The Normal Menstrual Cycle
Introduction
 Hormone release and control is as precise as a Mozart symphony
 One aspect is faulty ---- everything crashes
 Must understand only a few key points
 Without a clear understanding, diagnosis and treatment of bleeding
abnormalities is a whole lot more difficult
Hypothalamus controls everything
 Gonadotropin releasing hormone (GnRH)
o Secreted by the arcuate nucleus
o Cells form from olfactory area
 Both neuronal and endocrine activity
Gonadotropin releasing hormone (GnRH)
 Half life = 2-4 minutes
 Secreted in a pulsatile fashion
o Once per hour (2ng/ml) = max stimulatory effect
o 2-5 pulses/hour or increasing the amount of GnRH released with
each pulse
 loose stimulatory effect
o < 1 pulse per hour decreases LH, increases FSH
Control of GnRH release
 Norepinephrine = stimulation
 Dopamine = inhibition
Gonadadotropins
 FSH and LH secreted by gonadotrope cells
 Pulsatile secretion
Follicle Stimulating Hormone (FSH)
 Stimulated by GnRH
 Inhibited by estradiol
Luteinizing Hormone
 Stimulated by GnRH and estrogens
 Inhibited by progesterone
The ovary
 Follicle
o Developing ovum
o Biochemical factory
Ovarian Follicle
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Estrogen is good for follicular growth and development
Androgens are bad
Estrogens
 Growth spurt
 Breast development
o Stimulates ductal formation
o Increases breast size
 Bone
o Increases density
 Proliferative endometrium
o High mitotic count
o Continued growth
Estrogens and endometrial cancer
 Constant stimulation of mitosis
 Mutation leads to aneuploidy and abnormal, accelerated cell growth
(cancer)
 Sequence:
Proliferative  Hyperplasia  Atypical Hyperplasia  CIS
adenocarcinoma
Estrogen
 Cervical mucus
o Copious
o Thin
o Clear
o Spinnbarkeit
o Ferning
 Lower genital tract
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o
o
Skin
o
o
o
o
Lipids
o
o
Liver
o
Increased epithelial thickness
Pliability and moisture increased
Increased water and hyaluronic acid
Reduced collagen breakdown
Decreased sebum
Decreased epithelial proliferation
Decreased LDL
Increased HDL
Increased plasma proteins
 Thyroid-binding globulin
 Sex hormone-binding globulin
Coagulation
o Increased factor VII, VIII, IX, and Prothrombin
o Decreased antithrombin III
Types of Estrogens
 Estrone
o conversion of androstenedione (ovary and adipose)
o Less potent

17-b-Estradiol
o The most potent
Estriol
 Least potent
 Produced by placenta
Progesterone
 Antiestrogen
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Breast
o Glandular (alveolar) development
Endometrium
o Blocks estrogen receptors
o Lowers mitosis
o Secretes more mucus
Cervical mucus
o Thickens
o Impenetrable
o Mucus plug
Hair
o Blocks androgen receptors
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Bone
o Reduced resorption
Lipids
o Decreased HDL
No effect of coagulation
Androgens
 Follicular atresia
 Inhibits endometrial growth
 Course (terminal) hair growth
 Upper abdominal fat
 Estrogen receptor blockade
 Lower HDL
 Increased LDL
Putting the Menstrual Cycle Together
 Early Follicular Phase
o Follicular recruitment begins prior to the previous cycle and is FSH
independent
o Up to 1,000 follicles are recruited
o Goal: select the best follicle for ovulation
o Biochemical factories are immature, estrogen levels are low
 Low LH – low androgen production
 High FSH – all of the androgens are converted to estrogens
o Excellent environment
 Early Follicular Phase
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Mid-follicular phase
o Follicles are maturing
o Rising estrogen levels
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Higher LH – more androgens
Lower FSH – reduced ability to convert androgens to
estrogens
Mid-follicular phase
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Estrogen stimulates FSH receptors locally
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The best follicles produce more estrogens
o More FSH receptors
o Low FSH levels do not result in adrogenic build-up
o Follicular growth continues
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Poor follicles produce less estrogen
o Less FSH receptors
o Cannot convert androgens to estrogens
