What is the use of the ovary, and how can stem cells solve the ovarian crisis in modern women?

Written by: Nanshan Xiaoxian

Source: Stem Cell Man said

●  　  ●    　●

Xiaoxian's good friend Junjun finished a physical examination and came to consult about ovarian problems
.

Junjun: The six data of AMH and sex hormones in my physical examination report are normal, right?

Xiaoxian: It's normal
this time.

Junjun: Aren't the great aunt afraid if she doesn't come? Aren't you afraid of premature ovarian failure?

Xiaoxian: This issue of popular science, let me understand for you!

Confused big sister

With the progress of the times, the status of women in the family and society has been significantly improved
.
However, in fertility, no matter how hard women try, they cannot have equal rights with men
.
Human fertility is a function that nature gives to men and women, but the time for female fertility is more short-lived:

Due to the limitation of fertility time, many women are forced to give up the opportunity for job promotion and career development, and give priority to solving fertility problems, otherwise they will face the birth risk of advanced maternal age
.
Only by extending the time of female fertility for another 5~10 years can we achieve equal rights for men and women in the true sense, and can we better enjoy the future centenarian life
.

-01-

Mature ovarian function in women

Now, let's get down to business
.
Let's start
with the ovaries of women.
The so-called "ovary" refers to a pair of gonads in the female animal that produce eggs
.
Human ovaries are flattened oval, grayish-pink, and shaped like large grapes
.
The ovaries have two major physiological functions, one is to produce and discharge egg cells, and the other is to secrete sex hormones (estrogen and progesterone).

At different stages of a woman's life, the function and morphology of the ovaries vary
greatly.
When a woman is an embryo, the ovaries begin to develop
.

At 6-8 weeks of embryos, the primitive germ cells are constantly dividing and increasing in number
.
Between 16 weeks and 6 months after birth, primary oocytes form primordial follicles
.
At 20 weeks of embryos, the maximum number of primordial follicles is about 7 million, after which degenerative atresia occurs, and the primordial follicles gradually decrease.

When a newborn is born, there are about 2 million basal follicles
.
As we age, most follicles degenerate, and by puberty only about 300,000 remain.

The primordial follicle is the only form of egg cell reserve and is the basic reproduction
for females.

With the development of the female body, the follicles begin to mature and secrete estrogen, the mature eggs are regularly discharged, the ovarian function tends to mature, and "menstruation"
begins to form.
At this time, the month is often irregular, and after about 5-7 years of establishing periodic ovulation, menstruation is normal and women officially enter the reproductive period
.
It generally starts around the age of 15 and lasts about 30 years
.

The sex hormones synthesized and secreted by the ovaries are mainly estrogen, progesterone and other hormones and a small amount of androgens
.
Higher levels of estrogen maintain female reproductive function and change
periodically.
Lower levels of estrogen can maintain the development
of female secondary sex characteristics.

Environmental pollution, life pressure, and bad living habits have caused the number of female patients with premature ovarian failure in China to increase year by year, and premature ovarian failure is an important cause of
female infertility.

Therefore, Xiaoxian said: Please pay attention to ovarian function at a young age to avoid premature ovarian failure

-02-

Aging of ovarian function in women

When the ovaries are old, it not only affects the reproductive function of women, but also causes related diseases
of other target organs or systems due to the decline of endocrine function.
The two major threats to women's reproductive health by premature ovarian failure are reduced estrogen levels and loss of fertility, which increases a woman's risk of
osteoporosis and coronary heart disease.
Women in the reproductive period have early amenorrhea, loss of fertility, and are prone to depression, anxiety and other psychological problems
.

The ovaries are a warm house for human beings to give birth to new life, but some women are still in the reproductive period, and premature ovarian failure leads to infertility and loss of the possibility
of reproduction.
Premature ovarian failure (POF) refers to ovarian failure due to a variety of causes before the age of 40, which is considered an "incurable disease"
that causes infertility.

The anatomical and cellular basis of ovarian aging is a decrease in the number and quality of follicles.

With age, the number of oocytes continues to decrease, the quality of eggs decreases, the volume of ovaries continues to shrink, the epidermis of ovarian tissue changes, papillae and crypts are less common, epidermal cell microvilli become less and shorter, and the number of apoptosis and necrotic cells gradually increases
.
Eventually, due to depletion of the primary follicles, the ovaries fail until menopause
.
Women at this stage are affected by reduced estrogen levels, which often manifest as hot flashes, sweating, emotional instability, depression or irritability and insomnia
.

