Iron overload and hypogonadism

• 16 years old UAE national boy, aknown case of beta thalassemia intermedia and G6PD diagnosed at the age of 30 months.

• 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.

• 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.

• In 2008, bone mineral density was done – T score was -3 and Z score was -1.9 (osteoporosis) so he was started on zometa.

• In 2009 his echo was normal• He missed his appointment for MRI liver iron and MRI heart iron.

• 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)

• 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

Macrophage+

enterocytes

iron export protein ferroportin1(FPN1)

internalization and degradation of iron

reduces iron export into the plasma

HFE gene ,hypoxia,

increased erythropoietin

• 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.

in transfusion-induced iron overload

Iron+ transferrin

free non–transferrin-bound iron (NTB)

Liver and other tissuesTransferrin-bound iron (TBI)

increased in the hepcidin pathway

Liver and other tissues

high reduction-oxidation (redox) potential

generates oxygen-free radicals

damages DNA, proteins, and membrane lipids in the cell

chelatable labile plasma iron (LPInot found in healthy individuals

oversaturation

• 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• 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• No racial predilection has been described.

Sex• Hypergonadotropic hypogonadism is more common in males than in females • Incidence of hypogonadotropic hypogonadism is equal in males and females.

Age• Hypogonadism may occur at any age

Causes of hypogonadotropic hypogonadism in male and female

• CNS disorders

• Tumors – Craniopharyngioma – Germinoma – Pituitary tumor

• Miscellaneous causes – Vascular abnormalities of the CNS – Radiation therapy – Congenital malformations (especially associated with craniofacial anomalies) – Head trauma

• Genetic causes– 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 – 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

• Klinefelter syndrome • Inactivating mutations

– LH beta subunit – FSH beta subunit – LH receptor – FSH receptor

• Other causes of primary testicular failure – Chemotherapy – Radiation therapy – Testicular biosynthetic defects – Sertoli-cell-only syndrome – LH resistance – Anorchism and cryptorchidism

Causes of hypergonadotropic hypogonadism in females

• Turner syndrome

• Inactivating mutations – LH or FSH beta subunit – LH or FSH receptor

• XX and XY gonadal dysgenesis – 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 – Ambiguous genitalia

Symptoms during puberty – 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 – 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• Evaluation of the testes is the most important feature of the

physical examination.

• 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.

• Puberty should be staged using the Tanner criteria.

• 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 • loss of or non existent sense of smell

Physical examination

• Examination of the genitalia is important.

• Determine the extent of androgenization, which may be adrenal or ovarian in origin and is demonstrated in pubic and axillary hair.

• Determine the extent of estrogenization, as evidenced by breast development and maturation of the vaginal mucosa.

• 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

• The only issue of surgical relevance is whether gonadal tissue should be removed.

• 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.

• Males with nonfunctioning testicular tissue should undergo orchiectomy and replacement with prostheses.

Medical treatment• Although the simplest and most successful treatment for both

males and females with either hypergonadotropic or hypogonadotrophic hypogonadism is replacement of sex steroids.

• 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 gelTransdermal testosterone

• 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• Documented hypersensitivity• severe cardiac or renal disease• benign prostatic hypertrophy with obstruction• males with breast carcinoma• undiagnosed genital bleeding; for use only in males

Precautions• Too frequent or persistent erections• impaired liver or renal function

Testosterone (Andro-LA, Depo-Testosterone)

Testosterone patch (Androderm)

• 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

Interactions• Same as Testosterone (Andro-LA, Depo-Testosterone)

Contraindications• Same as Testosterone (Andro-LA, Depo-Testosterone)• hypercalcemia; for use only in males

Precautions• Same as Testosterone (Andro-LA, Depo-Testosterone)

Testosterone gel (AndroGel)

• 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

Interactions• None reported

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.

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• 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• Caution in hepatic impairment• migraine, seizure disorders• cerebrovascular disorders• breast cancer• thromboembolic disease

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• 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

Interactions• As in Ethinyl estradiol (Estrace)

Contraindications• As in Ethinyl estradiol (Estrace)

Precautions• 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

Estradiol, transdermal (Climara, Vivelle, Esclim, Alora, FemPatch)

Conjugated estrogen (Premarin)

Dosing• 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 progesteroneAfter 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• 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 agentsThese agents are added during the last 12-14 days of the menstrual

cycle.

Norethindrone (Aygestin)Transforms proliferative into secretory endometrium

Dosing • Adult:- 5 mg/d PO during final 12-14 d of menstrual cycle• Pediatric:- Administer as in adults

Contraindications• Documented hypersensitivity• thromboembolic disorders• Pregnancy• missed abortion• breast cancer• undiagnosed vaginal bleeding

Precautions• 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• Adult:- 5-10mg/d PO during last 12-14 d of menstrual cycle• Pediatric:- Administer as in adults

Interactions• As in Norethindrone (Aygestin)

Contraindications• Documented hypersensitivity• undiagnosed vaginal bleeding• Thrombophlebitis• liver dysfunction

Precautions• As in Norethindrone (Aygestin)

Follow upReevaluate patients receiving hormone replacement therapy every 6-12 months.

Prognosis• Men and women with hypogonadism can lead a normal life with

hormone replacement.

• 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

• Reports exist of women with mosaic Turner syndrome becoming pregnant without in vitro fertilization.

Thank you Any questions?