Unit 2: Gonadal Axis, Posterior Pituitary, and Bone Mineral Homeostasis

What are the anterior pituitary gland gonadotropins?

Luteinizing hormone (LH) and follicle stimulating hormone (FSH)

What regulates the anterior pituitary gonadotropins?

The hypothalamic release of the gonadotropin-releasing hormone (GnRH)

What are androgen and estrogen controlled by?

The anterior pituitary gland gonadotropins

How are gonadotropins inhibited in males?

Via negative feedback by testosterone

In females, what effects do estrogen have on gonadotropins?

Estrogen can exert both inhibitory and excitatory effects on gonadotropins depending on menstrual cycle and estrogen concentration

How do gonadotropins control hormone production?

By gonads, promoting synthesis of androgens and estrogen

What is gonadotropin-releasing hormone (GnRH)?

A decapeptide produced by hypothalamic neurofibres

What influences the release of GnRH?

Other hormones such as cortisol, insulin, IGF-1, prolactin, and gonadal steroids

What are the steps to increase the synthesis and secretion of LH and FSH?

1) The hypothalamus secretes GnRH in a pulsatile manner

2) GnRH travels through the hypothalamic-pituitary portal system to stimulate gonadotroph cells of the anterior pituitary gland

3) Stimulation of gonadotroph cells via G protein-coupled cell surface receptors increases the synthesis and secretion of LH and FSH

How many cell types control the production, stimulation, and release of LH and FSH?

One cell type produces both LH and FSH, but synthesis and release are controlled independently?

What causes GnRH receptor down-regulation?

Continuous stimulation and release of GnRH

What is inhibin?

A hormone produced by Sertoli cells of testes and granulosa cells of developing follicles

How does inhibin effect LH and FSH?

It inhibits further release of FSH with little effect on LH secretion

What is activin?

A paracrine factor that’s produced and acts locally in the pituitary and in the gonads

How does activin effect FSH?

It function sin the pituitary gland to stimulate primarily FSH secretion

What are LH and FSH structurally similar to?

Glycoproteins

What are the functions of FSH and LH in the ovaries?

FSH stimulates follicular development while LH stimulates ovulation

What are the functions of LH and FSH in the testis?

LH is the major regulator of testosterone production through activation of Leydig cells and FSH acts on Sertoli cells during spermatogenesis

What is gonadorelin?

A therapeutic agent that’s similar to GnRH and causes the pituitary gland to release FSH and LH; less common that FSH and LH analogues

What is gonadorelin used for?

To treat infertility caused by hypothalamic hypogonadotropic hypogonadism (result of GnRH deficiency)

What is menotropin/human menopausal gonadotropin (hMG)?

A substance extracted from urine of postmenopausal women and is used to stimulate ovarian follicular development in women and spermatogenesis in men (also used with LH analogues for infertility); it has FSH and LH-like activity (higher FSH activity)

What is human chorionic gonadotropin (hCG)?

An LH analogue produced by human placenta and excreted in urine by pregnant women; recombinant FSH and LH are also available but are more expensive

What is leuprolide?

An agonist at GnRH receptors which initially increases LH and FSH, however it’s administered continuously in a pulsatile fashion, desensitizing GnRH receptors and decreasing LH and FSH production, leading to hypogonadism

What is leuprolide used for?

Prostate cancer, uterine fibroids, endometriosis, or assisted tech with high sex hormones

What is hypogonadism?

Diminished function of testes and ovaries, leading to reduced production of sex hormones

What is the most important androgen secreted by the testis?

Testosterone, which is synthesized from cholesterol

Where is testosterone released from in men?

95% is released by the Leydig cells and \~5% by adrenal glands

Other than testosterone, what androgens are secreted from the testes?

Dihydrotestosterone (DHT) and androstenedione

Do women have testosterone?

Yes, small amounts are derived from the ovaries and adrenal glands and will be converted to estrogens in body fat and bones

How is testosterone delivered to target tissue?

In the blood, most circulating testosterone is bound to sex hormone-binding globulin (SHBG) while a small amount (1-2%) is found free in the blood

How is most testosterone metabolized?

In the target tissue via DHT by 5α-reductase at many sites and estradiol by aromatase in the liver, adipose, bone, and brain

What are the effects of sex steroids caused by in target cells?

Steroid nuclear receptor mechanisms

What are androgens responsible for?

Secondary sex characteristics, virilization, and growth promotion including: spermatogenesis, genetalia, secondary sex glands, deepening of voice, facial hair, libido, behavioral changes, lean body mass, erythropoiesis, and decreased HDL

What androgen is responsible for the closure of growth plates in long bones?

Estradiol

What is the androgen preparation of testosterone used for?

