66.1 Chronic Menstrual Disorders, Infertility & Sexual Dysfunction

Polycystic Ovary Syndrome (PCOS)

Polycystic Ovary Syndrome (PCOS) represents the most prevalent endocrine-metabolic disorder of reproductive-aged women, affecting 6% to 15% of the population worldwide. It is the leading etiology of anovulatory infertility and is intimately linked to chronic insulin resistance, metabolic syndrome, and significant oncologic risks.

Rotterdam Consensus Diagnostic Criteria

The international Rotterdam criteria (2003, reaffirmed in international consensus guidelines) establish a diagnosis of PCOS when a patient meets at least 2 of the following 3 features, provided other mimicking etiologies have been systematically excluded:

1. Ovulatory Dysfunction (Oligo- or Anovulation):

   • Manifests as cycle intervals $>35$ days (oligomenorrhea) or $<21$ days (polymenorrhea), or $<9$ spontaneous menstrual cycles per calendar year.
   • Complete cessation of menses for $\ge 3$ consecutive months (secondary amenorrhea).
   • Clinical Pearl: Some women with PCOS present with seemingly regular 28-to-30-day bleeding that represents anovulatory estrogen-breakthrough bleeding rather than true progesterone-withdrawal menses.

2. Hyperandrogenism (Clinical and/or Biochemical):

   • Clinical Hyperandrogenism: Characterized by hirsutism, evaluated objectively using the modified Ferriman-Gallwey (mFG) scoring system (quantifying terminal hair density across 9 androgen-sensitive body areas; a score $\ge 8$ in Caucasian/Black women or $\ge 4-6$ in Asian women confirms clinical hirsutism). Other clinical hallmarks include severe, cystic, treatment-refractory inflammatory acne and androgenic alopecia (terminal hair miniaturization with frontal/parietal vertex thinning).
   • Biochemical Hyperandrogenism: Elevated serum total testosterone and/or calculated free testosterone (free androgen index). Dehydroepiandrosterone sulfate (DHEA-S) is elevated in approximately 20–30% of patients, indicating adrenal androgen contribution.

3. Polycystic Ovarian Morphology (PCOM) on Ultrasound:

   • High-resolution transvaginal ultrasound (TVUS) criteria (per 2018/2023 international guidelines using high-frequency transducers $\ge 8$ MHz): presence of $\ge 20$ follicles measuring 2 to 9 mm in diameter ("string-of-pearls" peripheral follicular arrest) in either ovary, AND/OR an increased ovarian volume $\ge 10\text{ mL}$ (in the absence of a dominant follicle $>10\text{ mm}$ or corpus luteum).
   • TVUS is avoided or performed transabdominally in virginal adolescents; PCOM on imaging is non-specific in the first 8 years post-menarche and should not be used as a primary diagnostic criterion in adolescents.

                      ROTTERDAM CONSENSUS DIAGNOSIS OF PCOS

   Must meet AT LEAST 2 of the following 3 criteria (after excluding mimics):
   ════════════════════════════════════════════════════════════════════════════════════
   1. Oligo- or Anovulation        • Menstrual cycle length > 35 days or < 21 days
                                   • Fewer than 9 menstrual cycles per year
                                   • Secondary amenorrhea ≥ 90 days
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   2. Hyperandrogenism             • Clinical: Modified Ferriman-Gallwey score ≥ 8,
                                     severe recalcitrant acne, androgenic alopecia
                                   • Biochemical: Elevated total or calculated free testosterone
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   3. Polycystic Ovarian           • Transvaginal ultrasound showing ≥ 20 follicles
      Morphology (PCOM)              (2–9 mm diameter) in either ovary, OR
                                   • Ovarian volume ≥ 10 mL in either ovary
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Systematic Exclusion of Secondary Mimicking Disorders

PCOS remains a diagnosis of exclusion. To avoid catastrophic diagnostic misattribution, family physicians must order the following baseline laboratory panel:

