Approach to

Sex Disorder
Sithakom Phusanti, MD
27th September 2012

What do internists need to know?

Amenorrhea
Hirsutism
Delayed puberty
Hypogonadism
Gynecomastia
Male pseudohermaphrodite
Female pseudohermaphrodite
Ambiguous genitalia

History taking
Infantile: Birth weight
Maternal drugs use
Family history
Sex appearance, genitalia at birth
Puberty: Second sex characteristic
Breast development, growth spurt
Growth hairs, voice changes
Menarche and menstruation
Ejaculation and morning erection
Adulthood: Menstruation, Libido, Hairs,
Erection, Ejacuation, gynecomastia

Physical examination

Height, Arm span ? Eunuchoid appearance

Breast development, gynecomastia
Hair: axillary, pubic hairs
Genital examination:
clitoris, intactness of the hymen, depth of the vagina,
and presence of a cervix, uterus, and ovaries
Penis, urethra opening, median raphe, urogenital tract

Abnormal sign: virilization, hirsutism, acne

Classic physical features of Turner
syndrome.

How to measure arm span?

facing away from the
wall
back and buttocks
touching
the arms are
stretched out
horizontally.
Measure from one
furthermost finger tip
to the other.

Eunuchoid Proportion
Defects in estrogen
synthesis/estrogen
receptor deficiency
Delayed epiphyseal
fusion and lack a
pubertal growth
spurt
Decreased
upper/lower
segment ratio
Increased height

Eunuchoid Appearance
Hypogonadism start before
putertal period
Arm span > height >/= 2 cm
Lower > upper part >/= 2 cm

Tanners Staging
Testes, scrotum, penis-same size&
proportion as in early childhood
Vellus over the pubic region is not
further developed than that over the
abdominal wall( = no pubic hair).

Growth of the penis has occurred, at

first mainly in length but with some
increase in breadth
Hair is considerably darker, coarser,
and curlier and spreads sparsely over
the junction of the pubes.

Genitalia are adult in size and shape.

Hair is adult in quantity and type,
distributed as an inverse triangle.
The spread is to the medial surface of
the thighs but not up the linea alba or
elsewhere above the base of the
inverse triangle.
Most men will have further spread of
the pubic hair.

Scrotum and testes have enlarged;

the scrotal skin shows a change in
texture and also some reddening.
Sparse growth of long, slightly
pigmented, downy hair, straight or
slightly curled, appearing chiefly at
the base of the penis.

Penis is further enlarged in length

and breadth with development of
the glans. The testes and scrotum
are further enlarged. The scrotal
skin has further darkened.
Hair is now adult in type, but the
area it covers is still considerably
smaller than in most adults. No
spread to the medial surface of the
thighs.

Praders orchidometer
Andreas Prader
Pediatric endocrinologist,(University of Zurich) 1966

String of twelve numbered wooden or plastic

beads of increasing size from about 1 to 25 ml
Prepubertal sizes; 13 ml
Pubertal sizes;

4 ml

Adult sizes;

1225 ml

Tanners Staging
No glandular tissue

Glandular tissue
not more than areola

Glandular tissue more than areola

Same contour of areola and breast
Secondary mound
of areola and papilla

Areola returns to contour of breast,

with a projecting central papilla.

Gynecomastia
Glandular breast tissue > 4 cm
in diameter
DDx from lipomastia
Glandular tissue is firmer
Contains fibrous-like cords

Normal physiologic finding

Newborn, during puberty, aging

Pathologic conditions
Androgen deficiency or estrogen
excess

The relative risk of breast

cancer is increased in men with
gynecomastia

Enlargement of the male breast

Pathologic Gynecomastia
1. Androgen deficiency/ Androgen insensitivity
Increased estrogen/androgen ratio
Aromatization of residual adrenal and gonadal androgens.

