Endocrine 2 Flashcards
Major roles of Hypothalamus master gland
Controlling the internal
environment (homeostasis)
• Regulates the balance of
• Water/salt → thirst
• Nutrients/glucose→ hunger
Hypothalamic pituitary axes
- control endocrine system
- operate by negative feedback (short and long loops)
- type :
• Hypothalamic-Pituitary-Thyroid axis (HPT)
• Hypothalamic-Pituitary-Adrenal axis (HPA)
• Hypothalamic-Pituitary-Gonadal axis (HPG)
Pathways
- • Nerve impulse from brain to hypothalamus
• Hypothalamus secretes regulatory hormones to the anterior pituitary
• Anterior pituitary releases hormones to target organs/tissues - • Nerve impulse from the brain to
posterior pituitary
• Posterior pituitary releases
hormones to target organs/tissues
Hypothalamic modulators of anterior pituitary
- Thyrotropin releasing hormone TRH
Effects : increase release of thyroid stimulating hormone and release of prolactin - opamine or prolactin inhibiting hormone
Effects : decrease release of prolactin - Growth hormone releasing hormone
Effects : increase release of growth hormone
Hypopituitarism
Undersecretion
- decreased tropic hormones (postpartum pituitary necrosis)
- Target organs functioning reduced or lost :
Adrenal: increased cholesterol, fatigue
Breasts: no lactation
Gonads: atrophy, reproductive dysfunction
Thyroid: muscle weakness, decreased energy
Liver (GH): reduced energy
Oversecretion
- Acromegaly
Prolactin effects
- Promotes breast development and synthesis of milk proteins
• Levels low in absence of pregnancy due to dominant inhibitory effect
of dopamine
• Has been referred to a “parental hormone” because its injection into
animals can produce parental behavioral patterns such as nest- building
Prolactin regulations
Prolactin is under tonic inhibitory
control by the hypothalamus through
release of dopamine
Increased prolactin during nursing
decrease release of GnRH from the hypothalamus
• causes decrease in release of LH and FSH
- provides a natural form of contraception
Infertility hypothalamic origin
Treated with administration of GnRH (or a synthetic metabolically stable
analogue) given i.m. or nasal spray
Infertility
• Hyperprolactinemia: High circulating levels of prolactin – (eg caused
by a small prolactin secreting tumor)
• Treated with bromocriptine – a synthetic orally effective dopamine
agonist
Gonadotropic hormones
• Required for ovulation, spermatogenesis, biosynthesis of estrogens and androgens
• Used therapeutically to promote fertility
• Produced and secreted by gonadotrophs in anterior pituitary
FSH Follicle Stimulating Hormone
Principle function: stimulate follicular development in females and
spermatogenesis in males
• Actions of FSH on follicle and oocyte require LH
• FSH acts on sertoli cells in testes to stimulate production of androgen binding protein
LH Lutenizing Hormone
• Principle function : regulate gonadal steroid hormone production
• Acts on Leydig cells in testes to stimulate androgen production
• Acts on ovary with FSH to stimulate follicular development
Human Chorionic Gonadotropin
Glycoprotein hormone produced only during pregnancy by the embryo soon after conception and later by the placenta
• Prevents disintegration of the corpus luteum of the ovary ( involved in progesterone secretion)
Therapeutic Uses of Gonadotropic hormones
• Infertility: FSH, LH, and CG used in combination to promote follicular
development and spermatogenesis
• Diagnostic: GnRH used diagnostically to distinguish between delayed
puberty and hypogonadotrophy
Clinical applications of agents affecting the endocrine system
Use of hormones (or synthetic analogues) for replacement therapy in stages of congenital or pathogenic hormone deficiency
• Use of competitive hormone antagonists or inhibitors of hormone synthesis
• Use of hormones to decrease secretion of other hormones by negative feedback inhibitory effect
To reduce hormone level
• Use of agents interfering with hormone’s biosynthesis
• Use of competitive antagonists
• Reduce secretion of hormone in question by negative feedback inhibition
Mechanism of action of steroid hormones
• binds to specific cytoplasmic receptor
• translocation to nucleus
• alteration in gene transcription
Estrogen
Natural estrogens
• Estradiol
• Estrone
• Estriol
During the first part of the menstrual
cycle estrogens are produced in the
ovarian follicle by the theca and
granulosa cells
Synthetic estrogens
Steroidal
• Ethinyl estradiol (In oral contraceptives)
• Mestranol
• Quinestrol
Non-steroidal
• Diethylstilbesterol
• Chlorotrianisene
• Methallenestril
Clinical uses
• Primary hypogonadism (estrogen deficiency due to failure of
ovary, castration, premature menopause)
• Postmenopausal hormonal therapy
Menopausal hormone therapy
Conjugated equine estrogen, isolated from pregnant mare’s urine, first manufactured 1942, Ayerst
• For symptoms– hot flushes, vaginal dryness, night sweats
Selective estrogen receptor modulators SERM
Therapeutic effects
Agonistic :
• Prevention of osteoporosis in bone
• Induction of ovulation in infertility
• But – can result in endometrial hyperplasia (which can lead to cancer)
Antagonistic :
• Treatment of hormone dependent breast and uterine cancers
• Detrimental: osteoporosis
Progestin
Progesterone
• Necessary for maintenance of the endometrium during pregnancy
Therapeutic applications
• Contraception – “Norplant”
• Hormone replacement therapy
• Delay premature labor
Diagnostic Uses
• Used to test for estrogen secretion in amennorhic patients
Progesterone receptor antagonist
Mifepristone is use to induce first trimester abortion
Oral contraceptives
• First half of 28 days cycle called “follicular” or “proliferative” phase
