Guest post by Dr. Felice Gersh
There has been a great deal of attention given to a recent study, published in Nature Medicine, involving collaboration between several centers in Europe. It has been widely celebrated as a breakthrough for women suffering with Polycystic Ovary Syndrome (PCOS), the most common endocrine dysfunction of reproductive-aged women (and a life-long condition).
The study is being touted as “the big one,” explaining how PCOS develops in utero. A huge deal is being made of their findings of persistently high levels during pregnancy of a hormone known as anti-mullerian hormone (AMH) and of the effects of injecting pregnant rats with AMH towards the end of pregnancy – leading to increased testosterone production in the injected rat mom-to-be.
AMH and its function
As this is an incredibly complex subject, to understand my take on this study, and to comprehend what I see as very erroneous assumptions being made from its findings, we must begin with an overview of AMH, a signaling agent and hormone produced by the ovaries. It’s a hormone getting much attention these days in the infertility and PCOS worlds.
Normally AMH levels fall during pregnancy, as ovarian function ceases due to the placenta taking over the job of hormone manufacturing. The discovery that ovaries can continue to make AMH during a pregnancy, as found in some lean PCOS patients in this study, is certainly a major and interesting discovery. It is important to acknowledge that only lean PCOS women had this finding. The majority of women with PCOS are overweight or obese, so this is not an insignificant point.
AMH can be viewed as a hormonal recruiter of follicles. It stimulates the ovarian development of follicles at the beginning of each menstrual cycle. These follicles then begin to produce more and more estradiol, the critical hormone of all things female, including the stimulus to that most essential feature of reproduction: ovulation.
Many follicles begin to develop with the onset of the menstrual cycle, following the onset of the period. This first half of the menstrual cycle is appropriately known as the follicular phase. The follicular phase lasts until ovulation occurs, after which the menstrual cycle shifts into the luteal phase. The follicular phase is marked by elevating levels of AMH, leading to the growth of several follicles, the increased production of the special form of ovarian-produced estrogen, or estradiol, and the selection of one very special follicle to fully mature and then eject the matured egg, with the goal being successful fertilization and a conceived baby. Once the “special follicle” is chosen, AMH levels fall and regression of the other “supporting” follicles occurs. Should AMH remain high, ovulation cannot occur and the follicles cannot regress and even more get recruited, hence the signature ultrasound appearance of the PCOS ovary – many small follicle cysts surrounding the ovary’s outside rim.
The cycle involves the following: rising levels of estradiol during the follicular phase culminate in a giant spike in the production of estradiol, typically on day 12 of the cycle, which then triggers an egg to be released, known as ovulation, a day or so later.
During the luteal phase, progesterone is produced, along with a lower level of estradiol production, all designed to support the evolution of the uterine lining, growing into a suitable condition for implantation and nourishment of the fertilized egg. If the egg isn’t fertilized, the production of estrogen and progesterone falls, the uterine lining sheds as the menstrual period ensues, and all begins again.
AMH plays a key role in the reproductive cycle of women. As I said already, it is key to recruiting the follicles. Each follicle contains a precious egg, and each woman is born with a finite number of eggs and with age, that number declines. Each month several follicles are called up by AMH. The follicles reside in certain special cells of the ovary, called granulosa cells. These cells contain a critical enzyme called aromatase. This enzyme converts testosterone into estrogen (estradiol).
The following statement is not widely recognized, including by physicians: ALL estrogen is produced from androgens (so-called male hormones, which exist naturally in women at approximately one-tenth the amount found in men). Testosterone is aromatized to create estradiol, the key estrogen of women.
A side note on estrogen before we continue. There are three types of estrogen: estradiol, the primary estrogen of reproductive women and the main one made by ovaries; estrone, a less healthy primary estrogen of postmenopausal women; and estriol, the estrogen produced by the placenta in large amounts during pregnancy.
Testosterone, as well as estrogen and progesterone, is produced in ovaries. In fact, half of the testosterone in a woman’s body is made in the ovaries, the other half comes from the adrenal glands. Testosterone is produced in special cells called theca-lutein cells, stimulated to do so by the pituitary hormone LH – the same hormone which stimulates the release of the special egg for ovulation. And AMH triggers the production of LH, as a means to getting more estradiol produced. LH can be viewed as a preliminary hormone, ultimately leading to the production of estrogen. And rising levels of estrogen ultimately lead to the down-production of AMH. It’s all part of a beautiful circuit of up and down feedback loops.
Once you understand the miracle of the menstrual cycle – the recruitment of follicles, the selection of the egg, the regression of the other follicles, the hormonal rhythms of estrogen and progesterone, and even of testosterone – you soon realize it is interconnected with the hormone AMH, and, certainly, issues associated with abnormal levels and production of AMH relate to the key features of the syndrome of PCOS. Below-average levels of estrogen lead to persistently high levels of AMH which in turn leads to persistently high levels of testosterone.
Why many are misinterpreting the study
The conversion of testosterone to estrogen and the down-regulation of AMH isn’t happening properly in women with PCOS. But AMH is not the cause of the problems. AMH production is just a response to the signals the follicles are receiving, rather than being the ultimate responsible cause. Association does not mean causation. The recently published study, with all the associated hoopla, is missing that key point! Finding high AMH levels in a small PCOS subset or injecting it during a pregnancy and seeing a few of the symptoms of PCOS develop in a rat, does not mean that it is the foundational cause of PCOS.
Another perspective on the study
Here is another synopsis of the AMH story and PCOS. The normal feedback system, designed to reduce the production of AMH, depends on rising levels of estradiol and of FSH. This doesn’t happen properly and consistently in women with PCOS. And here is why.
