Exam 4 - Puberty and Menopause Flashcards
What is puberty?
transition period from sexually immature child to sexually mature, reproductively fertile adult
What is Tanner Stage 2 and what are the major hallmarks for males and females?
onset of puberty
female: sparse pubic hair and elevated breast and nipple
male: sparse pubic hair, slight enlargement of the penis and scrotum
Define thelarche, pubarche, axillary, and menarche.
What order to they occur in relation to growth spurt and fertility?
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)
What are the major changes in LH, FSH, estradiol, and testosteone during puberty relative to Tanner Stage 2?
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)
What is the Gonadostat theory? How does it relate to puberty and increase sex steroids?
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
How does negative energy balance affect reproductive function?
reproduction is energetically demanding
negative energy balance inhibits the reproductive axis in times of starvation, excessive exercise, anorexia, and lactation
How are Kiss1 neurons involved in metabolic and reproductive function?
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
How does leptin affect the Kiss1 system? How are mTOR and AMPK involved?
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.
What are estrogens desirable and undesirable effects?
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
What was the original rationale for HRT?
estrogen provides many benefits during years of ovarian estrogen protection, including protection against cardiovascular disease and bone loss
How is hormone production different pre-menopause and post-menopause?
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)
What is the average age of menopause in the US? What are major symptoms?
51 years
hot flashes, vaginal atrophy, and sleep disturbances
What are the major HRT drugs?
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)
What was the Women’s Health Initiative study?
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
What does a hazard ratio indicate? =1, >1, <1?
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
How does the data from the WHI paper show increased risk of cardiovascular disease that is statistically significant? What about hip fracture?
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)
How does the table from WHI show risk vs. benefit vs. no difference? What would you look for?
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.
What is a global index hazard ratio and what does it represent?
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
How did media coverage of the WHI paper affect sales of HRT?
They dropped dramatically
What is the timing hypothesis? Give the real name and explain why the WHI study did not address it.
“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
Define atherosclerosis and plaque. How does it affect blood flow?
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
What is the cardioprotective role of estrogens in women?
protect against coronary artery artherosclerosis
How does a ruptured artherosclerotic plaque lead to further risks? What are they and how does it happen?
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
Why can exogenous estrogens be harmful when given post-menopause?
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
How did the Stevenson analysis in 2009 support the timing hypothesis?
administration of treatment near menopause had a hazard ratio of 0.71/0.62 (prempro vs. premarin respectively)
What are current HRT recommendations?
HRT initiated around onset of menopause to treat symptoms and reduce risk of osteoporosis or possibly coronary heart disease
If nutrients are scarce and cell energy is low, how are mTOR and puberty affected?
mTOR decreases and puberty is delayed