Common symptoms of menopause in women

The natural conception ability of normal women disappears at about the age of 41, and the average age of menopause for Chinese women is about 52 years old
.
Women begin to undergo menopausal transition at the age of 40, which lasts about a few years or decades
.
Ovarian aging is very harmful to the female body, especially the loss of ovarian function after menopause, endocrine disorders, may cause organ and multi-system dysfunction (the occurrence of genitourinary system, cardiovascular system and nervous system diseases), and seriously affect family happiness and women's healthy life expectancy
.

Therefore, Xiaoxian suggests: after menopause, regular physical examination is particularly important
.
The risk of ovarian cancer is relatively increased
after menopause.
A simple ultrasound can help you detect ovarian tumors early for early diagnosis and treatment
.

-03-

How to tell if ovarian function is declining

The ideal ovarian function evaluation and prediction system is a characteristic indicator that can directly / indirectly reflect ovarian function, or protect or damage the ovaries.

At present, the indicators commonly used for ovarian function evaluation are endocrinological indicators and imaging indicators, mainly from the level of ovarian hormones and the change of follicle number as the main indicators
.

In summary, the indicators for judging ovarian aging are shown in the following table
.
The most widely used indicators are AMH and sex hormones, which can roughly determine whether ovarian function has
declined.

Table: Ovarian function evaluation and prediction system (drawn by Nanshan Xiaoxian himself)

AMH: anti-Muller's hormone; FSH: follicle-stimulating hormone; FSH/LH: follicle-stimulating hormone/luteinizing hormone; E2: estradiol; Inbibin B: inhibin B; Activin: activin; CCCT: clomiphene citrate stimulation test; GAST: gonadotropic technique release technique agonist stimulation test; EFORT: exogenous follicle estrogen ovarian reserve test; AFC: number of antral follicles; OV: ovarian volume; DHEA: dehydroepiandrosterone; IGF-I: IGF-I

Therefore, Xiaoxian once again suggests: after the age of 35, it is best to add ovarian function testing to the physical examination project to facilitate understanding of their ovaries, and if there is an abnormality, they can also intervene
early.

-04-

Biotechnology to repair ovarian function

I believe that with advances in biomedicine, the gap between men and women in reproduction will become smaller and smaller, and women will have more
choices in terms of reproductive age.

At present, there are many ways to delay premature ovarian failure or restore ovarian function
.
Below, we will introduce
you to the potential technologies related to biomedicine.

 1 

Stem cell technology

Ovarian function aging is a major problem
in today's medicine.
For ovarian aging, stem cell treatment has its unique advantages, and 6 stem cell clinical research projects
have been launched in China.
Cell sources include mesenchymal stem cells, amniotic epithelial cells, and embryonic stem cells
from various sources.

▉Mesenchymal stem cells

At present, the most studied sources of mesenchymal stem cells include: bone marrow source, umbilical cord source, peripheral blood source, placental source, amniotic membrane and fat source, etc
.
Among them, the Reproductive Medicine Center of Nanjing Gulou Hospital and the team of Professor Dai Jianwu of the Institute of Genetics and Development of the Chinese Academy of Sciences carried out clinical research projects such as "Clinical Research on Umbilical Cord Mesenchymal Stem Cell Treatment of Early-onset Ovarian Insufficiency" and "Clinical Research on Umbilical Cord Mesenchymal Stem Cell Transplantation Intervention in Patients with Premature Ovarian Failure and Infertility", mainly focusing on stem cell therapy
for ovarian function.

It is worth mentioning that the combination of stem cells and biomaterials has become a good remedy for the treatment of premature ovarian failure, solving many problems
.
Professor Dai Jianwu's team has designed and developed injectable smart collagen scaffold materials for ovarian function regeneration, which has been successful
.
In January 2018, the subject successfully gave birth to a baby
boy in Nanjing Gulou Hospital.
The collagen scaffold material combines stem cells, which not only utilizes the paracrine effect of stem cells, but also combines transplanted stem cells to maximize their retention in the damaged area and avoid the spread
of cells.

A large number of pre-clinical data and clinical data show that mesenchymal stem cells from different sources have similar efficacy in the treatment of premature ovarian failure, mainly by improving the microenvironment of ovarian tissue, immune regulation, promoting the development of follicles into granule cells, and promoting the phased recovery of ovarian function and fertility in patients with premature ovarian failure.

