W.11: Disturbances in Pituitary function Flashcards
Primary regulator/(-ors) of hormone synthesis?
Target glands such as thyroid, adrenal cortex, gonads.
Secondary regulator of hormone synthesis?
Anterior pituatary
Tertiary regulator of hormone synthesis?
Hypothalamus
Hormones have negative inhibition on what?
On the anterior pituitary.
Anterior pituitary have negative ihibition on what?
Hypothalamus
Pathway of hormone synthesis.
Hypothalamus –> Releasing hormones (TRH, CRH, GnRH) –> Ant. pituitary –> Tropic hormones (TSH, ACTH, FSH, LH) –> Target glands (thyriod, andrenal cortex, gonads) –> Hormones
Ant. pituitary hormones?
- Corticotropin- releated peptides
- ACTH, LPH, MSH, endorfins
- Somatomammotrops (peptides)
- GH, PRL
- Glycoproteins (2alfa, 2beta)
- LH, FSH, TSH
Defects that might cause a loss of pituitary function? (5)
- Congenital
- Pituitary tumors
- Functional
- Non- functional
- Non- pituitary tumors
- Craniopharyngioma
- Metastases
- Trauma
- Surgical
- Head trauma
- Inflammation
- Autoimmune hypophysitis
- Granulomatous disease
+ Histiocytosis X
+ Sarcoid
+ Tuberculosis
Typical progression of hormone loss?
GH –> LH –> FSH –> ACTH –> TSH
Definition of dwarfism (Nanosomia)
Height <147 cm.
Possible reasons for developing dwarfism? (6)
- Achondroplasia (70%)
- GH associated diseases
- Other endocrine diseases (hypothyreosis, Cushings- syndrome)
- Connective tissue diseases (Osteogenesis imperfecta)
- Genetic disorders, Turner syndrome
- Stress- psychogen dwarfism
Achondroplasia
FGF R3 mutation. 75% of individuals with achondroplasia are born to parents of average size due to new mutation or genetic change.
What might GH deficiency lead to? (7)
- Growth retardation (in children)
- High fat content, increased waist/ hip
- Decreased BMD 1-2 SD below age matched mean
- Increased fracture 2x
- Increased total cholesterol and LDL/ HDL
- Increased insulin, insulin resistance
- Fatigue, muscle weakness
Sporadic GH deficiency
- Acquired
- Hypothalamic
Genetic GH deficiency
- FSH and LH deficiency also present
- Monotropic GH defiencency (70% respond to GnRH)
Underlying cause of GH deficiency might be?
Pituitary or hypothalamic deficiency.
Clinical manifestations seen in GH receptor defect (Laron Dwarf)?
- Extreme short statue <122 cm
- Increased serum level of GH
- Absence of GH receptor in tissues
- GH secretion is not suppressible by glucose
- IGF-I level is low - tumor, DM decrease
Manifestations seen in Somatomedin- C (SM-C, IGF-I) defects?
- Total absence of IGF-I, IGF-II normal
- Failure of IGF-I to increase at puberty (seen in African pygmy)
- Absence of IGF-I receptors
- Post IGF-I receptor defect (normal binding, but decreased uptake of amino acids)
Treatment of hypopituitarism?
- Remove cause
2. Replacement therapy (depends on hormone lost)
Treatment in secondary hypothyroidism?
Thyroxine
Treatment of secondary hypoadrenalism?
Hydrocortisone
Treatment for induction of ovulation?
FSH+LH
GH excess may cause…
- Childhood
- Gigantism
- Adults
- Acromegaly
Etiology of GH excess?
- 98% GH- producing pituitary tumor
- 2% ectopic GHRH secretion
- SCC lung cancer
- Bronchial or intestinal carcinoid tumors
- Pancreatic islet cell tumor
- Pheochromocytoma
Clinical signs of acromegaly?
