Exam 4 - Puberty and Menopause

Question 1

What is puberty?

Answer 1

transition period from sexually immature child to sexually mature, reproductively fertile adult

Question 2

What is Tanner Stage 2 and what are the major hallmarks for males and females?

Answer 2

onset of puberty

female: sparse pubic hair and elevated breast and nipple

male: sparse pubic hair, slight enlargement of the penis and scrotum

Question 3

Define thelarche, pubarche, axillary, and menarche.
What order to they occur in relation to growth spurt and fertility?

Answer 3

thelarche: onset of breast development
pubarche: first appearance of pubic hair
axillary: armpit
menarche: first menstruation

females:
growth spurt, thelarche/pubarche about a year later, menarche/axillary a couple years later, fertility (aka ovulation) another year later (typically spanning ages 9-13 ish)

males:
growth spurt and pubarche at about the same time, axillary a couple years later, fertile ejaculate a couple years later (typically spanning ages 11-14)

Question 4

What are the major changes in LH, FSH, estradiol, and testosteone during puberty relative to Tanner Stage 2?

Answer 4

LH, FSH, estradiol, and testosterone all increase around Tanner Stage 2, with LH and FSH increasing a little bit before Tanner Stage 2 (first at night and then throughout the day as well)

Question 5

What is the Gonadostat theory? How does it relate to puberty and increase sex steroids?

Answer 5

pre-puberty, GnRH is inhibited by low levels of sex hormones and the hypothalamus is immature

in puberty, sensitivity of the hypothalamus to negative feedback decreases (unknown initial trigger)

less inhibition results in increased GnRH secretion, LH and FSH start increasing, then testosterone and estrogen production

Question 6

How does negative energy balance affect reproductive function?

Answer 6

reproduction is energetically demanding

negative energy balance inhibits the reproductive axis in times of starvation, excessive exercise, anorexia, and lactation

Question 7

How are Kiss1 neurons involved in metabolic and reproductive function?

Answer 7

Kiss1 neurons relay metabolic info (energy, nutrition, etc.) to the reproductive axis, probably regulated by leptin receptors
increase Kiss stimulation = increase GnRH neuron stimulation = increase reproductive function

Question 8

How does leptin affect the Kiss1 system? How are mTOR and AMPK involved?

Answer 8

Kiss neurons in the ARC (not AVPV) have leptin receptors that increase Kiss activity
GnRH neurons do not have leptin receptors but do have a positive response to Kiss neurons

leptin increasing mTOR and decrease AMPK. mTOR promotes cell growth and metabolism (as well as secretion of Kisspeptin) while AMPK inhibits mTOR. Rapamycin is an anti-fungal compound that inhibits mTOR.

AMPK is inactive (does not inhibit mTOR and decrease Kiss) unless cell energy is low. AMPK senses the AMP:ATP ratio. When the ratio is increase (low energy), AMPK increases and decreases mTOR affects on Kiss. This results in delayed puberty. However, increase cell energy decreases the ratio, decreases AMPK, and increases mTOR potentially accelerating puberty.

Question 9

What are estrogens desirable and undesirable effects?

Answer 9

desirable: maintain stable temperature, protect memory, produce milk, regulate cholesterol avoiding artherosclerosis, maintain bone density

undesirable: promote breast cancer and cancer of the uterine lining

Question 10

What was the original rationale for HRT?

Answer 10

estrogen provides many benefits during years of ovarian estrogen protection, including protection against cardiovascular disease and bone loss

Question 11

How is hormone production different pre-menopause and post-menopause?

Answer 11

ovaries stop producing estrogen and progesterone, so progesterone drops off (<1 ng/mL, not produced anywhere else) and estrogen is low (<40 pg/mL, a little from androgens in the adrenal gland)

Question 12

What is the average age of menopause in the US? What are major symptoms?

Answer 12

51 years

hot flashes, vaginal atrophy, and sleep disturbances

Question 13

What are the major HRT drugs?

