Mindy S. Christianson

Fertility Preservation for Prepubertal Girls: Update and Current Challenges

With increasing rates of diagnosis of childhood cancers and the evolution of more effective treatment options resulting in prolonged life spans, fertility preservation counseling is an integral component of the discussion at the time of diagnosis of childhood cancers. The primary fertility preservation option that exists for prepubertal girls is ovarian tissue cryopreservation. Although ovarian tissue cryopreservation is still considered to be experimental in nature, live births have resulted from orthotopic tissue transplantation. Fertility preservation should be offered to all prepubertal girls at high-risk for premature ovarian failure as a result of gonadotoxic treatment. Ethical and legal questions surrounding these issues must be considered as more and more pediatric patients pursue fertility preservation.

Recent advances in the field of ovarian tissue cryopreservation and opportunities for research

PurposeThe purpose of this study was to summarize the latest advances and successes in the field of ovarian tissue cryopreservation while identifying gaps in current knowledge that suggest opportunities for future research.MethodsA systematic review was performed according to PRISMA guidelines for all relevant full-text articles in PubMed published in English that reviewed or studied historical or current advancements in ovarian tissue cryopreservation and auto-transplantation techniques.ResultsOvarian tissue auto-transplantation in post-pubertal women is capable of restoring fertility with over 80 live births currently reported with a corresponding pregnancy rate of 23 to 37%. The recently reported successes of live births from transplants, both in orthotopic and heterotopic locations, as well as the emerging methods of in vitro maturation (IVM), in vitro culture of primordial follicles, and possibility of in vitro activation (IVA) suggest new fertility options for many women and girls. Vitrification, as an ovarian tissue cryopreservation technique, has also demonstrated successful live births and may be a more cost-effective method to freezing with less tissue injury. Further, transplantation via the artificial ovary with an extracellular tissue matrix (ECTM) scaffolding as well as the effects of sphingosine-1-phosphate (SIP) and fibrin modified with heparin-binding peptide (HBP), heparin, and a vascular endothelial growth factor (VEGF) have demonstrated important advancements in fertility preservation. As a fertility preservation method, ovarian tissue cryopreservation and auto-transplantation are currently considered experimental, but future research may pave the way for these modalities to become a standard of care for women facing the prospect of sterility from ovarian damage.

Fertility Preservation: A Key Survivorship Issue for Young Women with Cancer

Fertility preservation in the young cancer survivor is recognized as a key survivorship issue by the American Society of Clinical Oncology and the American Society of Reproductive Medicine. Thus, health-care providers should inform women about the effects of cancer therapy on fertility and should discuss the different fertility preservation options available. It is also recommended to refer women expeditiously to a fertility specialist in order to improve counseling. Women’s age, diagnosis, presence of male partner, time available, and preferences regarding use of donor sperm influence the selection of the appropriate fertility preservation option. Embryo and oocyte cryopreservation are the standard techniques used while ovarian tissue cryopreservation is new, yet promising. Despite the importance of fertility preservation for cancer survivors’ quality of life, there are still communication and financial barriers faced by women who wish to pursue fertility preservation.

Multiple sclerosis at menopause: Potential neuroprotective effects of estrogen

Multiple sclerosis (MS) is an autoimmune demyelinating and neurodegenerative condition of the central nervous system that preferentially afflicts women more than men. Low estrogen states such as menopause and the postpartum period favor exacerbations of multiple sclerosis in women with the disease. Existing and emerging evidence suggests a role for estrogen in the alleviation of symptoms and reversal of pathology associated with MS. While clinical evidence is sparse regarding the benefit of estrogen therapy for women at risk for MS exacerbations, scientific data demonstrates that estrogen potentiates numerous neuroprotective effects on the central nervous system (CNS). Estrogens play a wide range of roles involved in MS disease pathophysiology, including increasing antiinflammatory cytokines, decreasing demyelination, and enhancing oxidative and energy producing processes in CNS cells.