• Serum Thyroid-Stimulating Hormone (TSH): Excludes overt hypothyroidism (elevated TRH stimulates prolactin release and alters gonadotropin pulsatility) or hyperthyroidism.
• Serum Prolactin: Excludes prolactinoma/hyperprolactinemia (causes galactorrhea, hypogonadotropic anovulation, and amenorrhea).
• Early-Morning Follicular 17-Hydroxyprogesterone (17-OHP): Drawn at 8:00 AM. Excludes Non-Classic Congenital Adrenal Hyperplasia (NCCAH) caused by mild 21-hydroxylase deficiency. A baseline fasting 17-OHP $<200\text{ ng/dL}$ ($<6\text{ nmol/L}$) reliably rules out NCCAH. Values between $200-1000\text{ ng/dL}$ mandate an ACTH (cosyntropin) stimulation test.
• 24-Hour Urinary Free Cortisol or Overnight 1-mg Dexamethasone Suppression Test: Indicated when clinical features suggest Cushing Syndrome (moon facies, dorsocervical fat pad, violaceous wide striae $>1\text{ cm}$, proximal muscle weakness, spontaneous ecchymoses).
• Serum Total Testosterone and DHEA-S Elevation Thresholds: Marked, rapid-onset virilization (clitoromegaly, voice deepening, rapid male-pattern balding) with total testosterone $>200\text{ ng/dL}$ or DHEA-S $>700-800\text{ mcg/dL}$ indicates an androgen-secreting ovarian (Sertoli-Leydig cell tumor) or adrenal neoplasm requiring pelvic TVUS and adrenal multiphasic CT/MRI.

Neuroendocrine & Metabolic Pathophysiology

The core pathophysiologic defect in PCOS is a complex vicious cycle involving the hypothalamic-pituitary-ovarian axis and peripheral carbohydrate metabolism:

1. Accelerated GnRH Pulsatility: Abnormally rapid hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency preferentially drives pituitary transcription of luteinizing hormone (LH) over follicle-stimulating hormone (FSH). The resulting high LH:FSH ratio ($>2:1$ or $3:1$) delivers excessive LH stimulation to ovarian theca cells.
2. Theca Cell Hyperplasia & Androgen Excess: In response to LH, ovarian theca cells dramatically upregulate cytochrome P450c17alpha (17alpha-hydroxylase/17,20-lyase), hyper-secreting androstenedione and testosterone. Relative FSH deficiency impairs granulosa cell aromatase (CYP19A1), preventing conversion of androgens into estrogens, leading to follicular arrest at the 2–9 mm pre-antral stage.
3. Insulin Resistance & Compensatory Hyperinsulinemia: Independent of BMI (though markedly exacerbated by central adiposity), 70–80% of women with PCOS exhibit post-receptor insulin signaling defects in skeletal muscle and adipose tissue. Compensatory hyperinsulinemia acts as a co-gonadotropin:
   • Directly binds ovarian theca cell insulin and IGF-1 receptors to amplify LH-stimulated androgen production.
   • Suppresses Hepatic Sex Hormone-Binding Globulin (SHBG): Lower SHBG synthesis markedly increases the percentage of biologically active free testosterone, worsening peripheral virilization.
4. Endometrial Hyperplasia & Carcinoma Risk: Chronic anovulation leads to continuous, unopposed estrogen exposure without cyclical progesterone-mediated differentiation and withdrawal shedding. This chronic mitogenic stimulus yields a 3- to 5-fold increased lifetime risk of endometrial hyperplasia and type 1 endometrial adenocarcinoma.

