORAI) (3) Osteoporosis Index of Risk (OSIRIS) (4) Osteoporosis Self-Assessment Tool (OST) e. Recommended BMD testing i. All women 65 years and older and men older than 70. The USPSTF recommends osteoporosis screening for the prevention of fractures for women but stated that evidence was insufficient for weighing the risk-benefit for screening in men (JAMA 2018;319:2521-31). ii. Men 50–69 years of age with previous fractures or risk factors such as delayed puberty, hypogonadism, hyperparathyroidism, hyperthyroidism, or chronic obstructive pulmonary disease; drugs such as glucocorticoids or GnRH agonists; alcohol abuse or smoking; or other causes of secondary osteoporosis iii. All postmenopausal women with medical causes of bone loss iv. Postmenopausal women younger than 65 years with at least one of the following: (a) Previous fracture after menopause other than skull, facial bone, ankle, finger, or toe; thinness (body weight less than 127 lb [58 kg] or BMI less than 21 kg/m2); history of hip fracture in a parent; current smoking; rheumatoid arthritis, alcohol intake of 2 units/day or more (1 unit = 12 oz beer, 4 oz wine, 1 oz liquor) (b) With any risk factor listed in section B1 (c) Previous fracture not caused by severe trauma after age 40–45 (d) Thinness (body weight less than 127 lb [58 kg]), family history of spine or hip fracture (e) Low bone mass (osteopenia) identified radiographically (f) Starting or taking long-term systemic glucocorticoids for 3 months or longer (e.g., prednisolone 5 mg/day or equivalent dose). (g) When use of a clinical tool for screening (FRAX, SCORE, OST, ORAI, or OSIRIS) in women suggests BMD assessment is necessary (JAMA 2018;319:2521-31) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-563 Sexual & Reproductive Health f. Initiation of drug therapy i. If hip or spine fracture ii. If BMD T-score is -2.5 or below at spine, hip, or femoral neck iii. If BMD T-score is between -1.0 and -2.5 at the femoral neck or spine and the FRAX 10-year probability of hip fracture is 3% or greater, or the FRAX 10-year probability of major osteoporosis-related fracture is 20% or greater g. Length of drug therapy: American College of Physicians recommends 5 years of pharmacologic therapy for women with osteoporosis, NAMS recommends a bisphosphonate holiday only in those with low fracture risk who no longer meet criteria for therapy. h. Recommendations for follow-up on BMD-DXA vary. The 2021 NAMS position statement suggests repeat BMD testing 1–2 years after beginning treatment or when considering a change in therapy. The 2020 AACE/ACE guidelines discuss using bone turnover markers (BTMs) (e.g., propeptide of type 1 collagen [P1NP] for bone formation; C-terminal telopeptide type 1 collagen [CTX] for bone resorption) to assess treatment adherence and efficacy. A recent fracture can cause a transient elevation in BTM. The interval may be longer in patients with T-scores in the normal or upper bone mass range who do not have major risk factors. C. Osteoporosis Treatments 1. Bisphosphonates (Table 8) a. Inhibit normal and abnormal bone resorption b. First-line therapy (Ibandronate is considered second-line therapy) c. Efficacy: Reduces vertebral and non-vertebral fractures by 30%–50% (see individual agents; Ibandronate reduces only vertebral fractures) d. Adverse events (not dose-dependent) i. Gastrointestinal (GI): Flatulence, acid regurgitation, esophageal ulcer, dysphasia, abdominal distention, gastritis. To reduce the risk of GI adverse effects, avoid lying down for 30–60 minutes after taking the dose. ii. Miscellaneous: Headache, musculoskeletal pain, rash iii. Laboratory values: Decreases in serum calcium concentrations; decreases in serum phosphorus concentrations in the first month. iv. Osteonecrosis of jaw: Most are associated with dental procedures. Most cases occur in patients with cancer after prolonged therapy. High-dose intravenous administration (usually for cancer-related issues) has a greater risk than oral therapy. v. Atypical fractures: Potentially associated with longer duration of use; FDA recommends considering periodic reevaluation of continued need for therapy (FDA Drug Safety Communication, 2016) vi. Esophageal