Reproductive Endocrinologists have been trained for the most part to think of the 2 main causes of female anovulation/amenorrhea, or lack of ovulation/menstruation, to be fairly distinct entities, and in many respects they are. Polycystic Ovary Syndrome (PCOS) is a very common constellation of symptoms in women that is characterized by irregular cycles, excessive androgen production, and ovaries that possess an over-abundance of “resting” small follicles. Such women often tend to be obese or overweight, and close to 40% are either insulin resistant (pre-diabetic) or diabetic. Women suffering from hypothalamic amenorrhea (HA) tend to be lean and usually have an overly stressful lifestyle. Such stress can be emotional (“type A” personality, difficult working environment), physical (over-exercise), or nutritional (insufficient caloric intake, especially in fat calories). PCOS patients tend to overproduce hypothalamic GnRH, leading to increased pituitary LH production, which in turn leads to excessive ovarian androgens. Contrarily, HA patients tend to produce very little to no GnRH, FSH, or LH, leading to a very under-stimulated ovary that does not ovulate or produce any significant amount of estrogen.
Aside from absent ovulation/menstruation, the two couldn’t be any less alike, correct? As we often know in medical practice however, there are the classically described presentations of each disease that we come to know and use as our yardsticks, and then there is the reality we experience in which patients do not all readily fall into a nice neat category.
Research suggests that there may be a fluidity between PCOS and HA in many amenorrheic patients such that women may have significant cross-over between both entities. These patients tend to have low to no hormonal stimulation of the ovaries, but the ovaries intrinsically tend to move towards a polycystic state anyway and can even secrete an excess of androgens. What can cause this? Insulin resistance, hypothyroidism, as well as the daily stresses of life (that can lead to overproduction of the adrenal androgen DHEA) can catalyze an ovarian transition towards a polycystic appearance. Therefore these patients tend to appear at first glance like they have PCOS, but in actuality are a bit of a chimera.
Why does this matter? All of these women are amenorrheic aren’t they? Aren’t they all going to be stimulated to get the ovaries into gear?
It matters because if you have little to no natural ovarian stimulation (and as such low to no estrogen in your system) due to hypothalamic hibernation, taking medications like clomid or letrozole, that work by lowering one’s estrogen levels, will not work well, if at all. Such HA patients would be best served by altering their lifestyle to diminish any overt excessive stress, or, at the very least, use injections of gonadotropins.
It matters because the nature of the injectables that you use should be different between PCOS and HA patients that are undergoing ovarian stimulation. PCOS patients tend to have an excess of natural LH, and as such need little to no LH in their stimulation regimens. HA patients, on the other hand, have almost no natural LH production, and need significantly more in their stimulation protocols. Such patients often do better with a stimulation that incorporates hCG in daily tiny doses as it provides an LH like effect but with a much longer half-life.
It matters because the type of “trigger” shot that you use for these patients at the conclusion of their stimulation may or may not work depending on their diagnosis. Women with PCOS can respond nicely to a “trigger shot” of hCG as well as leuprolide, and often leuprolide is preferred as it tends to get the oocytes to mature well without fostering hyperstimulation symptoms of third space fluid retention and vascular dehydration. HA patients will not respond to a trigger shot of leuprolide and must be triggered with hCG. Therefore such patients who happen to assess polycystic appearing ovaries need to be stimulated with extra caution as there is no safety net option to use leuprolide to trigger pre-ovulatory oocyte maturation.
It matters because many doctors tend to presume that all overweight women with amenorrhea have PCOS and start them on an insulin-sensitizing medication like metformin for presumed insulin resistance. Often these women do not have PCOS, are not at an especially high risk for insulin resistance, and therefore would likely not need metformin. This provides a good argument to screen all oligomenorrheic/amenorrheic patients for insulin resistance rather than make presumptions about its presence, and to treat only those that truly need it.
In conclusion, the workup for amenorrhea should be comprehensive, and if dual features of HA and PCOS manifest in the assessment, the treatment plan should incorporate aspects that address both.