                  LONG-TERM METABOLIC COMORBIDITIES OF PCOS

   Comorbidity                 Mechanism & Screening Protocol (ABFM Guideline)
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   Dysglycemia / Type 2        • Hyperinsulinemia and peripheral insulin resistance.
   Diabetes Mellitus           • Mandatory: 2-hour 75-gram Oral Glucose Tolerance Test
                                 (OGTT) at baseline; repeat every 1–3 years.
                               • Fasting glucose and HbA1c ALONE miss > 50% of impaired
                                 glucose tolerance in PCOS.
   ────────────────────────────────────────────────────────────────────────────────────
   Metabolic Syndrome &        • Hypertriglyceridemia, low HDL (< 50 mg/dL), central waist
   Cardiovascular Disease        circumference > 35 inches (88 cm), elevated BP ≥ 130/85.
                               • Complete fasting lipid profile at diagnosis.
   ────────────────────────────────────────────────────────────────────────────────────
   Metabolic Dysfunction-      • Driven by visceral adiposity, hyperinsulinemia, and lipolysis.
   Associated Steatotic Liver  • Baseline liver biochemistries (ALT/AST); calculate FIB-4
   Disease (MASLD / NAFLD)       score; perform hepatic ultrasound if transaminases elevated.
   ────────────────────────────────────────────────────────────────────────────────────
   Obstructive Sleep           • Independent of BMI; driven by upper airway collapsibility
   Apnea (OSA)                   induced by hyperandrogenism and visceral fat.
                               • Formal screening with STOP-BANG questionnaire;
                                 polysomnography if symptomatic.
   ────────────────────────────────────────────────────────────────────────────────────
   Endometrial Hyperplasia     • Chronic unopposed estrogen mitogenesis lacking progesterone.
   and Adenocarcinoma          • Mandatory endometrial biopsy if abnormal uterine bleeding,
                                 amenorrhea > 3–6 months, or endometrial thickness > 7–10 mm.
   ════════════════════════════════════════════════════════════════════════════════════

Evidence-Based Management of PCOS

1. Foundational Lifestyle Modification

• Weight Reduction: A modest 5% to 10% total body weight reduction through caloric restriction (500–750 kcal/day deficit) and regular exercise (≥150 min/week moderate physical activity) reduces visceral adiposity, drops circulating fasting insulin, increases hepatic SHBG by up to 100%, lowers free testosterone, and spontaneously restores regular ovulatory cycles and natural conception in nearly 50% of overweight/obese women.

2. Pharmacotherapy for Patients NOT Desiring Immediate Pregnancy

• Combined Oral Contraceptives (COCs) — First-Line:
  • Mechanisms of Benefit: Suppress pituitary LH secretion (halting theca androgen production); deliver steady synthetic progestin to induce secretory transformation and endometrial atrophy (eliminating endometrial cancer risk); stimulate hepatic SHBG synthesis, reducing free circulating testosterone by 50%.
  • Formulation Selection: Use low-dose ethinyl estradiol (20–30 mcg) paired with a neutral or anti-androgenic progestin (e.g., drospirenone, desogestrel, norgestimate). Avoid high-androgenic progestins (e.g., levonorgestrel) if hirsutism is severe.
  • Clinical Pearl: Minimum duration of COC therapy required to observe clinical improvement in hirsutism is 6 months, due to the prolonged growth cycle of terminal hair follicles (anagen phase).
• Anti-Androgen Therapy — Spironolactone:
  • Dosing & Indication: Spironolactone 50 to 100 mg orally twice daily is added as second-line adjuvant therapy if moderate-to-severe hirsutism or androgenic alopecia persists after 6 months of optimized COC therapy.
  • Mechanism: Competitive antagonist at androgen receptors in the pilosebaceous unit; weak inhibitor of 17alpha-hydroxylase and 5alpha-reductase.
  • Mandatory Safety Rule: Spironolactone is a potent teratogen capable of causing feminization of a male fetus (hypospadias, cryptorchidism, ambiguous genitalia). It MUST ALWAYS BE CO-PRESCRIBED WITH RELIABLE CONTRACEPTION (typically a COC or intrauterine device). Monitor serum potassium and renal function for hyperkalemia.
• Insulin Sensitizers — Metformin:
  • Dosing & Clinical Role: Metformin 500 to 1000 mg twice daily (or 1500–2000 mg extended-release daily). Improves insulin sensitivity, reduces progression from prediabetes to overt T2D, and promotes mild weight reduction. However, metformin is inferior to COCs for hirsutism and cycle regulation, and inferior to letrozole for ovulation induction. Its primary primary-care indication is for glucose intolerance/prediabetes or as an adjunct when COCs are contraindicated.