- Somatotropic adenoma of pituitary
- Acromegalic facies
- Cardiomegaly
- Barrel chest
- Abnormal glucose tolerance secondaty to insulin resistance
- Degenerative arthritis
- Thickened skin (hypertrophy of sebaceous and sweat glands)
- Hyperostosis (thoracic vertebrae)
- Carpal tunnel syndrome
- Increased size (hands, feet)
- Growth of long bonws (children)
Patophysiology of acromegaly? (6)
- Increased GH secretion
- The nocturnal sruge is absent
- Glucose suppression is lost
- Paradox dopamine stimulation test
- Increased serum somatomedins
- Insulin resistance
Treatment of acromegaly?
- Surgical removal of the tumor
- Additional therapy:
- Somatostatin analouge
- Radiation
- GH- receptor antagonist
Frequency of pituitary tumors?
- PRL- secreting 35%
- Non- functioning 30%
- GH- secretion 20%
- Mixed GH- and PRL- secretion 7%
- ACTH and Lipotropin sec. 7%
- LH-, FSH-, or TSH- sec. 1%
Normal prolactin level?
<900 pmol/L
Main clinical manifestation seen in women/ men due to Hyperprolactinemia?
Women:
- Amnorhea 57- 90%
- Galactorrhea 30- 80%
Men:
- Decreased libido 75- 100%
- Impotence 68- 100%
Treatment of prolactinomas?
Dopamin agonist therapy will normalize prolactin and lead to timor regression in most patients with macro- and microprolactinomas.
ADH release is stimulated by?
- Plasma osmolality >280 mosm/L
- A fall in plasma volume
- Emotional factors and stress
- Sleep
- Other factors:
- Cholinergic stimulation, alfa- adrenergic stimulation
- Angiotensin II, prostaglandin E
- Opiates, Nicotine
- Histamine, Ether, Phenobarbitate
Definition of Diabetes Insipidus
DI is a disorder resulting from deficiency of anti- diuretic hormone (ADH) or its action and is characterized by the passage of copious amounts of diluted urine.
Central DI
Failure of pituitary gland to secrete adequate ADH.
Causes of Central DI?
- Idiopathic (30% of cases)
- Suprasellar tumors (30% of cases)
- Infections (encephaitis, TB, etc)
- Non- infectious granuloma (sarcoid, etc.)
- Trauma or skull srugery
- Leukemia
Nephrogenic DI
Results when the renal tubules of the kidney fail to respond to circulating ADH.
What does the renal concentration defect seen in nephrogenic DI lead to?
Loss of large volumes of diluted urine. This causes cellular and extracellular dehydration and hypernatremia.
Causes of nephrogenic DI (primary and secondary)?
- Primary familial:
X- linked recessice that is severe in boys and mild in girls. - Secondary to:
- Chronic pyelonephritis
- Hypokalemia
- Hypercalcemia
- Sickel cell disease
- Protein deprivation
- Drugs (Li) etc.
SIADH
Syndrome of Inappropriate secretion of ADH
When is SIADH seen?
SIADH occurs when ADH is released in amounts far in excess of those indicated by plasma osmotic pressure.
SIADH is characterized by?
- Fluid retention
- Serum hypoosmolality
- Dilutional hyponatermia
- Hypochloremia
- Concentrated urine in the presence of normal or increased intravascular volume
- Normal renal function
SIADH may be caused due to…
- Pulmonary conditions: pneumonia, TB, lung abscesses, positive pressure ventilation
- Trauma (most frequently head related)
- Meningitis, subarachnoid hemorrhage
- AIDS, Addison’s disease
Peripheral neuropathy, psychoses - Vomiting, stress and many medications
- Symtoms may also be caused by ADH secreting tumors
Which hormones are secreted by the ovary?
Graafian follicle:
- Estrogens (estradiol): Steroid
Corpus Luteum:
- Progestins (Progesterone): Steriod
- Relaxin: Polypeptide
Which hormones are secreted by the testis?
Leydig cells:
- Androgens (Testosterone): Steriod
Sertoli cells:
- Inhibin: Protein
Seminal vesicles:
- Contain leutinizing hormone receptors, may be regulated by the ligand, luteinizing hormone.
Which hormone/ hormones are secreted by the adrenal cortex?
Glucocorticoids (cortisol): Steroid
Which hormone/ hormones are secreted byt the placenta?
Human Chorionic Gonadotropin (hCG): Glycoprotein
Which hormone/ hormones are secreted by the endometrial cups?
- Equine Chorionic Gonadotropin (eCG): Glycoprotein
- Estrogens/Progestins: Steroids
- Realxin: Protein
- Placental Lactogen: Glycoprotein
Pricipal function of Estrogens?
Mating behavior, secindary sex characteristics, maintenance of female duct system, mammary growth.
Pricipal function of Inhibin (Folliculostatin)?
Regulates release of FSH from ant. pituitary.
Pricipal function of Porgestins (Progesterone)?
Maintenance of mammary growth, pregnancy and secetion.
Pricipal function of Relaxin?
Expansion of pelvis, dilation of cervix.
Pricipal function of Androgens (Testosterone)?
Male mating behaviour, spermatocytogenesis, maintenance of male duct system and accessory glands.
Pricipal function of Inhibin?
Regulates release of FSH.
Pricipal function of Prostaglandin F2- alfa?
Regression of CL. Stimulate myometrial contracions, ovulation. Produced by uterus when stimulated by oxytocin.
Pricipal function of hCG?
LH- like. Involved with establishment of pregnancy in human. Support and maintain CL.
Pricipal function of eCG?
FSH- like. Some LH activity, immunological protection of foal. Formation of accessory CL in mare.
Pricipal function of estogens/ progestins?
Regulate placental blood flow. Maintenance of pregnancy.
Pricipal function of Placental Lactogen?
Stimulates mammary growth and milk secretion.
How are the sex steriods transported?
They are bound to plasma proteins.
What does SHBG resp. DHT bind to?
SHBG binds to T and DTH: 66- 78%
and E: 37%.
What does CBG bind to?
90% of cortisol
28% of progesterone
What does albumin bind to?
60- 80% of E and P
20- 30% of T and DHT
85% of Androstenedione
Where is SHBG synthesized?
In the liver. E increases its synthesis and T decreases it. Why female levels are much higher.
Where are E and P metabolized?
In the liver.
Half life of P?
Approx. 5 min.
What stimulates the hepatic SHBG synthesis?
- E2
- T4
- Anticonvulsants
- Liver disease
- Age
What decreases tje hepatic SHBG synthesis?
- Testosterone
- Anabolic steriods
- Insulin (eg. in obesity)
How big amount of testoterone is excreted?
90%
Effect of testosterone?
- Wolffian duct
- Bone formation
- Muscle mass
- Spermatogenesis
Testosterone + 5alfa- reductase (6-8%) –>
DHT
Testosterone + Aromatase (0,3%)
–>
Estradiol
Effects of DHT?
- External genitalia features
- Prostate growth
- Acne
- Facial/ body hair
- Scalp hair loss
What does total testosterone include?
- Biologically inactive SHBG- bound testosterone (60%)
- Albumin- bound testosterone (38%)
- Unbound free testosterone (2%)
Testosterone deficinencies may cause? (4)
- In utero: Female external phenotype
- Post- natal: Micropenis/ crypotochid
- Childhood: Failure to enter puberty
- Adult- onset:
- Sexual dysfunction
- Osteopaenia/ sarcopaenia
- Central obesity/ dyslopidaemia
- Think skin and gynaecomastia
- Diminished muscle mass
- Absent/ reduced body hair
- Small, soft tetes
- Infertility
Laboratory evaluation of male reproductive function?
- Measure serum testosterone
- Calculate free testosterone from total testosterone and SHBG
- Stimulation test (hCG, clomiphene, GnRH)
- Semen analysis
- Testicular biopsy
Disorders of sexual differentiation?
- Seminiferous tubule dysgenesis: Klinefelter syndrome
- Gonadal dysgenesis and its variants: Turner syndrome
- Complete and incoplete form to XX and XY gonadal dysgenesis
- True hermaphroditism
Most common form of primary hypogonadism and infertility in male?
Seminiferous tubule dysgenesis (Klinefelter syndrome)
Clinical symptomes seen in Seminiferous tubule dysgenesis?
