The Menstrual Cycle
• Mean age of menarche: 12.4 y. Mean age of menopause: 51 y.
• 1st day of vaginal bleeding = day 1 of cycle; mean duration of bleeding is 4 ± 2 d; avg bld loss of 35 mL. Mean cycle length 21–34 d (Clin Obstet Gynaecol 2010;2:157)
• Follicular phase: Lasts 10–14 d, variable in duration, determines menstrual cycle length
• Ovulation: Estrogen reaches very high levels (around day 14) → LH surge → dominant follicle rupture/oocyte release. Follicle remnant → corpus luteum which secretes progesterone & maintains the endometrial lining (Am J Hum Biol 2001;4:465). If fertilization occurs, the trophoblast cells synthesize hCG to maintain the corpus luteum.
• Luteal phase: Lasts 12–15 d, constant in duration. In the absence of Preg, the corpus luteum regresses → progesterone levels drop → uterine lining is shed & marks the beginning of the next period.
Figure 17.1 Menstrual cycle and hormones
Hormones of Pregnancy
• hCG is secreted by placental trophoblast. Detected in the mother’s bld 8 d after conception. Maintains corpus luteum progesterone production. Structurally similar to LH, FSH, & TSH (same alpha-subunit). Doubles q48h early Preg. Max 8–10 w, ∼100000 mIU/mL → decline at 10–12 w → nadir at 20 w.
• hPL is produced by syncytiotrophoblasts. Detected at 2–3 w after fertilization. Levels rise steadily until 34–36 w to a peak 5–10 μg/mL. Effects include mat lipolysis → ↑ circulating free fatty acids to provide a source of energy for mother & fetus; anti-insulin action → increased mat insulin levels → increased prot synthesis; angiogenic action → fetal vasculature formation
• Progesterone is mainly produced by the ovary until 6–7 w gest when the placenta begins to produce. Maintains endometrial lining in early Preg & uterine quiescence. Production ∼250–600 mg/d (prepregnancy 0.1–40 mg/d).
• Relaxin is secreted by the corpus luteum → uterine relaxation, systemic vasodilation, & ↑ cardiac output. Serum concentrations peak at 1 ng/mL at 12–13 w → fall to 0.5 ng/mL for the remainder of the Preg (Am J Physiol Regul Integr Comp Physiol 2011:R267).
TYPE I DIABETES MELLITUS
Definition and Epidemiology (Diabetes Care 2012;35(suppl 1):S64)
• Gluc intolerance due to insulin insufficiency. Often caused by cell-mediated autoimmune Pancr β-cell destruction. Only about 5% of all diabetes.
• Incid increasing 2–5%. Prevalence 1 in 300 by age 18 (Endocrinol Metab Clin North Am 2010;3:481)
• A/w other autoimmune diseases (eg, Graves, Hashimoto, Addison dz) (Diabet Med 2011;28(8):896)
Etiology and Pathophysiology
• Genetic: 95% have either HLA-DR3 or HLA-DR4. Also positive for anti-GAD, anti-islet cell, & anti-insulin Abs.
• Environmental: Congen rubella infxn, enterovirus, coxsackievirus B, CMV, adenovirus, & mumps (Diabetes Care 2012(suppl 1):S64)
• Lymphocytic infiltration, β-cell ↓ → insulin deficiency (Diabetes Metab Res Rev 2011;8:778)
• Hyperglycemia at ∼80–90% β-cell loss
• Polyuria, polydipsia, polyphagia w/ weight loss, fatigue, weakness, muscle cramps, blurred vision, nausea, abdominal pain, changes in bowel mvmt
• Most present w/ acute sx of diabetes & markedly elevated bld gluc levels
• Screen high-risk individuals (h/o transient hyperglycemia or relative w/ type I DM)
• Islet auto Abs ↑ risk of developing type I DM. Criteria for DM same for type I or II (below).
Treatment and Medications (JAMA 2003;289(17):2254)
• Lifelong insulin therapy is started w/ either MDI therapy, or CSII. See insulin types, below.
• Gluc measurements can be done either preprandial only, or pre- & postprandial (shows greater improv in glycemic control) (Clin Med 2011;2:154)
• MDI nonphysiologic regimens – do not mimic nml insulin secretion
Once daily long-acting insulin (at bedtime)
Twice daily intermediate-acting insulin (breakfast & dinner time)
• MDI physiologic regimens – attempt to mimic nml insulin secretion
Twice daily intermediate-acting insulin w/ short-acting insulin (breakfast & dinner time)
Once daily long-acting insulin (at bedtime) w/ mealtime rapid-acting insulin
Twice daily intermediate-acting insulin (breakfast & bedtime) w/ rapid acting insulin w/ each meal
Premixed insulin (70% NPH/30% regular) given twice daily
• CSII – Rapid-acting insulin preparation administered through a catheter that is inserted into the SQ tissue. There is a basal insulin infusion rate (1 U/h) w/ patient-directed boluses given before meals.
• Nonpregnant goal: HgA1c <7%, fasting gluc 70–130 mg/dL, postprandial gluc <180 mg/dL
DIABETIC KETOACIDOSIS (DKA)
• An acute life-threatening complication due to insulin deficiency, w/ hyperglycemia, dehyd, & acidosis. Typically due to insulin noncompliance, acute illness/infxn, drugs, or new onset DM.
• Occurs in 5–10% of all pregnancies w/ DM. Can develop more rapidly & at less sev levels of hyperglycemia than in nonpregnant pts.