3. Management for Patients DESIRING Pregnancy (Ovulation Induction)

• Letrozole (Aromatase Inhibitor) — FIRST-LINE GOLD STANDARD:
  • Dosing Protocol: Administer 2.5 mg orally once daily for 5 days, initiated on cycle day 3, 4, or 5 following spontaneous or progestin-induced withdrawal menses. If ovulation does not occur, titrate stepwise to 5.0 mg daily, then up to a maximum of 7.5 mg daily in subsequent cycles.
  • Mechanism: Competitively inhibits peripheral aromatase, blocking the conversion of androgens to estrogens. The acute decrease in circulating estradiol removes negative feedback at the hypothalamus and pituitary, triggering a physiologic surge in FSH secretion that drives normal follicle maturation.
  • Evidence Base (PPCOS II Trial): The landmark NIH Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) randomized trial demonstrated that letrozole is significantly superior to clomiphene citrate in PCOS, achieving a significantly higher cumulative live birth rate (27.5% vs. 19.1%), higher ovulation rates, shorter time to pregnancy, and lower rates of multiple gestations (monofollicular ovulation).
• Clomiphene Citrate — Second-Line Ovulation Induction:
  • Dosing: 50 mg daily for 5 days starting on cycle day 3–5, titratable to 100–150 mg daily.
  • Mechanism: Selective Estrogen Receptor Modulator (SERM) that binds hypothalamic estrogen receptors, blocking negative feedback and increasing gonadotropin release. However, peripheral anti-estrogenic effects on the cervix (hostile, thick cervical mucus) and endometrium (thin, non-receptive lining) contribute to lower live-birth efficacy compared to letrozole.
• Exogenous Gonadotropins & Ovarian Drilling: Reserved for letrozole-resistant anovulation under reproductive endocrinology care.

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Infertility Evaluation in Primary Care

Clinical Definition & Timing of Workup

Infertility is defined by the American Society for Reproductive Medicine (ASRM) as the failure to achieve a successful pregnancy after 12 months or more of regular, unprotected sexual intercourse.

• Age-Based Triggers for Earlier Evaluation:
  • Women $\ge 35$ years: Initiate comprehensive diagnostic evaluation after 6 months of unsuccessful intercourse due to the accelerated, irreversible physiological decline in oocyte quantity and quality (diminished ovarian reserve).
  • Women $\ge 40$ years or with Known Risk Factors: Immediate evaluation is warranted without waiting (e.g., oligomenorrhea/amenorrhea, stage III/IV endometriosis, known bilateral tubal occlusion, history of pelvic inflammatory disease, prior pelvic surgery, or known male factor).

Systematic Three-Pronged Diagnostic Approach

Infertility is a couple-based disorder. Etiologies are distributed as: male factor (40–50%), female ovulatory dysfunction (25–30%), tubal/pelvic pathology (20–30%), and unexplained infertility (10–15%). Initial testing must occur in parallel across all three physiological domains:

                      SYSTEMATIC INFERTILITY DIAGNOSTIC WORKUP

   Factor Under Evaluation     Diagnostic Modality                       Normal Reference Values / Interpretation
   ═══════════════════════════════════════════════════════════════════════════════════════════════════════════════════
   1. Male Factor              Semen Analysis (WHO 2021 Criteria)        • Ejaculate volume: ≥ 1.4–1.5 mL
      (Mandatory First Step)   • Collected after 2–7 days of abstinence  • Sperm concentration: ≥ 15–16 million/mL
                               • Repeat in 4–12 weeks if abnormal        • Total motility: ≥ 40–42% (or ≥ 30% progressive)
                                                                         • Normal morphology (Kruger strict): ≥ 4%
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   2. Ovulatory Factor         A. Mid-Luteal Day 21 Progesterone         • Serum progesterone > 3 ng/mL confirms ovulation
                                  (Drawn 7 days prior to menses)           (levels > 10 ng/mL reflect robust luteal function).
                               B. Home Urinary LH Ovulation Kits         • Detects pre-ovulatory LH surge (positive 24–36h
                                                                           prior to follicle rupture).
                               C. Ovarian Reserve Screening              • Day 3 FSH and estradiol, Anti-Müllerian Hormone
                                                                           (AMH < 1.0 ng/mL suggests diminished reserve).
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   3. Tubal & Pelvic Factor    Hysterosalpingography (HSG) or            • HSG: Fluoroscopic radiopaque dye confirms bilateral
                               Hysterosalpingo-contrast sonography        tubal spillage into peritoneum & normal cavity.
                                                                         • Saline Infusion Sonohysterography (SIS): High
                                                                           resolution for polyps, submucosal fibroids, adhesions.
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• Male Factor Evaluation: Semen analysis is non-invasive, cost-effective, and should be ordered at the very first visit. If the initial semen analysis is abnormal, a confirmatory second semen analysis must be repeated 4 to 12 weeks later to account for standard biological variability across spermatogenic cycles (~74 days).
• Ovulatory Factor Evaluation: Mid-luteal serum progesterone is timed precisely to 7 days before anticipated menses (e.g., day 21 of an idealized 28-day cycle, or day 28 of a 35-day cycle). A value $>3\text{ ng/dL}$ confirms luteinization and ovulation.
• Tubal & Cavitary Factor Evaluation: Hysterosalpingography (HSG) is performed during the early follicular phase (cycle days 6 to 10, after menstrual bleeding ceases but prior to ovulation) to exclude pregnancy and thin the endometrial lining for optimal visualization. It documents bilateral tubal patency via free peritoneal contrast spillage and reveals intracavitary lesions (endometrial polyps, submucosal leiomyomas, intrauterine synechiae [Asherman syndrome], or congenital Müllerian anomalies).

