Endocrine-2 Flashcards

no med chem of male reproductive

1
Q

Naturally occurring estrogens

A

17β-estradiol > estrone > estriol

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2
Q

Estrogen is synthesized from what two things

A

androstenedione or testosterone

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3
Q

Anterior Pituitary Gonadotropins

A
  • Luteinizing Hormone (LH)
  • Follicle Stimulating Hormone (FSH)
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4
Q

Trophoblast gonadotrophin

A

Human chorionic gonadotropin (hCG)

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5
Q

Gonadotropin Receptors

A

FSHR: FSH
LHR: LH, hCG

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6
Q

Growth/maturation _________ follicle of ovary

A

Graafian

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7
Q

Corpus Luteum hormones

A

Progesterone, Estrogen

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8
Q

Endometrium:

A

endothelial lining, stroma

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9
Q

myometrium

A

smooth muscle

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10
Q

Perimetrium

A

outer serous coat

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11
Q

Follicular phase

A

estrogen builds endometrium
* Cell proliferation, increased thickness
* Induction of progesterone receptor

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12
Q

Luteal phase

A

progesterone prepares for implantation
* Ends estrogen effects on growth
* Stimulates endothelial secretions
* Blood vessel growth

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13
Q

Post-implantation

A

Stimulates LHR in corpus luteum to maintain
estrogen, progesterone synthesis

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14
Q

What does the ERalpha and ERbeta estrogen receptors do

A

ERα: female reproductive tract, mammillary gland, hypothalamus, endothelial cells, vascular smooth muscle
ERβ: Prostate, ovaries, lung, brain, bone, vasculature

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15
Q

Osteoblasts

A

↑ synthesis, type I collagen, osteocalcin, osteopontin

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16
Q

Estrogens plasma bound: _______________________ (SHBG) albumin

A

sex-hormone binging globulin

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17
Q

Single PR gene; two main isoforms: PR-A and PR-B which is inhibitory and which is excitatory

A

PR-A - inhibitory
PR-B - excitatory

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18
Q

Ligand-binding: dimerization, binding to what

A

progesterone response element (PRE)

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19
Q

What are Anti-progestins and Progestin Modulators used for

A

Early pregnancy termination

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20
Q

Ulipristal acetate (ELLA)

A

progesterone receptor modulator/partial PR agonist
inhibits ovulation
emergency contraception

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21
Q

Anti-Estrogens: “Pure” Estrogen Antagonists

A

Clomiphene and Fulvestrant

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22
Q

Estrogen Modulators/Anti-estrogens

A

Tamoxifen, Raloxifene, Clomiphene, Fluvestrant

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23
Q

Aromatase Inhibitors: steridal and non-steridal

A

Steroidal: formestane, exemestane (AROMASIN)
* irreversible
Non-steroidal: anastrozole (ARIMIDEX), letrozole (FEMERA), vorozole
* Reversible

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24
Q

Effects of estrogen

A

-Maturation of the female reproductive organs
-Maintains skin & blood vessels / & thickness of the vaginal lining
-↓ the resorption (breakdown) of the bone by osteoclasts
-↑ the coagulability of the blood
-Normal development of the endometrial (uterine) lining
-Can increase various hormone binding globulin

