Download “Approved” on the meeting of methodical board Department of

“Approved”
on the meeting of methodical board
Department of Obstetrics and Gynaecology
with the Course of Infantile and Juvenile Gynaecology
dated “__”_________ 20__, minutes № __
Deputy Chief, DMS ___________ professor O.A.Andriiets
Methodological Instructions №4
to organize independent student’s work on the topic:
“Abnormalities of sexual development of girls. Classification, clinical picture,
diagnostics and principles of treatment”
Subject:
Infantile
Gynaecology
Year: VI
Faculty: Medical
Number of hours: 2
and
Juvenile
Methodical instructions compiled by:
assistant lecturer Rak L.M.
Chernivtsi - 2008
I. Topic: Abnormalities of sexual development of girls. Classification, clinical
picture, diagnostics and principles of treatment
II. Class duration – 4 hours.
III. Educational objectives:
The student must know:
1. Special methods of examination in girls with abnormalities of sexual
development.
2. Deontology of communication with patients with such pathology in juvenile
age.
3. Estimate data of general clinical, special, hormonal, roentgenological,
medical and genetic examination of girls with abnormalities of sexual
development.
The student must be able to:
 Examine of a patient with abnormalities of sexual development.
 Make diagnostics and treatment.
 Interpret data of clinical and laboratorial and instrumental examination.
IV. Advice to the student.
Disorders of Puberty

Delayed Puberty
o Delay of puberty can be caused by anatomic abnormalities,
chromosomal disorders, neoplastic growths, or nutritional
deficiencies.
o Commonly presents as a physical delay in maturation combined with
amenorrhea.
o Causes of delayed puberty can be classified, based on the level of
follicle stimulating hormone (FSH) present, as outlined in Table 30.5.
o Hypergonadotropic Hypogonadism (High FSH)
A sufficient amount of gonadotropins are present, but the end organs
are not responsive and therefore do not produce sex steroids.

Gonadal dysgenesis

Present as phenotypic female with persistent prepubertal
development. Usually lack breast development.

May have some secondary sex characteristics and
spontaneous menstruation. Most often associated with
primary amenorrhea.
Table 30.5 An Overview of Causes of Delayed Puberty
FSH
Differential
Level Diagnosis
High >30

mIU/mL Gonadal dysgenesis syndromes: Turner's syndrome,
Sweyer's syndrome

Primary ovarian failure
Low <10
 mIU/mL Constitutional delay

Intracranial neoplasms

Isolated gonadotropin deficiencies

Hormone deficiencies

Kallmann syndrome

Prader-Labhart-Willi syndrome

Laurence-Moon-Biedl syndrome

Chronic disease and malnutrition
Normal
Anatomic deformities result in normal development with primary
amenorrhea.
Imperforate hymen
Transverse vaginal septum
MГјllerian agenesis




o
Turner syndrome (45, X) is most commonly associated
with gonadal dysgenesis. Occurs in 1 in 2,000 to 2,500
born girls and is present in approximately 6% of all
spontaneous abortions (3).
 Sweyer syndrome(46, XY) is also associated with
gonadal dysgenesis, but patients often have a normal-totall stature. Most often related to a mutation or structural
abnormality of the Y chromosome. Must remove gonads.
 Primary ovarian failure
 Ovaries develop but do not contain oocytes; may be
associated with chemotherapy, radiation, galactosemia,
gonadotropin resistance, autoimmune ovarian failure, or
ovarian failure secondary to previous infection.
 Treatment involves administration of exogenous estrogen
and progesterone to avoid osteoporosis and to facilitate
development of secondary sexual characteristics.
Hypogonadotrophic Hypogonadism (Low FSH)
An insufficient level of gonadotropins is present to permit follicular
development and therefore sex steroids are not produced.

