1) Downregulation of the anterior pituitary gland by a gonadotropin releasing hormone agonist (GnRH-agonist). 

The most commonly used GnRH-agonist in the USA is Lupron. The purpose of downregulation is to temporarily take away the ability for a region of the brain known as the anterior pituitary gland to release the LH surge. Normally, the anterior pituitary will release a surge of LH after a certain duration and elevation of estrogen levels. With COH, the LH surge may occur early, before the cohort of recruited follicles / eggs have reached maturity. By down-regulating the anterior pituitary gland, Lupron prevents the possible occurrence of a premature LH surge. In fact, with Lupron down-regulation, the LH surge cannot generally occur and the LH surge necessary to achieve final maturation of the eggs must be administered in the form of an injection of hCG (human chorionic gonadotropin, "Profasi," "Pregnyl," "Novarel").

When Lupron is administered, it will initially cause an increase in FSH and LH levels followed by a suppression or downregulation in FSH and LH levels. The suppression of endogenous FSH levels means more exogenous FSH must be administered to achieve a given level of ovarian stimulation (Horvath P, 1988). The traditional Lupron starting dose is 1 mg by subcutaneous daily injection.

2) Controlled Ovarian Hyperstimulation with Gonadotropins.

Once downregulation has been achieved, the daily Lupron dose is usually halved (e.g. from 1 mg to 0.5 mg) and stimulation of the ovaries with gonadotropins commences. Stimulation continues until follicle maturity is reached and the triggering injection of hCG is given. Gonadotropins come in a few forms with several different brand names:

Pergonal, Humegon, Repronex: from menopausal urine, contain FSH & LH, administered by intramuscular injections (Repronex has also been approved for subcutaneous injections) 

Fertinex: from menopausal urine, FSH only, subcutaneous injection

Gonal-F, Follistim: from recombinant technology, FSH only, subcutaneous injection

Strategies to Improve Ovarian Stimulation

Generally, the following strategies have not been vigorously studied or compared; some are used in combination. It is expected with time, some will prove untenable and be abandoned, a few will be found efficacious. There is no magic solution applicable to all poor responders; there will always be the need to individualized treatment. Lastly, some women will not develop any or only a single dominant follicle regardless of which COH treatment regimen is used. For these women, the choices are adoption, donor eggs, or in some selected cases, ART with a single dominant follicle.

• Limit or eliminate exposure to GnRH-agonist (Lupron)
  Because Lupron decreases endogenous FSH production, Lupron may make it more difficult to stimulate the ovaries (Horvath P, 1988). Therefore, avoiding Lupron all together (Jansen CA, 1998), or stopping Lupron after downregulation has been achieved (Pantos K, 1994; Faber BM, 1998) or decreasing the Lupron dosages (Olivennes F, 1996) have been advocated. Without Lupron, one risks the premature surge of LH. Even if a premature rise in LH does not cause premature ovulation, it can cause premature luteinization of the follicle and possible subsequent diminished oocyte fertilization, implantation, and pregnancy rates. At Reproductive Partners, we usually recommend half the usual Lupron dose for low responders. Controlled studies have not confirmed any benefit to stopping the GnRH agonist.

• Birth Control Pills
  Lupron had traditionally been started in the mid-luteal phase (about 1 week after spontaneous ovulation) or early in the menstrual cycle. Occasionally with midluteal phase start, Lupron would be inadvertently administered to someone who is actually pregnant. Preceding Lupron administration with birth control pills eliminates this possibility. Birth control pills may also decrease unwanted ovarian cyst formation and allows more flexibility in scheduling. Furthermore, it had been argued that birth control pills will suppress ovarian androgen (male-type hormone) levels, this may aid in ovarian stimulation. (Lindheim S, 1996; Mulangi AS, 1997)
   
• GnRH-antagonist (Antagon=Ganirelix, Cetrotide=Cetrorelix, Antide=Iturelix) (Figure 2)
  Remember Lupron is a GnRH-agonist. There is a stimulatory or "flare" phase prior to the inhibitory or down-regulation effect. In contrast, the newly released GnRH-antagonists, simply cause inhibition through competitive binding of the GnRH receptors. Potential benefits of GnRH-antagonist over GnRH-agonist are less time and gonadotropins required to complete a cycle. Possibly, one can have the best of both worlds with the antagonists, avoidance of the premature LH surge without negatively impacting ovarian stimulation. The experience of using GnRH-antagonist with poor responders is preliminary (Craft I, 1999).
   
• Growth Hormone (GH) or Growth Hormone Releasing Hormone (GH-RH)
  Because it is known that GH (through a hormone called insulin-like growth factor-I) can potentiate the effects of FSH, both GH and GH-RH have been used in poor responders. Unfortunately, since initial promising reports, there have been several well-designed studies indicating adjuvant GH did not improve ovarian response or cycle outcome (Levy T, 1993; Suikkari A, 1996). At Reproductive partners we generally do not use GH or GH-RH.
   
• Higher doses of gonadotropin or different combinations of gonadotropin
  Using the intuitive logic that more is better, studies have been conducted with high doses of gonadotropins given to poor responders. However, there appears to be little benefit when more than about 6 ampules of gonadotropins are given per day.

  FSH is actually a complex structure consisting of two peptide (protein) chains, each with two carbohydrate (sugar) side chains. Variations of the carbohydrate side chain leads to different "isoforms" of FSH. Different isoforms of FSH have different potencies and duration. FSH was originally derived from the urine of postmenopausal women (uFSH). FSH is now available from recombinant DNA technology (rFSH), synthesized in a Chinese hamster ovary cell line with transfected, inserted DNA. Studies have argued that rFSH may be more potent than uFSH. The relatively higher proportion of alkaline isoforms in rFSH might explain the possible increased potency of rFSH over uFSH. The alkaline isoforms of rFSH more closely resemble natural FSH composition around ovulation. (In a natural cycle, FSH isoforms are more acidic in the beginning of the cycle, relatively alkaline midcycle, and are more acidic again after ovulation.) 

  In reality, the story is much more complex than this, e.g. there are issues of sugar side chain complexity and potency, acidity (sialic acid content) prolonging half life and thus increasing potency, and controversies of lab potency versus clinical potency. What pattern or patterns of FSH isoforms are optimal for ovarian stimulation in women or for which women is still being investigated. 

  Therefore, although the pharmaceutical companies tout the superiority of newer, more costly, gonadotropin products, the real picture is less clear. There is no doubt that the composition of the rFSH product (Gonal F, Follistim) is more consistent and free of contaminating proteins than uFSH (Metrodin, Fertinex). These benefits aside, however, it is possible that there are women who respond better to the isoform pattern of uFSH. (This also leads to the interesting idea that perhaps there are women who respond better to clomiphene citrate than any exogenously administered FSH, uFSH or rFSH. This is because clomiphene works by inducing an increase in endogenous FSH release with its unique isoform pattern.)

  Lastly, complete absence of endogenous LH (levels <0.5 IU/L) is detrimental to follicular, luteal, and embryonic quality. There are three clinical situations where profound LH deprivation is likely and the newer products containing only FSH should be supplemented with gonadotropin products containing LH (Pergonal, Humegon, Repronex): 1) In women who are unable to produce endogenous gonadotropins (Balasch J, 1995), 2) In protocols where Lupron is discontinued (Sungurtekin U, 1995; Cedrin-Durnerin I, 2000), and 3) With use of the GnRH-antagonists. Finally, there is the possibility that better outcomes may also be achieved by adding LH after standard long protocol with full dose Lupron (1mg / 0.5mg) or birth control pill / Lupron protocols (Westergaard LG, 2000).
   
   

• Microdose-Lupron Flare (Figures 1, 2)
  As noted above, Lupron stimulates FSH and LH release prior to decreasing FSH and LH levels. "Flare" protocols utilize this initial stimulating effect of Lupron. After initial promising results, later studies have argued poorer outcomes with "flare" regimens. One possible explanation is that the initial rise in LH causes increases in progesterone production and testosterone levels that are detrimental to follicular / egg development. This lead to the development of "microdose-Lupron flare" regimens. These protocols are characterized by pretreatment with birth control pills, followed by an extremely low dose of Lupron. With this design, the elevations in LH, progesterone and testosterone are minimized (Surrey E, 1998). Microdose-Lupron flare is a valuable treatment in selected poor responders, resulting in successful COH and pregnancies. 
   
• Alternative Medicine
  Despite it's growing popularity, there is almost no data regarding the use of alternative medicine techniques such as acupuncture and acupressure to enhance ovarian responsiveness. Although it is difficult to adopt a different paradigm, a complete understanding of an alternative paradigm is not needed to evaluate its efficacy. A literature search finds most studies are merely descriptive, there are a few with statistical analysis and hopefully there will be more in the future (Gerhard I, 1992).

With the "long protocol," ovarian response may be enhanced in "poor responders" by:

• Preceding the start of Lupron with Birth Control Pills. 
• Decreasing the amount of Lupron administered (e.g. from the standard 1 mg / 0.5 mg to 0.5 mg / 0.25 mg). 
• Assuring the presence of a minimum amount of LH by administering gonadotropin with LH in clinical situations of profound LH deprivation. Other strategies may include: 
• Using the Microdose-Lupron Flare protocol to be able to achieve a better ovarian response and pregnancy in some women who have failed traditional "long protocol" COH. 
• Considering Antagon as there is preliminary promising experience with the use of the GnRH-antagonist with poor responders. 

Balasch J, Miro F, Burzaco I, Casamitjana R, Civico S. Ballesca JL, Puerto B, Vanrell JA. The role of luteinizing hormone in human follicle development and oocyte fertility: evidence from in-vitro fertilization in a woman with long-standing hypogonadotrophic hypogonadism and using recombinant human follicle stimulating hormone. Hum Reprod 1995; 10:1678-83.

Cedrin-Durnerin I, Bidart JM, Robert P, Wolf JP, Uzan M, Hugues JN. Consequences of gonadotrophin secretion of an early discontinuation of gonadotrophin-releasing hormone agonist administration in short-term protocol for in-vitro fertilization. Hum Reprod 2000;15:1009-14. 

