Menopause, mentruation, and aging

[GenGenimney]

There seems to be some confusion about possible mechanisms for continuing fecundity in mice under CR into old age, and I've seen suggestions in various places that CR might theoretically extend fertility in women.  

 

This isn't possible.

 

As far as reproduction goes...mice aren't human.  Here's an overview of folliculogenesis:  https://en.wikipedia.org/wiki/Folliculogenesis

 

Other than the solid overview, a point of interest is under "number of follicles."  The short version is this:  Humans don't produce more follicles after birth, period.

 

There is also a common misconception that I've seen that an anovulatory woman is somehow preserving/reserving her follicles for later recruitment.  This also simply isn't true.  Follicles are recruited continuously into the first stages of development roughly a year before ovulation.  If they pass through the upper stages without being subject to the right dose of FSH for recruitment into antral follicles, they will simply suffer from atresia and die.  Similarly, the "best" of the antral follicles--meaning the one that has the most FSH receptors at the time of FSH increase--will be the only one large enough to respond to a surge of LH and burst, causing ovulation.

 

Amenorrhea from any cause doesn't prevent or slow or otherwise attenuate the first stage of follicle recruitment.  Therefore, it has zero chance of either extending fertility or delaying menopause.

 

Damage to the ovaries, often from a chemical insult, can lower the number of primordial follicles and can potentially speed up menopause because low ovarian reserve is a major trigger for menopause.  Two major causes of a low number of primordial follicles are high androgens in utero and chemotherapy.  

 

Regardless of one's starting place, as the number of follicles for recruitment are depleted, so is a woman's fertility.  This process begins in one's early 20s--yes, early 20s!--and is complete by age 45 in most women.

 

Women need to understand that there is no benefit whatsoever from amenorrhea from any cause whatsoever to the aging process or to fertility length.  That said, amenorrhea can be perfectly normal and healthy--obviously during pregnancy but also during breastfeeding--and there is considerable benefit by lowering the risk of "female" cancers in this type of amenorrhea.  

 

However, amenorrhea from PCOS or from low weight/exercise/stress is pathological.  In the case of true, classic PCOS, it shows up with insulin insensitivity.  In the case of low eight/exercise/stress, it can rapidly deplete bone density, which can cause crippling and even deadly complications beginning as early as shortly after menopause, which will occur the same number of years after puberty regardless of your menstruation status.

[Michael R]

There seems to be some confusion about possible mechanisms for continuing fecundity in mice under CR into old age, and I've seen suggestions in various places that CR might theoretically extend fertility in women.  

 

This isn't possible.

 

As far as reproduction goes...mice aren't human.  Here's an overview of folliculogenesis:  https://en.wikipedia.org/wiki/Folliculogenesis

 

Other than the solid overview, a point of interest is under "number of follicles."  The short version is this:  Humans don't produce more follicles after birth, period.

This is still widely believed amongst clinicians, and there are still a significant number of reproductive biologists who believe it, but there is now substantial evidence that this isn't true: that in humans and rodents alike, the issue is not that no follicles are generated, but that they are inhibited from behaving as follicles (initiating new oocyte production) by factors in the local environment of the niche, or by damage to the (putative) resident germline stem cells. This was first suspected because of reports of young female cancer survivors who had been rendered menopausal by radiation or chemotherapy, but who subsequently exhibited restored ovarian function after haematopoietic stem cell transplantation.

 

Egg-making stem cells found in adult ovaries

Kendall Powell

 

For 60 years, everyone from high-school biology teachers to top fertility specialists has been operating under the assumption that women are born with all the eggs they will ever produce, with no way to replenish that supply. But the discovery of human egg-producing stem cells, harvested from the ovaries of six women aged 22 to 33, puts that dogma in doubt.

 

The work, published online in Nature Medicine by Jonathan Tilly and colleagues at Massachusetts General Hospital in Boston, parallels the findings of a Shanghai-based group that isolated similar stem cells from mice in 2009. However, both this and Tilly’s earlier work in mice remained controversial, with many experts sceptical that such stem cells existed.

