OPINIONs 005: August 4, 2014
Approximately 10% of all women have abnormally low functional ovarian reserve (LFOR) at young ages, carrying and, therefore, carry a diagnosis of premature ovarian aging (POA), also called occult primary ovarian insufficiency (OPOI) or a diagnosis of outright premature ovarian failure (POF), also called primary ovarian insufficiency (POI). In addition, most women above age 38, and certainly those above age 40 years, have LFOR due to the natural loss of follicles (and eggs) that happens to all women as they age (also called the “natural ovarian aging” process).
For women with LFOR to have the best possible chances of pregnancy through fertility treatments, whatever the cause of LFOR, they have to receive significantly different treatment(s) than women with normal functional ovarian reserve (NFOR). We are dedicating an OPINION to this subject because, unfortunately, this fact is not widely recognized.
Some progress has been made in recent years by U.S. colleagues demonstrating that older women will be more successfully treated and will conceive more quickly and at lower costs if they are quickly entered into in vitro fertilization (IVF), rather than standard fertility treatment algorithms.1,2 Unfortunately, many fertility centers still recommend such traditional algorithms, which include multiple unsuccessful intrauterine insemination (IUI) cycles before IVF is initiated. Similarly, many insurance companies still mandate such traditional approach of multiple failed IUIs then IVF, even though such an approach is clearly less effective and more costly.
Lack of understanding surrounding some very basic differences between patients with LFOR and women with NFOR still hampers the most effective treatments at many fertility centers. This often results in disappointing treatment outcomes and, consequently, premature referrals into egg donation cycles, when patients with LFOR still might have reasonable pregnancy chances with use of their own eggs with appropriate treatments.3
Timely diagnosis of LFOR
Once women reach the critical age of 38-40 years, a diagnosis of LFOR is easy and automatic. However, even at reputable fertility centers, a diagnosis is frequently missed in younger women, because most IVF centers still do not utilize age-specific parameters to assess FOR. In other words, unless anti-Müllerian (AMH) hormone, follicle stimulating hormone (FSH) and/or antral follicle count (AFC) are assessed in an age-specific manner, a timely diagnosis will not be possible. CHR investigators4,5 and others have reported age-specific values for AMH and FSH. Investigators from CHR, in addition, recently demonstrated that women with LFOR, whatever the underlying etiology, usually also demonstrate low androgen levels.6 A combination of low age-specific AMH, low age-specific AFC and/or high age-specific FSH with low androgen levels, therefore, allows for timely and accurate diagnosis of POA/OPOI.
Without reaching timely diagnoses of POA/OPOI, timely treatments, of course, cannot be administered, and treatment approaches in young women with POA/OPOI will not be adjusted appropriately.
Why treatment approaches have to be modified in association with LFOR
Ovaries of women with LFOR, whatever the underlying causes, contain a smaller number of follicles. With medical ovarian stimulation they, therefore, produce fewer and poorer quality eggs in IVF cycles. Poorer oocyte quality in women with LFOR has only recently again been demonstrated.7 Smaller egg numbers and poorer egg quality, therefore, have to enter risk/benefit assessment for treatments of patients with LFOR. This is the crucial point this OPINION attempts to address, and will return to on a number of occasions.
As noted before, androgens in association with LFOR are usually low.6 As well documented in recent years, the ovarian environment, however, requires “normal” androgen levels, especially during early stages of follicle maturation, immediately after resting follicles are “recruited” and start their journey of maturation.8 If androgens during these small growing follicle stages are too low, fewer follicles develop into later stages, where they can be further stimulated with administration of standard fertility drugs (in the so-called gonadotropin-sensitive phase). As a consequence, women with LFOR in IVF cycles produce a low number of follicles and eggs of poor quality.
Supplementation with dehydroepiandrosterone (DHEA), which in the female body is mostly converted to testosterone, has been reported to improve egg numbers and quality in women with LFOR. These improvements.9 Improvements are however, of course, limited, and reflect the initial severity of a patient’s LFOR.
Investigators have, therefore, advocated supplementation of women with LFOR with DHEA prior to IVF starts.9(Please note conflict statement at end of this OPINION).
