Pocket Obstetrics and Gynecology

PEDIATRIC AND ADOLESCENT GYNECOLOGY

PUBERTY

Definitions

• Puberty: Nml physiologic transition from childhood to reproductive & sexual maturity

• Adrenarche: Onset of increased adrenal androgen production, leads to pubarche

• Gonadarche: Pulsatile GnRH secretion & activation of HPO axis

• Thelarche: Onset of breast dev

• Pubarche: Onset of pubic & axillary hair dev

• Menarche: Onset of menstruation

• PHV: Growth spurt characterized by acceleration in growth rate age 9–10, leading to peak height velocity (PHV) around age 11–12

Physiology

• Requires intact HPO axis. Re-emergence of GnRH secretion → ↑ LH ↑ FSH → gonadal maturation & sex-steroid production.

• 20% pubarche precedes thelarche (esp AA). Avg thelarche → menarche, 2 y.

Figure 6.1 Tanner staging, female developmental stages

PRECOCIOUS PUBERTY

Definition (N Engl J Med 2008;358:2366)

• Dev of breast or pubic hair >2.5 SD below mean age. Traditional definition <8 yo. Trend of decreasing age of puberty → now <7 yo in C girls, <6 y in AA girls (Pediatrics 1997;99:505; Pediatrics1999;104:936).

Initial Workup

• Hx: Onset, family members’ ages of puberty, h/o neurologic dz or trauma, exposure to sex steroids, headache, sz, abdominal pain

• PE: Height, weight, growth chart, Tanner staging, fundoscopic exam (papilledema in ↑ intracranial pres), visual field eval (sellar mass lesion), skin exam.

• Bone age eval: Plain film X-ray of left hand & wrist

• Lab eval: Basal LH, LH following GnRH stimulation, FSH, estradiol

LH <0.1 IU/L = premature thelarche or nml

LH >0.3 IU/L = true precocious puberty

LH >5 mIU/L = central (gonadotropin-dependent) precocious puberty

Treatment Goals

• Postpone dev until nml pubertal age, maximize adult height, reduce risk of psychosocial problems a/w early sexual maturation

Gonadotropin-dependent (Central) Precocious Puberty (GDPP)

• Early maturation of HPO axis → breast & pubic hair dev, w/ usually nml sequence of pubertal events at nml pace, & isosexual (appropriate for gender)

• Etiology: Idiopathic – 90%; dx of exclusion. CNS lesions – tumors, irradiation, hydrocephalus, cysts, trauma, inflamm dz, midline developmental defects. Sev hypothyroidism (rare).

• Dx: Accelerated linear growth for age (>75% of height at dx), advanced bone age, pubertal levels of FSH, LH, estradiol, & ↑ w/ GnRH stimulation test. MRI in all pts to evaluate for CNS lesion. TFTs if clinical concern for hypothyroidism. Evaluate ↓ growth hormone if h/o cranial irradiation. Abdominopelvic US – repeated exposure to sex steroids from periph sources can induce secondary premature maturation of HPO axis.

• Rx: Treat intracranial lesions or hypothyroidism if present. Idiopathic GDPP, treat if:

sexual maturation progresses to next stage w/i 3–6 mo,

onset puberty <6 yo,

growth velocity >6 cm/y,

Bone age advanced by 1 y or more, or

predicted adult height below target range or decreasing on serial determinations.

Long-acting GnRH agonist → prepubertal hormone level, prevents pubertal dev, growth acceleration, & bone advancement (N Engl J Med 1981;305:1546). Treat until epiphyses fused or pubertal & chrono ages are appropriately matched.

Gonadotropin-independent (Peripheral) Precocious Puberty

• Due to excess exposure of sex steroid hormones from gonads, adrenals, or environment. May be contrasexual or isosexual. Pubertal sequence progression may be altered.

• Etiology: Functional ovarian follicular cysts – most common cause, w/ transient breast dev & vaginal bleeding, 1+ unilateral or bilateral ovarian cysts >15 mm, bone age nml. Ovarian tumors (rare) – granulosa cell tumor → isosexual, Leydig cell/gonadoblastoma → contrasexual. Adrenal – androgen-secreting tumors, CAH. McCune–Albright syndrome (rare) – triad of periph precocious puberty, café-au-lait spots, fibrous bone dysplasia → recurrent formation of follicular cysts & cyclic vaginal bleeding.

