Lecture 7- HPG axis Flashcards
The Hypothalamus-pituitary-gonadal axis is switched on during
puberty
The Hypothalamus-pituitary-gonadal axis involves
- Hypothalamus
- Pituitary
- Gonadal glands
examples of hormones produced by the AP
(1) prolactin (PRL), (2) growth hormone (GH), (3) adrenocorticotropic hormone (ACTH), (4) luteinizing hormone (LH), (5) follicle-stimulating hormone (FSH), and (6) thyroid-stimulating hormone (TSH)
examples of hormones produced by the PP
ADH and oxytocin
- HPG Axis Regulates the function of:
- The thyroid (hypothalamic-pituitary-thyroid axis HPT)
- Adrenal (hypothalamic-pituitary- adrenal axis HPA)
- Reproductive glands (Hypothalamus-pituitary-gonadal axis)
HPG also controls
- Somatic growth
- Lactation
- Milk secretion
- Water metabolism
puberty and HPG
pubertry is initiated in the
hypothalamus
- what precedes phenotype changes by several years
- Nocturnal GnRH pulsality (LH secretion) precedes phenotype changes by several year
- Phenotypic changes (breast buds/testicular enlargement seen)
- Onset of puberty associated with steady rise in
FSH and LH secretion
why is precocious puberty- early onset- rare
- Not common because hormone levels low
- Due to low GnRH secretion
GnRH
- Production occurs in the neurones of the hypothalamus and causes downstream production of sex hormones by the gonads
- Regulates puberty onset, sexual development and ovulatory cycles in females
- Intrinsic or extrinsic disruption to GnRH production can lead to development of
pathologic conditions in humans
- Pharmacologic analogs of GnRH are useful in the treatment of
gynaecological disease due to their ability to block oestrogen and progesterone secretion from the ovary
- Location of the GnRH receptor in the
- Location of the GnRH receptor in the anterior pituitary and is a GPCR
- When bound by an activating subunit, undergo conformation change and activate in intracellular pathways leading to modulation of genes within a target cell via phosphorylation events
- At birth the GnRH neurones are
complete, but functional maturation of synaptic connectivity is attained especially at puberty
GnRh release in early puberty
- Initially at puberty, GnRH is released in low-frequency but after maturation of synaptic connections, it matches male pattern
GnRh secretion in males
GnRH pulses occur after 2 hours
- GnRH secretion in females,
changes according to phases in menstrual cycle
GnRH-1 gene
primarily responsible for mammalian GnRH
- exclusively expressed in discrete popualtion of neurones int he hypothalamus
if GnRH production is blocked
lack of gonadotrophin synthesis and secretion and therefore alck of reproductive development
artifical administration of GnRH can
induce spermatogensis and ovarian maturation
Artificial administration to drive fertility must be
pulsatile in humans- constant admin causes desensitisation of cells in anterior pituitary glands
Anterior pituitary (adenohypophysis)
- Glandular
- Anterior lobe that together with the posterior lobe (neurohypophysis) makes up the pituitary gland (hypophysis)
- Secretion of GnRH by hypothalamus stimulates the anterior pituitary gland gonadotrophs
*
- FSH
- LH
- GnRH release is pulsatile (every 1-3 hrs)
- Intensity of GnRH stimulus is affected by
*
- Frequency of release
- Intensity of release
GnRH travels to pituitary in
hypophysial portal system
In young children, LH and FSH levels are insufficient to initiate
gonadal function
between which ages does blood levels fo LHa nd FSH increase
9-12
- Amplitude of LH and FSH pulses increases esp
during sleep
high levels of LH and FSH
- High levels of LH, FSH initiate gonadal development
Sleep dependent rise in nocturnal LH
- In adolescents boys the sleep related LH increase
- Stimulates a nocturnal rise of testosterone
- Androgen level increase account for some of the early pubertal changes seen in male
- Similar pattern in females with concomitant increase in oestrogen
negatiev feedback look of HPG
- Negative feedback will dampen hypothalamic release of GnRH
- High levels of androgens and oestrogen will give negative feedback to the hypothalamus
- To prevent constant release of GnRH- due to desensitisation of receptors in the pituitary
LH in males
- stimulates Leydig cells in testis to produce testosterone (steroid hormone- cholesterol)
- Once production starts in the medium long-term testosterone levels remain constant
- There is an effect on:
- Circadian rhythm
- Highest early morning
- Effects of environmental stimuli
- Both driven by brain
FSH in males
- FSH stimulates Sertoli cells
- Spermatogenesis
- Inhibin release- negative feedback on anterior pituitary and possibly hypothalamus
Role of testes
- *
- Each lobule contains 1-4 tightly coiled seminiferous tubules
- Each ST -60cm long
- 90% of testicular volume
- Location of spermatogenesis
- In between there is loose connective tissue and blood vessels
- Interstitial tissue contains Leydig cells
Seminiferous tubule cells
*
- Line by complex epithelium made up of 2 types of cells
- Supporting cells (Sertoli cells)
- Provide nutrition and hormonal support for germ cells
- Sensitive to FSH – increase sperm production
- Secrete inhibin- negative feedback on AP FSH
- Spermatogenic cells
- Supporting cells (Sertoli cells)
FSH in females
- Granulosa cells convert androgen to oestrogen
- Follicular development
- Releases inhibin
- Specifically inhibits FSH
Inhibin in women speficifically inhibits
FSH (not LH)
LH in females
-
LH stimulates theca interna cells
- Release androgens- converted to oestrogen by granulosa cells
- LH surge require for ovulation
- LH maintains corpus luteum after ovulation.
