BREAST HEALTH

BREAST PAIN (MASTALGIA)

Background

(JGIM 2012;27:817; Mayo Clin Proc 2004;79:353; Clin Evid 2011;01:812)

• Most common breast sx prompting consultation to PCP (up to 70% ♀ pts), premenopausal > postmenopausal, highest in pts 30–50 y; most commonly due to benign etiology: 0–3% pts w/ isolated pain found to have CA; localized pain = only presenting sx in <15% breast CA pts (AFP 2000;61:2371); no histologic correlations; 50–90% asx women have fibrocystic changes
• Classification: Helpful to organize differential (AFP 2000;61:2371)
  • Cyclic mastalgia: Assoc w/ menstrual cycle, most severe before menses or relieved by menses onset; typically b/l, poorly localized, radiating to axilla/arm, common in younger pts; likely due to hormonal stimulation of breast lobules; resolves spontaneously in 20–30% pts, but high recurrence risk (60% pts) (Clin Evid 2011;01:812) Noncyclic mastalgia: Unrelated to menstrual cycle or in postmenopausal pts; typically unilateral, sharp/burning, localized, most common in pts 40–50 y; Ddx: stretch of Cooper ligaments, fat necrosis, pressure from brassiere, focal/periductal mastitis, hidradenitis suppurativa, cyst, thrombophlebitis (Mondor disease), costochondritis, cervical arthritis w/ radiculopathy; often responds poorly to Rx but spontaneously resolves in ~50% pts (NEJM 2005;353:275; Clin Evid 2011;01:812)
• Differential diagnosis: Extramammary causes of chest pain include costochondritis, Tietze syndrome, MI, PNA, pleural pain, rib fx, zoster

Evaluation

(AFP 2000;61:2371; Obstet Gynecol Clin N Am 2013;40:459)

• History: Pain: Type, location, relationship to menses, bi-vs. unilateral, radiation, duration, resolution, erythema; Exacerbating factors: Irregular menses, stress; Medications: esp OCPs, HRT, spironolactone, SSRIs; infectious s/sx, prior breast infection/abscess, recent surgery or piercing, lactation, h/o chest wall trauma (including remote); smoking (strongly assoc w/ periductal mastitis)
• Exam: Thorough breast exam to exclude mass vs. possible infection; costochondral/chest wall palpation (including w/ pt lying on side vs. leaning forward); palpable cord-like SC induration suggests Mondor disease
• Red flags: H/o rapid onset breast erythema, edema, nipple crusting/retraction/inversion ± palpable mass or regional LAD strongly suggestive of inflammatory breast CA → prompt diagnostic U/S + mammography, bx if indicated (Ann Oncol 2011;22:515)
• Imaging (AFP 2012;86:343)
  • Diffuse pain: Pts >40 y → mammogram if none in past 12 mo, consider for pts >30 y if ⊕ RFs for breast CA (limited data to support) Focal pain: Pts ≥30 y → mammogram + targeted U/S, pts <30 y → targeted U/S
  • Note that some studies have shown benefit of ⊖ initial imaging for pt reassurance though may → add’l imaging, bx, f/u visits (JGIM 2012;27:817) Palpable mass: Mammogram + targeted U/S, consider referral to breast surgeon (see “Breast Mass”) Mastitis (lactational or periductal): U/S for possible abscess if no resolution w/ po abx

Treatment

(AFP 2000;61:2371; Obstet Gynecol Clin N Am 2013;40:459)

• General approach: Reassurance for the majority of pts w/ no abnormality on exam ± imaging, recommend regular exercise; review nl breast physiology; Rx indicated only if pain interferes w/ activity or lasts several d/mo (can ask pt to document daily pain freq/severity × 1 menstrual cycle prior to Rx)
• CAM: Conflicting evidence for efficacy of caffeine restriction, vit E supplementation, evening primrose oil (NEJM 2005;353:275)
• Initial treatment: NSAIDs (topical diclofenac > po), APAP, or ASA are 1st-line (NEJM 2005;353:275)
• Alternatives: Danazol (100–400 mg/d): Only FDA-approved Rx, reserve for severe sx not controlled w/ NSAIDs, r/o pregnancy before Rx, counsel about s/e (menorrhagia, acne, weight gain, voice deepening, hirsutism, muscle cramps); tamoxifen, bromocriptine have shown efficacy, former preferred due to more favorable s/e profile despite ↑ risk DVT, endometrial CA, consider use in consultation w/ specialist (J Reprod Med 2005;50:933; Clin Evid 2011;01:812)

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NIPPLE DISCHARGE

Background

(AFP 2012;86:343; NEJM 2005;353:275; Obstet Gynecol Clin N Am 2013;40:459)

• Second most common breast complaint after breast pain; benign in 97% cases, but pathologic discharge can be assoc w/ malignancy (~5– 15% of pts, ↑ risk in pts >40 y) (Ann R Coll Surg Engl 2007;89:124; Am J Surg 2010;200:73)
• Definitions:
  • Lactation: Physiologic response (milk production) to pregnancy or breastfeeding; some d/c is nl up to 1 y after pregnancy vs. weaning Galactorrhea: Milk production unrelated to pregnancy/nursing, occurs in response to inappropriate stimulus, e.g., prolactinoma (see “Hyperprolactinemia”)
  • Physiologic: Nl variant, originates from multiple ducts; up to 80% of reproductive age ♀ able to express small amount of d/c w/ compression Pathologic: D/c that is spontaneous, unilateral, bloody, serosanguineous, watery, or assoc w/ mass; most common etiologies = intraductal papilloma > duct ectasia > breast CA (5–15% pts) > infection

Evaluation

(AFP 2012;85:1073; AFP 2012;86:343)

• General approach: Exclude lactation, differentiate between physiologic vs. pathologic d/c, based on hx/PE
• History: Discharge: Unilateral vs. bilateral, spontaneous vs. only w/ compression, color, sanguinous or not, associated mass
  • Gyn hx: Menstrual hx, pregnancy, recent childbirth, fibrocystic / other prior breast disease Medical hx: Chest wall trauma, h/o breast surgery, hypothyroidism, pituitary disease Meds: OCPs, estrogen; verapamil, methyldopa, spironolactone; cimetidine, metoclopramide; SSRIs, MAOIs, TCAs, antipsychotics; opioids ROS: Endocrine ROS for thyroid disease, pituitary tumor (visual field defect, HA, amenorrhea, s/sx acromegaly) Social hx: Cocaine, heroin, methadone (assoc w/ galactorrhea); smoking (assoc w/ duct ectasia) Family hx: Breast, ovarian CA
• Exam: Thorough breast exam: inspect discharge, differentiate single vs. multiple duct involvement; inspect/palpate for associated mass or chest wall lesions (prior breast surgery, burns, zoster); also HEENT: Visual field testing, thyroid exam
• Red flags: Pathologic discharge, breast mass; erythema/dermatitis of nipple suggest Paget disease of the breast → refer for bx and mammogram
• Initial studies:
  • Physiologic: Repeat PE in 3–4 mo; consider mammogram in pts >35 y Pathologic: Examine d/c for occult blood, obtain dx mammogram (retroareolar magnification views may be helpful) +/– subareolar U/S followed by image-guided bx if abnl; refer for bx if BI-RADS 4–5, consider ductography if BI-RADS 1–3; cytology not recommended (poor Se/Sp, ↓ cost-effectiveness) Galactorrhea: Check β-hCG, TSH, PRL; consider Cr (see “Hyperprolactinemia”)

Treatment

(AFP 2000;61:2371)

• Physiologic: If exam ± mammogram nl → reassure, counsel to avoid nipple stimulation and to report any spontaneous d/c; if sx persistent/bothersome, refer for duct excision
• Pathologic: Refer all pts w/ spontaneous or unilateral d/c to surgery for terminal duct excision
• Galactorrhea: Stop potentially offending medications; if TSH or PRL abnl, Rx as indicated (see Endocrine section); if both nl, consider dopaminergic agonist to ↓ sx

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BREAST MASS

Background

(AFP 2000;61:2371; NEJM 2005;353:275; AFP 2005;71:1731)

• Nodularity (especially in upper outer quadrant) very common, as nl glandular breast tissue is nodular; fibroadenomas very common, including in younger pts
• Cysts: Common masses in premenopausal women >40 y; infrequent in younger pts or postmenopausal pts not on HRT; Risk factors: Late menopause, HRT, low BMI (NEJM 2005;353:275)
• Dominant mass: Single mass differing from surrounding tissue and from corresponding area in contralateral breast, persisting throughout menstrual cycle; may be discrete or poorly defined
• Differential diagnosis: Fibroadenoma, phyllodes tumor, hamartoma, fibromatosis, lactating adenoma, usual ductal hyperplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, ductal carcinoma in situ, invasive CA
• Although many palpable masses are benign, breast CA must always be considered

Evaluation

(AFP 2000;61:2371; NEJM 2005;353:275)

• History: Mass: Timing of appearance, duration, changes in size/character, associated pain, fluctuations w/ menstrual cycle (suggests cyst); h/o prior cyst at site; review RFs for breast CA (see “Breast Cancer Screening” subsection below)
• Exam: Thorough breast exam, including visual inspection (asymmetry, d/c, masses, skin changes, nipple retraction) and palpation of entire breast, axillae, supraclavicular areas b/l; document mass location (clockface & distance to nipple), size, texture, mobility
• Red flags: Associated skin changes; hard, fixed/immobile, or poorly defined mass
• Initial studies: Diagnostic mammogram + U/S

Management

(AFP 2000;61:2371; NEJM 2005;353:275; AFP 2005;71:1731; AFP 2012;86:343)

• Communication: Breast masses are source of anxiety for clinicians and pts; be open about potential for false ⊕ ⊖ results; encourage pts to fu promptly w/ persistent concerns; establish a plan for f/u and discussion of test results; document discussion/plan
• Normal mammogram misses 10–15% palpable malignant breast masses, thus ⊖ test does not exclude CA
• MRI not usually recommended, given poor Sp compared w/ mammogram; consider in pts w/ breast implants, s/p breast surgery, or extremely dense tissue
• Note that pts w/benign breast lesions may still be at ↑ risk of breast CA → discuss tamoxifen as preventive Rx if predicted Gail 5-y risk >1.67% No mass palpable: Reassure, recommend awareness of changes in breasts w/ prompt reporting (SBE controversial), confirm screening up- to-date, repeat exam in 2–3 mo
• Irregularity (i.e., vague nodularity/asymmetry) noted but no clear dominant mass
  • Women <30 y of average risk: Directed U/S
  • Women >30 y or high risk: Diagnostic mammogram w/ f/u midcycle exam in 1–2 mo, consider directed U/S (preferred in pt w/ dense breasts); refer for bx if persistent (even if imaging ⊖)
• Palpable mass w/ benign features: Diagnostic mammogram + directed U/S; consider FNA for pts with low pretest probability of CA (PE + imaging + FNA = “triple test,” >99% likelihood of benign mass if all 3 ⊖)

Palpable mass w/ suspicious features: Diagnostic mammogram + directed U/S, followed by image-guided bx (core needle biopsy vs. excisional) (see Figure 15-1)

Interpretation (AFP 2012;86:343)

Imaging Results and Management
BI-RADS* Classification	Management
0 = Incomplete assessment	Order additional imaging (more views vs. U/S)
1 = Negative findings	Consider further imaging +/– specialist referral for persistent palpable mass at rpt PE in 1–2 mo
2 = No e/o malignancy	Routine f/u if imaging result c/w clinical findings
3 = <2% risk of malignancy	CNB if clinical concern for CA Rpt mammogram +/– U/S q6mo × 2 y to ensure stability
4 = Suspicious abnormality	CNB; refer to specialist
5 = >95% risk of malignancy	CNB; urgently refer to specialist
6 = Bx-proven malignancy	Ensure completion of Rx and appropriate f/u

*BI-RADS = Breast Imaging Reporting and Data System

Further Evaluation

(Obstet Gynecol Clin N Am 2013;40:459)

• Cysts: Common incidental finding on mammography, no further w/u required
• Proliferative lesions w/o atypia: Fibroadenomas, intraductal papilloma do not require further w/u, refer for excision only if bothersome; refer pts w/ radial scar for excisional bx; consider excisional bx for pseudoangiomatous stromal hyperplasia (PASH) if imaging suspicious for secondary process
• Proliferative lesions w/ atypia: Atypia is assoc w/ ↑ risk of breast CA; includes atypical lobular hyperplasia (ALH), atypical ductal hyperplasia (ADH), flat epithelial hyperplasia → excisional bx given ↑ risk carcinoma in situ, consider ↑ risk in screening decisions

Figure 15-1. Breast care management algorithm

                BREAST CANCER SCREENING

Background

(AFP 2008;78:1361; AFP 2012;86:343; AFP 2013;87:274; JAMA 2014;311:1327)

• Breast cancer is the 2nd leading cause of CA-related deaths among US ♀; cumulative lifetime risk ~1:8; mortality ↓ over past 30 y, although how much to attribute to screening vs. improved tx remains uncertain (NEJM 2016;375:1438)
• Risk factors: ↑ age, female sex, overweight/obesity, white race, Ashkenazi Jewish heritage, dense breast tissue, h/o prior breast bx, h/o breast or ovarian CA, h/o XRT, 1st-degree relative w/breast or ovarian CA, BRCA1/BRCA 2, menarche <12 y, menopause >55 y, first delivery >35 y, nulliparity, EtOH >1 drink/d, current/prior use of HRT or OCPs

