Beruflich Dokumente
Kultur Dokumente
Syndrome in Adolescents
Robert L. Roseneld, MD
1156 ROSENFIELD
TABLE 3 Types of Abnormal Uterine Bleeding Found in Adolescent PCOS Measurements of total and/or free
Descriptor Denition testosterone are recommended to
Primary amenorrhea Lack of menarche by 15 y of age or by 3 years after
initiate documentation of
the onset of breast developmenta hyperandrogenemia.35,44 Elevated
Secondary amenorrhea Over 90 d without a menstrual period after initially menstruating serum free testosterone is the single
Oligomenorrhea (infrequent AUB) Postmenarcheal year 1: average cycle length .90 d (,4 periods/y) most sensitive indicator of
Postmenarcheal year 2: average cycle length .60 d (,6 periods/y) hyperandrogenemia because the
Postmenarcheal years 35: average cycle length .45 d
(,8 periods/y)
bioactive portion of the serum
Postmenarcheal years $6: cycle length .3840 d (#9 periods/y) testosterone is the free fraction. Sex
Excessive anovulatory AUB Menstrual bleeding that occurs more frequently than every 21 d hormone binding globulin (SHBG)
(19 d in yr 1) or is excessive (lasts .7 d or soaks .1 pad or serum concentrations govern the
tampon every 12 h) fraction of testosterone that is free;
Modied and reproduced with permission from Roseneld RL. Clinical review: Adolescent anovulation: Maturational they are lowered by obesity and
mechanisms and implications. J Clin Endocrinol Metab. 2013;98:35723583. AUB, abnormal uterine bleeding.
a Bone age of 15 y may be substituted for chronologic age in girls with earlier-than-average age at puberty onset. androgen excess itself. The cost-
b Encompasses frequent, intermenstrual, heavy, and/or prolonged AUB. Formerly termed dysfunctional uterine bleeding. effectiveness of routinely measuring
more androgens than total and free
The meager normative data that exist dermatologic therapy are ordinarily testosterone has not been
in adolescence suggest that an adult treated by combined oral documented, although
level of hirsutism is achieved by 2 contraceptive (COC) pills, which androstenedione may be
years after menarche or 15 years of lower ovarian androgen production, considered45 and
age37,38: upper lip scores of 3 to 4 or the systemic retinoid Accutane.41 dehydroepiandrosterone sulfate
increased over the course of puberty to Because COC therapy thus masks the (DHEAS) is widely used to assess
reach an adult prevalence of ,3% in hyperandrogenism of underlying adrenal hyperandrogenism. Although
Black and White US adolescents by the PCOS, it is recommended that dihydrotestosterone generated in
second postmenarcheal year (Fig 4). patients with moderate-severe target tissue mediates most
Acne, rather than hirsutism, may be inammatory acne unresponsive to testosterone effects, its serum level is
the only pilosebaceous manifestation topical treatments be assessed for of little diagnostic value.36
of hyperandrogenism.39 Comedonal hyperandrogenemia before instituting However, accurate determinations
acne is common in adolescent girls, systemic medical treatments. of total and free testosterone
but inammatory acne that is concentrations are often problematic.
moderate or severe (ie, .10 facial Biochemical Evidence of Diurnal rhythm, phase of menstrual
lesions, Table 4) is uncommon during Hyperandrogenism cycle, and SHBG concentrations are
the perimenarcheal years.40 Girls Documentation of hyperandrogenism biological variables that inuence
with acne that is persistent and requires reliable assays with well- total testosterone concentrations.
poorly responsive to topical dened normal ranges.4,42,43 Methodological problems regarding
testosterone determinations abound.
