Transcript Document

Iron overload and
hypogonadism
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16 years old UAE national boy, aknown case of beta thalassemia intermedia and
G6PD diagnosed at the age of 30 months.
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1st transfusion:- 7 years.
started on regular blood transfusion at the age of 10
SC desferal Started on Feb. 2006 And he was shifted to exjade on oct. 2006.
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Bone age was 8 when he was 13 years old and his serum calcium was 8.6 so on
February 2007 endocrinal consultation was done.
Patient was started by the endocrinologist on one alpha, Calcium carbonate,
Sustanon, growth hormone and he is on regular follow up in the endocrine clinic in
DH.
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In 2008, bone mineral density was done – T score was -3 and Z score was 1.9 (osteoporosis) so he was started on zometa.
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In 2009 his echo was normal
He missed his appointment for MRI liver iron and MRI heart iron.
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Apart from hepatosplenomegaly his physical examination was
unremarkable
His serum ferritin on may 2009 was 345ng/ml
Now his height:-149cm weight:-35.8kg less than the 3th centile
BMI:- 16 (UNDERWEIGHT)
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• During normal physiology, the amount of iron absorbed (1-2 mg/d)
is lost by sloughing of intestinal mucosa and skin, as well as small
amounts in the urine and bile .
• The day-to-day iron requirements, are met by recycling between
various compartments.
• In patients who become transfusion-dependent, iron gradually
accumulates in various tissues, causing morbidity and mortality.
• Each unit of transfused blood has approximately 250 mg of iron
Pathophysiology
hepcidin
HFE gene,
hypoxia,
increased erythropoietin
iron export protein ferroportin1(FPN1)
Macrophage
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enterocytes
internalization and degradation
of iron
reduces iron export into the plasma
• β-thalassemia, excessive intestinal absorption also adds to the
transfusion-induced iron overload
• In thalassemia intermedia, high erythropoietic drive causes hepcidin
deficiency.
• In thalassemia major, transfusions decrease erythropoietic drive and
increase the iron load, resulting in relatively higher hepcidin levels.
In the presence of higher hepcidin levels, dietary iron absorption is
moderated and macrophages retain iron, but body iron stores
increase due to the inability to excrete iron in transfused red blood
cells
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in transfusion-induced iron overload
Iron+ transferrin
oversaturation
free non–transferrin-bound iron (NTB)
Transferrin-bound iron (TBI)
Liver and other tissues
Liver and other tissues
chelatable labile plasma iron (LPI
not found in healthy individuals
high reduction-oxidation (redox) potential
increased in the hepcidin
pathway
generates oxygen-free radicals
damages DNA, proteins, and
membrane lipids in the cell
• Hemosiderin is an abnormal, insoluble form of iron storage.
It consists of ferritin trapped in lysosomal membranes.
• Major organs affected by this iron include the heart, lung, liver, and
endocrine glands
• Neutrophils from patients with secondary iron overload have an
increased iron and ferritin content and a phagocytosis
defect. Yersinia enterocolitica seems to have affinity for those
loaded with iron, causing abdominal infections and hepatic
abscesses.
• Degenerative arthropathy in thalassemia is also a sequela of iron
overload
hypogonadism
Pathophysiology of hypogonadism
Mortality/Morbidity
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No increase in mortality is observed in patients with hypogonadism. In women,
an increased risk of severe osteoporosis is noted. In men, hypogonadism
causes decreased muscle strength and sexual dysfunction.
Race
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No racial predilection has been described.
Sex
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Hypergonadotropic hypogonadism is more common in males than in females
Incidence of hypogonadotropic hypogonadism is equal in males and females.