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25
Progesterone during pregnancy and menstrual cycle regulation
During pregnancy – it maintains the endometrial lining Menstrual cycle regulation – cyclical development & shedding of the endometrial lining
26
Androgens
Androstenedione is a weak androgen; it is converted to testosterone in the periphery Testosterone & dihydrotestosterone (DHT) have significant androgen activity
27
_____ has a greater affinity for the androgen receptor and is the more potent androgen
DHT
28
Available LARC methods
copper IUD levonorgestrel IUD etonogestrel SUBDERMAL IMPLANT
29
copper IUD MOA
Primary – continual release of Cu++ into the uterine cavity Copper ions toxic to sperm; ↓ viability, ↓ motility
30
levonorgestrel IUD MOA
Primary – LOCAL effect; continual local release of progestin into uterine cavity -Thickens the cervical mucus (sperm traveling up to the uterus is difficult) -Over time causes changes to and thinning of the uterine lining
31
etonogestrel subdermal implant MOA
Primary – controlled release of progestin; suppresses ovulation Thickens cervical mucus & produces a thinner endometrium
32
LACR return to fertility
1-2 cycles
33
Estrogen component actions
Helps prevent ovulation (estrogen will inhibit FSH production) Regulates proliferation of the endometrial (uterine) lining; provides cycle control Prevents the adverse effects of estrogen deficiency on various things
34
Elimination of estrogen
extensive 1st pass hepatic metabolism primarily by CYP450 3A4 enzymes
35
ethinyl estradiol
the synthetic estrogen used in almost all CHC products Available in oral doses containing (usually 20mcg as starting dose)
36
Progestin component actions
-Suppression of LH - ↓ response of the ovary to FSH; LH surge is inhibited -Thickens cervical mucus -Slows ovum transport through Fallopian tubes -Continuous use produces an atrophic endometrial lining
37
____________ an analog of spironolactone; has anti-mineralocorticoid activity
drospirenone
38
Risk of Estrogen: venous thromboembolism
[deep vein thrombosis (DVT), pulmonary embolism (PE)]
39
Risk of estrogen: CV disease
↑ risk occurs in women > 35yrs; especially if a heavy smoker -contraindicated in smokers over 35 yo -contraindicated with any ASCVD event
40
Risk of estrogen: Hypertension
Systolic BP ≥160 or Diastolic BP ≥100 is a contraindication to CHC Systolic BP ≥140-159 or Diastolic BP ≥90-99 – generally should not use CHC, R>B
41
Risk of estrogen: breast cancer
several large population-based studies have NOT found a significant association btw the use of CHCs and breast cancer; do not use with a personal history of breast cancer
42
Risk of estrogen: headaches w/ focal neurological deficits what is contraindicated
Use of CHC
43
Risk of estrogen: breastfeeding concerns
Estrogen decreases breastmilk production CHC are approved if breast milk is well established Do not start until > 6 weeks postpartum
44
Traditional "21/7" cycles
mainly monobasic (same dose of E/P) -the progesterone ingredient has more effect on the side effects not the phases -the standard recommendation is to start on a monobasic
45
Who benefits from a entended or continuous cycle birth control
severe menstrual cramps excessive bleeding endometrial pain -increased breakthrough bleeding
46
What is the day 1 start
initial pack started on 1st day of bleeding no backup needed
47
What is a sunday start
initial pack started on 1st Sunday after period started back needed for 1st week no period on the weekend
48
What to do if 2 or more pills are missed
use a non-hormone backup method until active hormone tabs have been taken for 7 days
49
Side effects of too much estrogen
nausea/vomiting/bloating (take at night) HTN headache darkened pigmentation
50
Side effects of too little estrogen
amenorrgea vaginal dryness BTB
51
Side effects of too much progesin
fatigue mood changes headache
52
Side effects of too little progestin
BTB
53
Side effects of too much androgen activity
acne decreased libido increased appetite weight gain
54
Recommendations for adverse effects of birth control
an adequate trail for any pill should be 3 months most side effects disappear by 4th cycle
55
Birth control serious ACHES
abdominal pain chest pain headaches eye problems severe leg pain
56
Transdermal Patch for non-daily contraceptive
3 wk on / 1 wk off if women is >90 kg its a decreased efficacy increases risk of VTE
57
Vaginal ring for non-daily contraceptive
3 wk on / 1 wk off (use new ring) <3 hr then efficacy not affected no douching
58
Progestin-only contraceptives: norethindrone MOA
increase thickness of cervical mucus (harder for sperm to move) no placebo days late by 3 hrs is a missed pill
59
Why are POPs the preferred oral contraceptive pill during breast feeding
they do not effect milk production and no clotting risk can start right after pregnancy
60
What is the OTC progestin only pill
norgestrel (Opill)
61
Depo-injection
suppress FSH/LH endometrial thinning -cause weight gain -BTB -decreased bone mineral density (BMD) takes 6-12 months for fertility to return
62
Copper IUD emergency contraception
if placed w/in 5 days of intercourse it is the most effective method increased BMI does not decrease effectiveness
63
Ulipristal Acetate emergency contraception
SPRM (block progesterone from binding to receptor) Inhibits or delays ovulation from occuring give w/in 5 days
64
High dose progestin-only tablet for emergency contraception
inhibit or delay LH surge levonorgestrel (PlanB) take w/in 3 days
65
Yuzpe Method of emergency contraception
uses combo w/ high dose of progestin causes nausea and vomiting
66
Comparative effectiveness of EC (highest to lowest)
copper IUD ulipristal acetate OTC levonorgestrel Yuzpe
67
Indications for using topical corticosteroids
relieve dermatitis eczema ano-genital itching external vaginal itching