The testosterone in PCOS women is produced without a hitch by the theca-lutein cells. However, the granulosa cells do not produce estradiol well, so there is a deficiency of estradiol within the ovary itself and within the female body as a whole. This occurs because the enzyme aromatase isn’t working well and isn’t converting the testosterone into estradiol adequately. Rising estradiol levels are the feedback control designed to reduce the production of AMH, and to stop the further recruitment of follicles. Deficiency of estradiol means failure to put the brakes on AMH, along with the continued recruitment of follicles, and of course, this dysfunctional situation ultimately results in the absence of ovulation.
Meanwhile, the sensors of estradiol in the brain, located in the center called the hypothalamus, are acknowledging the deficiency of estradiol. So, what does the brain do to rectify the situation? It signals to the pituitary to release more LH, the hormonal signal telling the ovary to make more testosterone, on the mistaken assumption that with more testosterone available, the granulosa cells will do their job and aromatize lots of the testosterone into estradiol. But this doesn’t happen! On top of this, AMH itself triggers higher release of LH. Low levels of estrogen are produced, as there are inadequate amounts of FSH, the pituitary hormone whose job it is to get aromatization, converting testosterone into estradiol, done. And whatever FSH there is, it doesn’t necessarily work properly. There may even be something defective with the enzyme aromatase as well.
The complex underlying reasons for the deficiency in the production of estradiol and of FSH are not entirely understood yet, but they seem to be due to misprogramming of the receptors of these and other hormones, probably due to the presence of endocrine disruptors within the mom during her pregnancy with her daughter; ultimately, that grown up daughter becomes the PCOS woman we are discussing. The endocrine disruptor BPA has many negative effects on the ovaries, including being directly toxic to the eggs themselves and to the brain. Whatever the complex factors may be, genetically predisposed women are at the greatest risk.
Here is the ultimate summation: the beginning of a menstrual cycle has arrived, and a woman has several follicles recruited, all producing AMH. In the beginning of a menstrual cycle, this is supposed to occur, but in this woman with PCOS, the proper feedback needed to shut this process down as the menstrual cycle progresses just doesn’t occur. The higher and higher production of estradiol needed for this feedback system to work doesn’t happen. As it is the estradiol which is designed to provide the “brake” on the recruitment of follicles and production of AMH, abnormally low estradiol levels leave the system “brake-less.” Without the higher levels of estrogen, more and more follicles are recruited, none is chosen as the special one to ovulate, and the brain begins shouting at the ovary to make more estrogen, in the form of consistently high levels of LH. The high LH levels stimulate high production levels of testosterone, the precursor of estradiol and so the fateful cycle continues.
So do you now see this as it is? A woman with PCOS has high testosterone levels and high AMH levels. A signature finding of Polycystic Ovaries is lots and lots of tiny follicle cysts, lack of ovulation and hence lack of regular menstrual cycles, lower than normal levels of FSH and estradiol, but persistently high levels of LH.
AMH is a trigger to the brain to produce LH, as a function of its role in fostering estradiol production, and to provide down-regulation of itself to lower ovarian production of AMH. The high LH levels lead to even more testosterone production in the hope that there will be more estradiol produced.
The beautiful system known as the menstrual cycle has served humanity well for many thousands of years, but the correct functioning of this cycle depends on crucial hormonal levels to be perfectly controlled and regulated. Sadly, this is not the case in women with PCOS.
The body’s systems and mechanisms for self-regulation are truly amazing. But when things somehow get misprogrammed, and the finely tuned feedback regulating systems fail, true metabolic and reproductive chaos can follow. That is what is manifested as PCOS.
So, my analysis is this: all new information is wonderful and adds to our knowledge base. This study gives us more knowledge, and that’s a great thing. But it does not tell us how to cure PCOS, or how to prevent it. It simply tells us that AMH levels can be elevated in lean women with PCOS while they are pregnant. Rat studies show that injecting a pregnant rat with AMH in the last part of pregnancy causes testosterone levels to rise. Since we already know that is a specific function of AMH, that particular discovery should not be a shocking revelation.
It’s certainly not surprising that creating a drug is their first priority. That portents huge profits, and a drug to “cure” PCOS would be a blockbuster. But there will be no such curative drug coming from their study. They will not have one with such outstanding benefits. A drug which specifically blocks the production of LH, which is what they are working to develop, may indeed help women with PCOS artificially achieve a pregnancy or improve acne and hirsutism, which are all good goals, but it will not cure PCOS, and does not explain anything regarding the origins of PCOS over and above what we’ve already learned to date.
I don’t wish to be a party-pooper, but I must be honest with you. This new study is not the pot of gold at the end of the rainbow you’ve been dreaming of. It adds interesting information – and we need to be happy for that. Perhaps down the road they will have a drug which adds some benefit, though not a cure. Time will tell.
In the meantime, make the healthiest lifestyle choices, stay optimistic, laugh, develop human relationships, and know you are worth all the trouble and effort you are expending to be the best and healthiest woman possible.
Dr. Felice Gersh is one of only a small number of fellowship trained integrative gynecologists in the nation. She blends the best of the world of natural and holistic medicine with state of the art functional and allopathic medical treatment. Because of her extensive knowledge of the complex inter-relationships of the body’s organs, she recognizes the need to investigate all aspects of health, always working to re-establish a healthy gastrointestinal tract, adequate sleep, good mood, great nutrition, high energy, and balanced hormones.
Expert in all areas of women’s health, and particularly of gynecological and reproductive matters, Dr. Gersh deals in an integrative manner with such uniquely female issues as polycystic ovary disease (PCOS).
She is currently writing a book on Polycystic Ovary Syndrome and writing a chapter on the same topic for a medical textbook.
You may contact Dr. Gersh at:
Integrative Medical Group of Irvine, 4968 Booth Circle, Suite 101, Irvine, California 92604