Download 28. Endocrine Disorder

28. Endocrine Disorder
부산백병원 산부인과
R4 서 영 진
Hyperandrogenism

Hirsutism : result of androgen excess
→ abnormalities of ovary, adrenal gland
: increase expression of androgen effect

Virilization : rare
indicates marked elevations on androgen
caused by an ovarian or adrenal neoplasm
Hirsutism



Androgen ↑ : excessive growth of terminal hair
Pilosebaceous unit
: androgen-responsive area transforms
vellus hair (fine, nonpigmented, short)
→ terminal hair (coarse, stiff, pigmented, long)
Midline hair, sideburns, moustache, beard, chest,
intermammary hair, inner thigh, midline lower back,
intergluteal area

Androgen effects in hair vary in relation to specific
regions of the body surface
: no androgen dependence-lanugo, eyeblows, eyelashes
: minimal sensitivity-limbs, trunk
: sensitivity ↑- axilla, pubic region

Result from both increased androgen production &
skin sensitivity
:skin sensitivity–depend on local activity of 5α-reductase
: 5α-reductase - testosterone → dihyhrotestosterone
in hair follicles

Hair: cyclic activity – growth (anagen)
involution (catagen)
resting (telogen)
: duration –according to body region, genetic factor
age, hormonal effects

Hirsutism: relative > absolute, designation
Hypertrichosis and Virilization

Hypertrichosis: androgen-independent terminal hair
(nonsexual area: trunk, extremities)
- AD congenital disorder
metabolic disorder (anorexia nervosa, hyperthyroidism)
medication (acetazoamide, cirticosteroid, cyclosporine,
diazoxide, interferon, minoxidil..)

Virilization: coarsening of the voice, increase muscle,
clitoromegaly (width 3.4+1mm, length 5.1+1.4mm)
feature of defeminization (loss of breast volume)

Focus on the age at onset & rate of progression
: rapid- more severe degree of hyperandrogenism
(ex. ovaran or adrenal neoplasm, Cushing synd.)
: anovulation- probability of hyperandrogenism

Determining the extent of hirsutism
: questions about shaving & use of depilatories
: clinically mild, moderate, severe
: scoring scale- adrogen-densitive hair in nine body
scale of 0 to 4
→ hirsutism > score 8

PCOS, congenital or adult onset adrenal hyperplasia,
DM, cardiovascular disease, drug use

PEx: obesity, hypertension, galactorrhea,
male-pattern baldness, acne, hyperpigmentation

DDX :Cushing syndrome
Role of Androgen

Androgen and their precusors
: produced by both the adrenal glands and the ovaries
: response to ACTH and LH


Adrenal 17-Ketosteroids
: increases prepubertally
: independent of pubertal maturation of H-P-O axis
: adrenal steroid secretion- adrenarche
: in adrenal cortex (zona reticularis)
: growth of pubic hair, axillary hair and production of
sweat by the axillary pilosebaceous units
Testosterone
: 1/2 – peripheral conversion of androstenedione
1/2 – direct glandular (ovary, adrenal) secretion
: 66~78%-binding sex hormone-binding globulin(SHBG)
bologically inactive
20~32%-asssociated albumin
1~2%-unbound or free
: increases SHBG - high estrogen (pregnancy, luteal
phase, use of estrogen)
- thyroid hormone ↑, LC
(→ reduced free testosterone)
: decrease SHBG – free testosterone ↑
- androgenic ds(PCOS, CAH, Cushing)
medication, growth hormone, obesity,
hyperinsulinemia, pl]rolactin
Assessment of Hyperandrogenemia

Testosterone production ↑ ≠ total testosterone ↑
: because of depression of SHBG
: moderate – normal range total testorterone
: severe (virilization,
neoplastic production of testosterone)
- can be detected by measure of total testosterone
: free testosterone level can be measured to assess
increases in testosterone production

Free testosterone
: standard technique- equilibrium dialysis
but, expensive, complex, limited to settings
: assessment of testosterone binding albiumin & SHBG
AT = Ka [A] x FT
AT- albumin-bound testosterone
Ka – association constant of albumin for testosterone
FT- free tetosterone
A- albumin



The level of bioavailable testosterone
: based on albumin, total testosterone, and SHBG
Testosterone → DHT (dihydrotestosterone)
: active metabolite
: by 5α-reductase
· type I : skin
· type II : liver, prostate, seminal vesicle, genital skin
-type II>type I(20-fold higher affinity for testosterone)
the relative androgenicity of androgens
: DHT = 300
testosterone = 100
androstenedione = 10
DHEAS = 5
Laboratory Evaluation

Bioavailable testosterone level
(total testosterone, SHBG, and albumin level)
Calculated free testosterone level

Most clinical situations
: total testosterone, DHEAS, 17-hydroxyprogesterone
Normal values for serum androgens
Testosterone (total)
Free testosterone (calculated)
Percent free testosterone
Bioavailable testosterone
SHBG
Albumin
Androstenedione
DHEAS
17-OHP (follicular phase)
20-80 ng/dL
0.6-6.8 pg/mL
0.4-2.4 %
1.6-19.1 ng/dL
18-114 nmol/L
3,300-4,800 mg/dL
20-250 ng/dL
100-350 μg/dL
30-00 ng/dL



Hirsutism + absent or abnormal menstrual period
: LH, FSH, prolactin, TSH
Hypothyroidism & hyperprolactinemia
: reduce SHBG → unbound testosterone↑
→ hirsutism
Cushing syndrome
: 24hr urinary cortisol
overnight dexamethasone suppresion test
- 1 mg dexamethasone at 11:00 PM
blood cortisol checked at 8:00 AM
> 2 μg/dL → further workup

Total testosterone > 200 ng/dL
: ovarian & adrenal tumor

DHEAS > twice the upper limit
: adrenal hyperplasia
: upper limit 350 μg/dL (9.5 nmol/L)