Androgenic and anabolic effects; testosterone has a 1 androgen : 1 anabolic ratio and attempts have been made to alter preparations to produce more anabolic effects compared to androgenic

What is the goal of delivery of androgens?

To provide reliable drug levels; the half-life of testosterone can be varied by adding esters which allow for formulation of depot preparations (such as enanthate, cypionate, and undecanoate)

What deliveries of androgens are used?

Oral preparations (however these must by-pass the liver) or transdermal through a patch or organogel

What are the toxicity and side effects of androgens in men?

Prostatic enlargement, acne, moodiness/behavioral problems, hepatic dysfunction, cancer, suppression of spermatogenesis (causing sterility), atherosclerosis, and heart disease

What are the toxicity and side effects of androgens in women?

Masculinization and pregnancy complications

What are the uses of androgens and anabolic steroids?

1) androgen replacement therapy

2) reduce post-partum breast enlargement

3) protein anabolic agent following surgery, trauma, or other debilitating disease

4) growth stimulation

5) increase strength, aggressiveness, and performance

How are androgens used in androgen replacement therapy?

They replace/augment endogenous androgen secretion in hypogonadal men (caused by testis or pituitary deficiency); oral, intramuscular, and transdermal testosterone preparations are available; for individuals requiring spermatogenesis, gonadotropins can be used until puberty when testosterone is applied

How do androgens reduce breast enlargement?

They antagonize growth-promoting effects of estradiol on breasts; chemo patients for inoperable breast cancer or post-menopausal women may also receive androgen preparations; danazol (hyperandrogenic effects) can also be used to alleviate symptoms of endometriosis

What are precautions that need to be taken when using androgens for growth stimulation?

Decrease concentration with age and may potentially need supplementation as the hormone increases mass and hematocrit while reducing bone turnover in older men

What are some side effects of anabolic steroids?

Behavioural problems, aggression, depression, liver dysfunction, and liver cancers

What are some examples of anti-androgens?

Leuprolide, ketoconazole, spironolactone, finasteride, flutamide, and cyproterone

What is the mechanism of action of leuprolide as an anti-androgen?

It’s a GnRH agonist with continual delivery

What is the mechanism of action of ketoconazole and spironolactone as an anti-androgen?

Inhibition of testosterone synthesis

What is the mechanism of action of finasteride as an anti-androgen?

Inhibition of 5α-reductase

What is the mechanism of action of flutamide and cyproterone as an anti-androgen?

An androgen receptor antagonist

What is estradiol?

The most important natural estrogen secreted in premenopausal women; it’s produced by the ovaries

How are steroidal estrogens formed?

They’re formed from testosterone or androstenedione precursors in the follicular granulosa and theca cells in the ovaries by aromatase

What are estrone and estriol synthesized from?

Estradiol, mostly by the liver but some peripheral conversion of androgens occurs by aromatase in other tissues

Where are estrogen and estrone produced from in postmenopausal women?

Estrogen is produced by the adipose tissue and estrone is produced in the adrenal gland by dehydroepiandrosterone (DHEA)

What is progesterone?

The most important natural progestin that’s produced and secreted in women

Where is progesterone produced?

In the ovaries and adrenal gland, along with the placenta during pregnancy

What is progesterone a precursor for?

Estrogen, androgens, and adrenocorticoids

Where are progestins produced in men?

The testes

How does most circulating estrogen travel?

Bound to SHBG, while \~1-2% is bound to albumin

How does most circulating progestin travel?

Bound to corticosteroid-binding globulin (CBG), while \~ 1-2% is bound to albumin

What are the hormone effects of estrogens and progestins mediated by?

Nuclear receptor events resulting in protein synthesis and responses in target tissues

What are the two estrogen receptors?

α-estrogen and β-estrogen

What do estrogen and progestin contribute to in the reproductive system?

They’re important in normal sexual maturation and contribute to secondary sex characteristics, breast development, reproductive tract, and behaviours; they’re also involved in the menstrual cycle (specifically ovulation), development of endometrial lining, and control parturition (birth)

What non-reproductive roles do estrogen and progestin have?

Bone turnover and density, adipocyte deposition and blood coagulation, growth during puberty, and growth plate (epiphysis) closure

How are oral contraceptives used?

In fertile women to control fertility, reduce the risk of cancers (such as ovarian and endometrial) and ovarian cysts, reduce risk of ectopic pregnancy, improve acne, and treat symptoms of hirsutism and endometriosis

What are the two types of oral contraceptives?

Oral estrogens/progestins and continuous therapy with progestins

What is the most common oral contraceptive?

Combined contraception, which includes synthetic estrogen combined with 1-9 progestins

What is the mechanism of action of combined contraception?

