Gyne Rep Endo-Dr. Ona Cruz

8/14/2019 Gyne Rep Endo-Dr. Ona Cruz

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Reproductive

Endocrinology

J.ONA CRUZ,MD,MHPEd,FPOGS

OBSTETRICS & GYNECOLOGY

FEU-NRMF

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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

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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.

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Gyne Rep Endo-Dr. Ona Cruz