Pathophysiology (Clin Med 2011;2:154)
• Insulin deficiency → ↑ glucagon → ↑ hepatic gluconeogenesis & ↑ glycogenolysis → hyperglycemia → inability to use gluc → ↑ lipolysis → free fatty acids metabolized by liver (ketogenesis) as an alternative energy source → large quantities of ketones → acidosis
Clinical Manifestation (Hormones 2011;4:250)
• Nausea, vomiting, abdominal pain, confusion, Kussmaul respirations (deep labored breathing seen in metabolic acidosis).
• Bld gluc, bld gas (pH), Chemistry (bicarbonate, anion gap), serum ketones
• Treat the underlying cause (eg, infxn). Inpatient admission.
• Fluids: 1 L NS 1st hour, then 250–500 mL/h. When gluc <250 mg/dL → change to 5% dextrose in ½ NS, and continue insulin till ketonemia resolved.
• Insulin: 0.1–0.4 U/kg IV bolus → 0.1 U/kg/h continuous infusion (or 2–10 U/h). Try for 50–70 mg/dL/h correction of serum gluc, or about 25% in 1st 2 h. When plasma gluc is ∼200 mg/dL → ↓ insulin to 0.05 U/kg/h (or about 1–2 U/h) until urine ketones cleared. Adjust till gluc ∼150–200 mg/dL. When pt can tolerate food, start her usual SQ insulin injection regimen.
• Potassium: K >5 mEq/L, no additional req. (Insulin drives K into cells w/ gluc → ↓ serum K.)
K 4–5 mEq/L → add 20 mEq/L to each liter of replacement fluid
K 3–4 mEq/L → add 40 mEq/L to each liter of replacement fluid
K <3 mEq/L → hold insulin, give 10–20 mEq/h until K >3.3, then 40 mEq/L in IVF
• Bicarbonate: pH <6.9 → give 100 mEq & 20 mEq of KCl in 400 mL of H2O over 2 h
pH <7 or bicarbonate <5 mEq → give 50 mEq in 200 mL of water over 1 h until ph ↑ to >7
Do not give bicarbonate for pH >7
• Phosphate: If <1 mg/dL → give 20–30 mmol potassium phosphate over 24 h
• Calcium: Monit serum Ca level & replete prn
• Fetal HR monitoring for >24 w gest. Fetal loss 9–85% depending on severity of DKA.
TYPE II DIABETES MELLITUS
Definition and Epidemiology (Diabetes Care 2012;35(suppl 1):S64)
• Insulin resistance ± inadeq insulin production (ie, inadeq production for the sens of the target tissues). ∼26 million people w/ DM, ∼79 million prediabetes, & 1.9 million new cases of DM diagnosed in 2010 (National Diabetes Fact Sheet, www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf)
• Periph insulin resistance → ↑ insulin secretion → Pancr failure → defective insulin secretion in resp to ↑ gluc → increased liver gluconeogenesis → hyperglycemia
• Classical sx: Polyuria, polydypsia, polyphagia, fatigue, weakness, muscle cramps, blurred vision, nausea, abdominal pain, changes in bowel mvmt. Most are asx.
• Criteria for diagnosing T2DM outside of Preg: Hgb A1c ≥6.5%, fasting gluc ≥126 mg/dL, 2-h 75 g OGTT plasma gluc ≥200 mg/dL, or a random plasma gluc ≥200 mg/dL in a pt w/ classic sx or in hyperglycemic crisis
Treatment and Medications
• Goal of rx is to achieve & maintain HbA1c levels of <7%. See also for Preg, below.
• At dx: Lifestyle changes (weight loss, exercise) may ↓ HbA1c 1–2%
• Bariatric Surg consideration for adults w/ T2DM & BMI >35 kg/m2
• See appendix for oral hypoglycemic agent meds. See Ch. 1 for well-woman mgmt.
HYPEROSMOLAR HYPERGLYCEMIC STATE
Etiology and Pathophysiology (Emerg Med Clin North Am 2005;23:629)
• Extreme hyperglycemia + hyperosmolality, w/o ketoacidosis
• Infxn causing about 60% of cases → physiologic stress → ↓ effectiveness of circulating insulin → ↑ counter regulatory hormones (glucagon, catecholamines, cortisol, GH) → ↑ periph resistance → gluconeogenesis → hyperglycemia → glycosuria → hypertonic osmotic diuresis (dehyd) → unable to maintain adequate fluid intake (2/2 acute illness) → sev hyperosmolality & intracellular dehyd, renal failure
• Plasma gluc level of ≥600 mg/dL, serum osmolality of ≥320 mOsm/kg, ↑ serum urea nitrogen (BUN): Cr ratio, pH >7.3, small ketonuria, absent to low ketonemia, bicarbonate >15 mEq/L
• Treat the underlying cause. Mgmt very similar to DKA (above).
• 1st-line therapy is aggressive IV hydration, fluid deficit may be 8–12 L. Replace 1/2 of the fluid deficit in the 1st 12 h, & the remainder in the next 12–24 h w/ NS.
• Insulin infusion when potassium is ≥3.3 mEq/L. Regular insulin started at 0.1 U/kg/h w/ or w/o a 0.15 U/kg bolus.