Most notably, the multichannel
platform assays now commonly used
by hospital laboratories lack
sensitivity, specicity, and accuracy
for testosterone, although they are
good for SHBG and DHEAS
measurement. Some direct assays of
total testosterone are also inaccurate,
but others are as accurate as the
postchromatographic
radioimmunoassays that have been
available only through specialty
laboratories or the tandem mass
FIGURE 2
Probability that an adolescent with symptomatic anovulatory symptoms will have ongoing menstrual spectrometry methods that are
abnormality. All symptomatic anovulation curve represents the data of Southam et al.26 Hyper- beginning to supplant them.14,46,47
androgenic and Nonhyperandrogenic curves are hypothetical, based on data discussed in the The reliable free testosterone assays
text. Hyperandrogenic cases are predominantly a mix of physiologic anovulation and PCOS, with
PCOS persisting. Nonhyperandrogenic cases are a mix of physiologic anovulation and hypogonadal
calculate the free testosterone
cases, ranging from primary hypogonadism through hypothalamic amenorrhea to hypogonado- concentration as the product of the
tropic hypogonadism, with hypogonadal cases persisting. total testosterone and the fraction
that is free from SHBG binding (free percent free testosterone by dialysis. during adolescence, as discussed in
testosterone = total testosterone 3 Free testosterone assays are less well the previous section.2933
percent free testosterone).48 The standardized than total testosterone In summary, biochemical evidence of
most common methods calculate hyperandrogenism, as indicated by
assays, which has limited their
percent free testosterone from the persistent elevation of serum total
SHBG concentration or determine the usefulness.
and/or free testosterone levels above
The criteria used to dene adult norms and determined by a
hyperandrogenemia in adolescent reliable reference laboratory,
girls are confounded by provides the clearest support for the
developmental considerations. presence of hyperandrogenism in an
However, shortly after menarche, adolescent girl with symptoms of
serum testosterone of adolescents PCOS. In most such laboratories, the
attains adult levels (Fig 5).1,4 Thus, upper limit approximates 55 ng/dL
adult testosterone levels are an for total testosterone and 9 pg/mL for
appropriate criterion on which to free testosterone. However, an
base a diagnosis of elevated androgen level should not be
hyperandrogenemia. considered evidence of
However, testosterone levels increase hyperandrogenism in an otherwise
FIGURE 4 as adolescent anovulatory cycles asymptomatic adolescent with
Upper lip hirsutism scores(Ferriman-Gallwey) lengthen.4 Thus, the few available anovulatory symptoms unless the
in adolescents and adults. Data in relation to data suggest that prolonged hyperandrogenemia and anovulation
menarcheal stage from Lucky et al38; data in
physiologic anovulation accounts for persist. In the absence of the
relation to age from Ferriman and Gallwey.37
Young adult FG scores are normally achieved 2 the half of hyperandrogenemic availability of reliable androgen
years after menarche. anovulatory cycles that resolve assays, moderate-severe hirsutism
1158 ROSENFIELD
TABLE 4 An Acne Scoring System for criteria, current evidence suggests
Adolescentsa that a mean ovarian volume .12 cc
Severity Comedonal Inammatory (or single ovary .15 cc) be
Lesionsb Lesionsc considered enlarged in
Mild 110 110 adolescents.1,4,52
Moderate 1125 1125
Severe .25 .25 PCOM is variably related to
Based on Lucky AW, Biro FM, Simbartl LA, Morrison JA,
hyperandrogenism in adults.1 On one
Sorg NW. Predictors of severity of acne vulgaris in young hand, it is absent in 5% to 20% of
adolescent girls: Results of a ve-year longitudinal study. adult PCOS.1,18,53 On the other, PCOM
J Pediatr. 1997;130:3039; Eicheneld LF, Krakowski AC,
Piggott C, et al. Evidence-based recommendations for
is a common nding among healthy
the diagnosis and treatment of pediatric acne. Pediatrics. women. Many of these women have
2013;131(suppl 3):S163186; Deplewski D, Roseneld RL. mild PCOS features, that is, irregular
Role of hormones in pilosebaceous unit development. FIGURE 5
Endocr Rev. 2000;21:363392. Free testosterone plasma levels in normal menstrual cycles and/or hirsutism.
a Face, chest, shoulders, and back may be graded postmenarcheal adolescent and adult female When care has been taken to exclude
separately. volunteers with normal ovarian morphology those with such symptoms,
b Open (blackheads) or closed (whiteheads) come- (V-NOM) compared with those with polycystic
dones (.1 mm diameter). ovary morphology (V-PCOM) and PCOS. V-NOM approximately one-quarter of
c Pustules, papules (#5 mm) and nodules (.5 mm).
and V-PCOM were healthy eumenorrheic fe- apparently normal adults with PCOM
Scarring should be noted separately. males with no clinical signs of androgen ex- have mild subclinical androgenic
cess. Data on these subjects were previously ovarian dysfunction that is in the
constitutes clinical evidence of reported,1 but PCOM in adolescents has been re-
dened here as mean ovarian volume .12.0 mL, PCOS range (Fig 6); it has been
hyperandrogenism. Moderate-severe
consistent with current consensus. Adoles- postulated that these are carriers of
inammatory acne vulgaris cents (Adol), 1 year postmenarcheal to 17.9 PCOS or at risk for PCOS.
