Lectures 1,2 - Negative Feedback, Positive Feedback, Opposing Systems

NO, is inherently unstable and life threatening unless it is activated in very specific situations

is positive feed-back a stable state?

increasing circulating levels of T and decreased circulating levels of LH

A 26-year old man is diagnosed with testicular cancer that has spread to both testicles. Surgery is required to remove both organs. Six months after post-surgical chemotherapy, the man is found to be free of any obvious remaining cancer. During a series of post-surgical appointments at the Endocrine Clinic, the man is prescribed testosterone gel that he applies to his abdomen daily. Testosterone is absorbed into the general circulation through the skin. This treatment restores his circulating testosterone levels to their pre-surgery values since both testicles are no longer present. In comparing the man's blood hormones levels four weeks AFTER starting the T treatment with those obtained four weeks BEFORE starting the T treatment (and thus following the surgery when both testicles were surgically removed), the clinic finds the following: Increase/decrease/same levels of circulating T and increase/decrease/same levels of circulating LH

low circulating levels of T and low circulating levels of LH

A male sports athlete has been taking large amounts of an anabolic steroid for 5 years to help improve and maintain his muscle mass. This anabolic steroid (which is NOT testosterone) has 3-dimensional molecular shape and molecular properties that are similar to testosterone. It bids to the androgen receptor with testosterone-typical biological effects. If a blood sample is taken from a vein in this man's arm, what circulating levels of testosterone (synthesized in the testis) will be found compared to those in normal men, and what levels of LH? The testosterone assay measurement CANNOT detect the anabolic steroid the man is taking. High/low/normal circulating levels of T and high/low/normal circulating levels of LH

blood glucose levels fall below optimum levels (<70mg/dL), stimulating alpha cells in the pancreas to release glucagon into blood

After skipping a meal, blood glucose levels... do what? stimulate what and where?

defective, nonfictional androgen receptors

An 18-year old woman presents at an Ob/Gyn clinic, concerned at the complete absence of menstrual cycles. She has obviously gone through puberty, but never remembers having any menstrual bleeds at any time. As part of the physician's work-up, a blood sample is taken from a vein in the woman's left arm and is checked for a variety of reproductive hormones. Three days later, the endocrine lab finds two very unexpected values on analyzing the blood sample. Circulating testosterone levels are extremely elevated for a woman. Circulating LH levels are also elevated and exceed the normal range for women. Upon further examination, the woman is found to have a pair of intra-abdominal testes, but no ovaries or uterus. In this individual, the most likely explanation for the testosterone and LH findings involves: -defective, nonfunctional GnRH receptors -defective, nonfunctional LH receptors -defective, functional androgen receptors -an autonomously functioning tumor involving GnRH neurons in the hypothalamus (a tumor that secretes hormone without the need for any stimulation) devoid of response to testosterone negative feedback -an autonomously functioning pituitary gonadrotrope cell tumor (a tumor that secretes hormone without the need for any stimulations) devoid of response to testosterone negative feedback

Weight increases only Mr.A: 5'8, Desk job, 200lb, wants to decrease to 160lb Starting calorie intake: 3000 calories a day Calorie intake on 'diet': 2500 calories a day *Maintainance calories drop from 2950 to 2400 cal/day* so, he gains 1.5lb in 2 months 2950: positive energy balance 2400: body changes maintenance calories as calorie intake drops by 500 to be more efficient so still a positive energy balance

Analysis of Energy Balance Mr. A has a BMI of 20 and wants to lose weight. In order to accomplish this, he decides to cut his daily calorie intake by 500 calories/day (a common weight loss strategy). Predict the effect on his weight if he stays on this diet (or calorie restriction) for 2 months. -Weight increases only -Weight decreases only -Weight stays the same -Weight decreases and then increases -Weight increases and then decreases

Hypothalamus and anterior pituitary

At which of the following locations will testosterone exert negative feedback? -Portal veins -Anterior pituitary -Testis -Hypothalamus

There will be a specialized biological sensor (in a variety of organs, including neurons in the brain). The specialized sensor will interact with an integrator (usually specialized neurons) so that when an optimal level (or set point, usually a circulating level of a chemical in the blood) is either not attained or is exceeded an appropriate response is engaged (effector) to raise or lower the circulating levels, respectively, back to optimal levels

Biological Negative Feedback

Men given androgen-receptor blocking flutamide will have increased GnRH, LH, and T levels, as the hypothalamus will not be notified of increasing T levels and continues to release GnRH, stimulating LH release and therefore more T release.

