Puberty, Delayed

Christopher P. Houk MD
Peter A. Lee MD, PhD
Basics
Description
Lack of onset of physical changes of puberty (secondary sex characteristics)
by age 13 years or failure to reach menarche by age 14.5 years. An abnormally
slow pubertal pace after onset at a normal age may also be considered delayed.
The time between initial breast development and menarche averages 2.5 years,
and the total duration of puberty ranges from 45 years. Most girls with
pubertal delay have pathology.

May suggest hypothalamic-pituitary defect (hypogonadotropism) or gonadal

failure (hypergonadotropism):
o

Most common form is Turner syndrome, which may be diagnosed

before the age of puberty by characteristic findings at birth of because
of short stature:

Turner syndrome is associated with karyotypes, including loss

of key portions of 1 X chromosome, and the loss of the SHOX
gene.

May simply be a delay in normal development:

o

Constitutional

Secondary to chronic illness

Age-Related Factors
Ethnic differences exist:
White: If no breast development by age 13 or pubic hair by 13.2
African American: If no breast development by age 12.4 or pubic hair by 12.8

Latina: If no breast development by age 12.8 or pubic hair by 13.4

Alert
For all above ethnicities, menarche is considered to be delayed if it has not occurred
by age 14.5.
Epidemiology
General prevalence is unknown:
Kallmann syndrome is the most common form of permanent
hypogonadotropism in 1/50,000 females.
Turner syndrome occurs in 1/2,500 female births.
Risk Factors
Differ based on category:
Constitutional delay: Family history
Delay with normal potential: Chronic disease

Hypogonadotropism: Anosmia, pituitary hormone deficiency, brain tumor,

CNS-radiation

Hypergonadotropism: Turner syndrome, gonadal defects (anatomic/enzyme)

(disorders of sex development), gonadal radiation, chemotherapy

Genetics
Differ based on category:
Constitutional delay: Multifactorial
Hypogonadotropism: X-linked, autosomal dominant, autosomal recessive

Kallmann syndrome: Kal1 (Xp22.3) and Kal2 gene (8p12) autosomal

dominant form

Other mutations resulting in hypogonadotropic hypogonadism are:

DAX-1 gene (Xp21) (also associated with X-linked adrenal hypoplasia

congenita)

PROP-1 gene mutations, Prader-Willi syndrome

HESX1 (septo-optic dysplasia)

GnRH receptor mutations (4p13.1)

Hypergonadotropism:
o

Turner syndrome

Noonan syndrome

Bardet-Biedl syndrome

Leptin and leptin receptor gene mutations

Homozygous GALT enzyme gene (9p13) resulting in galactosemia

Pathophysiology
Hypogonadotropism secondary to damage to the hypothalamus, pituitary or
surrounding areas
Hypergonadotropism secondary to damage to or defects in ovaries

Delay with potential for normal pubertal development:

o

Malnutrition (anorexia nervosa)

Excessive exercise

Chronic disease

Inflammatory process (e.g., Crohn's disease)

Hypothyroidism

Hypogonadotropism:
o

Midline CNS defects (septo-optic dysplasia)

Hemochromatosis

HIV

Craniopharyngioma and other tumors

Head trauma

Surgery

Infections and infiltrative diseases

Associated Conditions
Hypogonadotropic hypogonadism is associated with other anterior pituitary
deficiencies (GH, TSH, ACTH).
Diagnosis
Signs and Symptoms
History
General health and growth
Radiation or chemotherapy exposure

Psychiatric disease or disordered eating (anorexia)

Intense exercise

Family history of age of onset of puberty and menarche

Review of Systems
Anosmia
Symptoms of hypothyroidism

Headaches

Learning difficulties

Physical Exam
Height, weight, BMI, upper-lower segment ratio (from sitting and standing
height)
Pubertal staging and genital inspection