2. Excess estrogen production

Sertoli cell tumors in isolation or in asso. with Peutz-Jegher synd or
Carney complex.
Tumors that produce hCG, stimulate Leydig cell estrogen synthesis

3. Increased conversion of androgens to estrogens

Increased availability of substrate (androstenedione) for extraglandular
estrogen formation (CAH, hyperthyroidism, and most feminizing adrenal
tumors)
Diminished catabolism of androstenedione (liver disease)

4. Drugs
Acting directly as estrogenic substances (e.g., oral contraceptives,
phytoestrogens, digitalis)
Inhibiting androgen synthesis (e.g., ketoconazole), or action (e.g.,
spironolactone)

Evaluation of gynecomastia

Treatment of Gynecomastia
Treatment of primary cause
Surgery
Indications for surgery
Severe psychologic and/or cosmetic problems
Continued growth or tenderness
Suspected malignancy

Antiestrogens; tamoxifen (20mg/d)

Aromatase inhibitors; anastrozole

Amenorrhea
Definition
-Primary (failure of menarche)
by 16 Y with 2nd sex
By 13 Y in without 2nd sex or short stature

-Secondary
Absence of menstruation for 6 months in a
woman with previous periodic menses.
(rule out congenital anatomic defect)

Physiology of menstruation

PRIMARY AMENORRHEA
1. Central levels CNS congenital anomaly
GnRH gene mutation, Kallmans
syndrome
Hypothalamic pituitary tumor
Prolactinoma
2. Gonad levels Chromosome abnormality:
turners syndrome, testicular
feminization, True hermaphrodite,
XX male syndrome
Gonadal agenesis
Gonadal dysgenesis
17- OHlase defeciency.

SECONDARY AMENORRHEA
Hypothalamic pituitary tumor
Prolactinoma

Primary ovarian failure

Chemotherapy
Post oopherectomy

3. Outflow tract
disease

Imperforate hymen
Mullerlian agenesis

Pregnancy
Uterine synechiae

4. Chronic
anovulation

Hypothalamic amenorrhea
PCOS
Prolactinoma

Hypothalamic amenorrhea
PCOS
Prolactinoma

Other hormones
Cushing syndrome, CAH, Hypothyroidism

Approach to secondary amenorrhea

Progesterone challenge test
+
FSH, (E2), TSH, Prolactin
FSH

Ovarian
failure

TSH

PRL

FSH, TSH, PRL

Thyroid
Hyer
Pituitary
disease PRLmia Hyperandrogenemia

Progesterone challenge test

Withdrawal
bleeding

No withdrawal
bleeding

Chronic anovulation , normal E2

Testosterone, DHEA-S,17 OH progesterone

T,DHEA-S,LH T,DHEA-S
mild
PCOS

17-OHP

nl T,DHEA-S

CAH

Hypothalamic
anovulation

marked
Androgensecreting tumor

Progesterone challenge test

No withdrawal
bleeding

Est,progest.challenge test
Withdrawal
bleeding
hypoestrogenic
Hypothalamicpituitary failure

No

outflow tract
obstruction

Secondary sex characteristic

E

No ( normal cervix and

uterus)
FSH

Hypothalamuspituitary

Gonodal failure
Turner syndrome

Constitutional delay

Gonadal dysgenesis

Kallman syndrome

Enzymatic defect of
gonad; CAH

Genetic defect

Secondary sex characteristic

Yes
Pubic hair
Yes

PV

No
Androgen
insentivity
syndrome

Uterus
Imperforate
hymen

Yes
PCOS, anovulation,
,
thyroid, PRL

No
Mullerian
agenesis

Hermaphrodite
Male pseudohermaphrodite
XY

Female pseudohermaphrodite
XX

Hirsutism

Ferriman-Gallwey score

Vellus

Terminal

Masculinization
Male hair pattern
Increased pectoral
musculature
Huskiness of the voice

Virilization
Masculinization and
Clitoromegaly (length >10 mm or an index
2
(WxL) >35 mm is considered above
normal, JCEM 2012 > 4 mm)

