gyne rep endo-dr. ona cruz
TRANSCRIPT
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Reproductive
Endocrinology
J.ONA CRUZ,MD,MHPEd,FPOGS
OBSTETRICS & GYNECOLOGY
FEU-NRMF
1
Learning Objectives1 Explain the Hypothalamic-Pituitary-Ovarian Interactions
2 Describe the GnRH structure and functions
3 Trace the major and alternative route of GnRH transport
4 Describe the manner of GnRH secretion in relation to the
menstrual cycle
5 Explain the regulatory mechanisms governing GnRH
secretion and release
6 Explain the therapeutic value of GnRH analogues
7 Describe gonadotrophins structure and function
8 Describe the manner of gonadotropins secretion in
relation to the menstrual cycle
2
Learning Objectives9 Explain the two-cell-two-gonadotropin theory of steroid
production
10 Tabulate the different growth factors and their effects on
gonadal function
11 Tabulate the different eicosanoids/prostaglandins andtheir role on ovarian physiology
12 Diagram ovarian steroid biosynthesis
13 State the ovarian steroids and their action
14 Describe ovarian gametogenesis and the development ofthe dominant follicle
15 Relate the key events in the menstrual cycle
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Unique among
releasing
hormones
Regulates secretion of FSH and
LH
Secreted in pulsatile manner to
be effective. (Half-life: 2 to 4
minutes)
GnRH
GonadotropinGonadotropin--releasing hormonereleasing hormone
SECRETIONSECRETION
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GnRHGonadotropin-releasing hormone
Regulation of SECRETION
The control of episodicGnRH secretion isextremely important for themaintenance of normalovulatory cyclicity.
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What regulates amplitude and frequency
of GnRH secretion?
LONG
feedback loop
Stimulation and inhibition by ovarian
steroids (E2, P4)
Stimulation and inhibition by
nonsteroidal secretions (inhibin,
activin, and follistatin)SHORT
feedback loop
Inhibition by gonadotropins (LH,FSH)
ULTRA-SHORTfeedback loop
Inhibition by GnRH
Neurotransmitters and
Neuromodulators and Brain peptides
(Catecholamines, dopamine,
endogenous opioid peptides) 12
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1 Catecholamines: Modulate GnRH pulsatile release by
influencing the frequency and amplitude of the pulses
Dopamine Inhibits GnRH release, (and indirectly inhibitgonadotropins)
Inhibits Pituitary prolactin secretion (Prl
Inhibiting Hormone???)
Norepinephrine Stimulatory to GnRH
2 Indolamine
Serotonin Does NOT affect GnRH release.
Stimulates PRF, thus stimulating Prl
ultimately inhibiting GnRH
Neurotransmitters and their Role inRegulation of GnRH secretion
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*How do medications affect
reproductive function?
How can some pharmacologic agents
cause galactorrhea and amenorrhea?
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Neuromodulators 1 Opiods: LH, Prl, GnRH
2 Prostaglandins (PG E2): GnRH
3 Catecholestrogens: Inhibits tyrosineOHlase
Brain Peptides 1 Neuropeptide Y
2 Angiotensin II
3 Somatostatin
4 Activin and Inhibin
5 Follistatin
6 Galanin
*Neuromodulators & Brain peptides:Role in Regulation of GnRH secretion
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*Learner Task : tabulate the differentneuromodulators and brain peptides as to
their basic description and functional
effects on GnRH and gonadotropin
secretion.
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GnRHa: ComparisonHall JE: ClinObstetGynecol7:44,1993
Agonist Antagonist
Suppression of
Gonadotropin
Desensitization Competitive receptor
blockade
Acute
Responses
Stimulate LH / FSH Inhibit LH, Partially
FSH
Chronic
response
Inhibit LH / FSH Inhibit LH / FSH
Experience Extensive Limited
Safety Long history of
safety
Effects of histamine
release
Cost Relatively low high21
GnRH Analogs: Clinical UseActivation of pituitaryGonadal function
Give in pulses
Delayed pubertyCryptorchidism
Functional Hypothalamic amenorrhea
Hypogonadotropic hypogonadism (Kallmannssyndrome)
Pituitary - gonadal
inhibition
Give in bolus
Precocious puberty
Hormone
dependent
tumors
Endometriosis
Uterine leiomyomas/Fibroids
Breast cancer
Prostatic cancer
Suppression of ovarian fucntion in PCOS and in IVF
PMS
DUB
Contraception
Give in bolus
Suppression of spermatogenesis
Ovulation inhibition
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GnRH antagonists: mechanism of actionLoy RA: Curr Opin Obstet Gynecol 6:262, 1994
Action
Pituitary-ovarian axis suppression
without flare effect
Compete with GnRH for its receptors
Prevent synthesis and release of
LH/FSH
Induce immediate and transient
hypogonadism
Suppress gonadal steroidogenesis
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Structure: FSH and LHGlycoproteins of high molecular weight. [LH 28,000
and FSH 37,000 daltons]
subunit 14,000 daltons, 90 amino acids
Similar to TSH & hCG
Different
subunits
Carbohydrates Biologic activity
Amino acids
Sialic acid Half life
LH 1 or 2 30 min
FSH 5 3.9 hrs26
Functions: LH1 Stimulates hormone production by activating cP450SCC
a Androgen in theca cells
b Progesterone in the corpus luteum
2 Acts synergistically with FSH
A on the granulosa cells to help follicular maturation
B to increase LH receptors and luteinization of follicle (thusincreasing progesterone production)
3 Induces ovulation
a stimulating a plasminogen activator that decreases tensilestrength of the follicle wall before follicular rupture occurs.