68
MOA of corticosteroids
anti-inflammatory decrease production of mediators immunosuppressive anti-proliferative
69
Potency of topical corticosteroids
chemical structure modification vasoconstrictor assay potency classification vehicle formulation
70
As a general rule ointments and gels are more or less potent than creams and lotions
more
71
Enhanced absorption effects of topical corticosteroids
skin hydration occlusive dressings
72
Age of patient in relation to topical corticosteroids
-younger and older tolerate lower potency -infants use the mildest topical in the diaper area -elderly should only use high potency in short bursts -very high potency should be avoided in children
73
Location of application in relation to topical corticosteroids
thinner the skin, the lower potency it should be medium-high to very high are needed for chronic, hyperkeratotic lesions and areas involving palms and soles
74
Indication/type of lesion in relation to topical corticosteroids
lower potency are best for inflammation medium to high good for chronic lesions in thicker areas super-potent reserved for short term use
75
Local adverse effects of topical corticosteroids
atrophy (occur where absorption is high, cause thinning) telangiectasia striae purpura steroid acne hypersensitivity rxns
76
Systemic adverse effects of topical corticosteroids
glucocorticoid excess (cushing, hyperglycemia, growth suppression) HPA axis suppression Cataracts and glaucoma
77
How much to apply "fingertip method"
tip of finger to first index
78
Occlusive technique increases skin penetration up to 10x when giving topical corticosteroids when should you use these
only used under the direction of a physician
79
What does the wolffian duct system consist of
epididymis, vas deferens, seminal vesicles
80
What do androgens cause in adulthood for males
male pattern baldness prostatic hyperplasia
81
What do androgens cause in senescence for males
decreased energy, muscle mass, bone density insulin resistance, truncal obesity, increase serum levels
82
Testosterone is secreted by ______ cells of testes
leydig
83
Androstenedione and dehydroepiandrosterone are what kind of androgens
weak androgens -they are then converted to testosterone peripherally
84
Androgen synthesis levels of 5 alpha reductase / aromatase _______ across tissues
differ
85
In androgen synthesis, liver metabolizes T to what two inactive metabolites
androsterone etiocholanolone
86
The active metabolites of androgens are 5 alpha reductase - dihydrotestosterone (DHT) which has a high affinity for ___ and aromatase which is _________ (ET)
AR estradiol
87
AR mutations what is androgen insensitivity syndrome
loss of function mutations CAG repeat extension (Kennedy's disease)
88
What are heptanoate and cyclopentyl propionate T esters
esters inhibit metabolism; low bioavailability; given IM; hydrolyzed to T
89
What is undecanoate T ester
oral, absorbed into lymphatic circulation, bypasses hepatic catabolism
90
Androgen Receptor Antagonists Flutamide MOA
AR blockage alone insufficient -LH compensates -given with GNRH analog
91
What is the common 5 alpha reductase inhibitor
Finasteride
92
Androgen Receptor Antagonists Spironolactone MOA
fluid retention, HTN gynecomastia; given with MR antagonist
93
Definition of menopause
absence of a menstrual period for 12 months
94
Characteristics of menopause
dysfunctional uterine bleeding/irregular menstrual cycles unpredictable fertility increasing FSH levels
95
Systemic symptoms of menopause
hot flashes insomnia / sleep disturbances psychological symptoms
96
Local symptoms of menopause
Atrophic vaginitis -vaginal dryness, burning, irritation -lack of lubrication, dyspareunia Urogenital atrophy -lower urinary tract symptoms -recurrent urinary tract infections -urge and stress incontinence
97
Diagnosis and assessment of menopause
Going to have bleeding changes symptoms consistent with menopause increase FSH levels women <40 they check FSH levels
98
Surgical menopause
removal of both ovaries before natural menopause occurs increased vasomotor symptoms receive E/P hormone replacement therapy
99
Women with h/o hysterectomy
no uterus, no periods, might experience symptoms, FSH levels could be measured if needed
100
Women using levonorgestrel IUD
eventually develop amenorrhea; no periods to monitor FSH levels could be measured
101
Non-drug / lifestyle recommendations for management of vasomotor symptoms
dress in layers of clothes identify and decrease triggers: spicy foods, hot beverages, caffeine, alcohol
102
Drug therapy for perimenopause symptoms
CHC -lower dose pill -vaginal ring
103
Drug therapy for menopause symptoms
need both therapies consider tissue-targeted therapy OTC vaginal moisturizers Vaginally inserted estrogen for more moderate to severe symptoms
104
Vaginal estrogen products
estrogen cream estrogen vaginal tablet estrogen vaginal ring
105
Key points of vaginal estrogen products
local effect low dose estrogen does not stimulate uterine lining progestin is not needed no time limit
106
Who should not receive systemic therapy in hormone therapy or hormone replacement therapy
women w/ h/o CHD women w/ h/o breast cancer women >60 yo or >10 yrs from menopause
107
Who should receive systemic therapy in hormone therapy or hormone replacement therapy
women w/ severe symptoms if <60 yo w/in 10 yrs of menopause use lowest dose short-term and taper off in 3-5 yrs transdermal therapy have lower risk of VTE and stroke than oral therapy
108
Example estrogens and progestin
estrogens: conjugated equine estrogens, estradiol progestin: medroxxyprogesterone (MPA), levonorgestrel (IUD)
109
Menopause treatment for women with a uterus
must use combo of estrogen and progestin to decrease risk of endometrial cancer (use every day) could use continuous E and cyclic P therapy (take P only 12-14 days)