cancer: FDA is monitoring the conflicting data; recommendation is to continue use as directed by physician (FDA Drug Safety Communication, 2017) vii. Atrial fibrillation: Possible increased risk of atrial fibrillation but not of stroke or cardiovascular mortality (Chest 2013;144:1311-22). One meta-analysis showed no increased risk of stroke, myocardial infarction, total cardiovascular events or death (PLoS One 2015;10:e0122646). e. Drug holidays are controversial; bone density may decrease 5 years after discontinuation of bisphosphonate therapy, but risk of hip fracture stays the same; however, higher risk of vertebral fracture may occur. i. American Society for Bone and Mineral Research recommends thatwomen be reassessed after 5 years of oral bisphosphonate use or 3 years of intravenous treatment. ii. Women at a high risk of fractures should continue oral therapy for up to 10 years and up to 6 years with intravenous therapy with intermittent follow-up (AACE/ACE). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-564 Sexual & Reproductive Health iii. Women whose fracture risk decreased after 3–5 years of use should stop treatment for 2–3 years (J Bone Miner Res 2016;31:16-35). f.  Drug-food interactions: Wait at least 30 minutes after taking bisphosphonate before taking any medications, food, or drinks except for water. Exceptions: oral ibandronate (must wait 60 minutes), risedronate sodium, delayed release (must be taken with food.) g. Administration considerations i. Alendronate: 10 mg/day or 70 mg/week. Alendronate (daily dose regimen) was shown to decrease vertebral fractures by 47% and hip fractures by 51% (Fracture Intervention Trial [FIT]) in women with previous fractures. ii. Alendronate with vitamin D: 70 mg/week with 2800 international units of vitamin D3 or 70 mg/week with 5600 international units of vitamin D3 iii. Alendronate 70-mg effervescent tablet/week (Binosto): Dissolve tablet in 4 oz water, wait for about 5 minutes for effervescence to stop, stir for 10 seconds, and drink contents. Has similar recommendations of waiting 30 minutes before eating or drinking and staying upright for 30 minutes after administration. iv. Risedronate: 5 mg/day or 35 mg/week or 150 mg once monthly. Decreases non-vertebral fracture risk by 33%–39% and vertebral fracture by 41%–49% v. Ibandronate: 150 mg once monthly orally, waiting at least 60 minutes before eating, drinking, or taking another drug, or 3 mg intravenously every 3 months. Increases BMD at spine and hip; however, studies show only a decreased risk of vertebral fractures. vi. Zoledronic acid: 5 mg intravenously annually for treatment and every 2 years for prevention (infuse over a minimum of 15 minutes); reduces non-vertebral fracture risk by 25%, hip fracture by 40%, and vertebral fracture risk by 70%. Lack of GI adverse effects; higher risk of atrial fibrillation with zoledronic acid than with placebo (1.3% vs. 0.4%); hypocalcemia may occur; patient must take calcium and vitamin D supplements. Infusion reactions occur, necessitating pretreatment with acetaminophen. Shown to decrease mortality in high-risk patients who have had a hip fracture (only bisphosphonate shown to decrease mortality) h. Dose adjustments may be necessary in renal impairment (see Table 8). Table 8. Bisphosphonates Drug Indications Alendronate (Fosamax, Binosto) Prevention and treatment of osteoporosis in postmenopausal women, increase BMD in men, glucocorticoidinduced osteoporosis Paget disease Alendronate + cholecalciferol (Fosamax Plus D) Risedronate (Actonel) Risedronate delayed release (Atelvia) Osteoporosis Dosing and Routes 10 mg PO daily 70 mg PO weekly, 70-mg effervescent tablet PO weekly, 70 mg/75 mL solution PO weekly 70 mg PO weekly + cholecalciferol 2800 international units/wk or 5600 international units/wk 5 mg PO daily for prevention 35 mg PO weekly for prevention Not recommended for CrCl < 35 mL/min Prevention and treatment of 5 mg PO daily osteoporosis in postmenopausal women, 35 mg PO weekly (immediate and delayed increase BMD in men, glucocorticoidrelease) induced osteoporosis 150 mg PO monthly Paget disease Not recommended for CrCl < 30 mL/min ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-565