Virilization
: total testosterone & DHEAS should be measured
Polycystic Ovary Syndrome(PCOS)




Most common cause of hyperandrogenism & hirsutism
Stein-Leventhal syndrome
: amenorrhea + bilat. Polycystic ovaries + obesity
Principally oligomenorrhea or amenorrhea
+ clinical or laboratory evidence of hyperandrogenemia
Diagnostic criteria
: Major – chronic anovulation
hyperandrogenemia
clinical signs of hyperandrogenism
other etiologies excluded
: Minor – insulin resistance
perimenarchal onset of hirsutism and obesity
elevated LH-to-FSH ratio
intermittent anovulation associated with
hyperandrogenemia(free testosterone,DHEAS)



Hirsutism : 70% of PCOS in U.S.A
10~20% in japan
→ difference in skin 5α-reductase activity
Amenorrhea & oligomenorrhea
Obesity : 50% in PCOS
insulin resistance
hyperglycemia (type 2 DM)


Abnormal lipoproteins
: total cholesterol. TG, LDL↑
: HDL, apoprotein A-I ↓
Other finding
: impaired fibrinolysis
Hypertension
atherosclerosis & cardiovascular disease
MI
Pathology

Macroscopically,
: 2 ~5 times the normal ovary
: White, thickened cortex with multiple cyst

Microscopically,
: superficial cortex- fibrotic and hypercellular
prominent blood vessel
: smaller atretic follicles
: luteinized stromal cells
Pathophysiology and Laboratory Finding

By abnormalities in 4 endocrinologically compartment
1) the ovaries
2) adrenal glands
3) the periphery (fat)
4) the hypothalamus-pituitary compartment

The ovaries
: most consistent contributor of androgen
: dysregulation of CYP17(androgen-forming enzyme)
: this hormone relates to ovarian androgenic activity
1. total & free testosterone level correlate directly
with LH levels
2. more sensitive to gonadotropic stimulation, as a
result of CYP17 dysregulation
3. GnRH agonist- suppresses testosterone and
androstenedione levels
4. large dose of GnRH agonist are required for androgen suppression than endogenous gonadotropininduced estrogen suppression

Testosterone level in PCOS
: no more than twice the upper normal (20-80 ng/dL)
: ovarian hyperthecosis- >200 ng/dL

Adrenal gland
: hyperfunctioning CYP17 androgen-forming enzyme
: DHEAS ↑ (50%) – hyeprresponsiveness to stimulation
with ACTH

Peripheral compartment (skin & adipose tissue)
1. 5α-reductase in skin determines the presence or
absence of hirsutism
2. fat cell: aromatase & 17β-HSD activity ↑
3. with obesity, estrogen metabolism ↓
4. E1 level ↑ : result of peripheral aromatization of
androstenedione
5. E1 : E2 ratio ↑

Hypothalamic-pituitary compartment
1. LH pulse frequency ↑: the frequent observation of
elevated LH & LH:FSH ratio
2. FSH : not increased with LH
result from the combination of increased
gonadotropin pulse frequency and synergistic
negative feedback of elevated estrogen and
normal ovary
3. prolactin ↑ : abnormal estrogen feedback to the
pituitary gland
Insulin Resistance

Insulin resistance & hyperinsulinemia
: ovarian dysfunction of PCOS
: most common cause- obesity
1. Hyperinsulinemia is not a characteristic of
hyperandrogenism in general but is uniquely
associated with PCOS
2. in obese women with PCOS, 30-40% have glucose
intolerance or DM, whereas ovulatory hyperandrogenic
women have normal glucose tolerance and insulin
 PCOS-obesity: synergistic
3. Suppression of ovarian steroidogenesis with long–
acting GnRH analogs in women with PCOS does not
change insulin levels or insulin resistance
4. Oophorectomy in patients with hyperthecosis
accompanied by hyperinsulinemia and
hyperandrogenemia does not change insulin
resistance, despite a decrease in androgen levels

Acanthosis nigricans
: reliable marker of insulin resistance in hirsute women
: thick, pigmented, velvety lesion- vulva, axilla, neck,
breast, inner thigh

Acanthosis nigricans
: reliable marker of insulin resistance in hirsute women
: thick, pigmented, velvety lesion- vulva, axilla, neck,
breast, inner thigh
: testosterone >150 ng/dL
fasting insulin > 25 μIU/mL
Max insulin response to glucose load(75g)>300 μIU/mL
Screening strategies for diabetes and insulin resistance



Fasting glucose:insulin < 4.5 : insulin resistance
2 hr GTT : nonobese(10%), obese(40-50%) with PCOS
- inpared glucose tolerance, type II DM
testing women with PCOS for glucose intolerance is of
value because their risk of cardiovascular disease
correlates with this finding
Interventions


In obese, insulin–resistant women, caloric restriction that
results in weight reduction will reduce the severity of
insulin resistance (a 40% decrease in insulin level with a
10–kg weight loss)
Insulin resistance/hyperinsulinemia has been
recognized as a cluster syndrome now called the
metabolic syndrome or dysmetabolic syndrome X

Female waist >35 inches
Triglycerides >150 mg/dL
HDL cholesterol <50 mg/dL
Blood pressure >130/85 mm Hg
Fasting glucose: 110–125 mg/dL
2–hour GTT (75 g): 140–199 mg/dL
Ultrasonographic studies

Most important finding
: bilateral increase in number if microcyst (0.5~0.8cm)
: more than five microcyst in any imaging plane in
each ovary
: but, neither sufficiently sensitive nor specific finding
Long-term Risks

Chronic anovulation
: persistently elevated estrogen, unopposed by
progesterone
 increase the risk of endometrial carcinoma
but, usually well-differentiated, stage I
cure rates approaching 100%

Prevention of endometrial cancer
: endometrial biopsy should be considered in PCOS
: influence factor:- abnormal bleeding, weight ↑, age

