Week 1 Flashcards
Hypothalamus
Region found at base of brain between midbrain and forebrain
Collection of brain nuclei or centres
Controls endocrine function via pituitary gland
Gonadotropin releasing hormone GnRH
Peptide hormone
Decapeptide derived from 92 aa prepropeptide
Kallmann syndrome: failure of GnRH secreting neurons to migrate during development- infertility
At puberty gonadal activation is triggered by activation of pulsatile GnRH secretion
In males frequency of pulses is fairly constant (every 2-3 hours)
In females varies during menstrual cycle- medium frequency-> FSH, high frequency -> LH, low frequency- luteal phase
Other factors also regulate FSH/LH eg E2, P4, inhibin
Continuous GnRH leads to down regulation of GnRHR on surface of gonadotroph cells in pituitary- no stimulation of FSH/LH release
Possible to block GnRH effects using an antagonist or agonist
Pituitary (hypophysis)
Pea sized gland at base of brain
Secretes a range hormones regulated by signals from hypothalamus and feedback loops involving circulating hormones
Anterior: ACTH, TSH, GH, LH, FSH, prolactin
Posterior: ADH, oxytocin
Anterior pituitary hormones important in reproduction
Gonadotropins- gonadotrophs
-follicle stimulating hormone FSH
-luteinising hormone LH
Proteins and peptides:
-adrenocorticotropic hormone ACTH- corticotrophs
-growth hormone GH- somatotrophs
-prolactin- lactotrophs
Gonadotropins
HPG axis- FSH and LH
(HCG)
Glycoproteins
Bind receptors on cell surface and signal via G-proteins
Luteinising hormone LH
Secreted by gonadotrophs (ant. Pit)
Acts on leydig, theca and granulosa cells
Structure: common alpha chain (116 aa), unique b chain (121aa), one N-linked carbohydrate chains
Receptor: LHCGR
Follicle stimulating hormone FSH
Secreted by gonadotrophs (ant.pit)
Acts on sertoli and granulosa cells
Structure: common a chain (116aa), unique b chain (111 aa) two n linked carbohydrate chains
Receptor: FSHR
Chorionic gonadotrophin hCG
Secreted by syncytiotrophoblasts (embryo)
Acts on luteal cells (corpus luteum)
Structure: common a chain (116 aa), unique b chain (145 aa), two n linked and four o linked carbohydrate chains
Receptor: LHCGR
Communication hypothalamus-> pituitary
- Direct i.e neural to posterior pituitary
- Indirect i.e vascular to anterior pituitary
Sex steroids
All derived from cholesterol (via acetate)
Three families:
-progestagens- pregnancy (placenta)
-androgens- maleness (<5% adrenals)
-oestrogens- femaleness (liver, adrenals, adipose, placenta)
Some exceptions
Lipid soluble- nuclear receptors
Act via steroid response elements (SREs)
Bound to carrier proteins- albumin, sex hormone binding globulin (SHBG), androgen binding protein (ABP)
Progestagens
Progesterone P4
17 a- hydroxyprogesterone 17a-OHP
20a-hydroxyprogesterone 20a-OHP
Functions: preparation and maintenance of endometrium (pregnancy), development of mammary glands, suppression of lactation, catabolic effects, regulation of gonadotropins
Receptors: PR-A and PR-B (PR-B has additional 164 aa) activate different genes
Androgens
5a-dihydrotestosterone DHT
Testosterone T
Androstenedione (A4)
Dehydroepiandrosterone (DHEA)
Functions: development and maintenance of male reproductive system, development of secondary sexual characteristics, sexual function, supports spermatogenesis, regulation of gonadotropins
Receptors: AR-polymorphic in exon 1 with isoforms showing differing sensitivities to androgen levels
Oestrogens
Oestradiol 17β (E2)
Oestriol (E3)
Oestrone (E1)
Reproductive Functions: development of secondary sexual characteristics Stimulate development and function of mammary glands Stimulate proliferation of endometrium for progesterone action Regulate gonadotropins
Receptors ERα and ERβ
Puberty to menopause – oestradiol
Pregnancy – oestriol
Post-menopause - oestrone
Potency
Depends on how well steroid ‘fits’ binding site on receptors
Varies within each class
Some bind receptors from other classes eg synthetic progestagens in contraceptive pill can be androgenic- side effects eg acne
Some bind but dont activate ie act as antagonists eg mifepristone (RU486)- anti-progestagen
Clinical problems- HPG axis
Affect fertility
Hypothalamus/pituitary- central or secondary hypogonadism- low FSH/LH
Ovary/testes- peripheral or primary hypogonadism -lack of feedback- high FSH/LH
GnRH rarely measured
Endocrine problems are a common cause of female fertility problems much less for men
Prolactin
Levels increase dramatically in pregnancy and during breast feeding
Inhibits gonadal activity through central suppression of GnRH (and thus decreased LH/FSH)
Induces lactational amenorrhea- family spacing
Hyperprolactinaemia- galactorrhea
Menstrual cycle- clinically
Normal duration= 26-32 days (average 28 days)