• Once the serum gluc ≤300 mg/dL, D5 should be added & the insulin infusion ↓ to 0.05 U/kg/h
• If serum potassium level is <3.3 mEq/L → replete w/ KCl at a rate of up to 40 mEq/L/h until levels are above 3.3 mEq/L. 20 mEq/L KCl can then be added to each 1 L of IV fluid. Goal is to maintain nml serum K levels. Check K every 1–2 h.
DIABETES IN PREGNANCY
• Pregestational diabetes in ∼1% of all pregnancies, mostly type II.
• 90% of diabetes in Preg is GDM (see GDM, below)
• Type I usually known prior to Preg. Type II may have been unrecognized, but if gluc intolerance before 20 w, consider pregestational. Goal preconception HgA1c <6.5%. Consider hospital admission for very poor control during organogenesis.
• Fetal malformation rate in a nml Preg is 2–3% vs. 6–12% in pregnancies c/b diabetes (Obstet Gynecol 2003;102:857). Rate of fetal malformations w/ Hgb A1c 7–8.9 = 5–10%; Hbg A1c 9–10.9 = 10–20%, HbgA1c >11 = >20%
• “Usual” defects include cardiac, renal, neural tube. Esp double outlet RV, truncus arteriosus, & caudal regression syn/sacral agenesis (considered pathognomonic).
• Risks of DM in Preg: ↑ malformations, ↑ SAB, ↑ IUGR, ↑ progression of nephropathy, retinopathy, cardiovascular dz, ↑ polyhydramnios, ↑ preeclampsia, ↑ labor dystocia & C/S deliv, ↑ fetal macrosomia, ↑ lacerations, ↑ shoulder dystocia, ↑ neonat RDS/hypoglycemia.
Screening for DM in Pregnancy
• Univ GDM screening std. Screen early if risk factors. Consider no screening by criteria.
• On 50 g oral gluc challenge test, serum gluc ≥140 mg/dL identifies 80% GDM; ≥130 mg/dL identifies 90% GDM. Serum gluc ≥200 mg/dL → GDM w/o other testing. Positive screening test → 3 h fasting gluc challenge (100 g test; diagnostic table, below).
• 3-h OGTT: Consume ≥150 g of carbohydrate per day for 3 d, then fasting. 100 g oral gluc challenge → fasting + 1-, 2-, 3-h post challenge bld gluc. 1 abn value = gluc intolerance (a/w fetal macrosomia). Dx of GDM made ≥2 abn values.
• New Endo one step Guideline differs from ACOG (J Clin Endo Metab 2013;98:4227)
Universal DM testing before 13w gest, repeat if abnormal on different day to confirm. 8–14hr Fasting gluc ≥126 mg/dL, untimed ≥200mg/dL, or HbA1C ≥6.5% = overt DM; Fasting 92-125 mg/dL = GDM
24-28w screen if not prev dx, w/ 75g OGTT (after 8hr fast)
Fasting gluc >126mg/dL or 2hr >200 mg/dL = overt DM;
Fasting 92–125 mg/dL or 1hr >180 mg/dL or 2hr 153–199 mg/dL = GDM
Management of DM in Pregnancy
Nutrition advice, diet/exercise, & 4×/d bld gluc testing (fasting + 1- or 2-h postprandial)
If inadeq control → oral hypoglycemic agents (glyburide), if inadeq w/ max dose → insulin
GDM-A1 no monitoring, no early deliv (routine induction at 41–42 or for OB indications)
GDM-A2 antenatal testing (NST/BPP from 32–34 w) & deliver by 40 w
• Pregestational diabetes
Diet: 1800–2400 kcal daily, w/ 20% prot, 60% carbs, & 20% fat. The American Diabetes Association recommends insulin for pregnant women w/ type I or II DM. NPH & rapid-acting insulin combination used (see Table with insulin types, above). Type I DM usually ↑ insulin 50–100%. Type II DM often ↑ >200% in Preg. Consider baseline HELLP labs, thyroid testing (40% type I DM – thyroid d/o) & 24-h urine prot early Preg.
Eye exam in 1st trimester, & baseline ECG (age >30 y or hypertensive).
Pregestational DM obtain early sonogram, confirm viability, offer mat serum AFP for NT defects, US for anatomy & fetal echocardiography.
1–2×/w fetal NST/AFI from 32–34 w or earlier. Serial fetal growth scans every 4–6 w to eval for IUGR or macrosomia. Deliv not later than 39–40 w, depending on gluc control in Preg.
Figure 17.2 Calculation and dose distribution for initial insulin management in pregnancy
Labor and Delivery for Diabetics
• Consider cesarean deliv for EFW >4500 g for pts w/ diabetes (>5000 g for nondiabetic)
• Insulin mgmt during labor: Usual intermediate insulin at bedtime. Morning dose insulin withheld. W/ active labor or gluc <70 mg/dL start D5NS IVF. Check bld gluc hourly in labor. Usually pregestational DM → IV insulin drip & titrate. Tight gluc control to avoid neonat hypoglycemia.
• Fetal lung maturity may be delayed in DM, even with reassuring FLM result.
• Usually insulin-dependent pregestational DM → resume prepregnancy regimen, or ½ of end Preg dose. GDM can stop rx, unless suspected DM 2. GDM resolves w/ deliv.
• Postpartum 75 g gluc tol test to identify nongestational DM for all GDM pts.
GESTATIONAL DIABETES (GDM)
Definitions, Epidemiology, and Pathophysiology
• GDM is carbohydrate intolerance w/ onset or 1st recognition during Preg
• Classification: A1GDM is diet controlled; A2GDM requires pharmacologic intervention
• GDM in ∼5–10% of pregnancies. 20–50% will → nongestational DM in 10 y; 30–50% → recurrent GDM.