Answer 13

premarin: conjugated equine estrogen (CEE); estrogen only, isolated from mare’s urine, conjugated with sulfate that is easily absorbed and converted into estradiol by the body
prempro: premarin (CEE) + medroxyprogesterone acetate (MPA)

Question 14

What was the Women’s Health Initiative study?

Answer 14

women were treated with either placebo, estrogen alone (CEE, premarin) or estrogen and progesterone (CEE+MPA, prempro)

Started in 1993-1998 planned for 8.5 yers, but CEE+MPA was stopped in 2002 and CEE alone was stopped in 2004 because there were increased risks identified compared to placebo groups.

Prempro: increase stroke, increase venous thromboembolic events, increase invasive breast cancer
but - decrease colorectal cancer and hip fractures

Premarin: increase stroke
but - decrease hip fractures

Question 15

What does a hazard ratio indicate? =1, >1, <1?

Answer 15

estimate of relative risk of an explanatory variable on the hazard of an event (ie, smoking on getting lung cancer)

> 1 = more risk than non-exposed group
<1 = less risk than non-exposed group
=1 = same risk as non- exposed group

Question 16

How does the data from the WHI paper show increased risk of cardiovascular disease that is statistically significant? What about hip fracture?

Answer 16

cardiovascular disease hazard ratio was 1.29 and 95% CI did not include 1 (29% more likely to have cardiovascular disease)

hip fracture hazard ratio was 0.66 and 95% CI did not include 1 (34% less likely to have a hip fracture)

Question 17

How does the table from WHI show risk vs. benefit vs. no difference? What would you look for?

Answer 17

looking at hazard ratio, greater than 1 indicates risk if 95% CI does not include 1. <1 indicates benefit if 95% CI does not include 1, and =1 or a 95% CI that includes 1 indicates no difference.

Question 18

What is a global index hazard ratio and what does it represent?

Answer 18

represents the summary of risk and benefit for the first event that each participant experienced among a list of the 8 most common events
(basically it is a measure of the balance between risk and benefit)

WHI study resulted in a global index of 1.15, 15% more likely to have an adverse outcome

Question 19

How did media coverage of the WHI paper affect sales of HRT?

Answer 19

They dropped dramatically

Question 20

What is the timing hypothesis? Give the real name and explain why the WHI study did not address it.

Answer 20

“therapeutic window of opportunity”
- estrogens have a beneficial effect if initiated around the entry to menopause

Not addressed in the WHI study because women were older, average age of 63, and have probably been in menopause for over 10 years

Question 21

Define atherosclerosis and plaque. How does it affect blood flow?

Answer 21

artherosclerosis is a build up of plaque (fat, cholesterol, calcium) in blood vessels that reduces the cross sectional area of an artery and decreases blood flow

Question 22

What is the cardioprotective role of estrogens in women?

Answer 22

protect against coronary artery artherosclerosis

Question 23

How does a ruptured artherosclerotic plaque lead to further risks? What are they and how does it happen?

Answer 23

fibrous cap separates and exposes the necrotic core (which can be destructive to blood)

can release a blood clot that could cause stroke or myocardial infarction

Question 24

Why can exogenous estrogens be harmful when given post-menopause?

Answer 24

exogenous estrogen can increase inflammatory response (promote growth of the plaque) and increase MMP expression (matrix metalloproteinases, digest the fibrous cap and expose the necrotic core)
both effects can contribute to the release of a blood clot that could cause stroke or myocardial infarction

Question 25

How did the Stevenson analysis in 2009 support the timing hypothesis?

Answer 25

administration of treatment near menopause had a hazard ratio of 0.71/0.62 (prempro vs. premarin respectively)

Question 26

What are current HRT recommendations?

Answer 26

HRT initiated around onset of menopause to treat symptoms and reduce risk of osteoporosis or possibly coronary heart disease

Question 27

If nutrients are scarce and cell energy is low, how are mTOR and puberty affected?

Answer 27

mTOR decreases and puberty is delayed