Describe the changed in GnRH, LH, and testosterone levels in the circulation of men given the anti-androgen and androgen receptor blocker (antagonist) flutamide for treatment of prostate cancer. (Prostate cancer is a testosterone-depedent caner. When flutamide binds to the androgen receptor it causes no biological action and effectively prevents testosterone from binding to its androgen receptor)

Negative feedback is a process involving a specialized biological sensor that works to keep an optimal level in order to maintain homeostasis. Negative feedback is in place for the maintenance of normal blood testosterone levels, or testosterone homeostasis, in men. This process involves a hormonal response that diminishes or elevates circulating testosterone (T) levels to maintain 3-8ng/ml optimal range. In the hypothalamus, gonadotropin-releasing hormone (GnRH) is synthesized by GnRH neurons and drained into the anterior pituitary gland through portal veins. The GnRH released stimulates gonadotrope cells to synthesize luteinizing hormone (LH), therefore LH release is dependent on GnRH. LH is then released into blood circulation which stimulates the testes to synthesize T, therefore T release is dependent on LH. When T is released into blood circulation, nerves cells in the brain reduce GnRH release which effectively reduces LH levels in the blood, resulting in decreased T output. These steps will repeat until optimum T levels are reached, exhibiting a negative feedback loop.

Describe the concept of negative feedback with reference to testicular testosterone

optimal internal conditions for an organism, or optimal "internal balance" or "steady state"

Homeostasis

a chemical synthesized in one organ or tissue and released into the blood circulation for action on other tissues or organs

Hormone

- greatly increased surface area - minimize distance for diffusion

How is efficiency of exchange or absorption maximized?

opposing systems

How is normal blood glucose maintained?

A: Hypothalamus at the base of the brain B: Portal veins C: Gonadotrope cells in the anterior pituitary gland D: General blood circulation E: Leydig cells in the testis F: Testosterone

Label A-F

Negative feedback OR opposing systems

Maintaining homeostasis can be done by ...

A: hypothalamus B: GnRH C: portal veins D: anterior pituitary E: gonadotropes F: LH G: systemic circulation H: Testis I: leydig cells J: testosterone K: Sertoli cells ?: sperm L: androgen Target Tissues: skeletal muscle, brain, hair follicles, genitals, prostate, etc

Negative Feedback regulation of testosterone in men Label A, B, C, D, E, F, G, H, I, J, K, ?, L, Target tissues?

1: estrogen 2: induces prostaglandin and oxytocin receptors on uterus smooth muscle 3: fetus stimulates placenta to make X: prostaglandins 4: stimulate contractions of uterus 5: head pushes cervix; opens under pressure, activates pressure receptor nerves 6: oxytocin 7: stimulates uterus to contract

Positive Feedback: Childbirth Label 1, 2, 3, X, 4, 5, 6, 7

blood glucose levels decline, stimulus for insulin release diminishes

What happens when blood and liver cells take up glucose?

*damage to structure* micro-fracture in blood capillaries, nerve cell degeneration, blindness, amputation of digits or limbs, kidney failure, heart attack

What happens when blood glucose is too high (diabetes type II)? (>100 mg/dl)

*damage to function* central nervous system collapse, coma

What happens when blood glucose is too low? (<50-55mg/dl)

achieving a biological 'goal' or completing a biological process, purpose is to AMPLIFY a process to completion

What is biological positive feedback, what is the purpose?

postive feedback

What is childbirth an example of?

about 70-90mg/100dL

What are homeostatic blood glucose levels?

3-8 ng/ml

What are normal T levels?