• ↑ human placental lactogen/cortisol/progesterone/estrogen → ↓ periph insulin sens → impaired gluc resp → hyperglycemia. Screening per above, under Diabetes in Pregnancy.
Treatment and Medications
• See mgmt in Diabetes in Pregnancy, above.
• Oral hypoglycemics considered if dietary mgmt fails. Glyburide equiv to insulin for gluc control (starting dose: 1.25–2.5 mg twice daily → ↑ 2.5 mg as needed; max 10 mg BID). Insulin needs ↑ markedly btw 28 & 32 w gest (Obstet Gynecol 2003;102(4):857). See starting insulin schematic, above. Consider lower dose for insulin naive pt.
Definition and Epidemiology
• Inadeq thyroid hormone to meet the requirements of periph tissues.
• Primary hypothyroidism: Hashimoto’s thyroiditis, surgical removal, radioactive ablation, invasive fibrous thyroiditis, iodine deficiency. Secondary hypothyroidism: Pituitary/hypothalamic neoplasm, trauma, ischemic necrosis (Sheehan’s syn), infxn.
• Subclinical hypothyroidism: Chronic autoimmune thyroiditis, partial thyroidectomy, radioactive iodine therapy for rx of hyperthyroidism, infiltrative disorders, drugs impairing thyroid fxn, inadeq replacement therapy for overt hypothyroidism, iodine deficiency
• 3.7% of the US pop. Females > males.
• In women, most common cause (95%) is autoimmune (Hashimoto’s thyroiditis).
• Hashimoto’s thyroiditis: Lymphocytic thyroid infiltration → gland atrophy & fibrosis
• Subclinical hypothyroidism: Elevated TSH w/o overt hypothyroidism or low T3/T4. Early, mild thyroid failure. ∼60–80% have ⊕ antithyroid peroxidase or antithyroglobulin Abs. Progression to overt hypothyroidism in women is about 4%/y. No need to treat TSH <10 mU/L & asx.
Clinical Manifestations and Diagnosis
• Weakness, dry skin, cold intolerance, hair loss, constip, weight gain, poor appetite, dyspnea, hoarse voice, menorrhagia, paresthesias, impaired hearing
• ↑ TSH, ↓ free T4, ⊕ anti-TPO & other thyroid Abs. May also see HoNa, hypercholesterolemia, anemia, & elevated serum Cr kinase.
• Daily levothyroxine 2 μg/kg body weight (typically 100–150 μg; start at 50–100 μg depending on severity). Adjust q4w 12.5–25 μg by TSH levels. Annual TSH levels recommended for nonpregnant.
Hypothyroidism in Pregnancy (Lancet 2012;379(9821):1142)
• Similar causes as nonpregnant. Also postpartum thyroiditis (autoimmune inflammation) → thyrotoxicosis → hypothyroidism. W/i 1-y postpartum.
• Mat hypothyroidism can ↑ SAB, placental abruption, preterm deliv, preeclampsia, mat HTN, postpartum hemorrhage, low birth weight, stillbirth, & ↓ intellectual & psychomotor dev of the fetus.
• Difficult to assess in early Preg: Total T3/T4 ↑ due to hCG cross reaction and stimulation of the TSH receptor & also ↑ TBG. In 1st trimester total T4 ↑ & TSH ↓, w/ no real hypo or hyperthyroidism.
• ACOG does not recommend routine screening of asx pregnant pts. Test if on therapy, goiter, nodularity, h/o thyroid d/o/neck irradiation, prior infant w/ thyroid dysfxn, type I DM, FHx.
• Rx similar to nonpregnant pts. Preg may ↑ thyroid hormone requirements; monit TSH & adjust.
• Treat subclinical hypothyroid → improved obstetrical outcome, but did not modify long-term neurologic dev in the fetus. Maintain TSH <2.5 mU/L in 1st trimester & <3 mU/L thereafter.
Definition, Epidemiology, and Etiology (Endocr Pract 2011;17(3):456)
• Hyperthyroidism is caused by excess synthesis & secretion of thyroid hormone
• The prevalence of hyperthyroidism is 1.2% (0.5% overt & 0.7% subclinical)
• The most common causes are:
Graves dz (80%): Autoimmune TRAbs → bind TSH-R → ↑ TSH. Accounts for 95% of hyperthyroidism in Preg. 5–10× more than .
Thyroiditis (10%): Painless inflammation of thyroid due to viral infxn or postpartum inflammation → release of preformed thyroid hormone. May resolve and → hypothyroid.
Toxic adenomas: Single or multinodular, autonomously functioning, secrete thyroid hormone. More common in setting of iodine deficiency.
Other: Amiodarone, struma ovarii (ovarian dermoid), TSH secreting pituitary adenoma, gestational trophoblastic dz, follicular cell carcinoma, iodine-induced, thyrotoxicosis factitia.
Clinical Manifestation and Physical Exam (Lancet 2003;362(9382):459)
• Nervousness, anxiety, heat intolerance, tremor, palps, weight loss, oligomenorrhea, tachy, exophthalmos, thyromegaly. Thyrotoxicosis in 1 of 500 pregnancies → ↑ preeclampsia, thyroid storm, CHF, IUGR, preterm deliv, stillbirth.