Age
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Hypogonadism may occur at any age
Causes of hypogonadotropic hypogonadism
in male and female
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CNS disorders
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Tumors
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Miscellaneous causes
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Vascular abnormalities of the CNS
Radiation therapy
Congenital malformations (especially associated with craniofacial anomalies)
Head trauma
Genetic causes
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Craniopharyngioma
Germinoma
Pituitary tumor
Kallmann syndrome (mutation in the KAL [anosmin] gene), with hyposmia or anosmia or without
anosmia
Congenital adrenal hypoplasia (mutation in the DAX1 gene)
Isolated LH deficiency
Isolated FSH deficiency
Idiopathic and genetic forms of multiple hormone deficiencies
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Chronic systemic disease and malnutrition
Exercise-induced amenorrhea
Miscellaneous disorders, including Prader-Willi syndrome, Laurence-Moon syndrome,),
hyperprolactinemia, marijuana use, and Gaucher disease
Cause of hypergonadotropic hypogonadism in males
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Klinefelter syndrome
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Inactivating mutations
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Other causes of primary testicular failure
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LH beta subunit
FSH beta subunit
LH receptor
FSH receptor
Chemotherapy
Radiation therapy
Testicular biosynthetic defects
Sertoli-cell-only syndrome
LH resistance
Anorchism and cryptorchidism
Causes of hypergonadotropic hypogonadism in females
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Turner syndrome
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Inactivating mutations
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XX and XY gonadal dysgenesis
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LH or FSH beta subunit
LH or FSH receptor
Familial and sporadic XX gonadal dysgenesis and its variants
Familial and sporadic XY gonadal dysgenesis and its variants
Other causes of primary ovarian failure
– Premature menopause
– Radiation therapy
– Chemotherapy
– Autoimmune oophoritis
– Resistant ovary
– Galactosemia
– Glycoprotein syndrome type 1
– FSH-receptor gene mutations
– LH/human chorionic gonadotropin (hCG) resistance
– Polycystic ovarian disease
Symptoms during fetal development
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Ambiguous genitalia
Symptoms during puberty
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Decreased development of muscle mass
Lack of deepening of the voice
Impaired growth of body hair
Impaired growth of the penis and testicles
Excessive growth of the arms and legs in relation to the trunk of the body
Development of breast tissue
Symptoms during adulthood
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Erectile dysfunction
Infertility
Decrease in beard and body hair growth
Increase in body fat
Decrease in size or firmness of testicles
Decrease in muscle mass
Development of breast tissue
Osteoporosis
Hypogonadism can also cause mental and emotional changes. As testosterone decreases,
some men may experience symptoms similar to those of menopause in women. These may
include:
– Fatigue
– Decreased sex drive
– Difficulty concentrating
– Hot flashes
Physical examination
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Evaluation of the testes is the most important feature of the physical
examination.
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Examining the genitalia for hypospadias is the next important step. Check
the scrotum to see if it is completely fused. Finally, evaluate the extent of
virilization.
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Puberty should be staged using the Tanner criteria.
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Look for signs of Klinefelter syndrome
Symptoms of hypogonadism in females
Effects of low estrogen levels in women may include: (not all are present in any
individual)
• Hot flashes
• Sleep disturbances
• Symptoms of urinary bladder discomfort like frequency, urgency, frequent
infections, lack of lubrication, discharge
• Shrinking of breasts
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loss of or non existent sense of smell
Physical examination
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Examination of the genitalia is important.
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Determine the extent of androgenization, which may be adrenal or ovarian
in origin and is demonstrated in pubic and axillary hair.
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Determine the extent of estrogenization, as evidenced by breast
development and maturation of the vaginal mucosa.
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Look for signs of Turner syndrome, such as short stature, webbing of the
neck (eg, pterygium colli), a highly arched palate, short fourth
metacarpals, widely spaced nipples, or multiple pigmented nevi.
treatment
Treat the primary cause if treatable
Surgical Care
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The only issue of surgical relevance is whether gonadal tissue should be
removed.
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Because of the significant risk of gonadoblastoma and carcinoma, gonadal
tissue should be removed in females with karyotypes containing a Y
chromosome. This situation is observed in females with XY gonadal
dysgenesis.
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Males with nonfunctioning testicular tissue should undergo orchiectomy
and replacement with prostheses.
Medical treatment
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Although the simplest and most successful treatment for both males and
females with either hypergonadotropic or hypogonadotrophic
hypogonadism is replacement of sex steroids.
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Sex steroid replacement does not result in increased testicular size in
males or fertility in either males or females. Gonadotropin or GnRH
replacement is offered to the patient when fertility is desired
Testosterone agents
Testosterone-Propionate
Testosterone gel
Transdermal testosterone
Testosterone (Andro-LA, Depo-Testosterone)
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Several testosterone salts (eg, enanthate, cypionate) are available in a long-acting
oil-based preparations.
dosing
Adult:- 200-400 mg/mo IM
Pediatric:- Initial dose (to initiate puberty): 100 mg/mo IM
Can increase up to adult maintenance dose
Interactions
Glucose metabolism altered with insulin
clotting factor metabolism altered with warfarin
Contraindications
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Documented hypersensitivity
severe cardiac or renal disease
benign prostatic hypertrophy with obstruction
males with breast carcinoma
undiagnosed genital bleeding; for use only in males
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Precautions
Too frequent or persistent erections
impaired liver or renal function
Testosterone patch (Androderm)
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Recent addition to the options for testosterone replacement. Several preparations are
available, including a scrotal patch (Testoderm) and several patches that may be
applied at other sites (Testoderm TTS, Androderm). Patches are changed daily.
dosing
Adult:- Topical patch: 2.5-6 mg/d
Pediatric:- Initial dose: 2.5-6 mg/d; dose should start with topical patch that releases
2.5 mg/d in boys who have had minimal prior testosterone exposure; increase
gradually to adult dose
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Interactions
Same as Testosterone (Andro-LA, Depo-Testosterone)
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Contraindications
Same as Testosterone (Andro-LA, Depo-Testosterone)
hypercalcemia; for use only in males
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Precautions
Same as Testosterone (Andro-LA, Depo-Testosterone)
Testosterone gel (AndroGel)
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An androgenic anabolic steroid. The preparation topically is administered as gel.
dosing
Adult:- 5-10 g (delivers approximately 50-100 mg) applied topically every am to
shoulders, upper arms, and abdomen
Pediatric:- Not established
None reported
Interactions
Contraindications
Same as Testosterone (Andro-LA, Depo-Testosterone)
boys <18 y
just after application, avoid direct contact with women who are pregnant
Precautions
Same as Testosterone (Andro-LA, Depo-Testosterone)
elderly patients
benign prostatic hypertrophy
Estrogen agents
Ethinyl estradiol (Estrace)
A small unopposed dose (0.02 mg) is administered daily for 3-6 mo, then the dose is
increased and cycled. After the first 6 mo, adding progestogen is often helpful.