Drugs induced Hirsutism

Androgenic medications

Testosterone
Danazole
ACTH
Metyrapone
Phenothiazine

Anabolic steroids
Androgenic progestins
Levonorgestrel
Norgestrel
Norethindrone

Acetazolamide
Valproic acid

Nonandrogenic medications

Cyclosporine
Phenytoin
Diazoxide
Minoxidil
Minocycline
High-dose glucocorticoids
Hexachlorobenzene
Penicillamine
Psoralens

Genital ambiguity

Hypospadia*

Clitoromegaly
Hyperpigmentation

* A single opening at the base of the phallus

Genital ambiguity

Urogenital sinus

*internal connection between the vagina and urethra.

Disorders of Puberty
Puberty
Boy: testicular enlargement with rugae
formation
Girl: breast development

Puberty is precocious if
Testicular enlargement at age 9
Breast or pubic hair present at age 8
(new criteria prefer 7 in white or age 6 in black)

Puberty is delayed if
No testicular enlargement by age 14 in boys
No breast development by age 13 in girls

Disorder of the Testes

and Male Reproductive System

Chromosome Y

SRY

Testicular descent
is controlled in part by Leydig cell production of INSL3,
which acts via a receptor termed Great

SRY= Sex determining region of the Y

Puberty
GnRH pulse generator
GPR54
Leptin

Testicular growth
= first sign of
puberty
Conversion
of testosterone
to DHT

Adrenarche occurs at between 6-8 yrs.

Growth spurt

600 m in length

The normal adult testes produce >100 million sperm per day.

E2 =17 estradiol
DHT= dihydrotestosterone

Testosterone
95% testicular secretion
5% adrenal + peripheral conversion of
androstenedione to testosterone

Conditions associated with alterations

in SHBG concentrations
Decreased SHBG

Moderate obesity
Nephrotic syndrome
Hypothyroidism
Use of glucocorticoids,
progestins, and androgenic
steroids

Increased SHBG

Aging
Hepatic cirrhosis
Hyperthyroidism
Use of anticonvulsants
Use of estrogens
HIV infection

Physical Examination
The clinical manifestations of androgen
deficiency depend upon the age of onset
During early gestation; ambiguous genitalia
Late gestation; micropenis
Childhood; delayed pubertal development
Adulthood; decreased sexual function,
infertility, loss of 2o sex characteristics

General appearance
Eunuchoidal proportions suggest androgen
deficiency antedating puberty.
Increased body fat and decreased muscle
mass suggest current androgen deficiency

Physical Examination
Skin
Loss of pubic, axillary and facial hair
Decreased oiliness of the skin
Fine facial wrinkling
Little /no beard development

Breasts
Gynecomastia suggests a decreased
androgen to estrogen ratio

Voice
Not deepening

Physical Examination
External genitalia
Exam. phallus and testes Tanner stage
Exam. scrotum
Absence of the vas, epididymal thickening,
varicocele, hernia

Measuring testicular size by Prader

orchidometer or calipers
In an adult man, testicular vol. < 15 mL and
testicular length < 3.6 cm are considered small.

Disorders of Puberty
Precocious puberty
Delayed puberty

Puberty in boys before age 9

Precocious Puberty
Isosexual precocity

Heterosexual precocity

Gonadotropin-dependent
(central)
1. Idiopathic
2. Hypothalamic hamartoma or
other lesions
3. CNS tumor or inflammatory state

Gonadotropin-independent
1. Congenital adrenal hyperplasia
2. hCG-secreting tumor
3. McCune-Albright syndrome
4. Activating LH receptor mutation
5. Exogenous androgens

Familial aromatase excess

Estrogen-producing tumors
in the adrenal gland
Sertoli cell tumors in the
testis
Marijuana smoking
Estrogen use
Germ cell tumors that
secrete hCG

McCune-Albright Syndrome
Caused by somatic (postzygotic)
activating mutations in the Gs
subunit that links G proteincoupled
receptors to intracellular signaling
pathways
Gonadotropin-independent
precocious puberty.
Autonomy in the adrenals, pituitary,
and thyroid glands
Cafe au lait spots
Polyostotic fibrous dysplasia
Rx bisphosphonate