• Tachy (&/or arrhythmias), HTN, warm/moist/smooth skin, lid lag, goiter, tremors
• Thyroid storm: Medical emergency, extreme hypermetabolism → seizures, arrhythmia, stupor, shock, coma. Do not delay therapy while FT4, FT3, TSH pending.
Diagnostic Workup (Endocr Pract 2011;17(3):456)
• Graves dz: ↓ TSH, ↑ FT4, ↑ FT3, ±antithyroid peroxidase Ab (TPO), ⊕TSI, ⊕TRAb, other antithyroid Abs poss.
When clinical presentation is not diagnostic, RAIU is performed (J Fam Pract 2011; 60(7):388): Diffuse, homogeneous = Graves dz; diffuse, heterogeneous = toxic multinodular goiter; focal = adenoma; no uptake = thyroiditis. IgG crosses placenta → fetal Graves
• Subclinical hyperthyroidism: ↓ TSH; nml FT4 & FT3. Asx.
Treatment (Endocr Pract 2011;17(3):456)
• Symptom mgmt: b-blocker to control tachy (propranolol also blocks T4 conversion to T3)
• ATDs: PTU is 1st-line drug during the 1st trimester; blocks both iodide organification & periph T4 → T3 conversion; monit liver fxn. Methimazole okay in 2nd trimester. Titrate meds to fT4 q2–4w.
• RAI: Started for pts w/ contraindications to ATD use. Pretreat w/ methimazole prior to RAI to prevent worsening of hyperthyroidism. Contraindicated in Preg.
• Surg: For symptomatic compression, large goiter, low uptake, documented or suspected malig
Figure 17.3 Approach to thyroid disorders
• Thyroid storm: PTU 600–800 mg oral load, then 150–200 mg q4–6h. + 2–5 drops saturated potassium iodide solution q8h. Also, dexamethasone 2 mg IV or IM q6h for 4 doses, propranolol 20–80 mg PO q4–6h, & Phenobarb 30–60 mg PO q6–8h PRN restlessness.
• Adrenal cortex: Zona glomerulosa = Mineralocort (aldosterone) → conserve sodium in nephron distal tubule & collecting duct → maintain BP; zona fasciculata = glucocorticoids (deoxycorticosterone, corticosterone, & cortisol) → ↑ bld sugar, suppress immune system, regulate metabolism; zona reticularis = androgens (DHEA, DHEA-S, & androstenedione) → estrogen precursors, other.
• Adrenal medulla = catecholamines (epinephrine, norepinephrine, dopamine), in resp to autonomic (sympathetic) nervous stimulation.
• Etiology: Cushing’s dz (65–70%), ectopic ACTH secretion by nonpituitary tumors (10–15%), adrenocortical tumors (18–20%), ectopic CRH secretion by nonhypothalamic tumors causing pituitary hypersecretion of ACTH (<1%).
• Clinical manifestations: Progressive central obesity w/ sparing of extremities, moon facies, buffalo hump, skin striae, easy bruising, hyperpigmentation (if ↑ ACTH), fungal infections, gluc intolerance, HTN, osteoporosis, hypokalemia, psychosis. → menstrual irregularities (33% amenorrhea, 31% oligomenorrhea, 36% other) (J Clin Endocrinol Metab 1998;83:3083). Androgen excess → adrenal glands are the major source of androgens in → hirsutism, thinning scalp hair, oily skin, increased libido.
Figure 17.4 Approach to suspected Cushing’s syndrome
• Rx: Surgical resxn of pituitary adenoma, adrenal tumor or ectopic ACTH-secreting tumor is gold std. Secondary options = pituitary XRT, bilateral adrenalectomy. Inhibitors for hypercortisolism if needed (ketoconazole, metyrapone, etomidate)
• Definition: Primary = adrenocortical insufficiency (Addison’s dz). Secondary = ACTH ↓.
• Etiologies: Autoimmune (most common in industrialized nations; isolated vs. polyglandular autoimmune syn); infectious (most common in developing nations; TB, CMV, histoplasmosis); vascular (hemorrhage, thrombosis, trauma); drugs (ketoconazole, rifampin, anticonvulsants); deposition dz (hemochromatosis, amyloid, sarcoid); metastatic dz.
Primary or secondary hypopituitarism; rapidly terminated glucocorticoid therapy (≥2 w at ≥10 mg/d) → HPA suppression; Megestrol (progest w/ glucocorticoid activity)
• Clinical manifestations: Fatigue, weakness, anorexia, orthostatic HoTN, nausea, vomiting, HoNa, hyperK, hyperpigmentation. ± manifestations of hypopituitarism. Consider AI w/ sev hyperemesis gravidarum.
• Adrenal crisis: All primary sx + sev abdominal or leg pain, syncope, dehyd, psychosis, seizures, lethargy, fever, hypoglycemia.
Early am cortisol <3 μg/dL = adrenal insufficiency. ≥18–20 μg/dL nml/ruled out.
High-dose ACTH test: 1st-line test for most pts. Check serum cortisol → inject 250 μg cosyntropin (synthetic ACTH) → check cortisol at 60 min. Tests cortisol release.
Low-dose (1 mg) ACTH test: Check serum cortisol → inject 1 μg cosyntropin → check cortisol at 30 min. Used if recent onset ACTH deficiency suspected.
Serum ACTH: ↑ in primary, low–normal or ↓ in secondary
Imaging if needed for pituitary or adrenal eval (MRI or CT).
