The Two Cell Model of the Ovary
Since everything affects everything else, there are many possible places to start, but let’s look at the ovary first. Bengt Falck first proposed the two-cell system in 1959, describing the interactions between the granulosa and theca cells.
The paracrine relationship from theca to granulosa cells:
At the start of the menstrual cycle, hormone levels are at their lowest level of the month. Granulosa cells already have some FSH receptors. Pituitary production of FSH induces further production of FSH receptors within the granulosa cells. It is a positive feedback circuit and results in increasing granulosa cell sensitivity to FSH. The theca cells respond mostly to LH production by producing the androgens, testosterone and androstenedione. These two androgens diffuse out of the theca cells and into the neighboring granulosa cells. The theca cells also make IGF II (Insulin Like Growth Factor II). It enhances LH stimulated production of androgens in the theca cells. It also diffuses out into the granulosa cells, stimulating FSH mediated aromatization of the androgens into estrogens. Testosterone is changed into estradiol and androstenedione is aromatized into estrone.
Important for overeating America
Although the theca cells make mostly IGF-II, both IGF-I and IGF-II act by attaching to the Type I- IGF receptor. The importance of this will be stressed again when dealing with PCOS, and excess insulin states in general. High insulin levels can be caused by insulin resistance or any high insulin state, including excess sugar and carbohydrate consumption. Insulin attaches to and reacts with IGF-I receptors. Excess insulin can result in theca overproduction of androgens. The granulosa cell then changes the excess androgens into estrogens, resulting in estrogen excess. Therefore, excess insulin results in a high estrogen state.
In the granulosa cell, in response to FSH, inhibin and activin are produced. Inhibin enhances LH stimulation of androgen synthesis in the theca cell whereas activin suppresses androgen synthesis. These two proteins modify expression of the P450c17 enzyme system.
Actually a three-cell system:
In the ovary, it is really a three-cell system; growing follicles are required. It is only in the presence of growing follicles, and one dominant follicle in particular, that Inhibin-B is produced. Granulosa cell production of Inhibin-B inhibits pituitary release of FSH and stimulates the release of LH. Rising estrogens, in a positive feedback loop, stimulate increased FSH production and thereby, further increases estrogen production. Inhibin-B puts the brakes on this runaway estrogen production. Inhibin B production sets the stage for the LH surge that results in ovulation and progesterone production by inhibiting FSH output and stimulating LH production.
As women age:
This is the key to Dr. John Lee’s perimenopause progesterone therapy.
As women age, the number and health of follicles declines. This causes a decline in Inhibin-B production. It is the decline in Inhibin-B production and not the decline in estrogen production, that results in the rise in FSH in the perimenopausal years. There are many women with elevated FSH who have average, elevated or even very high levels of estradiol and estrone. Unless a healthy egg is released following ovulation at midcycle, no progesterone will be produced or released into the blood stream. As estrogen rises, so does LH. Progesterone’s effects on the brain and hypothalamus bring LH back down for the next cycle. Without this resetting of the system, LH will remain elevated.
The PCOS like state of the perimenopause: (a positive feedback loop)
Without quality follicles, there is reduction in Inhibin-B production and little to no progesterone is being produced. This results in elevated FSH but an even higher LH. Androgen and estrogen production are high but no progesterone is produced. Progesterone is required to lower LH and reset the cycle. The elevated intra-ovarian androgens further inhibit ovulation. All of this results in Estrogen Dominance Syndrome. The over stimulated endometrium begins to bleed irregularly and heavily. The patient craves carbohydrates and deposits intra-abdominal fat — increased abdominal fat creates insulin resistance and Insulin resistance raises insulin output. The excess insulin hits the IGF-I receptors in the theca cells which stimulates excess testosterone and androstenedione production. The high FSH present stimulates the granulosa cells to convert these excess androgens into estrogens.
All of this results in excess estrogen production. In addition, the action of insulin on both insulin and IGF-I receptors in endometrial and breast tissue stimulates proliferation of these tissues. This causes endometrial and breast hyperplasia leading to excess uterine bleeding and breast proliferation and probably increases both endometrial and breast cancer risks. It is not a pretty picture.
By simply replacing progesterone and encouraging a low carbohydrate, reduced calorie diet, many of these problems subside or at least lessen.
The Complexity of Control: