1
Q
Causing Hyperprolactinemia?
A
- Pituitary tumor
- 1° hypothyroidism
- Pregnancy
- Renal insufficiency
- Chest trauma
2
Q
Medications that Cause of Hyperprolactinemia
A
- Metoclopramide ***
- Risperidone ***
- Phenothiazine ***
- Butyrophenones • SSRI • Tricyclics • Opiates • Verapamil • Estrogen • ? H2 blockers
3
Q
PRL - Effects on LH / FSH
A
- Decreases LH, FSH
- lowers estradiol/tetstosterone
- Increases galactorrhea + hypogonadism + bone loss
- amanorrhea
4
Q
Women with Elevated PRL / how do they present:
A
31-year-old female with PRL 60
- Amenorrhea
- Galactorrhea
- Infertility
- Microadenoma, PRL corresponds to tumor size
- Hypopituitarism rare
5
Q
Male with Elevated PRL / how do they present:
A
52 yo male w PRL 2000
- Diplopia
- Headache
- Macroadenoma
- Hypopituitarism
- Galactorrhea / gynecomastia rare
6
Q
Macroadenoma
A
>= 10 mm in size
7
Q
Prolactinomas Tx
A
- Transsphenoidal surgery associated with recurrent hyperprolactinemia (high rate)
- Long-term remission of hyperprolactinemia uncommon
- Cabergoline more potent, better tolerated
- BromocriPtine preferred when Pregnancy desired
- Neither drug teratogenic
- Microadenomas rarely grow / Macroadenomas require long-term therapy to prevent growth
8
Q
GH Secretion (origin / agonist / antagonist / effect)
A
Hypothalamus
+ GHRH -Somatostatin
Pituitary
GH
Liver
IGF
9
Q
Acromegaly
A
- Coarse facial features / does not have to be bone growth
- Soft tissue thickening
- “Spade-like” hands
- Excessive sweating / Body odor
- Goiter
- Macroglossia / may require trach
- Impaired glucose tolerance / DM
- PRL co-secretion
- Cardiac hypertrophy main cause of mortality
- Colonic polyps
10
Q
Dx of Acromegaly
A
- High IGF-1
- GH not suppressed after glucose
- Macroadenomas / radiographic confirmation
11
Q
Acromegaly Treatment
A
- Transsphenoidal surgery - 70-80% success rate
- Medical therapy
- Somatostatin | octreotide (Sandostatin) or lanreotide (Somatuline).
- Dopamine agonist is less effective | Bromocriptine (Parlodel) or Cabergoline.
12
Q
Nonfunctioning Pituitary Tumor - Treatment
A
- Most common Macroadenomas no evident hormone excess
- Elevated LH, FSH sometimes
- Alpha subunit glycoprotein hormone
- In men, clinical picture similar to that of a prolactinoma
- Hypopituitarism (partial or complete)
- Treatment is surgery, no effective medical therapy
13
Q
Evaluation of Pituitary Function
FLAT GP
A
Testosterone/estradiol
FSH/LH
Cortisol (ACTH)
FT4 (TSH)
(GH/IGF-1)
PRL
14
Q
Stalk compression leads to
?ADH, ? PRL, ? anterior pituitary hormones
A
- Decrease ADH / pituitary hormones
- Increase PRL
15
Q
Hypopituitarism
A
- Pituitary thyroid axis
- FT4, TSH
- Pituitary adrenal axis
- cortisol, ACTH
- Pituitary gonadal axis
- testosterone/estradio LH, FSH
16
Q
Causes of Hypopituitarism
A
- Infiltrative processes
- Sarcoidosis
- Hemochromatosis
- Metastases
- Pituitary apoplexy
- Sheehan Syndrome
17
Q
Replacement Therapy for Hypopitiutarism
A
- Thyroid - Levothyroxine - Monitor with FT4
- Adrenal - Prednisone usually OK
- Gonadal - Oral contraceptive - Androgen
18
Q
Empty Sella
A
- Normal pituitary function
- May be associated with benign intracranial hypertension
- Random findings on Imaging
19
Q
Pituitary apoplexy
A
- Severe headache / Neurosurgical emergency /ACTH deficiency common
20
Q
Sheehan Syndrome
A
Enlarged pituitary and tenuous blood supply with loss post hemorrhage
- One or more pituitary hormones affected
- Failure to lactate (PRL)
- Amenorrhea (LH)
- Loss of axillary/pubic hair (ACTH)
21
Q
Pituitary incidentolomas
A
If large need to follow up in 6-12 months with imaging
22
Q
Posterior Pituitary
A
ADH** and **oxytocin are synthesized in brain and transported to posterior pituitary and released directly
23
Q
Diabetes Insipidus Nephrogenic DI
-Treatments
A
Nephrogenic Dl
- Normal ADH levels
- Renal resistance to H2O retaining effect
- Lithium
- Hypercalcemia
TX: Low Na diet/ Thiazide or Amiloride
24
Q
Diabetes Insipidus Central DI Treatments:
A
- Lack of ADH
- Idiopathic
- Pituitary surgery
- Trauma
- TX: Intranasal Or Oral Desmopression
25
Diabetes Insipidus
- Polyuria - Dilute urine - Hypernatremia
26
TEST for DI
H2O deperivation Rasing Plasma Osmolality leads to increase in ADH and urine osmolality (once 300) give Desmopression Central DI will have 50% incrase in Urine osmolality
* Nephrogenic will see no change.