110
Menopause treatment for women w/o a uterus
estrogen therapy alone every day
111
What is the progestin drug that is used to induce withdrawal of bleeding
Provera -help diagnose workup for amenorrhea -may be used to treat women w/ dysfunctional bleeding
112
What are the two major components of the testes and what are their functions
Leydig cells – testosterone is the major hormone secreted (LH) Seminiferous tubules (lined with Sertoli cells) – sperm production (FSH)
113
What are the 4 functions of testosterone
Development of the male reproductive structures Male secondary sex characteristics at puberty Maintenance of libido (sex drive) and erectile function Required for the maturation of sperm
114
Primary hypogonadism in male reproductive
(Presents with low to normal testosterone levels, poor or no sperm...elevated FSH & LH) -Absence of testes -Lack of testosterone production -Lack of functional sperm
115
Secondary hypogonadism in male reproductive
(Presents with LOW gonadotropins (FSH/LH)...low testosterone levels, no sperm) -Pituitary adenomas -Hyperprolactinemia -Hypothyroidism
116
Drug therapy for primary male hypogonadism
testosterone replacement therapy -Restores virilization / masculinization -Restores libido and sexual performance and energy -Increase quality of life
117
Monitoring for primary male hypogonadism
Symptom improvement Testosterone levels – in the ~mid-normal range
118
ADRs for primary male hypogonadism
↑BP, major CV events, VTE, ↑ risk of prostate cancer, ↑BPH symptoms
119
Why is testosterone not given orally
1st pass metabolism causes many hepatotoxicity reactions
120
What is the intranasal gel, transdermal patch, and transdermal gel for primary male hypogonadism
Intranasal-Natesto Transdermal patch-Androderm Transdermal gel-Androgel
121
How to treat secondary hypogonadism if the man does not want children
Testosterone levels achieved in the blood do not ↑ testosterone levels in the testes that are high enough to cause the production of sperm
122
How to treat secondary hypogonadism if the man wants children
Give “Gonadotropins” to restore virilization and spermatogenesis The drugs are given by IM injection 3 times per week
123
What are the two steps in fixing secondary hypogonadism if the man wants children
-Give Human Chorionic Gonadotropin (hCG) - stimulates Leydig cells to make testosterone -Give a source of FSH - monitor sperm count; mix of FSH and LF
124
What is Benign prostatic hyperplasia (BPH)
a benign enlargement of the prostate gland that occurs as men age
125
What are the two prostate growth periods
Puberty through age 25-30yrs. Reaches normal size ~5-20gm Starts again at ~40yrs through 80yrs.
126
Prostate tissue: Glandular epithelial tissue composes 20-30% of BPH tissue
-Growth is stimulated by the androgen hormone dihydrotestosterone (DHT) -Men with large prostates (>40-50gm) may have more epithelial tissue -This tissue responds to 5-alpha reductase inhibitors (↓ DHT production) -5a-reducatase inhibitors can reduce the size of the gland
127
Prostate tissue: Smooth muscle tissue composes 70-80% of BPH tissue
-Smooth muscle tissue is less sensitive to androgen hormones -Smooth muscle tissue growth is stimulated by other mechanisms (i.e., estrogen) -Muscular tissue is under alpha-adrenergic tone -This tissue responds to alpha adrenergic blocker therapy
128
What is LUTS (lower urinary tract symptoms)
Symptoms are caused by many factors; both static (enlargement) and dynamic (muscle tone)
129
What are the obstructive symptoms of LUTS
Hesitancy Weak urine stream Intermittency Dribbling Bladder fullness
130
What are the irritative symptoms of LUTS
Frequency Urgency Urinary incontinence Nocturia
131
What are the 4 complications of BPH
-Urinary retention -Recurrent urinary tract infection (UTI) -Irreversible impairment of bladder function -Chronic renal failure
132
Assessment of BPH
-Medical history -Duration and description of LUTS -Sexual function -Overall health / other medical conditions *Current medications (antihistamines, decongestants, anticholinergic drugs etc.)
133
BPH: Objective / Recommended initial tests for a basic evaluation (of any man w/ LUTS)
Urinalysis Physical exam with Digital Rectal Exam (DRE) PSA level Frequency/volume charts
134
What should the PSA levels be in men over 60 and then in men under 60
If ≥60yoPSAshouldbe<4mg/ml If < 60yo PSA should be < 2.5 mg/ml
135
What is the key point when determining LUTS
Serum creatinine is NOT recommended for the initial evaluation for LUTS
136
Treatment of BPH non pharm “Watchful Waiting” strategy
patient is monitored but takes no active therapy follow-up with patient ~12months Appropriate for -Mild symptoms (AUA < 8) -Moderate symptoms (AUA 8-19) & patient is NOT bothered by them.
137
Treatment of BPH non pharm lifestyle modifications to reduce symptoms
Fluid restriction / Fluid restriction in the evening Decrease caffeine and alcohol consumption Avoid drugs known to worsen symptoms
138
Drug therapy for patients with BPH
Alpha-1 receptor antagonists (relax smooth muscle, urinary flow increased) monitor 2-4 wks
139
What are the two non-selective alpha blockers used in BPH
terazosin doxazosin
140
What are the three selective alpha blockers used in BPH
tamsulosin silodosin alfuzosin
141
What are the non-selective alpha 1 receptor antagonists associated with
first dose syncope
142
5 alpha-reductase inhibitors MOA
↓ conversion of testosterone to dihydrotestosterone (DHT) (reduces prostate size by 25%)
143
What are the use of 5 alpha-reductase inhibitors appropriate for
Men with enlarged prostates as evidenced by either: -Estimated size of at least 40gm -PSA level ≥ 1.5
144
Monitoring and follow-up for 5 alpha-reductase inhibitors
3 months takes 6-12 months to see new effect
145
