Week 3 - Female Endocrinology Flashcards
1
Q
What is estradiol converted from?
A
From Testosterone, or bidirectionally from Estrone (E1)
2
Q
What are 6 conditions associated with female hormone dysregulation?
A
PCOS Endometriosis Female infertility (of various aetiologies) Fibroids Adenomyosis Fibrocystic breasts
3
Q
What is estriol made from?
A
Estrone (E1) or Estradiol (E2)
4
Q
GnRH is released from _____
A
hypothalamus
5
Q
GnRH stimulates the release of _______ from the anterior pituitary
A
FSH & LH
6
Q
GnRH: pulsatile secretion every _____?
A
60-90 minutes
7
Q
GnRH: negative feedback from ______ via ______, estrogen and testosterone
A
ovaries, via inhibin
8
Q
FSH released from __________ in response to GnRH
A
anterior pituitary
9
Q
function of FSH?
A
initiates and maintains growth of follicle
10
Q
LH released from anterior pituitary in response to ____
A
GnRH
11
Q
function of LH?
A
directs maturation of final follicle and ovulation
12
Q
Estradiol released from the ovary during the proliferative phase has what effect on the hypothalamus?
A
positive feedback
- b/c estrogen causes the lining of the uterus to grow.
- estrogens initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium. The estrogen also stimulates crypts in the cervix to produce fertile cervical mucus, which may be noticed by women practicing fertility awareness
13
Q
Inhibin released from the ovary during the proliferative phase has what effect on the anterior pituitary?
A
negative feedback
14
Q
Estradiol released from the ovary during the secretory phase has what effect on the hypothalamus?
A
negative feedback
15
Q
inhibin released from the ovary during the secretory phase has what effect on the hypothalamus?
A
negative feedback
16
Q
During the secretory phase, the corpus luteum produces which hormone?
A
Progesterone.
The secretory phase is the final phase of the uterine cycle and it corresponds to the luteal phase of the ovarian cycle. During the secretory phase, the corpus luteum produces progesterone, which plays a vital role in making the endometrium receptive to implantation of the blastocyst and supportive of the early pregnancy, by increasing blood flow and uterine secretions and reducing the contractility of the smooth muscle in the uterus; it also has the side effect of raising the woman’s basal body temperature.
17
Q
What is the difference between the ovarian and uterine cycles?
A
The menstrual cycle can be described by the ovarian or uterine cycle. The ovarian cycle describes changes that occur in the follicles of the ovary whereas the uterine cycle describes changes in the endometrial lining of the uterus. Both cycles can be divided into three phases. The ovarian cycle consists of the follicular phase, ovulation, and the luteal phase whereas the uterine cycle consists of menstruation, proliferative phase, and secretory phase.
Ovarian cycle: - Follicular phase - Ovulation - Luteal phase Uterine cycle - Menstruation - Proliferative phase - Secretory phase
18
Q
Prolactin is secreted by the _____
A
pituitary
19
Q
function of prolactin?
A
stimulates milk production in mammary glands
levels increased during pregnancy
suppresses GnRH during lactation & inhibits FSH & LH
20
Q
Where is progesterone produced?
A
PRO GESTation hormONE
produced in ovaries by corpus luteum, in adrenal glands & in placenta during pregnancy
21
Q
role of progesterone in secretory/luteal phase of menstruation?
A
Maintains endometrial lining (prepares uterus for implantation)
Makes cervical mucus impenetrable to sperm
Decreases contractility of uterine smooth mm.
If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation. Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation does not occur and the corpus luteum does not develop, levels of progesterone may be low, leading to anovulatory dysfunctional uterine bleeding.
22
Q
What is estrogen produced?
A
ovaries, peripheral tissue, adrenal glands
23
Q
What is the predominant form of estrogen?
A
Estradiol (E2)
2 hydroxyl groups
24
Q
What is the least abundant form of estrogen?