Neurologic examination including funduscopic examination and visual fields

Assessment of subcutaneous fat, thyroid gland

Assessment for findings of Turner syndrome including characteristic facies,

micrognathia, epicanthal folds, low-set ears, low hairline, webbed neck,
prominent nevi, cubitus valgus, short 4th metacarpal, spoon-shaped nails, and
shield chest

Tests
Skeletal (bone) age x-ray
Labs
Serum LH, FSH, estradiol

GnRH or GnRH analog stimulation testing is usually not discriminatory at

presentation with delayed puberty.
o

Such a test can be used if bone age is advanced beyond the age of
pubertal onset or after lack of progression of spontaneous puberty to
verify low gonadotropin response.

Others based on history and physical findings to include DHEA-S,

prolactin, ACTH, 24-hour urine free cortisol, IGF-1, TSH, free T4,
CBC, electrolytes, liver functions, ESR, and karyotype

Imaging
MRI if intracranial mass suspected
Pelvic US for ovarian/uterine volume and description of endometrial stripe
Differential Diagnosis
Generally, since skeletal age reflects biologic age, if the bone age is >10.511
years, the hypothalamic axis should be activated:
o Hence, if gonadotropin levels are low, this suggests
hypogonadotropism.
o

When gonadotropins are elevated, this indicates hypergonadotropism

(gonadal failure).

If skeletal age is <10.5 years, biologic immaturity is suggested, either

constitutional or secondary to a chronic illness.

In cases of primary amenorrhea, a discordance between ample breast and

paucity of pubic hair development may suggest androgen insensitivity.

P.37
Differential of delayed puberty based upon the following categories:
Hypogonadotropic hypogonadism: Hypothalamic (GnRH) and pituitary (LH,
FSH) synthesis and secretory defects:
o Defects of GnRH secretion:

Idiopathic hypogonadotropic hypogonadism (IHH) (1/3

familial, 2/3 sporadic)

Kallmann syndrome, associated with anosmia

Hypergonadotropic hypogonadism: Hypothalamic-pituitary axis functional but

no negative feedback by sex steroids indicates ovarian disease and is always
pathologic.
o

Turner syndrome

Autoimmune

Mutations in gonadotropin (FSH, LH) genes or gonadotropin receptor

genes

Galactosemia

Irradiation:

Depends on age of exposure (prepubertal less susceptible),

dosage (>6 Gy associated with permanent ovarian failure) and
type of chemotherapy (cyclophosphamide, busulfan,
procarbazine, etoposide)

Infectious disease (mumps, Shigella, malaria, Varicella)

Infection
HIV infections cause both hypo- and hypergonadotropic hypogonadism (see above for
other infections associated with hypergonadotropic hypogonadism).
Hematologic
Hemochromatosis may damage either the pituitary and/or the ovary resulting in
hyper- or hypogonadotropic hypogonadism.
Metabolic/Endocrine
All categories of delayed puberty are a consequence of diminished function of the
HPO axis, either due to low gonadotropins (pituitary or hypothalamic defects) or low
sex steroids (ovarian dysfunction). Hyperprolactinemia results in hypogonadotropism.
Immunologic
Autoimmune disease may cause hypergonadotropic and hypogonadotropic
hypogonadism.
Autoimmune polyglandular syndromes (APS): Ovarian failure
(hypergonadotropism) occurs >50% of those with Type I (Addison's disease,
hypoparathyroidism, mucocutaneous candidiasis) and 10% with type II
(Addison's, autoimmune thyroid disease, type 1 diabetes mellitus). Presence of
side chain cleavage enzyme autoantibodies in type 1 APS is a strong predictor
of ovarian failure.

Pituitary hypophysitis may be associated with hypogonadotropism.