Options – similar clinical effectiveness for 5 alpha-reductase inhibitors in BPH
finasteride (Type II 5a-reductase inhibitor) dutasteride (Non-selective 5a-reductase inhibitor)
146
Sexual side effects of 5a-reductase inhibitor
↓ Libido; ejaculatory dysfunction (3-15%); erectile dysfunction (3-5%)
147
Clinical monitoring concerns of 5a-reductase inhibitor
-Patients need a baseline PSA level before starting therapy -5a-reductase inhibitors decrease PSA levels by 50% -A delay in prostate cancer diagnosis has been observed if this is not remembered
148
When to use surgical interventions in BPH
Patients with malignant or complicated disease Patients with moderate to severe disease unresponsive to pharmacologic therapy
149
Types of Sexual Dysfunction in Men
Decreased libido Increased libido Delayed ejaculation Premature ejaculation Retrograde ejaculation Infertility Erectile dysfunction
150
Erectile dysfunction: hormonal classification
hypogonadism, hyperprolactinemia, hyper/hypothyroidism, adrenal disease
151
Erectile dysfunction: neurologic classification
cerebral disease, stroke, spinal disease, peripheral neuropathy (diabetes)
152
Erectile dysfunction: vascular classification
atherosclerosis, CAD, PVD, HTN, hyperlipidemia; diabetes
153
Pathophysiology of ED
-With increasing age – collagen and elastic fibers in the penile structure decrease -Decrease of smooth muscle content in men over 65yrs -Decrease in sensitivity, metabolic imbalance of contractile and relaxing factors “Endothelial dysfunction”
154
Physiology of penile erection
Erection begins with stimulation the release of nitric oxide ↑cGMP development of an erection
155
What enzyme metabolizes cGMP
Phosphodiesterase (PDE)
156
Oral PDE-5 Inhibitors MOA
Inhibition of PDE5 prevents the metabolism of cGMP ↑ cGMP levels...helps to initiate & maintain an erection
157
What are the Oral Available products for PDE-5 Inhibitors
avanafil: 15 min before sex sildenafil: 60 min before sex vardenafil: 60 min before sex TADALAFIL: 30 min before sex (no more than 1 dose per 24 hrs)
158
Oral PDE-5 Inhibitors effectiveness
consider a trial of 7-8 doses If one drug does not work try another one assess how they are using it (are they engaging in foreplay)
159
Adverse effects of Oral PDE-5 Inhibitors
Headache, flushing, nasal congestion, heartburn Cyanopsia Hypotensive effects
160
Contraindications of Oral PDE-5 Inhibitors
Contraindicated with any organic nitrate due to severe hypotension that may result Examples: nitroglycerin, isosorbide dinitrate
161
Priapism Precautions in Oral PDE-5 Inhibitors
-Is an erection lasting > 4hrs -Is a medical emergency; immediate medical attention should be sought -Penile tissue damage and permanent loss of erectile function may result
162
Other treatments for erectile dysfunction
Alprostadil VED- Vacuum erection device Penile prostheses
163
Hypopituitarism for male reproductive
-Can be due to primary pituitary disease or secondary hypothalamic disease -Can be partial -Can be complete “panhypopituitarism” - historically refers to loss of all anterior pituitary hormones
164
Etiology of Hypopituitarism for male reproductive
Tumors - pituitary tumors are the #1 cause (Microadenoma < 10mm Macroadenoma >10mm) Infarction of the vasculature of the gland Trauma / Whiplash type injuries Neurosurgery or Radiation Autoimmune disease, Infection/Inflammation, Idiopathic
165
Symptoms of Hypopituitarism for male reproductive
You only need about 30% of the pituitary gland to function Symptoms usually appear when ~70-80% of the gland is destroyed
166
Hypopituitarism for male reproductive causes a hormone deficit of
GH (short stature in children, weight gain, metabolic disturbance, and fatigue in adults) FSH/LH (hypogonadism and infertility) TSH ACTH Prolactin
167
Diagnosis of Hypopituitarism for male reproductive
History & physical Imaging studies Laboratory analysis Stimulation testing
168
Treatment of Hypopituitarism for male reproductive if there is an ATCH deficit
Give a glucocorticoid to prevent adrenal insufficiency Increase dose during states of stress, e.g., infection, surgery
169
Treatment of Hypopituitarism for male reproductive if there is TSH deficit
levothyroxine
170
Treatment of Hypopituitarism for male reproductive if there is FSH/LH deficit
Males: Testosterone Females: CHC For Fertility: Gonadotropins (Menotropins), Synthetic hCG
171
Treatment of Hypopituitarism for male reproductive if there is growth hormone
the use of synthetic growth hormone is AGE dependent
172
What are the two components of the bone
Minerals: provide tensile strength Organic: proteins, bone cells
173
What are the the sources of calcium
Absorption of Ca++ from the GI tract Bones
174
The regulation of calcium homeostasis involves what 5 things
Parathyroid Hormone (PTH) 1,25(OH)2 D = calcitriol Bones GI tract Kidneys
175
What are the two functions of the parathyroid hormone
-to control ionized Ca levels in a very tight range -to do this it produces and secretes parathyroid hormone (PTH)
176
The result of increased PTH causes and increase in what levels
Calcium
177
What are three things that stimulate the increase of PTH secretion
The main trigger = Low Ionized Calcium Levels Low vitamin D levels High phosphorus levels*
178
Disorders of PTH: Primary Hypoparathyroidism
Due to loss of function or removal of PTH gland(s) -Will cause signs and symptoms due to hypocalcemia -Is managed with the administration of Calcium and Vit D supplements
179
Disorders of PTH: Primary Hyperparathyroidism
due to hyperplasia or increased activity of PTH gland -cause signs and symptoms due to hypercalcemia -managed with surgery
180
Disorders of PTH: Secondary Hypoparathyroidism
Occurs when there is a primary disorder that is causing hypercalcemia
181
Disorders of PTH: Secondary Hyperparathyroidism
