Lecture 9 - Thyroid Hormones and Drugs, Gonadal Steroid Hormones and Drugs

Describe the functions of Thyroid Hormones

• Responsible for metabolism, energy uptake

  • growth and development

• maintains homeostasis in nearly every tissue and organ

Where are thyroid hormones synthesized?

in the Anterior Pituitary (AP) in the Hypothalamus (Hypothalamic-Pituitary-Thyroid Axis)

Describe how Thyroid Hormones Synthesis is Regulated

• Thyrotropin-releasing hormone (TRH) is synthesized by neurons arising from the hypothalamus, which release TRH into the hypophyseal portal system

• TRH activates its own set of GPCRs in thyrotrophs which stimulates the release of thyrotropin (thyroid-stimulating hormone TSH) in the anterior pituitary

• TSH binds GPCRs on the cell surface of thyroid cells, which activates Adenylyl Cyclase, which in turn increases production of cAMP

• cAMP and Ca2+ are utilized as 2nd messengers which stimulates the production and growth of thyroxine (T4) and triiodothyronine (T3) - thyroid hormones

• Once T4 and T3 reach their target tissues, they will stimulate nuclear hormone receptors (thyroid hormone receptors) to regulate transcription of different genes

Describe the cascade of events behind thyroid hormone synthesis once TSH binds to specialized cells of the thyroid gland

iodide is incorporated into tyrosine residues to make thyroid hormone

• upon stimulation of the TSH receptors and changes of intracellular Ca2+, a sodium iodide transporter protein will be activated, bringing iodide and sodium into the cell

• iodide ions combines with thyroperoxidase +hydrogen peroxide, which allows thyroglobulin-bound tyrosines to be incorporated into thyroglobulin

  • thyroglobulin is coupled with many molecules of tyrosine, which are transported to the lumin of the follicle

• produces monoidodinated and diiodinated thyronine, which are coupled together to produce T3 and T4

• thyroglobulin molecule is taken back up by endocytosis, where it is packaged into lysosomes, where they then fuse with the extracellular membrane to release T3 and T4 into the bloodstream.

Describe the ratio of T4 to T3

• most physiological thyroid produced is T4

• only a tiny fraction (1/2000 T4 and 1/200 T3) is free (ie available to work)

• only free T4 and T3 is used to gauge thyroid gland function

• since T3 is 3 to 5 times more potent than T4, T4 can be metabolized to T3 in the thyroid and periphery by de-iodination of the third carbon of the external benzene ring of T4

• if internal benzene ring of T4 is de-iodinated, it produces a physiologically inactive form of T3 (reverse T3) that acts as a competitive inhibitor of T3 at the thyroid receptor

What is Protirelin?

• TRH receptor agonist (TRH replacement)

• used for diagnoses of Hypothalamic Insufficiency (a type of thyroid insufficiency)

What does Somatostatin do?

• inhibits secretion of TSH (thyroid-stimulating hormone) from anterior pituitary

What does naturally occurring (physiological) Iodide do?

• promotes thyroid hormone synthesis

What does excess/exogenous Iodide (30x requirement), and Thioureylenes do?

• can be used to suppress thyroid hormone function via thyrotoxicosis

What does radioactive iodide (131I) do?

• used for Thyroid cancer

  • used to oblate the thyroid

  • the thyroid preferentially takes up iodide, whereas most cells in the body do not.

  • when someone is given radioactive iodide, it gets concentrated in the thyroid gland to kill the cells of the thyroid gland.

  • rest of the free radioactive iodide is regularly excreted in the urine

What results in Goitres?

Overproduction of T4 Thyroid hormone

Describe the symptoms of Hypothyroidism

• impaired skeletal growth

• impaired growth and development of CNS

• impaired protein synthesis and carbohydrate absorption (metabolism in all tissues)

• impaired adrenocortical, gonadal, cardiac, renal, and liver functions

What is Hashimoto’s Disease?

• A disease resulting from Hypothyroidism

• Auto-immune disorder where the body produces antibodies to the thyroid gland, inhibiting synthesis of T3 and T4

What is Congenital hypothyroidism?

• A condition of severely stunted physical and mental growth due to untreated thyroid hormone deficiency at birth

How is hypothyroidism treated?

Replacement Therapy

• administration of Liotrix***

  • 4:1 combination of T4 to T3

    • mimics physiological concentration in the blood

    • can be titrated in the blod

    • drug of choice for treatment

• synthetic Levothyroxine (L-T4) is administered

  • has a long halflife

  • high bioavailability

  • first-line approach

• synthetic L-triiodothyronine (Liothyronine / L-T3)

  • more potent and faster onset than L-T4

  • shorter duration of action (reserved for acute emergencies)

What two conditions together generally result in the removal of the thyroid?