Chronic disease of malnutrition: Conditions including states of
malnutrition, including starvation, anorexia nervosa, cystic
fibrosis, Crohn's disease, diabetes mellitus, inflammatory
o
disease, and hypothyroidism, are thought to lead to a disruption
of gonadotropin-releasing hormone GnRH production,
therefore resulting in pubertal delay (4).
 Constitutional delay: A delay in the (GnRH) pulse generator
postpones the normal physiologic events of puberty.
 Intracranial neoplasms: Both craniopharyngiomas and pituitary
adenomas may cause delayed puberty. Visual symptoms are
often associated with these tumors, as is short stature and
diabetes insipidus. Diagnosis is by CT or MRI of the head.
Treatment includes either surgical excision or radiotherapy.
 Isolated gonadotropin deficiencies: often secondary to
abnormalities in genes encoding proteins related to GnRH,
FSH, or leutinizing hormone (LH) (3).
 Hormone deficiencies: Any aberration of growth hormone or
thyroid hormone levels will affect puberty. Therefore, these
levels should be investigated and treated appropriately. In
addition, hyperprolactinemia can cause a decrease in levels of
FSH and LH and thus delay puberty.
 Kallmann syndrome: A sporadic or X-linked syndrome with a
classic triad of anosmia, hypogonadism, and color blindness.
The hypothalamus cannot secrete GnRH due to dysfunction in
the arcuate nucleus. Few or no secondary sexual characteristics
are present.
 Prader-Labhart-Willi syndrome: an autosomal dominant
condition associated with extreme obesity, emotional
instability, and delayed puberty secondary to hypothalamic
dysfunction (4).
 Laurence-Moon syndrome: a rare autosomal disorder associated
with retinitis pigmentosa, hypogonadism, and spastic paraplegia
(4).
 Bardet-Biedl syndrome: a rare autosomal recessive disorder
associated with retinitis pigmentosa, hypogonadism, and
postaxial polydactyly (4).
Eugonadism (Normal FSH)
In cases of eugonadism, the hypothalamic-pituitary-gonadal axis
remains intact, and delay of puberty presents with primary
amenorrhea related to anatomic abnormalities in the genitourinary
tract, androgen insensitivity, or inappropriate positive feedback
mechanisms.

Anatomic abnormalities of the genitourinary tract resulting in
primary amenorrhea:
 Imperforate hymen: may be evident in a neonate and may
regress as the girl enters childhood. After menarche, the

imperforate hymen may become evident when
accumulating menstrual blood forms a hematocolpos and
may present as an abdominal mass. Surgical intervention
is required to incise the hymen and allow stored debris to
escape.
 Transverse vaginal septum: due to failure of canalization
of mГјllerian tubules and the sinovaginal bulb, leaving a
membrane present. May be associated with urinary tract
abnormalities as well. If the membrane is thin, it can be
incised and dilated. If it is thick, surgical excision with a
split thickness skin graft may be required.
 MГјllerian agenesis: failure of the mГјllerian tract to
develop results in a blind vaginal pouch without uterus or
fallopian tubes present. Ovaries are present and function
normally and, therefore, puberty progresses as usual with
primary amenorrhea as a presenting complaint. This must
be distinguished from androgen insensitivity, as
described later. One-third of these patients have
associated urinary tract anomalies, and 12% have skeletal
anomalies. A neovagina can be created by progressive
dilation or surgery.
 Vaginal atresia: The lower vagina is replaced by fibrous
tissue; differentiated from mГјllerian agenesis by the
presence of normal uterus and fallopian tubes.
 Androgen
insensitivity: discussed later under male
feminization. Karyotype XY males present as phenotypic
females with a blind vaginal pouch secondary to an insensitivity
of circulating androgens.
 Other causes of primary amenorrhea with eugonadism include
anovulation, androgen producing adrenal disease, and
polycystic ovarian syndrome.
Precocious Puberty
o Precocious puberty is a rare condition that occurs in only 1 of 10,000
girls (5).
o Defined as evidence of secondary sexual characteristics, including
breast or pubic hair development at an age more than 2.5 standard
deviations below the mean (5).
o According to a recent study, such findings should be investigated in
African American girls under age 6 and Caucasian girls under age 7
(6).
o Characteristic accelerated growth velocity in combination with rapid
bone growth and maturation can result in short adult stature (7).
o Common causes of precocious puberty can be divided into GnRHdependent disorders, or true or central precocious puberty, versus
GnRH-independent disorders, or pseudoprecocious puberty.
o
o
Central Precocious Puberty
 Most commonly idiopathic; secondary sexual characteristics
progress in normal sequence but more rapidly than in normal
puberty, and may fluctuate between progression and regression.
 Related to premature development of the hypothalamicpituitary axis and is therefore GnRH-dependent, but the
initiating cause is unknown (5).
 May be transmitted in an autosomal recessive fashion, so check
family history.
 Often ovarian follicular cysts are present due to elevated levels
of LH and FSH (5).
 Other causes of central precocious puberty involve central
nervous system disease:
 Disease
often involves areas surrounding the
hypothalamus; mass effect, radiation, or ectopic GnRH
secreting cells are thought to cause premature activation
of pulsatile secretion of GnRH from the hypothalamus.
 Diagnosis by CT or MRI of the head; history may be
significant for headache, mental status changes, mental
retardation, dysmorphic syndromes, along with the
premature
development
of
secondary
sexual
characteristics.
 Treatment should be directed at the underlying cause; the
location of many of such tumors makes resection
difficult, and, as a result, chemotherapy or radiation may
be involved.
 GnRH agonist administration can result in a short burst of
gonadotropin release followed by down-regulation and
desensitization resulting in an overall decrease in the level of
circulating gonadotropins. Follow estradiol levels to make
appropriate dose adjustments (8).
Pseudoprecocious Puberty
 Premature development of secondary sexual characteristics
occurs by a GnRH-independent mechanism.
 Differential diagnosis includes estrogen-secreting tumors,
benign follicular ovarian cysts, McCune-Albright syndrome,
Peutz-Jeghers syndrome, adrenal disorders, and primary
hypothyroidism.
 Estrogen secreting ovarian tumors
 Granulosa cell tumors (60%): usually >8 cm in size; 80%
are palpable on abdominal examination; others include
arrhenoblastomas, thecomas, lipid cell tumors, teratomas,
or choriocarcinomas.
Diagnose by sonography, manage surgically with
adjuvant chemotherapy, if indicated, and follow by
estradiol levels.
Benign follicular ovarian cysts
 Most common form of estrogen-secreting masses in
children
 May require a diagnostic laparoscopy versus exploratory
laparotomy to differentiate from a malignant tumor.
Removal of the cyst may be therapeutic.
McCune-Albright syndrome
 Triad: cafГ© au lait spots, polyostotic fibrous dysplasia,
and cysts of skull and long bones; precocious puberty is
present in 40% (9).
 Sexual precocity results from recurrent follicular cyst.
Removal of cyst is not helpful.
 Aromatase inhibitors (i.e., testolactone) may help
symptoms.
 Evaluate with serial pelvic sonograms to detect the
presence of gonadal tumors.
Peutz-Jeghers syndrome
 Commonly
characterized
by
mucocutaneous
pigmentation and GI polyposis
 Also associated with rare sex cord tumors, including
epithelial tumors of the ovary, dysgerminomas, or
Sertoli-Leydig cell tumors, whose estrogen secretion may
result in feminization and incomplete sexual precocity
 Girls with Peutz-Jeghers syndrome should be screened
with serial pelvic sonograms.
Adrenal disorders
 Some adrenal adenomas have been noted to secrete
estrogen alone and may therefore give rise to sexual
precocity.
Primary hypothyroidism
 Characterized by premature breast development and
galactorrhea without an associated growth spurt
Key points in evaluation and management of precocious
puberty
 Perform a detailed evaluation with Tanner staging.
 Laboratory data should include LH, FSH, estradiol,
progesterone, 17-hydroxyprogesterone, DHEA, DHEAS,
TSH, T4, hCG (5).
 A GnRH stimulation test would provide a definitive
diagnosis of central precocious puberty (5).