Because androgens have to affect small growing follicle stages, which still require at least 6-8 weeks of additional maturation to reach the gonadotropin-sensitive stages of follicles, DHEA supplementation (or supplementation with testosterone directly) has to be initiated for at least 6-8 weeks before IVF cycle start. CHR now actually monitors testosterone levels, and does not initiate IVF cycles until they reach desired ranges.
While androgen supplementation in women with LFOR appears to improve the number and quality of eggs in IVF cycles, it is important to repeat that women with LFOR will still produce only a relatively low number of eggs. Moreover, while egg quality will be improved, eggs and resulting embryos will, still, be more “marginal” in quality than in women with NFOR. Both of these inferior egg/embryo factors in women with LFOR are important reasons why, in addition to androgen supplementation, further IVF cycle treatment parameters have to be adjusted as well.
Egg numbers and egg quality
Women with LFOR produce relatively low egg and embryo numbers, often less than one might be ready to transfer. This is important because the medical literature in recent years has offered a number of new procedures, alleged to improve embryos selection (the ability to select “best” embryos), which often are indiscriminately applied as part of routine IVF cycles.
Consequently, poor prognosis patients with LFOR are undergoing IVF cycles like good prognosis patients with NFOR, utilizing identical embryo selection methods, including (i) embryo culture to blastocyst stage (days 5/6 after fertilization), (ii) preimplantation genetic diagnosis (PGS, see OPINION #2), which involves embryo biopsy at blastocyst stage to determine whether embryos are chromosomally normal (euploid) or abnormal (aneuploid) and, also increasingly, (iii) a new technique of automated fertilization and embryo observation by time-lapse photography in closed incubation systems (often called “embryoscopy,” see OPINION #3).
We in previous OPINIONs stressed that, based on CHR’s analysis of published worldwide data, neither blastocyst stage culture with PGS (OPINION #2) nor “embryoscopy” (OPINION #3) have so far established efficacy in improving IVF outcomes in general IVF populations.
For poor prognosis patients, who, as noted above, frequently produce fewer embryos than one would be willing to transfer, it is unclear why even proponents of embryo selection would support utilization of these techniques. In CHR’s opinion, in women with LFOR embryo selection, indeed, appears contraindicated because its utilization potentially reduces IVF pregnancy chances (for detail, see below). Embryo selection in women with LFOR, in addition, unnecessarily increases already often-unaffordable IVF cycle costs, and does so without producing any outcome benefits.
We also noted above the increased “fragility” of embryos in women with LFOR, even after androgen supplementation, In such patients CHR, therefore, recommend embryo transfer at cleavage stage (day-3 after fertilization), while other IVF centers, now, often indiscriminately, utilize embryo culture to blastocyst stage. Their argument in favor of blastocyst stage transfer is that embryos that do not survive between days-3 and blastocyst stage in the embryology laboratory also would not survive in utero if transferred on day-3 and, therefore would not lead to pregnancy.
This argument is, however, contradicted by two well documented observations: (i) Blastocyst-stage embryo transfer improves IVF pregnancy chances per embryo transfer only in good prognosis patients,10 and (ii) cumulative pregnancy chances from day-3 transfers are higher than from blastocyst stage transfers.11
CHR, therefore, believes that blastocyst stage embryo culture as well as PGS, individually and in combination, are contraindicated in women with LFOR since both, individually and in combination, reduce pregnancy and delivery chances in IVF. In women with LFOR these embryo selection procedures, therefore, have not been proven effective (these techniques, also in general infertility populations, have so far not been proven effective,OPINION #2 and OPINION #3) but have been demonstrated to actually reduce pregnancy and delivery chances if analyses of outcomes are correctly reported by “intent to treat” (i.e., with reference point cycle start, which does not falsely selects out good prognosis patients).12
Marketing and the media
Unfortunately, unrestricted embryo selection is aggressively marketed by economic interests, which are even successfully engaging lay media in these efforts. Recent reports on CNN (OPINION #2),13 in The Wall Street Journal14 and the The New York Times15 offered rather unbalanced opinions on the subject, and created the motivation for this and preceding OPINIONs.
CHR has previously expressed the opinion that embryo selection, as a concept, is not receiving critical enough review by the professions, including in medical journals (OPINION #2 and OPINION #3). Unbalanced reporting by the lay media, therefore, is not surprising.