 

“This is unequivocal proof that not only was the mouse biology correct, but what we proposed eight years ago was also correct — that there was a human population of stem cells in young adult tissue,” says Tilly. ...

 

To address the doubts, Tilly’s team began by developing a more sensitive method for identifying and collecting mouse ovarian stem cells. Their method, based on a technique called fluorescence-activated cell sorting (FACS), attaches a fluorescently labelled antibody to a protein, Ddx4, that is present on the outer surface of the stem cells but not on the surface of the later-stage egg cells or oocytes. The FACS instrument lines up cells in single file and sorts them one by one, separating the labelled ones from the rest; it also gets rid of dead or damaged cells, such as oocytes, in which internal Ddx4 might become accessible to the antibody. This method is more selective than previous isolation methods, which did not get rid of such cells.

 

Once the team confirmed that it had isolated mouse ovarian stem cells by this method, it set its sights on reproductive-age human ovaries. ... [using] frozen whole ovaries removed from sex-reassignment patients, all young women of reproductive age ... cells they pulled out, called oogonial stem cells (OSCs), spontaneously generated apparently normal immature oocytes when cultured in the lab. To look at the development of the putative human OSCs in a more natural environment, the team labelled the cells with green fluorescent protein to make them traceable, and injected them into fragments of adult human ovarian tissue, which were then transplanted under the skin of mice. After one to two weeks of growth, the OSCs had formed green-glowing cells that looked like oocytes and that also expressed two of the genetic hallmarks of this cell type.

 

“There’s no confirmation that we have baby-making eggs yet, but every other indication is that these cells are the real deal — bona fide oocyte precursor cells,” says Tilly. The next step, to test whether the human OSC-derived oocytes can be fertilized and form an early embryo, will require special considerations — namely, private funding to support the work in the United States (federal funding cannot by law be used for any research that will result in the destruction of a human embryo, whatever the source of the embryo) or a licence from the UK Human Fertilisation and Embryology Authority to do the work with collaborators in the United Kingdom....

 

She notes that there’s still no evidence that the OSCs form new eggs naturally in the body. However, if they could be coaxed in a dish to make eggs that could successfully be used for in vitro fertilization (IVF), it would change the face of assisted reproduction. ... t could mean an unlimited supply of eggs for women who have ovarian tissue that still hosts OSCs. This group could include cancer patients who have undergone sterilizing chemotherapy, women who have gone through premature menopause, or even those experiencing normal ageing. Tilly says that follow-up studies have confirmed that OSCs exist in the ovaries of women well into their 40s.

 

In addition, growing eggs from OSCs in the lab would allow scientists to screen for hormones or drugs that might reinvigorate these cells to keep producing eggs in the body and slow down women’s biological clocks. “Even if you could gain an additional five years of ovarian function, that would cover most women affected by IVF,” notes Tilly.

 

Ovarian germline stem cells.

 

It has long been established that germline stem cells (GSCs) are responsible for lifelong gametogenesis in ... some  ... lower vertebrates (for example, teleost fish and some prosimians)  ... However, accumulating evidence demonstrates the isolation and culture of putative GSCs from the ovaries of adult mice and humans. Live offspring have been reportedly produced from the culture of adult mouse GSCs, and human GSCs formed primordial follicles using a mouse xenograft model. If GSCs were present in adult female ovaries, it could be postulated that the occurrence of menopause is not due to the exhaustion of a fixed supply of oocytes but instead is a result of GSC and somatic cell aging. Alternatively, they may be benign under normal physiological conditions.  ... GSCs ...  may have a role in the field of fertility preservation, with women potentially being able to store GSCs or GSC-derived oocytes from their own ovaries prior to infertility-inducing treatments. Essential future work in this field will include further independent corroboration of the existence of GSCs in female mammals and the demonstration of the production of mature competent oocytes from GSCs cultured entirely in vitro.

 

If this is true, CR in mice and potentially humans may be acting by preserving the number or quality of GSCs, or sustaining the integrity of the niche or the systemic environment during aging.