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Pacific Fertility Center

55 Francisco Street,
Suite 500
San Francisco,
CA 94133
TEL: 888-834-3095
FAX: 415-834-3080
www.InfertilityDoctor.com
Info@PacificFertility.com



Our Promise

As a unified team, guided by the highest ethical standards, we provide our patients with the best quality, individualized, compassionate fertility care.
SCIENCE PULSE    Progesterone 101

Progesterone is the hormone that prepares the uterus and endometrial lining to support an early pregnancy (Progesterone = “Pro-gestation hormone”). Produced in the ovary between ovulation and the following menstrual period, and by the placenta in the early embryo, progesterone stimulates cells in the endometrial lining to become receptive to the early embryo and, after implantation, to support growth of the embryo. Without progesterone, implantation could not occur; if progesterone were to be removed in early pregnancy, miscarriage would be certain to follow.

Hormones are produced in the ovary by the developing follicle, or egg sac. In the first two weeks of the menstrual cycle, as the egg sac matures, stimulated by Follicle Simulating Hormone (FSH) and Luteinizing Hormone (LH) from the pituitary, the follicle increases its production of estrogen to a peak just before ovulation. At the mid-cycle surge of LH, the follicle abruptly shuts down its estrogen production pathway, converting over to producing large amounts of progesterone. The follicle becomes the corpus luteum, a richly vascularized progesterone production factory.

As the pregnancy is established, the placenta produces chorionic gonadotropin, hCG, a hormone that stimulates the corpus luteum to produce additional progesterone. hCG is very similar to LH, binds to the same receptors, and stimulates the ovary much like LH. Rising hCG stimulates rising progesterone, which strengthens the pregnancy and allows it to produce more hCG, again increasing progesterone; this feedback loop is essential to enabling a strong pregnancy.

Progesterone is essential to the development of the early embryo. Progesterone from the corpus luteum circulates through the bloodstream to the uterus, where the endometrium that has been prepared by estrogen starts to change to support the early pregnancy. This change in the endometrial lining, luteinization, is essential for the embryo. The role of the corpus luteum was demonstrated years ago in experiments where the ovary containing the corpus luteum was removed; miscarriage immediately followed. More recently, progesterone antagonists, such as RU-486, which block the progesterone receptor, have been used in animal studies to induce miscarriage when given in early pregnancy.

Progesterone also has effects on the immune system, stimulating protective proteins, such as HLA-G, in the early pregnancy (Yie, Xiao et al. 2006). Without HLA-G the maternal immune system would reject the embryo, therefore, production of HLA-G antigens are critical to protecting the early pregnancy. Progesterone plays an important role in stimulating HLA-G and preventing rejection of the embryo.

Progesterone also acts as a chemoattractant for sperm (Albano, Smitz et al. 1999; Teves, Barbano et al. 2006). Progesterone in tiny amounts will draw sperm, and may attract sperm to the egg after ovulation. Uterine contractions, which play a role in sperm movement, are also controlled by progesterone.

Because it aids in creating a receptive environment for the embryo, insufficient progesterone can be a source of infertility and miscarriage. Low progesterone levels will result in luteal phase defect, a condition in which there is insufficient hormonal support for the early pregnancy. Failure of implantation of an otherwise healthy embryo, or loss of an early pregnancy, may occur with luteal phase defect. Some women do not produce any progesterone at all, for example, after menopause, or when a menopausal state is temporarily induced using medications to prevent ovulation. Without progesterone, pregnancy cannot occur.

The progesterone receptor mediates the action of the hormone and is critically important to pregnancy; some cases of infertility may be related to abnormalities in the progesterone receptor (Spandorfer, Normand et al. 2006). A simple alteration in the genetic code for the progesterone receptor is common in patients with infertility, and appears to be associated with poorer pregnancy outcomes.

The method of In Vitro Fertilization (IVF) is associated with luteal phase defects and low progesterone levels (Albano, Smitz et al. 1999). With IVF treatment, many of the cells that produce progesterone are removed from the ovary in the course of oocyte retrieval. In addition, the use of GnRH agonists and antagonists (leuprolide, ganirelix, cetrorelix) prevent the release of LH and FSH from the pituitary, removing the primary stimulus for progesterone production from the ovary. Progesterone levels may not be adequate to support the pregnancy, resulting in a luteal phase defect, implantation failure, and early miscarriage.

