Learning Objectives

1 Explain the Hypothalamic-Pituitary-Ovarian Interactions

Reproductive 2
3
Describe the GnRH structure and functions
Trace the major and alternative route of GnRH transport

Endocrinology 4 Describe the manner of GnRH secretion in relation to the

menstrual cycle
5 Explain the regulatory mechanisms governing GnRH
secretion and release
J.ONA CRUZ,MD,MHPEd,FPOGS 6 Explain the therapeutic value of GnRH analogues
OBSTETRICS & GYNECOLOGY
7 Describe gonadotrophins’ structure and function
FEU-NRMF
8 Describe the manner of gonadotropins’ secretion in
relation to the menstrual cycle

1 2

Learning Objectives
9 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 and
their role on ovarian physiology
12 Diagram ovarian steroid biosynthesis
13 State the ovarian steroids and their action
14 Describe ovarian gametogenesis and the development of
the dominant follicle
15 Relate the key events in the menstrual cycle

1 | Gyne-Sec. B
 Gonadotropin-releasing hormone
GnRH SECRETION
Unique among Regulates secretion of FSH and
releasing LH

hormones Secreted in pulsatile manner to

be effective. (Half-life: 2 to 4
minutes)

Gonadotropin-releasing hormone What regulates amplitude and frequency

GnRH Regulation of SECRETION of GnRH secretion?
LONG Stimulation and inhibition by ovarian
The control of episodic feedback loop steroids (E2, P4)
GnRH secretion is Stimulation and inhibition by
nonsteroidal secretions (inhibin,
extremely important for the activin, and follistatin)
maintenance of normal SHORT Inhibition by gonadotropins (LH,
FSH)
ovulatory cyclicity. feedback loop
ULTRA-SHORT Inhibition by GnRH
feedback loop Neurotransmitters and
Neuromodulators and Brain peptides
(Catecholamines, dopamine,
11 endogenous opioid peptides) 12

2 | Gyne-Sec. B
Neurotransmitters and their Role in
Regulation of GnRH secretion
*How do medications affect
reproductive function?
1 Catecholamines: Modulate GnRH pulsatile release by
influencing the frequency and amplitude of the pulses
Dopamine Inhibits GnRH release, (and indirectly inhibit
gonadotropins)
Inhibits Pituitary prolactin secretion (Prl How can some pharmacologic agents
Inhibiting Hormone???) cause galactorrhea and amenorrhea?
Norepinephrine Stimulatory to GnRH

2 Indolamine
Serotonin Does NOT affect GnRH release.
Stimulates PRF, thus stimulating Prl
ultimately inhibiting GnRH
13 14

*Neuromodulators & Brain peptides:

Role in Regulation of GnRH secretion
Neuromodulators 1 Opiods: ↓LH, ↑Prl, ↓ GnRH
2 Prostaglandins (PG E2): ↑ GnRH
3 Catecholestrogens: Inhibits tyrosine
OHlase
Brain Peptides 1 Neuropeptide Y
2 Angiotensin II
3 Somatostatin
4 Activin and Inhibin
5 Follistatin
6 Galanin
18

3 | Gyne-Sec. B
*Learner Task : tabulate the different
neuromodulators and brain peptides as to
their basic description and functional
effects on GnRH and gonadotropin
secretion.

19

GnRHa: Comparison
Hall JE: Clin Obstet Gynecol 7:44,1993
GnRH Analogs: Clinical Use
Activation of pituitary Delayed puberty

Agonist Antagonist Gonadal function

Cryptorchidism
Functional Hypothalamic amenorrhea
Suppression of Desensitization Competitive receptor Give in pulses Hypogonadotropic hypogonadism (Kallmann’s
syndrome)
Gonadotropin blockade
Pituitary - gonadal Precocious puberty
Acute Stimulate LH / FSH Inhibit LH, Partially Hormone Endometriosis
inhibition
Responses FSH dependent Uterine leiomyomas/Fibroids
Give in bolus tumors
Chronic Inhibit LH / FSH Inhibit LH / FSH Breast cancer
Prostatic cancer
response
Suppression of ovarian fucntion in PCOS and in IVF
Experience Extensive Limited PMS
Safety Long history of Effects of histamine DUB
safety release Contraception Suppression of spermatogenesis

Cost Relatively low high Give in bolus Ovulation inhibition

21 22

GnRH antagonists: mechanism of action

Loy RA: Curr Opin Obstet Gynecol 6:262, 1994

Pituitary-ovarian axis suppression

without flare effect
Action Compete with GnRH for its receptors

Prevent synthesis and release of

LH/FSH
Induce immediate and transient
hypogonadism
Suppress gonadal steroidogenesis

24

4 | Gyne-Sec. B
 Structure: FSH and LH
Glycoproteins of high molecular weight. [LH 28,000
and FSH 37,000 daltons]
α subunit 14,000 daltons, 90 amino acids
Similar to TSH & hCG
Different β Carbohydrates Biologic activity
subunits Amino acids
Sialic acid Half life
LH 1 or 2 30 min
FSH 5 3.9 hrs
26

Functions: LH
1 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 (thus

increasing progesterone production)
3 Induces ovulation
a stimulating a plasminogen activator that decreases tensile
strength of the follicle wall before follicular rupture occurs.
b Stimulates prostaglandin synthesis.