b Stimulates prostaglandin synthesis.
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Functions: FSH1 Stimulates hormone production
a Estrogen (E1, E2) in granulosa cells by activating aromataseenzyme
b Interconversion of Androstenedione and Testosterone in the theca
cells by activating 3-OHSD
2 Acts synergistically with LH
A on the granulosa cells to help follicular growth & maturation
B to increase LH receptors and luteinization of follicle (thus increasingprogesterone production)
3 Rescue of follicles from degeneration (achieved by reducing
androgenicity of environment)
a indirectly by stimulating activin production
b directly metabolizing LH-induced thecal androgens to estrogens
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OVARIAN STEROIDOGENESIS Luteal phase
GRANULOSA
THECA
17-OH pregnenolone
Androstenedione
DHA
Testosterone
Acetate
Pregnenolone
Cholesterol
Estradiol
Estrone
Androstenedione
LDL
Cholesterol
Acetate
Progesterone
LDL
Cholesterol
Pregnenolone
FSH
LH LH
OVARIAN STEROIDOGENESIS: LUTEAL PHASE
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Activin & Inhibin
Mathews LS. Endocrine Rev
15:310, 1994
Involvement inovarian steroidsynthesis
Inhibins stimulate
progesterone and
inhibit estradiol
production
Activins inhibit
progesterone and
stimulate estradiol
production
OVARY
Cholesterol
Pregnenolone
Progesterone
Androstenedione
Estradiol
Inhibin
InhibinActivin
Activin+
+
-
-
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Production is regulated by FSH
Preferentially inhibits FSH over LH release
Actions: 1 stimulation of thecal androgenproduction
2 Inhibits oocyte maturationDecline in inhibin levels in the
perimenopause and menopause is
probably the permissive factor in the
rise of FSH levels at these times.
Inhibin
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Stimulates FSH release but NOT LH.
Actions: 1 stimulation of thecal androgenproduction
2 Inhibits oocyte maturation
Decline in inhibin levels in theperimenopause and menopause is
probably the permissive factor in the
rise of FSH levels at these times.
Activin
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Ovarian peptide
aka: FSH-suppressing protein
Actions: 1 inhibition of FSH synthesis andsecretion
2 Inhibition of FSH response toGnRH
3 Binds to activin and in thismanner decreases the activity ofactivin.
Follistatin
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*Learner Tasks:
Tabulate the different growth
factors and prostaglandins andtheir functions.
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AcetateCholesterol
Pregnenolone
Progesterone
17-Hydroxyprogesterone
Androstenedione
Estrone
P450scc
P450c17
17aOHlase
3-OHSD5,4 isomerase
17-Hydroxypregnenolone
Dehydroepidandrosterone
P450c17, 20 lyase P450c1717aOHlase
P450c17
17, 20 lyase
17-OHSD
17HSD
5 pathwayDHEA
pathway
4 pathwayProgesterone
pathway
P450arom
Testosterone
Estradiol
P450aromSperoff L, et al.