27
Assessment of Thyroid Function
* Free T4 (FT4)
* TSH
* Antithyroid antibodies
* 24-hr iodine uptake
* Technetium or iodine scan
* Ultrasound
28
Primary Hypothyroidism
* Ab to thyroid microsomes, thyroglobulin, and TSH receptor / however could be negative does not mean anything.
* With or without goiter
* More common in women
* Other autoimmune disease
* Low FT4, High TSH due to Hashimatos / autoimmune thyroiditis
* Anti-thyroid peroxidase / Thyroid Microsomal Ab (anti-TPO) - Hashimatos 90%
* Thyroglobulin antibodies - Hashimatos
* TSH receptor antibodies - Graves (eye dz)
* Thyroid-stimulating hormone - Graves
29
Secondary Hypothyroidism
* Pituitary/hypothalamic disease
* Look for other signs of pituitary dysfunction
* FT4 low, TSH low
* Don't use TSH to monitor therapy - Due to pituitary tumors / hypothelamic dz, trauma etc
30
Thyroid Hormone Replacement
* OK to start full replacement dose except in elderly and in patients with CV disease
* **_Levothyroxine best choice_** / Normal 1.7 mcg/kg
* Repeat TFTs in 8-10 weeks
* Annual visits after levels are normal
* Avoid T3 and T4/T3 combinations
* Conversions 200 mcg **_levothyroxin_** = 25 mcg liothyronin = 60-65 thyroid (porcine)= 1 grain liotrix
* T4 Levothyroxin has longer half life
31
Suppressive doses of T4
* Its done in some patients with history of Thyroid cancer but must becareful with
* Cardiomyopathy
* Bone loss
32
T4 Replacement in Pregnancy
* Need levothyroxine increases by about 50% / This is due to increase in Protien leves (Thyroglobulin )
* Increased need persists throughout pregnancy
* Hypothyroidism is mild
* TSH returns to normal after delivery
33
DDx Hyperthyroidism
FT4 TSH / High or low
Graves
Hot nodule
Thyroiditis
Toxic goiter
How to differentiate ?
FT4 TSH
Graves High Low
Hot nodule High Low
Thyroiditis High Low
Toxic goiter High Low
A thyroid scan and RAIU can help determine etiology.
34
Hyperthyroidism Sx
* Clinical features
* Weight loss, tremor, fatigue, amenorrhea,palpitations, heat intolerance, hyperdefecation
* Apathetic thyrotoxicosis in elderly
* FT4 levels do not always correlate with symptoms
35
Graves Disease
* Graves Disease
* Autoimmune
* Thyroid stimulating antibodies bind to TSH receptors
* Diffuse thyroid enlargement
* Orbitopathy
* Increase RAI uptake
36
Treat Graves
* Antithyroid Drugs
* Radioactive iodine
* Surgery
37
Treat Graves
Antithyroid drugs
* Antithyroid drugs
* Methimazole (once a day)
* Propylthiouracil (TID / 1st Trimaster of Pregnancy / advantage it also inhibits T4 to T3 conversion)
* PTU is associated with **_high liver toxicity during pregnancy after first trimaster_**
* Decrease TSIG (Thyroid stimulating IG) and block T4 synthesis
* 30-50% have spontaneous remission after year of therapy
* **_Agranulocytosis_** rare
* Rash
* Rare cholestatic hepatitis
38
Treat Graves
Radioactive Iodine
* Gland destruction
* TSH receptor antibodies persist after treatment
* Avoid RAI in patient with severe Graves ophthalmopathy
* 90% success rate after a single dose
* Slow process // some patients stay euthyroid
* post RAI / _**do free T4** as TSH does not come down for a while_
39
Graves Treatment
Surgery
* Recurrence is possible
* Potential hypocalcemia and recurrent laryngeal nerve damage
* Use for nodules or extremely large glands
40
Hyperthyroidism in Pregnancy
* Keep FT4 at upper limit of normal range
* Use PTU in first trimester
* Radioactive **_iodine contraindicated_**
**_Propylthiouracil_** (TID / 1st Trimaster of Pregnancy / advantage it also inhibits T4 to T3 conversion)
PTU is **_associated with high liver toxicity during pregnancy after first trimaster_**
41
Thyroid Storm
1. BBlk / Give Methimazole high dose / 100 mg hydrocortisone as well
2. Cold Iodine
* Exaggerated symptoms of hyperthyroidism
* Surgery, infection, iodine load
* First block T4 synthesis then block T4 release
* Glucocorticoids and PTU decrease T4 -\> T3 conversion
42
Random crap
1. Surreptitious Use of Thyroid hormone and Thyroglobulin hormone level
2 Graves disease and lenght of dz
3 Subacute thyroiditis and palpation
4. Toxic multinodular goiter and palpation
1. Thyroglobulin would be low / acute settings
2. Graves would be more chronic type of picture lenght wise
3. could be tender with high thyroglobulin levels
4. should palpate more nodules
43
Subacute or Painless Thyroiditis
* Painful gland, ear pain
* Elevated ESR
* Mild hyperthyroidism
* Hyperthyroid phase followed by transient hypothyroidism
* Usually resolves without Rx
44
**Graves vs Thyroiditis**
**_Graves_**
TSIG
I
thyroid hormone synthesis (seen on scan)
I
high T4 and T3
I
suppressed TSH
**_Thvroiditis_**
inflammation
I
release of thyroid hormone (n***o synthesis and not seen on sca***n)
I
high T4 and T3
I
suppressed TSH
I
Lower thyroid hormone synthesis
45
Postpartum Thyroiditis
* Silent, painless
* Hyperthyroid phase followed by hypothyroidism
* Decreased RAI uptake
46
A healthy 24 yo noted a thyroid nodule last week.
