PCOS Part One: Follicle growth PCOS is one tough cook to crack. Women with PCOS have a difficult time conceiving and some cases involve scar tissue from cyst formation. I have treated several women in my practice with this problem. Treatment time is long, but acupuncture and herbs are successful in decreasing the amount of cysts and promoting ovulation. I thought it would be interesting to understand why cysts form and how it correlates with Chinese medicine. The first part of post will focus on how a follicle grows. To start with here are some definitions: Aromatized – an enzyme that is involved in producing estrogen. The enzyme converts testosterone or an androgen into estrodiol (an estrogen). Aromatizing occurs in the granulosa cells found in the follicle. Granulosa cells – form a single flattened layer around the oocyte (the part of the egg containing DNA) in the ovarian follicle. Later granulosa cells develop/grow under hormonal influences and result in follicle development (folliculogenesis). As the follicle nears ovulation the granulosa cells form a multilayered lining (called the cumulus oophorus) surrounding the oocyte.The major functions of granulosa cells include the production of steroids, as well as a myriad of growth factors thought to interact with the oocyte (egg) during its development. Also FSH stimulates granulosa cells to convert androgens (coming from the theca cells) to estrodiol by aromatase. Theca Cells– appear on the outer most layer of the follicle. The cells contain abundant collagen and are mainly supportive. Theca cells express receptors for luteinizing hormone (LH) and interact with the LH secreted by the pituitary. LH kicks off the production of androgens by the theca cells, most notably androstendione, which are aromatized by granulosa cells to produce estrogens, primarily estrodiol. Receptors – are similar to your car’s door lock. The door will only open when the right key is placed in the lock. Receptors in the body are built to recognize one hormone (i.e.: key). If the right hormone latches onto the receptor, it will turn on (i.e.: open the door) a particular chemical action. If the receptor is call a FSH receptor, then only FSH can “turn on” the receptor to activate the hormonal function, such as follicular growth. Most infertility drugs use receptors to control the IVF cycles. Some drugs activate the receptor to produce an action, such as Follistim which promotes follicular growth. Other drugs block receptors, such as GnRH antagonists, ganirelix, which block the pituitary from releasing LH/FSH. In this case, ganirelix is a key that fits into the lock, but can’t open the lock. If you can imagine: a key in the door of your car would stop you from placing the working key in lock. The hormone that could activate the receptor is unable to latch onto it, thus the receptor is blocked and can not be activated. Key Points of Follicular Development A follicle is a fluid-filled cystic structure in the ovary that contains an oocyte (the DNA) and granulosa cells. A rise in pituitary FSH caused by the disintegration of the corpus luteum (which is decreasing the secretion of progesterone) at the conclusion of the menstrual cycle, precipitates the selection of five to seven follicles to participate in the new cycle. These follicles become active at the end of the menstrual cycle and transition into the follicular phase of the new cycle. The selected follicles compete with each other for growth-inducing FSH.
It appears that LH stimulates LH receptors in the theca cells to produce androgens from cholesterol. FSH activates FSH receptors in the granulosa cells to use the androgens (secreted from the theca cells) to make estrogen, or estrodiol. When estrogen reaches a certain level, the pituitary will slow down its release of FSH. Follicles that lack enough FSH receptors to respond to the lower hormone level will die. The remaining dominant follicle usually has many FSH receptors, easily reacts to the lower level of FSH and continues to grow.
Research believes estrogen, from the granulosa cells, encourages follicular growth. Without proper signaling from estrogen, cellular mass/growth is decreased and progression from an antral follicle to a dominant follicle does not occur. As the follicle proceeds to grow and secrete more estrogen (synthesized by the granulosa cells), it will stimulate the increased release of LH/FSH (from the piutiary) to produce ovulation. At this point estrogen allows more LH receptors to be formed in the theca cells to create more androgens, thus more estrogen can be produced via the granulosa cells. LH receptors are not exclusively found in theca cells; they are found in granulosa cells and increase the granulosa cellular response to FSH just prior to the LH surge. Researchers believe the last surge of estrogen, produced by granulosa cells, bring the follicle to full maturity. When FSH/LH surge, the follicle has reach maturation and brakes away from the ovary.
Both theca and granulosa cells are capable of producing progesterone from cholesterol. Though in the follicular phase primed LH receptors in granulosa cells with cholesterol appear to be largely responsible for the production of progesterone. Receptors for insulin have been found in theca cells and insulin appears to act through its own receptor in the ovary. Studies of normal human theca cells have demonstrated that insulin is capable of enhancing androgen production in response to LH as well as independently stimulating androgen production from other cellular structures in the ovary. It appears insulin is a key to granulosa cell sensitivity to FSH. As insulin activates receptors on the granulosa cells, the cells become more responsive to FSH. This is especially important during the phase when FSH decreases and the dominant follicle needs to be responsive to lowering FSH levels for continued growth Current research believes progesterone, androgens and estrogens are key for maturation of the dominant follicle. Follicular Growth from the Following Articles Ovarian Insufficiency by Lawrence M Nelson, MD, MBA
The reproductive phenotype in polycystic ovary syndrome by R Jeffrey Chang
Ovarian Steroids: The Good, the Bad, and the Signals that Raise Them by Michelle Jamnongjit1 and Stephen R Hammes1