A
Estrone (E1)
Can act as storage form of estrogen
1 hydroxyl group
25
When is estriol primary made?
pregnancy - by the placenta
| 3 hydroxyl groups
26
___ can be converted to E1 and back and both can be converted to __ (urine metabolite)
E2 can be converted to E1 and back and both can be converted to E3 (urine metabolite)
27
Why can phytoestrogens and xenoestrogens bind to estrogen receptors?
Estrogen receptors are able to bind to compounds with similar but relatively diverse structures (hence phytoestrogens and xenoestrogens)
28
The _________ cells make estradiol when provided with _________.
The granulosa cells make estradiol when provided with androgens.
29
ER alpha is found primarily where?
uterus
kidneys
liver
heart
30
ER beta is found primarily where?
```
ovaries
prostate
lungs
GI tract
hemopoietic system
CNS
```
31
Estrone preferentially binds to which receptor?
ERa
32
Estriol preferentially binds to which receptor?
ERb
33
Estradiol preferentially binds to which receptor?
equally strong to ERa & ERb
34
What are the effects of estrogen throughout the body at puberty?
- 20-fold increase in estrogen
- increases size of reproductive organs & external genitalia, breast development
- changes vaginal epithelium from cuboidal to stratified
- development of stromal & ductal breast tissue & deposition of fat
35
estrogenic effect on bone?
- maintains bone density, mass
| - closing of epiphyseal plates
36
estrogenic effect on brain?
- maintains mood
| - sudden lowering, or consistently low levels can lead to low mood
37
estrogenic effect on CV system
- improves arterial blood flow
- helps maintain healthy HDL/LDL levels
- generally cardioprotective
38
estrogenic effect on reproductive organs
- uterine cell proliferation & endometrial thickening
| - thickening of vaginal epithelium
39
What is the relationship between estrogen & cancer risk
- induces cell proliferation in some types of tissue causing an increase risk of cancer (by increasing risk of genetic errors)
- increases risk of breast cancer and uterine cancer
40
What is another name for aromatase?
estrogen synthase
41
what does aromatase do
- aromatase is responsible for the aromatization of androgens into estrogens
- primary mechanism of estrogen production in the body
42
where is aromatase found
ovaries
skin
adipose cells
43
factors that increase aromatase activity?
hyperinsulinemia, increased adiposity, obesity, aging
44
factors that decrease aromatase activity?
dietary phytoestrogens
| weight loss
45
Activity of estrogen also depends on available free estrogen (mostly ____). This depends on how much _________ is available.
Activity of estrogen also depends on available free estrogen (mostly E2). This depends on how much binding protein is available.
mainly SHBG & albumin
46
describe estrogen metabolism
primarily through (CYP) Phase I (hydroxylation) and Phase II (methylation, glucoronidation, sulfation)
then excreted through urine and feces
deactivation of estradiol includes conversion to estrone and estriol
47
phase I liver detox of estradiol converts E2 to what?
2-hydroxyestrone (2OH-E1)
4-hydroxyestrone (4OH-E1)
16-hydroxyestrone (16OH-E1)
48
2-hydroxyestrone (2OH-E1) is an estrogen agonist or antagonist?
antagonist (weak)
49
4-hydroxyestrone (4OH-E1) & 16-hydroxyestrone (16OH-E1) are estrogen agonists or antagonists?
agonists (strong)
| mostly 16OH-E1
50
what are the implications of the form of estrogen in premenopausal women?
comment on genetic polymorphisms.
Premenopausal women who had decreased ratio of 2OH-E1:16OH-E1 had a greater risk of developing breast cancer
Overall, is dependent on ratio (over 2.0 is best)
Genetic polymorphisms are sometimes responsible for conversion to 2OHE1 or 16OHE1
51
Why is estriol considered a dead end in the estrogen pathway?
Because it cannot be converted back to estrone or estradiol, and is therefore a urinary metabolite.
52
What is the difference in action between phytoestrogens and xenoestrogens at the receptor?
phytoestrogens - usually weaker action than endogenous estrogens
xenoestrogens - usually stronger than endogenous estrogens
53
what is SERM?