Hyperestrogenic state
: breast cancer, ovarian cancer ↑ (2-3 fold)
: the risk is greater in nonobase women,
not taking oral contraceptives
Treatment of Hyperandrogenism and PCOS

Depends on a aptient’s goals
: hormonal contraception, ovulation induction, et al
: ovulatory dysfuction
 progestational interruption of unopposed estrogen
effects on endometrium is required

Interruption of hyperandrogenism & control of hirsutism
: can be accomplished simutaneously
: if patient desires pregnancy, control of hirsutism may
not be possible
Weight Reduction

The initial recommendation
: reduce insulin, SHBG, and androgen
: restore ovulation with ovulation-induction agents

Weight loss of as little as 5~7%
: reduce bioavailable or calculated testosterone
: restore ovulation & fertility in more than 75% women
Oral Contraceptives

Combination OCs
: decrease adrenal & ovarian androgen production
: reduce hair growth in 2/3 hirsute patients
1. progesterone component- LH ↓
androgen production ↓
2. estrogen- increase hepatic production of SHBP
free testosterone ↓
3. circulating androgen ↓
4. by inhibition of 5α-reductase
- decrease conversion of testosterone to DHT in skin

When use OCS, a balance must be maintained
between the decrease in free testosterone levels and the
intrinsic androgenicity of the progestin
: progestin (norgesterol, norethindrone, norethindrone acetate)
- androgenic activity ↑
- new progestin (desogestrel, gestodene,
norgestimate, grospirenone)
Medroxyprogesterone Acetate
Directly affects the hypothalamic-pituitary axis by
decreasing GnRH production and release of
gonadotropin
 reduce testosterone & estrogen production in ovary
 Oral: 20~40 mg daily
IM: 150 mg every 6 weeks to 3 months
 Side effects: amenorrhea, bone density ↓, depression,
headache, hepatic dysfunction, Wt. gain

Gonadotropin-releasing Hormone Agonist




Allow the differentiation of androgen produced by
adrenal sources from that of ovarian sources
GnRH agonist : suppress ovarian steroids
Leuprolide acetate IM every 28 days
: decrease hirsutism & hair diameter
+ OCs or estrogen replacement
: prevent bone loss, menopause side effect
Glucocorticoids

Dexamethasone : treat adrenal or mixed adrenal and
ovarian hyperandrogenism
 0.25 mg nightly or every other nightly
: suppress DHEAS (<400 μg/dL)
 40 times the glucocorticoid effect of cortisol
: if daily over 0.5 mg, adrenal suppression &
Cushing syndrome
: maintain morning cortisol level (>2 μg/dL)
 Reduce hair growth rate & acne
Ketoconazole


Inhibits the key steroidogenic cytochromes
200 mg/day : reduce androstenedione
testosterone
calculated free testosterone
Spironolactone


Effective K sparing diuretics for treatment of HTN
Antagonist of aldosterone
: competitively binds to aldosterone receptors in the
distal tubular region of the kidney
1.
2.
3.
4.
competitive inhibition of DHT at intracellular receptor
testosterone biosynthesis ↓ by a decrease in the CYP
androgen catabolism ↑
inhibition of skin 5α-reductase activity

Using at least 100 mg daily for 6 months
: most common dosage- 50~100 mg twice daily
: reduce sexual hair, hair diameter, hair volume

Side effect
: menstrual irregularity (metrorrhagia)
: mastodynia, urticardia, scalp hair loss

Not recommended
: renal insufficiency, hyperkalemia
: check K, Cr level
Cyproterone Acetate

Synthetic progestin
: antiandrogenic properties
: competitive inhibition of testosterone, DHT at the
level of androgen receptor
: hepatic enzyme ↑- androgen clearance ↑

+ ethinyl estradiol
: reduce testosterone, androstenedione
suppress gonadotropin
increase SHBG

Reverse sequential regimens
: cyproterone acetate 100 mg/day on days 5 to 10
ethinyl estradiol 30-50 mg/day on days 5 to 26

Side effect
: fatigue, Wt. gain, libido ↓, nausea, headache,
irregular bleeding
Flutamide

Nonsteroidal antiandrogen
: used in prostate cancer
: inhibition of nuclear binding of androgen on tissues
: weak inhibitor of tetosterone biosynthesis

+ low dose OCs
: improvement hirsutism
: androstenedione, DHT, LH FSH ↓
: side effect- dry skin, hot flush, appetite ↑, dizziness,
libido ↓

+ ethinyl-drospirenone, metformin
: reduce excess total and abdominal fat
: dysadipocytokinemia in young women with
hyperinsulinemic PCOS
Cimetidine

Histamine H2 receptor antagonist
: weak ability to occupy androgen receptor
: inhibit DHT binding at the level of the hair follicle
Finasteride


Inhibitor of type 2 5α-reductase
5 mg daily
Ovarian Wedge Resection


Transient reduce androstenedion level
prolonged minmal decrease in testosterone
85%: maintenance of ovulatory cycle
Laparoscopic Electrocautery

Severe PCOS whose condition is resistant to
clomiphene citrate


Coagulation each microcyst
Risk: adhesion
Physical Methods of hair Removal



Depilatory, shaving, plunking, bleaching
Electorolysis: permanent
destroy hair follicles
Laser hair removal
Insulin Sensitizers

Metformin (glucophage)
: inhibit hepatic glucose production &
enhance peripheral glucose uptake
: 500 mg three times daily
→ improve ovulation (+ clomiphene citrate)
Cushing Syndrome

Adrenal cortex : three steroid hormone
glucocorticoid
mineralocorticoid
sex steroid (androgen, estrogen precursors)

Glucocrticoid ↑
: nitrogen wasting & catabolic sate
→muscle weakness, osteoporosis, skin atrophy,
nonhealing ulceration, ecchymoses
: immune resistance ↓
→bacterial or fungal infection
: guconeogenesis and antagonism to insulin action
→glucose intolerance