It is nontender; she feels great, and her exam is
normal. What is next?
Who is at a higher risk with malignant nodules?
TSH T4 levels & U/S
**_Higher risk for malignant nodules_**
* History of radiation exposure
* Family history
* Male
* Nodule t\* in size
* Age \< 20 or \> 70
47
What to expect after U/S FNA
48
Management after FNA
Management after FNA
• Malignant
- Surgery and RAI ablation
• Follicular neoplasm/nondiagnostic
- Surgery
• Benign
- Yearly follow-up / if has grown over 50% then fna
49
Thyroid Nodules Discovered Incidentally
• Ultrasound
- Cystic vs. solid
- Number and size of nodules
• Refer for ultrasound guided FNA if nodule(s)
\> 1 cm or suspicious characteristics
50
Multinodular Goiter
* Surgery if symptomatic
* Suppressive therapy not uniformly effective
* Thyroid cancer risk is the same in solitary nodules and multinodular goiter
* Usually euthyroid
* Dysphagia, hoarseness with substemal extension
* Nodule size and characteristics determine whether FNA is necessary
* Heterogeneous uptake on scan
51
Myxedema Coma?
Treatment:
• Rare with Extreme hypothyroidism
• Preexisting thyroid disease likely
• Stroke, infection may precipitate coma
• Mental status changes and hypothermia
Tx: with IV levothyroxine until oral is tolerated (usually with half the recommended)
- Glucocorticoid coverage
- Avoid T3 especially in elderly
52
Adrenal Disorders
* Gushing syndrome
* Adrenal insufficiency
* Adrenal incidentalomas
* Hyperaldosteronism
* Pheochromocytoma
53
Gushing Syndrome
* ACTH-secreting pituitary tumor
* Adrenal adenoma/carcinoma
* EctopicACTH production
* Exogenous glucocorticoid
Cushing Dz - relates to pituitary Dz
54
Cushings Features
* Centripetal obesity
* Violaceous striae
* Proximal muscle weakness
* Amenorrhea
* Thin skin/ Bruising
* Weight gain
* Glucose intolerance
* Hypertension
* Hypokalemia
* Edema
* Best two predictors : proximal weakness (cant do squads) Amenorrhea for women, Very thin skin (steriods breakdown collagen under the skin / easy to break)
55
Ectopic ACTH
• Small cell lung cancer
• Lack classic stigmata
• Hypokalemia
• Metabolic alkalosis
• Muscle weakness
**_• Hyperpigmentation_**
They will not be obese
Tiad : Hyperpigmented / hypokalemia refractory / muscle weakness
56
Screening for Cortisol Excess?
• 1 mg DST
-1 mg Dex at 11 p.m. then 8 a.m. cortisol
- If cortisol \< 2 meg Cushing's is excluded
• Urinary free cortisol
- Most sensitive
57
1 mg Dex test False positives ?
- False positives / Because these guys will not suppress
- Dilantin®, estrogen, obesity, stress, depression
58
Flow chart for Excess Glucocorticoid work up
1. Screening Test (1 mg Dex suppression test)
- Stop if negative
2. Confirm Test (increase dose)
- Stop if negative
3. Get ACTH
- If ACTH Undetectable (Adrenal)
If ACTH is Lelevated (Pituitary vs Ectopic ) will Need DST to differentiate
59
Elevated Cortisol levels
Patients with Adrenal Adenoma will not suppress and ACTH undectable
Patients with Ectopic ACTH will not suppress and have very High ACTH
Pateints with pituitary hyperfunction will suppress still elevated cortisol level and ACTH is elevated
60
Pituitary Tumor Treatment
1. Cushing
2. Prolactinomas
3. Acromegaly
1. Surgery TSS
2. Medical therapy
3. Surgery TSS
61
Treatment of Cushing's
1. Pituitary tumor
2. Adrenal adenoma/carcinoma
3. Ectopic ACTH
• Pituitary tumor
- Transsphenoidal surgery
• Adrenal adenoma/carcinoma
- Adrenalectomy
• Ketoconazole, aminoglutethimide for ectopic ACTH
or if surgery not feasible
62
Primary Adrenal Insufficieny
What is it?
Clinical Features of Primary Al?
Causes?
Laboratory Features of Primary Al
Hypo-Na, hyper-K, 4, hypo-CO2
hypoglycemia
low cortisol, high ACTH
**_Causes of 1°AI_**
• Autoimmune
• Adrenal hemorrhage
• Tuberculosis
• HIV associated
• Medication
- Ketoconazole / Megase
**_Clinical Features of Primary Al_**
• Fatigue and weakness
• Hyperpigmentation
• Hypotension
• Postural dizziness
• Abdominal pain
•Weight loss
63
Autoimmune dz
Polyendocrine Failure
• Hashimoto's
• Addison disease
• Diabetes
• Hypogonadism
• Hypoparathyroidism
• Pernicious anemia
• Vitiligo
64
How to test for primary adrenal Def
Short Cortrosyn Stimulation is much better then just sending levels
65
Therapy of 1° Adrenal Insufficiency
Treatment
Addison's
* Hydrocortisone ± fludrocortisone
* Prednisone and dexamethasone have no mineralocorticoid activity
* Monitor therapy clinically (BP) and with electrolytes / you can not measure cortisol / ACTH (usually stays high and does not come down)
* Add mineralocorticoid if K remains elevated or CO2 not improved
* Can't use ACTH or cortisol to monitor therapy
* Consider later onset of other autoimmune disease
66
2° Adrenal Insufficency
Features ?