Treatment Precocious Puberty

Treatment underlying disorder
Idiopathic central precocious puberty
Long-acting GnRH analogues

In children with gonadotropin-independent

precocious puberty
Inhibitors of steroidogenesis (ketoconazole)
AR antagonists

Puberty is delayed in boys if it has not ensued by age 14

Delayed Puberty
1.Constitutional delay of growth and puberty (60%)
2.Functional hypogonadotropic hypogonadism (20%)
3.Hypogonadotropic hypogonadism (10%)
4.Hypergonadotropic hypogonadism (15%)

Male Hypogonadism
Hypergonadotropic Hypogonadism
Hypogonadotropic Hypogonadism

Clinical Features
Prepubertal Onset
Postpubertal Onset
No 2o sex characterisitcs Decreased body hair
Decreased or absent beard/
Slow beard growth
body hair
Testicular volume 6 cm3,
Testes atrophic if longhypoplastic
standing
Testicular length 2.5 cm
Loss of libido
Penile length 5 cm
Importence
Smooth scrotum with no
rugae
Oligospermia/ azoospermia
Eunuchoidal skeletal
Decreased muscle and bone
proportion
mass
Female escutcheon

Normal: skeletal proportions, penis

High-pitched voice
length, scrotal rugae, prostate size
Accumulate fat at hip, face,
breast
Decreased m. mass

Intellectual, behaviour and

emotional abnormalities

Hypogonadotropic Hypogonadism
Congenital

Acquired
Systemic illness,
stress, exercise,
malnutrition
Obesity
SHBG, E2
Defect hypothalpituitary axis

Hyperprolactinemia
Sellar mass lesion
Hemochromatosis

Hypergonadotropic Hypogonadism

Klinefelter syndrome
Uncorrected cryptorchidism
Cancer chemotherapy
Radiation to the testes
Trauma, torsion, infectious orchitis
HIV infection
Polyglandular autoimmune syndrome
Anorchia syndrome
Myotonic dystrophy, spinobulbar muscular dystrophy,
paraplegia
Systemic disorder
Cirrhosis
Chronic renal failure

Chromosomal disorder
- mostly 47,XXY
- others: 48 XXXY , 46,XY/46,XXY
mosaicism, Translocation of
chromosome which contanining testisdetermining factor to an X
chromosome

Klinefelter syndrome

47 XXY karyotype
Maternal age-dependent
Incidence 1: 1000 male
Clinical:
Prepuberty:
Genitalia appear normal
Deminished verbal skills,
small head
Normal hormone
Puberty:
Gynecomastia
Small firm testis
Eunuchoid
Elevated LH, E2
low Testosterone,
normal adrenal androgen

Cardinal features:
hypogenitalism and
hypogonadism
with/without long legs,
dull mentality, and/or
behavioural problems
IQ: wide range
(above/below normal);
mean 85-90
Low U:L ratio
(eunuchoid)
Azoospermia
Small penis/testes
Gynaecomastia (1/3)

 Testis
Fibrosis of seminiferous tubule small, firm testis,
azoospermia

Primary testicular failure

Low testosterone, high gonadotropin, low inhibin B
puberty

Gynecomastia
LH chronic Leydigs cell simulation
Aromatase activity
Increased conversion of testosterone estradiol
Enhanced testicular secretion of estradiol relative to testosterone

Klinefelter syndrome
Associated complications:
Chronic bronchitis, bronchiectasis, emphysema
Extragonadal germ cell tumour, breast cancer, lung
cancer
Varicose veins, DVT
DM, hypothyroidism, osteoporosis
Autoimmune disease (SLE, Sjogren synd., RA)

Treatment:
Testosterone replacement from age 11-12 if studies
show deficient testosterone and elevated
gonadotrophins

Androgen Insensitivity Syndrome

Mutations in the AR
Resistance to the action of testosterone and DHT
X-linked, 1:1,000,000 male
Complete AIS (testicular feminization syndrome)
Female phenotype
Normal breast development
Short blind-ending vagina and the absence of Wolffian
ductderived structures (uterus, fallopian tubes)
No pubic or axillary hair

Partial AIS (Reifenstein syndrome)

Ranging from individuals with a predominantly female
appearance to individuals with ambiguous genitalia or with a
predominantly male phenotype.