Craft I, Gorgy A, Hill J, Menon D, Podsiadly B. Will GnRH antagonists provide new hope for patients considered 'difficult responders' to GnRH agonist protocols? Hum Reprod 1999;14:2959-62.

Faber BM, Mayer J, Cox B, Jones D, Toner JP, Oehninger S, Muasher SJ. Cessation of gonadotropin-releasing hormone agonist therapy combined with high-dose gonadotropin stimulation yields favorable pregnancy results in low responders. Fertil Steril. 1998;69:826-30.

Gerhard I, Postneek F. Auricular acupuncture in the treatment of female infertility. Gynecol Endocrinol 1992;6:171-81.

Horvath P, Styler M, Hammond J, Shelden R, Kemmann E. Exogenous gonadotropin requirements are increased in leuprolide suppressed women undergoing ovarian stimulation. Fertil Steril 1988;49:159-62.

Jansen CA, van Os HC, Out HJ, Coelingh Mennink HJ. A prospective randomized clinical trial comparing recombinant follicle stimulating hormone (Puregon) and human menopausal gonadotrophins (Humegon) in non-down-regulated in-vitro fertilization patients. Hum Reprod. 1998;13:2995-9.

Pantos K, Meimeth-Damianaki T, Vaxevanoglou T, Kapetanakis E. Prospective study of a modified gonadotropin-releasing hormone agonist long protocol in an in vitro fertilization program. Fertil Steril. 1994;61:709-13.

Levy T, Limor R, Villa Y, Eshel A, Eckstein N, Vagman I, et al. Another look at cotreatment with growth hormone and human menopausal gonadotropins in poor responders. Hum Reprod 1993;8:834-9. 

Lindheim S, Barad D, Witt B, Ditkoff E, Sauer M. Short-term gonadotropin suppression with oral contraceptives benefits poor responders prior to controlled ovarian hyperstimulation. J Assist Reprod Genet 1996;16:745-7.

Mulangi AS, Nelson-White TM, Racowsky C, Gelety TJ. Follicular phase endocrine response to oral contraceptives followed by GNRH-agonist for down regulation prior to COH for the purpose of IVF." American Society for Reproductive Medicine 1997 Annual Meeting Program Supplement, p. S7, abstract 0-010.

Olivennes F, Righini C, Fanchin R, Torrisi C, Hazout A, Glissant A, et al. A protocol using a low dose of gonadotropin-releasing hormone agonist might be the best protocol for patients with a high follicle stimulation hormone concentration on day 3. Hum Reprod 1996;11:1169-72.

Suikkari A, MacLachan V, Koistinen R, Seppala M, Healy D. Double-blind placebo controlled study: human biosynthetic growth for assisted reproductive technology. Fertil Steril 1996;65:800-5. 

Sungurtekin U, Jansen RPS. Profound luteinizing hormone suppression after stopping the gonadotropin-releasing hormone-agonist leuprolide acetate. Fertil Steril 1995;63:663-5.

Surrey E, Bower J, Hill D, Ramsey J, Surrey M. Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil Steril 1998;69:419-24.

Westergaard LG, Laursen SB, Anderson CY. Increased risk of early pregnancy loss by profound suppression of luteininzing hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction. Hum Reprod 2000;15:1003-8. 

High-Tech Internet Technology Helps High-Tech Fertility Technology 

We are pleased to announce the premiere of a new flash animation presentation at Reproductive Partners website, (www.2reproduce.com), called "A Lifetime of Hope in Just About 30 Days." Much of what happens in our lives is measured in 30-day cycles: the pages turned on a calendar, the time between utility bills and rent or mortgage payments. The 30-day time frame is also significant for couples with infertility, as it is the approximate interval it takes to complete an Assisted Reproductive Technology (ART) procedure.

"In the course of these procedures, couples invest infinitely more than their time and money," said RPMG physician Arthur Wisot, M. D. "Their most important hopes and dreams may become a reality based on events that take place during a 30-day period."

Dr. Wisot and RPMG scientific director David Meldrum, M. D. co-authored the books "New Options for Fertility: A Guide to In Vitro Fertilization and Other Assisted Reproduction" in 1990, as well as "Conceptions and Misconceptions: A Guide Through the Maze of IVF and Other Assisted Reproduction Techniques," in 1997.

RPMG's "A Lifetime of Hope" takes those seeking information step-by-step through a complete ART procedure with a flash animation presentation of in vitro fertilization. Stimulation of eggs, egg retrieval and embryo transfer procedures, along with instructions used at RPMG facilities are explained in depth on the web site, which has received more than 317,000 hits in just one month.

Flash animation is the standard for blazingly fast and beautiful web pages, including full-screen navigation interfaces, technical illustrations, and long-form animations. It loads faster, is scalable, and boosts higher quality than other graphics formats.

"A Lifetime of Hope" was produced by Reproductive Partners Medical Group, Inc., developed by Alan Dale Webmasters, and supported by an educational grant from Organon, Inc.