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Female Sexual Dysfunction

Female sexual disorders are classified in the DSM-5 into distinct clinical syndromes requiring significant personal distress lasting $\ge 6$ months:

1. Female Sexual Interest/Arousal Disorder (FSIAD) / Hypoactive Sexual Desire Disorder (HSDD):
   • Absence or marked reduction in sexual interest, erotic thoughts/fantasies, initiation of sexual encounters, and responsiveness to cues.
   • Etiologies: Psychosocial distress, relationship conflict, depression, selective serotonin reuptake inhibitors (SSRIs; 40–60% incidence of sexual dysfunction), oral contraceptives (high SHBG reducing free testosterone), hyperprolactinemia, and thyroid dysfunction.
   • Management: Psychosexual counseling, sensate focus exercises. Pharmacotherapy includes Flibanserin (100 mg PO at bedtime; 5-HT1A agonist / 5-HT2A antagonist; boxed warning for severe hypotension and syncope when combined with alcohol, CYP3A4 inhibitors, or severe hepatic impairment) and Bremelanotide (1.75 mg subcutaneous PRN 45 min prior to sexual activity; melanocortin receptor agonist; causes transient BP elevation and nausea).
2. Female Orgasmic Disorder: Marked delay, infrequency, or absence of orgasm despite adequate arousal and stimulation. Frequently SSRI-induced; management includes dose reduction, switching to bupropion or vortioxetine, or adding sildenafil.
3. Genitourinary Syndrome of Menopause (GSM): Formerly termed atrophic vaginitis; causes severe dyspareunia, entry tearing, and secondary avoidance of intercourse (see Section 66.2).

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Male Erectile Dysfunction (ED)

Clinical Definition & Etiologic Classification

Erectile dysfunction is defined as the consistent or recurrent inability to achieve or maintain a penile erection of sufficient rigidity to permit satisfactory sexual intercourse for $\ge 3$ months.

• Vascular Etiology (Most Prevalent; >70%): Atherosclerotic endothelial dysfunction of the penile cavernosal arteries (diameter 1–2 mm).
  • The Artery Size Hypothesis: Because the cavernosal arteries are smaller than coronary (3–4 mm) and carotid arteries, cavernosal endothelial dysfunction manifests clinically 2 to 5 years prior to acute coronary syndromes or stroke. Erectile dysfunction is an established, independent early clinical harbinger of occult coronary artery disease (CAD).
  • Mandatory Clinical Action: Any middle-aged male presenting with new-onset vascular ED mandates a formal cardiovascular risk assessment: blood pressure, fasting lipid panel, fasting blood glucose/HbA1c, smoking status, and calculation of the 10-year ASCVD risk score.
• Neurogenic Etiology: Peripheral neuropathy (diabetic autonomic neuropathy), spinal cord trauma, pelvic surgical trauma (radical prostatectomy damaging cavernous neurovascular bundles), multiple sclerosis.
• Endocrine Etiology: Primary or secondary hypogonadism (morning total testosterone $<300\text{ ng/dL}$ confirmed on two separate 8:00 AM fasting draws), hyperprolactinemia, thyroid disease.
• Psychogenic Etiology: Sudden onset, situational (occurs with partner but intact nocturnal or early-morning spontaneous erections), associated with performance anxiety, relationship discord, or acute psychosocial stress.
• Medication-Induced ED: Antihypertensives (particularly non-selective beta-blockers [propranolol] and thiazide diuretics), psychotropics (SSRIs, SNRIs, tricyclic antidepressants, antipsychotics), anti-androgens (spironolactone, finasteride, dutasteride, GnRH agonists), and substance misuse (heavy ethanol, opioids).