o Androgen build-up leads to follicular atresia
o Most follicles are lost in this fashion
Mid-follicular Phase
Late follicular phase and ovulation
 Progesterone begins to rise just before ovulation
o Facilitates the positive feedback of estrogen on LH
o Causes an FSH surge
 Promotes granulosa cell LH receptor formation
 Aides in corpus luteum formation
 Expansion and dispersion of cumulous cells
 oocyte becomes free floating
 Conversion of plasminogen to plasmin
 Protolytic enzyme
 Pituitary senses a surge of estrogens as the last remaining follicles mature
 When estradiol levels > 200 pg/ml
o Follicles are nearly mature
o Super positive feedback – LH surge
LH surge and Ovulation
 LH levels peak 24-36 hours after estrogen peaks
o Androgen levels rise
 Knocks off all but the queen of all follicles
 Increases libido
o Initiates resumption of meiosis
o Prostaglandin formation
 Essential for follicle rupture
 Ovulation (10-12 hours after peak LH)
o Luteinization of granulosa cells
 Corpus luteum formation
Rapid Fall of LH after ovulation
 Exact mechanism unknown
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Rising progesterone
Fall of estrogen
Late follicular phase and ovulation
Luteal Phase
 Progesterone levels rise
o Peak day 23 (non pregnant cycle)
o Temperature rise
 Secretory endometrium
o Procedes in a predictable and orderly fashion
o Endometrial dating accurate +/- 2 days
o Reported based on a 28 day cycle
o Low progesterone slows progress
Corpus Luteum lasts 14 days
 Decline begins 9-11 days post ovulation
 hCG maintains luteal function
Luteal Phase
Luteal Phase (Pregnancy)
The menstrual cycle (short version)
1. Estrogen levels are low initially but rise as follicles develop
2. LH rises increasing androgens - helps select best follicle
3. FSH falls as estrogen increases
4. Estrogens surge stimulating the LH surge and ovulation
5. Progesterone blocks estrogen receptors and converts the proliferative
endometrium to secretory
6. Corpus luteum survives only 14 day, progesterone levels fall, and
mentration begins
7. hCG maintains corpus luteum and menses does not occur
Clinical applications
 Determining day of ovulation
o 1st day of menses – count back 14 days
 Post coital test
 Dating endometrium
o Timing intercourse for pregnancy
 Follicular phase irregular causes failure
 LH surge assessment
What if dominant follicle fails to fully mature?
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Estrogen levels do not induce an LH surge
No ovulation
No corpus luteum formation
No progesterone
Follicle continues to live and produce estrogen
o Proliferative endometrium maintained
o No period
o Negative b-hCG
Next recruitment cycle
 Higher initial estrogens
o Lower FSH
o Higher LH
o Less chance for successful follicular maturation
Consequences of anovulation
 Unapposed estrogen stimulation of endometrium
o Thickened endometrium – irregular bleeding
o Endometrial cancer risk
o Heavy period if ovulation ever occurs
 Infertility
Long term consequences
 Estrogen rises above 200pg/ml
 LH surge
 High LH maintained
o No fall in estrogen
o No progesterone
Consequences of high LH
 Increased androgens
o No endometrial growth
 2o amenorrhea
 Negative progesterone withdrawl test
o Increased libido
o Hirsuitism
Overview of chronic anovulation
 High estrogen
o Multiple follicles survive and produce estrogen
 Low FSH
o No way for follicle to fully mature
o Infertility
 High LH
o High androgens and hirsuitism and amenorrhea
 Enlarged polycystic ovaries from maintained follicles
Treatment of chronic anovulation
 Pregnancy not desired
o Goals: Regulate cycles & prevent adenocarcinoma
o Cyclical progesterone
 Not a reliable birth control method
o Continuous progesterone
 Oral progesterone (“mini pill”)
 Depo-medroxyprogesterone acetate
 Norplant
o Combination oral contraceptive pills
 Pregnancy desired
o Clomiphene citrate
 Estrogen receptor blocker
 Fools hypothalamic-pituitary axis that estrogens are low
 Increased FSH production
o Injectable FSH
 Human menopausal gonadotropins
 Pure FSH (genetically engineered)
Conclusions
 Knowledge of the menstrual cycle crucial in diagnosis and management
 Only a few key points need to be remembered
 Many key points are testable!