Your periods are all over the place, you’ve struggled with weight, you’re intimidated by your own toe hair, but whenever you mention PCOS to anyone they assume you’re just worried about lumpy ovaries.
Researchers and doctors have also spent years feeling grumpy because of PCOS. Not because of the symptoms, but because of the confusing name.
For the past decade they’ve been working to rename PCOS to something that isn’t so focused on the lady parts but describes a complex systemic condition that affects hormones all throughout the body.
Now they’ve come up with one: Polyendocrine Metabolic Ovarian Syndrome.
But who is Poly, and why can’t she describe herself in fewer than 15 syllables?
PMOS before bros
The first clues to how PMOS/PCOS happens (we’ll go with PMOS from now on) actually came from researchers trying to work out how mice become manly.
Like most hormones, AMH has lots of little jobs to do in lots of different places.
“AMH [anti-Müllerian hormone] has a definite role in male embryology and male physiology,” begins Joop Laven, Professor of Obstetrics and Gynaecology at the Erasmus University Medical Center, past President of the Dutch Society of Reproductive Medicine and the Androgen Excess and PCOS society, and one of the world’s leading experts of PMOS.
One of AMH’s most well-known jobs is to stop embryos with a Y chromosome from developing a uterus or fallopian tubes (the Müllerian ducts).
“To get a little bit more insight into what the role specifically was, we made AMH knockout mice [mice that were genetically engineered to have no AMH] … These animals were still capable of having offspring. Some of the offspring were, of course, males, and they had the phenotype [body type] which we anticipated [they had Müllerian ducts].”
“But some of the offspring were female. And looking into the female phenotype, we saw that these females lost their ovarian reserve dramatically fast. Within four weeks after birth [as teenage mice], there were no follicles in the ovaries of these females left.”
“So that was the first clue we had, that we never anticipated, that AMH would have a role in female ovarian physiology.”
Mind ova matter
“We started to do experiments which showed, actually, that AMH has three distinct roles in the ovary,” continues Joop.
Joop’s team showed that AMH helps the ovaries to release eggs in an orderly fashion (around once a month in women), and stops testosterone from converting into too much estrogen.
However, this finely-tuned system can go awry if AMH is dialled up, because then it controls the ovaries too tightly, and doesn’t allow enough testosterone to be converted into estrogen (which is where most women’s estrogen comes from).
This results in unpredictable menstrual cycles, too much spare testosterone, and masculinising effects.
“There’s also an effect of AMH on the brain” says Joop.
“The brain is differently functioning in women with [PMOS]. That’s a definite thing which we know.”
People with PMOS suffer higher rates of depression, anxiety disorders, low self esteem and attention deficit disorders. Some of this could be the direct result of AMH on the brain, but some of it could be the self-perpetuating hormonal imbalance PMOS instigates.
During the majority of a monthly menstrual cycle, a part of the brain called the hypothalamus releases Gonadotropin-Releasing Hormone (GnRH) in slow, regular pulses. GnRH then goes over to the pituitary gland and tells it to make a specific ratio of Follicle-Stimulating Hormone (FSH) and Luteinising Hormone (LH) (all of these hormones have very pragmatic names).
But mid-cycle, the hypothalamus releases GnRH in faster, stronger pulses, which prompts the pituitary gland to go all-in on the LH. Once released by the pituitary, FSH and LH pop down to the ovaries to respectively stimulate some follicles and trigger ovulation. This complicated but biologically essential game of telephone is called the hypothalamic–pituitary–gonadal axis.
AMH can get in the middle of this process because it affects the same neurons as GnRH usually would.
“The effect [of AMH] in the brain is probably disturbing your GnRH pulsatility [pulse pattern].” Joop states.
“Experimental animal studies have shown that … if you administer AMH to the midbrain, this … is leading to a release of predominantly LH and less FSH, which in turn stimulates theca cells [in the ovary] which are the main source for androgen production.
“The resulting lack of FSH might prevent adequate follicle stimulation and cause follicles to arrest in their growth.
“[This] causes follicles not to ovulate and to accumulate in the ovary, which again leads to more AMH production, [and] more androgen production.”
But that’s not the only way PMOS becomes a self-fulfilling prophecy.
“If AMH is also increasing your endogenous intraovarian androgen levels [the amount of testosterone your ovaries make], we know that that is also obstructing follicular growth in a way. So it’s a kind of vicious circle … you have already more follicles than normal, they produce more AMH, and that produces higher intraovarian androgen levels.”
In this way, AMH and testosterone literally egg each other on.
The pmositives of PMOS
Because AMH works so closely with the ovaries to manage their egg supplies, blood tests for AMH are sometimes used as proxy to figure out how many eggs a person might have left. And it turns out that PMOS might actually help eggs last longer, resulting in higher fertility later in life compared to people without PMOS.
“What you see is a lot of women with PMOS, is that around age 35 onwards, or 40 plus onwards, they get regular cycles because the phenotype seems to ameliorate [the effects of PMOS reduce].”
“And so it’s not a very uncommon finding that women with PMOS are still fertile between 40 and 45 years of age,” says Joop.
“It might be that there is an evolutionary advantage for PMOS,” he speculates.
“There have been a few studies done in which they looked at embryo quality [and PMOS]. What we know, of course, is that a lot of our patients [as gynaecologists] are somewhere around 40 or even older, [who] are trying to get pregnant through IVF, and they have fairly very low chances to become pregnant at the end of the day.
“And it has to do with the fact that embryo quality is compromised, because oocyte [egg] quality is compromised in these women. Although they have strict regular [menstrual] cycles, the oocyte quality is bad, and that is probably to do with DNA damage which [their bodies] do not properly repair.
“What we found in our genetic studies, which were done in Rotterdam and all over the world … [was that] women with PMOS are genetically better equipped to deal with DNA damage.
“In a specific study, which was done in … South Korea, they looked at embryo quality in women with PMOS. And that embryo quality did not decrease that much in these 40, 45 year old women with PMOS. So that gives you the impression that this DNA damage repair system, which is better in women with PMOS, also leads to more vital oocytes, resulting in better embryo quality.
“[One] problem which you can measure in these IVF embryos is aneuploidy – [a condition in which] the DNA amount is not correct. If you look at aneuploidy rates in women between 40 and 45 years of age, that approaches 80%, so there’s only 20% of embryos which have the proper DNA amount.
“In women with PMOS, it was exactly the opposite … in that specific study. [This demonstrates my] claim that DNA repair in women with PMOS is better, and therefore nature grants them a … prolonged reproductive lifespan.”
Being great at DNA repair doesn’t just mean that women with PMOS have better eggs than women of the same age. It might also help to mitigate the long-term health risks that tend to come with PMOS – cardiovascular disease, diabetes, high blood pressure, and obesity.
“If you can deal better with DNA damage, then you are probably much better equipped to deal with these risk factors,” suggests Joop.
“At the end of the day, they [the risk factors] might be there, but not impact that much on you because you have this better DNA repair.”
Like a scatterbrained fairy godmother, PMOS arrives mysteriously, offloads an armful of mixed blessings into your lap, and then enigmatically wanders off around middle-age.
“Later on in life, the system recovers, and a lot of the PMOS features disappear,” says Joop.
“The only remnant of PMOS which you see after menopause is slightly elevated … androgen levels.”