Features of 2° Al
* • Fatigue
* • Weight loss
* • Loss of axillary and groin hair
* • Normal lytes
* • Normal BP
67
2° Adrenal Insufficency
## Footnote
Causes?
* Pituitary tumor
* Sarcoidosis
* Hemochromatosis
* Glucocorticoid therapy
* Megestrol acetate
• Cortisol deficiency is due to absent ACTH, not to adrenal dysfunction
• Symptoms nonspecific
- Fatigue prominent
• No hyperpigmentation
• Normal electrolytes and B/P
• Cortisol Low , ACTH Low
68
2° Adrenal Insufficency
Test?
Treatment?
Test Cortrosyn Simulation /
* Glucocorticoid only usually
* Prednisone OK
* Monitor clinically not with cortisol or ACTH
* Be sure to address thyroid function
69
Dexamethasone suppression test
The test is given at low (usually 1–2 mg) and high (8 mg) doses of dexamethasone and the levels of cortisol are measured to obtain the results
To Differentiate between cushing's
* **_Primary Adrenal Cushing syndrome is likely._**
**_ACTH_**: undetectable or low **_Cortisol_**: Not suppressed by high or low doses.
* **_Ectopic ACTH syndrome_**
**_ACTH: _**normal to elevated **_Cortisol: _** is not suppressed by high or low doses
If an adrenal tumor is not apparent, a chest CT and abdominal CT is indicated to rule out a different tumor secreting ACTH.
* **_Cushing's disease should be considered._**
**_ACTH_**: elevated **_Cortisol_**: is not suppressed by low doses, but is suppressed by high doses
A pituitary MRI would be needed to confirm.
70
Cortrosyn Stimulation
Cosyntropin stimulation test
if \> 18 AI ruled out //// If \< 18 then ACTH level
If ACTH Low/Normal - Secondary or Tertiary AI
IF Elevated ACTH then Primary AI
71
Secondary AI
What else should wathc out for?
• May be accompanied by global pituitary
dysfunction
• 2° hypothyroidism
- Low FT4, Low TSH
• Hypogonadism
-Low T or E, Low FSH
72
Adrenal Incidentaloma
Size?
Active hormones to watch for?
* *_• Size?_**
- \> 4 cm send to surgery
* *_• Hormonally active?_**
- Glucocorticoid excess
- Mineralocorticoid excess
- Adrenal androgen excess
- Catecholamine excess
73
What to screen for in All Adrenal Incidentalomas?
1 and 2 are important
**_1. Pheochromocytoma_**
- Urine or plasma catecholamines
**_2. Do a 1 mg DST to screen for Cushing's 8 a.m._**
cortisol \< 2 normal / This is to rule out subclinical cushings
**_Screen for mineralocorticoid excess if_**
• Patient is hypertensive
- Measure potassium and plasma renin/aldo ratio
**_• Screen for androgen excess in hirsute woman_**
- DHEA-S
- Androstenedione
**_Follow-Up_**
• Repeat **_CT 6-12 months_**
• Surgery if mass increases in size
• No consensus on need or timing of repeat hormone testing
74
Pheochromocytoma
* **_Plasma-free_** metanephrines (if negative your free to go but if positive you need to do Urine)
* **_Fractionated urine_** metanephrines and catecholamines
* CT scan with contrast
* May be hyperintense on T2 weighted MRI
* Surgery definitive treatment, pretreat with **_phenoxybenzamine _**
* Most secrete norepinephrine
* 90% arise in adrenal
* 90% of patients have sustained hypertension
* Triad of **_headache, diaphoresis, palpitations classic_**
* Avoid B-blocker until adequate a blockade
**_MEN IIb (2Ms,1P)_** - Medullary Thyroid Ca, Marfanoid habitus/mucosal neuroma, Pheochromocytoma
75
MEN I
MEN II a
MEN II b
* *_MEN I (3 Ps)_** - Pituitary, Parathyroid, Pancreas
* *_MEN IIa (1M,2Ps)_** - Medullary Thyroid Ca, Pheochromocytoma, Parathyroid
* *_MEN IIb (2Ms,1P)_** - Medullary Thyroid Ca, Marfanoid habitus/mucosal neuroma, Pheochromocytoma
76
Primary Aldosteronism
Test:
Treatment:
* Hypertension / Hypokalemia / Low Renin
* Plasma **_aldo/renin ratio \> 20 _**
* _Bilateral hyperplasia_ or single adenoma
* If PAC/renin ratio is high, see if the **elevated aldosterone** can be suppressed using an IV or oral saline load
* If can not suprress then get CT
**_Treatment_**
* *_• Bilateral hyperplasia_**
- Spironolactone or eplerenone
* *_• Adenoma_**
- Surgery
77
Gonadal Disordersl
primary or secondary Amenorrhea
Androgen excess
PCOS
Male hypogonadism
Gynecomastia
78
Amenorrhea
Primary / Secondary
Tests used
• **_Primary_**
- No menses by age 16
- Gonadal or pituitary origin
• **_Secondary (More common)_**
- Absence of periods for 6 months
- Gonadal or pituitary origin
**_Tests:_**
**• Pregnancy test**
• Estradiol / will be low
• LH/FSH
• Prolactin / causes amenorrhea
• Free T4/TSH
• Progesterone challenge test
79
Causes
Central
Gonadal/other
* **Central Causes of Amenorrhea***
- Hypothalamic
- Pituitary tumor
- Craniopharyngioma
- Kallmann syndrome
* **Gonadal/Other Causes of Amenorrhea***
- Turner's
- Premature ovarian failure
- Androgen excess
* **Central **
* Low, LH, FSH
* Low, estradiol
* **Ovarian**
* High LH, FSH
* Low, estradiol
80
Ovarian Failure and younger than 30
Ovarian Failure
• If woman younger than 30, do karyotype even if
classic stigmata of Turner's are lacking.