Selective Estrogen Receptor Modulator
54
What is the SERM effect of phytoestrogens?
Effect is relational to level of circulating estrogens (both endogenous and exogenous) may increase or decrease activity at receptors
May have either agonist or antagonist effect (depending on receptor type and previous point)
55
What are the 3 main dietary types of phytoestrogens?
| & give examples
- Isoflavones - genistein; daidzein; puerarin (soy, licorice root, legumes, alfalfa)
- Lignans - matairesinol; pinoresinol; secoisolariciresinol (flaxseed, whole grains, legumes)
- Coumestans - sprouts, sunflower seeds
56
Provide examples of xenoestrogens
```
dioxins
PCBs - polychlorinated biphenyls
bisphenols (pesticides, petrochemicals, plastics)
parabens
phthalates
DDT
```
57
What days of the menstrual cycle constitute the Follicular phase?
1-13
58
What days of the menstrual cycle constitute the Luteal phase?
15-28
59
What day of the menstrual cycle is ovulation?
day 14
60
What day does body temperature jump in a menstrual cycle? Which hormone is responsible for this jump?
day 14 - at ovulation
| Progesterone
61
When do we start counting day 1 of a new menstrual cycle?
Day 1 of menstruation
62
At what point in the cycle does estradiol drop drastically?
day 14 - ovulation
63
what hormones peak at ovulation and why?
LH & FSH
| cause the remaining parts of the dominant follicle to transform into the corpus luteum
64
Which hormone dominates during the luteal phase and why?
progesterone
Luteal cells secrete estrogen & progesterone.
After ovulation, the anterior pituitary hormones FSH and LH cause the remaining parts of the dominant follicle to transform into the corpus luteum. It continues to grow for some time after ovulation and produces significant amounts of hormones, particularly progesterone and, to a lesser extent, oestrogen. Progesterone plays a vital role in making the endometrium receptive to implantation of the blastocyst and supportive of the early pregnancy; it also has the side effect of raising the woman's basal body temperature.
65
What happens to FSH during menstruation
Steady rise of FSH which is responsible for the recruitment of a new cohort of follicles. This FSH rise occurs late in the luteal phase and is often defined as the luteal–follicular transition, however, it is not yet established whether it consistently occurs on one particular day, or is affected by the process of reproductive ageing.
66
Which hormones are at their lowest level during menstruation?
LH
estrogen
progesterone
67
What happens to the follicle during menstruation
initiation of follicular maturation by FSH receptors
68
What happens to the endometrium during menstruation
- desquamation of superficial and middle layers
| - liquification and discharge
69
What happens hormonally during the proliferative/follicular phase?
days 5-14
- first FSH peak
- increasing estrogen levels suppress hypothalamus & anterior pituitary
70
What happens to the follicle during proliferative/follicular phase?
continuing maturation
71
What happens to the endometrium during proliferative/follicular phase?
- increasing thickness, # stromal cells, glands & blood vessels
72
What happens hormonally during peri-ovulation?
days 12-14
| - estradiol peaks --> surge of GnRH --> 2nd FSH peak & LH peak
73
What happens to the follicle during peri-ovulation?
- final maturation
| - ovarian rupture
74
What happens to the endometrium during peri-ovulation?
continuing to thicken
75
What happens hormonally during secretory/luteal phase?
days 14-22
- 2nd rise of estradiol & progesterone secretion by corpus luteum
- inhibin secretion
- suppression of hypothalamus and anterior pituitary
76
What happens to the follicle during secretory/luteal phase?
maintenance of corpus luteum
77
What happens to the endometrial gland during secretory/luteal phase?