Gonadotropin suppression, inhibiting ovulation by estrogen and progestin feedback inhibition on hypothalamic-pituitary axis; as a result, cervical mucus thickens which inhibits sperm penetration and reduces motility in the fallopian tubes

What are the pros and cons of the progestin-only oral contraceptives (mini pills)?

Avoids the adverse effects of estrogen; has a slightly higher failure rate and causes more menstrual disturbances

What do progestin-only oral contraceptives contain?

Progestin and either norgestrel or norethindrone

What are some contraceptive methods, other than the daily pill?

* Norplant-2 and L-norgestrel are silicone capsules placed subcutaneously in the arm and lasts \~5 years
* Medroxyprogesterone (depo) is an intramuscular injection of crystals every 3 months
* Progesterone intrauterine devices (IUDs) offer a low dose delivered continuously and locally

What is mifepristone (RU486)?

A potent selective progesterone receptor modulator that blocks progesterone’s action on the endometrium and results in endometrial shedding and luteolysis and is used to induce abortion at up to 70 days pregnancy

Can estrogen and progesterone be used for post-coital contraception?

Yes, an example is levonorgestrel

What is the purpose of hormone replacement therapy?

It supplements a lack of, or substitutes for, naturally occurring hormones

What are some uses of hormone replacement therapy?

* treatment of congenital primary hypogonadism
* menopausal women who have had their ovaries removed, causing decreased estrogen and progesterone
* estrogen and progestin are both used for symptoms

What causes congenital primary hypogonadism?

A failure of ovarian development, leaving women infertile

How is hormone replacement therapy generally dosed to individuals?

A low dose of estrogen on days 1-21 of each cycle and progestin is added when initial uterine bleeding occurs

What does decreased estrogen and progesterone cause?

Atrophy of genetalia, depression, decreased libido, lack of energy, hot flashes (vasomotor spasms), loss of bone density (osteoporosis), and cardiovascular disease

What percent of infertility is caused by anovulatory conditions?

About 20-30%

What agents are used to treat anovulatory conditions?

GnRH analogues (functional pituitary gland and ovary) and FSH/LH analogues (only functional ovary)

What is clomiphene citrate?

A partial estrogen receptor agonist that can induce ovulation by inhibiting negative feedback inhibition of estrogen on the hypothalamic-pituitary-gonadal axis, causing FSH levels to increase which enhances follicular recruitment

How often does ovulatory induction therapy need to be repeated?

Until the women is pregnant as normal ovulatory function won’t likely return after a single dose

What are gonadal inhibitors used for?

Individuals undergoing cancer therapy

What is tamoxifen?

A selective estrogen receptor modulator (SERM) that can be used in the treatment of breast cancer

How does tamoxifen treat breast cancer?

It acts as an estrogen receptor antagonist in estrogen receptor positive breast cancers

What is exemestane?

An aromatase enzyme inhibitor that can be used with tamoxifen or by itself to treat breast cancer

What agents are used to treat prostate cancer?

5α reductase inhibitors (finasteride) or androgen receptor antagonists (flutamide and spironolactone)

What are some mild adverse effects of estrogen and progestin?

Nausea, headaches, and endocrine changes

What are some moderate adverse effects of estrogen and progestin?

Weight gain, vaginal and uterine tract infections due to reduced mucus, breakthrough bleeding, and depression

What are some severe adverse effects of estrogen and progestin?

Hepatic dysfunction and dyslipidemias, breast cancer, thromboembolic disease due to increased coagulation activity, myocardial infarctions and atherosclerosis, & hypertension and cerebrovascular disease

What two hormones does the posterior lobe of the pituitary gland (neurohypophysis) secrete?

Antidiuretic hormone (ADH) and oxytocin

What does ADH/vasopressin regulate?

Plasma value and osmolality

What is oxytocin?

A peptide hormone that’s structurally similar to vasopressin

Where is oxytocin synthesized?

Mainly in the paraventricular nuclei, less in the supra optic nuclei of the hypothalamus, and also in the luteal cells of the ovary, uterus, and fetal membranes

Where is oxytocin secreted from?

Nerve endings of neurons which end in neurohypophysis

What causes release of oxytocin?

Oxytocin responds to sensory stimuli from the cervix and vagina at birth (enhances frequency and force of uterine contractions under permissive effects of estrogen priming) or suckling by a newborn (stimulates milk ejection through contractions of myoepithelium)

What antagonizes the effects of oxytocin?

Progesterone

Is oxytocin a positive or negative feedback system?

A positive feedback regulation, the initial stimulus results in production of more hormones

What is vasopressin?

A peptide hormone that functions as the primary antidiuretic hormone in humans

Where is vasopressin synthesized?

Synthesized by the same neurofibers as oxytocin

What stimulates vasopressin production?

Increasing tonicity through activation of osmoreceptors in hypothalamus and decrease in blood pressure through activation of baroreceptors