• Thyroid cancer

• Hyperthyroidism

What is Graves Disease?

• Results from Hyperthyroidism

  • auto-immune disease where an antibody (TSIs) is sent to the TSH receptor and activates it, causing high levels of circulating T4

    • causes goitres, bulging eyes

    • common in middle-eastern populations

    • 4x more prevalent in women than men

What is neonatal hyperthyroidism?

• antibodies (TSIs) cross placenta and activate T4 production in fetus

  • T4s cross back into maternal blood system and are very soluble

  • requires quick treatment

How is Hyperthyroidism treated?

• Inhibition of thyroid hormone synthesis

  • propylthiouracil (PTU) blocks iodination of tyrosine and the coupling of iodotyrosine to thyroglobulin

• Inhibition of Thyroid hormone release - excess iodide ion (30x physiological concentration) prevents thyroid hormone release from thyroglobulin by inhibiting lysosomal proteases

  • used for treatment of thyroid storm in neonatal hyperthyroidism

• Ablation of the thyroid gland - radioactive iodine (I131) is rapidly taken up by the thyroid and the radioactivity kills thyroid cells

  • used for thyroid cancer

  • used for residual cancer cells after surgical removal or cancerous thyroid cells.

What are the Gonadal and Gonadotrophic hormones responsible for?

Sex hormones

• conception

• embryonic development

• development at puberty

• desire and ability to procreate (arousal, fertility)

How does the hypothalamus control gonadotrophs (sex hormones)?

• Gonadotrophin releasing hormone (GnRH) is produced in cell bodies of neurons originating in the hypothalamus

• GnRH reaches the anterior pituitary via the hypophyseal portal system and binds GPCRs on gonadotrophs - specialized cells that produce gonad stimulating hormones

  • stimulates Phospholipase C to act, increasing intracellular Ca2+ concentrations

    • stimulates release of two gonadotrophins

      • leutinizing hormone (LH)

        • supports growth of the follicle in ovarian cycle

      • follicle-stimulating hormone (FSH)

        • induces ovulation and supports growth of corpus luteum

Describe the Ovarian Cycle

• a continuation of hypothalamic control of gonadotrophs

• GnRH release is pulsatile and targets GPCRs on the anterior pituitary

• days 1-14 of menstruation cycle are the follicular phase, where FSH is released into the ovary

• days 15-28 are the luteal phase where LH is released into the ovary

• Anterior pituitary releases both FSH and LH into the ovary, producing follicles

• follicles rupture at cortex of ovary, releasing an ovum

• remainder of follicle degenerates, producing corpus luteum

  • produces progesterone, which is involved in maintenance of the endometrium and negative feedback of anterior pituitary AND hypothalamus

• if LH produced is greater than FSH produced, follicle will produce estrogen

• if FSH produced is greater than LH, corpus luteum will produces progesterone

What is the proliferative phase of the ovarian cycle?

• estrogen is at it’s peak to maintain endometrial regeneration

  • responsible for rupture of the follice/release of ovum

  • endometrium increases in thickness and vascularity

  • estrogen binding to endometrium causes endometrium to produce progesterone receptors, making endometrium sensitive to progesterone

  • estrogen stimulates cervix to produce a protein/carb rich mucus to facilitate entry of sperm

• Luteinizing Hormone concentration in the plasma spikes just prior to secretory phase

  • stimulates rupture of follicle

  • stimulates development of corpus luteum

What is the secretory phase of the ovarian cycle?

• progesterone is secreted by corpus luteum and promotes growth of endometrium to facilitate implantation of fertilized ovum

• if implantation of fertilized ovum doesn’t occur, corpus luteum will degenerate, and production of progesterone will stop, leading to menstruation

• if implantation of fertilized ovum does occur, the ovum will secrete human chorionic gonadotrophin (HCG) which maintains lining of uterus during pregnancy

Describe the male reproductive cycle

• similar to ovarian cycle, it’s controlled by the hypothalamus, which release GnRH onto the gonadotrophs of the anterior pituitary

• stimulation of the anterior pituitary will also release FSH and interstitial cell-stimulating hormone (ICSH), which is the same as LH in females

  • ICSH stimulates production of testosterone from interstitial cells

    • has an effect on primary and secondary sex characteristics

      FSH and testosterone maintains seminiferous tubules which support sperm production (gametogenesis) through Sertoli cells

  • testosterone and dihydrotestosterone are secreted into the blood are also responsible for secondary sex characteristics (eg body hair)

What is the result of abnormally high FSH/LH Levels in the blood?