Luteal phase- 14 days, follicular phase varies
Day 1= first day of menses
FSH/LH- day 2 or 3- ovarian reserve
Testing for ovulation- P4 day 21/28
Oligomenorrhea- <9 cycles in last 12 months
Amenorrhea- no bleed in last 6 months
Primary (never) or secondary (ceased)
Menorrhagia, dysmenorrhea
Menopause
Females are born with a finite number of oocytes
Around the age 50 ovarian reserve is depleted and ovulation ceases
No production of progesterone or oestrogen by ovary
Loss of negative feedback by sex steroids leads to high FSH/LH levels
Ovarian reserve- FSH day 2 or 3
Exploiting knowledge of HPG axis
Hormonal contraception- synthetic progestagens and oestrogens- suppresses ovulation, thickens cervical mucus thins endometrium
Fertility treatment- IVF/ICSI- ovarian stimulation, down regulate HPG axis with GnRH agonist/antagonist, stimulate with FSH, induce oocyte maturation with hCG
Treatment of prostate cancer: GnRH antagonist to suppress T production
Histological zonation of the adrenal gland
Zona glomerulosa: mineralocorticoids -aldosterone
Zona fasciculata: glucocorticoids- cortisol
Zona reticularis: androgens- DHEA
In medulla- catecholamines
Adrenal cortex and medulla
Too little
– Glucocorticoid deficiency
– Mineralocorticoid deficiency—adrenal insufficiency
– Adrenal androgen deficiency
Too much
– Glucocorticoid excess Cushing’s syndrome
– Mineralocorticoid excess Conn’s syndrome
– Androgen excess (congenital adrenal hyperplasia, PCOS)
Adrenal Tumours
– Adrenal incidentaloma, adrenocortical carcinoma
– Phaeochromocytoma (catecholamine excess)
Congenital adrenal hyperplasia CAH
A group of genetic disorders rare 1:10000 newborns
21 hydroxylase deficiency is most common form of CAH
A gene mutation results in lack of one of the enzymes needed to make one or more of these hormones
Normally glucocorticoids and mineralocorticoids
Leads to increased ACTH release and excess androgens produced
Adrenal hyperplasia
Adrenal insufficiency
Salt wasting- lack of aldosterone
Increase androgens- ambiguous genitalia
CAH due to 21 hydroxylase deficiency
17OHP marker of diagnosis
Androstenedione and 17OHP- markers of disease control
CAH a spectrum of severity
CAH severity depends on the degree of 21 hydroxylase deficiency (different mutations have different effects on the enzyme)
Non classic CAH: >90% cases, slight Upregulation ACTH, presentation resembles PCOS overproduction facial hair, irregular menstrual cycle
Less severe mutation dominates phenotype (AR disease)
Classic CAH: simple virilising, salt wasting (aldosterone deficiency too, symptoms: weight loss, vomiting, failure to thrive, poor feeding)
1 in 50 people carry a CYP21A2 mutation on one of their two alleles
CAH symptoms
Androgen excess: ambiguous genitalia, excess body hair hirsutism, early sexual development, irregular periods, infertility
Cortisol deficiency: fatigue, weight loss, muscle weakness, adrenal crisis
Aldosterone deficiency: low blood pressure, salt cravings, salt wasting crisis at birth
Treatment of CAH
Glucocorticoid therapy: cortisol replacement, androgen excess control
-Replacement of deficient corticosteroids: glucocorticoid replacement (hydrocortisone, prednisolone, Dexamethasone), Mineralocorticoid replacement (not always, fludrocortisone)
-suppression of ACTH driven androgen excess: higher glucocorticoid doses, modified release hydrocortisone (taken before bed, released into body few hours after)
Treatment CAH balancing act
Mitigate androgen excess while avoiding iatrogenic glucocorticoid excess
Too little: adrenal androgen excess: hirsutism, acne, menstrual irregularities, reduced fertility
Too much: Cortisol over replacement: weight gain, central obesity, metabolic syndrome, osteoporosis
Fertility in women and men with CAH
Too much glucocorticoid: suppression of LH and FSH, oligo/amenorrhea
Not enough glucocorticoids: androgen and progesterone excess, anovulation, oligomenorrhea, failure to implant
Testicular adrenal rest tissue TART
Development of adrenal and gonads occurs close together, when separate gonads take cells that have both
Arises from urogenital ridge, adrenal and gonadal features
If you have ACTH stimulation CAH these can expand and compress normal spermatogenesis
In particular in patients with poor control, impairs fertility
If left untreated for long time- irreversible
PCOS- signs and symptoms
Chronic (or intermittent) anovulation defined as frequent bleeding at intervals <21 days or infrequent bleeding at intervals >35 days. Mid luteal D-21 progesterone in women with 21-35 day intervals
Androgen excess AE: clinical signs: hirsutism, acne, androgenic alopecia (male pattern baldness). Biochemical evidence: increased serum testosterone