- Gynecomastia
- Diminished facial and body hair
- SMall phallu, poor muscular development
- Eunochiod tall body habits
- Increased incidence of:
- Mild DM
- Varicose veins
- Chronic pulmonary disease
- Carcinoma of breast - Progressive testicular lesion
Clinical features seen in Syndrome of Gonadal Dysgenesis (Turner syndrome)?
- Sexual infantilism
- Short stature
- Lymphedema of the extremities
- Typical face
- Short neck, shieldlike chest
- Coarctation of the aorta
- Hypertension, renal abnormalties
- Obesity, DM, Hashimoto’s thyroiditis, rheumatoid arthiritis etc.
Features of pseudohermaphroidism, female?
- Normal ovaries
- Extragonadal hypersecretion of androgen
- Masculinization, clitoral hypertrophy
Features of pseudohermaphroidism, male?
- Teste, genital ducts or extragenitals are not completely masculinized
- Deficient testosterone secretion
What might deficient testosterone secretion seen in pseudohermaphroidism lead to?
- Failure of testicular differentiation
- Failure of secretion of tesosterone or Müllerian duct inhibitory factors
- Failure of target tissue response to T or DHT
- Failure of conversion of T to DHT
Clinical features of true hermaphroditism?
- Uterus
- Ovotestis
- Breast development
- Menses (50%)
Causes of true hermaphroditism?
- Sexchromatin mosaicism or chimerism
- Y to autosome; Y to X chromosome translocation or exchange
- Autosomal mutant gene
Disorders of puberst, causing Precocious puberty?
- Central, Gondaotropin dependent
- Idiopathic
- Hypothalamic hamartoma or other lesions
- CNS tumor or inflammatory state
- Perfipheral, GnRH- independent (precocious pseudopuberty)
- Isosexual sexual precocity
- Heterosexual sexual precocity
- -> gynecomastia
Causes of Isosexual sexual precocity?
- Congenital adrenal hyperplasia
- hCG- secreting tumor
- McCune- Albright syndrome
- Activating LH receptor mutation
- Exogenous androgens
Causes of Heterosexual sexual precocity?
- Estrogen producing tumor
- Familial aromatase excess
- Marijuana smoking
- Germ cell tumors - secrete hCG
Causes of delayed puberty, GnRH dependent?
- Idiopathic
- Sporadic or familial (associated with constitutional growth delay)
- Chronic diseases
- Malnutrition, anemia, acidosis, anorexia nervosa, cystic fibrosis, chronic renal insufficiency
- Psychosocial deprivation
- Hypothalamic- pituitary causes:
- Congenital disorders: GnRH receptor mutation, adrenal hypoplasia, Kalmann syndrome.
- Acquired with other pituitary hormone deficinecies: Pituitary tumors, cranial irradiation, granulomatous disease, hemosiderosis.
Causes of delayed puberty, GnRH independent?
- Congenital:
- Anorchia
- Chromosomal abnormalties: Klinefelter syndrome, Noonan’s syndrome
- Acquired:
- Autoimmune inflammation (APS)
- Orchitis
- Bilateral undescendent testes or anorchia
- Radio- or chemotherapy
- Trauma
- Surgery
Which are the primary congenital disorders of male reproductive functions during adulthood?
- Klinefelter’s syndrome
- Noonan’s syndrome
- Inborn errors of testosterone biosynthesis
- Androgen resistance states
Primary acquired disorders of male reproductive functions during adulthood?
- Undescended testes
- Bilateral torsion of the testes
- Bilateral orchitis
- Orchidectomy
- Gonadal toxins (radio- and chemotherapy)
- Acute and chronic systemic disease
Secondary congenital disorders of male reproductive functions during adulthood?
- Isolated GnRH deficiency
- Isolated LH deficiency
- Prader- Willi syndrome
- Laurence- Moon- Biedl syndrome
Secondary acquired disorders of male reproductive functions during adulthood?
- Piruitary tumors and infarct
- Trauma
- Craniopharyngioma
- Hyperprolactinaemia (primary and secondary)
- Haemochromatosis
- Neurosarcoid
- Ageing
How much T do females produce in 24h?