• infertility/sub-fertility

• normal in women who have recently undergone menopause

• abnormal in normal reproductive years, can be a result of

  • premature menopause

  • poor ovarian reserve

  • gonadal dysgenesis

  • Turner Syndrome (females with only 1 X chromosome)

  • Castration

  • testicular failure

What is the result of abnormally low FSH/LH levels in the blood?

• infertility

• failure in gonadal function (hypogonadism)

  • in males: low levels of sperm and/or testosterone produced

  • in females: cessation of reproductive cycle

• Polycystic Ovarian Syndrome

  • high LH, low FSH

  • associated with higher male hormone levels in women

    • physical signs in secondary sex characteristics

• Hypothalamic suppression and Hypoptuitarism: individuals who have this before puberty do not go through puberty

• Gonadotrophin deficiency

• gonadal suppression therapy - use because of gonadal tumours

  • GnRH antagonist

  • GnRH agonist

What can be used to treat abnormal levels of FSH and LH?

Human Chorionic Gonadotropin (HCG)

• very similar to LH

• induces ovulation in females

• stimulates testosterone/sperm production in males

Menotropin - a combination of LH and FSH used to mimic LH surge

Follitropin - recombinant FSH

• used to stimulate ovulation and fertility

Lutropin - recombinant LH

• used to stimulate ovulation and fertility

How is estrogen synthesized?

• derived from cholesterol (like all steroidal hormones)

• undergoes high serum binding (like thyroid hormone); only free fraction is “free” (physiologically available)

  • large pool of circulating estrogen that is responsible for more than sexual arousal/fertility.

    • response to external stimuli

    • waking up

    • maintenance of bones

    • central effects

• binds estrogen receptors intracellularly

  • 2 subtypes of estrogen receptors

    • alpha

    • beta

    • membrane-bound GPCR (recently discovered)

  • receptors are transcription factors

    • regulate gene expression

What are the roles of Estrogen?

• growth and development of female sex organs

• development of secondary sex characteristics

• prevention of bone reabsorption/osteoporosis (failure of calcium mobilization)

• sexual and maternal behaviour

• sensitization of tissues to progesterone; estrogen turns on progesterone receptors, activating progesterone gene transcription

• negative feeback regulation of gonadotrophs

How is estrogen metabolized?

• estrogen (17beta-estradiol/E2) is not very water soluble, so it must be metabolized to estrone and estriol, which are hydrophillic entities, to be excreted

  • also weak agonists of estrogen receptor (therefore more readily excreted)

• estrogen conversion to E2 is reversible, so it is in equilibrium with E2

What are the three clinical uses of estrogen analogs?

• Hypogonadism - replacement therapy in females who do not produce enough estrogen

• Contraception - used in combination with progestogens to inhibit production and release of GnRH, LH, and FSH, preventing ovulation

  • Morning After Pill - high doses of ethinylestradiol taken shortly after sex

    • hastens passage of ovum through fallopian tube through withdrawal bleeding, preventing embryo implantation

  • Oral Contraceptive

    • Combined Pills (estrogen and progestogen)

      • taken 21 of 28 days

      • estrogen inhibits FSH release, progesterone inhibits LH release

    • Progestogen-only pills

      • taken continuously

      • less reliable but taken by people at high risk for estrogen-sensitive breast cancer

• Postmenopausal Hormone Replacement Therapy - prevents vasomotor instability (hot flash), headache, osteoporosis

What are some synthetic preparations of estrogen and what are they used for?

found in contraceptives

• 17beta-estradiol - used in a dermal patch, topical cream, tablet

  • used for gonadal insufficiency, post-menopausal syndromes

• Ethinylestradiol - found in oral contraceptive

  • ethinyl substitution on one of the carbons of 17beta-estradiol that makes it orally active

• Mestranol - first synthetic oral contraceptive, converted to ethinylestradiol in liver

What are some adverse effects of estrogen analogs?

usually resulting from prolonged use, increasing the incidence of:

• coronary heart disease due to calcium mobilization

• breast cancer since breast tissue is estrogen sensitive

• uterine cancer

• embolism (blockage of blood vessel)

What are some Estrogen receptor antagonists and what are they used for?

