In humans, oogenesis begins in
embryonic development with the transformation of
oogonia into primary oocytes, a process called oocytogenesis. From one single oogonium, only one mature oocyte will rise, with three other cells called polar bodies. Oocytogenesis is complete either before or shortly after birth.
Number of primary oocytes It is commonly believed that, when oocytogenesis is complete, no additional primary oocytes are created, in contrast to the male process of spermatogenesis, where gametocytes are continuously created. In other words, primary oocytes reach their maximum development at ~20 weeks of gestational age, when approximately seven million primary oocytes have been created; however, at birth, this number has already been reduced to approximately 1-2 million per ovary. At puberty, the number of oocytes decreases even more to reach about 60,000 to 80,000 per ovary, and only about 400500 mature oocytes will be produced during a woman's life, the others will undergo atresia (degeneration). Two publications have challenged the belief that a finite number of oocytes are set around the time of birth generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. The renewal of ovarian follicles from germline stem cells (originating from bone marrow and peripheral blood) has been reported in the postnatal mouse ovary. In contrast, DNA clock measurements do not indicate ongoing oogenesis during human females' lifetimes. Thus, further experiments are required to determine the true dynamics of small follicle formation.
Ootidogenesis The succeeding phase of
ootidogenesis occurs when the
primary oocyte undergoes meiosis to develop into an
ootid stage of an immature ovum. However, although this process begins at prenatal age, it stops at
prophase I. In late fetal life, all oocytes, still primary oocytes, have halted at this stage of development, called the
dictyate. After
menarche, these cells then continue to develop, although only a few do so every
menstrual cycle.
Meiosis I Meiosis I of ootidogenesis begins during embryonic development, but halts in the
diplotene stage of prophase I until puberty. The mouse oocyte in the dictyate (prolonged diplotene) stage actively repairs DNA damage, whereas DNA repair is not detectable in the pre-dictyate (
leptotene,
zygotene and
pachytene) stages of meiosis. For those primary oocytes that continue to develop in each menstrual cycle, however,
synapsis occurs and
tetrads form, enabling
chromosomal crossover to occur. As a result of meiosis I, the primary oocyte has now developed into the
secondary oocyte.
Meiosis II Immediately after meiosis I, the
haploid secondary oocyte initiates
meiosis II. However, this process is also halted at the
metaphase II stage until
fertilization, if such should ever occur. If the egg is not fertilized, it is disintegrated and released (
menstruation) and the secondary oocyte does not complete meiosis II (and does not become an
ovum). When meiosis II has completed, an ootid and another polar body have now been created. The polar body is small in size.
Ovarian cycle The ovarian cycle is divided into several phases: •
Follicologenesis: Synchronously with
ootidogenesis, the
ovarian follicle surrounding the ootid has developed from a
primordial follicle to a preovulatory one. The
primary follicle takes four months to become a preantral, two months to become antral, and then passes to a mature
(Graaf) follicle. The primary follicle has
oocyte-lining cells that go from floor to cubic and begin to proliferate, increasing the
metabolic activity of the oocyte and
follicular cells, which release
glycoproteins and
proteoglycans acids that will form the
zona pellucida, which accompany the installation. In the preantral
secondary follicle, internal and external
theca cells begin to form.
Aromatase, produced by follicular cells, transforms
androgens produced by the inner theca into
estrogens under the stimulation of
FSH.