Clinical Gynecologic
Endocrnolgy and
Infertility, ed 6, Lip-
pincott, 1999
GONADAL STEROIDOGENESIS
3-OHSD5,4 isomerase
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Ovarian Steroids: Estrogen &ProgesteroneDailySecretion
estradiol: 0.1 to 0.5 mg (lowest duringmenses, highest just before ovulation)
progesterone: 0.5 mg (follicular phase,by the adrenals) to 20mg (luteal phase, bythe corpus luteum)
Metabolism LiverKidneys
Transportproteins
SHBG: Estrogen & Androgens
CBG: Progesterone
Clinical application: Estradiol, obesityand hyperthroidsm increases SHBG. Androgensand hypothyroidism decreases them
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Functions of Ovarian SteroidsEstrogenEstrogen stimulation of synthesis ofstimulation of synthesis of
estrogen and progesteroneestrogen and progesterone
receptors in target tissues such asreceptors in target tissues such as
thethe endometriumendometrium
ProgesteroneProgesterone inhibition of synthesis of estrogeninhibition of synthesis of estrogen
and progesterone receptorsand progesterone receptors
increase intracellular synthesis ofincrease intracellular synthesis of
estrogenestrogen dehydrogenasedehydrogenase (converts(converts
estradiolestradiol to less potentto less potent estroneestrone
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OVARIAN DEVELOPMENT: CHRONOLOGY
6 weeks
12-24 weeks
Birth
Puberty
Reproduction span
Primordial germ cells
Oogonia proliferation
migrate
Genital ridge
400 oocytes
400,000 oocytes
2,000,000 oocytes
Primary oocytes in
meiotic arrest
7,000,000
ATRESIA
1ST Meiotic Division
Meiotic Division
Diplotene Stage(Prophase)
Resumption of the
Miotic Division
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The dominant follicleThe
dominant
follicle
established
by day 7 of
the cycle.
1 Secretes highest amount of
estrogen
2 Most sensitive to FSH
3 Has greatest number of
receptors
4 Has the greatest mitotic activity
and number of granulosa cells
5 More vascularized theca cells so
more FSH reaches its receptor52
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THE END
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THE MENSTRUAL CYCLE
KEY EVENTS OF THE MENSTRUAL CYCLE (Dr. Alenzuelas Note)
At the start of each menstrual cycle, gonadal hormones are low and has been declining since the end of the luteal
phase of the previous cycle.
With the demise of the corpus luteum of the previous cycle, FSH levels begin to rise and follicular recruitment of
the next cycle begins. Under the influence of FSH, these follicles grow and each secrete increasing amounts of
estradiol. The rising estrogen causes proliferation of the endometrium.
Estrogen stimulate growth and differentiation of the functional layer of the endometrium and work synergistically
with FSH for follicular development.
Rising levels of estradiol sends a negative feedback the pituitary and hypothalamus resulting into inhibition of FSH
release and FSH declines at midpoint of the follicular phase. Also, the granulose cells secrete inhibin which help
suppress FSH. LH on the otherhand, is initially stimulated by secretion of estrogen throughout the follicular phase.
The midpoint decline of FSH causes atresia of all except one follicle- the dominant follicle. The dominant follicle
produces about 80% of the daily estradiol production of 500g. The rapid rise of estradiol and small amounts of
progesterone from the dominant follicle is the HPO signal that the follicle is ready to be ovulated. When a critical
estradiol level isreached (200pg/ml or more for two or more days), the initial negative feedback reverses into a
positive one and causes the LH and FSH surge at midcycle. The LH surge initiates ovulation.
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At the end of the follicular phase just before ovulation, FSH-induced receptors appear on the granulose cells. LH
stimulation modulates progesterone secretion.
LH surge initiates germinal vesicle disruption and metaphase I is completed. The oocyte enters metaphase II and
the first polar body appears. (It is only upon sperm penetration into the zona pellucida when meiosis is completed
and the second polar body is extruded).
Prior to rupture, LH stimulates synthesis of PGF2 and PGE and collagenase. FSH stimulates production of
plasminogen activator which converts plasminogen to plasmin, a proteolytic enzyme. These facilitates follicular
rupture and egg extrusion.
After extrusion of the oocyte, there is a decrease in follicular fluid , the follicular wall convolutes and there is a
marked decrease in diameter and volume of the follicle. The granulosa cells become vascularized allowing LH to
reach more receptors. Both granulose and theca cells become luteinized and acquire yellow coloration.
Under LH, the corpus luteum produces significant amounts of progesterone. Estradiol levels meanwhile decreases
just before ovulation and continues to lower in the early luteal phase. Its levels pick up at midluteal phase as a
consequence of corpus luteum production (second estradiol peak).
The decrease in LH frequency in the luteal phase is due to the negative feedback effect of progesterone on thehypothalamus which decreases GnRH release. (Increased -endorphin levels probably mediates this event). The
decrease in LH amplitude is due to the negative feedback of progesterone on the pituitary.
Estradiol and progesterone levels remain elevated throughout the lifespan of the corpus luteum. However, its
existence is dependent on LH. With continuing decline in LH levels, there is demise of the corpus luteum and sex
steroid levels delines. In 4-6 days after this fall menstruation ensues and the next cycle begins. If however,
fertilization occurs, there is rescue of the corpus luteum as a consequence of HCG production which acts as a
surrogate for LH.