Evaluation

• Risk assessment: Assess 5 y and lifetime risk for all pts, e.g., Breast Cancer Risk Assessment Tool; avg risk ≤15%, mod risk = 15–20%, high risk ≥20%: high-risk patients include those w/ strong FHx, including BRCA mutations, h/o chest XRT age <30 y, h/o lobular carcinoma in situ (LCIS) or atypical hyperplasia (ADH, ALH)
• Screening Modalities (AFP 2013;87:274; Ann Int Med 2016;164:268)
• Screening mammography: Primary screening modality; assoc w/ ↓ breast CA mortality and also ↑ overdiagnosis: risk–benefit profile varies by age, screening interval, individual risk and preferences (see table)

Estimate of Benefits & Harms of Annual Mammography
If 1000 women at this age underwent annual mammography for 10 years…
Age	Benefits	Harms
40	0.1–0.6 women will avoid dying from breast cancer	510–690 will have a “false alarm” requiring further tests (for 60–80, this will include biopsy) 0–11 will be overdiagnosed and treated for breast CA
50	0.3–3.2 women will avoid dying from breast cancer	490–670 will have a “false alarm” (for 70–100 this will include biopsy) 3–14 will be overdiagnosed and treated for breast CA
60	0.5–4.9 women will avoid dying from breast cancer	390–540 will have a “false alarm” (for 50–70 this will include biopsy) 6–20 will be overdiagnosed and treated for breast CA

Adapted from JAMA Intern Med 2014;174:448

• Ultrasound: No data to support U/S screening alone; mammogram + U/S in high-risk ♀ w/ dense breast tissue → ↑ Se but also ↑ false ⊕; no clear benefit from automated breast U/S vs. hand-held U/S in pts w/ dense breasts
• Breast self-awareness: Counsel pts to recognize nl appearance/feel of their breasts and promptly report any changes; formal/regular breast self-exams no longer recommended in avg-risk pts, given ↑ false ⊕ and no ↓ in breast CA dx mortality rates (JNCI 2002;2:1445)
• Clinical breast examination (CBE): Variable evidence on Se/Sp of CBE in conjunction with screening mammography but no clear ↓ in mortality; USPSTF reports insufficient evidence, ACS no longer recommend screening breast exam, ACOG recommends as part of annual exam
• MRI: Controversial, generally not recommended in avg-risk pts; ↑ Se but also ↑ false ⊕; consider as adjunct to mammogram in pts w/ high lifetime risk of breast CA ⊕/⊖ dense breast tissue
• Digital breast tomosynthesis (DBT): Controversial, generally not recommended; in conjunction w/ mammogram, may ↑ Sp and ↓ false ⊕/recall rates for pts w/ dense breasts but ↑↑ radiation exposure

Management

(AFP 2013;87:274; Med Clin North Am 2015;99:451; JAMA 2015;314:1615)

• Shared decision-making: All decisions assoc w/ screening (to screen or not, and if so at what age and what interval) present risks and benefits; incorporate individual risk of breast cancer as well as individual values into screening plan and then document plan; see “Disease Screening”
• Individual guidelines are somewhat controversial (see NEJM 2012;367:e31 “Clinical Decisions” for divergent expert opinion); generally, consensus that for women of average risk, screening mammogram be offered to those 50–74 y; screening mammogram q2y in women 50–74 y is cost- effective; consider local practice patterns in light of medicolegal risk (JAMA 2013;309:2555)

Selected Breast Cancer Screening Guidelines for Average-Risk Patients
	USPSTF	ACOG	ASC
Avg risk, 40– 49y	Consider mammogram q2y per individual values, RFs, esp if ⊕ FHx (Grade C)	Discuss benefits/harms of screening; mammogram q1y in pts who desire screening	Consider mammogram q1y for pts 40–44 y; start mammogram q1y at 45 y
Avg risk, 50– 74 y	Mammogram q2y (Grade B)	Mammogram q1y	Mammogram q1y for pts 50–54 y; consider transition to q2y at 55 y
Avg risk, ≥75y	Insufficient evidence to continue screening (Grade I)	Discuss benefits/harms of screening, in conjunction w/ LE, comorbidities	Continue mammogram q1–2 y for pts in good health with LE ≥10 y

• High-risk patients: Offered enhanced screening, ACOG recommends SBE, CBE q6m, annual mammogram + MRI, and risk reduction tx starting at age 40; ACS recommends annual mammogram + MRI starting age 20–40 per pt risk factors (insufficient evidence for pts w/LCIS, ALH, ADH, or personal hx breast CA) (ACS, JAMA 2015;314:1599; ACOG, Obstet Gynecol 2011;118:372)
• When to refer: High-risk patients often start screening <40 y; refer to specialist for determining optimal screening plan/modality and for consideration of risk reduction methods (SERMs/aromatase inhibitors, prophylactic b/l mastectomy, BSO) (Curr Opin Obstet Gyn 2015;27:6); those w/ suspected or confirmed genetic BRCA mutations should also be referred to genetics counselor

CERVICAL CANCER SCREENING

Background

• Cervical cancer: Malignancy of squamous (most common) or glandular cervical cells; progressive, disease w/ predictable course involving clearly defined precursor lesions → well suited for screening; incidence in US ↓ >50% since screening began (www.seer.gov)
• Epidemiology: ~12,200 new diagnoses of invasive cervical CA & >4,200 cervical CA deaths annually in US; incidence/mortality rates ↑ in ethnic minorities (Hispanics/Latinos > African-Americans > Native Americans > whites), women living in rural areas or poverty, HIV⊕; disparities primarily mediated by ↓ screening & ↓ f/u care (Canc Epi Biomarkers Prev 2012;21:1402)
• Pathophysiology: Essentially all cervical CA thought to be assoc w/ HPV infection, acquired through sexual contact; >90% infections clear spontaneously w/in 2–5 y, but persistent HPV can → dysplasia → malignancy (Lancet 2001;357:1831)

Human Papilloma Virus (HPV)

(Ann Int Med 2012;156:880)

• Classification: dsDNA infecting mucocutaneous tissues; 30 strains trophic for genital area; of these, “low-risk” strains (6, 11) generally assoc w/ anogenital warts; “high-risk” strains (16, 18) account for 70% cervical CA cases, included in HPV vaccine (see “Immunizations”) Epidemiology: HPV prevalence (all types) in US women 20–34 y ranges 40–58%, ↓ w/ age; since introduction of vaccine, ↓ in 4vHPV type prevalence in women <24 y but no change in older pts (Pediatrics 2016;137:e20151968)
• Risk factors for HPV acquisition/persistence: Multiple sexual partners, early-onset sexual activity, high-risk sexual partners, hx STIs, immunosuppression (incl HIV)

Cytologic Classification of Intraepithelial Cell Abnormalities

(JAMA 2002;287:2114)

• Squamous cell: in ↑ order of severity
  • ASC-US: Atypical squamous cells of undetermined significance
  • ASC-H: Atypical squamous cells of high grade
  • LSIL: Low-grade squamous intraepithelial lesion; usually assoc w/ active HPV, mild dysplasia; typically corresponds to cervical intraepithelial neoplasia (CIN)-1 on histology HSIL: High-grade squamous intraepithelial lesion; moderate/severe dysplasia; CIN2–3 or carcinoma in situ on histology Squamous cell carcinoma
• Glandular cell: in ↑ order of severity; (1) Atypical glandular cells (AGC): Endocervical, endometrial, NOS or “favor neoplastic”; (2) Endocervical adenocarcinoma in situ; (3) Adenocarcinoma

Screening Modalities

• Cytology (Papanicolaou smear): Sampling of endocervical/ectocervical cells; colposcopy + bx required to dx/stage dysplasia/CA
• HPV testing: Indicated in some instances (below) as component of 1° screening & to aid in risk stratification and f/u strategy
• Visual inspection: If concern for cervical malignancy on exam, refer for colposcopy regardless of cytology or HPV findings

Guidelines

(Ann Int Med 2012;156:880, CA Cancer J Clin 2013;63:87)

• Recommendations have evolved over time; 2012 USPSTF, ACOG, & ACS updates suggest ↓ screening frequency to prevent overdiagnosis & overtreatment of HPV-related abnormalities that would clear spontaneously
• Cotesting: HPV & cytology for 1° screening; preferred screening strategy of ASCCP & ACOG for women >30 y (not appropriate strategy for women <30 y)
• Adequate screening: Defined as 3 consecutive ⊖ Pap tests or 2 consecutive ⊖ Pap + HPV tests w/in 10 y, w/ most recent tests w/in 5 y

Screening Recommendations (for pts w/o prior abnl screenings)
Patient Group	Recommendation
≤21 y	No screening
21–29 y	Pap q3y (do not check HPV unless for f/u of abnl Pap)
30–65 y	Pap + HPV q5y (preferred) or Pap q3y (cytology alone)
Over 65 y	Stop screening if pt has had adequate screening & ≥20 y elapsed since resolution of CIN2–3 (if ⊕ hx)
S/p complete hysterectomy for benign reasons	No screening if no other RFs
Immunocompromised, HIV, h/o cervical CA, h/o in utero DES exposure	Annual screening Pap indefinitely for HIV, some ↓ frequency w/cotesting or nl prior exams (see “HIV Primary Care” in “HIV/AIDS”)

Management

• Given myriad potential results & clinical scenarios, only selected guidelines included here; full American Society for Colposcopy & Cervical Pathology (ASCCP) 2012 updated consensus guidelines include 19 algorithms → see Obstet Gynecol 2013;121:829
• If screening using Pap alone ⊕/⊖ reflex HPV, see “Selected Cytology Results and Follow-Up”; if screening using cotesting (pts >30 y only), see “Selected Cotesting Results and Follow-Up”

Selected Cytology Results and Follow-Up
Result	Management
Unsatisfactory (inadequate sample)	Repeat Pap
Negative but lacking endocervical cells	Routine screening; no early repeat
Negative for intraepithelial malignancy (“normal”)	Routine screening, as above
ASC-US in women 21–24 y	Repeat cytology at 12 mo (preferred) or reflex HPV Reflex HPV Testing: If HPV ⊖ → routine screening If HPV ⊕ → repeat cytology at 12 mo 12-mo cytology: Negative, ASC-US, or LSIL → repeat in 12 mo ASC-H, AGC, HSIL → colposcopy 24-mo cytology: Negative × 2 → routine screening ≥ASC-US → colposcopy
ASC-US in women >24 y	Reflex HPV (preferred) or repeat cytology at 12 mo Reflex HPV testing: If HPV ⊖ → cotest at 3 y If HPV ⊕ → refer for colposcopy If reflex HPV unavailable → repeat cytology at 12 mo 12-mo cytology: Negative → resume routine screening ≥ASC-US → colposcopy
ASC-H, any age	Refer for colposcopy
LSIL in women 21–24 y	Repeat cytology at 12 mo 12-mo cytology: Negative, ASC-US, LSIL → repeat in12 mo ASC-H, AGC, HSIL → colposcopy 24-mo cytology: Negative × 2 → routine screening ≥ASC-US → colposcopy
LSIL in premenopausal women >24 y	If no HPV test or HPV ⊕ → colposcopy If HPV ⊖, repeat cotesting at 12 mo preferred, but colposcopy acceptable 12-mo cytology: Negative & HPV ⊖ → resume routine screening, HPV ⊕ and/or ≥ASC-US → colposcopy
LSIL in postmenopausal women	Refer for colposcopy or Repeat cytology at 6 mo & 12 mo or HPV test: If ⊕, refer to colposcopy; if ⊖, repeat cytology in 12 mo
LSIL in pregnant women	Refer for colposcopy
HSIL	Refer for colposcopy
AGC	Refer for colposcopy, HPV test, ± endometrial bx
AGC-endometrial	Refer for endometrial bx/endocervical sampling

(Am J Obstet Gynecol 2007;197:346; J Low Genit Tract Dis 2013;17:S1; Obstet Gynecol 2013;121:829)

Selected Cotesting Results and Follow-Up
Result	Management
Negative for intraepithelial malignancy & HPV ⊖	Continue routine screening; repeat combined screening in 5 y
Negative for intraepithelial malignancy & HPV ⊕	Immediate HPV genotyping for 16 or 16/18: If ⊕ → colposcopy If ⊖ → repeat cotesting at 12 mo Or: Repeat cotesting at 12 mo: If both ⊖ → repeat cotesting at 3 y If either ≥ASC-US or HPV⊕ → colposcopy
ASC-US & HPV ⊖	Repeat cotesting at 3 y
ASC-US & HPV ⊕	Refer for colposcopy
LSIL & HPV ⊖	Repeat cotesting in 12 mo (preferred) or colposcopy
LSIL & HPV ⊕	Refer for colposcopy
ASC-H or HSIL w/ any HPV result	Refer for colposcopy
AGC w/ any HPV result	Refer for colposcopy + endometrial ± endocervical sampling

When to Refer

• Colposcopy: Identifies macroscopic changes in cervical epithelium contour, color, & vasculature assoc w/ malignancy/premalignancy; accuracy varies w/ experience of colposcopist
• Dysplasia: PCP can provide general education re: “what to expect”: CIN1: Managed expectantly if preceded by low-grade lesion or if present for <24 mo; CIN2–3: Managed w/ ablative (e.g., cryotherapy/laser) or excisional (e.g., loop electrosurgical excision) tx
• Cervical CA: Management depends on staging, comorbidities, desire to preserve fertility

MENOPAUSE

Background

(Obstet Gynecol Clin North Am 2011;38:425)

• Menopause: Permanent cessation of menstruation 2/2 loss of ovarian follicular activity, defined retrospectively after 12 consecutive months of amenorrhea w/o other cause
• Perimenopause: Defined by the onset of clinical/endocrinologic changes immediately prior to menopause until 1 y after final menstrual period (FMP)
• Menopausal transition: Period of menstrual variability preceding FMP (mean = 4 y)
• Epidemiology: Median age 51 y (studies in white women in industrialized countries); cigarette smokers undergo menopause on average 2 y earlier, typical US range 40–60 y
• Early menopause (FMP ≤40 y): assoc w/ ↑ CVD risk, earlier cognitive decline; inconclusive evidence that early menopause may be assoc w/ ↓ SES, residence in rural/developing areas, African-American/Latina heritage, ↓ parity, lack of OCP use

