Hormones by Guest Blogger Barry Jacobs, M.D

What is a Reproductive Endocrinologist? A Reproductive Endocrinologist is a sub specialist in OB-GYN who has spent extra years studying, doing research and learning the actions and issues related to hormones of women’s reproductive systems. Historically, most of the patients Reproductive Endocrinologists have seen since the origin of the discipline have been couples trying to achieve or maintain pregnancies. It is no secret that the demographic of our population is changing. We now have a burgeoning population of women over the age of 40. Their ovaries no longer function as they did at the age of 20 or even 30. It is more than just ovarian function that changes. The adrenal glands, which also make sex hormones, are changing, too. As a result, women begin to find they have less energy and less interest in many of the activities which previously gave them pleasure.
     
What are sex hormones? The one most commonly discussed is estrogen. Actually, estrogen is the name of a family of hormones. The potent estrogen made by ovaries is estradiol. There is a far less potent estrogen, estrone, also made by the ovaries. Estrone has about 1/10th the potency of estradiol. There is also a natural estrogen made by the placenta of pregnancy, estriol, but estriol is not normally present in the non-pregnant woman. It apparently has no role in the non-pregnant state.

In addition to the natural estrogens, science has created synthetic estrogens for use in birth control pills. The most common of these is ethinyl estradiol. Basically, a chemical addition has been tacked on to the estradiol molecule to protect it from destruction by the intestine and liver.

Everything we swallow, which gets absorbed from the intestine goes to the liver. The liver processes all food and medication. In the process, most swallowed natural hormones are almost completely destroyed by the liver. If we give a high enough dose of a natural hormone, some escapes destruction and can provide the desired hormone effect. The problem we face is that high doses of estrogen in the liver also change liver physiology. One of the most critical changes induced by oral estrogen is the increased production of clotting factors, which can increase the risk of developing blood clots.

What is a bio-identical hormone? In the case of estrogen, it is estradiol. To be more specific, there is a specific configuration of the structure of the estradiol molecule which is biologically active. The configuration is referred to as estrdiol-17-β. Other configurations do not have much biologic activity. All estrdiol-17-β preparations are bio-identical to what the ovaries make. The body really does not care where the molecule came from, only that it is the right molecule in the right configuration. What may be significant is the route of administration of the hormone. Since route of administration is an issue for all hormones, let’s identify the others that may have an impact on mature women.

Estrogens are important for the health of all the soft tissues of a woman’s pelvis, as well as the preservation of bone mass. Estrogens actually decrease the rate at which bone calcium is lost. Estrogens also decrease the risk of blood vessel disease which can lead to heart attack and stroke. By the way, high estrogen levels usually make a woman feel good.

Another hormone made by the ovaries is progesterone. Progesterone is made after ovulation, so if a woman does not ovulate, she does not make progesterone. There are 2 important issues related to lack of ovulation and lack of progesterone. Obviously, if a woman does not ovulate, she will not become pregnant. The other is related to the fact that progesterone is a natural antagonist to estrogens. One of the things estrogens do is to stimulate growth of the uterine lining, endometrium. If estrogen stimulation of endometrial growth is not opposed, there is an increased risk of developing a cancer of the uterine lining. Women using estrogen replacement need to also use progesterone or a synthetic progestin, to protect their uterine linings, unless they have already had a hysterectomy. Progesterone, as a natural estrogen antagonist, has an effect beyond the uterus. Whereas estrogen generally improves a woman’s mood, progesterone frequently causes a depression of mood and mental activity.

The ovaries produce more than estrogens and progesterone. Ovaries make testosterone. Yes, that is the male hormone made in testicles. It is also made in ovaries. In fact, estradiol is made from testosterone. If the ovaries did not make testosterone, they could not make estradiol. Some investigators have data which imply that testosterone, as well as estrogens, may be mediators of libido, or sex drive. Some data indicate that women with low testosterone levels may have more energy and improved libido if they are provided with some testosterone supplementation. Since there seems to be some conversion of testosterone to estradiol in the brain, it is uncertain if it is actually testosterone, or estradiol which is the primary mediator of libido in women.

Estrogens, progesterone, and androgens (male hormones like testosterone) are all steroid hormones. They have the same basic skeletal configuration. DHEA, a pre-hormone for these very active hormones, has received a fair amount of attention in the popular literature. There are even a few studies which imply that there may be some significant biologic activity of DHEA. You might say that DHEA is a pre-steroid. All of the steroid hormones are made from DHEA after various chemical and structural changes. Unfortunately, not as much research has been performed related to the effects of DHEA, itself. One study from Monash University seems to indicate that the administration of DHEA to depressed women improved their recovery. Interestingly, DHEA production peaks at about the age of 30, and declines significantly, after that.

All of the hormones we have discussed are made by the ovaries. They are also made by the adrenal glands, but to a lesser extent. Just as we observe a decline in ovarian function with time, there also seems to be decreasing adrenal production of hormones. Actually, the adrenal glands are an important source of DHEA.

Another hormone which may need replacement is thyroid hormone. Thyroid hormone regulates the physiology of all the cells of the body. Low thyroid hormone levels can cause a person to have low energy levels and cause cold intolerance and fluid retention. Although low thyroid, itself, does not make someone fat, the decreased activity level associated with low thyroid hormone levels may lead to obesity.

There are a number of other hormones made by the body, but as a general rule, they do not decline much after the age of 40. Certainly it is possible to develop a form of diabetes related to low insulin levels, but that form of diabetes is generally identified in children. It is the steroid hormones which seem to be issues in the mature adults. Fortunately, we have hormones to provide supplementation or replacement, and various ways to deliver these hormones.

Almost everyone is aware of estrogen pills. One of the best known is Premarin®. Premarin is a mixture of estradiol, estrone and 2 estrogens made by horses, equilin and equilenin. Premarin is extracted from the urine of stallions. That’s right, male horses. Testicles make estrogens, just as ovaries make androgens. The only component of Premarin which provides any real benefit is the estradiol portion. Premarin is quite an old product, and, to my thinking, over priced. As an oral preparation, its first stop is the liver, where much of it is destroyed and it alters liver activity. Perhaps a better pill, and certainly cheaper, is a pure estradiol preparation. It actually is bio-identical to what a woman’s ovaries make. The other pill form of administering estrogen is the synthetic estrogen of birth control pills.

If we do not want to blast the liver with estrogen, there are alternate ways to administer the preparation. Years ago, a semi-synthetic estrogen was injected monthly as a depot of hormone. It was uncomfortable and required frequent returns to the physician. There are creams and gels, but they wash off, sweat off and swim off. They also can get deposited on other people by direct contact. It is probably undesirable for a pre-pubertal child to come in contact with much of the topical estrogen. There are also patches which deliver estradiol. They do work well, if they stay on. Also, the adhesive can cause local skin irritation for some women. Finally, estradiol can be fashioned into a pellet, which is inserted under the skin. It does need to be replaced every 3 to 4 months, as it is used up. The advantage is that there is no direct stimulation of the liver and no concern about maintaining the dosage. There is a constant, steady release of hormone for several months, and requires no further management other than replenishment after it is used up.

Progesterone can also be delivered in several ways. A semi-synthetic form of progesterone, Provera® is generally well tolerated. It seems to behave just like the natural hormone, even though it has been slightly modified to survive the intestine and liver. There is an oral progesterone preparation, Prometrium®. Unfortunately, the blood levels of progesterone after Prometrium ingestion vary widely and are quite unreliable. We still use daily intramuscular injections of progesterone in oil for our IVF patients. They don’t much like that. Since the real need for progesterone is to protect the endometrium, we really do not need a significant blood level, except to get the hormone to the uterine lining. Actually, progesterone is very well absorbed through the vagina, and vaginal administration provides excellent tissue levels in the endometrium, without providing a significant blood level. That decreases the problem of mood suppression related to high blood levels of progesterone. The down side is that vaginal progesterone, whether suppository, gel or capsule, is messy. The 2 commercial progesterone vaginal gels on the market are a bit expensive. Whereas progesterone vaginal capsules are not as much of a mess as the suppositories, they do produce a bit of discharge.

Testosterone treatments are available as injections, gels and pellets. The same discussion applies to administration of testosterone as does to estradiol. I am not aware of an oral testosterone preparation, but it would face the same fate as an oral estradiol pill.

DHEA is marketed over the counter at many pharmacies and in health food stores to consume orally. It is not likely to provide much benefit as an oral preparation. Some compounding pharmacists do provide a DHEA pellet, just like they do estradiol and testosterone.

Hormone replacement or supplementation can markedly improve the health and feeling of wellbeing for women. It is, however, important to determine which hormones need to be administered and to select the route of administration that best suits the needs of each patient. As noted, each has its advantages and drawbacks. Although nothing is perfect, it is usually possible to devise a treatment plan that satisfies the needs of each individual. We have a number of delivery systems available, and women have the opportunity to determine which ones they prefer.

My goal in providing hormone replacement or supplementation for patients is to try to restore their hormone levels to what they would be if my patient were about 30 years old. I think most women feel best at that age, and if I can help restore that sense of well being by recreating that kind of hormonal environment, I have improved quality of life.

Dr. Jacobs is a Reproductive Endocrinologist, practicing in Carrollton, Texas, a northern suburb of Dallas. He completed his residency training in obstetrics and gynecology at Baylor College of Medicine in Houston, and remained at that institution to become its first fellow once Baylor achieved accreditation for an advanced training program in Reproductive Endocrinology and Infertility. Dr. Jacobs has served on the faculty of several medical schools and was director of Reproductive Endocrinology at Texas Tech Health Science Center in Amarillo. Currently, in addition to his clinical activities caring for infertile patients and those with recurrent pregnancy loss, he is Chairman of the IVF committee at Baylor Medical Center in Carrollton.


Barry Jacobs, M.D., 4323 M. Josey Lane, Suite #201, Carrollton, TX 75010 www.texasfertility.com
Phone: 972-394-9590 Fax: 972-394-9597






Sharon LaMothe
Infertility Answers, Inc.
http://infertilityanswers.org/
LaMothe Services, LLC
http://lamotheservices.com/
*Please note: Sharon LaMothe is not a MD, is not an attorney nor does she hold a mental health degree. All advice given is solely the experienced opinion of Ms. LaMothe. If you have any medical, legal or psychological questions or concerns, please contact your own Doctor, Attorney or Mental Health Professional.

Evaluation of the Infertile Couple Part Three: By Dr. Barry Jacobs

This is the last of the 3 part series entitled Evaluation of the Infertile Couple. To read more articles by Dr. Jacobs please visit Infertility Answers, Inc. where he writes about pregnancy loss and endometriosis.

Sharon LaMothe

Evaluation of the Infertile Couple Part Three: By Dr. Barry Jacobs

We need for sperm to meet eggs. In nature, that takes place in the female reproductive tract. At intercourse, sperm are deposited in cervical mucus. Remember, estrogens stimulate cervical mucus production and secretion. Cervical mucus has a rather characteristic molecular structure, in that the molecules are long chains that line up to create “highways” for sperm to travel through the cervix into the uterine cavity. Although cervical mucus may look like egg white, it is quite different. I have seen recommendations from non-professionals that women with poor cervical mucus should put egg white in their vaginas as a substitute. Don’t do that!

The uterine cavity, in the non-pregnant state, is not really a cavity. It is a potential space, leading to the fallopian tubes where fertilization takes place. Assuming everything is normal. Sperm are in the fallopian tubes to greet an egg shortly after intercourse. Since we are evaluating an infertile couple, we cannot assume all is normal.

Obviously we need for this entire passageway to be intact. There are a number of ways to evaluate the uterine cavity and fallopian tubes. The least invasive way is to perform a hysterosalpingogram or HSG. An HSG is an X-ray study performed by injecting an X-ray contrast solution into the uterine cavity while watching on a fluoroscope. The contrast material outlines the uterine cavity and should pass through the fallopian tubes and spill freely into the pelvic cavity. Radiologists pass a small catheter with a balloon on the end into the uterus and inflate the balloon. I do not like that technique. Inflating a balloon in the uterus hurts, and the balloon can hide things I may need to see. Instead, I use an older technique of applying a canula, sort of a glorified soda straw, to the opening of the cervix. Through the canula I slowly inject the X-ray contrast and take pictures of the uterine cavity and fallopian tubes. If the cavity is not formed normally, it may increase the risk of miscarriage. Polyps, benign fleshy growths, in the cavity may impair the ability of an embryo to implant. Fibroids, benign fibrous tumors of the uterine wall can interfere with pregnancy if they are right under the endometrium (uterine lining). If tubes are blocked, well, I think it is fairly obvious that will prevent a pregnancy. There are some other more subtle findings that the radiologists commonly do not identify. Sometimes we see kinking of the fallopian tubes. That implies there is some scarring around the tubes, frequently related to endometriosis. After injecting the X-ray contrast and taking pictures, I remove all the instruments, and take 1 more picture of my patient’s pelvis while she is standing. I want to see the distribution of X-ray contrast material in the pelvis. If my patient has scarring in the pelvic cavity, the contrast material will not all form a layer over the pelvic floor. It will become trapped in pockets which can be identified while she is upright.

I have now covered the basic testing of the infertile couple. There is one other test I discuss with my patients. I recommend this test for my IVF patients because I think it is cheap insurance. If my patient does not need IVF, I think this test provides useful information, but I am less certain as to the economic value. I offer it to those who do not need IVF, but do not feel justified in pushing them to do it.

Let me provide some background about this final test. There are 4 families of adhesion molecules which allow our cells to stick together, so we do not end up as puddles on the floor. One of these families of adhesion molecules is called integrins. There are 3 integrins in the endometrium regulated by progesterone, the hormone made after ovulation. These 3 integrins come and go at different points in time during the 2 week interval between ovulation and subsequent menstrual period. All 3 are present at the time an embryo should implant in the endometrium – about a week after ovulation. One of them is present only at that time, so we use it as a marker for the receptivity of the endometrium – how likely is an embryo to stick there and grow.

There are 3 things we know of that can impair production of our marker integrin. One of them is low progesterone levels. Well, that’s s no-brainer. If you need progesterone to make the integrin, and progesterone is low, you will probably not have the integrin. The second thing that impairs production of the integrin is fluid collection in fallopian tubes which have been severely damaged by an infection like Chlamydia or gonorrhea. The fluid in those tubes contains inflammatory proteins which do impair production of the integrin. The third thing that can interfere with production of this integrin is endometriosis. So far, all of my patients who have not made this integrin when they should have had endometriosis. Since I started treating endometriosis in this sub set of patients who did not make our integrin, my IVF pregnancy rates went up 10 percentage points. That is significant increase.

Once an evaluation of the infertile couple is complete, we can start developing a treatment plan. Sometimes, it may be necessary to deal with one or more intermediate issues, such as trying to improve semen parameters, or treating endometriosis. The only times I treat endometriosis, today, is if my patient does not make the integrin we discussed, or in an effort to relieve menstrual main, which may be associated with endometriosis. Again, I do not think it appropriate to start treating a patient without knowing what I am treating. The entire evaluation can be performed in the span of a single menstrual cycle, and, if performed diligently, can actually save time and money.


Dr. Jacobs is a Reproductive Endocrinologist, practicing in Carrollton, Texas, a northern suburb of Dallas. He completed his residency training in obstetrics and gynecology at Baylor College of Medicine in Houston, and remained at that institution to become its first fellow once Baylor achieved accreditation for an advanced training program in Reproductive Endocrinology and Infertility. Dr. Jacobs has served on the faculty of several medical schools and was director of Reproductive Endocrinology at Texas Tech Health Science Center in Amarillo. Currently, in addition to his clinical activities caring for infertile patients and those with recurrent pregnancy loss, he is Chairman of the IVF committee at Baylor Medical Center in Carrollton.
Barry Jacobs, M.D., 4323 M. Josey Lane, Suite #201, Carrollton, TX 75010 www.texasfertility.comPhone: 972-394-9590 Fax: 972-394-9597

Evaluation of the Infertile Couple Part Two: By Dr. Barry Jacobs

This is a continuation of Dr. Barry Jacobs article on how he evaluates infertile couples who come to him for help. Your comments are welcomed!

Sharon LaMothe
http://infertilityanswers.org/

Evaluation of the Infertile Couple Part Two

By Dr. Barry Jacobs

Now we can talk about spending a little money. Ovulation predictor kits test for the presence of LH in urine. LH is a hormone from the pituitary gland which is supposed to trigger ovulation. If ovulation actually does occur, it takes place about 36 hours after the surge in the level of LH, and about 24 hours after it is detected in the urine. At least now you have some predictive value to a test – if you actually ovulate. Again, among the infertile population of women, we see evidence of an LH surge, without rupture of the follicle to release the egg. There is still progesterone production, so the level of progesterone may be appropriately elevated, but you have still not ovulated. For that reason, testing your blood for progesterone level is not entirely reliable, either.

There are only 2 reliable ways to know if you ovulate. One of them is ridiculously obvious. You become pregnant. OK, if you do, you don’t need this article. The other reliable way to know if you ovulate is to perform ultrasound evaluations of the pelvis starting on the 12th day after the start of the menstrual cycle. If you are going to ovulate, you should see a follicle about 17 mm in average diameter on one of your ovaries. Two days later it should be gone. You ruptured the follicle to release the egg – ovulated. Some times we see that the pre-ovulatory follicle has become significantly larger, and there is progesterone in the blood. The follicle has gone through the hormonal changes of ovulation without releasing the egg. The resulting un-ruptured follicle is called a luteal cyst. If this happens, do not be alarmed. In young women, 98% of all ovarian cysts go away without any treatment, at all. You do not need any treatment, especially surgery if it is gone within 2 menstrual cycles.

Women who do ovulate regularly have clock-work regular menstrual flows, every 28 days. Ovulation should occur on cycle day 13 to 14 and, if no pregnancy occurs, there is menstrual flow 2 weeks later. There are a number of subtle ovulation dysfunctions which impair fertility. A variance from a 28 day cycle may signal a problem. Late ovulation and a short interval from ovulation to subsequent menstrual flow will probably prevent a pregnancy form becoming established.

We need an adequate number of good quality sperm. Performance of a thorough semen analysis is an essential part of the evaluation. Too often, semen analysis is delayed until after treatment efforts have been initiated, only to discover that there is a male factor problem contributing to the couple’s impaired fertility. We have now wasted both time and money. In the interest of cost effectiveness, semen analysis should be part of the initial evaluation. Often I have heard, as an excuse not to provide a specimen that he has a child from a previous relationship, or simply, “I know it is not him.” Things can, and often do change in the male, and until appropriate evaluation is performed, you do not know. Remember, also, that a male factor problem does not always prevent pregnancy, but merely decreases the chance one can be achieved. A previous mild male factor problem may not have prevented pregnancy in the past, but may contribute to the current problem. The mild problem may have become worse. Do your part, guys. Your wife has a lot more to deal with, even if the primary problem is a male factor issue.

~Part three will be posted next week


Dr. Jacobs is a Reproductive Endocrinologist, practicing in Carrollton, Texas, a northern suburb of Dallas. He completed his residency training in obstetrics and gynecology at Baylor College of Medicine in Houston, and remained at that institution to become its first fellow once Baylor achieved accreditation for an advanced training program in Reproductive Endocrinology and Infertility. Dr. Jacobs has served on the faculty of several medical schools and was director of Reproductive Endocrinology at Texas Tech Health Science Center in Amarillo. Currently, in addition to his clinical activities caring for infertile patients and those with recurrent pregnancy loss, he is Chairman of the IVF committee at Baylor Medical Center in Carrollton.
Barry Jacobs, M.D., 4323 M. Josey Lane, Suite #201, Carrollton, TX 75010 www.texasfertility.comPhone: 972-394-9590 Fax: 972-394-9597

Evaluation of the Infertile Couple Part One: By Dr. Barry Jacobs

This is a special 3 part series written by Dr. Barry Jacobs.If you are interested in reading more of his articles, visit Infertility Answers, Inc. where we have articles on pregnancy loss and endometriosis.