81
Turner Syndrome
Turner Syndrome
• XO gonadal dysgenesis
• Bicuspid aortic valve
• Hypertension
• 1° hypothyroidism
• Glucose intolerance
• Short stature
• Estrogen and GH
82
Causes of 2° Amenorrhea
Causes of 2° Amenorrhea
• PCOS
• Prolactinoma
• Cushing's
• Hypothalamic
- Tumor
- Infiltrative
• Chemotherapy
83
Premature Ovarian Failure
Premature Ovarian Failure
• Secondary amenorrhea before menopause
• Generalized ovarian sclerosis and decreased follicles
• Irradiation, chemotherapy
• Autoimmune dysfunction
• Look for other autoimmune disease —thyroid/adrenal
84
Hypothalamic Amenorrhea
Hypothalamic Amenorrhea / Athletics usualy
• Low body wt
• Low body fat
• I GnRH secretion from hypothalamus
85
Kallmann Syndrome
* Rare / Hypogonadism + Anosmia (hypothalamus)
* Isolated GnRH deficiency
* Mid line defects (cleft palets)
* Anosmia
* Low Estradiol, Low LH, Low FSH
86
Polycystic Ovarian Syndrome
* Amenorrhea/oligomenorrhea
* Hirsutism / Acne / Obesity / Insulin resistance
* High LH:FSH ratio **(Diagnostic with PCOS)**
* Testosterone mildly Elevated
* DHEA-S mildly Elevated
**_PCOS Treatment_**
• Weight loss
• _Oral contraceptive (hair growth)_
- Low androgen progestin
• _Metformin_
**_-_ Lowers testosterone**
• _Medroxyprogesterone (every three months they need provera)_
- Endometrial protection
87
Spironolactone
Remember Oral Contraceptives have same effect
* lowers Testosterone synthesis
* Competes with testosterone at receptor / DHT at hair follicles
* 9-12 months to see an effect
* Contraindicated in pregnancy
88
Causes of Androgen Excess
Causes of Androgen Excess
• Ovarian tumor ( most important not to miss / causes virilization / increase testostrone)
• Adrenal tumor
• PCOS
• Congenital adrenal hyperplasia (21 hydroxylase def)
• Drugs
- Danazol
- Cyclosporine
* Last onset Congenital Adrenal Hyperplasia / 20's hair growth / menstral issues
89
Hirsutism vs Virilization
**_Hirsutism_**: Excessive growth of hormone dependent
pubic, axillary, abdominal, chest, and facial hair
**_Virilization_**: Clitoromegaly
temporal balding
hirsutism
Increase muscle mass
**_Virilization_** (ovarian vs Adrenal)
Will need a Pelvic exam.
90
Diagnostic Studies
• Adrenal androgens
- DHEA-S
- Androstenedione
• Testosterone
- Derived from ovaries and conversion from androstenedione
91
Ovarian tumor vs Adrenal tumor
* Virilization represents serious cause of androgen excess
* Ovarian tumor, very high testosterone
* Adrenal tumor, very high DHEA-S
* Transvaginal ultrasound and/or abdominal CT
92
Congenital Adrenal Hyperplasia
• 21-hydroxylase deficiency
• Rare: 0.1-1% of women
• Hirsutism at menarche, oligo, oramenorrhea in early adulthood
• 17-OH progesterone before and after ACTH
**_Treat_** with glucocorticoid to suppress ACTH stimulation of adrenal
93
Menopausal Issues
* Hot flashes occur in 75%
* Sleep and mood disturbances
* **Short-term estrogen treatment of choice**
* **SSRI effective** — use with caution in breast cancer
* Gabapentin (not very well tested)
* Progesterone (not as effective)
* Efficacy of alternative therapy not established
94
Male Hypogonadism
**_Central_**
• Hypothalamic
• Pituitary tumor
• Craniopharyngioma
• Kallmann syndrome
**_Gonadal_**
• Chemotherapy
• Injury
• Klinefelter's
95
Klinefelter's Syndrome
* Low Testosterone, High LH/FSH
* XXY karyotype
* Arm span \> height
* Eunuchoid habitus
* Atrophic testicles
* Infertility
* Gynecomastia
96
Gynecomastia
Causes?
Workup?