                  DIAGNOSTIC & PHARMACOTHERAPEUTIC MATRIX FOR ED

   Agent / Class       Onset & Half-Life (t1/2)          Dosing Pearls & Key Considerations
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   Sildenafil          • Onset: 30–60 minutes            • Initial dose: 50 mg PO PRN 1 hour before intercourse
   (Viagra)            • Duration: 4–6 hours               (titrate 25–100 mg).
                       • t1/2: ~4 hours                  • Must be taken on an EMPTY STOMACH (high-fat meals
                                                           delay absorption by > 60 minutes).
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   Tadalafil           • Onset: 30–45 minutes            • Dosing options:
   (Cialis)            • Duration: Up to 36 hours          - PRN: 10–20 mg PO 30–60 min before activity.
                         ("The Weekend Pill")              - Daily: 2.5–5.0 mg PO once daily (FDA-approved
                       • t1/2: ~17.5 hours                   for concurrent BPH and lower urinary tract symptoms).
                                                         • Food does not affect absorption.
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   Vardenafil          • Onset: 30–60 minutes            • Dosing: 10–20 mg PO PRN.
   (Levitra)           • Duration: 4–5 hours             • Fatty meals delay absorption; causes mild QTc prolongation.
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   Avanafil            • Rapid Onset: 15–30 minutes      • Dosing: 100–200 mg PO PRN 15–30 min prior to sex.
   (Stendra)           • Duration: > 6 hours             • High selectivity for PDE-5; lowest visual disturbance rate.
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Mechanism of Action & Adverse Effect Profile of PDE-5 Inhibitors

During sexual stimulation, non-adrenergic non-cholinergic (NANC) cavernous nerves and endothelial cells release nitric oxide (NO), activating soluble guanylyl cyclase and generating cyclic guanosine monophosphate (cGMP). cGMP induces intracellular calcium efflux and smooth muscle relaxation in the corpora cavernosa, allowing arterial engorgement and veno-occlusion. PDE-5 inhibitors competitively block the phosphodiesterase type 5 enzyme that degrades cGMP, sustaining intracavernosal cGMP and promoting rigid erection. PDE-5 inhibitors require intact sexual desire and stimulation to be effective.

• Adverse Effects: Facial flushing (10–15%), headache (10–16%), nasal congestion, dyspepsia/GERD (relaxation of lower esophageal sphincter), low back/myalgia (PDE-11 cross-inhibition with tadalafil), and transient cyanopsia ("blue-tinted vision" due to PDE-6 inhibition in retinal photoreceptors with sildenafil).
• Rare Emergencies: Non-arteritic anterior ischemic optic neuropathy (NAION; sudden painless monocular vision loss) and priapism (painful, persistent erection lasting $>4$ hours, requiring urgent cavernosal phenylephrine aspiration to prevent permanent cavernosal fibrosis and impotence).

[!CRITICAL] Strict Nitrate Contraindication Concomitant use of any PDE-5 inhibitor with organic nitrates (e.g., sublingual nitroglycerin, isosorbide mononitrate, isosorbide dinitrate) or guanylate cyclase stimulators (e.g., riociguat) is ABSOLUTELY CONTRAINDICATED. Nitrates stimulate cGMP production while PDE-5 inhibitors block cGMP breakdown; this synergistic accumulation of cGMP triggers profound, life-threatening, refractory vasodilation, cardiogenic shock, and fatal myocardial infarction.

• Mandatory Safe Washout Periods Prior to Nitrate Administration:
  • At least 24 hours after the last dose of sildenafil, vardenafil, or avanafil.
  • At least 48 hours after the last dose of tadalafil (due to its prolonged 17.5-hour half-life).
  • If a patient develops acute chest pain after taking a PDE-5 inhibitor, organic nitrates must be withheld, and alternative anti-ischemic therapies (beta-blockers, supplemental oxygen, morphine, unfractionated heparin, urgent catheterization) administered.