Hypothalamic–Pituitary–Gonadal Axis

What is the hypothalamic–pituitary axis?

A regulatory system where the hypothalamus controls pituitary hormone secretion.

How does the hypothalamus communicate with the anterior pituitary?

Via the hypothalamic–hypophyseal portal system (blood vessels).

What structure connects the hypothalamus to the pituitary gland

infundibulum

Which hormones are transported to the posterior pituitary from the hypothalamus & are released from the posterior pituitary

ADH (vasopressin) and oxytocin

How are posterior pituitary hormones released

Produced in the hypothalamus —(axons from hypothalamic neurons)→(pituitary stalk)→ posterior pituitary → Released directly into the bloodstream

Which anterior pituitary hormones are released in response to hypothalamic signals

ACTH, TSH, LH/FSH, GH, Prolactin

Name 3 hypothalamic hormones that stimulate anterior pituitary hormone release

GnRH (gonadotropin-releasing hormone)

TRH (thyrotropin-releasing hormone)

CRH (corticotropin-releasing hormone)

Which hormones do each of these stimulate the release of:

GnRH:

TRH:

CRH:

GnRH → Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH)

TRH → Thyroid Stimulating Hormone (TSH)

CRH → Adrenocorticotropic hormone (ACTH)

Name a hypothalamic hormone that inhibits anterior pituitary hormone release

Dopamine

What hormone does dopamine inhibit the release of

Prolactin

Which hypothalamic hormone inhibits growth hormone release

Somatostatin

Name an important clinical condition related to the posterior pituitary gland

Diabetes insipidus

What’s the problem in Diabetes insipidus

Deficiency of ADH or a reduced response to this hormone in the kidney.

Treatment for Diabetes insipidus

Desmopressin

Oxytocin is also released from the posterior pituitary. What is a clinical use of oxytocin?

Used for labour induction

4 key roles of anterior pituitary hormones

•Growth and metabolism

•Lactation

•Regulation of gonadal function

•Control of reproductive physiology

4 possible causes of Hyperprolactinemia

• Pituitary adenomas (prolactinomas)

• Hypothalamic or pituitary stalk lesions

• Drugs that inhibit dopamine signalling (e.g. antipsychotics)

• Pregnancy/lactation (physiological increase)

4 clinical features of Hyperprolactinemia

• Amenorrhoea
• Galactorrhoea
• Infertility
• Reduced libido

(body acts like it’s pregnant → no period, breast milk production, no need to get pregnant again)

What hormonal changes does Hyperprolactinemia cause that produces these clinical features

↓ Kisspeptin

↓ GnRH

↓ LH & FSH

3 types of treatment for Hyperprolactinemia

Dopamine agonists

Oral contraceptive pill / HRT

Surgical debulking (rarely)

Name 2 Dopamine agonists

Cabergoline

Bromocriptine

Which D receptor (no.) do the Dopamine agonists affect

D2

D2 receptor agonists inhibit prolactin secretion from what type of pituitary cells

Pituitary lactotroph cells

Dopamine Agonists are derived from what

Ergot-derived (fungi)

Which Dopamine Agonist has a short/long half life

• Bromocriptine

• Cabergoline

Bromocriptine: Short (2–8 hour)

Cabergoline: Long (65 hours)

Which Dopamine Agonist has a higher D2 receptor affinity

• Bromocriptine / Cabergoline

Cabergoline

How often is Bromocriptine administered

Multiple times daily

AEs of Bromocriptine

Nausea

Postural hypotension

CNS side effects

How often is Cabergoline administered

Once / Twice weekly

2 advantages of Cabergoline over Bromocriptine

Better tolerated

Improved clinical response

Growth hormone–releasing hormone (GHRH) secretion is stimulated/inhibited by what

• also say where each stimulator/inhibitor comes from

Stimulated by Ghrelin (stomach hormone)

Inhibited by Somatostatin (hypothalamus) & IGF-1 (Insulin-like growth factor 1)(liver)