▉ Pluripotent stem cells

The treatment of premature ovarian failure by functional cells derived from pluripotent stem cells is also a hot topic
in stem cell therapy.
Pluripotent stem cells have strong multidirectional differentiation potential and have been directed induction into sperm or oocytes in mice
.
In addition, differentiation into other cells that help support ovarian function, such as mesenchymal stem cells
, can also be induced.
The team of Academician Zhou Qi of the First Affiliated Hospital of Zhengzhou University and the Institute of Zoology, Chinese Academy of Sciences carried out the "Clinical Tolerability Study of Human Embryonic Stem Cell-derived Mesenchymal-like Cells in the Treatment of Primary Ovarian Insufficiency", which is also the use of embryonic stem cell-derived mesenchymal-like cells, and clinical research is still being recruited
.
Not long ago, the top international journal "Nature" also reported that Japanese scientists successfully used the induced pluripotent stem cells of mice to cultivate a large number of eggs and successfully reproduce offspring
.

Xiaoxian believes that the current stem cell treatment of ovarian aging mainly focuses on the following two points:

 2 

Mitochondrial transplantation

Ovarian dysfunction is one of the important factors that lead to a decline in women's quality of
life.
Oocyte mitochondria are the place where oocytes undergo oxidative metabolism, provide energy for the maturation and fertilization of oocytes, and are of great significance
for the normal development and proliferation of oocytes.
At the same time, mutations in the mitochondrial DNA (mtDNA) of oocytes may impaired the metabolic function of the oocytes and die
.

▉ Mitochondrial replacement therapy

Mitochondrial replacement therapy (MRT): The nucleus of an egg or fertilized egg is implanted into
a donor's nucleus-removed egg cell.
In 2015, the UK approved MRT, becoming the first country
in the world to allow the technology for clinical use.
There are three types of mitochondrial replacement therapy: oocytoplasmic transfer, prokaryotic transfer, and polar body transfer
.

ooplasmic transfer (OT): Part of the cytoplasm of a young donor oocytes is transferred into an old recipient oocytes in the hope of improving the normal fertilization and development of the oocytes or
embryos.

Pronuclear transfer: On the day of fertilization, the nucleus in the fertilized egg is transferred to a donor egg containing healthy mitochondria (the nucleus has been removed).

Polar body transfer (PBT): The polar body is used as the maternal nuclear donor to complete the nuclear transfer process
before or after fertilization.
Because the polar body carries only a very small amount of egg cytoplasmic components, it carries very little maternal mitochondrial genetic material, thus increasing the safety of
transplantation.

 3 

gene therapy

About 10% of premature ovarian failure comes from genetic factors, including mutations in sex chromosomes and autosomes
.
Clinically, hormone therapy is mainly adopted, but the treatment does not cure the root cause and cannot fundamentally solve the fertility problem
.
If gene editing is used, "correcting" the genetic mutations that induce premature ovarian failure is undoubtedly the best hope
.
Limitations of gene vectors, off-target effects, and ethical issues all influence the development of
gene therapy.
With the discovery of gene mutations that induce premature ovarian failure (BRCA1, BRCA2, SA-Like4, BNC1, etc.
), more researchers have entered this research field, looking forward to solving the problem
of premature ovarian failure from the genetic level.

 4 

In vitro activation of follicles

In vitro activation (IVA) refers to the technique
of applying signaling pathway activators in vitro to instantaneously treat ovarian tissue to activate primordial follicles in the ovaries.
There are usually ovarian tissue cryotransplants and fresh ovarian tissue transplants
.
Cryopreserved or fresh ovarian tissue is activated in vitro to complete the activation of the primordial follicle and transform it into the primary follicle to trigger the development of the follicle in combination with the technique of ovulation induction to obtain mature follicles.

At present, in vitro activation technology is mainly used for the treatment of patients with residual primitive follicles in the ovaries, and can also be used for in vitro activation of frozen ovaries in cancer patients, and dozens of cases of live birth in patients with early-onset ovarian insufficiency have been reported
so far.

-05-

Summary and outlook

Pay attention to ovarian aging, women are as positive and enthusiastic as they are about weight loss, but delaying ovarian aging is 1000 times
more difficult than weight loss.
It's a subject
for doctors and scientists to study.

Knocking on the blackboard, Xiaoxian has something to say:

Stem cell technology or other technologies, no matter which technology, it is a technology that countless women dream of restoring ovarian function, hoping to enter clinical application
as soon as possible.
I believe that in the future, biomedicine will allow 50-year-old women to have healthy babies
.
The future is bright and tortuous, and everything is waiting for the development of
technology.

References (omitted).

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