Sharon LaMothe

Evaluation of the Infertile Couple

By: Dr. Barry Jacobs

An evaluation of the infertile couple should seek to find all reasonable explanations for the presenting problem. Commonly, an infertile couple has more than 1 problem. It is important to consider even subtle ovulatory problems, as well as male factor issues and to evaluate the anatomy of the woman’s reproductive tract.



When should a couple seek evaluation and treatment for difficulty starting or growing a family? The general rule of thumb is that if the woman is younger than 35 years old, try for a year. If she is over 35, don’t wait more than 6 months to seek professional assistance. There is some good reasoning behind these suggestions. If a young healthy couple has unprotected intercourse (does nothing to prevent pregnancy), there is an 85% to 90% probability she will become pregnant within a year. After the age of 35, a woman’s fertile potential declines dramatically and progressively. In fact, about 70% of women over the age of 35 will require some assistance to become pregnant. After the age of 40, potential for a pregnancy falls off the cliff. Well, it is reasonable advice to try for 6 months to a year, if there is no known problem. Many couples have known issues which impair fertility. To me, it makes no sense to wait a year to pursue medical intervention if you already know there is a problem. Please remember that most issues impairing fertility do not totally prevent pregnancy. Most problems merely decrease the odds that a couple will achieve a pregnancy. It is also important to remember that the most anyone providing professional help can do is shift the odds in favor of the couple being treated. Another point that should be recognized is that most infertile couples have more than 1 problem. I try to try to identify all of them before developing a treatment plan.

Obviously, a woman cannot become pregnant if she does not ovulate. There are all kinds of things you can buy which claim to tell you if you ovulate. Well, not really. Let’s talk about some of them. A free recommendation is to look for copious clear egg white-like mucus coming from your vagina. That is cervical mucus. Production of cervical mucus is stimulated by estrogen. High estrogen levels can produce a lot of cervical mucus, but that really has nothing to do with ovulation. True, estrogens are high right before ovulation, but many women have high estrogen levels without ovulating.

Another technique which some people use to try to detect ovulation is to graph basal body temperatures. When you sleep, your body actually cools off a few tenths of a degree Fahrenheit. If you take your temperature before you get out of bed to use the toilet, even before you kiss your husband good morning, you will record the lowest temperature your body is all day – your basal temperature. The hormone made after ovulation, progesterone will cause basal temperature to raise a few tenths of a degree. There are 2 problems with this technique, other than forgetting to do it. One is that it provides no predictive value. The rise of basal temperature takes place a few days after progesterone production. By then, it is too late to try to become pregnant that cycle. An even greater weakness of the technique is that women can go through all the hormonal changes of ovulation without releasing the egg – ovulating. You won’t become pregnant that way. This is not an uncommon problem for infertile couples.

~Stay Tuned for Part Two~


Dr. Jacobs is a Reproductive Endocrinologist, practicing in Carrollton, Texas, a northern suburb of Dallas. He completed his residency training in obstetrics and gynecology at Baylor College of Medicine in Houston, and remained at that institution to become its first fellow once Baylor achieved accreditation for an advanced training program in Reproductive Endocrinology and Infertility. Dr. Jacobs has served on the faculty of several medical schools and was director of Reproductive Endocrinology at Texas Tech Health Science Center in Amarillo. Currently, in addition to his clinical activities caring for infertile patients and those with recurrent pregnancy loss, he is Chairman of the IVF committee at Baylor Medical Center in Carrollton.
Barry Jacobs, M.D., 4323 M. Josey Lane, Suite #201, Carrollton, TX 75010 www.texasfertility.comPhone: 972-394-9590 Fax: 972-394-9597