-Triggered by hypocalcemia -Triggered by low vitamin D levels (vitamin D insufficiency / deficiency) -Triggered by hyperphosphatemia* (CKD is the most common cause)
182
Vitamin D2 (ergocalciferol)
Diet - soy, yeast... Fortified foods – milk, OJ, some cereals OTC Dietary supplements Rx products
183
Vitamin D3 (cholecalciferol)
Diet – cod liver oil, sardines, salmon Fortified foods – milk, OJ, some cereals OTC Dietary supplements Rx products Synthesized in the skin from UVB exposure
184
The first hydroxylation takes place in the LIVER Vit D2/D3 is metabolized to calcidiol (25(OH) D) what are the important points of this
storage form indicates Vit D status used to monitor therapy physiologically inactive
185
The second hydroxylation takes place in the KIDNEY 25(OH) D is converted into calcitriol (1,25(OH)2 D) what are the important points of this
-Calcitriol is the physiologically ACTIVE form of vitamin D -Blood levels are kept very low and are tightly regulated -PTH stimulates the conversion
186
Primary effects of active 1,25 (OH)2 D (calcitriol) in calcium homeostasis
Increases absorption of Ca from the GI tract Increases calcium and phosphate reabsorption by the kidney
187
Calcitonin is secreted by the __________ cells of the thyroid gland
parafollicular
188
What is the primary function of calcitonin
inhibit bone resorption by inhibiting osteoclasts
189
Calcitonin salmon products MOA
potent inhibitor of osteoclasts
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Therapeutic uses of calcitonin salmon injections
Adjunct treatment in hypercalcemic crisis Paget’s disease of the bone
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Therapeutic uses of calcitonin salmon nasal spray
Postmenopausal osteoporosis (only in women who are > 5yrs postmenopausal)
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Etiology of Vit D deficiency
-Nutritional deficiency/malnourishment -GI procedures -malabsorption -lack of sun -CKD
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Clinical Presentations of Vit D deficiency
Fractures Bone pain Muscle weakness
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Classic bone disorders associated with severe Vitamin D deficiency
Osteomalacia (“soft bones”) – in adults Rickets – in children (bones are under mineralized, most caused severe deficiency for long periods of time)
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Vit D insufficiency results in hypocalcemia which causes secondary hyperparathyroidism resulting in what
an increase in bone resorption to increase calcium levels in the blood an increase in the excretion of phosphorus in the urine
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At risk populations for Vit D insufficienct
Elderly Dark skinned racial groups Living above latitude 35oN
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In Vitamin D replacement therapy 1 mcg = how many units
40 units
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Vitamin D replacement therapy: Drisdol
50,000 IU/cap VitD2 (ergocalciferol) Requires activation by the liver & the kidney
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Vitamin D replacement therapy: Rocaltrol
0.25, 0.5 mcg capsules, 1mcg/ml liquid, 1mcg/ml injection Calcitriol 1,25(OH)2D the active form of vitamin D
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Too little free calcium causes what and too high free calcium causes what
* Too low = neuronal hyper-excitability * Too high = neuronal depression
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What are the three control points for calcium regulation
Absorption – intestines Excretion – kidneys Storage – bones
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What does Parathyroid Hormone (PTH) do to serum calcium and serum phosphate
increase calcium decrease phosphate (produced by chief cells)
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Osteoblast vs Osteoclast
Osteoblast: promotes bone formation Osteoclast: promotes bone resorption (PTH promotes precursor differentiation, PTH stimulates signaling)
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Calcium feedback regulation of Parathyroid Gland: PTH ↑ Serum Calcium
↓ Calcium Excretion ↑ Active Vitamin D Metabolites ↑ Bone Calcium Resorption
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Calcitonin are produced in C-cells of thyroid gland: ↓ serum calcium
↓ bone resorption ↑ renal excretion
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What are the three pharmacological effects of Calcitonin
-Attenuates absorptive ability of osteoclasts -Inhibits formation of new osteoclasts -Has weak effect in kidney and intestine
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What is converted to 25-Hydroxycholecalciferol as a precursor in the liver
Vitamin D3
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What is converted to 1,25-Dihydroxycholecalciferol to active form in the kidney
Vitamin D3
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Adverse effects of bisphosphonates
erosion of esophagus
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What are the Bisphosphonates drugs that : inhibit osteoclast-mediated resorption
-pamidronate, zeldronate IV -alternative form raloxifene which is a selective estrogen receptor modulator
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What is cortical bone
it is dense and stiff, a major component of the long bones of the legs, arms
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What is trabecular bone
more flexible; provides shock absorption
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Defn of osteoporosis
a skeletal disorder of compromised bone strength which predisposes a person to ↑ fracture risk
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Establishment of optimal peak bone mass in osteoporosis