Symptoms
: weight gain, central & over clavicle fat redistribution
(neck, trunk, abdomen, cheeks)
: cortisol excess- insomnia, mood disturbance, overt
phycosis, depression

Sex steroid precursor overproduction
- hyperandrogenism (hirsutism, acne, oligomenorrhea,
amenorrhea, thinning scalp hair)

Mineralocortocoid overproduction
- arterial HTN, hypokalemic alkalosis
→ fluid retention may cause pedal edema

Laboratory finding associated with hypercortisolism
: granulocytosis, lymphocytes ↓, urinary Ca ↑
Cause
Category
Cause
Relative incidence
ACTH-dependent
Cushing syndrome
Ectopic ACTH-secreting tumor
Ectopic CRH-secreting tumor
ACTH-independent Adrenal cancer
Adrenal adenoma
Micronodular adrenal hyperplasia
Iatrogenis/factitious
60%
15%
10%
15%
10%
rare
common

ACTH-dependent
: result from ACTH secreted by pituitary adenomas or
from an ectopic source
: hallmark- normal or high ACTH with increased cortisol

Pituitary adenoma
: microadenomas (<10mm)
: resistant to the feedback effect of cortisol

Ectopic ACTH syndrome
: 1/2- small-cell carcinoma in lung
: bronchial & thymic carcinomas, pancreas carcinoid
tumor, thyroid medullary cercinomas

ACTH-independent cause
: most common- iatrogenic or factitious
: corticosteroid- variety of diseases with an
inflammatory component
Diagnostic Workup for Cushing Syndrome

Screening
: 24hr urinary free cortisol
- normal range (30~80 μg/day)
: overnight dexamethasone suppression test
- previous night 11:00 PM 1 mg dexamethasone
next day 8:00 AM cortisol

Confirmation if diagnosis
: 2-day, low-dose dexamethasone suppression test
- 0.5 mg every 6 hours for 2 days
- Cushing syndrome is ruled out
urinary 17-hydroxycorticosteroid < 3 mg/24hr
plasma cortisol < 4μg/day
urinary free cortisol < 25 μg/24 hr

Differentiation of Cushing syndrome
: high-dose dexamethasone suppression test
: used to differentiate from other cause
: 2 mg every 6 hours for 2 days
: suppresses ACTH in most Cushing syndrome
(Cushing’s disease)
: no effect- ectopic or adrenal Cushing syndrome

Differentiation of ectopic ACTH syndrome
: high plasma ACTH
- >4.5 pmol/L or >20 pg/mL
- ectopic ACTH production from adrenal gland
: low plasma ACTH
- <1.1 pmol/L or <5 pg/ml
- adrenal Cushing syndrome

ACTH-independent and –dependent
: ACTH-independent
- adrenal scan or MRI
prepared for adrenal surgery
: ACTH-dependent
- CRH test
- CRH ( 1μg/kg IV over 1 min)
simultaneous sampling 3~5 minutes later of
both the inf. petrosal sinuses/peripheral vein ratio
- 95% of Cushing syndrome > 2 ratio
- if not, indicate ectopic ACTH secretion
→ check chest & abdominal CT
Laboratory Diagnosis of Cushing Syndrome
Dagnosis
ACTH
24hr urinary cortisol
ACTH-dependent
Cushing synd (60%)
↑
Pituitary adenoma
Basophilic hyperplasia
Nodular adrenal hyperplasia
Cyclic Cushing synd
Ectopic ACTH (15%)
↑
Ectopic CRH(rare)
↑
ACTH-independent
Adrenal neoplasia
↑
Adenoma (10%)
carcinoma (15%)
1’ adrenocorticorid
nodular dysplasia(<1%)
Pseudo-Cushing synd
↑
(alcohol-relate,<1%)
Exogenous glucocorticoids/ ↑↓
factitious (not cortisol)
DEX low-dose
↑
DEX high-dose
↓
normal
↑
↑
↑
↑↓
↑
↑
↑
↑
↓
↑
↓
↓
normal
↓
↓
Treatment of ACTH-independent Form of
Cushing Syndrome

Exclude iatrogenic or factitious etiology

Usually, adrenal cancers
(tumors are relatively inefficient in steroid synthesis)
: >6cm- detected by CT or MRI
: large, irregular image
: unilateral adrenalectomy is preferable
in malignancy, complete resection is impossible
: postoperative chemotherapy (mitotane)

Adrenal adenomas (<3cm)
: usually unilateral
: children, adolescents, young adults
: contain numerous small (>3mm) nodule
: identified by CT or MRI
: treatment of choice
- surgical removal unilaterally
cure rate- 100%
- after surgery. cortisol replacement needed
because H-P-A axis is suppressed by autonomous
cortisol production
Treatment of Cushing Disease

Treatment of choice
: transsphenoidal resection
: cure rate- 80% (microadenomas)
50% (macroadenomas)

Radiation therapy
: 4,200~4,500 cGy
: total improvement- 15~25% of adults
80% of chilren

Medical therapy
: mitotane after pituitary radiation
: maintain cortisol levels while a patient awaits the full
effect of radiation
: adrenal enzyme inhibitors
- aminoglutethimide, ametyrapone, trilostanes,
etomidate
: ketoconazole
- inhibits adrenal steroid biosynthesis
- 600~800 mg/day for 3 months to 1 year

Nelson syndrome
: adenomatous progression of ACTH-secreting cells
in patient with Cushing syndrome treated by bilateal
adrenalectomy
: 10~50% of bilateral adrenalectomy cases
: sellar pressure symptoms
- headache, visual disturbance, ophthalmoplegia
: high ACTH level- severe hyperpigmentation
: treatment- surgery + radiation
Congenital Adrenal Hyperplasia

Autosomal recessive disorder

Failure to synthesize the fully functional enzyme
1.a relative decrease in cortisol enzyme
2.a compensatory increase in ACTH level
3. hyperplasia of the zona reticularis of adrenal certex
4. an accumulation of the precursors of the affected
enzyme in bloodstream
21-Hydroxylase Deficiency