300 mikrogram (25% in the ovary)
Which androgens are produced by the ovary?
T, DTH and androstenedione
Abnormalities associated with androgen excess seen in females?
- Acne
- Alopecia
- Android obesity
- Cardiovascular disease
- Dyslipidemia
- Glucose intolernace/ insulin resistance
- Hirsutism
- Hypertension
- Infertility
- Menstrual dysfunction
Name three female reproductive disorders.
- Premenstrual syndrome (PMS)
- Dysmenorrhea (= painful menstruation)
- Polycystic ovarian syndroma (PCOS)
Definition PMS
Occurs prior to menstruation and is charachterized by irratibility, bloating, weight gain, breast tenderness and headaches.
Primary dysmenorrhea
Is thought to resylt from periodic uterine contractions due to uterine PG. Pain can be accompanied by nausea and diarrhea.
Secondary dysmenorrhea
Results from problems such as endometriosis or congenital anomalies.
Polycystic ovrian syndrome (PCOS)
Characterized by anovulation and high circulating androgen, estrogen and LH. The ovaries are enlarged with many follicles undergoing atresia due to low FSH.
What might PCOS result in?
Due to that high amount of estrogen is aromatized –> hirsutism and acne.
Most common cause of hirsutism?
PCOS
Clinical features PCOS?
- Oligomenorrhoea
- Anovulation
- Hirstuism
- Acne
- Obesity
- Hypertension
- Glucose intolerance
- Dyslipideamia
Biochemical features seen in PCOS?
- Increased LH:FSH in follicular phase
- Increased prolactin
- Increased testosterone
- Low SHBG
- Raised fasting insulin
- Dyslipidaemia
(- Increased DHEAS Androstenedione)
Dynfunctions of which organs cause amenorrhea?
Dysfunctions of:
- Hypothalamus
- Pituitary
- Ovaries
- Uterus
- Vagina
Amenorrhea can be both primary and secondary. Give the definitions.
Primary: Absence of mearche by the age of 16.
Secondary: absence of menses from more than three cycle internals or six monthsin women who were previously menstruating.
Cause of primary amenorrhea?
- Chromosomal abnormalties : 45%
- Physiologic delay of puberty : 25%
- Müllerian agenesis : 15%
- Transverse vaginal septum or imperforate hymen : 5%
- Absent hypothalamic production of GnRH : 5%
- Anorexia nervosa : 2%
- Hypopituitarism : 2%
Name the conditions where secondary amenorrhea can be seen?
- Pregnancy
- Anovulation
- High PRL
- Abnormality in the outflow tract
- Destruction of uterine endometrium by curretage or chronic infections
Definition of hirsutism.
The development of androgendependent terminal body hair in a woman in places in which terminal hair is normally not found.
Definition hypertrichosis.
A diffuse increase in total body hair. It is not androgen dependent.
Name the common causes of hypertrichosis.
- Drugs
- Systemic illness
(hypothyroidsm, anorexia nervosa, malnutrition, porphyria, dermatomyositis) - Paraneoplastic syndrome in some cancers
Common etiology of hirsutism.
- Idiopathic hirsutism (47,7%)
- PCOS (50%)
- Ovarian testosterone producing tumour
- Cushing’s syndrome
- Congenital adrenal hyperplasia
Clinical manifestation PCOS.
- Hirsutism
- Frontal balding
- Acne
- High serum androgen
- Menstrual irregularity (oligo- or anovulation)
Clinical manifestation idiopathic hirsutism.
- Hirsutism
- No other clinical abnormalties
- No menstrual irregularity
- May be a mild variant of PCOS
Name the less common causes of hirsutism (2,3%).
- Hyper- PRL
- Drugs
- CAH
- Ovarian tumors
- Adrenal tumors
- Acromegaly
How does obesity affect androgen production?
It causes and increase in the androgen production and clearance rates.
Effect of hyperinsulinemia (female reproduction).
Hyperinsulinemia caises ovarian hyperandrogenism, by acting via theca- cell receptors for IGF-I.