unresponsive to topical medications years of age, were similar to 18- to 39-year-old
is an indication to test for adults in each group. The free testosterone In summary, the uncertainty about
hyperandrogenemia. upper limit reference range (dotted line = 97th appropriate criteria for PCOM in
percentile = 9.3 pg/mL) was based on pooled adolescents is too great to use PCOM
adolescent and adult V-NOM, after excluding
1 outlier whose level was .3.0 SD from the as a diagnostic criterion in
THE QUANDARY OF POLYCYSTIC OVARY mean of the entire group. V-PCOM had signi- adolescents.
MORPHOLOGY IN ADOLESCENCE cantly higher free testosterone than pooled V-
NOM (P = .03). Elevated levels were found in 2
Histopathologically, the polycystic of 6 adolescent and 4 of 30 adult volunteers
ovary is characterized by an excessive with PCOM. To convert to pmol/L, multiply free THE ROLE OF INSULIN RESISTANCE AND
number of small antral follicles that testosterone by 3.47. METABOLIC SYNDROME IN THE
are arrested before the preovulatory DIAGNOSIS OF PCOS
stage of development (which accurate antral follicle count cannot Insulin resistance out of proportion to
accounts for the polycystic be dened by the abdominal that conferred by obesity is variously
appearance), ovarian enlargement, ultrasonographic approach reported in one- to two-thirds of
capsular thickening, and thecal- necessary in virginal adolescents.51 PCOS subjects.5456 Obesity
stromal hyperplasia and For another, even if an accurate prevalence likewise varies widely
luteinization.1 Ultrasonographically, follicle count is obtained by magnetic among populations, averaging
polycystic ovary morphology (PCOM) resonance imaging, the adult criteria approximately 50%.57 The insulin
has been dened in adults by for PCOM overlap with criteria for a resistance of PCOS seems to be
consensus criteria as an ovary with a multifollicular ovary, which is associated with increased abdominal
volume .10.0 mL by a simplied dened by the presence of $6 fat depots independent of BMI,58 and
formula or a small antral follicle (29 follicles of 4- to 10-mm diameter superimposed excess adiposity
mm diameter) count $12 per without increase in ovarian volume further increases all fat depots and
ovary.17,49 However, it has become and is known to be a normal variant insulin resistance.55,59
apparent that these criteria are unrelated to hyperandrogenism.4 Metabolic syndrome, a cluster of
problematic in young adults, Furthermore, although data vary glucose abnormalities, central
particularly because the newer high- considerably, current data suggest (android) obesity, hypertension, and
denition vaginal imaging techniques that ovarian volume is slightly larger dyslipidemia, is the variable result of
show that small antral follicle counts in adolescents than in adults.1,4 insulin resistance interacting with
up to 24 are normal.50,51 Consequently, one-third to half of obesity and age.60,61 Its prevalence is
Adult PCOM criteria are especially normal adolescents meet adult highest in obese subjects.4 It is
problematic when applied to criteria for PCOM.52 Until further present in 25% of adolescents with
adolescents. For one thing, an research establishes denitive PCOS.11,6264 The comorbidity of
1160 ROSENFIELD
TABLE 5 Causes of Androgen Excess in (.1000 ng/dL = 30 nmol/L), an hydroxyprogesterone hyperresponds
Adolescents adrenocorticotropic hormone test is to gonadotropins (indicative of
A. Physiologic adolescent anovulation recommended to conrm the typical FOH): this involves
B. Functional gonadal hyperandrogenism diagnosis of NCCAH.74 administering either a test dose of
1. PCOS/primary functional ovarian
hyperandrogenism (common form of PCOS) Pelvic ultrasonography is seldom gonadotropin-releasing hormone
2. Secondary functional ovarian necessary for diagnosis because agonist or of human chorionic
hyperandrogenism criteria for PCOM in adolescence are gonadotropin and determining the
a. Virilizing congenital adrenal hyperplasia 17-hydroxyprogesterone level 20 to
b. Ovarian steroidogenic blocks
uncertain, as discussed earlier.