Treatment Hypogonadism
Gonadotropins
Human menopausal gonadotropin(hMG)
hCG
hFSH

GnRH
Testosterone

Fertility

Treatment
Formulation

Regimen

Advantages

T enanthate or
cypionate

100 mg/wk or
200 mg every 2 wk
im

inexpensive,
Flexibility of dosing. Requires im injection.
Peaks and valleys

Oral T undecanoate

40 to 80 mg orally 2 Convenience
or 3 x daily with meals

Long-acting T
undecanoate in oil

1000 mg injected im, infrequent

followed by 1000 mg administration
at 6 wk, and 1000 mg
every 12 wk

Disadvantages

Not approved in USA

Variable clinical
responses
Requires im injection of
a large volume (4 ml)

Contraindications to testosterone therapy

Very high risk of serious adverse outcomes
- Metastatic prostate cancer
- Breast cancer

Moderate to high risk of adverse outcomes

- Undiagnosed prostate nodule or induration
- Unexplained PSA elevation (> 3 ng/ml)

- Erythrocytosis (Hct > 50%)

- Severe lower urinary tract symptoms associated with BPH as
indicated by American Urological Association- International
Prostate Symptom Score (AUA/IPSS) > 19
- Unstable severe congestive heart failure (class III or IV)

Monitoring testosterone levels

Therapy should restore serum testosterone levels
to the mid-normal range.
T cypionate or enanthate: measure testosterone
levels midway between injections. If greater than
700 ng/dl or less than 350 ng/dL, adjust dose or
frequency.
Transdermal patch: assess testosterone levels 3 to
12 hours after application
Buccal tablet: assess levels immediately before
application of fresh system.
Transdermal gel: assess testosterone level after
patient has been on treatment for 1 to 2 weeks

Potential Risks Associated with

Testosterone-Replacement Therapy

Recommendations for Monitoring

Testosterone-Replacement Therapy

Testosterone therapy in adult men with

androgen deficiency syndromes:
an Endocrine Society Clinical Practice Guideline.
The Task Force recommends making a diagnosis of
androgen deficiency only in men with consistent
symptoms and signs and unequivocally low serum
testosterone levels.
The Task Force recommends against screening for
androgen deficiency in the general population.
The Task Force recommends against a general clinical
policy of offering testosterone therapy to all older men
with low testosterone levels.
J Clin Endocrinol Metab 91: 19952010, 2006

Symptoms and signs suggestive of

androgen deficiency in men
Incomplete sexual development, eunuchoidism, aspermia
Reduced sexual desire (libido) and activity
Decreased spontaneous erections

Breast discomfort, gynecomastia

Loss of body (axillary and pubic) hair, reduced shaving
Very small or shrinking testes (especially 5 ml)

Inability to father children, low or zero sperm counts

Height loss, low trauma fracture, low BMD
Reduced muscle bulk and strength

Hot flushes, sweats

Other symptoms and signs associated with

androgen deficiency that are less specific
Decreased energy, motivation, initiative,
aggressiveness, self confidence
Feeling sad or blue, depressed mood, dysthymia
Poor concentration and memory
Sleep disturbance, increased sleepiness
Mild anemia (normochromic, normocytic, in the
female range)
Increased body fat, BMI
Diminished physical or work performance

Clinical disorders that testosterone

measurement is considered
Sellar mass, or other diseases of the sellar region
Treatment with medications that affect testosterone
production or metabolism
HIV-associated weight loss
ESRD and maintenance hemodialysis
Moderate to severe COPD
Infertility
Osteoporosis or low trauma fracture, especially in
a young man
Type 2 diabetes mellitus