Manifestations

• General: In longitudinal studies adjusted for confounders, only vasomotor sx, vaginal sx, and sleep disturbances consistently assoc w/ menopausal transition (NEJM 2006;355:2338)
• Vasomotor instability (hot flashes/flushes): Exact hormonal mechanism(s) unclear, likely involve estrogen w/d, ↑ FSH; sx prevalence/severity vary markedly (e.g., by ethnicity, smoking, stress) but peak in late menopausal transition, affect up to 65% women; most spontaneously improve w/in 2–3 mo (30–50% pts) vs. w/in 4–5 y (85–90% pts); sx continue for years in only 10–15% pts (Ann NY Acad Sci 1990;592:52)
• Genitourinary syndrome of menopause: Formerly known as atrophic vaginitis; constellation of vaginal, urinary, and sexual sx assoc w/ menopause
  • Vaginal sx: ↓ estrogen → vaginal atrophy, ↓ secretions; incidence from 30% (early postmenopausal) to 47% (late), as sx tend to ↑ w/ aging (Obstet Gynecol 2000;96:351) Urinary sx: Vaginal fluid pH ↑ after menopause → ↑ UTI-related enteric organisms, ↓ estrogen → vaginal shortening; no clear correlation w/ menopausal transition (Obstet Gynecol 2000;96:351) Sexual sx: Very common but underreported; multiple manifestations, including dyspareunia, ↓ desire, ↓ arousal, and/or difficulty w/ orgasm; assoc w/ ↓ satisfaction w/ relationships and sexual function; emphasize ↓ desire is expected and that contributing factors can be individually addressed (see “Treatment,” below)
• Psychological sx: Menopause well characterized as being a high-risk period for development or worsening of depression (Women’s Health 2015;11:397)

Evaluation

• General approach: Dx is primarily clinical, based on hx and PE History: Assess for menopause vs. features suggestive of alternate cause for AUB / amenorrhea (e.g., pregnancy, ↑ PRL, PCOS, meds; see “Menstrual Disorders”)
  • Menstrual hx: Age; menstrual timing, freq, duration, quantity, and/or cessation ROS: Presence/severity of hot flashes, night sweats, disturbed sleep, mood swings, depressed/anxious mood, difficulty concentrating, memory loss, HA, fatigue, dyspareunia, vaginal dryness/itching, ↓ libido, urethral irritation/other UTI sx PMHx: Systemic disease that might impact Rx choice (CAD, breast/uterine cancer, DVT, acute liver disease) FHx: Any h/o early menopause; age of menopause in mother/sisters closely correlated (Menopause 2008;15:940) Other causes of vasomotor instability: EtOH consumption; panic attacks; carcinoid; dumping syndrome; thyroid dysfunction; pheo; opioid w/d; use of nitrates, niacin, CCBs, GnRH agonists, antiestrogens
• Exam: Pelvic exam (vaginal pallor, dryness, ↓ mucosal rugosity = atrophy; r/o trauma, infxn); consider HEENT, neck, abdominal, skin exams if hx suggests alternate etiology of vasomotor instability
• Labs: In ♀ late 40s–mid-50s w/ classic sx, no role for labs; LH, FSH not routine as both may be nl during menopausal transition (NEJM 2006;355:2338); ✓FSH in younger ♀ w/ vasomotor sx s/p hysterectomy; ✓ β-hCG if younger pts: >1% annual unintended pregnancy rate in women 40–44 y (Contraception 2011;84:478)

Menopausal Transition Stages (NEJM 2006;355:2338)
	Premenopause	Menopausal Transition	Postmenopause
Menstrual cycle	Regular →         Variable (↑ missed cycles/y) →     absent

 

Hot flashes (%)	10 →	40 →	65 → 50 →	10–15
Estradiol (pg/mL)	50–200 →		40 →	0–15
FSH (mU/mL)	10a →	≥10a →		>100
LH (mU/mL)	10a →	≥10a →		>100

aOn d 2–4 of menstrual cycle.

Treatment

(NEJM 2006;355:2338; AFP 2016;94:884)

• General approach: Intent of treatment is to manage bothersome sx; not all women desire treatment for menopausal symptoms; those who do often seek Rx for vasomotor/vaginal sx; counseling/education important part of Rx; sx-based approach below

Symptom-Based Approach to Menopausal Symptoms
Symptom	Treatment
Vasomotor	Notes: Subjective improvement w/ placebo alone; counsel pts that for most pts, duration of sx is limited to a few months Behavioral modifications: Dress in layers, ↓ ambient temp, ↓ EtOH, healthy diet/exercise Hormone replacement therapy: for mod–severe disease, can ↓ freq of flashes by 80–95%, regardless of type/route, w/ dose-related response (see “Estrogen Therapy,” below) Alternate tx: SSRI/SNRIs (esp. paroxetine); gabapentin/pregabalin (sedating s/e), no clear benefit from clonidine CAM: Best evidence: Soy, sage, black cohosh, yoga Mixed evidence: acupuncture Poor evidence: DHEA, dong quai, evening primrose, ginseng, kava, St. John’s wort, valerian, wild yam, or vit E
Sexual	Notes: Pts w/ more frequent sexual activity ↓ likely to develop vaginal atrophy; may refer for vaginal dilators if medical Rx contraindicated Vaginal estrogen: Sx improve in 80–100% pts, minimally ↑ serum levels; no need to add progestin w/ std dosing; PO generally not indicated for isolated vaginal sx Vaginal lubricants/moisturizers: Replens (moisturizer) shown to have similar sx relief as vaginal estrogens Alternate Tx: Ospemifene: SERM approved for dyspareunia 2/2 vulvovaginal atrophy; Contraindications: estrogen-dependent neoplasia, h/o VTE, stroke, MI, or breast CA; s/e: hot flashes, vaginal d/c, muscle spasms Bupropion: ↑ Libido in premenopausal pts (no studies in perimenopausal pts)
Urinary	PV estrogen: May ↓UTI recurrence Estrogen (PO or PV): may ↓ subjective urinary incontinence sx, no clear impact on urodynamic testing
Psych	Notes: Fatigue, ↓ concentration/memory likely 2/2 poor sleep,

(naturaldatabase.therapeuticresearch.com; Am J Ob Gyn 2016;215:704; AFP 2014;90:338; BJU Int 2010;106:832; Obstet Gynecol 1996;87:20S; 1996;88:745)

Estrogen Therapy

• Indications: Those w/ mod–severe vasomotor or vaginal sx (very effective); ± for urinary, psychological sx
• Contraindications: hx or high risk for CVD, breast/uterine cancer, DVT, active liver disease, inability to obtain routine mammogram
• Progestin: Unopposed estrogen may → endometrial hyperplasia/CA ∴ all pts w/ intact uterus receiving PO/transdermal estrogen should receive combination Rx (not necessary for PV estrogen)
• Side effects: Estrogen tx (w or w/o progestin) assoc w/ ↑ stroke risk; risk may be less w/low-dose (<50 mcg) transdermal estrogen (BMJ 2010;340:c2519); combination Rx assoc w/ ↑ relative risk MI, DVT/PE, breast CA (AFP 2016;94:884; JAMA 2004;291:1701); common s/e include uterine bleeding, breast tenderness; use may also ↓ hip fractures
• Dosing: Prescribe lowest effective dose for shortest possible time; peak effect reached w/in 4 wk (standard dosing) vs. 8–12 wk (lower dose); attempt d/c q6–12 mo w/ gradual taper

Estrogen + Progestin Preparations for Vasomotor Sx (AFP 2016;94:884)
Combination Estrogen/Progestogen
Preparation	Generic Name	Brand Name	Dosing (mg)
Oral	Estradiol/norethindrone acetate	Activella, Femhrt	Activella: 0.5/0.1, 1.0/0.5 (daily); Femhrt: 0.25/0.5 (daily)
Oral	Estradiol/ drospirenone	Angeliq	0.5/0.25, 1.0/0.5 (daily)
Oral	Conjugated equine estrogen/bazedoxifene	Duavee	0.45/20.0 (daily)
Oral	Estradiol/norgestimate	Prefest	1.0/0.09 (daily—see package insert for dosing details)
Oral	Conjugated estrogen/ medroxyprogesterone	Premphase, Prempro	Premphase: 0.625/5.0 (daily— see package insert for dosing details); Prempro:0.3/1.5, 0.45/1.5, 0.625/2.5, 0.625/5.0 (daily)

 

Transdermal patch	Estradiol/levonorgestrel	Climara Pro	0.45/0.015 (weekly)
Transdermal patch	Estradiol/norethindrone acetate	CombiPatch	0.05/0.14, 0.05/0.25 (twice weekly)
Vaginal Estrogen for Vaginal Sx
Cream	Estradiol	Estrace	0.5g PV daily × 1–2 wk, then 2× weekly
Cream	Conjugated estrogen	Premarin	0.5g PV 2× weekly
Insert	Estradiol	Vagifem	10 mcg PV daily × 2 wk, then 2× weekly
Ring	Estradiol	Estring	Replaced by provider or pt q90d
Estrogen-Only Preparations for Vasomotor Sx (for women w/o uterus)
Oral	Conjugated estrogens	Enjuvia, Premarin	0.3, 0.45, 0.625, 0.9, 1.25 (daily)
Oral	Estradiol	Estrace	0.5, 1.0, 2.0 (daily)
Oral	Esterified estrogen	Menest	0.3, 0.625, 1.25, 2.5 (daily)
Transdermal patch	Estradiol	Alora, Climara, Minivelle, Vivelle Dot	Climara: 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 (weekly); All others: 0.025, 0.0375, 0.05, 0.075, 0.1 (twice weekly)
Transdermal gel	Estradiol	Divigel, Elestrin, Estrogel	Use daily, doses vary based on product
Transdermal spray	Estradiol	Evamist	1.53 per spray, use 1–3 sprays (daily)
Vaginal insert	Estradiol acetate	Femring	0.05, 0.1 (every 90 d)

MENSTRUAL DISORDERS

Background

• Physiology: Pulsatile GnRH release by hypothalamus → LH, FSH release by anterior pituitary → ovulation, estrogen/progesterone production by ovaries; estrogen causes uterine lining proliferation, progesterone induces maturation → corpus luteum atresia → progesterone levels ↓ → shedding of uterine lining
• Normal menstrual cycle: 21–35 d w/ avg duration of menses = 5 d, blood loss <80 mL
• Definitions & classification of menstrual disorders:
  • Abnormal uterine bleeding (AUB): Abnormal menstrual cycle pattern (subtypes below) Heavy menstrual bleeding (HMB): Heavy/prolonged menses; previously “menorrhagia”
  • Polymenorrhea: Cycle length <21 d (↑ freq); previously “metrorrhagia”
  • Irregular bleeding: Cycle length >35 d (↓ freq), <9 cycles/ y; previously “oligomenorrhea”
  • Intermenstrual bleeding: Bleeding at any time other than nl menses Amenorrhea: Absence of menses (subtypes below)
  • Primary amenorrhea: Absence of menarche in ♀ >15 y w/ 2° sex characteristics or ♀ >13 y w/o 2° sex characteristics Secondary amenorrhea: Absence of menses × 3 mo in ♀ w/ previously nl menstruation or 6 mo in ♀ w/ previous irregular menstrual bleeding
• Dysmenorrhea: Painful menses
  • Primary dysmenorrhea: Painful menses w/ nl pelvic anatomy
  • Secondary dysmenorrhea: Painful menses 2/2 pelvic d/o (e.g., endometriosis, fibroids)

ABNORMAL UTERINE BLEEDING

 Background

(AFP 1999;60:1371; Obstet Gynecol 2012;120:197)

• Abnormal uterine bleeding (AUB) accounts for 1/3 outpt gynecology visits overall & >70% gynecologic consults for peri- & postmenopausal pts
• Dysfunctional uterine bleeding (DUB): Dx of exclusion in pts w/ AUB not due to pregnancy, pelvic pathology, medications, or systemic disease

Genital tract lesions	Malignancy, benign lesions (including polyps, leiomyomas, adenomyosis, endometriosis, ectropion), infection, pregnancy
Trauma	Foreign body, pelvic trauma, sexual intercourse, abuse
Medications	Contraception, HRT, steroids, antipsychotics, phenytoin, anticoagulants, supplements (ginseng, ginkgo, soy)
Systemic disease	Coagulopathy in up to 20% of women w/ heavy bleeding (von Willebrand, ↓ PLT, leukemia), ESLD, endocrine disease (thyroid, Cushing, adrenal hyperplasia, ↑ PRL), hypothalamic suppression (wt loss, excess exercise, stress), ESRD

(Am J Obstet Gynecol 1996;175:766; NEJM 1991;324:1710; AFP 2004;69:1915)

Evaluation

(AFP 1999;60:1371; Obstet Gynecol 2012;120:197)

• General approach: Medical & menstrual hx to characterize menstrual pattern, menopausal status, nature of bleeding; r/o nongenital sources (e.g., urinary/rectal)
• Menstrual pattern:

Ovulatory: Regular cycle length, ⊕ cervical mucus, ⊕ premenstrual sx; if present → determine subtype/bleeding pattern (HMB, polymenorrhea, irregular bleeding, or intermenstrual bleeding) Anovulatory (more common: Irregular flow/duration of menses, premenstrual sx often absent)

