Lakhasly

By 12 weeks of gestation some germ cells (oogonia) start to
enter into meiosis and become primary oocytes surrounded
by flattened granulosa cells to form primordial follicles. The
primary oocytes are arrested in the prophase stage of the first
meiotic division (diploid cell). The remaining oogonia have
ongoing cycles of mitosis and reach a peak number of 5–6 million
at 20 weeks’ gestation.
The few primary oocytes that survive are those that are
surrounded by flat, spindle-shaped follicular or pregranulosa
cells. This oocyte–pregranulosa cell complex is enclosed
by a basement lamina. At this stage of development, the primary
oocyte with its surrounding single layer of pregranulosa
cells is called a primordial follicle. Primordial follicles are
30–60 μm in diameter. The first primordial follicle usually
appears around 6 weeks into intrauterine life, and the generation
of primordial follicles is complete by about 6 months
after birth.3,4
The first step in follicular growth is that a primordial follicle
becomes a primary follicle. The primary follicle forms as
the spindle cells of the primordial follicle become cuboidal
cells. In addition, the oocyte enlarges. Thus, the primary follicle
contains a larger primary oocyte that is surrounded by a
single layer of cuboidal granulosa cells.
The secondary follicle contains a primary oocyte surrounded
by several layers of cuboidal granulosa cells. The
granulosa cells of a primary follicle proliferate and give rise to
several layers of cells. In addition, stromal cells differentiate,
surround the follicle and become the theca cells. These theca
cells are on the outside of the follicle’s basement membrane.
The oocyte increases in size to a diameter of about 120 μm.
As the developing follicle increases in size, the number of
granulosa cells increases to about 600, and the theca cells
show increasing differentiation. The progression to secondary
follicles also entails the formation of capillaries and an increase
in the vascular supply to developing follicular units.
The increasingly abundant granulosa cells secrete fluid into
the centre of the follicle creating a fluid-filled space called the
antrum. At this stage, the follicle is now called a tertiary follicle.
In tertiary follicles, gap junctions are formed between
theca and granulosa cells. In addition, tight junctions and
desmosomes
exist between adjacent cells. Gap junctions may
also exist between the oocyte and the granulosa cells closest
to the oocyte and may function as channels to transport
nutrients and paracrine signals from the granulosa cells to
the oocyte and vice versa. The granulosa cells closest to the
oocyte also secrete a layer of mucopolysaccharides (the zona
pellucida).
These stages occur independent of gonadotrophin stimulation
and under the effect of local autocrine and paracrine
factors such as growth differentiation factor (GDF) and anti-
Müllerian hormone (AMH). The latter is produced from the
granulosa cells and reaches the systemic circulation in levels
proportional to the secondary follicle pool. In the absence of
further gonadotrophin stimulation the secondary follicles
undergo apoptosis and atresia.
This process of gonadotrophin-independent recruitment
to secondary follicles and apoptosis in absence of gonadotrophins
is continuous during intrauterine, pre-pubertal
and reproductive life till depletion of the follicular pool at
the age of menopause. Unlike spermatogenesis, the atretic
follicles cannot be replenished; therefore the ovarian
reserve of follicles is a finite pool. On average the number
of primordial
follicles is about 1–2 million at birth and
decreases to about 400,000 at initiation of puberty and is
less than 1000 by the age of menopause, with only about
500 oocytes destined to ovulate during a woman’s reproductive
lifespan. The rate of loss of the primordial follicle pool
is variable among individual females, with variable age of
loss of fertility and menopause (40–55 years). It is believed
that natural fertility is lost around 10 years earlier than the
age of menopause (fixed-interval hypothesis). The duration
of the gonadotrophin-independent phase is around
74–80 days