Name 4 target tissues of GH

GH works through what 3 molecular signalling pathways

JAK2–STAT pathway

PI3K pathway

MAPK pathway

What causes the problem in Growth Hormone Deficiency

Caused by insufficient GH secretion from the anterior pituitary

4 Clinical features of Growth Hormone Deficiency

• Growth failure in children
• Increased fat mass
• Reduced muscle mass
• Reduced bone density

Growth Hormone Deficiency treatment (what type of med & name the drug)

Recombinant human growth hormone (Somatropin)

What is Growth Hormone Excess called in children vs adults

Gigantism (children)

Acromegaly (adults)

Compare growth pattern of Gigantism (children) & Acromegaly (adults)

Gigantism (children): excessive linear growth

Acromegaly (adults): enlargement of hands, feet and facial features, macroglossia, prognathism

What are 2 complications of acromegaly

Cardiomyopathy

Metabolic complications (insulin resistance, osteoporosis)

Cause of Growth Hormone Excess

GH-secreting pituitary adenoma

4 treatment options for Growth Hormone Excess

• Transsphenoidal surgery (first-line)

• Somatostatin analogues

• GH receptor antagonist

• Dopamine agonists

Name a GH receptor antagonist used in the treatment of Growth Hormone Excess

Pegvisomant

Somatostatin Analogues MOA

Bind somatostatin receptors (SSTR2, SSTR5) on pituitary somatotroph cells• Inhibit growth hormone (GH) secretion• Reduce IGF-1 production

Name the main 2 Somatostatin Analogue drugs

Octreotide

Lanreotide

You can get short/long acting formulations of Somatostatin Analogues. What is used for the short acting formulation & what is it’s duration of action

Octreotide

Duration of action: ~12 hours

What 2 drugs can be used for the long acting formulation & what is the duration of action

Octreotide LAR (Long-Acting Release)

Lanreotide

Intramuscular injection every 2–4 weeks

4 AEs of Somatostatin Analogues

• Gastrointestinal upset (~50%)
• Gallstones (~25%)
• Glucose metabolism alterations / diabetes (<5%)
• Local injection-site reactions

3 other clinical uses of Somatostatin Analogues (other than GH excess)

• Neuroendocrine tumours
• Acute variceal bleeding (via splanchnic vasoconstriction)
• TSH-secreting pituitary adenomas (TSHoma)

Pegvisomant MoA

GH receptor antagonist

4 effects of Pegvisomant

Reduces IGF-1

Increases growth hormone

May increase tumour size

Symptom control

How is Pegvisomant administered

Subcutaneous administration - daily injection

How is the action of Pegvisomant monitored

Measuring IGF-1 levels

In the Hypothalamic–Pituitary–Gonadal (HPG) Axis, what stimulates the release of GnRH

Kisspeptin

In the HPG axis, what is the action of GnRH

GnRH is released in pulses and acts on the anterior pituitary, stimulating the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

Effects of FSH in females

FSH stimulates granulosa cells, promoting follicle development and oestrogen production

Effects of LH in females

LH acts on theca cells to produce androgens and later triggers ovulation and progesterone production

Effects of FSH in males

FSH acts on Sertoli cells to support spermatogenesis

Effects of LH in males

LH stimulates Leydig cells to produce testosterone

How does feedback happen in the HPG axis

Sex steroids such as oestrogens and testosterone provide negative feedback to the hypothalamus and pituitary, helping regulate the system

What’s the problem in Hypogonadotropic Hypogonadism

Reduced gonadal function due to insufficient stimulation by LH and FSH

3 causes of Hypogonadotropic Hypogonadism

• Hypothalamic dysfunction
• Pituitary disorders
• Chronic illness or medications

What (if any) changes do you see in what hormones in Hypogonadotropic Hypogonadism

• Low testosterone / oestrogen
• Low or inappropriately normal LH and FSH

3 options for treatment of Hypogonadotropic Hypogonadism

Hormone replacement therapy (HRT)

Pulsatile GnRH therapy

Gonadotropin therapy

For what goal would Hormone replacement therapy (HRT) be used over the other 2 options