• Menopausal status: Perimenopausal: ⊕ onset of clinical/endocrinologic changes (hot flashes, vaginal dryness, irregular menses) but menses persistent; Menopausal: >12 mo amenorrhea (see “Menopause”)
• Medical history: PMH: Coagulopathy, ESLD, ESRD/HD, endocrine disease; sexual hx; FHx: menstrual irregularity, fibroids/endometrial disease/CA; Meds: see above—if on HRT or OCPs, review adherence (irregular use may → spotting); ROS: wt loss, stress, endocrine sx Exam: Pelvic exam to r/o genital tract lesion, eval uterus/adnexa, Pap if due, ± STI testing
• Initial labs: Must r/o pregnancy (β-hCG); ✓ CBC, TSH; if uterine enlargement or irregularities → TVUS; consider w/u for nongenital tract causes
• Endometrial biopsy: Indicated in perimenopausal women >45 y w/ AUB, women <45 y w/ persistent abnl bleeding, h/o unopposed estrogen, or no response to Rx, & postmenopausal women who do not undergo TVUS or w/ abnl TVUS

Management

• Postmenopausal: Bleeding usually 2/2 vaginal/endometrial atrophy, but CA must be excluded → transvaginal ultrasound (TVUS) or endometrial bx to r/o malignancy (cause of 5–10% of AUB)

Endometrial bx: If abnl → refer as above; if nl but bleeding persists → TVUS, refer for hysteroscopy or sonohysterography; if nl & bleeding resolves can observe, o/w repeat bx TVUS: Endometrial stripe <4 mm c/w atrophic endometrium; ≥4 mm or irregular appearance → bx, refer per pathology, as above (Obstet Gynecol 2009; 114:409)

Premenopausal AUB Management by Subtype
Anovulatory pattern	(1)  Assess for thyroid dysfunction, hyperprolactinemia: TSH, PRL (2) Assess for hypothalamic dysfunction (e.g., stress, eating d/o, chronic disease); if ⊕, see “Amenorrhea” subsection below (3) Consider systemic disease (see Ddx above) (4) Eval for PCOS and its Ddx (see “PCOS), chronic anovulation (FSH nl/↓); for either dx, consider OCPs, levonorgestrel IUD, or q3mo PG
Polymenorrhea	Trial OCPs; consider evaluation for luteal phase defect
Irregular bleeding	Seen w/ prolonged follicular phase; trial OCPs
Intermenstrual bleeding	(1)  R/o cervical pathology (pelvic exam + Pap) (2)  Remove IUD if present (3)  Trial OCPs
Heavy menstrual bleeding	(1)  R/o bleeding disorder (2)  TVUS for fibroids/uterine pathology (3)  If above nl, trial OCPs, NSAIDs, or levonorgestrel IUD
Perimenopausal AUB Management
(1)  R/o genital tract lesion (pelvic exam) (2) Evaluate for endometrial hyperplasia with TVUS and/or bx: If normal or atrophic → observe vs. trial of OCP or levo-IUD if abnormal (atypical, hyperplasia, carcinoma) → gyn referral; hyperplasia often tx w/progesterone, D&C if persistent (Obstet Gynecol 2012;120:197)
Postmenopausal AUB Management
Bleeding usually 2/2 vaginal/endometrial atrophy (95%), but CA (5%) must be excluded (1) TVUS (may also go directly to endometrial bx) If endometrial stripe <4 mm (i.e., atrophic) → observe If endometrial stripe ≥4 mm or irregular → endometrial bx (2) Endometrial biopsy: If normal & bleeding resolves → observe If nl but bleeding persists or atypia/hypertrophy on bx → TVUS (if not yet done) and gyn referral for hysteroscopy or sonohysterography (Obstet Gynecol 2009;114:409)

Postmenopausal pts on HRT: ↑↑ incidence of AUB (40–60%) (Maturitas 2009;63:45), particularly soon after initiation; assess HRT adherence (poor adherence can ↑ bleeding) & RFs for endometrial CA → use shared decision-making & clinical judgment re: observation vs. endometrial assessment; if bleeding (1) lasts ≥6 mo, (2) present prior to HRT initiation, (3) heavy/persistent despite ↑ progestin dose, or (4) develops after period of amenorrhea while on HRT → initiate w/u (AFP 1999;60:1371)

When to Refer

• For endometrial bx: Premenopausal pts <45 y w/ persistent abnl bleeding, h/o unopposed estrogen exposure, or no response to Rx; postmenopausal pts w/ abnl TVUS
• Severe/heavy bleeding which does not respond to initial tx, consideration of surgical tx
• Persistent AUB after initial Rx should undergo TVUS → if abnl, refer for hysteroscopy ± bx or sonohysterography
• If uterine enlargement/irregularities on exam→ consider TVUS, referral for f/u sonohysterography/hysteroscopy/ablation

---

AMENORRHEA

 Background

(AFP 2006;73:1374)

• Epidemiology: Incidence of primary amenorrhea = 0.3% general population, secondary amenorrhea = 1–3% general population; can be assoc w/ infertility, osteopenia, ↑ CV risk

Etiologies

• Primary amenorrhea: Rare, initial w/u usually w/ pediatrician; etiologies include causes of 2° amenorrhea, anatomic & genetic defects (incl craniopharyngioma, primary ovarian insufficiency, Turner syndrome, Kallmann syndrome, androgen insensitivity); eval for 2° sex characteristics, presence of uterus/vagina; refer to endocrine or gyn
• Secondary amenorrhea: Always consider pregnancy first; PCOS, hypothalamic amenorrhea, hyperprolactinemia, & ovarian failure are most common medical causes

Selected Etiologies of Secondary Amenorrhea
Cause	Examples
Thalamus	Hypothalamic: Often 2/2 eating d/o (esp anorexia nervosa), excess exercise/wt loss, ↑ stress; female athlete triad (restrictive eating + amenorrhea + osteoporosis) Also: Hypothalamic destruction, CNS tumor, cranial XRT
Pituitary	Hyperprolactinemia: 2/2 pituitary adenoma, medications, breastfeeding, idiopathic (see “Hyperprolactinemia”) Hypopituitarism (↓ LH, FSH): Infiltrative, Sheehan’s
Ovarian	PCOS: Anovulation w/ hyperandrogenism (see “PCOS”) Ovarian insufficiency or failure: “Premature” = age <40 y; can be primary (POI) or 2/2 autoimmune disease, iatrogenic/chemo/XRT, genetic d/o, mumps, or pelvic XRT
Uterine	Asherman syndrome (uterine scarring 2/2 D&C, infxn) Cervical stenosis (seen more w/ 1° amenorrhea)
Other	Pregnancy, hypo/hyperthyroidism, celiac disease, ↑ androgens (Cushing’s, nonclassical CAH, steroids)

Evaluation

• General approach: Majority of diagnoses can be made w/ careful hx & basic labs
• History:
  • Gyn: Age at menarche, pattern of missed periods, prior pregnancies, sexual hx, contraception hx, prior D&C/PID (Asherman’s), current breastfeeding Medical: Obesity, DM (PCOS); thyroid disease, genetic d/o, prior pelvic or CNS XRT
  • Medications: OCPs, antipsychotics, H₂-blockers, opiates, cocaine, SSRIs, glucocorticoids Lifestyle: Exercise patterns + wt changes (eating d/o, ♀ athlete triad), stress
  • FHx: Irregular menses, infertility, premature menopause, congenital abnormalities
• ROS: HA, visual disturbances, galactorrhea (pituitary tumor); hot flashes (ovarian failure); breast tenderness (pregnancy); s/sx of adrenal/thyroid disease, cyclic abdominal pain (Müllerian agenesis or outflow tract obstruction); anosmia (Kallmann syndrome)
• Exam: Height, weight, BMI, 2° sex characteristics, pelvic exam (imperforate hymen, transverse vaginal septum); signs of androgen excess (hirsutism, acne, clitoromegaly), insulin resistance (acanthosis nigricans), estrogen deficiency (vaginal mucosal atrophy), Cushing disease (striae, buffalo hump, central obesity, ecchymoses, HTN, proximal muscle weakness), thyroid disease (nodules, goiter, skin changes, abnl reflexes), pituitary adenoma (galactorrhea, visual field defects)
• Initial labs: β-hCG, TSH, PRL, LH, & FSH

Figure 15-2. Diagnostic w/u of amenorrhea (in absence of structural abnormality)

• Additional testing: May be useful in specific circumstances

Progesterone Challenge (“Withdrawal”) Test
Purpose/Physiology	Progesterone should → mature uterine lining, and w/d should → menses, lack of response suggests low-estrogen state
Test characteristics	Poor Se/Sp (e.g., 50% of POI pts have some w/d bleeding) thus unreliable (Fertil Steril 2008;90:S219)
Sample dosing	Medroxyprogesterone acetate (Provera) 10 mg PO QD × 7–10 d
Pt instructions	Can start anytime; expect bleeding 3–7 d after last dose

• • Progesterone/estrogen challenge test: Evaluates uterine response to nl hormone levels; w/d should → menses; abnl test suggestive of uterine abnormality
  • Free T, DHEAS: To detect hyperandrogenism when PCOS suspected; if c/w PCOS, check fasting glucose or 2 h GTT, r/o other causes of androgen excess Serum estrogen: Variable in physiologic or disease states; may help interpret FSH levels Pelvic U/S: Consider if uterine pathology suspected (e.g., Asherman syndrome)

Treatment

(NEJM 2010;363:365)

• Based on causative factor & desire for fertility; general goals: prevention of complications (osteoporosis, endometrial hyperplasia, CVD, preservation of fertility)
• Thyroid (see “Thyroid Disease”): Return of nl menses may take several mo after tx
• PCOS: Wt loss via diet, exercise; OCPs or cyclic progestational agents to maintain nl endometrium; metformin (see “PCOS”)
• Female athlete triad: Counsel re: need for ↑ caloric intake and/or ↓ energy expenditure; consider DEXA scan, encourage adequate Ca/vit D, consider estrogen tx in conjunction w/ specialist; CBT to ↓ stress may restore ovulation (Fertil Steril 2003;80:976)

When to Refer

• Suspected ovarian insufficiency, unclear dx, lack of response to tx, or desired pregnancy in setting of persistent amenorrhea → Reproductive Endocrinology (Gynecology)
• Prolactinoma (see “Hyperprolactinemia”), hyperthyroidism or other endocrinopathies → Endocrinology
• Consideration of estrogen tx (outside of menopause) → Gynecology or Endocrinology
• Uterine pathology or outflow obstruction → Gynecology

---

DYSMENORRHEA

 Background

• Pathogenesis: Prostaglandin release w/ endometrial sloughing → frequent, uncoordinated contractions → ↑ intrauterine pressure > arterial pressure → uterine ischemia, ↑ anaerobic metabolites → stimulates type C pain neurons (Obstet Gynecol 2006;108:428)
• Epidemiology and risk factors: Affects 50–90% of reproductive-age ♀; prevalence highest in adolescents, ↓ w/ age; most have 1° dysmenorrhea; Risk factors: Nulliparity, heavy menstrual flow, smoking, depression (AFP 2005;71:285)
• Secondary causes of dysmenorrhea: Endometriosis, PID, adenomyosis, leiomyomata, ectopic pregnancy, interstitial cystitis, chronic pelvic pain

Evaluation

• General approach: Primary dysmenorrhea is a clinical dx
  • (1) Exclude 2° causes (endometriosis, PID, adenomyosis, leiomyomata, ectopic pregnancy, interstitial cystitis, chronic pelvic pain–see “Pelvic Pain”), (2) Assess severity, (3) Assess prior tx attempted (AFP 2014;89:341)
• History: (1) Confirm history typical: recurrent, midline pelvic pain at/near onset of menses × 1–3 d w/o other explanation; onset usually in adolescence (atypical should prompt additional consideration for Ddx, above); (2) assess severity of sx/desire for tx; (3) assess prior tx attempted
• Red flags: Onset > age 25 y, pain not related to menses, AUB, nonmidline pelvic pain, ⊕ dyspareunia, ↑ sx severity → refer to OB/GYN
• Exam: Should be nl in primary dysmenorrhea; evaluate for abdominal masses, point tenderness; pelvic exam important to r/o STI (e.g., GC/CT)
• Diagnostics: Not indicated if hx/PE c/w 1° dysmenorrhea; may test for STI as appropriate; r/o ectopic or miscarriage w/ β-hCG if recent onset of sx & irregular menses; pelvic U/S if suspect pelvic pathology (mass, ovarian cysts, endometriosis) or severe dysmenorrhea refractory to initial Rx

Management

• Management below is for 1° dysmenorrhea; refer for severe sx or suspected 2° causes
• Goals of treatment: Adequate pain relief to resume daily activities; complete resolution of sx is often unrealistic
• Nonpharmacologic: Heat: Equal efficacy to ibuprofen, better than APAP (Obstet Gynecol 2001;97:343; J Reprod Med 2004;49:739); pt may find cumbersome; Exercise, low-fat vegetarian diet, dairy, fish oil, vit B, D, E: Varied results in limited, small studies
• Pharmacologic: NSAIDs, hormonal contraception are mainstay, but may not be effective in severe pain (JAMA 2001;285:2347); no RCT directly comparing NSAIDs & hormonal contraception, can initiate either (Cochrane Database Syst Rev 2009;4:CD002120)
  • NSAID approach: Depending on cost, pt preference, convenience, can start w/ cheaper options (e.g., ibuprofen, naproxen) then → prescription/costly ones (e.g., mefenamic acid); start w/ onset of sx or menses, continue for 2–3 d based on pt’s usual sx pattern
  • Hormonal approach: Initiate depending on pt preference as mostly = efficacy; can initiate cyclic OCP & → continuous if no response
• If no response after 3 mo, change to or add additional class of Rx
• If refractory to combination NSAID + hormonal contraception × 3 mo, consider 2° cause & gynecology referral for laparoscopy
• Complementary/alternative medicine: No high-quality data on effectiveness of CAM (e.g., herbs, acupuncture), though some herbal preparations merit further review (Cochrane Database Syst Rev 2008;2:CD005288; 2016;3:CD002124; 2016;4:CD007854)