• **_Causes_**: Puberty (upto 60%) , old age, estrogen
hyperthyroidism / testicular tumors
Klinefelter syndrome
androgen therapy (testostrone therapy)
estrogen, spironolactone, digoxin
**_Gynecomastia Workup_**
• B-HCG (testicular Ca) / • Estradiol / • Prolactin / • Testosterone / •FT4
97
Testosterone Replacement
To deferintiate between central or gonadal low testostrone do FSH levels
• Testosterone enanthate/cypionate
- Injection q 2-3 weeks
• Daily topical androgen
• Adverse events
- Gynecomastia
- increases PSA
- increases Hct
- Prostatic enlargement
- Increase HDL
- Worsens sleep apnea
- Use with caution in **_elderly_** and those with
heart disease
- Don't use in individuals with obstructive
sleep apnea
98
Calculate LDL
LDL = TC - HDL - TG/5
99
ATPIII Guidlines:
Major Risk Factors CAD/
When to start therapy LDL
* Smoking
* BP\> 140/90
* Men \> 35, women \> 55
* HDL \< 40
* Family history of premature CAD (male \< 55, female \< 65)
100
Statins
* Block HMG Co-A reductase
* Lowering CHD events mortality by 25%
* Myalgias rarely
* Myopathy worse with **gemfibrozil / Niacin**
USE pravastatin on Elderly
101
Statins and TLC in All Diabetics
Any DM has to be on a STATING
• Overt CVD
• With no overt CVD and age \< 40 consider statin if
LDL \> 100 with multiple CVD risk factors
• With no overt CVD primary goal is LDL \< 100
• With overt CHD a goal of \< 70 is an **_option_**
102
Triglycerides and HDL Targets
**• Triglycerides**
-
**• HDL**
- \> 40 in men
- \> 50 in women
**• LDL is primary target**
103
Nicotinic Acid
* Blocks LDL synthesis
* Lower LDL
* Increase HDL **_\*\*_**
* Lower TG
* Flushing, hyperuricemia, hepatotoxicity / Try to not use with DM
104
Fibrates
• Gemfibrozil
- Lower TG **_\*\*\*_**
- Increase HDL
-Lower LDL
• Fenofibrate best combination with a statin
105
A 50 yo had the lipid profile below at a recent office
visit. She does not smoke, takes no medications,
and herBPis 119/80.
TC 220, HDL 40, LDL 125, TG 250
When TG is 200-250, estimate non-HDL
cholesterol.
Non-HDL = TC - HDL
non-HDL goal is 30 mg/dL higher than LDL goal
non-HDL = 220-40 = 180
106
CVA - LDL treatment goals
Coronary artery equivalent disease. The goal is
\< 100, and a statin would be first-line therapy.
107
Diagnosis of Diabetes
• **_A1c\>6.5%_**
or
• **_FPG\>126_**
or
• **_2-hr glucose \> 200 on 75 gm OGTT_**
or
• **_Random glucose \> 200**_ and _**symptoms_**
108
Prediabetes
• FBG 100-125
or
• A1c 5.7-6.4%
or
• 2-hr glucose 140-199 on 75 gm OGTT
109
Pramlintide
* Synthetic amylin
* Use with insulin before meals
* Prolongs gastric emptying
* Reduces postprandial glucose
* Appetite suppression
* Hypoglycemia
Mechanism of Action: amylin, a small peptide hormone that is released into the bloodstream by the β-cells of the pancreas along with insulin, after a meal.[1] Like insulin, amylin is completely absent in individuals with Type I diabetes.[2]
110
Testing in Asymptomatic / SCREENING
Testing in Asymptomatic
• Adults with BMI \> 25 and 1 other **_risk factor_**
- Family history
- Gestational DM
- Hypertension
-CVD
• In others, test at 45 and then at 3-year intervals
if normal
111
**_Glycemic Control and Complications / Studies_**
* **_DCCT and UKPDS_**
* 60% and 25% reduction in microvascular complications (eye and Kidney can be improved)
* **_ACCORD (NEJM 2009)_**
* Increased mortality, no CV benefit / A1C lowered but no macrovascular
* **_ADVANCE and VADT (NEJM 2008)_**
* No increase in mortality, no CV benefit / lower levels of A1C but no improvement
112
DM Retinopathy Screening / Neuropathy / Nephropathy
***_Retinopathy Screening_***
* Adults with Type 1 within 5 years after onset
* Type 2 shortly after diagnosis
* Retinal photography is a screen not an eye exam
113
DM Targets
• Blood pressure -\< 130/80
- When RX necessary, use ACE inhibitor or ARB
- Pregnant patients 110-129/65-79
- No ACE or ARB in pregnancy
**_Aspirin (75-162 mg/day)_**
• Primary prevention in those with increased CV risk (10-yrrisk\> 10%)
• Risk of bleeding may offset beneficial effects for those with DM and low CVD risk
• Secondary prevention in those with DM and history of CVD
• For ASA allergy, use clopidogrel
114
/ Neuropathy screening in DM
* Screen annually with simple clinical tests
* Electrophysiologic testing rarely needed
* Optimize sugar control, use medication to improve QOL
115
Nephropathy in DM /Screening
• Urine albumin annually
- Type 1 after 5 years
- All Type 2 at diagnosis
• Serum creatinine and estimated GFR annually
• ACEI and ARBs delay progression of nephropathy
116
Insuline and Surgery
Pt with Type I never stop long acting insuline / can stop Lispro
Type I in MICU / Gtt keep sugars between 140-180
117
Effectiveness Lowering A1c
* Metformin 1.0-2.0%
* Sulfonylurea 1.0-2.0%
* Thiazolidinediones 0.5-1.4%
* Acarbose 0.5-0.8%
* Meglitinide 0.5-2.0%
118
Metformin
* No weight gain or hypoglycemia
* Start with 500 mg daily, increase slowly to 2,500 mg maximum
* Renal/Liver function
* Takes 8-12 weeks to see effect
Renal function cr \> 1.4 / CHF / Elderly
Mechanism of action: primarily by suppressing glucose production by the liver (hepatic gluconeogenesis)
119
Sulfonylureas / Glipizide, Glibenclamide (glyburide), Glimepiride
* Effectiveness decreases over time
* All cause hypoglycemia
* Use short-acting ones to reduce hypoglycemia
* Glipizide half-life 14-16 hours
* Glimepiride and glyburide half-life 24 hours
**_Mechanism of action:_** They act by increasing insulin release from the beta cells in the pancreas.
120
Meglitinides / nateglinide (Starlix) , repaglinide (Prandin)
* Repaglinide, nateglinide
* Rapid acting, short half-life
* Effect on postprandial glucose
**_Mechanism of Action:_** bind to an ATP-dependent K+ (KATP) channel on the cell membrane of pancreatic beta cells in a similar manner to sulfonylureas but at a separate binding site.