Polycystic ovarian appearance of ovaries (US): defined by presence of 12 or more follicles 2-9mm, in diameter and/or increased ovarian volume >10mL (without a cyst of dominant follicle in either ovary)
PCOS diagnostic consensus criteria
Rotterdam ESHRE/ASRM 2004: 2 out of 3
-oligo and or anovulation
-androgen excess
-polycystic ovaries
Acanthosis nigricans
Sign of insulin resistance
Dark skin on neck
PCOS - a life’s journey
PCOS affects 1 in 10 women
PCOS is a lifelong metabolic disorder with no specific treatment and no means of metabolic risk stratification
Renaming polycystic ovary syndrome
Androgen excess: irregular periods, difficulties to conceive
Insulin resistance: dyslipidaemia (high blood fats), type 2 diabetes (high blood sugar), hypertension, fatty liver disease, cardiovascular disease
FAME: female andrometabolic syndrome
What needs to be excluded prior to a diagnosis of PCOS
Congential adrenal hyperplasia
Cushing’s disease
Adrenal cancer
Ovarian hyperthecosis
Adrenal adenoma
Ovarian tumours
Adrenal incidentalomas
Incidentally discovered adrenal tumours
Is it malignant: overall risk 5-8%, adrenocortical cancer, other malignant mass
Does it produce hormones: overall risk 30-60%, mild autonomous cortisol secretion, Cushing’s, aldosterone excess primary aldosteronism, phaeochromocytoma, functioning adrenocortical cancer
Clinical assessment
Laboratory testing
Imaging
Importance of imaging to diagnose malignancy
Adrenocortical carcinoma ACC: a highly malignant tumour with poor prognosis is rare but accounts for up to 4% adrenal masses undergoing work up
Differentiating adrenocortical adenomas ACA from ACC represents a continuous challenge: imaging is mainstay of differential diagnosis but provides poor sensitivity and specificity
Adenoma is benign- darker more fat
Carcinoma: malignant, large, heterogenous, has haemorrhages and necrosis
Determining tumour size is key
And lipid content
> 4 cm higher risk of malignancy
Hounsfield units HU:
->20 HU (or heterogenous) increased risk of malignancy or phaeochromocytoma
Contrast enhanced CT scans add no values to the risk stratification
Unenhanced HU <10 conclusively exclude malignancy (both primary and secondary) and phaeochromocytoma
Tumour radiodensity or tumour attenuation value (measured in hounsfield units)
The hounsfield unity HU is a relative quantitative measurement of radiodensity used by radiologists in the interpretation of computed tomography CT images.
The absorption/attenuation coefficient of radiation within a tissue is used during CT reconstruction to produce a greyscale image
0HU= density of distilled water
Adrenal myelolipomas fatty benign tumour with very low HU
Hormone excess work up
Exclude cortisol excess:
-serum cortisol at 8-9am after 1mg Dexamethasone at 11pm =1mg overnight Dexamethasone suppression test (1mg-DST)
Exclude aldosterone excess (primary aldosteronism): BP increase, or K decrease: paired plasma renin and plasma aldosterone
Exclude adrenal androgen excess: serum DHEAs, androstenedione, 17OHP (in tumours >4cm)
Exclude phaeochromocytoma: plasma metanephrines
Mild autonomous cortisol secretion: MACS
Non functioning adrenal tumours NFAT
Mild autonomous cortisol secretion MACS
Clinically overt cortisol excess (Cushing’s syndrome)
Absent over features of Cushing’s syndrome and abnormal 1mg overnight Dexamethasone suppression test
MACS is most common hormonal abnormality found in benign adrenocortical tumours
MACS associated with increased risk mortality, cardiometabolic disease, and reduced QOL
Phaeochromocytoma
Hypertension and hyperadrenergic spells (headaches, palpitations, profuse sweating)
2/3 phaeochromocytoma present as incidentalomas nowadays
Have HU>10
Most sensitive test: plasma meatnephrines
Slightly less sensitive test but slightly more specific: 24 hour urinary metanephrine
Phaeochromocytoma treatment
A-blockade (phenoxybenzamine, doxazosin)
Surgery with special anaesthesia requirements
Ensure fluid resuscitation before during and after surgery
Phaeochromocytoma genes
RET protooncogene- gene encodes transmembrane receptor tyrosine kinase, mutated in various cancers or developmental disorders
Multiple endocrine neoplasia MEN type 2:
-phaeochromocytoma
-medullary thyroid carcinoma
-parathyroid hyperplasia/tumour (MEN2A) or mucocutanoeus neuroma MEN2B
VHL: von hippel Linda’s syndrome:
-haemangioblastoma (cerebellum, retina, spinal cord)
-phaeochromocytoma, renal angioma, renal cancer
NF-1: neurofibromatosis type 1 ( von recklinghausen)
Succinyl dehydrogenase complex SDHx:
-SDHA, SDHD- familial head and neck paraganglioma (phaeochromocytoma less common)
-SDHB: familial phaeochromocytoma, extra adrenal paraganglioma (abdomen/pelvis, chest), frequently malignant