- tortuous endometrial glands
- spiral arterioles
- swelling & secretory function of stromal cells
- increased lipid and glycogen content of stromal cells
- decreased uterine mobility
78
What happens hormonally during pre-menstruation?
days 22-28
- drop in estrogen and progesterone
- release of pituitary suppression --> rise in FSH
79
What happens to the follicle during pre-menstruation?
involution of corpus luteum
80
What happens to the endometrium during pre-menstruation?
spasming of endometrial arterioles --> ischemia of endometrium
81
Purpose of testing E2
This test may be ordered to check:
How well your ovaries, placenta, or adrenal glands work
If you have signs of an ovarian tumor
If male or female body characteristics are not developing normally
If your periods have stopped (levels of estradiol vary, depending on the time of month)
The test may also be ordered to check if:
Hormone therapy is working for women in menopause
A woman is responding to fertility treatment
The test may also be used to monitor persons with hypopituitarism and women on certain fertility treatments.
82
When to test progesterone
day 21 / 3/4 of way through cycle / 7 days after ovulation
This day is chosen on the assumption that the women are having a 26-30 day cycle, and luteal phase is normal and lasts about 10-14 days after ovulation. Thus, assuming ovulation is between Days 12-16 , Day 21 is the middle of the luteal phase when the production of progesterone from the corpus luteum gland peaks in an ovulatory cycle (and if there was then pregnancy, the HCG would prevent the corpus luteum from then dying and it would produce even more progesterone). If ovulation has occurred later than Days 12 – 16, then the progesterone check would be better done a few days later so as to strike the middle of the luteal phase. Conversely, if ovulation has occurred earlier than Day 12, an earlier progesterone test at about Day 18 is required.
83
Purpose of testing progesterone
The corpus luteum is the gland formed in the ovary from the ovulated follicle(s). It makes progesterone and and estradiol that is secreted in to the blood and causes the lining of the uterus to become secretory. Blood level of progesterone in the middle of the luteal phase > 30nmol/l suggest that the endometrial effect of the progesterone is likely to be sufficient to assist an embryo implanting in the uterus. This progesterone in the blood also feeds back to the pituitary to ensure that little FSH is produced. There is no value in measuring the hormones FSH, LH and E2 at the same time as a Day 21 progesterone because their interpretation is not of any value if the progesterone is raised, as it should be in the mid-luteal phase.
1. Progesterone > 30nmol/l – ovulation has occurred and the corpus luteum is producing sufficient progesterone to induce adequate secretory changes in the endometrium to assist implantation.
2. Progesterone 3-30 nmol/l – ovulation has occurred > 10 days ago or < 5 days ago, or if ovulation did occurr 5-10 days ago, the level is probably not adequate to sustain endometrial growth for satisfactory implantation.
3. Progesterone >120 nmol/l – two or more follicles have been recruited
4. Progesterone < 3nmol/l – no ovulation in previous 14 days.
84
When to test estradiol
Day 2.
At this time, estradiol is at its lowest so FSH should be at its highest. If the estradiol level on Day 2 is > 200pmol/l, then follicle growth will have already started, and the measurement of the FSH is not reliable because the raised estradiol will have already started to suppress the FSH level. This commonly happens in older women. From a functional point of view, early follicle growth may mean the endometrium does not have enough time to develop before ovulation occurs, leading to asynchronicity between the egg and the endometrium , and hence a reduced chance of implantation.
When the brain realises that there is low estradiol around (ie at the time of a period), and a further group of follicles should be recruited to start another cycle, the blood level of FSH rises, but generally to not more than 9iu/l. If more FSH than 9iu/l is produced at the time of a period, the brain has somehow realised that to stimulate follicles to grow, more FSH is required than is normal – and the usual reasons for this are that the number of follicles in the ovary is low, or there is some problem within the follicles that the FSH needs to overcome to stimulate another menstrual cycle.
Estradiol is the steroid hormone that is produced by the cells lining the ovarian follicles in response to FSH, and the very high levels of estradiol within the leading follicle nourish and mature the egg. Some estradiol reaches the blood to cause the lining of the uterus to grow, the secretion of ovulatory cervical mucus, and to provide feedback to the brain and pituitary that another cohort of follicles has been recruited and is growing. The level of FSH then falls due to negative feedback by estradiol.