121
Thiazolidinediones (Rosiglitazone (Avandia), Pioglitazone (Actos))
• Enhance insulin secretion
• Weight gain, edema
• CHF (FDA warning)
• Myocardial ischemia
• Fractures / bladder cancer
Arch Intern Med 169, 2009
122
When to initiate insulin therapy
* A1c\>10%
* Severe symptoms of hyperglycemia
* Consistently high glucose
123
Exenatide (Byetta, Bydureon)
* GLP agonist (glucagon-like peptide-1 agonist )
* Weight Reduction
* Increases Insulin secretion
* Lowers Gastric emptying (becareful with Gastroparesis)
* Lowers Glucagon
* Pancreatitis?
* Thyroid C cell tumors?
124
DPP-IV Inhibitors / Dipeptidyl peptidase-4 inhibitors /
Vildagliptin
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Berberine
* Raise endogenous GLP-1
* No weight change
* Nasopharyngitis
* ? Effect on (3-cell apoptosis)
**_Mechnism of Action:_** Inhibition of the DPP-4 enzyme prolongs and enhances the activity of incretins that play an important role in insulin secretion and blood glucose control regulation.
125
FYI
A1C Cost/Yr
Exenatide 0.5-1.0% $2,800
Sitagliptin 0.5-0.8% $1,700
Pramlintide 0.2-0.5% $2,556
126
Pramlintide
* Synthetic amylin
* Use with insulin before meals
* Prolongs gastric emptying
* Reduces postprandial glucose
* Appetite suppression
* Hypoglycemia
a small peptide hormone that is released into the bloodstream by the β-cells of the pancreas along with insulin, after a meal. Reduction in glycated hemoglobin and weight loss have been shown in insulin-treated patients with type 2 diabetes taking pramlintide as an adjunctive therapy.
127
Hypoglycemia
A. Insulinoma
B. Surreptitious use of insulin
C. Surreptitious use of Oral meds
**_Tests_**
* Drug levels
* if sugar is low and insulin is low its most likely normal
* C-peptide levels / insulin levels after fasting 72 hrs once drops \> 50 need to do levels
128
Hyperosmolar Nonketotic State
* Glucose \> 600
* pH\>7.3, CO2\>15
* Minimal ketonemia/ketonuria
* **_Correct Na for hyperglycemia_** (for each 100 mg/dL glucose \> 100 add 1.6 mg to serum sodium)
* If K is \< 3.3, hold insulin and give K
129
DKA
IVF
K Keep \> 3.3
IV insulin once K \> 3.3
Once glucose 200 can reduce IV insulin 50% and change to d5W1/2
Adjunct KCL / Vasopressors / Bicarb / phosphate (no definite benefit found)
130
Calcium and Bone
* Hyper and hypocalcemia
* Vitamin D deficiency
* Osteomalacia
* Osteoporosis
* Paget disease
131
**_PTH_**
Increases (Renal) Ca absorption - PO4 secretion
Conversion of 1,25 OH2-D which increases (GI ) Ca and PO4 absorption
Also increases Ca and PO4 levels from bone
132
DDx Hypercalcemia
1. **Primary hyperparathyroidism**
2. **Malignancy (Squamous / small C Ca )**
3. **Lithium, thiazides (dont test if they are on these meds)**
4. Vitamin D excess
5. Hyperthyroidism / Adrenal insuff
6. Sarcoidosis 10% patients will have it / because macrophages make vitD
7. Multiple myeloma
133
1° Hyperparathyroidism
* high Ca / PTH, low P04
* Hypercalciuria
* Common in elderly women
* 85% single adenoma, 15% bilateral hyperplasia
* Usually asymptomatic
MEN I / MEN IIa
134
Treatment of 1° HPT
• Parathyroidectomy
- 95% cure rate
- Pre-op localization
- Hypoparathyroidism rare
• No effective medical Rx
• Treat symptomatic patients
135
Ordering Dexa in hyper PTH patients
Must order a Radius + Hip and spine
136
When to Operate in Asymptomatic Patients
• **Calcium** \> 1 mg/dL above normal
• **GFR** \< 30 mL/min
• **Age** \< 50
**• T-score** \< -2.5 hip, spine, or **_forearm_**
137
MEN 1
Multiple Endocrine Neoplasia
3 P's | if so it will be very hard to do surgery
* 1° HPT (parathyroid hyperplasia)
* Pituitary tumor
* Pancreatic tumor (gastrin)
* Gene maps to chromosome 11q13
* Autosomal dominant
138
MEN II
* 1° HPT (parathyroid hyperplasia)
* Medullary thyroid cancer (Calcitonin levels are the markers)
* Pheochromocytoma
* Chromosome 10
* **_RET proto_** oncogene
* Genetic testing for presymptomatic individuals
139
Hypercalcemia of Malignancy
• High levels lead to obtundation, coma, lethargy
• Treat volume depletion
- Loop diuretic not necessary (no benefit)
• IV bisphosphonate / Zoledronic acid more potent
• Response in 2-4 days
* Calcitonin is not as effective very short acting
* Glucocorticoids would be beneficial in Vit D toxicity / lymphoma
140
Hypercalcemia of Malignancy
* high Ca, low PO4, low PTH, high PTHrP
* Lung (squamous cell) - PTHrP
* Renal cell - PTHrP
* Lymphoma, leukemia
* Multiple myeloma -OAF
* Metastatic disease
141
**_Sarcoid_**
* Some other granulomatous diseases
* Macrophages make vitamin D
* high Ca, Low PO4, Low PTH (its low because Ca is high)
* T 1,25(OH)2 vitamin D
**_GENERAL RULE_** when PTH is low with high CA look for other reasons CA is high
142
Hypocalcemia
* Hypoparathyroidism (autoimmune / like pts with hashimatos)
* Vitamin D deficiency (usually must be very sever)
* Hypomagnesemia — Low PTH release