Genetics Physical activity Ca & Vit D intake Proper endocrine function (GH, thyroid , sex hormones)
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Contributions to bone loss as we get older
Decreased osteoblast function Decreased calcium intake and absorption from the gut Decreased sun exposure ↓vitamin D production In women…postmenopausal loss of estrogen (and in older men, loss of testosterone)
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Risk factors for low bone mass / osteoporosis
Genetic Lifestyle: smoking, inactivity Nutrition: lactose intolerance Medical disorders / Drug therapy
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How is BMD measured? (bone mineral density)
DXA scan (Dual-energy X-ray Absorptiometry) -has the best correlation with fracture risk; the gold standard test
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Where is BMD measured?
“Central bones” (lumbar spine or hip/femoral neck) – give the best predictor of risk “Peripheral bones” (forearm, heel, fingers) Less predictive of risk than central measurement; for screening purposes only
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What is T score
Compares patient’s BMD with the mean BMD of a healthy young person of the same gender -represents the # of standard deviations from the mean BMD
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What is a normal t-score
scores > -1.0
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What is the t-score of low bone mass
T-score between –1.0 and –2.5
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What is the t-score in patients that have osteoporosis
T-score ≤ –2.5
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Recommendations for BMD measurement / monitoring: Initial Screening
-To identify those at risk for OP fractures – no consensus exists -Women > 65yrs -Men > 70yrs (postmenopausal >50 yrs who have age-related fracture)
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Follow up and monitoring for BMD measurement
If T-score is normal...recheck in 5yrs If T-score indicates Low Bone Mass, recheck in ≥ 2yrs If T-score indicates osteoporosis, drug therapy is recommended to treat osteoporosis If drug therapy started, recheck in 2-5yrs depending on the treatment chosen
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Dorsal kyphosis / “Dowager’s hump"
Loss of height Back pain Loss of mobility / function
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Fragility fracture defn
a fracture that occurs in the absence of a major trauma
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Common sites of fragility fractures
spine, ribs, hip, pelvis, wrist, forearm
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Common causes of fragility fractures
fall from standing height bending, lifting, or twisting coughing, sneezing
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Risk factors for falling
Poor health Loss of balance Use of sedating medications Environmental...rugs, no bath rails, obstacles…
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Risk PREDICTORS for clinical bone FRACTURES are:
Low BMD Age >65yrs Personal history of adult fragility fracture Family history of fragility fracture due to OP Current cigarette smoking Current glucocorticoid steroid use Low BMI (underweight) Excessive alcohol use
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What is the FRAX risk assessment tool
Calculates a person’s 10year risk for hip or other major OP fracture
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What are the complications of osteoporosis
fracture fracture pain loss of mobility nursing home placement depression death
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Primary Osteoporosis defn
is due to the aging process; is not due to some other cause
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“Postmenopausal osteoporosis”
After the peak BMD in 20-30s, bone loss begins…it accelerates at menopause 10-25% of bone is lost in the decade after menopause; up to 15% in the first 5years mainly loss of trabecular bone
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What can slow down postmenopausal osteoporosis
having enough calcium and vitamin D
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Secondary osteoporosis defn
is caused by or is exacerbated by other diseases or drugs
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What is the most common cause of secondary osteoporosis
Chronic glucocorticoid therapy
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Secondary osteoporosis should be suspected if a fracture/fragility fracture occurs
In pre-menopausal women In men < 70yrs In someone with no risk factors Patients with multiple low trauma fractures
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What is Z score
-Compares patient’s BMD with the mean BMD of a control group matched for age & sex -If the Z-score is less than –2 secondary osteoporosis should be suspected
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Strategies for prevention of osteoporosis
Achieve the highest peak bone mass as possible while younger Reduce bone loss Prevent falls Adequate Calcium and Vit D intake
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UL of calcium
2,000 mg per day, increase risk for kidney stones
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Frequency of dosing practical issues related to calcium
as dose increases, the % of calcium absorbed decreases single dose should not be more than 500-600 mg typically given in divided doses, one dose at bedtime if possible
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What are the two calcium salts to use
calcium carbonate (Tums, needs stomach acid for absorption) Calcium Citrate (citracal)
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Calcium drug interactions