Obtain an x-ray to determine bone age. Head CT or MRI
can rule out an intracranial mass. Abdominal/pelvic
ultrasound can be used to evaluate the ovaries (5).
Goals for management include maximizing adult height
and delaying maturation until a normal age of puberty.
Treat the intracranial, ovarian, or adrenal pathology if
present and attempt to reduce associated emotional
problems (8).
Male Feminization
o Genetic males (XY) undergo feminization related to androgen
insensitivity.
o Complete androgen insensitivity, or “testicular feminization”
(10).
 Transmitted in a maternal X-linked recessive fashion
 Pathophysiology: Androgen presence is unable to induce the
Wolffian duct to mature and, as a result, seminal vesicles, vas
deferens, and epididymis do not form. AntimГјllerian hormone
is present so mГјllerian duct formation remains inhibited such
that uterus, cervix, and fallopian tubes do not form either. The
resulting phenotype is female, with a vagina derived from the
urogenital sinus that ends in a blind pouch, and testes that often
descend through the inguinal canal.
 Clinical presentation: primary amenorrhea, Tanner stage V
breast development, scant axillary and pubic hair
 Management: gonadectomy is recommended secondary to an
increased incidence of malignancy; exogenous estrogen therapy
is also recommended.
o Incomplete androgen insensitivity (10)
 Less common with presentation ranging from near complete
masculinization to near complete failure or virilization.
 As minimal sensitivity to androgens is present, the Wolffian
duct system develops to some extent, although spermatogenesis
usually remains absent.
 Physical exam may include a range of clitoromegaly or
ambiguous genitalia.
 Sex assignment depends on the degree of masculinization
present; if a male sex assignment is made, caution should be
taken because gynecomastia may occur during puberty, if
androgen receptor presence is inadequate.
o 5-alpha reductase deficiency is a condition in genotypic males (XY)
who are phenotypically female in the prepubertal state and become
phenotypic men at puberty. No breast development is present, which
distinguishes this condition from androgen insensitivity. Normal
testicular function is present.
Female Virilization
o
o
o
o
Genetic females (XX) are exposed to increased androgen levels that
lead to inappropriate virilization, most often an indicator of organic
disease in girls.
Virilizing congenital adrenal hyperplasia (CAH): most commonly
associated with deficiency of 21-hydroxylase, an autosomal recessive
disorder. Many present as the newborn girl with ambiguous genitalia
and possible associated salt-wasting due to mineralocorticoid
deficiency. Virilization may also be delayed until later childhood,
related to androgen excess at that time (11).
Cushing's disease: may result from an adrenal carcinoma and may
manifest as growth failure, with or without virilization, obesity, striae,
or moon facies.
Ovarian tumors: arrhenoblastoma is the most common virilizing
ovarian tumor. Others include lipoid cell tumor and gonadoblastoma.
VIII. Premature Thelarche