– Developing follicles produce increasing amounts of estrogen, stimulates endometrial lining
• Second half = “luteal” or “secretory” phase where progesterone secretion increases and proteins required for implantation of fertilized egg are synthesized
Oral contraceptive moa
• Combination preparations : contain estrogen and progestin
• Monophasic – constant dosage of both components during cycle (eg Alesse, Yasmin, Orthocyclin)
• Biphasic or triphasic forms – dosage changed once or twice during cycle (Orthonovum, Ortho-Tri-Cyclin)
• Progestin only preparations “minipill”: contains only a progestin
Combination oral contraceptive
- Exogenous estrogen prevents conception by inhibiting release of LH and FSH
• Estrogen component promotes endometrial growth ( increase risk of endometrial cancer)
• Addition of progestin limits this proliferative effect on endometrial growth
(progesterone is “antiproliferative” – promotes secretion than proliferation)
Minipill
- involves exposure to continuous low doses of progestin
• Ovulation is prevented 70-80% of the time
• Considered > 95 % effective
MOA :
inconsistently inhibit ovulation in ~50% of cycles (low dose)
rely on progestogenic effect of thickening cervical mucus
SIDE EFFECTS :
• breakthrough bleeding in 40% women
• amenorrhoea
• Weight gain
Safety of oral contraceptive
• Decrease risk of endometrial cancer because progestin component inhibits endometrial proliferation
• Risk of blood clot formation is increased except for women who smoke
• Women over 35 recommended not to take oral contraceptives because of the risk of cardiovascular complications
Postcoital contraceptive
• morning after pill
• Administration of 2 doses of estrogen alone or in combination of progestins within 72 hours after coitus will induce menstruation 99% of the time
Androgens
• dihydrotestosterone
• Testosterone enters cell and converted to dihydrotestosterone
via 5α-reductase
• Dihydrotestosterone binds to the androgen receptor
Negative feedback
testosterone is the hormone that controls androgen levels in the body by a negative feedback at the level of both the hypothalamus and anterior pituitary
Antiandrogens
Steroid synthesis Inhibitors
• Ketoconazole (antifungal) – inhibits adrenal and gonadal steroid synthesis but not ovarian aromatase
Conversion of Steroid Precursors to Androgens
• Finasteride – steroid like inhibitor of conversion of testosterone to
dihydrotestosterone (5α-reductase)
• Treatment of benign prostate hypertrophy. Genetic deficiency of this reductase makes males assume a female phenotype
• hair loss treatment
Receptor Inhibitors
• Competitive antagonists compete with dihydrotestosterone and testosterone for binding to the cytoplasmic receptor
• Flutamide – treat metastatic prostate cancer and benign prostatic hypertrophy
• Spironolactone – inhibitor of aldosterone, competes with
dihydrotestosterone for androgen receptors
Reproductive pharmacology oral contraceptives pharmacokinetic
Ethinyl estradiol
• Well absorbed orally, peak plasma levels reached in 1 hr
• Undergoes considerable first pass metabolism
• Effective plasma concentrations maintained by enterohepatic circl
(low dose prep)
Norethisterone (norethindrone)
• Derived fr testosterone
• Rapidly & completely absorbed fr gut
• Extensive first pass metab
Oral contraceptive preparation
• The 21-pill pack has 21 “active” pills (with hormones) to take for 3 weeks, followed by 1 week without pill
• The 28-pill pack has 21 “active” pills (with hormones) to take for 3 weeks, followed by 1 week of reminder pills
• Withdrawal bleed bet day 21- 28
When to start oral contraceptives
Day 1 – 5 of menstrual cycle →provide effective contraception
• If started at any other time in the menstrual cycle
– effective contraception after 7 consecutive days use active pills
• Taken the same time every day (12 hr window period)
Oc be impaired by
1) missing more than one active pill in a packet
2) delay in starting the next packet of active pills ( extending the pill - free, inactive or placebo pill period beyond 7 days)
3) intestinal malabsorption of active pills due to vomiting or diarrhea
Oc adverse effect
Mild
• Nausea, mastalgia, oedema
• Headache / worsen migraine
• Amenorrhoea / breakthrough bleeding
Moderate
• Breakthrough bleeding
• Weight gain, Acne, Hirsutism
• Pigmentation
Oc contraindication
• Pre-existing cardiovascular disease
• Thromboembolic phenomena
• thrombophlebitis
• severe obesity
• hypercholesterolaemia
Oc warning signs and must return
• Abdominal pain (sharp)
• Chest pain (severe)
• Headache (severe)
• Eye (blurred vision, brief loss of vision)
• Sharp leg pain
EHC emergency hormonal contraceptives indication and moa
• Reduced efficacy of other forms of contraception :
• Torn, leaking
• Missed pills
• Late implant or injection
• Detached contraceptive
Moa
• Either prevents or delays ovulation, prevents fertilisation or prevents implantation of fertilised egg
Injectable progestin
- for compliance
- 150 mg intramuscularly every three
months)
MOA:
• completely inhibit follicular development and ovulation
• thicken cervical mucus
SIDE EFFECT
• weight gain
• menstrual cycle changes
• Breakthrough bleeding
Progestin implant
- implanted in the skin in upper arm by creating a small incision and insert capsules in fanlike shape
- Norplant (levonorgesterel)
Moa :
• Prevent ovulation
• Thicken cervical mucous
• thinning the lining of the uterus
Progestin intrauterine system
- Mirena TM
Moa :
• inconsistently inhibit ovulation in ~50% of cycles
Side effects :
• frequent light bleeding first three months after insertion
• Three to six months, most
women experience dramatically
reduced bleeding
• 20% of women will have amenorrhea after 12 months
