The Endocrinology of the Uterus

The endocrine system is the system of hormones that affect many body functions. Hormones are produced in many different organs (termed endocrine organs) and circulate throughout the body in the bloodstream to cause many different body changes. The entire reproductive system starts in the brain in both men and women. In the part of the brain called the hypothalamus, a small protein hormone called gonadotropin-releasing hormone (GnRH) is produced by specialized nerve cells. These nerve cells release a burst of GnRH approximately once an hour. This intermittent or pulsatile (pulse-like) release of GnRH is critical to reproductive function. Having either too little or too much GnRH shuts down the entire system.

The Role of the Hypothalamus and Pituitary in Reproduction

Most of the GnRH never gets out into the body circulation. Instead, it travels just a short distance to another part of the brain called the pituitary. A large net of blood vessels arises in the hypothalamus and leads to the pituitary. The pituitary gland hangs down slightly from the brain and is located in the region right behind the bridge of the nose. The pituitary gland has been called the master gland because it controls so many important bodily functions. The GnRH that is released in a pulse is directed through this net of blood vessels to the pituitary. Together, the pituitary and the hypothalamus control reproduction.

The anterior, or frontal, part of the pituitary has specialized cells that release several specific body-control hormones. The cells we are most interested in are the gonadotropes. They produce the hormones that control the gonads (in women, the ovaries; in men, the testes). The two hormones that the gonadotropes release are gonadotrophins, or growth hormones for the gonads: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH are secreted in increased quantities at the time of puberty, which leads to the development of the sexually mature ovaries and testes. The names of these hormones come from their function in women, but they carry out similar functions in both men and women.

In the ovary, FSH and LH play different roles. FSH dominates during the first half of the menstrual cycle, as the ovarian follicle forms. The follicle is the clear fluid-filled space where the egg grows and matures. Therefore, FSH is in many ways the egg-stimulating hormone. FSH also controls the production of the major female hor-mone estrogen, which is made as the egg develops. Estrogen goes back to the brain to suppress FSH production as the egg matures. From the point of view of the uterus, however, estrogen’s most important task is to cause the uterine lining (and potentially the fibroids) to grow and thicken in preparation for the implantation of the egg.

The name luteinizing hormone comes from the fact that after ovulation LH stimulates the production of the corpus luteum. Corpus luteum means “yellow body” in Latin; it is a yellowish part of the ovary where cholesterol (typically yellow in color) is converted to progesterone following ovulation.

An initial surge of LH first triggers release of the egg. The corpus luteum is then formed after the egg follicle has ruptured and released the egg. Blood vessels grow into this space delivering cholesterol from the bloodstream, and the enzymes stimulated there convert cholesterol in the blood to the steroid hormone progesterone. Thus, LH plays the dominant role in the second half of the menstrual cycle, after the egg is released, stimulating and maintaining the production of the hormone progesterone.

When progesterone is released after ovulation, it functions to organize the uterine lining and stabilize it so that it can fall off in an orderly fashion if pregnancy does not occur that cycle. Progesterone is also the major influence on preparing the uterus for a pregnancy (thus its name, from “pro-gestation”). These hormones play analogous roles in men: FSH is the major control for sperm production, and LH is the major control for testosterone production.

This system is very finely tuned. Both the amount of GnRH released and the frequency with which it is released send a signal to the pituitary to influence the proportion of FSH to be made relative to the amount of LH. Therefore, the system is easily shut down if the precise sequence of signaling is not maintained. If the pulse system of GnRH is disrupted so that GnRH is continually present, the system will shut down. This mechanism can be exploited by drugs, as explained in this article: Gnrh-agonists, add-back-therapies and gnrh-antagonists as treatments for fibroids

There are several other hypothalamic and pituitary hormones that we will discuss later which do not act to stimulate the ovary. These hormones include prolactin and vasopressin.

Steroid Hormones

The gonadal steroid hormones (estrogen, progesterone, and testosterone) also act on the brain, letting it know that the stimulation has been successful. This is called negative feedback because the hormones lead to the repression of the stimulating hormones. These steroid hormones also affect many body tissues, including breasts, bone, hair follicles, and muscle.

Typically when people hear the term steroid hormones, they think about the anabolic steroids athletes use to bulk up. These “steroids” are only a small part of this important class of hormones. The category is based on their molecular structure, which helps them pass easily into cells.

In women, the uterus is quiescent or quiet (as it is before puberty) until stimulated by estrogen and progesterone. Most of the study of uterine function has concentrated on the endometrium, the thin layer of uterine lining that is shed during menstruation and is transformed into the bed for the placenta during pregnancy. In the endometrium, as mentioned earlier, estrogen tends to build up the lining, and progesterone organizes it in preparation for menstruation or pregnancy. Estrogen and progesterone also affect the muscle layer where fibroids arise. It is less clear how this part of the system works.

It is not clear that the uterus sends hormonal signals back to the rest of the reproductive system, but there is evidence of at least some communication from the uterus to the ovary. Several studies have shown that having a tubal ligation or a hysterectomy while leaving the ovaries in place decreases the risk of ovarian cancer.  

There are also fine points to the action of these steroid hormones in target tissues like fibroids but also in the brain, bone, and breast. Steroid hormones can easily pass through the cell membrane and carry out their action in the nucleus of the cell, the control center where the DNA directs the action. The key to understanding the action of these hormones is that they bind with proteins called receptors; it is the hormone-receptor complex that brings about the changes by binding to DNA. Hormones and receptors fit together like locks and keys. The analogy is apt. You can have an office-specific key as well as a pass key that fits all the locks in the office; similarly, different hormone-receptor combinations can give different results. You can also have a key that fits into the keyhole but does not open the door; in the language of hormones this “key” is called a hormone blocker or antagonist.

The first level of control for steroid hormone action is the exact hormone present—in other words, which key is used. For estrogen, there are several different natural estrogens, with estradiol being the most common estrogen in women with fibroids. There are also many different formulations of estrogen supplements—both natural estrogens from plants or animals and synthetic estrogens—all of which need to interact with receptors to carry out their action. The exact estrogen used can be important in determining the result.

A special class of drug compounds commonly called “designer estrogens,” but more correctly termed selective estrogen receptor modulators (SERMs), have been designed to perform special jobs. One ideal role for a SERM is to act like an estrogen at the sites in the body where estrogen is beneficial (like the brain and bone) but to act like an estrogen blocker at the breast to decrease the risk of breast cancer. All hormones have some mixture in their action, which is why women may respond differently to different compounds. Progesterone-like substances are termed progestins. Progesterone is far and away the most important natural compound, but there are a number of synthetic progestins like medroxyprogesterone acetate (used in hormone replacement) and norethindrone and levonorgestrel (used for contraceptives). The hormone can be changed to make it easier to use—for example, so that it can be taken as a pill instead of as a shot or so that doses don’t need to be given so frequently—but altering the hormone may also change its action.

There are compounds analogous to SERMs for progesterone, termed selective progesterone receptor modulators (PRMs or SPRMs), but these are further behind in commercial development. Two PRMs that are undergoing clinical trials for the treatment of uterine fibroids are Asoprisnil (previously called J867) and Proellix (previously called Progenta).

Androgens are thought of as male hormones, but they are present in women, too. Both the ovaries and the adrenal gland (another endocrine gland, located next to the kidney) make androgens that are present in the circulation. Women have low levels of testosterone and other natural androgens, including androstenedione and dehydroepi-androsterone (DHEA), compared with men, but these hormones play important roles.

Androgens act on hair follicles and likely have a role in sex drive and mood. Importantly, androgens are used to make estrogens. In fact, the ovarian follicle makes androgens and converts them to estrogens using an enzyme called aromatase. This is why women who don’t ovulate can have androgenic side effects like acne and increased body and facial hair. Body fat also “aromatizes” androgens to estrogens, which is why heavier women have higher levels of estrogen.

There are also synthetic androgens we use for treatment of gynecologic disease. The most common one used in women is danazol, which is primarily used for the treatment of endometriosis.

Although we divide steroid hormones into the categories of estrogen, progestin, and androgen, some molecules will fit into more than one category. Different parts of the steroid molecules are like different notches on the key. Many synthetic progestins have androgen-like effects and thus cause androgenic side effects like acne and increased hair growth. Also, there are molecules like tibolone that work like an estrogen and a progestin (two keys in one!).

The dose or amount of the steroid hormone is also important in determining its action. Just as with any medication, a high dose will likely cause different effects and side effects than a low dose of the same compound.

Duration of exposure to steroid hormones is also important. When you take an antibiotic to treat a urinary tract infection and the directions are to take a tablet twice a day for 10 days, you won’t have the same chance of curing the infection if you take all 20 at one time. This is a special issue for the endometrium and its exposure to progestins: you often need a lower dose longer to get the desired effect.

Finally, the route of delivery makes a difference in hormonal action. Pills or other kinds of oral medications enter the body through the digestive tract and reach the liver in very high concentrations compared with medication delivered by a patch, which is absorbed by the skin (the blood vessels from the gut are routed through the liver). Because the liver makes factors that affect blood clotting, oral preparations are more likely to cause blood clots as a side effect.

