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Estrogen Progesterone and The Ovary

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Estrogen and Progesterone
Both Estrogen and Progesterone are produced by ovarian follicles
Maturing follicles produce
estrogen
Follicles at or near full maturation are the major source
The corpus luteum produces both estrogen and progesterone Corpus luteum forms from the
follicle following ovulation
Estrogen and Progesterone
Other tissues, such as adipose tissue, also have some ability to
synthesize estrogen in the male and female
Progesterone is the hormone of pregnancy
Is synthesized by the
ovary and the placenta
Both estrogen and progesterone have at least
two receptors
Estrogen and Progesterone
Ovary
At birth,
each ovary contains ~ 1 million oocytes
At puberty, each ovary contains ~ 250,000 ooctyes
Of these, ~400 to 500 are actually released from the ovary through ovulation
Ovary has two main regions:
Cortex: Contains ovarian follicles
Medulla: A loose connective tissue with many blood vessels, lymphatic vessels, nerves
Ovarian Follicles:
Primordial
Primary
Secondary
Graafian (Tertiary)
At puberty, ovarian cycles begin
With each new cycle,
, approximately 16 primordial follicles begin a process of maturation - usually only one completes it
The others will become atretic, i.e., degenerate and disappear; process unknown
A primordial follicle consists of a primary oocyte surrounded by
a thin layer of flattened epithelial Granulosa cells
Follicular maturation growth processes involve
the oocyte, granulosa cells, and surrounding tissue
Ovarian Primordial Follicle
In embryogenesis, primary oocytes are arrested in prophase of meiosis I
Following embryogenesis, primary oocytes remain in primordial follicles until
they begin the maturation process
Ovarian Follicles
Germline stem cells and follicular renewal in the
postnatal mammalian ovary.
Follicular Maturation, General Changes:
Granulosa cells around oocyte proliferate
Tissue around follicle forms Theca layers
Granulosa cells secrete thick glycoprotein layer around oocyte, the Zona Pellucida
Nearing maturation, fluid accummulates between granulosa cells, forms antrum
Oocyte Maturation, Major Changes:
Approximately 12 hours prior to ovulation, maturing oocyte completes first meiotic division forming a secondary oocyte and primary polar body
Secondary oocyte immediately enters meiosis II, but stops at metaphase
Human secondary oocyte remains at metaphase II until fertilization
Follicular Maturation
Granulosa cells (filopodia) maintain contact with oocyte surface (microvilli)
In fluid filled follicle, three regions of granulosa cells may be described;
Around the oocyte is the Corona radiata
Attaching the oocyte to the follicle wall is the Cumulus oophorus
a third group is located at the border of the follicle
Surrounding cells from the body of the ovarian cortex =
interstitial cells form an envelope around the developing follicle
This envelope is the theca (= envelope)
Theca in two layers; Theca interna is important site of
hormone synthesis
Follicular Maturation
Fluid eventually accumulates between some of the granulosa cells; forms a vesicular or secondary follicle
Fluid eventually froms one large vesicle =
Antrum (cavern)
The fully mature follicle is the Graafian Follicle (Tertiary), and by this time is bulging from the surface of the ovary
[Follicles in cortex; medulla = supply, support]
Of the several follicles that begin maturation each cycle, usually only one completes it
This one may have the best response to FSH (# of receptors, more intracellular signaling components, etc.)
Fully mature follicle is the
Graafian follicle
Ovulation
At ovulation some granulosa cells leave with the
secondary oocyte
(Corona Radiata)
Following Ovulation
After ovulation, granulosa cells remaining in the empty follicle accumulate cholesterol
The empty follicle becomes the Corpus Luteum. At the end of the cycle, the Corpus Luteum is reabsorbed and becomes filled with connective tissue
This is the
Corpus Albicans
Ovarian Steroid Hormones
Produced by cells of the ovarian follicle:
Progestagens, Androgens, Estrogens
Hormone production: cells
Granulosa cells, Theca cells
Theca cells make all 3
Estrogens from the theca enter bloodstream; theca is at the outer border of the follicle (is outside the basement membrane of the follicle)
Theca; two regions
Outer = connective tissue = theca externa
Inner = glandular, vascularized = theca interna
Granulosa cells make estrogens from androgens produced in theca cells
Estrogens from granulosa cells are secreted into
follicular fluid
Follicle not Vascularized
Hormone Functions, Estrogen:
Targets:
Female genitalia
Skin
Mammary glands
Liver
Bone
Hypothalamus Via negative feedback
Pituitary Via negative feedback
Hormone Functions, Estrogen:
Targets: functions
Female genitalia; Promotes growth uterine wall in preparation for implantation developing embryo
Skin: function is
Mammary glands: function is
Liver: function is
Bone: promotes growth possibly in both male and female and cessation of growth at end of puberty
Hypothalamus Via negative feedback
Pituitary Via negative feedback