Clomiphene - fertility drug

• blocks negative feedback of estrogen, increasing release of GnRH, LH, FSH

Tamoxifen - treatment for breast cancer

• mixed agonist/antagonist

Raloxifene - treatment for osteoporosis and reduces risk of invasive breast cancer in postmenopausal females

• antagonist for ER-beta, weak agonists for ER-alpha

Where is progesterone produced?

• primarily in corpus luteum

• additionally in placenta, tests, adrenal cortex

What are the physiological effects of progesterone?

• effects mediated through progesterone binding to its receptors in the affected tissues

  • in the uterus, progesterone is secreted by corpus luteum, which transforms the endometrium into a tissue that allows for implantation of a fertilized ovum

  • in the hypothalamus and pituitary, progesterone inhibits secretion of GnRH and gonadotropins thus preventing further follicular maturation and ovulation, which is needed for pregnancy to proceed

What are some examples of progesterone analogs/progestogens and their clinical uses?

Levonorgestrel and medroxyprogesterone - progesterone analogs

• uterine bleeding

• endometriosis (abnormal endometrial proliferation)

• metastatic cancers of the endometrium and breast

• amenorrhea (absence of menstruation)

• birth control (causes amenorrhea)

Mifepristone - progesterone receptor partial agonist

• abortion/medical termination of pregnancy

What is the role of Androgens?

• development of male reproductive organs during puberty

• development of secondary sex characteristics (hair distribution, voice)

• somatic development (bone structure, skeletal muscle)

Describe testosterone fate in testis

• produced in Leydig cells upon stimulation by LH/ICSH

• converted to active metabolite dihydrotestosterone (DHT)

• bind the androgen receptor (AR) a nuclear hormone receptor transcription factor

Describe Androgen Synthesis

• starts with cholesterol (like other steroid hormones)

• androstenedione is a precursor produced either directly from cholesterol or from progesterone

• androstenedione is further converted to either testosterone or to estrone by assistance of aromatase enzyme

  • estrone can be reversibly converted to estradiol (estrogen)

  • aromatase can also convert testosterone to estradiol (estrogen)

• 5alpha-reductase can convert testosterone in the plasma to dihydrotestosterone, which is a powerful, active androgen in the body

What is Anastrozole?

• Aromatase inhibitor

• used in androgen therapy for the treatment of estrogen-positive breast cancers

What is Finasteride?

• anti-androgen

• used for treatment of androgen-sensitive prostate cancer

• inhibits testosterone conversion to dihydrotestosterone/ inhibits 5alpha-reductase

Describe the illicit effects of Testosterone and its analog(s)

Anabolic effects

• increased bone density/mass

• increased muscle mass

• increased metabolism (increased uptake of AA’s and carbs by muscle cells)

• reduced recovery time

Androgenic effects

• reproduction

• development at puberty

• secondary sex characteristics (abuse is obvious)

Pure Testosterone - readily absorbed through GI tract but subject to first-pass metabolism, therefore is administered usually through transdermal patches or subcutaneously

Nandrolone - synthetic androgen primarily used for metabolic effects

• doping in sports

What are some clinical uses of Testosterone analogs?

Androgen Replacement Therapy

• Testicular hypotfunctin, pituitary failure, testicular cancer

Anabolics

• illicit use among athletes for increasing bone or muscle mass

Female Hyposexuality following ovariectomy

• restores plasma testosterone to normal female concentrations and improve sexual function

What are some anti-androgens and their clinical uses?

Cyproterone - Direct androgen receptor (AR) Antagonist

• used to treat early puberty in males (precocious puberty)

• used to treat masculinization and acne in women

• decreases libido and can be used to treat hypersexuality in male sex offenders

Flutamide - Direct AR Antagonist

• used to treat prostate cancer

• must also be administered with GnRH agonist or antagonist because it blocks negative feedback exhibited by testosterone thus leading to increased LH release

Finasteride - indirectly inhibits androgen function by blocking alpha-reductase so testosterone cannot convert to dihydrotestosterone

• used to treat benign prostatic hyperplasia

• used to treat prostate cancer

Enzalutamide - AR antagonist

• used for metastatic, castration-resistant and castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer

Describe how contraction of the non-pregnant uterus works

• Myometrial cells are smooth muscle cells in the uterus that act as pacemakers that mediate a tonic contraction of non-pregnant uterus

  • can produce action potentials that are regulated by female sex hormones

    • non-pregnant uterus then goes through a pulsatile cycle of contractions that increase in strength as the cycle progresses

• Sympathetic neurons affect uterus contraction

  • Adrenaline inhibits uterine contraction

  • Noradrenaline stimulates contraction

What does pregnancy cause in the uterus?