LH stimulates theca cells to produce androgens. In the
antral follicle, there is an
antrum containing a follicle liquor, which contains estrogen, to allow the passage from the antral follicle to the Graaf follicle. The follicular antrum moves the oocyte and becomes eccentric; the oocyte is always surrounded by the pellucid zone and by follicular cells that form the
cumulus oophorus. The innermost ones are called the
corona radiata or radiated corona cells. At this stage, the oocyte produces
cortical granules containing acid
glycoproteins. • Dominant follicle selection: The follicle with more FSH receptors will be more favored, simultaneously inducing the death of the other follicles (3-10 antral follicles that enter this phase each month). Low concentration estrogen will inhibit further production of FSH by the
pituitary gland with negative feedback, so the follicles left behind will accumulate in the follicular antrum instead of androgens. • Graaf follicle: Estrogen at other concentrations induces LH release, with the peak of LH called
LH surge, which induces stages that will lead to follicle burst. LH receptors also appear on follicular cells, which stimulate the oocyte to become a
secondary oocyte, blocked in
metaphase, waiting for
fertilization. LH also stimulates oophore cumulus cells to release
progesterone. •
Ovulation: bursting of the follicle, oocyte leakage with pellucid zone, and radiated corona cells. The lining membrane is thinned on the
ovary where the follicle bursts and the cells attached to it emerge from the stigma. The ovary is collected from the
uterine tube, where fertilization can take place in the
ampullate zone, the widest part of the oviduct where fertilization typically occurs. • Formation of the
corpus luteum: From the remaining structures of the follicle, the corpus luteum is formed. At first, there is a clot, which is then replaced by
loose connective tissue; the cells that form solid cords are follicular cells and cells of the [outer theca (Tecali lutein cells) and internal (
granulosa cells). The luteal body increases the concentration of progesterone, which LH constantly stimulates. If the egg is not fertilized, the corpus luteum degenerates (
corpus albicans); if it is implanted, it remains until three months of pregnancy, where its function is replaced by the
placenta (production of progesterone and estrogen). The level of LH (necessary to keep the corpus luteum alive) is replaced by
human chorionic gonadotropin.
Uterine cycle The uterine cycle occurs parallel to the ovarian cycle and is induced by estrogen and progesterone. The
endometrium, formed by a monostratified cylindrical epithelium, with
uterine glands (simple tubular), connective with a functional superficial layer (divided into a spongy layer, a compact layer, and a deeper basal layer, which is always maintained, presents four phases: • Proliferative phase: From the 5th to the 14th day of the
ovarian cycle, it is conditioned by
estrogens. The functional layer of the uterus is restored, with mitotic division of the basal layer. • Secretive phase: from the 14th to the 27th day of the ovarian cycle, influenced by the
progesterone produced by the
corpus luteum. Cells become
hypertrophic, and tubular glands begin to produce glycogen • Ischemic phase: beginning of the menstrual phase from 27 to 28 days • Regressive or desquamative phase from 1 to 5 days, the spiral-shaped arteries undergo
ischemia, and the functional layer detaches If, instead, there is fertilization, the uterine mucosa is modified to accommodate the fertilized egg, and the secretive phase is maintained.
Maturation into ovum Both polar bodies disintegrate at the end of
meiosis II, leaving only the ootid, which then eventually undergoes maturation into a mature ovum. The function of forming polar bodies is to discard the extra haploid sets of chromosomes that have resulted as a consequence of meiosis.
In vitro maturation In vitro maturation (
IVM) is the technique of letting
ovarian follicles mature
in vitro. It can potentially be performed before an
IVF. In such cases,
ovarian hyperstimulation is not essential. Rather, oocytes can mature outside the body prior to IVF. Hence, no (or at least a lower dose of) gonadotropins have to be injected in the body. Immature eggs have been grown until maturation
in vitro at a 10% survival rate, but the technique is not yet clinically available. With this technique, cryopreserved ovarian tissue could possibly be used to make oocytes that can directly undergo
in vitro fertilization. In 2016, two papers published by Morohaku et al. and Hikabe et al. reported in vitro procedures that appear to reproduce efficiently these conditions allowing for the production, completely in a dish, of a relatively large number of oocytes that are fertilizable and capable of giving rise to viable offspring in the
mouse. This technique can be mainly benefited in
cancer patients where in today's condition their
ovarian tissue is
cryopreserved for preservation of fertility. Alternatively to the
autologous transplantation, the development of culture systems that support oocyte development from the
primordial follicle stage represent a valid strategy to restore
fertility. Over time, many studies have been conducted with the aim to optimize the characteristics of ovarian tissue culture systems and to better support the three main phases: 1) activation of primordial follicles; 2) isolation and culture of growing preantral follicles; 3) removal from the follicle environment and maturation of oocyte cumulus complexes. While complete oocyte in vitro development has been achieved in mouse, with the production of live offspring, the goal of obtaining oocytes of sufficient quality to support embryo development has not been completely reached into higher mammals despite decades of effort. ==Ovarian aging==