However, it is indicated if clinical 24 hours later.
c. Insulin resistance syndromes
d. Acromegaly ndings are suggestive of a virilizing Making a positive diagnosis of FOH by
e. Epilepsy 6 valproic acid therapy tumor (eg, rapid progression, testing ovarian androgenic function
3. Disorders of sex development clitoromegaly, pelvic mass, or a total
4. Pregnancy-related hyperandrogenism
also makes possible another
C. Functional adrenal hyperandrogenism
testosterone level .200 ng/dL) or distinction that is seldom made but
1. PCOS/primary functional adrenal disorder of sex development. In the has practical implications:
hyperandrogenism (uncommon form of absence of tumor, ultrasonography determining whether PCOS is due to
PCOS) can be reassuring evidence that simple obesity, a category of PCOS
2. Virilizing congenital adrenal hyperplasia the cysts of PCOS are not tumor- considered pseudo-PCOS. Excess
3. Other glucocorticoid-suppressible adrenal
hyperandrogenism
related. adiposity itself suppresses ovulation
a. Hyperprolactinemia Currently the only certain way to (via LH suppression) and causes
b. Cortisone reductase deciency hyperandrogenemia (via adipose
differentiate the hyperandrogenemia
c. Apparent dehydroepiandrosterone tissue formation of testosterone from
sulfotransferase deciency of PCOS from that of physiologic
4. Glucocorticoid-nonsuppressible adrenal adolescent anovulation is by the androstenedione).77 Neither an
hyperandrogenism persistence of PCOS into adulthood. ovarian nor adrenal source of
a. Cushings syndrome This is particularly problematic in hyperandrogenism was demonstrable
b. Glucocorticoid resistance by ovarian androgenic function tests
cases with otherwise asymptomatic,
D. Peripheral androgen metabolic disorders
but hyperandrogenemic, adolescents in 10% of our PCOS cases (National
1. Obesity
2. Idiopathic with abnormal menstrual bleeding Institutes of Health criteria), and the
3. Portohepatic shunting patterns: the data reviewed here great majority of these were
E. Virilizing tumors indicate that approximately half of obese.1,14,78 These cases were
F. Androgenic drugs generally characterized by mild
these will remit and the other half
Modied and reproduced with permission from Rosen-
persist as PCOS. The distinction is less elevation of serum free testosterone,
eld RL, Barnes RB, Ehrmann DA. Hyperandrogenism,
problematic in cases with menstrual normal total testosterone, normal LH,
hirsutism, and the polycystic ovary syndrome. In:
Jameson JL, DeGroot LJ, eds. Endocrinology: Adult and irregularity with symptomatic and normal ovarian volume.
Pediatric. 7 ed. Philadelphia: Elsevier; 2015:22752296.
hyperandrogenism, that is, moderate- A fasting lipid panel and oral glucose
severe hirsutism or inammatory tolerance test are advisable for early
laboratory ndings or patient acne: the foregoing data reviewed detection of diabetes mellitus and
preferences may dictate a more here indicate that the great majority metabolic syndrome in PCOS
complete endocrinologic evaluation (perhaps all) will persist as PCOS. patients with obesity or family risk
for rare disorders (Table 5) in some It may be possible to make the factors. Obese PCOS patients should
cases.3,71 distinction between PCOS and also be screened for sleep-
physiologic adolescent anovulation disordered breathing. Evaluation for
The 8 AM 17-hydroxyprogesterone
early by testing ovarian androgenic metabolic syndrome should also be
level requires interpretation; normal
function to diagnose the presence of considered in primary relatives in
random values do not completely
FOH.33 Further research will be view of the familial component(s) of
exclude NCCAH because of marked
PCOS.
diurnal variation. An 8 AM value .200 necessary to test this possibility. Two
ng/dL (6.0 nmol/L) is suggestive of kinds of tests are available (Fig 6). A
NCCAH, although it is also compatible dexamethasone androgen- PRINCIPLES OF TREATMENT OF
with recent ovulation or tumoral suppression test is the most sensitive, ADOLESCENT PCOS
hyperandrogenism.72 This cutoff but least specic, of these tests: The treatment of PCOS is symptomatic
displayed 92% to 98% sensitivity in elevated testosterone post- and is individualized according to
detecting NCCAH73,74 and 12% to dexamethasone indicates a patient complaints and goals. The
25% specicity in discriminating it nonadrenal source, which is usually main considerations in treating
from PCOS.75,76 Thus, unless the 17- ovarian. The more specic adolescent PCOS are menstrual
OHP level achieves a diagnostic level test determines whether 17- irregularity, cutaneous manifestations
1162 ROSENFIELD
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