Tumor/Malignancy
Prolactinomas
Craniopharyngioma
Trauma
Head trauma or severe abdominal/pelvic trauma can destroy the hypothalamic GnRH,
pituitary LH and FSH, or ovarian sex steroid synthesizing ability.
Drugs
Chemotherapeutic drugs are associated with hypogonadism, particularly ovarian
function.
Management
General Measures
1st step is to establish pubertal delay by age, tempo, or developmental cutoffs.
Subsequent evaluation aimed at eliminating pathologic causes.
Medication (Drugs)
Induction of puberty using progressive doses of estrogens, generally starting
with lowest available dosage
May benefit from Provera withdrawal if normal endometrial stripe

Progestational agent is added if breakthrough bleeding occurs or after 11.5

years of estrogen therapy if uterus is present. OCP preparation may be used.

Surgery
As appropriate for brain tumors
Followup
Disposition
Issues for Referral
When underlying cause of delay is not apparent, or if there is no evidence of
progression of puberty after skeletal age of 11 years is reached, referral is appropriate.
Prognosis
All girls with hypergonadotropism will have progressive and permanent
ovarian failure.
Outcomes in girls with hypogonadotropism depend on underlying etiology.

Assisted fertility may be possible among those with hypogonadotropism with

hormonal therapy for ovulation induction and among those with
hypergonadotropism who have a competent uterus with egg donation.

Note that patients with Turner syndrome may have cardiovascular risks
making pregnancy unwise.

Patient Monitoring
Patients receiving pubertal induction using progressive doses of estrogens
should be monitored at intervals of 46 months.
Once a diagnosis of permanent hypogonadism has been made, response to
therapy and dosage adjustment is based primarily upon findings of history and
physical exam.
Bibliography
Reindollar RH, et al. Delayed sexual development: A study of 252 patients. Am J
Obstet Gynecol. 1981;140:371380.
Sedlmeyer IL, et al. Delayed puberty: Analysis of a large series from an academic
center. J Clin Endocrinol Metab. 2002;87:16131620.
Miscellaneous
Clinical Pearls
Referral center percentages of categories among girls presenting with pubertal delay:
30% constitutional delay
19% delay with normal potential because of systemic disease
20% hypogonadotropic hypogonadism
26% hypergonadotropic hypogonadism
5% other causes
Alert
In the majority of instances, pubertal delay in girls is not a benign entity.
Often, time is the only method to verify whether hypogonadism or delay of pubertal
hormone secretion is present.
In a healthy patient, the maturing HPO axis will:
Become manifest in the patient with the potential for puberty
Or gonadotropins will become elevated, verifying hypergonadotropism

 It is possible within months after oncology therapy (chemotherapy and radiation

therapy) that somewhat elevated gonadotropin levels suggest gonadal failure:
If permanent failure is present, such levels continue to rise.
Occasionally, normal levels suggest restoration of gonadal function. Such patients
are clearly at risk of hypogonadism.
Some patients with Turner syndrome, usually with mosaic karyotypes, may have
ovarian function adequate for normal puberty.
Abbreviations
ACTHAdrenocorticotropic hormone
DAX1Dosage sensitive sex reversal-adrenal hypoplasia congenita gene on the X
chromosome, gene 1
DHEASDehydroepiandrosterone sulfate
FSHFollicle stimulating hormone
GALTGalactose-1-phosphate uridyltransferase
GHGrowth hormone
GnRHGonadotropin-releasing hormone
HPOHypothalamic-pituitary-ovarian
IGF1Insulin-like growth factor 1 (aka Somatomedin C)
LHLuteinizing hormone
OCPOral contraceptive pills
TSHThyrotropin-releasing hormone
Codes
ICD9-CM
253.2 Hypopituitarism
256.3 Ovarian failure
259 Delayed puberty
307.1 Anorexia
626 Amenorrhea
758.6 Turners syndrome
Patient Teaching
Inform the patient and her parents by disclosing knowledge of delayed puberty,
together with an explanation of pubertal development and causes of delay using
appropriate language.
Consequences of hypogonadism and therapies should be discussed, including the
fact that physical development and sexual function can be expected to become normal
with hormonal therapy.
Discuss fertility options.