Today’s ignorance of hormonal importance:
In 2006, the cover article for Contemporary OB/GYN was written about perimenopause. Suggested management options include:
All of these are common contemporary modes of treatment, but they do not treat the problem — they simply help control the symptoms of the problem, which is progesterone loss.
Some common problems:
All of these are common problems. However, the last two patients might have had their problems overlooked without some physician awareness and lab work. Let’s learn some physiology and figure out how to solve these problems safely, naturally and physiologically.
Quick Menstrual Cycle Review: (yes, this is the quick review)
IGF-I and IGF-II
What are they?
IGF stands for Insulin-Like Growth Factor. The name is due to the similarity in structure to insulin. They are protein hormones of significant size. The gene that codes for their structure resides near that of insulin on the same chromosome and is similar to it. IGF-I is manufactured in large quantities by the liver and is carried in the blood by special carrier proteins, IGFBP-1-6.
IGF-II is manufactured in the ovary and is the main IGF active within the ovary.
What do they do?
The IGF proteins are intimately involved with the steroid hormones and the functions they induce and promote around the body. Insulin-like growth factors promote cellular mitosis and differentiation. They are an intermediary between estrogen and progesterone and the effects they have in multiple locations around the body. IGF-I is involved in estrogen’s effects on growth within the endometrium. IGF-II is involved in the differentiation in response to progesterone. IGF-I is the primary regulator of myometrial growth in response to estrogen.
Why so many IGF binding proteins?
Within cells, the various binding proteins act as regulators controlling the functions that the steroid hormones stimulate. In the serum, IGF-I is mostly carried by IGFBP-1. Most of the IGF-I in the blood is bound to the carrier protein.
Within the cell, IGF-I and IGF-II bind to special receptors. IGF-II, the main IGF within the ovary, binds to both its own IGF-II receptor and also the IGF-I receptor. Outside of the ovary, IGF-I is mostly active and binds to the IGF-I receptor. The activity level of the IGF hormones, regulated by their carrier proteins, is central to the actions of the steroid hormones, estrogen and progesterone, and the levels of the hormones themselves. The multitude of actions from the steroids around the body happen through the intermediary actions of the IGF proteins.
Why do I need to know about IGF proteins?
The biggest issue is their similarity to insulin. Insulin has the ability to bind to the IGF-I receptor. For the most part, insulin is free in the serum. Insulin resistance, high intake of sugar and insulin use by diabetics, all increase insulin in the blood. Here is the link between insulin resistance and abnormal cycles in PCOS: Insulin, especially in excess quantities, will bind to IGF-I receptors and promote estrogen effects throughout the body.
What is normal?
Under Patient Work-Up, I provide a couple of articles regarding normal laboratory values of various hormones. Here is a more central question: In the balance between estrogen and progesterone, what is considered normal? When oral contraceptives were invented, the twenty-one day on and seven day off pattern was chosen to mimic the twenty-eight day menstrual cycle. In fact, this was fairly arbitrary. Speroff has a nice review of the developers of The Pill.
One had the hope of receiving official Catholic Church approval if it reproduced the twenty-eight day cycle. That didn’t happen. In fact, over the course of history, few women spent their lives having periods. Most women were pregnant from an early age — pregnancy generates high estrogen levels that are dominated by estriol and progesterone. It is primarily a progesterone dominant state. Pregnancy was followed by a year or more of breast-feeding; a low estrogen state. After a few cycles, a new pregnancy began. Normal was a few months of periods followed by pregnancy and breast-feeding.
With a significantly lower death rate among children along with new medical technology, the late 20th century ushered in the era of family planning. Most women now spend their lives with pregnancy and breast-feeding as a rare event. Birth control pills are progestin dominant.
Inhibin B (the imperfect cycle):
As women age, they are constantly losing eggs. The eggs that remain are less likely to function properly. Fertility rates peak in the early twenties and slowly decline until age thirty-five. After age thirty-five, the decline in fertility is more rapid. Declining fertility is just a reflection of lower ovulation rates as well as poor egg quality and lower progesterone levels. Estrogen, however, is not declining at this time.
The role of Inhibin B:
Lets go back to the review of the menstrual cycle above. As the egg matures, the granulosa cells in the ovary produce Inhibin B. This hormone feeds back on the hypothalamus-pituitary to suppress FSH production. With fewer viable eggs, Inhibin B production goes down. This means that FSH will not be as well suppressed. For women in their late 30's and 40's, the granulosa cells work just fine. FSH is rising because of reduced production of Inhibin B, not because of lower estrogen. If you measure estrogen levels on women with slightly elevated FSH, you will find that estradiol and estrone levels are frequently quite high.