Acute adrenal insufficiency
Rapid IV fluid hydration w/ isotonic saline
4 mg dexamethasone IV q12h (dexamethasone does not interfere w/ serum cortisol level)
Chronic adrenal insufficiency
Hydrocortisone 20–30 mg PO daily in BID or TID divided doses (eg, 10/5/2.5 mg), or prednisone 2.5–7.5 mg PO daily. ↑ dose 2–3× for up to 3 d during acute illness.
Fludrocortisone (not necessary in secondary adrenal insufficiency) 0.1 mg/d
Preg: If adequately treated beforehand, most have Uncomp Preg, labor, & deliv. During labor, consider “stress dose steroids.” Hydrate w/ IVFs & give hydrocortisone 25 mg IV q6h. At deliv, ↑ dose to 100 mg. After deliv, taper dose rapidly to maint dosing w/i 3 d. Only needed for >5 mg × >3 w of exog steroid.
• Definition: Rare catecholamine secreting chromaffin cell tumor originating from adrenal medulla (90%) & sympathetic ganglia (10%).
• Epidemiology: 0.8 per 100000 person years incid. <0.2% of pts w/ HTN. Rule of 10’s: 10% extra-adrenal, 10% in children, 10% multi/bilateral, 10% recurrence, 10% malig, 10% familial.
• Etiology: MEN 2A/2B (2A = pheo/MTC/parathyroid hyperplasia; 2B = pheo/MTC/mucosal neuromas), von Hippel–Lindau, neurofibromatosis-1, familial paraganglioma.
• Clinical manifestations: HTN most common (sustained or paroxysmal), HA, sweating, palps, palor. Can be triggered by stress, abdominal manipulation, maybe IV contrast.
• In Preg → paradoxical supine HTN
High risk (familial syndromes, personal Hx): Plasma free metanephrines (99% sens/89% spec)
Low risk (all other): 24-h urine fractionated metanephrines & catecholamines (99% sens/98% spec). False + w/ sev illness, renal failure, OSA, labetalol, TCAs, sympathomimetics.
Imaging after biochemical confirmation = CT/MRI abd/pelvis (98–100% sensitive). Consider MIBG scintigraphy if CT/MRI neg w/ + clinical/biochem. Also, consider genetic testing.
• Rx: α-adrenergic blockade (phenoxybenzamine) ± β blockade (propranolol) → Surg. In Preg → same as above. Laparoscopic resxn if previable fetus. C/S + tumor resxn at deliv.
• Definition: ↑ primary adrenal androgens (DHEA & DHEA-S). Converted to androstenedione → testosterone (& also to estrogen). adrenarche = DHEA + DHEA-S ↑ → pubic hair dev. Can have ± hyperaldo, ± Cushing’s syn.
• Etiology: Adrenal tumors (adenoma, carcinoma, bilateral macronodular adrenal hyperplasia), CAH (ACTH hypersecretion). Also in diff: Exogenous androgens, hyperprolactinemia, placental aromatase deficiency, PCOS. See also Ch. 6 (CAH) & Ch. 8 (PCOS).
• Dx: Clinical exam (hirsutism, androgenic alopecia, oily skin, acne, muscle hypertrophy, clitoromegaly, virilization, acanthosis nigricans)
Labs: serum testosterone, DHEA-S (>500 μg/dL in sugg adrenal tumor), 17-OHP (nml 100–300 ng/dL), prolactin (nml <20 ng/mL; prolactin acting on receptors in adrenal → ↑ DHEA-S), thyroid fxn tests, gluc tol testing (fasting +2-h OGTT). Fasting gluc:insulin ratio <4.5 sugg insulin resistance.
Imaging: MRI or CT
• Rx: Depends on etiology; Surg is recommended for adrenal tumors
Polycystic Ovary Syndrome (See Ch. 8)
• Definition: Ovarian interstitial cells differentiate into islands of luteinized theca cells → ↑ steroid production. ↑ periph conversion to estrogen → ↑ endometrial hyperplasia.
• Dx: Menstrual irregularities, obesity, hyperandrogenism. Can be postmenopausal (unlike PCOS only in younger).
• Rx: Combination OCPs, weight loss, GnRH agonist (⊘LH secretion), surgical resxn.
• Other ovarian tumors: See Ch. 21 for other sex hormone producing tumors (teratoma, gonadoblastoma, granulosa cell, Sertoli-Leydig cell)
Definition, Pathophysiology, and Epidemiology
• Excessive male pattern growth of coarse terminal hair in women.
• Conversion of testosterone to DHT by 5α-reductase → irreversible conversion of soft, vellus hair to coarse terminal hair.
• Ethnicity-related trends in hair follicle conc & thus propensity toward hirsutism; distinguish hypertrichosis from hirsutism. Mediterranean descent > northern Europeans > Asians.
• Overall 5–10% of reproductive age . Typical onset in adolescence to early 20’s.
• PCOS (70–80%), meds (anabolic steroids, danazol, progestins, metoclopramide, methyldopa), idiopathic, nonclassical 21-OH CAH, adrenal tumors, hyperthecosis, ovarian tumors, Cushing’s syn, hyperprolactinemia
• Terminal hair on lip, chin, chest, abd, arms, legs, back. Ferriman–Gallwey score to grade (95% of are nml w/ score <8; score >8, consider androgen-excess).
Figure 17.5 Ferriman-Gallwey scoring chart
Diagnosis – See Hyperandrogen/PCOS Workup (Chap. 8)
• Combined OCPs 1st line (use lower androgenic progest products) → other treatments as for hyperandrogenism. Mechanical hair removal (shaving, waxing, laser).