Definition: bilateral breast development without other signs of sexual
maturation in girls before age 8 (12).
Commonly occurs by age 2 and is rare after age 4.
The etiology behind premature thelarche is unclear, but an exogenous
estrogen source must be excluded. Not known to be associated with central
nervous system pathology and is not known to be a familial condition. The
mechanism is thought to be related to a temporary activation of the
hypothalamic-pituitary-gonadal axis with increased FSH secretion (12).
Upon finding during physical examination, precocious puberty must be ruled
out:
o Document the appearance of the vaginal mucosa, breast size, and
presence or absence of a pelvic mass on pelvic/rectal examination.
o Determine bone age with radiographic imaging; should be within
normal range in premature thelarche and advanced in precocious
puberty.
o Pelvic sonography should demonstrate a normal prepubertal uterus.
o Plasma estrogen levels may be mildly elevated, but dramatic
elevations suggest another etiology. Stimulated responses of LH and
FSH may be obtained and are both generally elevated in precocious
puberty, whereas only stimulated FSH is elevated in premature
thelarche (12).
Also, review recently used medications and topical creams as application of
topical conjugated estrogens (Premarin) for longer than 2 to 3 weeks, which
may result in breast changes.
Prognosis: In idiopathic cases, a regression in breast enlargement often
occurs after a few months but may persist for several years. In
approximately 50% of patients, breast development can last 3 to 5 years.
V. Self-assessment tasks:
1. What is premature development?
2. Methods of diagnostics of premature sexual development.
3. Make a plan to treat the patient with premature sexual development.
4. What is sexual development delay? Clinical picture.
5. Methods of diagnostics and treatment of syndrome of sexual development
delay.
VI. Literature.
1. American Academy of Pediatrics Committee on Quality Improvement,
Subcommittee on Urinary Tract Infection. Practice Parameter: The diagnosis,
treatment and evaluation of the initial urinary tract infection in febrile infants and
young children. Pediatrics 1999;103;4:843–852.
2. Sanfilippo JS. Pediatric and Adolescent Gynecology, 2nd Ed. Philadelphia: WB
Saunders, 2001:227–231.
3. Reiter EO, Lee PA. Adolescent endocrinology: delayed puberty. Adolesc Med
2002;13 (1):101–118.
4. Larsen PR. Williams Textbook of Endocrinology, 10th Ed. Elsevier,
2003:1171–1202.
5. Stenchever MA. Comprehensive Gynecology, 4th Ed. Mosby, 2001:280–288.
6. Kaplowitz PB. Reexamination of the age limit for defining when puberty is
precocious in girls in the United States: implication for evaluation and treatment.
Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric
Endocrine Society. Pediatrics 1999;104 (4 Pt 1):936–941.
7. Antoniazzi F, Zamboni G. Central precocious puberty: current treatment
options. Paediatr Drugs 2004;6 (4):211–231.
8. Speroff L, Glass RH, Kase NG. Clinical Gynecologic Endocrinology and
Infertility, 5th Ed. Baltimore: Williams & Wilkins, 1994:380–382.
9. Eugster EA, Rubin SD, Reiter EO, et al. Tamoxifen treatment for precocious
puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr 2003;143
(1):60–66.
10. Speroff L, Glass RH, Kase NG. Clinical Gynecologic Endocrinology and
Infertility, 5th Ed. Baltimore: Williams & Wilkins, 1994:340–342.
11. Sanfilippo JS. Pediatric and Adolescent Gynecology, 2nd Ed. Philadelphia:
WB Saunders, 2001:277–287.
12. Sanfilippo JS. Pediatric and Adolescent Gynecology, 2nd Ed. Philadelphia:
WB Saunders, 2001:605–608.