85
Purpose of LH test
In women, an increase in LH level at mid-cycle causes release of eggs (ovulation). Your doctor will order this test to see if:
You are ovulating, when you are having trouble getting pregnant or have periods that are not regular
You have reached menopause
If you are a man, the test may be ordered if you have signs of infertility or lowered sex drive. The test may be ordered if you have signs of a pituitary gland problem.
In women, a higher than normal level of LH is seen:
When women of childbearing age are not ovulating
When there is an imbalance of female sex hormones (such as with polycystic ovary syndrome)
During or after menopause
Turner syndrome
When the ovaries produce little or no hormones (ovarian hypofunction)
In men, a higher than normal level of LH may be due to:
Absence of testes or testes that do not function (anorchia)
Problem with genes such as Klinefelter syndrome
Endocrine glands that are overactive or form a tumor (multiple endocrine neoplasia)
In children, a higher than normal level is seen in early (precocious) puberty.
A lower than normal level of LH may be due to the pituitary gland not making enough hormone (hypopituitarism).
86
When during cycle to test LH
day 11 - about to ovulate
87
Purpose of free testosterone test
A testosterone test is done to:
See why a man is having problems in fathering a child (infertility). A low amount of testosterone can lead to low sperm counts.
Check a man's sexual problems. Having a low level of testosterone may lower a man's sex drive or not allow him to have an erection (erectile dysfunction).
See whether a high level of testosterone is causing a boy younger than age 10 to have early signs of puberty.
Find out why a woman is developing male features, such as excessive facial and body hair (hirsutism) and a deep voice.
Find out why a woman is having irregular menstrual periods.
See if testosterone-lowering medicines are working in a man with advanced prostate cancer.
Find the cause of osteoporosis in a man.
88
When to test free T
morning (7-9am) b/c testosterone levels highest
89
When to test prolactin
How is it used?
Prolactin levels may be used for several reasons. Prolactin is a hormone produced by the pituitary gland and its primary role is to help initiate and maintain breast milk production in pregnant and nursing women.
Prolactin testing may be used, along with other hormone tests, to help:
Determine the cause of breast milk production not associated with pregnancy or breast-feeding (galactorrhea)
Diagnose the cause of infertility and erectile dysfunction in men
Diagnose the cause of menstrual irregularities and/or infertility in women
Detect and diagnose tumors that produce excess prolactin (prolactinomas), monitor their treatment, and detect recurrences
Evaluate anterior pituitary function or other pituitary disorder
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When is it ordered?
Prolactin testing may be ordered when:
A person has symptoms of a prolactinoma, such as unexplained headaches, visual impairment, and/or unexplained breast nipple discharge
A woman is experiencing infertility or irregular menstrual periods
A man has symptoms such as decreased sex drive (libido), nipple discharge, or infertility or has a low testosterone level
When a person has a prolactinoma, prolactin levels may be ordered periodically to monitor the progress of the tumor and its response to treatment. They may also be ordered at regular intervals to monitor for prolactinoma recurrence.
Prolactin levels may be ordered, along with other hormone levels such as growth hormone, when a health practitioner suspects that a person has a pituitary disorder such as hypopituitarism.
When a person has a condition or is taking medications that may affect dopamine production, prolactin concentrations may sometimes be monitored.
90
When during day to test prolactin
Prolactin levels highest during sleep and shortly after waking up.
Also higher during emotional or physical stress.
91
General principles for hormone modulation
Increase/improve natural liver metabolism/excretion of hormones
Improve fecal and urinary excretion of hormones
Promote healthy estrogen metabolic pathways where possible
Decrease intake of harmful compounds (exogenous sources of E)
Decrease endogenous production
Balance hormones that may be unbalanced
92
Exercise's effect on estrogen?
- reduces production & increases excretion
| - promote healthy weight: adipose tissue decreases production of E2
93
b-glucoronidase effect on estrogen?