• Dx: Low or nml FSH & LH levels, do not ↑ w/ GnRH stimulation. Labs: Testosterone, estradiol, FSH, afternoon cortisol (screen Cushing syn), DHEA, DHEAS, 17-OHP (screen CAH). Abdominopelvic US for ovarian cyst/tumor.

• Rxs: Surgical removal (tumor); tamoxifen for vaginal bleeding, bisphosphonate for bone dysplasia; aromatase inhibs lack long-term effectiveness; exogenous estrogens as cream, ointment, spray (contrasexual); remove exogenous source; for functional cysts → observation, usually self-limited, surgical removal if persistent or torsion; GnRH agonist ineffective for gonadotropin independent.

Isolated Precocious Puberty

• Isolated premature thelarche or adrenarche. Usually benign nml variants. If bone age nml, precocious puberty unlikely.

• Expectant mgmt w/ re-evaluation at 6 mo. ∼20% progress to gonadotropin-dependent precocious puberty. Requires regular exams.

• Isolated premature thelarche: Unilateral or bilateral, <8 y, absence of other secondary sexual characteristics, nml linear growth, nml bone age. Estradiol level usually prepubertal – girls typically <3 yo, nonobese. Unk cause.

• Isolated premature adrenarche: Isolated pubic &/or axillary hair <8 y. Dx: DHEA-S appropriate for pubic hair stage. Girls typically overweight. 17-OHP & testosterone appropriate for age. Bone age & growth rate ↑ but w/i nml limits. Risk factor for PCOS. Further w/u: ACTH stimulation to r/o CAH when bone age advanced, predicted adult height abnormally low, or serum testosterone & DHEA-S elevated – may be only manifestation of mild CAH. Rx: Observation, regular exams to detect other signs of precocious sexual dev.

Figure 6.2 Approach to precocious puberty

DELAYED PUBERTY

Definition (N Engl J Med 2012;366:443; Pediatr Clin North Am 2011;58:1181)

• Absence of secondary sexual characteristics by age 13 (≥2 SD from mean age), or absence of menses by age 15.

Etiology (J Clin Endocrinol Metab 2002;87:1613)

• 30% const del, 26% hypergonadotropic hypogonadism, 20% permanent hypogonadotropic hypogonadism, 19% transient (functional) hypogonadotropic hypogonadism, 5% other causes.

Clinical Manifestations

• Hx: Anorexia, bulimia, excessive exercise, chronic dzs (eg, celiac dz, Crohn dz), radiation, chemo, meds, nutritional status, psychosocial functioning

• Sx: Neurologic sx, inability to smell, weight gain or loss, chronic dz

• FHx: Relatives w/ delayed puberty, heights of relatives, age of menarche & fertility status of female relatives, relatives w/ genetic abnormalities (CAH, adenocarcinoma in situ (AIS), gonadal dysgenesis), relatives w/ autoimmune dz

Physical Exam

• Height & weight measurements, growth chart, Tanner staging, examine for stigmata of Turner syn, midline facial defects, scoliosis, thyromegaly.

• Arm span greater than height >5 cm sugg delayed epiphyseal closure

• Neurologic exam: Optic fundi, cranial nerves, visual fields, sense of smell

• Pelvic exam: Clitoral enlargement, hymenal ring patency, degree of vaginal rugation, presence or absence of mucus (indicates degree of estrogen effect)

Workup

• Hx, physical exam, bone age, labs (LH, FSH)

Elevated FSH/LH = hypergonadotropic hypogonadism

Low FSH/LH = hypogonadotropic hypogonadism

• Further w/u if LH, FSH nml:

PRL – screen for hyperprolactinemia

TSH, FT4 – screen for thyroid dzs

MRI – when si/sx CNS lesion present or if indicated by other eval (hyperprolactinemia, Kallmann syn); otherwise may defer until age 15

CBC, ESR, LFTs – screen chronic dzs (IBD, liver dz, anorexia)

Pelvic US – determine presence/absence uterus if undetermined by physical exam

• Unusually no apparent alternate cause on initial eval – const del likely dx; no test can reliably differentiate const del from hypogonadotropic hypogonadism; therefore, observe, & diagnose isolated hypogonadotropic hypogonadism if endogenous puberty has not begun by age 18; eventual nml progression of puberty confirms const del.

