Lectures
Hypoandrogenism in association with diminished functional ovarian reserve

Speaker: Norbert Gleicher, MD, FACOG

Hypoandrogenism in association with diminished functional ovarian reserve

Lecture Type: Research in Brief

Dr. Gleicher discusses a recent publication in Human Reproduction that defines diminished ovarian reserve at all ages as androgen-deficiency state. Hum Reprod 2013;28(4):1084-91.

ABSTRACT
STUDY QUESTION: Is diminished functional ovarian reserve (DFOR) associated with low androgen levels?
SUMMARY ANSWER: Low androgen levels are associated with DFOR at all ages.
WHAT IS KNOWN ALREADY: Androgen supplementation via dehydroepiandrosterone (DHEA) has been reported to improve functional ovarian reserve (FOR); pregnancy rates in IVF cycles are associated with how well DHEA converts to testosterone (T); and androgen effects through the androgen receptor have been demonstrated in mice to beneficially affect early stages of follicle maturation.
STUDY DESIGN, SIZE, DURATION: In a controlled cohort study we investigated consecutive women presenting to our center with two forms of DFOR, premature ovarian aging/occult primary ovarian insufficiency (POA/OPOI) and physiologic diminished ovarian reserve (DOR). As controls for POA/OPOI patients, infertile women with normal age-specific FOR were recruited.
ARTICIPANTS/MATERIALS, SETTINGS, METHODS: The study involved 140 women with POA/OPOI, defined as age <38 years and abnormally low FOR by age-specific FSH and/or anti-Müllerian hormone (AMH), 166 women with DOR, defined as women age >40 years. Forty-nine control patients <38 years demonstrated normal FOR by FSH and/or AMH. In all three patient groups dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS), total testosterone (TT) and free testosterone (FT) at the time of initial presentation to our fertility center were assessed. In a small subgroup of women early morning cortisol levels were also assessed.
MAIN RESULTS AND THE ROLE OF CHANCE: DHEAS marginally varied between the three groups (P = 0.04), with older women with DOR actually demonstrating higher levels than controls (P = 0.03). TT differed between the three groups more profoundly (P = 0.005), with women with POA/OPOI demonstrating significantly lower levels than controls (P = 0.009). Adjustment for body mass index, age and race in principle maintained observed differences in TT between groups, while adjustment for FMR1 (fragile X mental retardation 1) genotypes/sub-genotypes eliminated all differences. All three patient groups demonstrated low morning cortisol levels.
LIMITATIONS, REASONS FOR CAUTION: While results support lower androgen levels in women with DOR, and even more so in women with POA/OPOI, presented data should be viewed as preliminary, considering the known variability of androgen levels and the small number of women in whom morning cortisol levels were available.
WIDER IMPLICATIONS OF THE FINDINGS: Especially at young ages DFOR appears associated with significant hypoandrogenism (low T) in comparison with young control patients with normal FOR, raising the question whether this hypoandrogenism originates in adrenals or ovaries. POA/OPOI, thus, phenotypically mimics the polycystic ovary syndrome, where similar questions arise, though in regard to hyperandrogenism.

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Mouse model for the Fragile X primary ovarian insufficiency

Invited Speaker: Karen Usdin, PhD

Mouse model for the Fragile X primary ovarian insufficiency

Lecture Type: Grandrounds

Only relatively recently recognized, incidence of Fragile X-associated primary ovarian insufficiency is not always widely appreciated. Risk prediction is complicated due to the nature of the underlying mutation and the incomplete penetrance whose basis is not understood. Awareness that this disorder constitutes approximately 14% of familial cases of infertility and 3.5% of idiopathic cases should be particularly considered when there is a history of intellectual disability in close male relatives. This lecture aims to raise awareness of the incidence and risk factors for this disorder.

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Mitochondrial role in female reproductive aging

Speaker: Vitaly A Kushnir, MD FACOG

Mitochondrial role in female reproductive aging

Lecture Type: Grandrounds

Mitochondrial function is integral to both somatic cell and gamete aging. Novel therapies aimed at the mitochondria may help to delay or reverse reproductive aging and transmission of mitochondrial diseases. One of the most promising therapies for female fertility is CoQ10 supplementation. CoQ10 may improve female fertility by supporting energy metabolism within the oocytes. In this lecture, a review of mitochondrial genetics and mechanisms of female reproductive aging will be supplemented with a review of past and future treatments involving oocyte mitochondria. In addition, recent human and animal data on which current understanding of oocyte biology will be reviewed.

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The “Center for Human Reproduction”: The essential roles of sperm centrosome during fertilization, infertility and ART

Invited Speaker: Gerald P Schatten, PhD

The “Center for Human Reproduction”: The essential roles of sperm centrosome during fertilization, infertility and ART

Idiopathic infertility, both male and female, are likely the result of defects in the organelles and components which are essential for successful fertilization but are transmitted as extra-nuclear elements. Diagnosis of these types of cytoplasmic and epigenetic anomalies is predicted to help with improved ART success rates, since some patient couples may find that they are unlikely to enjoy benefits without donor gametes. Further, the missing components may be introduced and finally understanding of these critical elements vital for fertilization and the onset of development may lead to improved contraceptive strategies. Male factor infertility may result in the embryo failing to divide even after it is scored as a successful fertilization. Physicians and their laboratory colleagues will be encountered to expand their diagnostic horizons regarding the reasons why development arrests.