Adult Men with Androgen Deficiency Syndromes

Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes:

An Endocrine Society Clinical Practice Guideline 2006

Disorder of the Ovary and

Female Reproductive Tract

At age 10 to 11
Thelarche; development of the breast buds
Pubarche; development of pubic hair
adrenal
androgens
Adrenarche; development of axillary hair
At age 12-13
Menarche


corpus luteum
persist

progesterone

Corpus luteum
Progesterone,
17-hydroxyprogesterone
Theca and stromal cells
Androstenedione, testosterone
Granulosa cells
Estrogen synthesis
(aromatase enzyme)

Estrogen

Estradiol
Estrone
Estriol

Promote development of the 2o sexual

characteristics in women
Uterine growth
Thickening of the vaginal mucosa
Thinning of the cervical mucus
Development of the ductule system of the
breasts
Alter lipid profiles
Exert effects on the vascular endothelium

Progesterone
Induction of secretory activity in the
endometrium of the estrogen primed uterus in
preparation for implantation of the fertilized egg
Induces a decidual reaction in endometrium
Inhibition of uterine contractions
Increase in the viscosity of cervical mucus,
glandular development of the breasts
Increase in basal body temperature
(thermogenic effect)

FSH
Neg feedback by estradiol, inhibin
LH
Positive feedback by estradiol

Mittelschmerz
Pain asso. with ovualtion

Disorders of Ovarian Function

Prepubertal years
Reproductive years

Breast budding begins before age 8 or

menarche occurs before age 9

Precocious Puberty
Isosexual precocity
A. True precocious puberty
1. Constitutional
2. Organic brain disease
3. Congenital adrenal hyperplasia
B. Precocious pseudopuberty
(Gn-independent)
1. Ovarian tumors
2. Adrenal tumors
3. McCune-Albright syndrome
4. Hypothyroidism
5. Russell-Silver syndrome
6. Estrogen-containing medications
C. Incomplete sexual precocity
1. Premature thelarche
2. Premature adrenarche
3. Premature pubarche

Heterosexual precocity
A. Ovarian tumors
B. Adrenal tumors
C. Congenital adrenal hyperplasia

Turners Syndrome
1:2,500-5,000 female live
births
45,XO (90%)
Cause: missing of SHOX
(Short Stature Homeobox)
(Xp22.3) and surrounding
region in X chromosome
45,XO; 45,XO/46,XX Mosaic;
45,XO/46,XY Mosaic; or
46,X,i(Xq) etc.

Cardinal features: short female + sexual infantilism

Signs in Turners Syndrome

Short, webbed neck
Low posterior hair line
Triangular facies with
midfacial hypoplasia,
micrognathia
Epicanthal folds, ptosis
Nail abnormalities
Low set and deformed
ears
Shield chest, widely
spaced nipples, mild
pectus excavatum
Congenital lymphoedema

High arch palate

Cubitus valgus
Short 4th/5th
metacarpal/metatarsal
Bone dysplasia with coarse
trabecular pattern
Delayed bone maturation
Renal anomalies: horseshoe
kidney; double or cleft renal
pelvis; minor renal alterations
IQ ~ 90

Turners Syndrome
Cardiac defects:

Bicuspid aortic valve

Coarctation of aorta
Valvular aortic stenosis
MVP
Aortic dissection (adult life)

Monitor for cardiac complications esp dissecting aorta

Recurrent risk: Sporadic
Associated complications: HT, DM, CVD, autoimmune thyroid
disease, osteoporosis, chronic liver disease, inflammatory
bowel disease, hearing loss, increased risk of keloid
formation
Y chromosome risk gonadoblastoma
Infertile, but pregnancy possible with donated embryo

Height management

Start before estrogen replacement

Recommend
GH without oxandrolone in whom height < 2 SD
or 5%tile younger 8 years
GH with oxandrolone for older age

Aim final height 150 cm or bone age reaches 14 yrs.