First-Line Pharmacologic Therapy
Class	Sample Rx w/ Usual Dosing	Notes
NSAID	Ibuprofen 800 mg q8h × 3 d Mefenamic acid 500 mg × 1, then 250 mg q6h × 3 d Naproxen 500–550 mg BID	Efficacy > placebo/acetaminophen in RCTs (Cochrane Database Syst Rev 2010:CD001751); unclear if specific NSAIDs better than others

 

OCP	Any preparation (low or high dose estrogen) 1 tablet QD Extended or continuous cycle > relief than cyclic (Contraception 2010;81:215)	Efficacy > placebo; no evidence 1 preparation better than another (Cochrane Database Syst Rev 2009:CD002120)
Other Hormone	Vaginal ring Depot medroxyprogesterone acetate	Efficacy: Ring = OCP 50% pts amenorrheic in 1st y of depot; no studies w/ relief of dysmenorrheal as 1° outcome (Contraception 2009;80:113) Avoid if planning to conceive w/in 1–2 y
IUD	Levonorgestrel-IUD	N.b. nulliparity not contraindication

Patient information: acog.org/Resources_And_Publications/Patient_Education_FAQs_List (see “Dysmenorrhea (FAQ046)” under Gynecological Problems)

POLYCYSTIC OVARIAN SYNDROME

Definition

(JCEM 2013;98:4565; Endocr Pract 2015;21:1291; NEJM 2016;375:54)

• Polycystic ovarian syndrome (PCOS) is a common, heterogeneous endocrine disorder affecting 6–10% of reproductive-aged women
• Pathophysiology: Underlying causes still unknown; some genetic predisposition; role/prominence of obesity in causing PCOS undefined, although it may worsen syndrome; 2 pathways below play role
  • (1) Rapid GnRH cycling → ↑↑LH and ↓↓FSH → ↑ androgen production and impaired ovarian follicular development; (2) Insulin resistance → hyperinsulinemia → ↑ androgen production by ovaries and adrenal glands and ↓SHBG production which ↑ free T levels

PCOS Diagnostic Criteria (must meet 2 of 3)
Criteria	Notes
Androgen excess	Evidence may be clinical or biochemical
Ovulatory dysfunction	Anovulatory bleeding pattern or amenorrhea
Polycystic ovaries	Exclusion of other disorders

• Comorbidities: PCOS assoc w/ obesity, depression, OSA, NAFLD, DM, CVD, dyslipidemia, infertility, pregnancy complications (related to obesity and/or glucose intolerance), endometrial CA

Evaluation

(JCEM 2013;98:4565)

• General approach: (1) Assess for above criteria (2) Rule out PCOS mimics
• History: Assess OB/GYN hx including menses frequency and onset, infertility, hirsutism (interpret in context of familial patterns, ask about use of hair removal methods), acne, alopecia, CV disease risk (smoking hx, family hx), alternative diagnoses (see below)
• Exam: Assess body habitus, terminal hair growth (Ferriman Gallwey score), acne, androgenic alopecia, acanthosis nigricans, skin tags
• Laboratory: Standard testing and values below; additional tests guided by clinical suspicion

Standard Laboratory Testing and Expected Values in PCOS
Laboratory Test	Findings
SHBG	↓
DHEAS (adrenal androgen)	↑
Total testosterone (ovarian)	↑ but <200; ♀ ULN = 40–60 ng/dL
Morning 17-OHP	Normal (<200 ng/dL); obtain in first 10 d of menstrual cycle
TSH, PRL	Normal
Other	No role for LH/FSH in diagnosis of PCOS; can help with Ddx of amenorrhea (see “Menstrual Disorders”)
PCOS Differential Diagnosis (Adapted from JCEM 2013;98:4565)
	Distinguishing Features	Laboratory Findings
Disorders to Always Exclude
Thyroid disease	See “Thyroid”	TSH ↑ or ↓
PRL excess	See “Hyperprolactinemia”	PRL ↑
Nonclassical congenital adrenal hyperplasia	Family hx infertility or hirsutism; Ashkenazi Jewish heritage	17-OHP >200 ng/dL (AM, early follicular phase); confirm with stimulation test
Medications	Anabolic steroids, valproic acid, cyclosporine	None

 

Disorders to Consider Excluding (see “Menstrual Disorders: Amenorrhea”)
Pregnancy	Amenorrhea, breast fullness, nausea, uterine cramping	⊕ β-HCG
Hypothalamic amenorrhea	Amenorrhea + low BMI, excessive exercise or stress	↓ FSH, ↓ estradiol
Primary ovarian insufficiency	Amenorrhea + hot flashes, vaginal dryness; autoimmunity	↑ FSH, ↓ estradiol
Androgen-secreting tumor	Rapid onset of severe hyperandrogenism (e.g., Δ voice, clitoromegaly)	↑↑ Total testosterone, DHEAS, obtain vaginal u/s, MRI adrenals
Cushing syndrome	Easy bruising, violaceous striae, myopathy, plethora	24-h urine free cortisol, see “Cushing’s”
Acromegaly	Increased shoe/glove size, frontal bossing, macrognathia	↑ IGF-1

(NEJM 2005;352:1223; JCEM 2013;98:4565)

• Progesterone: If concern for anovulation, may obtain a week before anticipated bleed (usually ~day 21); should be ≥3–4 ng/mL; if low, pt warrants progesterone tx (to protect uterus against unopposed estrogen)
• Imaging: Pelvic ultrasound recommended if hyperandrogenism with regular menses or suspicion for ovarian tumor (rapid onset, T >200 ng/dL)

Management

(Am J Med 2007;120:128; NEJM 2005;352:1223)

• CV risk stratification: BMI, waist circumference, blood pressure, 2-h 75-g oral glucose tolerance test (preferred to HbA1c), lipid panel
• Medical therapy (see below)
• Weight loss and exercise to improve metabolic dysfunction; may also reduce androgen levels and restore ovulation
• When to refer: Refer to a specialist if fertility desired, if tx below ineffective, or dx uncertain

PCOS Medical Therapies
Medication	Mechanism and Effects	Considerations
Estrogen/progestin combined contraceptives (1st-line therapy, includes OCPs, patch, vaginal ring)	↓ LH → ↓ ovarian androgens ↑ SHBG → ↓ bioavailable androgens Endometrial protection	Provides contraception ↑ risk of VTE (esp if older, smoker, obese) No specific formulation proven superior; norgestimate is progestin with low androgenic potential and lower risk of VTE
Spironolactone (for severe hirsutism refractory to hormonal contraceptives)	Androgen receptor antagonist	Uptitrate to 100 mg twice a day Pregnancy must be avoided (teratogenic)
Metformin (for impaired glucose tolerance)	↓ Insulin resistance May ↑ ovulation	Gradually uptitrate to minimize gastrointestinal side effects
Progestin (episodic)	Endometrial protection	Induce withdrawal bleed every 1–3 mo
Levonorgestrel-releasing IUD	Endometrial protection	Provides contraception

(NEJM 2016;375:54; NEJM 2005;352:1223)

FEMALE INFERTILITY

Background

(Clin Ob Gyn 2012;55:692; Fertil Steril 2008;90:S60; Hum Repro 2005;20:144)

• Baseline fertility rates: 50% of heterosexual couples who are not using contraception conceive w/in 3 mo, 72% w/in 6 mo, 85% w/in 1 y (Obstet Gynecol Clin N Am 2015;42:15)
• Definitions:
  • Infertility: Failure to conceive by heterosexual couple despite regular, unprotected intercourse for defined period; timeframe is based on the age of ♀ partner: ♀ <35 y = failure to conceive after 1 y, ♀ ≥35 y = failure to conceive after 6 mo Impaired fecundity: Physical difficulty becoming pregnant and/or carrying a pregnancy to live birth (e.g., includes miscarriage/stillbirth) (Natl Health Stat Report 2014;67:1)
• Epidemiology: 6% of married US ♀ 15–44 y meet definition of infertility, 11% of all US ♀ 15–44 y have impaired fecundity (Natl Health Stat Report 2014;67:1; 2014;73:1)
• Etiology: May be caused by endocrine, genetic, structural, immunologic, or infectious causes in either partner; infertility rates correlate w/ age in ♀ > ♂, w/ ↓ fecundity for ♀ at age 32 y and ↓↓ age >37 y 2/2 ↓ oocyte numbers/quality and ↑ incidence of tubal disease, endometriosis, other structural problems; ~ 20–25% of all cases of infertility are unexplained; when known, ♀ factors contribute to 50–75% of cases, ♂ factors contribute to 25–50%, >1 factor may be present

Selected Female Infertility Etiologies
Category	Diagnoses
Ovulatory dysfunction (32%) See “Abnormal Uterine Bleeding” and “Amenorrhea” in Menstrual Disorders	Hypothalamic–pituitary dysfunction (↑ stress, eating d/o, ↑ exercise) Anovulation (~80% related to PCOS, see “Polycystic Ovary Syndrome”) Endocrinopathy (↑ PRL, thyroid disease, metabolic syndrome, obesity) Ovarian insufficiency (idiopathic, age-related, medication-related, s/p ovarian surgery, s/p viral illness, h/o chemo/XRT)
Tubal pathology (22%)	Occlusion or other abnormalities, often in setting of prior PID or intra- abdominal surgery
Endometriosis (15%)	Anatomic distortion; possible effect of cytokine release interfering w/ ovulation, fertilization, implantation
Pelvic adhesions (12%)	2/2 intra-abdominal surgery, infection, trauma
Other (19%)	Structural: Uterine fibroids, polyps, Asherman syndrome, reproductive tract anomaly, cervical stenosis s/p prior procedure Genetic: Turner syndrome, androgen insensitivity syndrome Immunologic: SLE, APLAS, celiac disease; Meds: OCPs, progestins, Ψ medications, corticosteroids, chemotherapeutics

(WHO Tech Report Series 1992;820:1; NEJM 2010;363:965)

Evaluation

(Clin Ob Gyn 2012;55:692; Womens Health 2010;6:753)

• General approach: Consider as a problem affecting couples rather individuals; ♂ infertility assoc w/ ↑ pt risk of genetic abnormalities, CA, potentially heritable conditions (Fertil Steril 2013;100:681–685) ∴ both partners should be evaluated, even if IVF planned (see “Men’s Health”)
• History: (Can Fam Physician 2003;49:1465)
  • Reproductive hx: Age (both partners); duration of infertility, frequency of coitus, sexual dysfunction (both partners), pregnancy/paternity hx, menstrual hx (age at menarche, cycle length, frequency, regularity), h/o PID, h/o abnl Pap, h/o gyn procedure, prior contraception PMHx: H/o chemo/XRT, endocrinologic disease, celiac disease, autoimmune disease Medications: Include herbal preparations, OTC, vitamins
  • FHx: Early menopause, endometriosis; both partners: infertility, birth defects, CF, genetic mutations, developmental delay Social hx (for both partners, if known): EtOH, tobacco, illicits, stress, toxic exposures ROS: ⊕ PMS sx (suggest ovulatory cycles), ↓ estrogen (vaginal dryness, hot flashes), galactorrhea, sx of hyperandrogenism
• Exam: BMI, BP, HR, general appearance, secondary sex characteristics, thyroid exam, breast exam (galactorrhea), signs of androgen excess (acne, hirsutism, baldness, virilization), speculum exam (purulent d/c, cervical/vaginal structural abnormalities), pelvic exam (uterine size/mobility, tenderness, masses, nodularity in posterior cul-de-sac)

Studies to Evaluate Female Infertility
Lab/Study	Notes
TSH, PRL	If both elevated, tx hypothyroidism 1st (see “Thyroid Disorders” & “Prolactinemia”)
FSH/estradiol in early follicular phase (d 3 of cycle)	Evaluates ovarian reserve: estradiol >60–80 pg/mL + nl FSH (<10 IU/L) consistent w/ ↓ ovarian reserve, ↑ FSH + ↑ estradiol = likely poor response to assisted reproductive technology (ART)
Hysterosalpingogram	Assess tubal patency, uterine cavity (e.g., fibroids)
PCOS evaluation	(see “Polycystic Ovary Syndrome”), d 21–25 progesterone level → level >3 ng/mL confirms ovulation
STI testing	Including chlamydia Ab; as indicated by Hx/PE

(NEJM 2010;363:965; Obstet Gynecol Clin N Am 2015;42:15)

Treatment

(Am J Obstet Gynecol 2008;199:596; Obstet Gynecol Clin N Am 2015;42:15)

• Treat underlying cause as indicated; Lifestyle modifications as indicated: Weight loss/gain, mod exercise, smoking cessation, ↓ EtOH, ↓ stress, ↓ caffeine (note that data lacking/inconclusive w/ exception of maintaining nl weight); PCOS: Consider metformin vs. clomiphene +/- other anti-estrogenic therapies in conjunction w/ specialist, although inconclusive data re: efficacy for fertility (Cochrane Database Syst Rev 2016;12:CD002249)
• General recommendations to increase fertility: Intercourse every other day on d 12–18 of cycle; women should be on multivitamin w/ 400–800 μg folic acid/d to ↓ risk of neural tube defects; male partners should avoid ejaculatory abstinence of >2 d; avoid water-based lubricants (e.g., K-Y) as these may ↓ sperm motility (J Reprod Med 2004;49:289; PLoS One 2012;7:e46276)
• When to refer: Consider gyn referral in all pts; genetics referral as per Hx/PE
  • Infertility specialist: Prompt referral for pts >35 y, pts w/ ↓ ovarian reserve or pts w/ suspected POI for additional testing of ovarian reserve (e.g., clomiphene citrate challenge test, inhibin B, antimullerian hormone); refer for other pts requiring advanced tx, incl further evaluation of structural causes, or possible ART (including ovarian hyperstimulation, intrauterine insemination, in vitro fertilization)
• Patient information: acog.org/Patients/FAQs/Evaluating-Infertility