In Vitro Activation A Possible New Frontier for Treatment of Primary Ovarian Insufficiency

In vitro activation (IVA) represents a new frontier in the treatment of women with primary ovarian insufficiency as well as patients with cancer desiring fertility preservation. Here, we review the biological basis of IVA and the recent translation of IVA to humans by targeting Hippo and Akt-signaling pathways. We then provide a new integrated viewpoint on IVA, highlighting basic science research on the aspects of follicular development and ovarian tissue transplantation which may potentially optimize future translational research on IVA. Specific topics discussed include cryopreservation techniques, additional IVA pathway targets, the roles of actin polymerization, paracrine and endocrine factors, and the role of mechanical signaling and associated tissue rigidity in controlling ovarian follicular activation. Further research and improved understanding is needed to optimize success of IVA.

Menopause education: Needs assessment of American obstetrics and gynecology residents

Objective This study aims to understand the current teaching of menopause medicine in American obstetrics and gynecology residency programs. Methods A Web-based survey was e-mailed to all American obstetrics and gynecology residency directors, with a request that they forward it to their residents. Results Of 258 residency program directors contacted, 79 (30.6%) confirmed forwarding the survey. In all, 1,799 people received the survey, with 510 completions, for a response rate of 28.3%. Most residents reported that they had limited knowledge and needed to learn more about these aspects of menopause medicine: pathophysiology of menopause symptoms (67.1%), hormone therapy (68.1%), nonhormone therapy (79.0%), bone health (66.1%), cardiovascular disease (71.7%), and metabolic syndrome (69.5%). Among fourth-year residents who will be entering clinical practice soon, a large proportion also reported a need to learn more in these areas: pathophysiology of menopause symptoms (45.9%), hormone therapy (54.2%), nonhormone therapy (69.4%), bone health (54.2%), cardiovascular disease (64.3%), and metabolic syndrome (63.8%). When asked to rate the most preferred modalities for learning about menopause, the top choice was supervised clinics (53.2%), followed by case presentations (22.2%), formal lectures (21.3%), small groups (14.7%), Web-based learning (7.8%), and independent reading (5.2%). Only 20.8% of residents reported that their program had a formal menopause medicine learning curriculum, and 16.3% had a defined menopause clinic as part of their residency. Conclusions It seems that some American residency programs do not fulfill the educational goals of their residents in menopause medicine. A curriculum would be beneficial for increasing knowledge and clinical experience on menopause issues.

Scavenger receptor class B type 1 gene polymorphisms and female fertility.

Purpose of reviewMultiple studies have demonstrated a role for scavenger receptor class B type 1 (SR-B1) in female fertility. Recent studies have implicated specific SR-B1 gene polymorphisms in decreased progesterone production and suboptimal fertility outcomes. Recent findingsThe lipoprotein receptor SR-B1 has been known to mediate selective uptake of lipids into steroidogenic tissues such as the ovaries. SR-B1 plays a major role in the ability of the corpus luteum to produce progesterone, which is known to play a key role in sustaining early pregnancy. Animal studies have demonstrated that deficiency in SR-B1 results in subfertility that can be restored with addition of SR-B1 function. Single-nucleotide polymorphisms in SCARB1, the gene encoding SR-B1, have been associated with human lipid levels. Women undergoing infertility treatment with low SR-B1 expression in granulosa cells were noted to have plasma estradiol levels half the normal levels and a significantly lower number of retrieved oocytes. In vitro, deficiency of SR-B1 is associated with lower progesterone secretion in human granulosa cells. Certain SR-B1 polymorphisms have been associated with lower follicular progesterone levels and a significantly lower clinical pregnancy rate. SummaryDeficiency of SR-B1, particularly due to single-nucleotide polymorphisms, could explain some features of female human infertility.

A retrospective comparison of clinical outcomes and satisfaction using reconstituted recombinant gonadotropins (rFSH) or cartridge rFSH with a pen device in donor oocyte cycles

ABSTRACT Background: Use of recombinant follicle stimulating hormone (rFSH) in a cartridge pen device offers obvious benefits for donor oocyte cycles including the administration of fewer and more patient-friendly injectable medications. Methods: In a University-based IVF program, a total of 98 oocyte donor cycles using rFSH either reconstituted or as a pen device given to 118 recipients (eight split cycles) were retrospectively reviewed. Following discontinuation of oral contraceptive, controlled ovarian hyperstimulation was begun using either reconstituted rFSH (n = 19) or rFSH with a cartridge pen device (n = 79) (150–300 IU qd). GnRH-antagonists (Ganirelix, Organon) and an additional 75 IU of rFSH/day were begun when lead follicles were 13–14 mm in greatest diameter. The primary endpoints analyzed included cycle stimulation characteristics for each donor group and donor medication tolerance assessment with respect to each rFSH formulation, while secondary outcome measures included clinical pregnancy and implantation rates. Results: Oocyte donors using the pen required significantly less rFSH (2734 IU vs. 3276 IU, p < 0.05) and scored significantly higher medication tolerance scores (3.9 ± 0.4 vs. 3.1 ± 0.6, p < 0.05). No other differences in cycle stimulation for oocyte donors and clinical outcomes for recipients were seen including pregnancy rates (pen, 77% vs. reconstituted, 55%, p – NS) and clinical pregnancy rates (61% vs. 45%, p – NS). However, significantly greater implantation rates (57% vs. 31%, p < 0.01) occurred in the pen group. Conclusion: Compared to reconstituted formulations, the pen device results in lower gonadotropin requirements and provides a simplified dosing method with better tolerance.

Effectiveness of a 2-year menopause medicine curriculum for obstetrics and gynecology residents.

Objective:Previous work has shown American obstetrics and gynecology (OB/GYN) residents are lacking in menopause training. Our objective was to assess the effectiveness of a 2-year menopause medicine curriculum in improving OB/GYN residents’ knowledge and self-assessed competency in menopause topics. Methods:We developed a menopause medicine-teaching curriculum for OB/GYN residents at our academic hospital-based residency program. The 2-year curriculum was composed of year 1: four 1-hour lectures and one 2-hour lab with cases presentations, and year 2: three 1-hour lectures and one 2-hour lab. Core topics included menopause physiology, hormone therapy, breast health, bone health, cardiovascular disease, and autoimmune disease. Pre- and posttests assessed resident knowledge and comfort in core topics, and a pre- and postcurriculum survey assessed utility and learning satisfaction. Results:From July 2011 to June 2013, 34 OB/GYN residents completed the menopause curriculum annually with an average attendance at each module of 23 residents. Pre-/posttest scores improved from a mean pretest score of 57.3% to a mean posttest score of 78.7% (P < 0.05). Before the curriculum, most residents did not feel comfortable managing menopause patients with 75.8% reporting feeling “barely comfortable” and 8.4% feeling “not at all comfortable.” After the 2-year curriculum, 85.7% reported feeling “comfortable/very comfortable” taking care of menopause patients. The majority of residents (95.2%) reported the menopause curriculum was “extremely useful.” Conclusions:A 2-year menopause medicine curriculum for OB/GYN residents utilizing lectures and a lab with case studies is an effective modality to improve resident knowledge required to manage menopause patients.

Reproductive ovarian testing and the alphabet soup of diagnoses: DOR, POI, POF, POR, and FOR

There are large variations in the number of oocytes within each woman, and biologically, the total quantity is at its maximum before the woman is born. Scientific knowledge is limited about factors controlling the oocyte pool and how to measure it. Within fertility clinics, there is no uniform agreement on the diagnostic criteria for each common measure of ovarian reserve in women, and thus, studies often conflict. While declining oocyte quantity/quality is a normal physiologic occurrence as women age, some women experience diminished ovarian reserve (DOR) much earlier than usual and become prematurely infertile. Key clinical features of DOR are the presence of regular menstrual periods and abnormal-but-not-postmenopausal ovarian reserve test results. A common clinical challenge is counseling patients with conflicting ovarian reserve test results. The clinical diagnosis of DOR and the interpretation of ovarian reserve testing are complicated by changing lab testing options and processing for anti-mullerian hormone since 2010. Further, complicating the diagnostic and research scenario is the existence of other distinct yet related clinical terms, specifically premature ovarian failure, primary ovarian insufficiency, poor ovarian response, and functional ovarian reserve. The similarities and differences between the definitions of DOR with each of these four terms are reviewed. We recommend greater medical community involvement in terminology decisions, and the addition of DOR-specific medical subject-heading search terms.