>90% of adrenal hyperplasia

Salt wasting-severe form
: congenital manifestation during the first 2 weeks of life
: hypovolemic salt-wasting crisis, hyponatremia,
hyperkalemia, acidosis
With or without salt-wasting & new born adrenal crisis
: genital virilization (clitoromegaly, labioscrotal fusion,
abnormal urethral course)


In simple virilizing CAH
: diagnosed as virilized newborn girls or as rapid
growing masculinized boys at 3 to 7 years 0f age
: diagnosis is based on basal level of
21-hydroxylase ↔17-hydroxyprogesterone (17-OHP)
1. Basal follicular phase 17–OHP less than 200 ng/dL
virtually excludes the disorder; no further testing is
required
2. Basal 17–OHP greater than 500 ng/dL establishes the
diagnosis; there is no need for further testing
3. Basal 17–OHP greater than 200 ng/dL and less than
500 ng/dL requires ACTH stimulation testing
4. In the ACTH stimulation test, plasma levels of 17–OHP
are checked 1 hr following intravenous administration
of a bolus of 0.25 mg ACTH 1–24 (cosyntropin [Cortrosyn]).
17–OHP levels after ACTH stimulation in adult–onset
adrenal hyperplasia are generally greater than
1,000 ng/dL.
5. Individuals who are heterozygous (carriers) for both
adult–onset adrenal hyperplasia and CAH reveal
stimulated 17–OHP values less than 1,000 ng/dL.
In many cases, an overlap with the values seen in the
normal population is observed
Nonclassic Adult-onset
Congenital adernal hyperplasia
Nonclassic type of 21-hyoroxlase deficiency
: partial deficiency in 21-hydroxylation
: late-onset, milder hyperandrogenemia
: result from mutation both alleles for 21-hydroxylase
 Symptoms of AOAH present during of after puberty

1. Those with ovulatory abnormalities and features
consistent with PCOS (39%)
2. Those with hirsutism alone without oligomenorrhea
(39%)
3. Those with elevated circulating androgens but without
symptoms (cryptic) (22%)
Genetic of 21-hydoxylase deficiency
1. The 21–hydroxylase gene is located on the short arm
of chromosome 6, in the midst of the HLA region.
2. The 21–hydroxylase gene is now termed CYP21. Its
homologue is the pseudogene CYP21P .
3. Because CYP21P is a pseudogene, the lack of
transcription renders it nonfunctional. The CYP21 is the
active gene.
4. The CYP21 gene and the CYP21P pseudogene alternate
with two genes called C4B and C4A, both of which
encode for the fourth component (C4) of serum
complement .
5. The close linkage between the 21–hydroxylase genes
and HLA alleles has allowed the study of 21–hydroxylase
inheritance patterns in families through blood HLA typing
Prenatal diagnosis and treatment


Women with CAH or AOAH
: high frequency of mutation in 21-hydroxylase
In families at risk for CAH, one partner expresses the
CAH or AOAH
: first trimester- chorionic villus sampling
: in involvement, dexmethasone treatment
(20 mg/kg tid, no later than 9 weeks)
Dexamethasone cross placenta & suppress ACTH
effectively reduces genital ambiguity in genetic female
(but, 2/3 still require surgical repair of genitalia)
11β-Hydoxylase Deficiency





5~8% of CAH, or 1 in 100,000 birth
Common symptom: hypertension
Two isoenzyme: CYP11-B1 & CYP11-B2
middle of long arm of chromosome 8
- synthesis of cortisol and aldosterone
Diagnosis
: 11-deoxycortisol > 25 ng/mL 60 min
after ACTH stimulation
1/3: Lt. ventricular hypertrophy
death is reported from cerebrovascular accident
3β-Hydoxysteroid Dehydrogenase
Deficiency



Both the adrenal glands & ovaries
Transforming Δ-5 steroid into the Δ-4 compounds
Marked elevation of DHEA & DHEAS of mildly elevated
testosterone & androstenedione
→ screening protocol using exogenous ACTH stimulation
Treatment of Adult-onset
Congenital Adranal Hyperplasia

Dexamethasone: suppress the H-P axis
evening 0.25~0.5 mg, most effective
: maintain cortisol level ( > 2 μg/dL)

progestin for endometrial regulation
clomiphene citrate or gonaditropin for ovulation induction
progestin & androgen for control hirsutism
Androgen-secreting
Ovarian and Adrenal Tumors



Hirsutism, vorolization, rapidly progressing signs of
androgen excess
Determination if levels of testosterone & DHEAS
: testosterone- 2.5 times the upper normal or 200 ng/dL
→ ovarian androgen-secreting tumor
: DHEAS > 800 μg/dL
→ adrenal tumor
Evaluation
: first, USG in ovarian neoplasm
: Duplex Doppler
: CT, MRI, selective venous catheterization
Adrogen-producing Ovarian Neoplasms

Granulosa cell tumors
: 1~2% (postmenopausal > premenopausal women)
: usually associated with estrogen production
: TAH c BSO
: malinancy potential- 60~90%
depend on stage, tumor size, histologic atypia

Thecomas
: rare, older age, seriod-type (luteinized thecomas)
: rare malinant, rare bilateral
: simple oophorectomy

Sclerosing stromal tumor
: benign, <30 years
: a few case, estrogenic or androgenic manifestations

Sertoli-Leidig cell tumors
: previously, androblastoma, arrhenoblastoma
: 11% of solid ovarian tumors
: contain Sertoi cells, Leydig cells, fibroblasts
: most common virilizing tumor in reproductive age
but, musculinization- 1/3
: bilateral 1.5%, 80%- stage IA
: Tx: USO
TAH c BSO + adjuvant Tx (in advanced stage)

Pure sertoli cell tumors
: usuallly unilateral
: if premenopausal with stage I
→ USO
: maliganat tumors are rapidly fatal