CONTRACEPTION

Background

• Almost half of all US pregnancies are unintended (pregnancy not desired at time of conception); 33% of women use contraception inconsistently, incorrectly, or not at all → 95% of unintended pregnancies, resulting in increased morbidity, mortality, and healthcare costs (Perspect Sex Repro Health 2006;38:90; guttmacher.org; AFP 2016;94:942)
• Half of US women are at risk of unintended pregnancy (sexually active, fertile, not currently pregnant); appropriate to discuss contraception w/ all pts of reproductive age
• Risk factors: ↑ rates of unintended pregnancy in women 18–24 y, women living in poverty, nonwhite ethnicity, ↓ education (Contraception 2011;84:478)
• Conditions w/↑ health risks from unintended pregnancy: Estrogen–sensitive CA, cyanotic CHD, recent bariatric surgery, transplant, epilepsy, HTN, SLE, APS, sickle-cell

Choosing a Method

• Counsel pt to choose most effective method she and partner able to use successfully
• Women w/ medical issues: Refer to CDC US Medical Eligibility Criteria for Contraceptive Use, 2016: MMWR Recomm Rep 2016;65:1

First-Year Contraceptive Failure Rates (Selected)
	Annual # of pregnancies/100 using method
Method	Perfect Use	Typical Use
Implant (Implanon)	<1	<1
Sterilization (tubal or vasectomy)	<1	<1
IUD (Copper-T or Mirena)	<1	<1
Depo Provera	<1	6
Pill (combined or progestin only)	<1	9
Patch/Ring	<1	9
Male condom	2	18
Diaphragm	6	12
Withdrawal	4	22
Periodic abstinence	—	24
Calendar	5	—
Ovulation method	4	—
Symptothermal	<1	—
No method	85	85

(Adapted from Guttmacher Institute; guttmacher.org/pubs/fb_contr_use.html)

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LONG-ACTING REVERSIBLE CONTRACEPTION

Background

(Obstet Gynecol 2011;118:184; AFP 2012;85:403; MMWR 2016;65:1)

• Long-acting reversible contraception (LARC): 3 methods available in US: (1) copper IUD (ParaGard), (2) levonorgestrel IUD (Mirena, Skyla, Liletta), and (3) etonogestrel-containing contraceptive implant (Nexplanon)
• Benefits: Very effective, no maintenance; good option for women who desire to avoid pregnancy for >3 y; avoids estrogen exposure; no evidence of subsequent long-term fertility problems
• Onset of efficacy: Copper IUD is effective immediately; all other forms of LARC take ~7 d to achieve efficacy, pts may continue prior form of contraception or be counseled to use barrier methods for this period
• Risk of ectopic pregnancy: ↓ overall risk compared with pts who do not use contraceptives, but ↑ risk if pregnancy occurs (Am J Obstet Gynecol 2004;190:50)

Evaluation

• Prior to placement: β-hCG generally recommended; STI testing should be offered, but is not required unless clinical suspicion; antibiotic ppx unnecessary; for IUD, pre-placement misoprostol not generally thought to offer benefit
• Contraindication for IUDs: Uterine distortion, active pelvic infection (wait 3 mo before insertion), pregnancy, unexplained serious uterine bleeding, active cervical/endometrial CA; pelvic TB; postpartum sepsis; not contraindicated in adolescents/young adults, nulliparous women, or during breastfeeding; may be placed immediately postpartum
• Training: Must be performed by trained providers; training opportunities/information at acog.org/-/media/Departments/LARC/Clinical-Training-Opportunities.pdf

Long-Acting Reversible Contraceptives
Class	Mechanism	Notes
Levonorgestrel- releasing IUD	Interferes w/ sperm migration, inhibits ova fertilization; partially inhibits ovulation	S/e: irregular bleeding Benefits: ↓ menstrual bleeding (amenorrhea for many women w/ higher dose formulations), ↓ dysmenorrhea
Copper T-380A IUD	Interferes w/ sperm migration, prevents fertilization	S/e: heavier menses

 

Nexplanon subdermal implant	Continuous-release progestin (etonogestrel) inhibits ovulation		S/e: irregular bleeding (1° reason for discontinuation); can cause menses to be heavier or lighter Fertility returns soon after removal
LARC Duration of Use
Trade Name (active ingredient)		Duration
Mirena (levonorgestrel 52 mg)		Approved for 5 y, likely effective longer
Liletta (levonorgestrel 52 mg)		Approved for 3 y, likely effective longer
Kyleena (levonorgestrel 19.5 mg)		Approved for 5 y
Skyla (levonorgestrel 13.5 mg)		Approved for 3 y
ParaGard (Copper)		Approved for 10 y, likely effective longer
Nexplanon (etonogestrel 62 mg)		Approved for 3 y

(Int J Women’s Health 2016;8:589)

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COMBINED HORMONAL CONTRACEPTION

 Background

(NEJM 2003;349:1443)

• Definition: Synthetic estrogen (usually ethinyl estradiol [EE]) and progestin (multiple types); can be delivered orally, transdermally (patch), or transvaginally (ring)
• Estrogen suppresses gonadotropin surge → prevents ovulation
• Progestin affects cervical mucus, tubal peristalsis, endometrial lining → ↓ sperm motility, prevents egg fertilization/implantation; also inhibits GnRH → ↓ ovulation (Contraception 2002;65:21)
• Benefits: Improvement in menorrhagia, dysmenorrhea, anemia, PMS, acne, hirsutism; ↓ risk ovarian/endometrial cancer
• Risks: HTN, venous thromboembolic disease (up to 3–4x ↑ risk if no underlying RFs; up to 1.8x further ↑ w/ 3rd-and 4th-gen progestins; absolute VTE risk low, much < risk than pregnancy), MI, CVA; risks ↑ w/ older preparations (EE >50 μg)
• Efficacy in overweight/obese pts: Some studies suggest 50–70% higher failure rates in women w/ BMI >25 (Womens Health 2013;9:453)
• Absolute contraindications: Include h/o DVT/PE, CVA, MI, uncontrolled HTN, known thrombogenic mutations, migraine w/ aura or neuro s/sx, smokers ≥35 y, active liver disease, known/suspected estrogen-dependent tumor, SLE, h/o solid-organ transplant (CDC MMWR 2016;65:1)

Transdermal & Vaginal Hormonal Contraception

• Vaginal ring: NuvaRing (15 μg EE, 150 μg etonogestrel); flexible plastic ring inserted by pt; intravaginal × 3 wk, remove × 1 wk; high pt satisfaction rates
• Transdermal patch: Ortho Evra/Xulane (35 μg EE, 150 μg norelgestromin/d); apply q1wk; ↓ efficacy in pts >90 kg (Fertil Steril 2002;77:S13); ↑ systemic estrogen exposure w/ patch than w/ OCP of equivalent EE dose; ↑ risk VTE

Combination Oral Contraceptive Pills (OCPs)

• Initiating OCPs: Obtain BP, careful review PMHx for contraindications; confirm not pregnant via hx ± β-hCG; no role for pelvic exam (for this purpose); prescribe 1 y Rx at a time (1 28-d supply + 12 refills) Contraindications: Include women ≥35 y who smoke; HTN (esp uncontrolled) those w/ estrogen contraindications (incl hx VTE, thrombophilia), complicated valvular heart disease, advanced DM, migraine with aura, known ASCVD or at ↑↑ risk, cirrhosis (MMWR Recomm Rep 2016;65:1)
• General approach to prescribing: After review of PMHx and contraindications (above):
  • (1) Decide on planned pattern of use (cyclic vs. extended cycle vs. continuous) (2) Select estrogen dose
  • (3) Select progesterone formulation
  • (4) Set initiation plan w/ pt (quick 1st day vs. Sunday start)
  • (5) Discuss indications for backup methods
  • (6) Counsel re: s/e
• Pattern of use: Cyclical: 21 active pills → 7 hormone-free pills or 24 active pills → 4 hormone-free pills (possible ↑ efficacy, ↑ breakthrough bleeding)
  • Extended-cycle regimen: Typically 84 active pills → 7 hormone-free pills, Extended/Continuous: May be preferred in women w/ premenstrual sx or for lifestyle; efficacy, safety equivalent to cyclic use
• Notes on formulations: In general, all OCPs equally effective; no evidence of benefit for multiphasic compared to monophasic; preparations w/name ending in “Fe” include iron; preparations with “Tri” in name usually multiphasic
• Estrogen formulations: Ethinyl estradiol (EE) most common: Low- dose (10–20 μg) to high-dose (50 μg) formulations; standard = 20–35 μg; breakthrough bleeding may ↑ w/ doses ≤20 μg; 50 μg mestranol considered equivalent to 30–35 μg EE
• Progestin formulations: Multiple options, vary in androgenic activity (least → most by generation: 4th → 3rd → 1st → 2nd); note different progestins not equivalent on a mg basis; 3rd/4th gen may have relative ↑VTE risk (drospirenone higher risk, LNG lower risk)
  • 1st gen: Norethindrone acetate, norethindrone, ethynodiol
  • 2nd gen: Levonorgestrel (↑ androgenic), norgestrel
  • 3rd gen: Norgestimate, desogestrel (least androgenic)
  • 4th gen: Drospirenone (antiandrogenic + antimineralocorticoid activity), dienogest
• Sample Rx: Norgestimate 0.25 mg/ethinyl estradiol 30 μg a reasonable initial Rx for most pts

Selected OCP Formulations (Med Letter 2015;57:e133)
Progestin	Estrogen	Sample Rx	Notes
Norethindrone (NE)	EE	Necon 1/35 or 0.5/35	Chewable available
Multiphasic Norethindrone	EE	Necon 10/11 (10 d of 0.5 mg NE → 11 d mg of 1 NE) Nortrel, Ortho-Novum
Norethindrone	Mestranol	Necon 1/50
Norethindrone acetate (NEA)	EE	Loestrin 1.5/30	24-d available
Multiphasic Norethindrone acetate	EE	Lo Loestrin (1/10) (no generic)	Lowest dose of EE available
Norethindrone acetate	Multiphasic EE	Estrostep FE (5 d of 20 μg EE → 7 d of 30 μg EE → 9 d of 35 μg EE)	Approved for acne

 

Ethynodiol	EE	Kelnor, 1/35
Levonorgestrel	EE	Amethyst (has 20 μg EE, 0.09 mg LNG) Seasonale (84 d of 30 μg EE /0.15 mg LNG)	Amethyst intended for continuous use
Levonorgestrel	multiphasic EE	Seasonique (84 d of 30 μg EE/0.15 mg LNG → 7 d of 0.1 μg EE LoSeasonique (84 d of 20 μg EE/0.15 mg LNG →7 d of 0.1 μg EE)	Intended for 91-d cycles
Multiphasic Levonorgestrel	Multiphasic EE	Enpresse, Trivora
Norgestrel	EE	Cryselle, Lo-Ogestrel, Ogestrel
Norgestimate	EE	Ortho-Cyclen 35 μg EE/0.25 mg NG
Multiphasic Norgestimate	EE	Ortho Tri-Cyclen (7 d of 35 μg EE/0.18 NG → 7 d of 35 μg EE/0.215 NG → 7 d 35 μg EE/0.250 NG)	Approved for acne
Desogestrel (DG)	EE	Apri (30 μg EE/0.15 DG)
Multiphasic Desogestrel	Multiphasic EE	Kariva, Viorele
Drospirenone	EE	Loryna, Ocella, Yasmin, Yaz	All indicated for acne
Dienogest	Estradiol Valerate	Natazia	Both multiphasic; no generic

• Initiation Plan: multiple options available
  • Quick start (preferred): Take 1st pill as soon as prescription filled; ↑ compliance w/o ↑ s/e; need backup contraception × 7 d (Obstet Gynecol 2007;109:1270) 1st day start: Take 1st pill on 1st day of period; backup contraception not needed Sunday start: Take 1st pill on Sunday after period begins; need backup × 7 d
• Backup method indications:
  • Missed pills: Use backup contraception × 7 d after ≥2 missed pills Medication interactions: Efficacy ↓ by meds that ↑ liver microsomal enzyme activity (e.g., anticonvulsants, griseofulvin, rifampin, St. John’s wort); no clinical evidence of interaction w/ other abx, case reports w/ PCN, tetracyclines (Obstet Gynecol 2001;98:853)
• Side effects/monitoring:
  • S/e: Counsel pts re: anticipated s/e (see below), typically resolve w/in 2–3 mo; also discuss risk/benefits of combined hormonal tx (above) F/u: Consider f/u at 3 mo to check BP, evaluate for tolerance and s/e; can switch pill to adjust amount of EE or type of progestin per s/e Pregnancy: If pregnancy occurs while on OCPs, d/c upon dx, reassure pt no adverse outcome assoc w/ using OCPs at time of conception

Adjusting OCP Formulation for Side Effects (AFP 2010;82:1499)
Side Effects	Cause	Adjustment
HA, nausea, mastalgia	Estrogen excess	Try dosing QHS vs. low EE pill (↑ risk breakthrough bleeding); consider LARC
Hirsutism, acne, weight gain	Progestin and/or androgen excess	→ 3rd/4th-gen progestin
Mood changes, ↓ libido	Progestin excess	→ 3rd-gen progestin or LARC
Breakthrough bleeding	Often multifactorial	Consider alternate etiology (polyp/infection), missed dose Early cycle/continuous: → ↑ EE or consider LARC Late cycle bleeding: → ↑ progestin (desogestrel > norgestimate) or change to multiphasic preparation vs. LARC
Amenorrhea	Pregnancy; nonpathologic suppression of endometrial shedding	Pregnancy test: If ⊕, d/c OCP; if ⊖, reassure; if pt desires menses → ↑ EE or choose progestin w/ ↑ endometrial activity (e.g., 1 mg norethindrone → 5 mg); multiphasic pill may be effective