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Dosing
Adult:- 0.02-0.1 mg/d PO alone for first 14-20 d of theoretical menstrual cycle,
followed by 12-14 d of additional progesterone preparation
Pediatric:- 0.02-0.1 mg/d PO
May be administered unopposed initially; after 6-12 mo, should be administered as in
adults
Interactions
May reduce hypoprothrombinemic effects of anticoagulants.
estrogen levels may be reduced with coadministration of barbiturates, rifampin.
an increase in corticosteroid levels may occur when administered concurrently with
ethinyl estradiol; use of ethinyl estradiol with hydantoins may cause spotting,
breakthrough bleeding, and pregnancy.
increase in fluid retention caused by estrogen intake may reduce seizure control.
Contraindications
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Documented hypersensitivity
known or suspected pregnancy
breast cancer
undiagnosed abnormal genital bleeding
active thrombophlebitis or thromboembolic disorders
history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with
previous estrogen use
for females only
Precautions
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Caution in hepatic impairment
migraine, seizure disorders
cerebrovascular disorders
breast cancer
thromboembolic disease
Estradiol, transdermal (Climara, Vivelle,
Esclim, Alora, FemPatch)
A very low starting dose of estrogen is desired in young girls with bone ages at or below
12-13 y.
If necessary, patches with a matrix-release mechanism (eg, Climara, Vivelle) may be cut
to deliver a smaller dose.
Dosing
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Adult:- Apply topical patch that delivers estradiol at rate of 0.025-0.1 mg/d; replace
qwk or 2 times/wk according to specific patch directions
Pediatric:- administer as in adults; start with lowest dose
As in Ethinyl estradiol (Estrace)
Interactions
Contraindications
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As in Ethinyl estradiol (Estrace)
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Certain patients may develop undesirable manifestations of excessive estrogenic
stimulation, such as abnormal or excessive uterine bleeding
estrogens may cause some degree of fluid retention
prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia
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Precautions
Conjugated estrogen (Premarin)
Dosing
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Adult:- 0.625-1.25 mg/d PO
Pediatric:- May be administered PO to initiate pubertal development in girls starting
at lower dose (0.3 mg/d) and advancing to higher dose (0.625 mg/d)
When dose is increased, may add progesterone
After 1-2 y, may increase to adult dose (1.25 mg/d on days 1-21 of cycle)
Contraindications
As in Ethinyl estradiol (Estrace)
Precautions
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Certain patients may develop undesirable manifestations of excessive estrogenic
stimulation, such as abnormal or excessive uterine bleeding or mastodynia;
estrogens may cause some degree of fluid retention (exercise caution); prolonged
unopposed estrogen therapy may increase risk of endometrial hyperplasia
Progesterone agents
These agents are added during the last 12-14 days of the menstrual cycle.
Norethindrone (Aygestin)
Transforms proliferative into secretory endometrium
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Dosing
Adult:- 5mg/d PO during final 12-14 d of menstrual cycle
Pediatric:- Administer as in adults
Contraindications
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Documented hypersensitivity
thromboembolic disorders
Pregnancy
missed abortion
breast cancer
undiagnosed vaginal bleeding
Precautions
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During lactation
impaired liver function,
congestive heart failure, or hypertension
fluid retention
depression
glucose intolerance
thromboembolic phenomena may occur
perform follow-up testing with Pap smears
Medroxyprogesterone (Provera, Amen,
Cycrin)
Dosing
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Adult:- 5-10mg/d PO during last 12-14 d of menstrual cycle
Pediatric:- Administer as in adults
Interactions
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As in Norethindrone (Aygestin)
Contraindications
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Documented hypersensitivity
undiagnosed vaginal bleeding
Thrombophlebitis
liver dysfunction
Precautions
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As in Norethindrone (Aygestin)
Follow up
Reevaluate patients receiving hormone replacement
therapy every 6-12 months.
Prognosis
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Men and women with hypogonadism can lead a normal life with hormone
replacement .
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Approximately 20-25% of females with Turner syndrome have some
spontaneous puberty.
Spontaneous estrogenization occurs more commonly in women with mosaic
karyotypes and those karyotypes with an abnormal second X chromosome
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Reports exist of women with mosaic Turner syndrome becoming pregnant
without in vitro fertilization.
Thank you
Any questions?