Treatment Goals

• Induce appearance of secondary sexual characteristics or acceleration of growth to mitigate pubertal delay & short stature, & promote nml bone mass

• Predict adult height w/ Bayley-Pinneau tables, although overestimate adult height in const del.

Figure 6.3 Approach to delayed puberty

Hypergonadotropic (Primary) Hypogonadism

• Dx: Elevated LH & FSH due to lack of negative feedback from gonads. Additional w/u: Karyotype, autoimmune dz eval.

• Etiology: Primary ovarian insufficiency (idiopathic, resistant ovary syn, autoimmune oophoritis, 17a-hydroxylase deficiency, galactosemia, aromatase deficiency), Gonadal dysgenesis (45,X; 46,XX; 46,XY), radiation, chemo. Special cases:

Turner syn: 45,X (Semin Reprod Med 2011;29:342) – phenotype: Female, short stature, ptosis, low-set ears, micrognathia, short “webbed” neck, broad shield-like chest, hypoplastic areolae, short 4th &/or 5th metacarpals, renal abnormalities (eg, horseshoe kidney), cardiovascular abnormalities (eg, coarct of the aorta). Risk of aortic dissection & rupture (1.5%). “Streak” gonads consist of fibrous tissue w/o germ cells. External female genitalia, uterus, fallopian tubes develop normally until puberty when estrogen-induced maturation fails to occur. Menstruation & Preg may occur in mosaic karyotype (45,X/46,XX). Rx: Growth hormone prior to estrogen initiation.

Swyer syn: 46,XY complete gonadal dysgenesis. Phenotype: Female, w/ vagina, cervix, uterus, fallopian tubes, & external genitalia. Rx: Requires early gonadectomy due to risk of gonadal tumors.

Primary ovarian insufficiency: See Chap. 8.

Permanent Hypogonadotropic (Secondary) Hypogonadism

• Dx: Low to nml LH & FSH due to hypothalamic or pituitary disorders.

• Etiology: GnRH deficiency, CAH, CNS tumors, combined pituitary hormone deficiency, chemo, radiation

Kallmann syn: Anosmia or hyposmia; 1/50000 females

• Further w/u: MRI

• Rx: Initial low-dose estrogen titrated to mimic nml puberty to initiate sexual maturation

After 6–9 mo, cyclic progesterone to induce endometrial shedding

Transition to combination OCP when breast dev optimized for hormonal replacement

If fertility desired, pulsatile GnRH or injectable gonadotropin

Transient (Functional) Hypogonadotropic Hypogonadism

• Dx: Low LH & FSH due to delayed maturation of HPO axis due to underlying condition

• Etiology: Systemic illness (IBD, celiac dz, anorexia nervosa or bulimia, hypothyroidism, hyperprolactinemia, DM, Cushing dz), CNS disorders (tumors [eg, craniopharyngioma, prolactinoma], infxn, trauma), adrenal (Cushing syn, Addison dz), psychosocial (excessive exercise, stress, depression), drugs (marijuana).

• Rx: Treat underlying cause (treat dz or modify behavior)

• Const Del:

Dx: Low LH & FSH, HA = bone age < chrono age. Adrenarche & gonadarche often later than avg; isolated hypogonadotropic hypogonadism has adrenarche at nml age.

Rx: Expectant observation. If puberty has started (clinically or biochemically) & stature not a major concern, reassurance w/ adult height prediction.

Hormone rx is controversial (goal of preventing developmental psychosocial stress). Use low-dose estrogen until puberty progresses, then stop. Progesterone not needed as similar long period of unopposed estrogen in early puberty. Growth hormone, anabolic steroids, aromatase inhibs not recommended.