As women age, fewer cycles produce perfect ova and ovulation. Frequently, progesterone levels are low or progesterone is not produced at all. Inhibin B levels are low, resulting in elevated FSH. The ovary is over stimulated and makes high levels of estrogen. In addition, without progesterone, LH levels are not brought back down to normal during the second half of the menstrual cycle. There is no progesterone to induce brain opiate production and LH levels will not reduce. After a few months without ovulation, LH levels grow. The woman gets into a state similar to PCOS with high LH. This stimulates the theca cells to over produce testosterone and androstenedione. FSH levels are also high because of the lower levels of Inhibin B. The over stimulated granulosa cells have no trouble turning the excess testosterone and androstenedione into excess estradiol and estrone. Estrogen becomes dominant and the needed progesterone is not present to mitigate its effects. Read more...
High estrogen levels will overstimulate the endometrium and will grow thicker and thicker. Eventually, it will start to come apart and cause irregular, heavy bleeding. If there are fibroids, they will grow.
Before reviewing the roles of estrogen and progesterone and estrogen dominance, let me tell you the bottom line:
Treating a patient with real, bioidentical progesterone will:
Let's go over the physiology of estrogen and progesterone:
The roles of estrogen and progesterone:
Estrogen and progesterone live in a push-pull balance in many areas of a woman’s body. Many of the roles of testosterone in men are expressed in women with progesterone. The receptors for testosterone, progesterone and cortisol are all very similar and all three hormones can attach to any of the three receptors. In many tissues, testosterone and progesterone have similar stimulatory effects, while cortisol has a down regulating effect. This is true of the osteoblast cells in the bone, of muscle production and thyroid.
Men make testosterone on a constant basis. A young man’s testosterone level is approximately two hundred and fifty times his estradiol level. A man in his fifties still has testosterone approximately one hundred times his estradiol, unless he has excess abdominal fat or poor liver function. This means his estrogen levels will rise and upset the balance.
For women, progesterone is only present during pregnancy and in the second half of the menstrual cycle. Progesterone levels range from twenty to one hundred times those of estradiol during the normal cycle.
Balancing differences between estrogen and progesterone.
Estrogen Dominance Syndrome:
So, what would this estrogen dominance state look like? We see these women every day. As women age beyond thirty-five, ovulation becomes less frequent. If they don’t ovulate for a few months in a row, LH becomes persistently high. This induces a chronic state of elevated intra-ovarian androgens, which inhibit ovulation. The situation becomes self-perpetuating.
But wait, there’s more.
Excess estrogen causes increased carbohydrate craving. Because of this, the patient starts to gain weight, especially around the waistline. Intra-abdominal fat has the ability to make the enzyme aromatase. Aromatase will convert adrenal produced testosterone and androstenedione into estradiol and estrone. This drives estrogen excess even higher, increasing and speeding up the process — we have a positive feedback circuit.
All of this estrogen promotes the growth of the endometrium and that growth is continuous. It is not mitigated by progesterone. Eventually, heavy bleeding will come at irregular intervals. The estrogen will also promote the growth of fibroids and polyps.
Even if there is a growing egg, if it is defective (a more common occurrence with age), it will not ovulate. With the extra FSH around, the follicle will grow into a follicular cyst. If anovulation is chronic, the rising LH will cause extra intra-ovarian testosterone and androstenedione. That inhibits the maturation of follicles. The stimulated follicles don’t die off as easily either, a process called apoptosis. We get a bunch of follicles frozen in an intermediate state of neither growth nor apoptosis. These strings of small follicles form the typical appearance of the PCOS ovary.
Insulin and IGF-I:
Were you wondering why I brought up IGF and insulin earlier? Well, here it comes. With weight gain comes increased insulin resistance. These women crave carbohydrates such as eating a lot of bread and sweets. Some are drinking those dainty 32 oz. soft drinks that come with Value Meal #1. Today’s soft drinks are sweetened with high fructose corn syrup, pure, monosaccharide glucose. It is very rapidly absorbed and drives blood glucose levels up. This is followed by a rapid rise in insulin. The insulin drives the sugar into the abdominal fat, causing an increase in central obesity. This is a second positive feedback circuit.
Remember, insulin and IGF are very similar in size and shape. Insulin fits on the IGF-I receptor. Insulin stimulates the receptor just as if it were IGF-I. With all of that extra insulin around, the target tissues think there is a lot of estrogen driving IGF-I activity. So, the target tissue does the same thing it would do if there were a lot of estrogen. In the endometrium, this means growing thicker and heavier bleeding. In the myometrium, this stimulates fibroids to grow bigger and endometrial polyps to grow. In the breast, this stimulates ducts and glands to proliferate, but not to differentiate. Women with insulin resistance have elevated rates of breast cancer. In the ovaries, follicular cysts are increased. This is our third positive feedback circuit in these women. Giving Metformin may help, but a reduction in carbohydrate and total calorie intake is essential.
The estrogen dominant women may have:
Back to the common problems listed at the beginning of this section. For therapy instructions, see “Hormone Workup - A Quick Guide to Natural Hormone Use.”