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Diminished ovarian reserve can be effectively treated with DHEA

Speaker: Norbert Gleicher, MD, FACOG

Diminished ovarian reserve can be effectively treated with DHEA

Lecture Type: Conferences

Recently developed evidence in mouse models very conclusively demonstrates the crucial importance of androgens for normal folliculogenesis, and, therefore, female fertility. This stands in stark contrast to long-held believes in clinical reproductive endocrinology that androgens are detrimental to normal follicle maturation. These new animal data further suggest that androgen effects are the strongest at early follicle maturation stages, between pre-antral through antral stages, and are mostly mediated via effects on granulosa cells. Moreover, androgen effects at these early developmental stages appear to FSH effects.These new findings offer additional experimental support for the clinical effects reported in recent years with dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve (DOR), suggest the possibility of radically new ovarian stimulation protocols, affecting follicle maturation at much earlier stages than current gonadotropin protocols, geared only at the last two weeks of gonadotropin sensitivity, and, finally, also support a new concept of ovarian aging, which no longer proposes that oocyte age as women age but that it is the ovarian environment, in which recruited oocytes go through follicle maturation, that ages.

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PGS, as currently practiced, is associated with inferior results and should not be offered routinely

Speaker: Norbert Gleicher, MD, FACOG

PGS, as currently practiced, is associated with inferior results and should not be offered routinely

Lecture Type: Conferences

The premature introduction of PGS into routine IVF, likely, represented the largest misstep in the development of IVF. Now we are facing the risk of a repeat performance, as the development of more accurate techniques for single cell chromosomal analyses, once again, threatens the premature introduction of an untested procedure. While inadequate diagnostic technology, undoubtedly, was one reason for the failure of PGS in its earlier incarnation, it was not the only reason. Equally important, as an embryos election technique, PGS cannot be expected to show the same utility in all patients. Until benefits in specific patient populations are, unequivocally, established, PGS, therefore, should be considered experimental, and only offered under study conditions, and with appropriate informed consents.

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Systematic single embryo transfer (sET) should not be used to prevent all multiple pregnancies

Speaker: Norbert Gleicher, MD, FACOG

Systematic single embryo transfer (sET) should not be used to prevent all multiple pregnancies

Lecture Type: Conferences

An international trend has recently arisen to prevent twin pregnancies through mandatory elective single embryo transfer (sET). The reasoning by the proponents of mandatory sET is that twin pregnancies are an adverse outcome of assisted reproductive technologies (ART). However, literature search via PubMed and MEDLINE to assess maternal and perinatal/neonatal risks as well as cost comparisons for singleton vs. twin pregnancies reveal that twin pregnancies are sometimes a desirable outcome of ART. Most risk assessments of twin pregnancies after fertility treatment have used spontaneous conceptions data, which reflect different treatment paradigms and outcome benefits from pregnancies after fertility treatments. IVF twins demonstrate approximately 40% lower outcome risks than spontaneous twin conceptions. Most risk assessments in the literature are calculated with pregnancy as the primary outcome, but in a fertility-treatment paradigm, where patients want more than one child, the statistically correct risk assessment should refer to born children as the primary reference. If published data are corrected accordingly to achieve statistical commonality of outcome (i.e., one child in singleton versus two children in twins), twin pregnancies no longer demonstrate a significantly increased risk profile and/or higher cost for mothers or individual offspring. For infertile patients who want more than one child, twin deliveries represent a favorable and cost-effective treatment outcome that should be encouraged, in contrast to the current medical consensus.

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The most important, unknown gene in human reproduction and beyond: the <i>FMR1</i> gene

Speaker: Norbert Gleicher, MD, FACOG

The most important, unknown gene in human reproduction and beyond: the FMR1 gene

Lecture Type: Grandrounds

The aging ovary represents one of the major remaining challenges in reproductive medicine. It was chosen as the main theme of research at CHR about a decade ago. Two key events proved groundbreaking: the discovery that DHEA supplementation improves ovarian reserve and pregnancy chances in women with diminished ovarian reserve (DOR), and confirmation of the hypothesis that the FMR1 gene may be involved in regulating ovarian function. During 2011/2012, CHR completed an important second phase of this research: we started understanding how DHEA effects take place, and how wide spread effects of the FMR1 gene are, reaching far beyond our medical specialty. This second phase of our research will be presented in this year’s Research Update. With expansion of our basic science team in the laboratory, we are now entering a very important third phase, attempting to elucidate the molecular biology of ovarian aging.

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Androgens and ovulation

Speaker: David H Barad, MD, MS, FACOG

Androgens and ovulation

Lecture Type: Grandrounds

The aging ovary represents one of the major remaining challenges in reproductive medicine. It was chosen as the main theme of research at CHR about a decade ago. Two key events proved groundbreaking: the discovery that DHEA supplementation improves ovarian reserve and pregnancy chances in women with diminished ovarian reserve (DOR), and confirmation of the hypothesis that the FMR1 gene may be involved in regulating ovarian function. During 2011/2012, CHR completed an important second phase of this research: we started understanding how DHEA effects take place, and how wide spread effects of the FMR1 gene are, reaching far beyond our medical specialty. This second phase of our research will be presented in this year’s Research Update. With expansion of our basic science team in the laboratory, we are now entering a very important third phase, attempting to elucidate the molecular biology of ovarian aging.

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