AMENORRHEA

Definitions (Pediatrics 2006;118:2245; Obstet Gynecol Clin North Am 2003;30:287)

• Primary amenorrhea: Absence of menstruation by age 13–14 in absence of growth or sexual dev, or age 15–16 in presence of nml growth & sexual dev

• Secondary amenorrhea: Absence of menses for ≥3 consecutive menstrual cycles in women w/ previously nml menses

Epidemiology

• Primary amenorrhea 1–2% prevalence in US. Amenorrhea not caused by Preg ≤5% prevalence during menstrual lives. Most common causes of primary amenorrhea: Ovarian failure (48.5%), Müllerian agenesis (16.2%), gonadotropin deficiency (8.3%), constitutional delay (6%) (Am J Obstet Gynecol 1981;140:372).

History

• Hx: Stress, change in weight, diet, exercise, sugg functional hypothalamic etiology

New meds – evaluate for hyperprolactinemia due to meds

New illnesses – sugg chronic illness etiology

Acne, hirsutism, deepening of voice – sugg hyperandrogenism: PCOS or adrenal etiology

Headache, visual field defects, fatigue, polyuria, polydipsia – sugg CNS lesion

Hot flashes, vaginal dryness, poor sleep, decreased libido – sugg primary ovarian insufficiency

Galactorrhea – sugg hyperprolactinemia

H/o postpartum hemorrhage, D&C, endometritis – sugg Asherman or Sheehan syn

Physical Exam

• Height, weight (BMI <18.5 at risk for functional hypothalamic amenorrhea; BMI >30 in ∼50% pt w/ PCOS.

• Tanner staging if primary amenorrhea. Assess estrogen status: Adequate if breasts present, moist & rugated vaginal mucosa, abundant cervical mucus.

• Assess for presence of uterus, cervix, or signs of obstructed tract.

• Assess for signs of excessive testosterone: Hirsutism, acne, acanthosis nigricans

• Evaluate for galactorrhea

• Parotid gland swelling &/or erosion of dental enamel sugg bulimia nervosa

• Evaluate for stigmata of Turner syn.

Initial Workup

• History & physical exam. Lab: Urine hCG, TSH, FSH, PRL (↑ by stress, sleep, intercourse, meals, nipple stimulation). If signs of hyperandrogenism: Testosterone, ± 17-OHP (CAH), DHEA-S (adrenal etiology).

• Progesterone challenge test: Determine if adequate estrogen present, competent endometrium, patent outflow. Medroxyprogesterone acetate 10 mg PO daily for 7–10 d.

• Withdrawal bleed expected w/i 2–7 d of stopping progesterone:

+ bleed: Nml estrogen production & ovarian fxn

– bleed: Hypoestrogenic or anatomic outflow tract obst

Congenital Anatomic Lesions

• Menses cannot occur w/o an intact uterus, endometrium, cervix, vaginal conduit. Clinical manifestations: Cyclic pelvic &/or lower abdominal pain from accum & subseq dilation of vaginal vault &/or uterus by menstrual bld.

• Imperf hymen: Bulging membrane just inside the vagina, often purple-red discoloration.

• Transverse vaginal septum: Occurs at any level btw hymenal ring & cervix; absence of bulging hymen as septum much thicker.

• Vaginal agenesis: See Chap. 8.

• Rx: Surgical correction

Asherman Syndrome (Semin Reprod Med 2011;29:83)

• Acq scarring of the endometrial lining, usually secondary to postpartum hemorrhage or endometrial infxn followed by dilation & aggressive curettage. Prevents nml buildup & shedding of endometrial cells → very light or absent menses.

• HSG shows uterine filling defects. No withdrawal bleed following estrogen & progesterone. Hysteroscopic eval demonstrates uterine synechiae.

• Rx: Surgical lysis of adhesions by hysteroscopy. Estrogen postoperatively to help promote endometrial regeneration.

Primary Ovarian Insufficiency (Premature Ovarian Failure)

See Chap. 8.

Hyperprolactinemia (Curr Opin Obstet Gynecol 2004;16:331; J Reprod Med 1999;44:1075)

• Etiology: Hypothyroidism, PRL-secreting pituitary adenomas (20% secondary amenorrhea), pituitary or hypothalamic tumors, meds (amphetamines, benzodiazepines, metoclopramide, methyldopa, opiates, phenothiazines, reserpine, tricyclic antidepressants, SSRIs). Occurs due to dopamine receptor antagonism.