• Antiandrogens effective but only monotherapy in reproductive aged w/ contraception. Spironolactone (also aldosterone receptor antag), flutamide, cyproterone, drospirenone (very weak antiandrogen, only available in combined OCP).
• PTH is the primary regulator of Ca & phosphorus (PO4) levels. Regulated by negative feedback via parathyroid calcium sensing. Secreted by chief cells.
• PTH → ↑ Ca release from bone, ↓ renal excretion, ↑ 1–25 Vit D → ↑ serum calcium
• PTH → ↑ renal PO4 excretion, ↑ intestinal Absorp (w/ Ca), ↑ release from bone (w/ Ca) → on balance ↓ phosphorus.
• PTHrP similar to PTH, synthesized in many tissues. Levels gradually ↑ in Preg & lactation. High conc in human breast milk. Pathologically ↑ in some cancers causing humoral HyperCa of malig (eg, squamous cell lung cancer)
Primary Hyperparathyroidism (PTH-related Hypercalcemia)
• ↑ PTH due to a d/o of the parathyroid tissue (gland production). Usually age >60. ∼85% adenoma, ∼15% hyperplasia, 1% carcinoma, drugs (thiazides, lithium).
• Dx: ↑ PTH or an inappropriately high-nml PTH in pt w/ ↑ Ca; exclude FHH, below.
• Clinical manifestation: Usually asx HyperCa (80%). Also a/w nausea, vomiting, constip, abdominal pain, nephrolithiasis (sx of high Ca). Osteitis fibrosa cystica = demineralization of bone, subperiosteal resorption, bone cysts, osteoclastomas/“brown tumors,” & pathologic fractures.
• Dx: Total & free serum Ca. Decreased PO4. High serum PTH for Ca level. Consider: PTHrP, 25-OH Vit D, urinary calcium, SPEP, UPEP, ACE, CXR/CT, mammogram. Neck sono eval & localize.
• Rx: HPTH has risk for mother & fetus: If Ca <12 mg/dL close monitoring, furosemide can be used for calciuresis. If Ca >12 mg/dL, parathyroidectomy better than medical mgmt, Surg ideally during 2nd trimester. ∼50% of neonates of w/ HPTH have low Ca/tetany, at risk for IUGR, LBW, IUFD as a result of fetal PTH suppression.
Nonpregnant → surgical mgmt for symptomatic pts or for asx pts w/:
Ca >1 mg/dL above the UL of nml (J Clin Endocrinol Metab 2009;94(2):335)
CrCl <60 mL/min
Bone T score <–2.5 &/or prev fragility fx
Age <50 y
Secondary Hyperparathyroidism in Renal Disease
• ↑ PTH due to appropriate resp to HypoCa
• When GFR <∼40 mL/min → ↓ calcitriol & ↑ phosphorus → HypoCa & ↑ PTH
• Ca binds w/ PO4 & can deposit in tissues
• Outside of Preg, treat w/ PO4 binders, Vit D
Familial Hypocalciuric Hypercalcemia (FHH)
• Autosomal dominant mut in Ca sensing receptor causes shift in set point for Ca
• Critical to differentiate from PTH problem, as a benign condition
• Ca ↑, but usually <12; PTH inappropriately nml or mild ↑
• Urine Ca <200 mg/24 h, & Ca/CrCl <0.01 (24-h Uca × Scr/Sca × 24-h Ucr) supports dx
• ↑ Ca always recurs after Surg unless total parathyroidectomy, rx rarely indicated
• In Preg, neonate at risk for HypoCa/tetany unless inherits gene & then asx
• Father w/ FHH → neonate at risk for HyperCa postpartum
• Acq: Neck Surg w/ incidental removal of parathryoid glands (most commonly for HPTH), hypomagnesemia. Hereditary (rare): DiGeorge, polyglandular autoimmune type I. Dx is made w/ ↓ PTH in setting of ↓ calcium
• Pseudohypoparathyroidism (resistant to PTH due to mut) dx: ↑ PTH in setting of ↓ Ca
• 2∞ hypoparathyroidism (appropriate ↓ PTH due to ↑ Ca) dx: ↓ PTH in setting of ↑ Ca
• In Preg: Avoid mat HypoCa → precipitates neonat HPTH → bone fractures
• Postpartum: May develop HyperCa, monit Ca postpartum & stop Vit D if develops
• Rx: Calcitriol + elemental Ca 1 g/d, titrate calcitriol weekly to low nml serum Ca level
• Treated pts are at risk for nephrolithiasis. If 24-h Uca >300 mg/d → ↓ Vit D, can add thiazide diuretic to ↓ urinary calcium excretion
• Sx: Carpopedal spasm, oral paresthesias, Trousseau + Chvostek sign. Confirm w/ ionized Ca (preferred) or corrected calcium level for albumin. Corrected Ca (mg/dL) = measured total Ca (mg/dL) + 0.8 (4 – serum albumin [g/dL]).
• Etiology: Measure PTH, Vit D
Low PTH: ↓ magnesium, neck Surg
Nml PTH: Calcium sensor defect
High PTH: Vit D deficiency, rhabdo, tumor lysis syn, pseudohyperparathyroidism, meds, pancreatitis, hydrofluoric acid exposure.