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OTHER CONTRACEPTION METHODS

 Barrier Methods

• Condoms: Consistent, correct use protects from STI transmission; latex condoms ↓ HIV risk 80–95% (Cochrane Data 2001:CD003255; Soc Sci Med 1997;44:1303)
  • Latex allergy: 1–6% of US; synthetic and natural membrane available but ↓ efficacy ♀ condoms: Polyurethane sheath; option if cannot use ♂ condom Spermicides: Do not protect against STIs; irritation may ↑ risk infection
• Diaphragm, cervical cap: Require fitting by trained clinician; only effective when used w/ spermicide; do not prevent transmission of STIs

Sterilization

• Tubal obstruction: Permanent; prevents pregnancy by disrupting tubal patency via tubal ligation or hysteroscopic sterilization device (Essure); laparoscopic (general anesthesia) vs. hysteroscopic (often local anesthesia)
• Vasectomy: Interruption or occlusion of the vas deferens; can be performed in outpt setting w/ local anesthesia; safest, least costly method of surgical sterilization

Progestin-Only Methods

• Progestin-only (“mini-”) pills (norethindrone; Camila, Micronor): Option for pts w/ contraindication to estrogen (including lactation); ↑ risk breakthrough bleeding; must take at same time every day
• Injectable: Depot medroxyprogesterone acetate (DMPA); IM/SC injection q 3mo
  • Benefits: No need for daily pt adherence, amenorrhea w/ ongoing use, ↓ endometrial CA; no need for specialized provider training; S/e: Irregular bleeding (frequent cause for discontinuation of this method), ↑ weight, HA; can ↓ BMD, esp in adolescents (FDA Black Box Warning)

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EMERGENCY CONTRACEPTION 

Background

(ACOG Practice Bulletin 152. 2015)

Indications: Pts who have had unprotected intercourse, including failure of another method w/in previous 120 h; improved access does not ↑ sexual risk taking or STI acquisition (Obstet Gynecol 2006;108:1098) Efficacy: ↓ pregnancy risk up to 88% (levonorgestrel EC); does not interrupt established pregnancy

Access: Plan B One-step available w/o prescription regardless of age; other options available to women aged 17 and over w/o Rx and to younger women w/ Rx

Management

• Who: anyone of childbearing age; contraindications (VTE, migraines, liver disease) to daily OCPs do NOT apply to EC
• Options: May refer pts to www.not-2-late.com
  • Levonorgestrel EC: 1 (1.5 mg) dose (Plan B One-Step, Take Action, Next Choice One Dose, My Way) or 2 × 0.75 mg taken 12 h apart; single dose as effective; safer, more effective than Yuzpe regimen w/ ↓ rates of N/V, but minimally effective for women >154 lb (70 kg) (Contraception 2014;91:97) Yuzpe regimen (EE + progestin): 2 × (100 μg EE + 0.5 mg levonorgestrel); many OCPs can be used; less effective than progestin-only, ↑ N/V
  • Ulipristal acetate (Ella): Rx only; most effective oral option, especially in women >154 lb; pregnancy rate = 1.3% w/ ulipristal acetate vs. 2.2% w/ levonorgestrel (use 0–120 h after intercourse) (Lancet 2010;375:555; Contraception 2014;91:97) Copper IUD: Most effective form of EC (>10× efficacy of pills), provides continuing contraception; insert w/in 5 d of intercourse; avoid w/ active gonorrhea/chlamydial infection (CDC MMWR 2010;59:64; Hum Reprod 2012;27:1994)
• Counseling: Emphasize regular contraception use (can start OCPs immediately after EC or schedule LARC placement); consider screen for sexual assault; “I’m glad you came in to get help. Can I ask if the sex happened with your consent?” consider screening for STIs; ✓ pregnancy test if no menses in 3–4 wk

PELVIC INFLAMMATORY DISEASE

Background

(CDC MMWR 2015;64:1; AFP 2012;85:791)

• Definition: Acute infection of the upper genital tract in women; includes endometritis, salpingitis, TOA, pelvic peritonitis; may be acute, subacute, or subclinical
• Etiology: Upward migration of organisms (STIs, vaginal flora) through cervix & into uterus, fallopian tubes, and/or peritoneal cavity
  • Pathogens: Often polymicrobial & never identified, N. gonorrhoeae, C. trachomatis most common; can also be due to aerobic & anaerobic vaginal flora (e.g., G. vaginalis, H. influenzae, Mycoplasma genitalium, enteric GNRs; S. agalactiae, Prevotella, Bacteroides, Peptostreptococcus); high prevalence of coexisting BV
• Incidence: ~1 million pts diagnosed w/ PID annually in US; most common among pts 15–29 y & most frequent Gyn cause for ED visits, though many episodes go undiagnosed; subclinical PID (endometritis) equally common as clinically diagnosed PID, can → same rate of complications (Infect Dis Obstet Gyn 2011;2011:561909)
• Complications/sequelae: Tubo-ovarian abscess (TOA), chronic pelvic pain (up to 30%) (Am J Obstet Gynecol 2002;186:929), infertility, ectopic pregnancy; risk ↑ w/ number/severity of episodes (sx >3 d), delays in care, infection 2/2 Chlamydia; recurrent PID assoc w/ 2x ↑ in infertility & 4x ↑ in chronic pelvic pain (Sex Transm Dis 2011;38:879)

Evaluation

(AFP 2012;85:791; Lancet 1992;339:785)

• History: Sx include lower abdominal pain (usually bilateral, ↑ w/ intercourse, palpation, or Valsalva), dyspareunia, fever, chills, back pain, vomiting, & sx of lower genital tract infection (abnl vaginal d/c or bleeding, itching, odor); sx may be mild or absent
• Risk factors: Age <25 y; multiple, new, or symptomatic partners; h/o PID or STIs; lack of barrier contraception, IUD (↑ risk only w/in 3 wk of insertion), douching
• Physical exam: VS: only 50% present w/ fever
  • Abd: Tenderness in lower quadrants; if RUQ pain, suggests perihepatitis/Fitz–Hugh–Curtis syndrome Pelvic exam: Purulent endocervical d/c and/or acute cervical motion tenderness or adnexal tenderness w/ bimanual exam; adnexal tenderness = 95.5% Se for histologic endometritis (Am J Obstet Gynecol 2001;184:856)
• Labs: Urine hCG, U/A, vaginal wet prep (87–91% Se for PID if 3+ WBCs/hpf; 95% NPV if no WBCs), CBC, GC/CT, CRP/ESR (Se = 74–93%); HIV, HBV SAg/Ab, syphilis
• Imaging: TVUS indicated to dx TOA if clinically ill, severe pain, or adnexal mass; thickened, fluid-filled tubes on TVUS definitive for PID; do not delay tx for imaging
• Differential diagnosis: Consider “neighboring structures” (appendix, colon, bladder, urinary tract), other gynecologic phenomena (miscarriage, ectopic, ovarian pathology); see “Pelvic Pain”

Treatment

(CDC MMWR 2015;64:1)

• Treatment: For all sexually active pts, initiate empiric tx if pt has any adnexal, uterine, or cervical motion tenderness w/o other apparent cause; pts w/ even minimal findings have high likelihood of subclinical PID (cdc.gov/std/pid)
• Follow-up: All pts should be clinically reassessed at 72 h for improvement
• All Rx regimens should be effective against N. gonorrhoeae & C. trachomatis; FQs & PO cephalosporins not recommended due to ↑↑ gonorrhea resistance; consider adding MNZ to treat coexisting BV

CDC 2015 Recommendations for PID Treatment
Oral/IM Re-evaluate at 72 h; if not responding → IV abx, inpt or outpt	Ceftriaxone 250 mg IM × 1 and doxycycline 100 mg PO BID (± MNZ 500 mg PO BID) × 14 d OR Cefoxitin 2 g IM × 1 and probenecid 1 g PO and doxycycline 100 mg PO BID (± MNZ 500 mg PO BID) × 14 d OR Other parenteral 3rd-gen ceph (e.g., ceftizoxime or cefotaxime) × 1 and doxycycline 100 mg PO BID (± MNZ 500 mg PO BID) × 14 d
Parenteral	Cefotetan 2 g IV q12h OR cefoxitin 2 g IV q6h and doxycycline 100 mg PO or IV q12h OR Clindamycin 900 mg IV q8h & gentamicin IV IM 2mgkg loading dose → 1.5 mg/kg q8h

(https://www.cdc.gov/std/tg2015/pid.htm)

• Sex partners: Examine/treat ♂ partners from previous 60 days (ceftriaxone 250 mg IM × 1 plus either azithromycin 1 g PO × 1 or doxycycline 100 mg PO BID × 7 d)
• IUDs in women with PID: Insufficient evidence to recommend removal, but close clinical f/u mandatory to confirm resolution Prevention/counseling: All pts evaluated for PID should be tested for HIV, HBV, syphilis; discuss safe sex practices, offer HPV immunization for pts aged <26 y; regular screening for GC/CT in pts <26 y (see “STIs,” “Screening,” and “Immunizations”)
• When to Refer: If cannot exclude surgical emergencies (e.g., appendicitis), ⊕ hCG, inability to adhere to/tolerate PO meds, severe clinical illness (high fever, N/V, severe abdominal pain), TOA or pelvic abscess → ED

VAGINITIS

Background

(JAMA 2004;291:1368; AFP 2011;83:816)

• Definition: Vaginal inflammation 2/2 infectious or noninfectious cause; may be associated with unusual discharge, pruritus, and/or pain
• Epidemiology: Vaginal complaints account for 10 million visits/y; most common gynecologic complaint; despite ↑ awareness/Rx, only 50% of cases adequately addressed (JAMA 2010;303:2043; NHANES, CDC 2010)
• Etiologies: In US pts w/ vaginal sx, bacterial vaginosis (BV) 40–50% > vaginal candidiasis (VC) 20–25% > trichomoniasis 15–20%

Evaluation

(AFP 2011;83:816; CDC 2015 STD Treatment Guidelines; CID 2008;47:1426)

• General approach: S/sx often nonspecific; demographics, PE, diagnostic studies are key
• History: HPI: Sx: Onset, nature of d/c (see Exam), pruritus (vaginal candidiasis [VS], noninfectious); pain/dyspareunia (PID, trichomoniasis, noninfectious, esp desquamative inflammatory vaginitis); systemic sx (PID)
  • Potential triggers: Contact w/ feminine hygiene products, detergents, soaps, contraceptive materials, pessaries, sex toys, medication, clothing (irritant/contact dermatitis); tight-fitting/nonbreathable clothing (VC) PMHx: DM, immunosuppression, recent abx use (VC); h/o atopy (irritant/contact dermatitis); menopausal (atrophic vaginitis) Social hx: Smoking (BV, trichomoniasis); diet high in refined sugars (VC) Sexual hx: New/multiple partners (BV, trichomoniasis, GC/CT, PID); sex w/ women, vaginal douching (BV); barrier contraception (contact dermatitis, latex allergy); IUD/diaphragm/spermicide (BV, VC); unprotected intercourse (BV, trichomoniasis); orogenital sex (VC); hx STIs (trichomoniasis, GC/CT, PID)
• Exam: Pelvic exam, w/ attention to appearance of vaginal introitus and d/c
  • BV: Malodorous (fishy) clear/white/gray d/c; no vulvar/vaginal inflammation VC: White/thick/odorless d/c; ⊕ vulvar excoriations, vaginal inflammation Trichomoniasis: Green/yellow/frothy d/c; ± vestibular and/or cervical inflammation (“strawberry cervix”)
  • Noninfectious causes: Presence of d/c, vulvovaginal inflammation varies
• Point-of-care testing: Vaginal wet mount preparation (“wet prep”): when prepared, can take 5–10 min to complete and may offer definitive dx

Vaginal Wet Prep Examination Process
Equipment	Cotton swab, test tube with 0.5-mL sterile saline, 2 glass slides, 2 cover slips, microscope
Exam room	Obtain sample of vaginal discharge and place swab in test tube
Sample prep + Whiff test	Saline sample: Using swab, place drop of solution onto glass slide, then cover w/ coverslip KOH sample: Using swab, place drop of solution onto glass side, add 1 drop 10% KOH; sniff immediately and evaluate for fishy odor (“whiff test”–-BV or trichomonas), then cover w/ coverslip
Microscope	Start w/10x, focus & adjust condenser/diaphragm level to ensure good contrast, scan field for areas of interest, then adjust to 40x
Saline sample	May observe squamous cells (normal), PMNs (suggest inflammation), clue cells (BV–-squamous cells that look “pressed in sand”), or trichomonads (jerky motion, ↓ w/ time since sample collected, flagellae often not visible)
KOH sample	May observe pseudohyphae and budding yeast (KOH lyses cell walls of cells seen in saline sample, allows clearer view of Candida)

Figure 15-3. Common findings on Wet Mount Microscopy

• Treatment considerations: Consider effectiveness/preference of PO vs. topical preparations, pregnancy status, need to Rx sexual partner(s) (see below)
• When to refer: If sx persist despite Rx, dx unclear, or “other” causes (see below)

Bacterial Vaginosis

(AFP 2011;83:816; AFP 2004;70:2125; CDC 2015 STD Treatment Guidelines)