28

Functions: FSH
1 Stimulates hormone production
a Estrogen (E1, E2) in granulosa cells by activating aromatase enzyme

b Interconversion of Androstenedione and Testosterone in the theca

cells by activating 3ß-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 increasing

progesterone 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

29

5 | Gyne-Sec. B
 OVARIAN OVARIAN : LUTEAL PHASE
STEROIDOGENESIS Luteal phase
STEROIDOGENESIS

LDL

THECA
GRANULOSA

Acetate Acetate LDL

Cholesterol
Cholesterol
LH
LH Pregnenolone
Pregnenolone

17-OH pregnenolone Progesterone

Estradiol

DHA FSH Estrone

Androstenedione
Androstenedione

Testosterone 34

Activin & Inhibin

Involvement in OVARY
ovarian steroid Cholesterol
synthesis
Inhibins stimulate Pregnenolone
progesterone and Inhibin + - Activin
inhibit estradiol
production Progesterone

Activins inhibit Androstenedione

progesterone and
Activin + -
stimulate estradiol Inhibin
production
Estradiol
Mathews LS. Endocrine Rev
15:310, 1994

36

6 | Gyne-Sec. B
 Inhibin Activin
Production is regulated by FSH Stimulates FSH release but NOT LH.
Preferentially inhibits FSH over LH release Actions: 1 stimulation of thecal androgen
Actions: 1 stimulation of thecal androgen production
production 2 Inhibits oocyte maturation
2 Inhibits oocyte maturation Decline in inhibin levels in the
Decline in inhibin levels in the perimenopause and menopause is
perimenopause and menopause is probably the permissive factor in the
probably the permissive factor in the rise of FSH levels at these times.
rise of FSH levels at these times.
37 38

Follistatin
Ovarian peptide
aka: FSH-suppressing protein *Learner Tasks:
Actions: 1 inhibition of FSH synthesis and
secretion Tabulate the different growth
2 Inhibition of FSH response to
factors and prostaglandins and
GnRH
3 Binds to activin and in this
their functions.
manner decreases the activity of
activin.

39 40

GONADAL STEROIDOGENESIS Ovarian Steroids: Estrogen &

Cholesterol Acetate Progesterone
Daily estradiol: 0.1 to 0.5 mg (lowest during
P450scc menses, highest just before ovulation)
Secretion
∆5 pathway ∆4 pathway
Pregnenolone progesterone: 0.5 mg (follicular phase,
DHEA Progesterone 3β-OHSD
P450c17 pathway pathway ∆5,4 isomerase
17aOHlase by the adrenals) to
20mg (luteal phase, by
17-Hydroxypregnenolone Progesterone
the corpus luteum)
P450c17, 20 lyase P450c17 Metabolism Liver
17aOHlase

Dehydroepidandrosterone 17-Hydroxyprogesterone Kidneys

3β-OHSD P450c17
∆5,4 isomerase 17, 20 lyase
Transport SHBG: Estrogen & Androgens
17β-OHSD proteins CBG: Progesterone
Androstenedione Testosterone

P450arom
Clinical application: Estradiol, obesity
Speroff L, et al. P450arom
and hyperthroidsm increases SHBG. Androgens
Clinical Gynecologic
Endocrnolgy and 17βHSD and hypothyroidism decreases them
Infertility, ed 6, Lip- Estrone Estradiol
pincott, 1999 41 42

7 | Gyne-Sec. B
Functions of Ovarian Steroids OVARIAN DEVELOPMENT: CHRONOLOGY
Estrogen stimulation of synthesis of 6 weeks Primordial germ cells
estrogen and progesterone
migrate
receptors in target tissues such as
the endometrium Genital ridge
Progesterone inhibition of synthesis of estrogen 12-24 weeks 1ST Meiotic Division Oogonia proliferation 7,000,000
and progesterone receptors Meiotic Division Primary oocytes in
increase intracellular synthesis of
Diplotene Stage
(Prophase) meiotic arrest A
Birth T
estrogen dehydrogenase (converts 2,000,000 oocytes R
estradiol to less potent estrone Puberty Resumption of the E
Miotic Division 400,000 oocytes S
Reproduction span 400 oocytes I
A

43 44

8 | Gyne-Sec. B
 The dominant follicle
The 1 Secretes highest amount of
dominant estrogen
follicle 2 Most sensitive to FSH
established 3 Has greatest number of
by day 7 of
receptors
the cycle.
4 Has the greatest mitotic activity
and number of granulosa cells
5 More vascularized theca cells so
more FSH reaches its receptor
52

9 | Gyne-Sec. B
 THE END


10 | G y n e - S e c . B
 THE MENSTRUAL CYCLE

KEY EVENTS OF THE MENSTRUAL CYCLE (Dr. Alenzuela’s 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 500µg. 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.

11 | G y n e - S e c . B
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 PGF2α 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 the
hypothalamus which decreases GnRH release. (Increased β-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.

12 | G y n e - S e c . B