tetracyclines, fluoroquinolones, bisphosphonates, levothyroxine (need to separate the drug dose from the calcium; take 1hr before or 4hrs p Ca++)
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UL of vitamin D
4000 units (should have around 800 units per day)
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Lifestyle changes to prevent osteoporosis
stop smoking increase physical activity fall prevention
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When to use bisphosphonate drugs for prevention of osteoporosis
T score of 1 to -2.5 AND frax >3% hip or >20% major osteoporotic
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Non drug therapy for primary osteoporosis
Lifestyle modifications Adequate Calcium + Vitamin D intake
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Diagnosis of Osteoporosis
-T-score ≤ –2.5 -History of a fragility fracture (regardless of bone mineral density) -Incidentally found (asymptomatic) vertebral compression fracture
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Bisphosphonates MOA
inhibits osteoclast activity; ↓ resorption of bone
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What are the bisphosphonates drugs that are used to treat primary osteoporosis
Alendronate Risedronate Zoledronic Acid
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Oral administration counseling points for bisphosphonates
at least 30 min before eating or drinking take only with water must be separated from other meds
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Adverse effects of bisphosphonates
GI, nausea, ab pain, heartburn (stay upright 30 min after taking) Jaw Atpyical femoral fractures
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What is the duration of ORAL bisphosphonate treatment
5 years
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What is Denosumab (Prolia®) is used for primary osteoporosis, what is its MOA
Denosumab is a monoclonal antibody with affinity for RANKL -blocks the interaction between RANKL and RANK
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When to use Denosumab (Prolia®)
Treatment of osteoporosis Prevention of bone loss in certain patients Treatment/prevention of of glucocorticoid-induced osteoporosis
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Effects of Denosumab
Increase BMD decrease vertebral, non-vertebral and hip fractures
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Adverse effects of denosumab
generally, well tolerated (atypical femoral fractures have been reported)
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What is the duration of denosumab treatment
5-10 years
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What is the second line therapy drugs for osteoporosis
Raloxifene PTH
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Raloxifene MOA
it is a SERM Agonist: Mimics effects of estrogen on bones and lipids Antagonist: Blocks effects of estrogen in the breast & uterus
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Effects of raloxifene
Increase BMD spine and hip decrease spinal fractures effects on the bone stop when the drug is stopped
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Adverse effects of raloxifene
hot flashes blood clots
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When are the parathyroid hormone drugs teriparatide and abaloparatide used
moderate to severe osteoporosis in postmenopausal women men and women w/ GIOP w/ high risk of fracture (only teriparatide) OP in men w/ hypogonadal disorders and increase risk of fracture (teriparatide)
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MOA of teriparatide and abaloparatide
Has anabolic activity if given once a day Helps to build bone; increases bone density Effects on the bone stop when the drug is stopped
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Adverse effects of teriparatide and abaloparatide
osteosarcoma Do not use in pts with prior skeletal irradiation therapy Do not use with unexplained increase in alkaline phosphatase or Paget’s disease
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Use of PTH drugs for osteoporosis are limited to ___ years
2
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What is the last line therapy for osteoporosis
Calcitonin salmon Nasal Spray -used for treatment of OP in women who are 5 years postmenopausal -reduce spine fractures
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Glucocorticoid Induced Osteoporosis (GIOP) background
The greatest bone loss is during the first 6-12 months of therapy
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Pathogenesis of Chronic Glucocorticoid exposure
Decreases osteoblast function by affecting the activity of IGF-1 (resulting in decreased bone formation) Promotes hypocalcemia (increases bone resorption)
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Prevention and Treatment of Glucocorticoid Induced Osteoporosis (GIOP)
Use the lowest dose of steroid Adequate Calcium + Vitamin D intake (Elemental Calcium 1500mg and vitamin D 800 -1000 IU per day)
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Drug therapy use in Glucocorticoid Induced Osteoporosis (GIOP)
Bisphosphonate therapy for any patient starting prednisone >5mg daily if duration of therapy is expected to last > 3 months Denosumab treatment for glucocorticoids at a daily dose equivalent to ≥7.5 mg of prednisone for an anticipated duration of at least 6 months Obtain a BMD in any patient that has already received GC therapy > 6 months
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How often to repeat BMD if the patient has already received GC therapy >6 months and when should you start a bisphosphonate drug in this case
BMD yearly Start bisphosphonate drug if the T-score is < -1