• increased amount of estrogen made during pregnancy hyperpolarizes (making a membrane potential more negative) myometrial cells so that there is no action potential forming and thus no contractions.

• estrogen stimulates expression of oxytocin receptors in the uterus, causing the uterus to become sensitive to the peptide hormone oxytocin

Describe the synthesis and transport of Oxytocin

• most produced in neurons arising from the paraventricular nuclei of the hypothalamus

• these neurons project into the posterior pituitary via the hypophyseal tract

• they terminate in the areas of the posterior pituitary that are rich in vascular beds

  • thus, oxytocin is taken up freely in the bloodstream and circulates throughout the body

What are the two main effects/uses of oxytocin?

Milk Ejection - stimulates the contraction of myoepithelial cells surrounding glandular ducts that contain milk

• occurs after parturition (immediately after childbirth); cells become sensitized to oxytocin and oxytocin levels increase (postpartum effect)

• suckling from the baby causes physiological stimulation for oxytocin release

• oxytocin can be administered to stimulate milk ejection if there is milk “let-down” impairment (where milk does not fill glandular ducts of breasts)

Uterine Contraction - facilitation (not initiation) of labour

• stimulates peristaltic contraction in the uterus and causes cervix to relax

• third-trimester pregnant uterus is very susceptible to oxytocin because there are tons of oxytocin receptors on the smooth muscle cells of the uterus

• oxytocin given very slowly via IV can be used to stimulate labour contractions (too quick administration of oxytocin can cause hypoxia of the fetus) or to “clamp” the uterus down (to control postpartum bleeding)

What are Ergot Alkaloids and some examples?

uterus stimulators that are derived from a fungus that grows on wheat and grains

• vasoconstrictive effects (can cause gangrene)

• Ergometrine - highly selective for oxytocin receptors in the uterus

  • causes strong contractions in BOTH pregnant and non-pregnant uterus

  • has been previously used to induce abortion, but very dangerous

  • can be used to treat postpartum bleeding and hemorrhage

  • can be used to treat migraines due to vasoconstrictive effects (although there are far better drugs to treat migraines with)

How does Prostaglandin E2 and its analogs stimulate the uterus?

• promotes coordinated contractions of the pregnant uterus, relaxes the cervix

  • thus promotes onset of labour

What is Dinopostone?

• PGE2 Analog

• used as an alternative to oxytocin to induce labour in late stage pregnancy or abortion in early and middle stage pregnancy

• delivered by suppository to reduce systemic effects

What is Ritodrine and Salbutamol?

• drugs that inhibit uterine contraction

• selective beta2-adrenoceptor agonists

• inhibit oxytocin induced uterine contraction; cause uterine relaxtion

What is Atosiban?

• drug that inhibits uterine contraction

• oxytocin receptor antagonist

• delays the onset of premature labour

Describe how male erections work

• determined by both physiological and psychological factors

• vasodilation of arteries and arterioles increase blood flow to the penis allowing engorgement of spongy tissue

• compression of penile venules prevents blood from returning from penile tisue, causing erection

• innervation is mediated by nitric oxide

What are some physiological causes of erectile dysfunction?

• arterial disease

• hypogonadism

• neuropathies (eg diabetes)

What are some psychological causes of erectile dysfunction?

• stress

• anxiety

• guilt

• depression

what are some drugs that can treat psychologically or physiologically caused erectile dysfunction?

• anti-psychotics

• antidepressants

• antihypertensive agents

What is Papaverine and Alprostadil?

• used to treat Erectile Dysfunction (ED)

• vasodilators injected directly into the penis

• can cause a prolonged and painful erection with possible permanent tissue damage

What is Sildenafil and Tadalafil?

• used to treat ED

• Sildenafil = Viagra

• phosphodiesterase type V inhibitors

• can be taken orally

• enhance erectile response to sexual stimulation (ie does not work independently of sexual desire)

• may cause vasodilation in other vascular beds, causing hypotension and headaches

Describe how a penile erection is achieved

• sexual stimulation causes nitrergic nerves and the endothelium of the penis to release nitric oxide (NO)

• release of nitric oxide activates guanylyl cyclase, which converts GTP to cGMP

• cGMP has two fates

  • conversion/inactivation to inactive product via the PDE V/5 enzyme

    • Sildenafil (Viagra) is a PDE V inhibitor that promotes penile erection

  • conversion to PKG, which causes vasodilation in the penis, thus promoting a penile erection