• Rx: Calcium (& treat hypomagnesemia)
Asx or mild: Oral calcium 0.5–1 g elemental BID
Sev: IV Ca-gluconate (preferred due to less tissue necrosis) or Ca-chloride. Treat Vit D deficiency also.
• Confirm w/ ionized Ca (preferred) or corrected calcium level for albumin (see above for correction)
• Clinical manifestations: Renal stones, abdominal pain, polyuria, depression, fatigue
• Rx: Indicated for pts w/ total calcium >14 mg/dL or mod/sev sx
Simultaneous hydration w/ isotonic saline, bisphosphonate ± calcitonin
Bisphosphonate onset of action is 1–2 d
Calcitonin works in hours, but tachyphylaxis occurs after ∼24 h
Zolendric acid more effective than pamidronate in malig (J Clin Oncol 2001;19(2):558)
• Anter pituitary: GH, TSH, ACTH, prolactin, LH, FSH, MSH
• Post pituitary: Oxytocin, ADH
• Etiology: Primary – Surg, tumors, ischemia (Sheehan syn → postpartum pituitary necrosis due to hypovolemic shock after deliv, watershed effect), radiation, infxn, autoimmune (lymphocytic hypophysitis). Secondary (hypothalamic) – Surg, tumors, infxn, trauma, autoimmune.
• Clinical manifestations: Based on specific hormones. Can include HoTN, weakness, inability to lactate, sexual dysfxn, loss of pubic & axillary hair, lethargy, polyuria, polydipsia. Also tumor mass effect: HA, visual changes, cranial nerve palsies.
• Dx: Hormone levels → low if chronic, nml if acute. Imaging by pituitary MRI.
ACTH deficiency: Hydrocortisone 15–25 mg/d – may also consider prednisone or dexamethasone
Mineralocort replacement unnecessary (regulated by angiotensin II & potassium)
LH/FSH deficiency: Estrogen/progest therapy to simulate nml physiology; estradiol on cycle days 1–25 + progesterone days 16–25. Ovulation induction w/ gonadotropins for fertility.
GH deficiency: Recombinant human growth hormone 2–5 mcg/kg/d. Monit w/ serum IGF-1.
• Etiology: 50% of adenomas cause hyperprolactinemia (prolactin → stimulates lactation → ↓ GnRH → ↓ FSH + LH → can ↓ menses); drugs (SSRIs, estrogen, methyldopa, verapamil, morphine, dopamine receptor agonists [metoclopramide, domperidone, haloperidol, risperidone]); Preg, hypothyroidism, liver dz, kidney dz.
• Clinical manifestations: Amenorrhea, galactorrhea, infertility, ↓ libido, visual changes (bitemporal visual field losses w/ large adenomas)
• Dx: Serum prolactin. Brain MRI.
Asx + microadenoma (≤10 mm) → follow w/ MRI. <2% progress to macroadenoma.
Symptomatic ± microadenoma → dopamine agonist (bromocriptine 2.5 mg QD, or cabergoline 0.25 mg 2×/w). Side effects = N/V, orthostasis. Surgical: Transsphenoidal Surg. Radiation 3rd line.
In Preg, microadema unlikely to grow. Macroadenoma (>10 mm) = 23% w/ sign if enlargement during Preg if no prior Surg or radiation; 5% if + prev Surg/radiation. Dopamine agonist before Preg to shrink adenoma. Monit at least q3mo. Serum prolactin <400 ng/mL reassuring. Consider MRI if visual changes or headaches. Breastfeeding does not ↑ growth
Prolactinoma & fertility: Dopamine agonist → lower serum prolactin → ovulation induction
• Definition: Physiologic nipple discharge (milky white, brown or green, elicited after manual expression from milk ducts). Pathologic discharge is bloody, serous, spont.
• Etiology: Preg, postpartum, nipple stimulation, pituitary adenoma (prolactinoma), hypothyroidism, craniopharyngioma, Cushing dz, acromegaly, neoplastic processes (breast, renal adenoCa, lymphoma), hydatidiform mole. See diff dx for hyperprolactinemia also.
• Clinical manifestations: Breast exam to elicit nipple discharge & for mass. Multi ducts/expressed manually/bilateral → more likely physiologic.
• Dx: Occult bld testing & microscopy. Diagnostic mammography, mammary ductography.
Gigantism and Acromegaly
• Definitions: Gigantism → elevated GH & IGF-1 before fusion of the epiphyseal plates → extremely tall stature. Acromegaly (10% adenomas) → elevated GH + IGF-1 after fusion of the epiphyseal plates. May be seen in familial syndromes such as MEN-1 & McCune–Albright syn.
• Clinical manifestations: Large hands & feet, coarsening of facial features, macroglossia, HA, OSA, acanthosis nigricans, arthralgias, carpal tunnel syn, jaw enlargement, hoarseness, extremely tall stature (gigantism), may coexist w/ amenorrhea & or galactorrhea in adol girls.
• Dx: Serum IGF-1 is single best test. OGTT: Serum GH should be <1 ng/mL 2 h after ingesting 75 g gluc load. In pts w/ acromegaly, postingestion serum GH >2 ng/mL in >85% cases (JCEM2001;86(9):4364). Random serum GH not appropriate given pulsatile secretion. Brain MRI to look for pituitary tumor.
• Rx: Transsphenoidal resxn for pituitary tumor. Octreotide (mimics somatostatin → more potent inhib of GH & insulin than natural hormone), bromocriptine (dopamine agonist), XRT (rarely used in children).