B-glucoronidase (enzyme possessed by pathogenic bacteria in the gut) uncouples the bond by excreted estrogen and glucoronic acid so estrogen can re-enter the enterohepatic recirculation
B-glucoronidase activity increases with a diet high in fat and low in fiber
Reduced by establishing proper bacterial flora by eating a diet high in plant foods and supplementing with L. acidophilus, B. infantis (and other probiotics)
94
how to increase efficacy of phase II liver detox?
Increase efficacy of phase II liver detoxification (to reduce exposure to metabolic intermediates)
Anti-oxidants serve to sequester intermediates
Cruciferous vegetables, green tea, flavanoids, Taraxicum officinale, Humulus lupulus, Rosmarinus officinalis
95
relationship between blood sugar levels & estrogen?
Excess insulin in the bloodstream prompts ovaries to secrete excess testosterone and decrease SHBG
in the presence of aromatase enzyme in adipose tissue is converted to estrogen
decrease in SHBG causes increase in free sex hormones
96
Alcohol's relationship to estrogen?
Alcohol consumption increases estrogen levels
Even moderate consumption increases breast cancer risk in women
Synergistically enhanced when combined with estrogen replacement therapy (OCP and HRT)
97
common sources of xenoestrogens?
cosmetics (nail polish, soaps, gels, hairsprays), lotions, plasticized receipts, pesticides, plastic bottles (hard and soft), liner on canned goods, plastic cookware
98
effect of cruciferous indoles on estrogen metabolism?
Cruciferous indoles - support the healthy metabolic pathways of estrogen metabolism (to 2OH -E1 vs. 16OH-E1)
due to components of DIM (100mg/day) and indole-3-carbinol (I3C) (300-400mg/day), research mostly based on supplementation but dietary supplementation with food seems to be effective
99
Soy & flaxseed effect on estrogen metabolism?
Soy and flaxseed can significantly promote hydroxylation of C2 and increase the 2OH-E1:16OHE1 pathway
Flaxseed consumption increased the urinary excretion of 2/16 OHE1 in a dose-dependent relationship (5-10gm).
Both are sources of phytoestrogens
lignans (found in flaxseed in high concentrations)-
decrease levels of free estrogen in circulation
inhibit aromatase activity
have been shown to inhibit estrogen sensitive breast cancer cell proliferation
consuming 10g of flaxseed/day - longer menses, higher progesterone:estrogen ratio, fewer anovulatory cycles, improved ovarian function
100
Coffee's effect on estrogen
Consuming 200 milligrams or more of caffeine from coffee mirrored the findings for overall caffeine consumption, with Asians having elevated estrogen levels, whites having lower estrogen levels, and the results for blacks not statistically significant. However, consumption of more than one cup each day of caffeinated soda or green tea was associated with a higher estrogen level in Asians, whites, and blacks.
The changes in estrogen levels among the women who took part in the study did not appear to affect ovulation. Studies conducted in animals had suggested that caffeine might interfere with ovulation.
Moderate consumption of caffeine was associated with reduced estradiol concentrations among white women, whereas caffeinated soda and green tea intakes were associated with in- creased estradiol concentrations among all races. Further research is warranted on the association between caffeine and caffeinated beverages and reproductive hormones and whether these relations differ by race. Am J Clin Nutr 2012;95:488–97.
8oz cup brewed coffee = 95-200mg caffeine
8oz cup brewed decaf = 2-12mg caffeine
espresso = 47-75mg caffeine
101
Magnesium's relationship with estrogen metabolism?
Magnesium- cofactor for the excretion (methylation) of estrogen
102
B vitamins relationship with estrogen metabolism?
B vitamins - involved in estrogen metabolism via Phase II pathway
103
herbs acting on liver - improve liver enzyme activity & increase estrogen clearance
Silybum marianum
Bupleurum falcatum
Rosmarinus officianalis
104
SHBG affect on estrogen modulation
Preferentially binds to androgens, but also binds to estrogen
increase concentration will decrease free androgens as well as free estrogens in blood
soy isoflavones increase SHBG concentrations in women with low levels
lignans increase the production of SHBG in the liver