For treatment, progesterone usage falls into two broad groups, progesterone supplementation, where progesterone is produced in the ovary and supplemented with medication, and progesterone replacement, where there is no natural progesterone production. Progesterone replacement would be used in an oocyte donation recipient. Since ovulation occurs in the donor, and there is no natural progesterone in the recipient, all progesterone must be administered. Progesterone replacement is also common for cryopreserved embryo transfers, though natural cycles can also be used in many women with regular menstrual cycles. Medical supplementation might be used in a variety of conditions associated with luteal phase defect or to reduce the risk of early miscarriage associated with low progesterone levels.

Progesterone is supplemented medically to reduce the risk of pregnancy problems arising from low progesterone levels. Progesterone may be given orally, by vaginal supplement, by injection, or its production enhanced by injection of hCG, which stimulates the corpus luteum to produce additional progesterone(Pouly, Bassil et al. 1996).

Oral progesterone is relatively weak in its effect. Absorbed through the upper intestine, progesterone taken orally is metabolized in the liver. This is known as “first pass effect”, because the hormone passes through the liver first before traveling to its site of action. These metabolites are not effective in inducing luteinization and can induce effects on the central nervous system such as sedation. Very little active progesterone is available after oral use (Friedler, Raziel et al. 1999).

Vaginal progesterone, in the form of creams, gels, and suppositories, is highly effective in supplementing or replacing natural progesterone, and has been the most popular form of progesterone supplementation. Progesterone is absorbed through the vaginal wall and moves through local circulation directly to the endometrium. Levels are sufficient to induce the normal changes in endometrial lining to support the early pregnancy (Pritts and Atwood 2002). The primary clinical concern with vaginal progesterone is the variability in absorption. While most women absorb progesterone vaginally without difficulty, some may not; as an indirect mode of administration, one cannot be certain of the amount that is absorbed.

Progesterone by intramuscular injection is well absorbed, and in some ways closest to natural ovarian secretion (Lightman, Kol et al. 1999). High serum levels of progesterone are achieved with effective preparation of the endometrium. Traditional intramuscular injections, in an oil base, require a relatively large needle; local reactions to the oil base at the site of injection are common. Newer preparations of intramuscular progesterone, such as progesterone ethyl oleate, are considerably easier to inject, but still require daily administration. Injectable progesterone remains the primary progesterone for those patients that produce no natural progesterone, such as for a donated oocyte recipient, or for a frozen embryo transfer in a medicated cycle.

hCG, by acting directly on the ovary, is a good stimulant to progesterone production (Herman, Raziel et al. 1996). Its use requires that an active corpus luteum be present, so it can only be used in a natural or stimulated ovulation cycle. It produces good progesterone levels and reduces the risk of luteal phase defect (Mochtar, Hogerzeil et al. 1996). hCG requires periodic injections and may increase the risk of ovarian hyperstimulation syndrome in patients that have been on fertility drugs. As the hormone that is measured in a pregnancy test, hCG causes a false positive pregnancy test, potentially confusing the diagnosis of early pregnancy. hCG is used occasionally to supplement progesterone production in women with an active corpus luteum.

Vaginal and injectable progesterone appear to be similar in actions on the endometrial lining (Khan, Richter et al. 2007); while the amount of progesterone absorbed can be dramatically different, the clinical effects are similar. Progesterone receptors appear to be saturated at fairly low levels of progesterone in the blood, and additional progesterone does not seem to increase pregnancy rates or reduce miscarriage rates. The specific route or agent for progesterone supplementation is probably not as important as assuring that at least some progesterone is present. Equivalent pregnancy rates have been shown using vaginal gels, progesterone vaginal capsules, and progesterone in a dissolving effervescent vaginal tablet (Schoolcraft, Miller et al. 2007). Vaginal and injected progesterone, in general, show higher bioavailability than oral progesterone.

