Sanjay K. Agarwal, MD

1
Ovarian Senescence- a prelude to reproductive
aging and menopause -

• Sanjay K. Agarwal, MD
• Associate Professor of Reproductive Medicine,
  UCSD
• San Diego, CA

2
Learning Objectives At the end of this
lecture the student should be able to describe
Slide 1

• The changes that occur during reproductive aging
  and their impact on female fertility
• The physiological basis of menopause

3
Statement of the problem The age of the
menopause is genetically determined. The average
age of the menopause( 51 years) has not changed
over the years. but, the life expectancy for
women has increased to 84 years. Today women are
living 30 years after the menopause. Extending
care to older women is an important part of
medicine.
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Primordial Follicles
Slide 4

• Primordial follicles represent a pool of
  non-growing follicles from which all growing
  follicles are derived.
• Thus, without primordial follicles there can be
  no dominant follicles, no ovulations, and no
  menstrual cycles e.g., menopause.

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Primordial follicles are formed in the fetus. At
birth, the ovaries contain a fixed number of
primordial follicles (eggs or Ovary Reserve, OR)
which steadily declines with age.
On average, the human ovaries at birth contain a
total of 2 million primordial follicles (OR).
The number of primordial follicles (OR)
declines with age reaching 1,000 at 50 years of
age.
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Photomicrographs illustrating the age-related
decline of primordial follicle numbers in human
ovaries that results from the process called
recruitment
Birth 2 x 106 total
25 years old 2.5 x 105 total
50 years old 1 x 103 total
7
What is recruitment? Recruitment is the
process by which an arrested primordial follicle
is activated to begin growing i.e., the entry of
a primordial follicle into the pool of growing
follicles. This process leads to the decrease
in primordial follicles
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• How is recruitment regulated?
• Although the mechanisms regulating recruitment
  are poorly understood, there is evidence to
  support the concepts that
• Recruitment is controlled by local ovarian growth
  factors via autocrine/paracrine mechanisms.
• Recruitment can be stimulated by high levels of
  FSH.

9
Inhibin A and B are products of the corpus luteum
and Graafian follicles, respectively. All
Graafian follicles (healthy and atretic) secrete
Inhibin B during the follicular phase.
Consequently, plasma Inhibin B levels in women
are determined by the total number of Graafian
follicles present in the ovaries and decrease
with age
Inhibin B
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The number of developing Graafian follicles
present within the ovaries declines with age.
Patient Mean number of Graafian
follicles in both ovaries Age 2-3 mm
4 mm Total (range) 22 - 25 (n10) 14 23
37 (23 - 63) 30 - 34 (n12) 4 20
24 ( 5 - 38) 39 - 42 (n9) 4 11
15 ( 4 - 75)

• This results in a decrease in Inhibin B which in
  turn leads to a rise in plasma FSH.

11
The age related rise in FSH occurs over the
entire menstrual cycle.
Slide 13
LH
Older(40-45)years)
FSH
Younger (20-25 years)
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Ovarian senescencemechanisms
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Consequences of ovarian aging1. An age-related
decline in female fertility
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At 37 years of age the rate of recruitment
increases 2-fold. This results in an accelerated
loss of primordial follicles or Ovary Reserve
(OR).
OR is 25,000 Primordial follicles (eggs)
Number of primordial follicles
Accelerated loss of OR
37
Age in years
15
Female fecundity declines with age.
FSH Antral follicle count
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Consequences of ovarian aging2. Menopause
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Menopause
What is it? Menopause is defined by the final
menstrual period What causes it?
Menopause occurs when the number of
primordial follicles fall below the critical
threshold (1,000) necessary to generate a
dominant follicle which in turn, after ovulation,
generates a menstrual cycle.
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At 37 years of age the rate of recruitment
increases 2-fold. This results in an accelerated
loss of primordial follicles or Ovary Reserve
(OR).
Number of primordial follicles
OR is 1,000
Age in years
Menopause
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Premature ovarian failure

• - Menopause before the age of 40 years -

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Etiology

• Autoimmune
• Genetic gonadal dysgenesis, familial
• Iatrogenic - Chemotherapy Radiation Surgical
• Infectious viral oophritis
• Idiopathic

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Management

• Fertility issues oocyte donation
• Hormone replacement
• Contraception?

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Ovarian senescence summary
NOTE In some situations such as XX or XY (true)
gonadal dysgenesis, there are no oocytes in the
ovaries
?
Increased FSH

Decreased Inhibin B
Age related decline in fertility
Menopause