Insulin also decreases serum SHBG.
Diagnosis of hirsutism?
- No labs. if long- standing mild to moderate hirsutism.
- Testosterone: mild to moderate hirsutism.
- DHEA-S in addition to T: if progressive hirsutism, irrgeular menses and any signs of virilization
- Prolcatin, FSH, LH: if irregular menses
Relation LH/ FSH in PCOS?
LH > FSH
Level of prolactin in prolactinoma?
> 100- 200ng/ mL
Definition of endometriosis.
Presence of endometrial tissue, including both endometrial glands and stoma outsde the lining of the uterine cavity.
Most common sites of endometriosis?
- Ovary: chocolate cyst Peritoneum of the rectovaginal cul-de-sac of the Pouch of Douglas - Uterosacral ligaments - Sigmoid colon - Broad ligament
Less common sites of endometriosis?
- Cervix
- Round ligament
- Urinary system: bladder, ureter
- Umbilicus
- Appendix
- Laparotomy scars
- Lung, brain etc.
Name the signs and symptoms of endometriosis.
- Chronic pelvic pain
- Dysmenorrhea
- Abnormal uterine bleeding
- Dyspareunia
- Infertility
- Pelvic mass (endometrioma)
- Misc: Tenesmus, hematuria, hemoptysis
Name the risk factors of endometriosis.
- Early menarche
- Short menstrual cycle
- Alcohol
- Caffeine
Name the protection factors of endometriosis.
- Term pregnancy
- Regular extercise
- Smoking
Mean age at time of diagnosis of endometriosis.
25- 30 years.
Give a short description of the Implantation theory, retrograde menstruation.
- Endometrial cells in menstrual fluid are capable of implating on peritoneal surfaces
- Woman with endometriosis have higher volumes of reflux
- Peritoneal endometrial cells recovered during menses can atach to and penetrate the peritoneum
- Endometriosis is most commonly seen in dependent portions of pelvis.
- Endometriosis occurs in patients with uterine outlet obstruction
- Most woman have some degree of retrograde menstruation but only 6- 10% have endometriosis.
Give a short description of the Coelemic metaplasia, transformation of embryonic tissue.
- Peritoneal mesothelium, Müllerian epithelium and germinal epithelium may be derived from a common ambryonic tissue
- Metaplastic change in the coelomic epithelium (peritoneum and pleura): spontaneous or induced.
Supporting eviences of theory based on Coelemic metaplasia, transformation of embryonic tissue.
- Endometriosis have been found in prepubertal girls
- Pleural and pulmonary endometriosis
- Endometriosis in men treated with high doses of estrogen
- In vitro, ovarian surface epithelium can be induced by estradiol to form endometrial glands
- Unusual sites such as knee, thumb, eye
Name some theories in the pathogenesis of endometriosis.
- Implantation theory, retrograd menstruation
- Lymphatic and vascular dissemination theory
- Coelomic metaplasia
- Immune theory
- Genetic theory
Briefly describe the Lymphatic and vascular dissemination theory.
The theory may explain endometriosis in distant sites outside plevis eg. brain, colon.
Briefly describe the Immune theory and mechanisms supporting the theory.
- Not all women with seeding of menstrual debris into plevis develop endometriosis.
- Evidence for decreased cellular immunity
- Increased prevalence of humoral antibodies against endometrial tissue
- INcreased number of macrophages –> promote disease by secreting a variety of cytokines and growth factors that stimulate endometriotic attachment, invation, proliferation and neovascularization.
Briefly describe the Genetic theory.
- First degree relatives have 6- 7 times higher risk.
- Detoxification enzymes –> susceptibility to envionmental stimuli (dioxin)
- Genes associated with malignant transformation (eg. tumor suppressor genes).
Describe the molecular mechanism of endometriosis.
Estrogen production plays a key role in endometriosis.
- Ovaries secrete estradiol
- Aromatase in adipose tissue and skin
- - Androstenedion –>Etrone –> Estradiol - Endometriotic tissue expresses a complete set of sterogenic genes, incl. aromatase-
- - Cholesterol –> Estradiol