LH synthesis

What does GnRH release stimulate?

testosterone synthesis

What does LH release stimulate?

glucagon

What stimulates glucose release?

insulin

What stimulates glucose uptake?

released into portal veins (portal venous blood circulation) that drains into the anterior pituitary

Where is GnRH released and where does it drain?

GnRH-synthesizing neurons in the hypothalamus

Where is GnRH synthesized and by what?

into blood circulation

Where is LH released?

gonadrotrope cells in the anterior pituitary gland

Where is LH synthesized and by what?

into blood circulation

Where is testosterone released?

testes

Where is testosterone synthesized?

Gonadotrope cells in the anterior pituitary gland

Which biological component has GnRH receptors?

Leydig cells in the testis

Which biological component has LH receptors?

Hypothalamus at the base of the brain

Which biological component is repressed by (A) -General blood circulation -Testosterone -Hypothalamus at the base of the brain -Leydig cells in the testis -Portal veins -Gonadotrope cells in the anterior pituitary gland

Portal veins

Which biological component is repressed by (B) -General blood circulation -Testosterone -Hypothalamus at the base of the brain -Leydig cells in the testis -Portal veins -Gonadotrope cells in the anterior pituitary gland

Gonadotrope cells in the anterior pituitary gland

Which biological component is repressed by (C) -General blood circulation -Testosterone -Hypothalamus at the base of the brain -Leydig cells in the testis -Portal veins -Gonadotrope cells in the anterior pituitary gland

General blood circulation

Which biological component is repressed by (D) -General blood circulation -Testosterone -Hypothalamus at the base of the brain -Leydig cells in the testis -Portal veins -Gonadotrope cells in the anterior pituitary gland

Leydig cells in the testis

Which biological component is repressed by (E) -General blood circulation -Testosterone -Hypothalamus at the base of the brain -Leydig cells in the testis -Portal veins -Gonadotrope cells in the anterior pituitary gland

Testosterone

Which biological component is repressed by (F) -General blood circulation -Testosterone -Hypothalamus at the base of the brain -Leydig cells in the testis -Portal veins -Gonadotrope cells in the anterior pituitary gland

Hypothalamus at the base of the brain

Which biological component is responsible for the production of gonadotropin-releasing hormone (GnRH)?

Gonadotrope cells in the anterior pituitary gland

Which biological component is responsible for the production of luteinizing hormone (LH)?

Leydig cells in the testis

Which biological component is responsible for the production of testosterone?

Hypothalamus, anterior pituitary, and testis

Which biological component(s) have androgen receptors? -Hypothalamus -Anterior pituitary -Portal veins -Testis

B

Which of the above data sets (A,B,C) representing relationships between circulating levels of Luteinizing hormone (LH in ng/ml) and testosterone (T in ng/dL) indicate negative feedback regulation of testosterone on LH in normal men?

stages 3-7

Which stages are involved in ever-increasing positive feedback loop until baby is completely pushed through the cervical opening and out into the birthing canal?

rise above optimal levels (>90) stimulating beta cells in the pancreas

about 1-2 hour's after a meal, blood glucose levels in the blood... do what? stimulating what and where?

stimulate body cells to take up more glucose from the blood, liver takes us glucose and stores it as glycogen

what do increased insulin levels in the blood result in?

the liver to release stored glucose into blood

what does glucagon stimulate?

release of glucagon into blood

what does stimulation of alpha cells in the pancreas result in?

release of insulin into blood circulation from pancreas

what does stimulations of beta cells in pancreas result in?

blood glucose levels rise, stimulus for glucagon release diminished

what happens when liver breaks down glycogen releases glucose

nerve cells within the brain reduce GnRH release and so diminish stimulation of the anterior pituitary gland, the anterior pituitary gland releases less LH, and blood LH levels fall, the reduced LH stimulation of the testes leads to reduced output of testosterone into the blood

when blood testosterone levels exceed the optimal blood level...

GnRH neurons within the brain increase their stimulation of the anterior pituitary gland by increased release of GnRH, and the pituitary gland releases more LH, and blood LH levels rise

when blood testosterone levels fall below optimal blood level...