• Background: Most prevalent cause of vaginal d/c or malodor, often chronic; >50% ♀ w/ BV are asx; may develop into posthysterectomy cuff cellulitis
• Pathogens: Gardnerella vaginalis, Lactobacillus, Mobiluncus, M. hominis, anaerobic GNRs, polymicrobial
• Expected findings: pH >4.5, Whiff test ⊕
• Microscopy: >20% clue cells w/ addition of NS
• Other tests: No role for cx or cervical cytology; consider PCR if microscopy unavailable
• Treatment: Metronidazole (MNZ) is standard; recurrence risk highest w/in 1 y,
  • Recommended tx: MNZ 500 mg PO BID × 7 d, counsel against EtOH use during Rx; intravaginal MNZ (0.75 gel, QD × 5 d) vs. clindamycin (2% crm, QD × 7 d) ~equivalent efficacy but ↑ recurrence rates Alt: Tinidazole 2 g PO daily × 2 d or 1 g PO daily × 5 d; PO clindamycin/intravaginal clindamycin ovules ↓ effective; single-dose PO MNZ (2 g) not recommended Sex partners: Tx not recommended

Vaginal Candidiasis

(AFP 2011;83:816; AFP 2004;70:2125; CDC 2015 STD Treatment Guidelines)

• Background: Highest incidence, 75% of women have ≥1 episode
• Pathogens: C. albicans > C. glabrata, C. tropicalis
• Expected findings: pH 4–4.5, Whiff test ⊖
• Microscopy: Hyphae/pseudohyphae visible w/ addition of 10% KOH Other tests: Pap smear ↑ Sp but ↓ Se; OTC rapid yeast detection kit convenient, inexpensive; PCR ↑ Se but expensive; Cx if recurrent sx w/⊖ microscopy
• Treatment: Determine if uncomplicated vs. complicated:
  • Uncomplicated (healthy, nonpregnant, mild–mod disease, <4 episodes/y, ⊕ hyphae): Short antifungal course; PO (fluconazole 150 mg × 1) or topical preparations (multiple azole agents, most 1-, 3-, & 7-d course) similarly effective Complicated (recurrent, pregnancy, systemic sx, immunocompromise): see below Recurrent (>4 episodes/y): Consider suppression w/ fluconazole 150 mg q72h × 3 doses, followed by fluconazole 150 mg weekly × 6 mo; if recurrence: repeat regimen but weekly dosing × 1y; repeat PRN, low incidence of resistance Pregnancy: Topical agents (clotrimazole or miconazole) preferred over PO; 7-d course Systemic/severe symptoms: Fluconazole 150 mg q72h × 3 doses
  • Immunocompromise: Fluconazole 150 mg q72h × 3 doses; alert pt that worsening sx may require hospitalization.
  • Sex partners: Tx not recommended

Trichomonas

(AFP 2011;83:816; AFP 2004;70:2125; CDC 2015 STD Treatment Guidelines)

• Background: Highly transmissible, frequent coinfection w/ other STIs; may develop into posthysterectomy cuff cellulitis
• Pathogen: Trichomonas vaginalis
• Expected findings: pH >5.4, Whiff test ⊕
• Microscopy: ⊕ trichomonads; leukocytes > epithelial cells
• Other tests: Cx, rapid Ag ↑ Se compared w/ microscopy (operator dependent); PCR most Se/expensive
• Treatment: Cure rate 90% w/ most PO nitroimidazoles
  • Initial tx: MNZ 2 g PO × 1 effective but ↑ GI sx, metallic taste; 500 mg BID × 7 d or tinidazole 2 g PO × 1 ↓ s/e; intravaginal tx not recommended due to ↓ cure rate Resistant: MNZ 2–4 g/d × 7–14 d; PO and intravaginal Rx more effective than PO alone Sex partners: Should be treated simultaneously; counsel to avoid intercourse until both pt and partner have completed Rx and are asx

Other Vaginitis Etiologies
Causative Factor/Pathogen	Notes
N. gonorrhoeae or Chlamydia trachomatis	Often asx; test all pts <25 y w/ vaginal sx; test/tx all pts w/ sx + multiple partners or PID sx (see “Pelvic Inflammatory Disease,” “Sexually Transmitted Infections”)
Mycoplasma genitalium	Most strongly assoc w/ cervicitis and PID; assoc w/ urethritis in ♂; common co-infxn w/ other pathogens, esp C. trachomatis. Tx: Azithro 1 g PO × 1; Alt: Moxifloxacin 400 mg × 7, 10, or 14 d; Sex partners: Tx not recommended
Dermatitis (Allergic, Contact)	Diseased vulvar skin more prone to irritation; irritation dermatitis > allergic (Dermatol Clin 2010;28:639) Irritants: Excessive washing, cleansers/deodorizers, condoms, topical antibacterial/antifungals Allergens: Latex, antifungals
Atrophic vaginitis	10–40% of postmenopausal ♀; ↓ Estrogen → vaginal atrophy, ↓ secretions (see “Menopause”)
Other	Lichen planus, pemphigus vulgaris, cicatricial pemphigoid, desquamative inflammatory vaginitis, Behcet syndrome, foreign bodies (retained tampons) GYN, derm, or rheum referral, as appropriate

PELVIC PAIN

Background

(AFP 2010;82:148; AFP 2016;93:380)

• Definition: Pain localized to the pelvis, anterior abdominal wall at/below the umbilicus, lower back, or buttocks, severe enough to cause functional disability or require Rx
• Epidemiology: 30–40% women of reproductive age in primary care have pelvic pain outside of menstruation at some point; no dx found in up to ~1/3 of acute cases
• General approach: Distinguish acute (≤3 mo) vs. chronic (≥6 mo); in determining cause, consider age & pregnancy status, then Ddx by organ system: GI, GYN, MSK, psych/neuro, urologic, other

Differential Diagnosis of Pelvic Pain
	Acute	Chronic
General approach	R/o most common emergent causes: PID, appendicitis, ovarian torsion, ectopic pregnancy, cyst rupture	Up to 40% have >1 dx; dysmenorrhea, dyspareunia & IBS are frequently reported comorbidities
GYN	PID/TOA, ruptured ovarian cyst, ectopic pregnancy, ovarian torsion, miscarriage, torsion/degeneration of uterine fibroid, endometriosis, mittelschmerz	Endometriosis, dysmenorrhea, chronic PID/endometritis, adhesions, adenomyosis, uterine fibroid, pelvic congestion syndrome, ovarian cyst, malignancy

 

Non-GYN	GI: Appendicitis,	GU: Interstitial cystitis, radiation cystitis, recurrent
	diverticulitis, bowel obstruction, mesenteric venous thrombosis, IBD flare, perirectal abscess GU: Cystitis, pyelonephritis, nephrolithiasis Ψ/neuro: Somatization d/o (anxiety, depression, physical or sexual abuse: see “Somatoform Disorders”) Note: Malignancy must be considered if postmenopausal	UTI, bladder CA GI: IBS, IBD, constipation, inguinal hernia, celiac disease, diverticulitis, colitis, colon CA MSK: Fibromyalgia, coccydynia, piriformis syndrome, levator ani syndrome, hip arthritis, DJD, stress fx Neuro: Abdominal cutaneous nerve entrapment syndrome Ψ: Depression, sleep d/o, somatization

Evaluation

(AFP 2010;82:148; AFP 2008;77:1535; AFP 2016;93:41; AFP 2016;93:380)

• History: Onset (acute vs. chronic); age, location (radiating: appendicitis, kidney stone, ovarian torsion, discitis); quality, exacerbating & alleviating factors; assoc sx (menses, constipation, diarrhea, hematochezia, hematuria, dysuria, vaginal d/c, postmenopausal bleeding); PMHx, PSHx; FHx (sickle cell, coagulation d/o); Social hx (trauma; h/o physical, sexual, or domestic abuse, SUD); thorough Reproductive/sexual hx: Infertility (endometriosis), STI hx (PID), menorrhagia (fibroids)
• Exam: VS, general level of comfort/distress, bowel sounds, palpate for abdominal/pelvic masses; Carnett sign: have pt raise legs off table while supine w/ finger on painful area → ↑ pain consistent with myofascial rather than visceral pain; CVA tenderness: pyelonephritis/nephrolithiasis; Pelvic exam: Erosive/vesicular lesions (HSV), vaginal d/c, cervical d/c, cervical motion tenderness (PID), nodules/tenderness in posterior cul-de-sac (endometriosis), rectal exam
• Diagnostics: As dictated by history
  • Acute: Urine β–hCG if premenopausal; GC/CT; U/A ± UCx; CBC w/ diff; vaginal wet prep /Cx (see “Vaginitis”); TVUS = 1st-line imaging study; CT occasionally helpful, particularly for RLQ pain (appendicitis, abscess) Chronic: If initial H&P nondiagnostic, w/u as above + TVUS, ESR; attempt Rx (below)

Treatment

(Obstet Gynecol 2003;101:594; AFP 2016;93:380)

Treatment of Pelvic Pain, by Etiology
Treatment	Therapy
PID, TOA	See “Pelvic Inflammatory Disease”; early surgical c/s and inpt mgmt for TOA
Genital HSV	See “Herpes Simplex Virus”
Dysmenorrhea	See “Menstural Diorders”; OCPs + NSAIDs vs. APAP
Endometriosis	OCP (monthly → if inadequate improvement, trial continuous); consider medroxyprogesterone acetate (continuous progestin), GYN referral for possible GnRH agonist (leuprolide), danazol (progestin-like effects), or laparoscopy for dx & tx; levonorgestrel-releasing IUD may ↓ recurrence after laparoscopic tx
Adhesions	Evidence inconsistent re: laparoscopy for adhesiolysis
Chronic pelvic pain	Surgical: No shown benefit over nonsurgical (except adenomyosis) Nonsurgical: Trial empiric tx for endometriosis (above) Other modalities: NSAIDs, consider SSRI for concomitant depression, TCAs, SNRIs or anticonvulsants for neuropathic pain Multidisciplinary: Pelvic floor PT, trigger point injections, topical analgesics, heat, acupuncture, somatocognitive tx, TENS

When to Refer

• Pregnant or postpartum: Pts w/ pelvic pain should be managed by OB-GYN
• Acute pelvic pain: ⊕ peritoneal signs, systemically ill, or concern for severe PID → ED
• Chronic pelvic pain: Dx uncertain or not responsive to initial Rx → GYN; pts w/ unresponsive chronic pelvic pain may benefit from multidisciplinary pain center referral
• Patient information: familydoctor.org/condition/chronic-pelvic-pain/ (Chronic Pelvic Pain)

INTIMATE PARTNER VIOLENCE

Background

(AFP 2013;87:577; JAMA 2011;306:513; NEJM 1999;341:886)

• Definition: Intimate partner violence (IPV) involves psychological, emotional, physical, & sexual abuse
• Epidemiology: 25–33% of women experience IPV in their lifetime, and 14% of men; ♂ → ♀ most common, but may be found in any relationship
• Obstacles to leaving an abusive relationship: Fear, threats, financial dependence, lack of knowledge, family/societal pressure, love, children Complications of abusive relationships: Death, disability, HIV/STIs, poor pregnancy outcomes, lost work days, loss of housing, chronic disease, PTSD/depression/anxiety
• Associations: Higher prevalence of chronic pain, neurologic disorders, GI disorders, migraine headaches, depression and SI, among those experiencing IPV
• Screening: USPSTF recommends screening all women of childbearing age; evidence insufficient for other groups (Ann Intern Med 2013;158:478)

Evaluation

(Ann Intern Med 2013;158:478; NEJM 2012;367:2071)

• Clinical pearls: Maximize pt sense of control (e.g., does pt want door open/closed), engage (shared decision-making) & educate about what to expect (e.g., labs); emphasize that it is not patient’s fault & he/she is not alone; acknowledge how difficult it is to be in an abusive relationship & that he/she does not deserve this treatment
• Screening: Always screen pt alone—ask partner to leave room; suggested approach: “Domestic violence is a common problem & affects people’s health, so I ask all my pts about it. Do you feel safe at home? Does anyone in your life make you feel scared or intimidate you?” HITS: “Does your partner Hurt, Insult, Threaten, or Scream at you?”
• History: Severity, frequency, type of abuse (incl forced sex); screen for comorbid psych disease, SUD; safety of others in household; assess immediate safety
• Exam: Bruises at different stages of healing, unwitnessed head, neck, and facial injuries (Trauma Violence Abuse 2010;11:71) “baby zone” injuries (breasts/abdomen), inner thigh bruising (sexual trauma); photograph injuries
• Workup: STI, HIV testing

Management

(JAMA 2003;289:589; 601)

• Evidence for benefit of counseling, information cards, community service referrals, and mentoring support (Ann Intern Med 2012;156:796)
• Contraception: Self-empowering methods (i.e., ring, IUD, ♀ condom, diaphragm, hormone injection)
• Referrals: Psychiatry as needed, social work for all pts, financial services
• Pre-exposure HIV prophylaxis: Consider in high-risk situations Emergency resources: Provide contact info pt can use in an emergency
• Mandatory reporting: Typically not applicable unless also involves abuse of a child (<18), or disabled person (physical or mental); injury involving a firearm or knife may be reportable in some states
• Create a safety plan: Call 911 if immediate danger, have a back-up friend/neighbor to call 911, teach kids to call 911, go over safety plan w/ kids & have place for them to go (neighbors, closet); emergency kit w/ important documents, money, keys, emergency place to stay; know where local police precinct is
• Signs of escalation: Perpetrator is violent outside the home, gun in home, violence toward children, escalating threats, forced sex, drug/EtOH abuse by partner, choking, use of weapon or threats w/ weapon, stalking behavior, abusive during pregnancy
• Patient information: thehotline.org, 1–800–799-SAFE, futureswithoutviolence.com