Gynandroblastoma
: benign, well differentiated, testicular elements
: Tx- USO or unolateral oophorectomy

Sex cord tumors with annular tubules (SCTATs)
: associated with Peutz-jeghers syndrome
(G-I polyposis, mucocutaneous melanin pigmentation)
: mophology- between granulosa cell tumor and
Sertoli cell tumor
: with Peutz-jeghers syndrome
- bilateral & benign
without Peutz-jeghers syndrome
- almost always unilateral & mailgnant
Steroid Cell Tumors


Composed entirely of steroid-secreting cells
Virilization or hirsutism
: 3/4 of Leydig cell tumors
Stromal Hyperplasia and
Stromal Hyperthecosis

Stromal hyperplasia
: nonneoplastic proliferation of ovarian stromal cell
: 60~80 years
: associated with hyperandrogenism, endometrial
carcinoma, obesity, HTN, glucose intolerance

Stromal hyperthecosis
: presence of luteinized stromal cell at distance from
the follicles
: order age- mild, reproductive age- severe
: virilization, obesity, hyperinsulinemia, HTN
: with HAIR-AN syndrome
- hyperandrogenism, insulin resistance and
acanthosis nigricans
: ovarian androgen ↑(testosterone,DTH,androstenedione)
: Tx
- wedge resection
but, in severe case, only transient
- bilateral oophorectomy
GnRH agonist
Virilization during Pregnancy

Frequently. luteomas of pregnancy
: maternal & fetal musculinization
: usually regresses postpartum
: 30%- maternal virilization
65%- virilized female newborn

Krukenberg tumor, mucinous cystic tumor, Brenner
tumor, serous cystadenoma, ecdodermal sinus tumor,
dermoid cyst
Virilizing Adrenal Neoplasm



Most common: adrenal carcinoma
- DHEAS ↑, hypercortisolism
- often large and detectable on abd. examination
Less commonly, testosterone-secreting adenomas
- normal or moderately elevated DHEAS
Pure virilizing adrenal neoplasm
- 90% benign,
- peak age: 20~40 years
(pure testosterone-secreting adenomas: menopause)
- unilateral
Prolactin Disorder



A product of the anterior pituitary (1933)
Be found in nearly every vertebrate species
Primary function
: initiation and maintenance of lactation
: roles for reproductive system
Prolactin secretion
199 amino acids
 Molecular weight: 23,000 daltons
 Human growth hormone, placental lactogen
: lactogenic activity
: but, 16% & 13% amino acid sequence homology with
prolactin
 Chromosome 6 encodes prolactin
5 exons & 4 introns
 Three fomrs : monomer- little (50%)
dimer- big
multimeric- big-big
: proportion- physiologic, pathologic,
and hormonal stimulation


do not require glycosylation for primary activities



Inhibitory control mediated by dopamine
: by the tuberoinfundibular dopaminergic neuron into
the poral hypophyseal vessel
: dopamine receptor- on pituitary lactotrophs
TRH: releasing factor
GABA, neurohormone & transmitter: inhibitory factors
Hyperprolactinemia



Physiologic disturbance, pharmacologic agents,
compromised renal function
Acute stress, painful stimuli
Most common: pharmacologic cause
(antipsychotics, antidopaminergic agents)
Evaluation
5~27 ng/mL throughout the normal menstrual cycle
 Pulsatile secretion: 14 pulse/24 hrs (late follicular phase)
↓
9 pulse/24hrs (late luteal phase)
 Diurnal variation
: lowest- midmorning (← sample preferably)
: rise 1 hour after onset of sleep and continue to rise
until peak values (5~7AM)
 Sample should not be obtained
: after awakes, procedure, stressful event, breast stimuli,
previous venipuncture, PEx,

Physical Signs

Amenorrhea without galactorrhea (15%)
: the cessation of normal ovulatory process resulting
from elevated prolactin level, via hypothalamic
mediation, on GnRH pulsatile release

Isolated galactorrhea
: within normal range of prolactin (50%)
: because of prior episode of hyperprolactinemia or
other factor, sensitivity of breast to the lactotrophic
stimulus by normal prolactin levels

Both galactorrhea & amenorrhea
: 2/3- hyperprolactinemia
(1/3 pituitary adenoma)

Delayed puberty
: check prolactin & TSH levels !!!
: pituitary abnormalities (craniopharyngioma, adenoma)
multiple endocrine neoplasia type-I (MEN-I)
(gastrinoma, insulinoma, parathyroid hyperplasia, pituitary neoplasia)
Imaging Techniques


Larger microadenomas & macroadenoma
: prolactin > 100 ng/mL
Smaller aicroadenomas & suprasellar tumors
: prolactin < 100 ng/mL

MRI of sella & pituitary gland with enhancement
: provide best anatomical detail
: differentiate microadenoma from macroadenoma
: identify other potenial sellar or suprasellar masses



90% of untreated women, microadenoma do not
enlarge over a 4- to 6-year period
Prolactin level correlate with tumor size,
but, both elevation & reduction may occur without
any change in tumor size
If prolactin increase significantly or CNS Sx.,
repeat imaging
Hypothalamic Disorders


Dopamine
: arcuate nucleus
→ median eminence
→ hypophyseal portal system
→ anterior pituitary
Disrupt dopamine pathway
: disrupt dopamine release
→ hyperprolactinemia
Pituitary Disorder (Microadenoma)



25% of autopsy series of U.S. population
40% stain positively for prolactin
Clinically significant tumor: 14/100,000 individuals

1/3 of hyperprolactineima: radiologic lesion
microadenoma (< 1cm)

Generally benign course,
gradually regress spontaneously

Monoclonal in origin
: genetic mutation→ release stem cell growth inhibition
→ autonomous ant. pituitary hormone production

Rarely progress to macroadenoma
: only 7%

Chronic headache, visual disturbance,
extraocular muscle palsies
[Expectant management]
 In women, do not desire fertility
menstrual function intact