• Clinical manifestations: ± galactorrhea.

• Dx: Elevated serum PRL; r/o hyperthyroidism. Further w/u: MRI to evaluate for pituitary tumor if persistent ↑ PRL or >100 ng/mL

• Rx: Dopamine agonist (bromocriptine or cabergoline) or transsphenoidal resxn of CNS lesion.

Sheehan Syndrome

• Acute infarction & ischemic necrosis of pituitary gland from postpartum hemorrhage & hypovolemic HoTN. More common in low resource settings.

• Clinical manifestations: Failed postpartum lactation, fatigue, weight loss, loss of sexual hair

• Dx: Hx, growth hormone, LH, FSH, PRL, ACTH, TSH deficiencies.

Functional Hypothalamic Amenorrhea (N Engl J Med 2010;363:365)

• Abn GnRH pulses → decreased gonadotropin pulsations → low/nml serum LH concentrations → absent LH surge → absence of follicular dev, anovulation, low estradiol.

• Etiology: Stress, weight change, decreased nutrition, excessive exercise, anorexia nervosa or bulimia, chronic dz (DM, ESRD, malig, AIDS, IBD), isolated gonadotropin deficiency (congen, Kallmann syn), Sheehan syn.

• W/u: MRI for CNS/hypothalamic/pituitary dz.

• Rx: Behavior modification if indicated, treat chronic dz, hormonal therapy to prevent bone loss, ovulation induction w/ clomiphene citrate, gonadotropin injection, pulsatile GnRH.

Polycystic Ovarian Syndrome (PCOS)

See Chap. 8.

Figure 6.4 Approach to amenorrhea

ANDROGEN INSENSITIVITY SYNDROME

Definition and Epidemiology (J Pediatrc Surg 2005;40:133; J Clin Endocrinol Metab 2001;86:4151)

• Male pseudohermaphroditism from muts in AR & decreased end organ sens. 1.1% incid of CAIS in a premenarcheal child w/ inguinal hernias.

• 1 in 20000–99000 genetic males

Etiology

• 70% of AR muts are X-linked recessive leading to decreased resp to androgens; 30% de novo sporadic muts. Multi syns.

Pathophysiology

• Nml male dev only occur if adequate androgen production acting on target tissues (sex differentiation). Muts in AR leads to a defective resp to androgens at all stages of dev. Production of testosterone occurs at ∼8–16 w via placental hCG; after 16 w, fetal LH controls circulating androgens.

• Testosterone (produced by Leydig cells in testes) is responsible for Wolffian dev & formation of the epididymis, vas deferens, & seminal vesicles. DHT is responsible for formation of male external genitalia & fusion of labioscrotal folds. Androgens control descent of testes into scrotum → in AIS, testes remain in pelvis.

• Androgens → secondary male sex characteristics at puberty (axillary & pubic hair) & spermatogenesis. MIS is produced normally by Sertoli cells in testes causing regression of Müllerian ducts → no uterus, oviducts, & upper vagina.

Figure 6.5 The major pathways of male and female sexual differentiation

Clinical Manifestations

• Karyotype 46XY

• Male pseudohermaphroditism: Variety of phenotypes ranging from male infertility to nml female external genitalia. May present w/ ambiguous genitalia or infantile male genitalia. + MIS → short vagina, absent uterus & cervix.

• Primary amenorrhea/infertility

• CAIS: No activity at the AR → nml female phenotype. Nml breast dev w/ pale areola (estrogens produced by testes & circulating androgens fail to antagonize estrogens). Sparse or absent pubic & axillary hair (vellus hair only, if present). Nml or slightly advanced height, however decreased bone density. 50% w/ inguinal hernias: Gonads (testes) intra-abdominal or in the inguinal rings. Serum testosterone in the range of pubertal male. No issues regarding gender identity or sexual preference given they are not exposed to male androgen levels → brain dev along w/ physical dev is female.