* Anticonvulsants (Dilantin and phenobarb - excelerate vit D metabolism)
* Malabsorption
* Gastric bypass
143
Symptoms of Hypocalcemia
* Asymptomatic
* Paresthesias
* Perioral numbness
* _Chvostek/Trousseau_ signs
* Tetany
* Laryngeal spasm
144
Acute Treament of Hypocalcemia
* **_Calcium gluconate_**
* Vitamin D / and Ca combo
* Maintain Ca in range of 8-8.5 as over-replacement can lead to hypercalciuria
* Vitamin D and calcium need careful titration
145
Laboratory Diagnosis of Hypocalcemia
• **_Hypoparathyroidism_** (autoimmune)
low Ca, high PO4, low PTH
• **_Hypomagnesemia_** (alcohol)
low Ca, high P04, low PTH
146
2° Hyperparathyroidism
* Clinical picture is classic anticonvulsant, elderly, minimal sun exposure, bone pain
* Vitamin D replacement should restore PTH to normal
147
IOM Recommendations
IOM Recommendations
Age IU/dav
* 19-70(M / F) 600
* \> 71 800
148
Osteomalacia
Osteomalacia
• Inadequate bone mineralization
• Vitamin D deficiency
• Malabsorption
• Anticonvulsant therapy
• Renal tubular acidosis
• Chronic renal failure
• Hypophosphatemia
• Bone pain
• Proximal myopathy
• Low Ca
• Low PO4
• high PTH
• Low Vitamin D
149
Paget Disease
* Usually asymptomatic
* high Bone turnover -\> structurally weak bone
* very high Alkaline phosphatase 100's
* Treat if pain is severe, pagetic lesions in**_ weight-bearing**_ areas, or _**lytic lesions_**
So do not treat if not symptomatic / first step to go to NSAIDs then Bisphosphonates/Calcitonin
150
Familial Hypocalciuric Hypercalcemia
* Rare
* Lower Sensitivity of Ca-sensing receptor and higher Ca levels are needed to suppress PTH
* Familial /Autosomal Dominnant
* 24-hr urine calcium \< 100
Will have a very low urine calcium | Ca / ratio \< 0.01
Treatment not recommended
151
Panretinal laser photocoagulation
results in retained central vision but poorer peripheral and night vision
152
adrenal incidentalom
metastatic cancer is nearly 2% for tumors less than 4 cm in diameter but increases to 25% for tumors 6 cm or larger
Hounsfield units \> 10-12 we start to worry
153
Evaluate secondary amenorrhea
Question: menarche at age 13 years and had normal menstrual cycles until 6 months ago.
Pregnancy test
FSH (\> 35 ovariand insufficiency |
PRL /T4 and TSH normal
Progestrone withdrawal is last / if no bleed must look at central causes of low estrogen
154
tuberculosis-induced hypercalcemia.
excessive production of _1,25-dihydroxyvitamin D_ by the _tuberculous granulomas_. The ***granulomas*** of tuberculosis (and other granulomatous diseases, such as **_sarcoidosis, Crohn disease, and leprosy_**) are composed of macrophages that possess the 1α-hydroxylase enzyme needed to convert 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D.
Low PTH, PO4 high
with Malignancy Hypercalcemia High PTH /prPTH and low PO4
155
Graves ophthalmopathy.
Luedde Exophthalmometer - to measure extend of dz
The medical treatment for ophthalmopathy trial of corticosteroids. In sever cases thyroid surgery (this is in pts intolerance to iodine or antithyroid drugs, large or obstructive goiters, or ophthalmopathy).
Pathology: lid changes, proptosis or exophthalmos, and inflammatory eye changes, such as chemosis, conjunctival injection, periorbital edema, or iritis. Extraocular muscle involvement can result in double vision, whereas optic nerve compression can result in reduced visual acuity and even blindness.
156
Woman with low bone mass. How to treat?
The NOF recommends antiosteoporotic therapy for persons whose risk of major osteoporotic fracture over the next 10 years is 20% or greater or whose risk of hip fracture over the next 10 years is 3% or greater.
**_Denosumab_**, osteoclast formation, reserved for patients with a high risk of fracture, including those with multiple risk factors for fracture or a history of previous fractures.
**_Estrogen_** is contradicted in this patients with dx of breast cancer.
**_Raloxifene_**, a selective estrogen receptor modulator, approved for osteoporosis prevention by the FDA. However, significant hot flushes.
**_Teriparatide_** (recombinant human parathyroid hormone) is also contraindicated in persons with malignancy involving bone, Paget disease, or existing hyperparathyroidism or hypercalcemia.
**_Bispho alendronate_** is the most appropriate drug to use for osteoporosis prevention in patients with osteopenia and a history of radiation therapy
157
Sestamibi parathyroid scintigraphy
parathyroid adenoma
158
Thyroid Scan
123-Iodine
* Patient needs fast
* Amount of radioactivity documented, the patient swallows the tracer
* Imaging about 4-6 hours after the tracer is swallowed.
* Repeat in 24 hrs
99m-Technetium
* No special prep instructions
* The tracer is injected about 15-30 minutes after imaging starts
159
Med Study
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