Hyperprolactinemia-induced estrogen deficiency
: develop osteopenia
: therefore, estrogen replacement or contraceptives

In absence of symptoms,
imaging may be repeated in 12 months to assess
further growth of the microadenoma
[Medical Treatment]
 Ergot alkaloids: mainstay of therapy
Bromocriptine
- strong dopamine agonist
decrease prolactin level
decrease lesion size within 1~2 weeks
- decrease prolactin synthesis, DNA synthesis, cell
multiplication, and overall size of prolactinoma
- result in normal prolactin level or return of ovulatory
menses in 80~90% of patients
- excreted via the biliary tree, caution in the liver ds.
patients
- adverse effect: nausea, headache, hypotension,
dizziness, fatigue, drowsiness, vomiting,
constipation, nasal congestion
‘hallucination, delusion, mood change’
- regimen: increased gradually
1 wks- 1.25 mg every evening
2 wks- 1.25 mg every morning & evening
3 wks- 1.25 mg morning, 2.5 mg evening
4 wks- 2.5 mg every morning & evening
Cabergoline
- long half life, twice per week
- slow elimination by pituitary tumor,
high affinity binding to dopamine receptor
entensive enterohepatic recirculation
- fewer adverse effect
Pergolide or methergoline

Discontinuation of medication
: successful to maintain normal prolactinlevel
: recerrence rate- macroadenoma > microadenoma
Pituitary Disorder (Macroadenoma)

> 1cm

Bromocriptine & transsphenoidal surgery

Symptom
: severe headache, visual field change, DI, blindness
[Medical Treatment]
 Bromocriptine: decrease prolactin & tumor size
 Discontinuation: tumor regrowth, so long-term Tx
 Repeat MRI & prolactin every 6 months
[Surgical Intervention]
 Unresponsive to medical treatment
Monitoring Pituitary Adenomas
During Pregnancy




Rarely complications during pregnancy
but, recommended visual field Ex. & fundoscopy
If, persistent headache, visual deficit
: MRI scanning
While taking bromocriptine, become pregnant
: discontinuation medication
: but, not teratogenecity in animals
data do not suggest it is harmful to fetus in human
Breastfeeding: not contraindicated in microadenoma or
macroadenoma
Thyroid Disorder
10 times more: women > men
1% of female in U.S.A
 Iodide (critical component of thyronines)
→ triiodothyronine (T3) & thyroxine (T4)
 Thyroid follicular cell: synthesis hormones
- sodium-iodide symporter (NIS)
- TSH: uptake stimulation with Na-K ATPase
- thyroid peroxidase (TPO): MIT,DIT formation within
thyroglobulin
: secondary forms T3, T4


Thyroglobulin
: major protein formed in the thyroid gland
: iodine content- 0.1~1.1% by weight
: 33% of iodine- form of T3 & T4
(remainder- MIT,DIT)
: storage capacity- keep euthyroid state for 2 months

T3
: primary physiologically functional thyroid hormone
: T4>T3 40~100 times
but, T4- slow turnover, lower binding affinity
T3- high turnover, higher binding affinity

Thyroid hormone
: increased oxygen consumption
heat production
metabolism of fat, protein, and carbohydrate
→ balance fuel efficiency
carburetor function in an engine
Iodide Metabolism

Iodine
: 150~300 mg/day
: indigested in the form of iodized salt
: dietary iodine insufficient region
- goitrous hypothyroidism among adult
inadequate fetal thyroxine ( endemic goiter, cretinism)
Risk Factors
for Autoimmune Thyroid Disorders

Environmental factor
: pollutants, Ab to Yersinia enterocolitica

Immunoglobulin produced against the thyroid are
polyclonal, and the multiple combination of various
Ab present
Evaluation- Thyroid Function


T3RU % x T4 total = free T4 index
: T3,T4- binding protein TBG
: resin uptake- compete with TBG for T3 binding
: high T3 resin uptake
- reduced TBG receptor
→high T4 index→ hyperthyroidism
TSH
: best way to screen for thyroid dysfunction
Immunologic Abnormalities

Antithyroglobulin Ab (anti-Tg)
: hashimoto thyroiditis, Graves ds., acute thyroiditis,
nontoxic goiter, thyroid cancer

Antithyroid peroxidase Ab (anti-TPO)
: antimocrosomal Ab
: hashimoto thyroiditis, Graves ds., postpartum thyroiditis
: histology- lymphocyte thyroiditis

TSH receptor Ab (THSR-Ab or TRAb)
Autoimmune Thyroid Disease



Most common thyroid disease
: autoimmune thyroid disorder
combined effects of multiple Ab production
Transplacental transmission of immunoglobulin
: autoimmune disorder
: Hashimoto thyroiditis, Addison ds., ovarian failure,
RA, Sjogren synd., DM I, vitiligo, MG, ITP
Assessment of thyroid function
: infertile & pregnant women, AF, hyperemesis, DM I,
Hx. of postpartum thyroiditis, et al.
Hashimoto Thyroiditis




Chronic lymphocytic thyroiditis
Hyper-or hypothyroidism, euthyroid goiter, diffuse goiter
High level antimicrosomal & antithyroglobulin Ab
Histology
: cellular hyperplasia, follicular cell disruption
infiltration of lymphocyte, monocyte, plasma cell
: interstitial cell- fibrosis, lymphocyte infiltration
Clinical characteristics
: relatively asymptomatic with painless goiter and
hypothyroidism
: hypothyroidism- cold intolerance, constipation, fatigue,
carpal tunnel synd., dry skin, hair loss,
lethargy, Wt. loss
: hyperthyroidism- 4~8%
similar symptoms with Graves ds.
 Diagnosis
: elevated TSH, antithyroglobulin & antomicrosomal Ab
: ESR ↑ - depend on the course of disease


Treatment
: thyroxine (levothyroxine) replacement
- does not reduce gland size
but, prevents further growth
: monitor TSH at least 6 weeks
: 0.025~0.075 mg gd