In patients with no ovarian function, recipients of egg donors, or those patients utilizing cryopreserved embryos in medicated (estrogen/progesterone replaced) cycles, all progesterone must be supplied medically. These patients require a reliable source of progesterone, and injectable progesterone has been established as the best standard (Prapas, Prapas et al. 1998). Vaginal progesterone has also been used successfully, though less commonly. In these patients, progesterone replacement must be continued for an extended period. Because there is no corpus luteum in the ovary, the rising hCG from the placenta cannot stimulate progesterone production, as it would in a conventional pregnancy.

In those patients with an active corpus luteum, such as after in vitro fertilization, external progesterone is required for only a limited time period. In the first two weeks after ovulation, the pregnancy is critically dependent on ovarian progesterone. After a positive pregnancy test, progesterone administration can be stopped entirely (Proctor, Hurst et al. 2006), relying on the embryo to stimulate the corpus luteum through the placental hCG effect on the ovary.

Leuprolide, a GnRH agonist, seems to supplement progesterone and its actions. A single injection of a GnRH agonist releases LH from the pituitary, stimulating progesterone production in the ovary, and may act directly on the endometrium and the embryo, enhancing implantation (Pirard, Donnez et al. 2006). With more study, this may prove to be a useful adjunct to use of progesterone.

 Philip Chenette, MD

References

Albano, C., J. Smitz, et al. (1999). "Luteal phase and clinical outcome after human menopausal gonadotrophin/gonadotrophin releasing hormone antagonist treatment for ovarian stimulation in in-vitro fertilization/intracytoplasmic sperm injection cycles." Hum. Reprod. 14(6): 1426-1430.

Friedler, S., A. Raziel, et al. (1999). "Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotrophin-releasing hormone agonist: a comparative study between vaginal and oral administration." Hum. Reprod. 14(8): 1944-1948. Herman, A., A. Raziel, et al. (1996). "The benefits of mid-luteal addition of human chorionic gonadotrophin in in-vitro fertilization using a down-regulation protocol and luteal support with progesterone." Hum. Reprod. 11(7): 1552-1557.

Khan, Richter, et al. (2007). "Case-Matched Comparison of Intramuscular Versus Vaginal Progesterone for Luteal Phase Support After In Vitro Fertilization and Embryo Transfer." Fertility and Sterility 87(4): S13-S13.

Lightman, A., S. Kol, et al. (1999). "A prospective randomized study comparing intramuscular with intravaginal natural progesterone in programmed thaw cycles." Hum. Reprod. 14(10): 2596-2599.

Mochtar, M. H., H. V. Hogerzeil, et al. (1996). "Endocrinology: Progesterone alone versus progesterone combined with HCG as luteal support in GnRHa/HMG induced IVF cycles: a randomized clinical trial." Hum. Reprod. 11(8): 1602-1605.

Pirard, C., J. Donnez, et al. (2006). "GnRH agonist as luteal phase support in assisted reproduction technique cycles: results of a pilot study." Hum. Reprod. 21(7): 1894-1900.

Pouly, J. L., S. Bassil, et al. (1996). "Endocrinology: Luteal support after in-vitro fertilization: Crinone 8%, a sustained release vaginal progesterone gel, versus Utrogestan, an oral micronized progesterone." Hum. Reprod. 11(10): 2085-2089.

Prapas, Y., N. Prapas, et al. (1998). "The window for embryo transfer in oocyte donation cycles depends on the duration of progesterone therapy." Hum. Reprod. 13(3): 720-723.

Pritts, E. A. and A. K. Atwood (2002). "Luteal phase support in infertility treatment: a meta-analysis of the randomized trials." Hum. Reprod. 17(9): 2287-2299.

Proctor, Hurst, et al. (2006). "Effect of progesterone supplementation in early pregnancy on the pregnancy outcome after in vitro fertilization." Fertility and Sterility 85(5): 1550-1552.

Schoolcraft, Miller, et al. (2007). "Efficacy of a Novel Form of Vaginal Progesterone on Continuing Pregnancy Rates in Women Undergoing IVF with Elevated BMI and Advanced Age." Fertility and Sterility 87(4): S24-S24.