• PAIS: Varying degrees of female virilization or male feminization due to differing degrees of AR activity. Labial fusion, bifid scrotum, hypospadias, micropenis, &/or clitromegaly. Blind vas deferens. Testes in labioscrotal folds. Nml breasts & pubic & axillary hair. Higher rates of bisexuality, homosexuality, & gender identity d/o.

• Mild AIS: Phenotypic & genotypic males. Male infertility (oligospermia w/ nml T & LH). Gynecomastia in young men. Minor hypospadias.

Physical Exam

• Female infant or toddler w/ an inguinal hernia → attempt to pass a sterile Q-tip into vagina (consider exam under anesthesia in toddlers). Consider karyotype.

• Adol → full physical exam (note breast dev, pubic & axillary hair, & external genitalia including hymenal anatomy), rectal exam to r/o lower vaginal obst.

Diagnostic Workup/Studies

• CAIS: ↑ T & ↑ LH. Diff:

MRKH syn or Müllerian agenesis; distinguish by karyotype; XX genetic females; nml testosterone; presence of pubic & axillary hair (absent in CAIS)

Swyer syn = XY complete gonadal dysgenesis. No breast dev & short stature; XY genetic males.

• PAIS: Nml T & ↑ LH (Clin Endocrinol Metab 2006;20:577), MRI (gold std) or pelvic US to document internal anatomy, localize testes, r/o testicular tumors, karyotype, genetic counseling for parents.

Differential diagnoses (DDx)

Partial gonadal dysgenesis

17β-hydroxysteroid dehydrogenase deficiency

5α-reductase deficiency

Mixed gonadal dysgenesis w/ mosaic Turner syn (45XO/46XY)

Defect in LH receptor

Treatment

• Prophylactic gonadectomy in CAIS b/c of ↑ rate of malig degeneration & formation of dysgerminomas/gonadoblastomas after pubertal dev, then estrogen replacement

• Incid of 0.5% malig in CAIS, 5.5% in overall AIS pop; as high as 50% in PAIS if gonads in nonscrotal position (intra-abdominal location inc risk for malig). If dx prior to puberty, serial US monitoring for pelvic masses (Acta Endocrinol 1990;123416; Int J Gynecol Pathol 1991;10:126; J Clin Endocrinol Metab 2005;90:5295)

Rate of malig in pts w/ AIS prior to puberty is 0.8% (CAIS) & 5.5% (overall) (Endocrine Rev 2006;27:468; J Pathol 2006;208:518)

• Hormone replacement

CAIS → estrogen replacement during late adolescence/early adulthood to aid final Tanner 5 breast dev, help build bone, Vit D, regular weight-bearing exercise; DEXA or bisphosphonates prn

PAIS → large doses of androgens to promote phallic growth

• ± vaginal dilators for increased vaginal length; d/c once regular vaginal intercourse

• ± genital reconstructive Surg when pt voices desire to proceed

• Multidisciplinary support including a mental health provider, social worker, geneticist

CONGENITAL ADRENAL HYPERPLASIA (CAH)

Definition and Epidemiology

• Autosomal recessive disorders of cortisol &/or aldosterone biosynthesis, result in cortisol deficiency, ± aldosterone deficiency, & androgen excess. There are two forms:

• Classic CAH (sev form, 1/15–16000 live births)

(a) salt wasting (67%)

(b) nonsalt losing (simple virilizing; 33%)

• NCAH (mild or late onset); asymptomatic or postnatal

Pathology & Pathophysiology

• Caused by a mut in cortisol producing enzymes.

• ↑ corticotrophin → adrenal hyperplasia

• ↑ cortisol precursors which are diverted to the biosynthesis of sex hormones → androgen excess → ambiguous genitalia in newborn girls, rapid postnatal growth in both sexes

• Aldosterone deficiency → salt wasting → FTT, hyponatremic hypovolemia, shock

• HyperK

Classic CAH – abn cortisol, sex hormone, ± aldosterone production

NCAH – nml cortisol & aldosterone, but mild to mod ↑ sex hormones

• Muts:

CYP21 (CYP21A2; 95% of cases; codes for adrenal 21-hydroxylase) → CYP21 mut → 21-hydroxylase deficiency → inadeq cortisol synthesis → inadeq negative feedback to hypothalamus & pituitary → increased ACTH secretion → adrenal gland hyperplasia. Adrenal steroids are converted to adrenal androgens.