Women with LFOR, whatever the underlying pathophysiology, require distinctively different clinical treatment strategies than women with NFOR. Strategies include pretreatment with androgen supplementation for weeks to months prior to IVF cycle start until androgen levels have normalized and, because of small egg/embryo numbers and poorer egg/embryo quality, avoidance of embryo selection techniques, which actually create risk for further reduction in pregnancy and delivery chances at unnecessary additional costs.
While these represent the main differences between CHR’s clinical treatment approach to women with LFOR and many, if not most, other IVF centers, treatment differences also include additional factors, like different ovarian stimulation protocols (microdose-agonist cycles, as initially recommended by Surrey et al16), differences in ovulation trigger timing (recently initiated at CHR) and close attention to additional patient-specific pathologies (like immune problems), which may require additional treatments.
CHR’s IVF cycle outcomes (reported on CHR’s website and to CDC as well as SART registries) in women with LFOR document the effectiveness of here proposed different approaches for women with LFOR. Readers interested in more detail are referred to a recent publication.3 Colleagues interested in more information are encouraged to contact CHR physicians directly.
CHR and some CHR investigators are inventors of a number of patents, which claim therapeutic benefits in women with LFOR from supplementation with androgens, including DHEA. These patents have been licensed to Fertility Nutraceuticals, LLC, and CHR and some CHR investigators receive patent royalties from this company. CHR’s Medical Director is also a shareholder in that company.
- Reindollar RH, Regan MM, Neumann PJ, Levine BS, Thornton KL, Alper MM, Goldman MB. A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertile Steril 2010;94:888-899
- Goldman MB, Thornton KL, Ryley D, Alper MM, Fung JL, Hornstein MD, Reindollar RH. A randomized clinical trial to determine optimal infertility treatment in older couples: the Forty and Over treatment Trial (FORT-T). Fertil Steril 2014;101:1574-1581
- Gleicher N, Kushnir VA, Weghofer A, Barad DH. The “graying” of infertility services: an impending revolution nobody is ready for. Reprod Biol Endocrinol 2014; 12:63
- Barad DH, Weghofer A, Gleicher N. Age-specific levels for basal follicle-stimulating hormone assessment of ovarian function. Obstet Gynecol 2007;109:1404-1410
- Barad DH, Weghofer A, Gleicher N. Utility of age-specific serum anti-Müllerian hormone concnetrations. Reprod Biomed Online. 2011;22:284-291
- Gleicher N, Kim A, Weghofer A, Kushnir VA, Shohat-Tal A, Lazzaroni E, Lee HJ, Barad DH. Hypoandrogenism in association with diminished functional ovarian reserve. Hum Reprod 2013;28:1084-1091
- Sunkara SK, Khalaf Y, Maheshwari A, Seed P, Coomarasamy A. Association between response to ovarian stimulation and miscarriage following IVF: an analysis of 124 351 IVF pregnancies. Hum Reprod 2014;1218-1224
- Prizant H, Gleicher N, Sen A. Androgen actions in the ovary: balance is key. J Endocrinol 2014; Epub ahead of print.
- Gleicher N, Barad DH. Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). Reprod Biol Endocrinol 2011;9:67
- Pandian Z, Maioribanks J, Ozturk O, Serour G, Bhattacharya S. Number of embryos for transfer following in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2013;7:CD003416
- Glujovsky D, Blake D, Farquhar C, Bardach A. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev 2102;7:CD002118
- Gleicher N, Kushnir VA, Barad DH. Preimplantation genetic screening (PGS) still in search of a clinical application: a systemic review. Reprod Biol Endocrinol 2014;12:22
- Reddy S. Fertility study warns of risks from multiple births. Wall Street Journal. http://online.wsj.com/news/articles/SB10001424052702304393704579529562629972886
- Pollack A. Fertility clinics scan for the strongest embryo. New York Times. http://www.nytimes.com/2014/07/12/health/fertility-clinics-scan-for-the-strongest-embryo.html
- Surrey ES, Bower J, Hill DM, Ramsey J, Surrey MW. Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil Steril 1998;69:419-4124