Spandorfer, Normand, et al. (2006). "O-7 A G->A POLYMORPHISM AT POSITION +331 IN THE PROGESTERONE RECEPTOR GENE IS STRONGLY ASSOCIATED WITH IVF OUTCOME." Fertility and Sterility 86(3): S3-S4.

Teves, Barbano, et al. (2006). "Progesterone at the picomolar range is a chemoattractant for mammalian spermatozoa." Fertility and Sterility 86(3): 745-749.

Yie, S.-m., R. Xiao, et al. (2006). "Progesterone regulates HLA-G gene expression through a novel progesterone response element." Hum. Reprod. 21(10): 2538-2544.

Philip Chenette, MD has spent over a decade specializing in the treatment of patients with complex infertility diagnoses, especially in women with decreased ovarian reserve and women over 40. As a member of the International Society for Stem Cell Research, he is working to apply the concepts of stem cell therapy to help others have healthy children. His expertise is recognized by peers who select him as “Best Doctor” in national surveys (See www.BestDoctors.com).

               
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PATIENT ODYSSEY    Salvaging Our IVF Cycle

  My husband and I have a long history together. We met in high school, and after 10 years of marriage, we were ready to have a family. My sister had experienced trouble getting pregnant, so as a result I worried that I might have the same problem.

My worries were partially confirmed when my husband and I unsuccessfully tried to conceive. In our case, we discovered we had the unlucky combination of both male and female factor infertility. At that point we were under the care of our gynecologist. On our doctors' recommendation, we went through IUI near the end of 2003. It was a nightmare for a lot of reasons. I reacted poorly to Clomid and did not conceive.

While I was still trying to conceive, my sister was happily on her way to having a family. She had gone to the next level of care: an expert reproductive endocrinologist at Pacific Fertility Center. We were of course delighted to hear the news of her pregnancy, but at the same time frustrated because we were still not pregnant. We had always thought that once we were ready to have a family, we would be able to get pregnant easily and naturally.

After our disastrous IUI cycle, we tried again naturally, but to no avail. Frustrated and tired, we took a break. After a while, I spoke with my sister Alison, who referred us to Dr. Herbert at Pacific Fertility Center. He was wonderful and had great bedside manner. He was positive and upbeat despite our combined infertility diagnosis. We went straight to IVF with Gonal F and Repronex. Unfortunately, my body didn't respond well.

I really appreciated Dr. Herbert during this discouraging time. He was frank with us and indicated that my follicles were not looking good. Without good follicles, the ability to retrieve a reasonable number of quality eggs was in question, so we did not continue our IVF cycle. Dr. Herbert was very flexible; he listened, explained our options and didn't dictate what we should do. He suggested IUI as a way to salvage the IVF cycle and much to our surprise, we became pregnant! When I got the good news that my husband and I were going to be parents for the first time, I was “over-the-top” happy calling everybody I knew. In addition, on our first ultrasound, we saw two beating hearts. We not only were pregnant, but also were pregnant with twins!

The irony is that after my sister Alison had twins, I too envisioned having twins. During our initial OB ultrasound, Dr. Herbert indicated that he saw two heartbeats. We had a scare at one point as we thought I had experienced a miscarriage. However, I had just had some bleeding and passed a blood clot. I appreciated Dr. Herbert during this time, as he remained calm at all times. Much to our delight, I gave birth to a healthy, beautiful set of twins (Justin and Eva) who are now over a year old.

I thoroughly enjoyed my experience at PFC. They were great from a logistical standpoint, and were great about getting all of the paperwork out of the way quickly. I appreciate the nurses—Anne was awesome and whenever we called she was very kind and understanding. I loved going to appointments as it was such as positive experience. Additionally, I appreciate PFC for their professionalism. Dr. Herbert was so experienced and knew what he was doing the whole time; I trusted him a lot. I truly love our children. It is wonderful for my sister and me to be able share experiences as we learn about the joys of parenthood firsthand. It is sweet irony indeed.