- Releases progesterone and oestrogen
- Last 12-14 days unless further stimulated by pregnancy hormone beta hCG (released after implantation
- Moderate titres of oestrogen and GnRH secretion
-
Moderate titres of oestrogen reduce GnRH secretion
- Negative feedback
- Progesterone increases inhibitory effects of moderate oestrogen
- High titres of oestrogen and GnRH
-
High titres of oestrogen alone promotoe GnRH secretion
- Positive feedback
- LH surge- ovulation
- Progesterone prevent positive feedback of high oestrogen
oestrogen reduces GnRH by
pulse
- Progesterone reduces GnRH by
frequency of pulses
- Inhibin on FSH
- Secreted from granulosa cells
- Inhibits secretion of FSH (same as male)
- Has small inhibitory effect on LH
summary of the hormonal feedback loop
hormonal changes in puberty
- increased TSH
- increased metabolic rate
- promotes tissue growth
- increased androgens= retention of mineals in body to support bone and muscle growth–> leadin to growth sput
The role of leptin
*
- An adipocyte- derived protein hormone
- Signals info about energy store to CNS
- Important role in regulating neuroendocrine function
- Reproductive dysfunction associated with leptin deficiency
- Leptin can accelerate the onset of repro function
- Leptin has ……. release pattern signif associated with variations in LH
- Leptin has pulsatile release pattern signif associated with variations in LH
- Leptin can regulate GnRH levels and its secretion may, in turn, be influenced by gonadal steroids but appears to be independent of LH control
percocious puberty can be
central or peripheral
Central precocious puberty
Precocious puberty with elevated GnRH levels (due to hypothalamus)
cause sof central precocious puberty
- Idiopathic or constitutional
- CNS lesion
- Pituitary gonadotropin-secreting tumours
- Systemic conditions- tuberous sclerosis, neurofibromatosis
- Obesity- levels of leptin
pathophysiology of central precocious puberty
- Premature activation of the hypothalamus-hypophyseal axis–> abnormally early initiation of pubertal changes–> early development of secondary sexual characteristics and gonadarche
- Diagnosis- lab tests
- Basal LH and FSH= increased
- GnRH stimulation test (gold standard): gonadotropin (LH and FSH) levels increase after intravenous admin of GnRH
- increased testosterone and oestrogen
Peripheral precocious puberty
Precocious puberty without elevated GnRH levels (not a problem with the hypothalamus)
causes of peripheral precocious piberty
- icnreased androgen production
- ovarian cyst (most common)
- congentiala drneal hyperplasia
- Virilizing ovarian and adrenocortical tumours
- leydig-cell tumour
- Increased oestrogen
- HCG- secreting germ cell tumours e.g. granulosa cell tumour
- rarely: adrenal gland tumors that produce oestrogen
- McCunes-albright syndrome
- icnreased B-HCG production e.g. hepatoblastoma
- primary hypothydroism
- obestiy related precoous sexual development due to compensatory hyperinsulinemia
lab tests for Peripheral precocious puberty
- icnreased oestrogen or testosterone
- decreased LH and FASH (GnRH suppressed by eleavted gonadal hormones)
Delayed onset of puberty
Absent or incomplete development of secondary sex characteristics by the age of 14 or 13 in girls
causes of Delayed onset of puberty
- constitutional growth delay (most common cause of delayed puberty)
- malnutrition and other chronic diseases e.g. IBD, hypothyrodism, psychosocial deprivation
- hypogonadism
constitutional growth delay
a temporary delay in growth and osnet of puberty that is not caused by a pathological process
e. g. inherited autosomal dominant, recessive, or X-lined trait
diagnosis: X ray showing bone age that is less than the individuals chronological age
treatment: no treatment is needed, as catch-up growth eventually occurs and the individual reaches normal height
Delayed onset of puberty lab test
basal LH and FSh