There is also a difference between systemic delivery (the medication is delivered through the whole body to reach the place where it is really needed) and local or targeted delivery (the highest concentration is where you want it to be). Using a medicated intrauterine device (IUD) or vaginal delivery of medication provides targeted delivery for the uterus.

The kind of receptor (the lock) in a tissue also contributes to the way steroid hormones act. There are two different kinds of receptors for estrogen (ER-αand ERβ) and progesterone (PR A and PR B). Fibroids have both different amounts and different ratios of these receptors than normal myometrium.  Moreover, many steroid hor-mone receptors work in pairs. So, for example, with the progesterone receptor, 3 combinations are possible: PR A–PR A, PR A–PR B, and PR B–PR B.

Finally, each tissue in the body has specific factors that regulate steroid hormone action. Not only does the breast potentially have a different mix of estrogen and progesterone receptors than does bone, but all kinds of other tissue-specific factors also come into play. The DNA folding may make it easy for hormones to stimulate RNA production, or it may have other molecules that block these binding sites. There are a number of other terms like promoters, repressors,and coactivators that describe molecules that specific cells may have that make hormone-stimulated RNA synthesis (production) easier or harder.

The complexity of the hormone system thus makes it impossible to say, for example, that progestins cause fibroids to shrink. To adequately determine whether this is the case, many questions need to be asked: what specific progestin, what dose, for how long, in a pill or in an IUD, and so on. Understanding the biology does not always lead to simple answers.

Protein Hormones

In addition to steroid hormones like estrogen and progesterone, the endocrine system produces a number of protein hormones such as insulin, the hormone that is lacking in Type I diabetes, and growth hormone, too little of which results in dwarfism and too much causes a disease called acromegaly. FSH and LH belong to this class of hormones.

We don’t know a lot about how protein hormones influence uterine fibroids, but proteins do appear to influence fibroid biology in a few areas. Protein hormones may provide new targets for innovative therapies in the future.

Proteins are large, bulky molecules that do not easily pass into the cell. They exert their influence on the cell by binding to receptors (other proteins that are the lock to the hormone’s key) on the outside of the cell. The binding of the hormone to the receptor causes new small molecules to be formed inside the cell that carry out its action. These intracellular molecules are called second messengers and start a cascade of events that lead to specific genes being turned on in the nucleus.

Growth Factors

Growth factors are smaller proteins (also called peptides) that can carry out actions inside and between the cells. In fibroid research several different families of growth factors have been identified as important: angiogenic growth factors, fibrotic growth factors, and insulin-like growth factors.

Angiogenic growth factors influence the formation or function of blood vessels. The best-described angiogenic growth factor in fibroid biology is basic fibroblast growth factor (bFGF). This growth factor is overproduced in fibroids, and the protein is stored in the extracellular matrix (ECM).  It also appears that the receptor for bFGF in the endometrium is not regulated correctly.  Thus, abnormalities of the bFGF system may be responsible for abnormal menstrual bleeding with fibroids.

Fibrotic growth factors influence the formation of the ECM and are another major growth factor family. These hormones are important in normal wound healing, but when they lead to the production of too much ECM, scar tissue and conditions such as fibroids can form. Transforming growth factor beta (TGF-ß) is the best studied of the fibrotic factors. There are several subtypes of TGF-ßs and sev-eral different receptors. Some are distinctly abnormal in the majority of women with fibroids.

Additional components of the fibrotic factor pathway appear to be abnormally regulated in leiomyomas. Related molecules like Smads (molecules that transmit the signals generated by TGF-ßs), matrix metaloproteinases (MMPs, which are enzymes that break down ECM), and tissue inhibitors of metaloproteinases (TIMPs, which are substances that keep MMPs inactive) all are involved in the fibrotic biology of fibroids. Particular ECM proteins, including collagens type 1 and III and dermatopontin, are also important.

 Finally, the insulin-like growth factor (IGF) system likely is also important in fibroid biology.  Again, as with the TGF-ß family, there are several IGFs and several IGF binding proteins (IGFBPs) that keep the factors inactive, as well as multiple receptors. These small molecules have some insulin-like action.

Most of the currently available medical therapies come from the knowledge (gained through basic science experiments) that fibroids and normal myometrium respond differently to estrogen and progesterone or have different susceptibility to these hormones. Understanding other biological differences between myometrium and fibroids gives us prospects for new treatments that exploit these differences. Thus, understanding growth factors may lead to new treatments with fewer side effects in the future.