CYP11B1 mut → 11b-hydroxylase deficiency → ↑ 11-deoxycortisol & 11-deoxycorticosterone → salt retention → hypervolemia, HTN.

HSD3B2 mut → 3β-hydroxysteroid dehydrogenase deficiency → sev adrenal insufficiency, ↑ ACTH → ↑ pregnenolone, 17-hydroxypregnenolone, & DHEA → mild virilization, ± salt wasting.

Clinical Manifestations

• Salt-losing adrenal crisis in neonat period for 3/4ths newborns w/ classic CAH.

• 46 XX female pseudohermaphroditism: Nml uterus, fallopian tubes & ovaries but varying levels of ambiguous genitalia depending on degree & type of enzyme deficiency

• Ambiguous genitalia: Classic CAH – newborn ambiguous genitalia (clitoral hypertrophy, labioscrotal fusion – partial or complete, common urogenital sinus). Boys have no overt sx except hyperpigmentation & penile enlargement. NCAH – presents in adolescence; rapid growth, premature pubic or axillary hair, hirsutism.

• Hyperandrogenism: Hirsutism, acne, oligomenorrhea/amenorrhea, polycystic ovaries, precocious puberty.

• Infertility: 80% women w/ simple virilizing & 60% women w/ salt-wasting CAH are fertile. (Endocrinol Metab Clin North Am 2001;30:207)

• Metabolic syn/insulin resistance/obesity

• Short stature: Untreated, long-term sex hormone exposure leads to advanced skeletal age & premature epiphyseal fusion. Mean adult height = 10 cm below nml pop.

• Issues of gender & sexuality (Endocrinol Metab Clin North Am 2001;30:155)

• Iatrogenic Cushing syn

Workup

• Serum electrolytes, aldosterone, & plasma renin: HyperK, ↓ aldosterone, hyperreninemia (use age-specific reference for renin).

• Random 17-OHP: >242 nmol/L (nml 3 nmol/L) at 3 d in full-term infants. False positives in premature infants. Use weight & gestational age–based reference ranges.

• Corticotrophin-stimulation test: 250 μg cosyntropin followed by measurement of 17-OHP 60 min later. 17-OHP level >10 ng/mL (30.3 nmol/L)

• Early morning (before 0800 h) 17-OHP: >2.5 nmol/L in children & >6 nmol/L in women during follicular phase r/o NCAH

• Genetic analysis, neonat screening or gene-specific prenatal dx

Treatment

• Glucocorticoids (short acting in children to avoid growth suppression). Stress dosing during febrile illness, Surg, trauma, etc. (Double or triple daily dose.)

Hydrocortisone 12–18 mg/m2 divided into 2 or 3 doses. Longer-acting glucocorticoids can be used in adults.

Prednisone 5–7.5 mg QD in 2 doses or dexamethasone 0.25–0.50 mg QHS. Good in Preg (does not cross the placenta). Goal early morning 17-OHP 12–36 nmol/L.

• Mineralocorticoides

• Fludrocortisone 100–200 μg QD; adjust to maintain plasma rennin in midnormal range

• NaCl suppl (salt-losing CAH) 1st 6–12 mo of life

• Infertility → ovulation induction

• Hirsutism → antiandrogens (w/ OCPs as antiandrogens are teratogens)

• Prenatal rx: Mat dexamethasone suppresses fetal HPA axis & ↓ genital ambiguity

Start prior to 8 w of gest when masculinization of external genitalia begins

CVS or amniocentesis for gender, if male or unaffected female → d/c steroids

85% of prenatally treated female infants are born w/ nml or slightly virilized genitalia

• Neonat rx: Hydrocortisone dose ≤25 mg/m2 QD. Monit weight, length, adrenal steroid conc, plasma renin, & electrolytes.

• Surgical mgmt of ambiguous genitalia (controversial): Age 2–6 mo in virilized girls; technically easier than at later ages (std of care) vs. later ages when psychosexual identity is established.