During development, anatomically the embryo becomes female in the absence of testosterone
At puberty, estrogen is responsible for
the development of female secondary sex characteristics
In the ovary, Estrogens from granulosa cells are secreted into follicular fluid:
[Estrogen] is very high in ovarian follicular fluid
Steroid
Egg highly specialized
A possible function is maternal mRNA production in the maturing oocyte
Hormone Functions, Progesterone:
Targets:
Female genitalia
Skin
Mammary glands
Hypothalamus Via negative feedback
Pituitary Via negative feedback
Hormone Functions, Progesterone:
Responsible for preparation of uterus for and maintenance of pregnancy
Androgens:
Growth spurt at puberty, secondary hair growth
Several peptide/protein signaling molecules identified
produced in the ovary, have some function in this process
Ovarian maturation factors from granulosa cells inhibit
meiosis
Growth factors including epidermal growth factor and fibroblast growth factor regulate follicular development and maturation
Use
auto/ paracrine mechanisms
Growth factors include hormones similar to insulin-like growth factors (IGF's) such as Relaxin
In pregnancy, Relaxin relaxes the symphysis pubis facilitating partuition (childbirth)
Inhibins produced by follicular cells, have
negative feedback on FSH levels
Estrogen function, Male
Mouse:
In mice lacking estrogen receptors, testes atrophy, sperm count is reduced, and there appear to be alterations in behaviors
Estrogen may be required for the masculinization of neuronal clusters in the hypothalamus that control sex and aggression
Recall that estrogen has testosterone as its precursor making estrogen levels in tissues of the male embryo potentially higher than those in the female embryo
Estrogen function, Male
Human: Epiphyseal fusion:
a 28 year old man, apparently otherwise normal, lacked a functional estrogen receptor, was 6' 8" with unfused epiphyses, and had a bone age of 15
Human: May be important in maintaining levels of HDL (good) cholesterol and protecting against cardiovascular disease in both male and female
Ovarian cycle: Hormonal
The ovarian cycle is dependent upon the cyclical or pulsatile release of GnRH from the hypothalamus, the "GnRH pulse generator"
Release controlled by neural input from the brain
Estrogen and Progesterone
Following puberty, at the start of the follicular phase, the hypothalamus is producing LRH =LHRH = GnRH, so
FSH and LH levels are high
High FSH stimulates follicle development
Estrogen
As follicle develops, theca develops, produces Estrogens
Estrogen levels rise
Estrogen stimulates
proliferation of uterine lining
Cells of immature follicles do not have receptors for LH and do not respond to it
Estrogen
High estrogen levels feedback negatively on
hypothalamus and pituitary
Causes FSH and LH levels to drop
Sustained high levels of estrogen causes a switch:
The hypothalamus, instead of being suppressed, increases release of GnRH
The Pituitary increases its Receptors for the releasing hormone and responds to the increase in GnRH by releasing large amounts of FSH and LH
One follicle has become fully mature (Graafian)
Graafian follicle has active receptors for LH
Peak LH levels cause
ovulation
Ovulation, Mechanism
1. Possible that LH peak induces Progesterone synthesis as part of ovulation process, may have following effects:
2. Cyclooxygenase activity in granulosa cells surrounding the oocyte is stimulated by rising LH levels (progesterone) resulting in local prostaglandin production.
3. Induction proteolytic enzymes, possibly by prostaglandins; Matrix metalloproteinases, plasminogen activator system.
4. Digestion collagen framework, basement membrane around follicle.
5. Prostaglandins may cause contraction capsule of ovary, forcing ooctye out.
Granulosa cells left behind in the follicle that has released its egg continue to respond to LH (Luteinizing Hormone), form the
Corpus Luteum
The Corpus Luteum produces estrogen and progesterone
Estrogen and Progesterone
Corpus Luteum:
When sufficient levels of progesterone and estrogen are released, these two hormones feedback negatively again on the hypothalamus and pituitary causing
causing FSH and LH levels to drop
Corpus Luteum: The Corpus Luteum needs LH to function
Without LH, Corpus Luteum disintegrates
Without Corpus Luteum to make them, Progesterone and Estrogen levels drop
Without Progesterone to maintain it, the thickened lining of the uterus is lost
FSH and LH, which had been inhibited by high progesterone and estrogen are now released from that inhibition and recover

This recovery of FSH and LH levels allows a
new follicular cycle to begin
Ovulation
Please note that the follicle that completes maturation and undergoes ovulation during any monthly cycle did not begin the maturation process that month, but rather several months ago
The time for follicular maturation is approximately
90 days
Probably most (all) of the estrogen that gets secreted during the follicular phase of the cycle is produced by the most mature follicle(s) approaching ovulation during that cycle, and that most (all) of the estrogen produced during the luteal phase of the cycle is produced by
the corpus luteum that results from this follicle