Goal: Restoration of sex hormone levels

Effective on: libido, bone density, muscle mass, sexual development

For what goal would Pulsatile GnRH therapy be used

Goal: Fertility

(when the defect is hypothalamic)

For what goal would Gonadotropin therapy be used

Goal: Fertility

What does Gonadotropin therapy consist of

hCG (LH-like activity)

FSH

In the menstrual cycle, when are LH & FSH peaking

Day 14

Does LH/FSH promote steroidogenesis

LH —(thecal cells)→ Steroidogenesis

Name 5 drug types that modulate the HPG axis

• GnRH agonists
• GnRH antagonists
• Gonadotropins
• Estrogens and progestins
• Androgen therapy

GnRH agonists MoA

• Continuous stimulation of GnRH receptors
• Initial flare effect
• Subsequent suppression of LH and FSH

4 uses of GnRH agonists

• Endometriosis
• Prostate cancer
• Precocious puberty
• Assisted reproduction

6 AEs of GnRH agonists

• hot flashes

• decreased libido

• vaginal dryness

• erectile dysfunction

• mood changes

• bone mineral density loss (long-term

Name 2 GnRH antagonists

Cetrorelix

Ganirelix

GnRH antagonists MoA

Competitive blockade of GnRH receptor

Immediate suppression of LH and FSH

GnRH antagonists use

Assisted reproduction (IVF)

Name 3 Gonadotropins

• FSH
• LH
• hCG (LH-like activity)

3 Clinical uses of Gonadotropins

• Ovulation induction
• Infertility treatment
• Hypogonadotropic hypogonadism

Oestrogens actions

• Development of female secondary sexual characteristics
• Endometrial proliferation
• Regulation of the menstrual cycle
• Feedback on the hypothalamic–pituitary axis

3 uses of oestrogens

• Contraception
• Post-Menopausal hormone replacement therapy
• Endocrine disorders (e.g. hypogonadism

Synthetic oestrogens have what added benefit over natural

Improved oral bioavailability

Route of admin for Oestrogens

Transdermally/Topically

Progesterone/Progestins actions (4)

• Preparation of the endometrium for implantation
• Maintenance of pregnancy
• Regulation of the menstrual cycle
• Negative feedback on LH and GnRH secretion

3 clinical uses of Progesterone/Progestins

• Hormonal contraception
• Hormone replacement therapy
• Treatment of gynecological disorders (e.g. endometriosis)

True/False progesterone has high oral bioavailability

False - Extensive hepatic metabolism

Route of admin for progesterone

Orally (synthetic progestins developed with improved stability)

Intramuscularly

Intrauterine devices (levonorgestrel)

What improved with each generation of progestin preparations

Reduced androgen activity

Name 4 1st gen progestin preparations

First generation (estrane): norethindrone, norethynodrel, norethindrone acetate, ethynodiol diacetate

Name 3 2nd gen progestin preparations

Second (gonane): levonorgestrel, norethisterone, norgestrel

Name 4 3rd gen progestin preparations

Third (gonane): desogestrel, gestodene, norgestimate, drospirenone

Name 5 4th gen progestin preparations

Fourth: dienogest, drospirenone, nestorone, nomegestrol acetate and trimegestone

Name 2 Emergency Contraception drugs

Levonorgestrel

Ulipristal acetate

Which of the 2 Emergency Contraception drugs is a progesterone receptor modulator / a progestin

Levonorgestrel (progestin)

Ulipristal acetate (progesterone receptor modulator)

MoA of Emergency Contraception drugs

• Delay or inhibition of ovulation
• Prevent LH surge
• Reduce probability of fertilisation

(Does not terminate an established pregnancy!!)

Levonorgestrel must be taken within how many hours

72 hrs

Ulipristal must be taken within how many hours

120 hours

What do Selective Oestrogen Receptor Modulators (SERMs) do

They act as oestrogen receptor agonists or antagonists depending on the tissue

Selective Oestrogen Receptor Modulators (SERMs) MoA

• Bind to estrogen receptors (ERα / ERβ)
• Tissue-selective activity due to recruitment of co-activators or co-repressors
• Can produce estrogenic or anti-estrogenic effects