Hypothyrodism
: decreased fertility resulting from ovulatory difficulties
& spontaneous abortion
: amenorrhea, anovulation
→ replacement therapy reverse these defects
Graves Disease




Suppressor T lymphocyte
→ develop helper T-cell population
→ that react to multiple epitopes of thyrotropin receptor
→ B-cell-mediated response
→ feature of Graves disease
TSAb (thyroid-stimulating Ab)
: 90% of Graves ds.
HLA II Ag
: upregulated by chronic stimulation of TSH receptor
→ reduction in the iodinating capacity of thyroid tissue
Use of interferon-α

Clinical characteristics
: triad- exophthalmos, goiter, hyperthyroidism
: frequent bowel movement, heat intolerance, irritability,
nervousness, palpitation, tachycardia, tremor, Wt. loss,
lower extremity swelling
: PEx.- lid leg, nontender thyroid enlargement, thick skin
cervical venous bruit
: severe- acropathy, chemosis, dermopathy, clubbing,
conjunctivitis, pretibial myxedema, vision loss

Diagnosis
: check T4, T3, and TSH
: useful in evaluating medical Tx, prognosis, and
anticipating neonatal thyrotoxicosis
: smoking- independent risk factor
Treatment

Iodine-131 Ablation
: single dose of radioactive iodine-131
: effective cure on about 80%
: nonpregnant women
: miscarriage rate ↑
but, no reported increase in the rate of stillbirths,
preterm labor, low birth weight, congenital malformation
or death
: postablative hypothyroidism in 50%
replacement levothyroxine
<Thyroid-stimulating receptor Ab in Graves disease>
: TSHR-Ab or TBII
: parallels the degree of hyperthyroidism
: measurement of TSHR-Ab
- useful marker of disease severity
- predictive of subsequent outcome

Antithyroid Drugs
: Propylthiouracil (PTU)
- 100mg tid over 1 months
high dose- control of thyrotoxic symptom
- blocks intrathyroid synthesis of T3
peripheral conversion of T4 to T3
- not cross placenta !!!
- S/E: appetite, emotional change, insomnia, tremor,
pruritus, granulocytosis, et al.
: Methimazole
- 10 mg every 8 to 24 hours
- nonpregnant women
→ if pregnant: skin lesion, aplasia cutis congenita
- but, longer dosing interval & lower cost
: iodine
- congenital goiter
: lithium
- Ebstein’s anomaly

Surgery
: subtotal thyroidectomy
: most rapid & consistent method for euthyroid state
: children, young women, pregnant, coexistent thyroid
nodule → potential candidates for thyroidectomy
: postoperative complication
- hypoparathyroidism, recurrent laryngeal nerve palsy,
anesthetic & surgical risk, hypothyroidism, failure to
relieve thyrotoxicosis

β- Blocker
: propranolol- hypersensitive to other medical therapy
Thyroid Storm

In severe hypothyroidism
: physiologic stress
- childbirth, systemic infection, surgery
: symptom
- diarrhea, vomiting, fever, dehydration, mental status
: treatment
- β-blocker, glucocorticoid, PTU, iodide
Hyperthyroidism in GTD and
Hyperemesis Gravidarum

Because weak TSH-like activity of hCG,
high hCG may be associated with biochemical and
clinical hyperthyroidism

Removal of GTD or resolution of hCG
: regress symptom
Thyroid Function in Pregnancy

High level of hCG at the end of 1st trimester
: thyrotropic effects of TSH
: TSH level may show transient depression

So, replacement thyroid hormone
: fetal or infant neurodevelopmental outcome ↑
Reproductive Effects of Hyperthyroidism

High level of TSAb in Graves ds.
: fetal-neonatal hyperthyroidism (2~10%)

Severe thyrotoxicosis
: Wt. loss, irregular menstruation, amenorrhea
: increased spontaneous abortion
: increased congenital anomalies
→ treated with methimazole

Risk of exposing a fetus to TAHR-Ab
: fetal-neonatal hyperthyroidism- 2~10%
: transplacental passage of TSHR-Ab
- 16% neonatal mortality
FDIU, stillbirth, skeletal anomaly
Postpartum Thyroid Dysfunction


Symptom appear 1 to 8 months postpartum
Be confused with postpartum depression
Diagnostic criteria
1) no Hx. of thyroid disorder before or during pregnancy
2) documented abnormal TSH level during the first year
postpartum
3) absence of positive TSH-receptor Ab titer (Graves ds.)
or toxic nodule





Incidence: 5%
: 25% of these women- permanent hypothyroid
Histologically,
: lymphocytic infiltration & inflammation
: antimicrosomal Ab
Familial Hx. or autoimmune ds. Hx.
: risk ↑
Clinical characteristics
: often begin with transient hyperthyroid phase
: type I DM- risk 3 times
: previous postpartum thyroiditis- 70% recurrence
TSH, T4,T3, T3 resin uptake, antimicrosomal Ab titer

Treatment
: T4 replacement
: 10~30% permanent hypothyroidism
: TSH follow up for discontinuation of replacement Tx.
Antithyroid Antibodies and
Disorder of Reproduction

Increased risk of spontaneous abortion

Serve as peripheral markers of abnormal T-cell function
and implicate an immune component as the cause of
reproductive failure
Thyroid Nudules
Common finding on PEx.
 Demonstrated by USG (>50%)
 Clinical and laboratory evaluation
: DDx. functional or malignant
 If notfunctional “cold” nodule
: FNA for R/O malignancy
: 2~20%- malignant
→ surgical biopsy

Gonadal Dysgenesis and Down Syndrome

Gonadal dysgenesis (ex. Turner syndrome)
: high prevalence of autoimmune thyroid disorders
: 50%- anti-TPO & anti-TG autoantibodies
: subclinical or clinical hypothyroidism

Down syndrome
: autoimmune thyroid disorder ↑
: most common- Hashimoto thyroiditis
50% of patients over 40 ages