 Leslie

Leslie's journey to a successful pregnancy was a bit unconventional but contains several important messages for you, our patients. The stimulation of her ovaries during her first IVF attempt did not progress as we had hoped. There were fewer follicles and some were large and others small (follicle disparity). Had this been her final attempt on very high doses of medication, we might have proceeded on to egg retrieval. However, we felt the stimulation was suboptimal and we expected to improve this process in another cycle by changing the medication regimen. As Leslie and her husband were diagnosed with unexplained infertility, we also felt she might conceive by ovulating the few larger follicles which were present and using intrauterine insemination. Fortunately we were correct, and Leslie now has two wonderful children. These conversions from a planned IVF cycle to IUI cycle can produce pregnancies as often as 10% of the time as long as there are no other fertility factors like tubal damage or severe sperm problems and the age of the woman is not advanced (less than 38 years). Leslie's story is a good example of persistence in spite of initial disappointment, of using all the options available in the most effective manner, and of “keeping the faith”. We hope Leslie's story can be an inspiration to others who may face similar disappointments on their journey to parenthood.

 Carl Herbert, MD

               
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 Many women are aware that very low body weight and low percentages of body fat can compromise ovulation and chances for successful conception. What many don't realize is that excess body fat can also affect one's chances.

A review of the literature shows that the majority of studies published report decreased chances of conceiving with in vitro fertilization (IVF) if a woman in significantly overweight. IVF data is useful to study this issue because all the women undergo similar treatments and because follow-up data on pregnancies is usually readily accessible to researchers. It may also be true that excess body weight is a negative factor in spontaneous conception and non-IVF treatment as well.

How much of a factor is weight in decreasing conception? One study from the Netherlands reported a higher cycle cancellation rate due to poor response to stimulation and lower fertilization rates1 than normal weight women. Another study from Norway reported higher requirements for stimulation medications and a higher miscarriage rate in the first 6 weeks of pregnancy2. One of the largest studies was from Cornell and reported on 960 women undergoing IVF. Although they did not find a statistically significant decrease in clinical pregnancy rates, rates of cycle cancellation were higher and gonadotropin dose requirements were greater in the obese patients3. Another large study from Iowa (1,293 patients) looked at outcomes in women who were obese and morbidly obese. Again, this study found that clinical pregnancy rates per egg retrieval were similar to normal-weight women but cancellation rates and gonadotropin dose requirements were much higher in the obese women. Furthermore, rates of pregnancy complications such as preeclampsia, gestational diabetes and cesarean section were higher in the obese women4.

How much weight is significant for this effect? Most studies calculate weight as Body Mass Index, or BMI. This calculation takes in weight vs. height. To calculate your BMI, many websites such as the one at the Centers for Disease Control ( www.cdc.gov/nccdphp/dnpa/bmi/index.htm) can provide a calculator. There is also a chart at the federal government's website www.consumer.gov/weightloss/bmi.htm. You just need to know your height in feet and inches and weight in pounds. A normal BMI is between 18.5 and 24 and overweight is a BMI of 25 to 30. A BMI of 30 or more is considered obese and 40 or more is considered morbidly obese.

In general, it appears that excessive body weight can negatively impact a woman's chances for conception and for a healthy, uncomplicated pregnancy and birth. It makes sense that being a normal body weight and in good shape is a good idea and should be a goal for aiding successful conception.

 Carolyn Givens, MD

References

1. Gynecol Obstet Invest. 2005;59(4):220-4. Epub 2005 Mar 7. Obesity and Clomiphene Challenge Test as predictors of outcome of in vitro fertilization and intracytoplasmic sperm injection.van Swieten EC, van der Leeuw-Harmsen L, Badings EA, van der Linden PJ.

2. Hum Reprod. 2004 Nov;19(11):2523-8. Epub 2004 Aug 19. Impact of overweight and underweight on assisted reproduction treatment. Fedorcsak P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N, Omland AK, Abyholm T, Tanbo T.

3. J Reprod Med. 2004 Dec;49(12):973-7 Obesity and in vitro fertilization: negative influences on outcome. Spandorfer SD, Kump L, Goldschlag D, Brodkin T, Davis OK, Rosenwaks Z.

4. Obstet Gynecol. 2006 Jul;108(1):61-9. Obstetric outcomes after in vitro fertilization in obese and morbidly obese women. Dokras A, Baredziak L, Blaine J, Syrop C, VanVoorhis BJ, Sparks A.

               
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