Sex steroid replacement

Start low dose 0.3 of CEE at 15 yrs for 6-12 mnths.
Increase dose to 0.6 mg of CEE for another 6-12 mnths
(to develop sex characters and height)

Start cyclic HRT after first bleeding or post estrogen 1-2 yrs

Follow up Adults with Turners Syndrome

Diagnostic Criteria PCOS

NIH consensus criteria (1990)
Menstrual irregularity due to
oligo- or anovulation
Hyperandrogenism
Exclusion of other causes of
hyperandrogenism and
menstrual irregularity
CAH, androgen-secreting
tumors, hyperprolactinemia

Rotterdam criteria (2003) 2 in 3

Oligo- and/or anovulation
Hyperandrogenism
Polycystic ovaries (by
ultrasound)
12 in each ovary; 2-9 mm in
diameter and/or increased
ovarian volume (>10 mL)

Exclusion (CAH, androgensecreting tumors, Cushing's

syndrome)

AES criteria (2006)

Androgen excess
Ovarian dysfunction
(oligo-anovulation and/or polycystic ovarian morphology)
Exclusion of other androgen excess or ovulatory disorders

PCOS

FSH
Clomiphene
hMG
GnRH

Weight loss

Metformin
TZD

Wedge resection
Oral Contraceptive

 diagnosis

Precocious puberty
8 yr , 9 yr
Delayed puberty
13 yr , 14 yr
1o amenorrhea
16 yr
Premature menopause 40 yr

 Menopause
Permanent cessation of menstruation due to loss of
ovarian follicular function
Diagnosed retrospectively after 12 months of
amenorrhea

Perimenopause
Time period preceding menopause, when fertility wanes
and menstrual cycle irregularity increases, until the first
year after cessation of menses.

HRT (Hormonal Replacement Therapy)

observational studies HRT

cardiovascularchronic diseases
Randomized trials;
Womens Health Initiative (WHI)
Heart and Estrogen/progestin Replacement (HERS)
Overall unfavorable risk-benefit ratio associated
with estrogen-progestin therapy

HRT (Hormonal Replacement Therapy)

Definite benefits
Symptoms of
menopause
Osteoporosis
(BMD, fracture)

Definite risks
Endometrial cancer
(unopposed estrogen)
Venous thromboembolism
Breast cancer (use 5 yrs)

Probable risks/uncertain
Cardiovascular disease (probable risk)
Gallbladder disease (probable risk)
Colorectal cancer (probable risk)
Cognitive dysfunction (unproven risk)

Contraindications to HRT

Unexplained vaginal bleeding

Active liver disease
Venous thromboembolism
History of endometrial cancer (except stage 1
without deep invasion) or breast cancer.
Relative contraindications
Hypertriglyceridemia (400 mg/dL)
Active gallbladder disease
Transdermal estrogen is an option

Disorders of Sexual Differentiation

WT1, Wilms tumorrelated gene 1

SF1, steroidogenic factor 1
SRY, sex-related gene on the Y chromosome
SOX9, SRY-related HMG-box gene 9
DHH, desert hedgehog
ATRX, -thalassemia, mental retardation on the X
DAX1, dosage sensitive sex-reversal, adrenal hypoplasia congenita on the X chromosome, gene 1
AMH, anti-mullerian hormone


45,Y not
viable

Female
Male
Pseudo
Pseudo
hermaphrodite hermaphrodite

True
Hermaphrodite

Chromosome
sex

46,XX

46,XY

46,XX ; 46,XY

Gonadal
structure

Ovary

Testis

Ovalotestes

Genital sex

Male

Female

Female/Male

Approach to abnormal sexual

differentiation
History taking:

Virilization during pregnancy

maternal androgen
History of consanguinity
AR genetic disease
Medication
exogenous androgen
Family history of unexplained infant death.
CAH
Family tree with females who are amenorrhea TF

Approach to abnormal sexual

differentiation
Physical examination:

General exam:
BP, sign of dehydration
Height: short or Eunuchoid
Associated finding: stigmata, facial dysmorphism

Genitalia:

Gonads location: palpable symmetrical of gonads

Urethral opening: ventral urethra or urogenital sinus tract
Clitoral size
Penile length
Second sex characteristics, gynecomastia
Pubic axillary hairs
Hirsutism

gonad

Not palpable

XX
XY with undescended testis

Palpable

XY

Investigations for DSD

Chromosome
defects
Karyotype
FISH for SRY

Gonadal defects
US, CT gonad
Retrograde cystogram
Explore Lap
Gonad biopsy
Hormone: E2, T, FSH, LH,
HCG stimulation test

Phenotypic
defects
E lyte
17 OHP
DHEAS
T, DHT levels

Common DSD needed to know

Turners syndrome
Klinefelters syndrome
Congenital adrenal hyperplasia
17- OHase deficiency
21- OHase deficiency
11- OHase deficiency

Testicular feminization

Pathways of adrenal coritsol synthesis

46 XX, DSD
Female pseudohermaphroditism
E2, FSH, LH
T, DHEAS

46, XX DSD
No Stigmata

Low estrogen

Gonadal dysgenesis
CAH (17-OH def)
Elyte, BP
CT or MRI for gonad

High testosterone

- CAH (21, 11)

- Androgen producing Tumor

- 17 OHP,
- CT or MRI

Congenital adrenal hyperplasia

Clinical Presentation
Classic salt-losing
Females: genital ambiguity
Males: failure to thrive, dehydration,
hyponatremia, and hyperkalemia typically at 7
to 14 days of life.

Classic non-salt-losing (simple-virilizer)

Early virilization (pubic hair, growth spurt,
adult body odor)
Typically present at 2 4 years of age.

Nonclassic (late-onset)

Diagnosis
Classic CAH (Normal levels<100 ng/dl)
Basal 17-OHP > 3500 ng/dl
Stimulated 17- OHP > 10000 ng/dl

Non-classic CAH
Basal 17-OHP > 200 ng/dl (6 nmol/L)
After ACTH stimulation test
17-OHP > 1500 ng/dl ng/dl.

Newborn female
with ambiguous genitalia
BP
Healthy
Karyotype 46,XX
E lyte = Na 125, K 5.2
Testosterone , DHEAS
ACTH

21 OH deficiency

18 year old female with

primary amenorrhea
PE: BP 200/100
Proximal muscle weakness
No 2nd Sex
Karyotype: 46XX
K = 2.8 mg/dl

17 OH deficiency

46 XY, DSD
Male pseudohermaphroditism

T Levels

46, XY DSD
No Stigmata

HCG stim test

High Testosterone

Low testosterone

T = 520
Androgen action

- Testis development defects

- Androgen synthesis defect

Androgen insensitivity syndrome - CT or MRI

- exploration for testis
- HCG stim test

30 years old female with amenorrhea

Testicular feminization
female habitus
No hair, good breast development
Female external genitalia, blind vaginal pouch,
absent cervix, uterus, tube.
Present with primary amenorrhea
Inguinal gonad
Increase risk of germinoma because of leydig cell
hyperplasia
Testes may be located in the abdomen, the inguinal
canal, or the labia majora.
Normal breast development

Testicular feminization
Incidence 1 : 20000
3rd most frequent cause of primary ameorrhea
The most common cause of male
pseudohermaphrodite.
Absence or near abcence of all Wolffian and
Mullerian structures.
Female psychologic orientation.
Androgen receptor is on X chromosome.
X link recessive disease.
46,XY karyotype, negative for intraabdominal
uterus

Disorders of sexual differentiation with

increased risk of gonadal neoplasm
Pure gonadal dysgenesis
Mixed gonadal dysgenesis
Dysgenetic male pseudohermaphrodite
Variants of Turner syndrome with Y cell line
True hermaphrodite

Androgen insensititvity syndrome