Santoro N. FSH: The Goldilocks Hormone, Too Little, Too Much, Just Right. Fertil Steril. 2022 Dec 5:S0015-0282(22)02058-1. doi: 10.1016/j.fertnstert.2022.12.003. Epub ahead of print. PMID: 36481419.

In this Views and Reviews, Dr. Nanette Santoro discusses the complexities related to FSH dosing during IVF. Recent research has supported the use of higher dosages of FSH during ovarian stimulation, but these high doses of FSH may affect tissues outside the desired gonadal targets. The current literature surrounding the topic suggests that there is still much to learn regarding FSH and ovarian stimulation.

Go KJ, Romanski PA, Bortoletto P, Patel JC, Srouji SS, Ginsburg ES. Meeting the challenge of unclaimed cryopreserved embryos. Fertil Steril. 2022 Dec 4:S0015-0282(22)01744-7. doi: 10.1016/j.fertnstert.2022.09.323. Epub ahead of print. PMID: 36476953.

As the number of IVF treatment cycles with supernumerary embryos and freeze-all cycles continues to increase across the United States, many practices are faced with the storage and responsibility of a growing number of unclaimed embryos. Authors examine the importance of thorough and inclusive informed consent for embryo cryopreservation, discuss patients’ attitudes and decisions while they have embryos in storage, practice obligations, and alternative dispositions options for patients rather than embryo discard in the laboratory.

Christmas M, Janssen I, Joffe H, Upchurch D, Santoro N, Kravitz HM. Menopause hormone therapy and complementary alternative medicine, quality of life, and racial/ethnic differences: the Study of Women’s Health Across the Nation (SWAN). Menopause. 2022 Dec 1;29(12):1357-1364. doi: 10.1097/GME.0000000000002087. Epub 2022 Oct 16. PMID: 36256923.

A SWAN survey was completed by 2,514 midlife women with vasomotor and/or genitourinary symptoms of menopause from seven sites across the United States to investigate a relationship between hormone therapy or complementary alternative medicine and self-reported quality of life, and if race/ethnicity influences hormone therapy and complementary alternative medicine’s relationship with quality of life. The major findings from the study include: across all ethnicities/races, neither contemporary alternative medicine nor hormone therapy were associated with self-reported quality of life; white women using hormone therapy reported higher quality of life; Black and Hispanic women reported the lowest use of hormone therapy but more frequent menopausal symptoms, compared to other ethnicities and races.

DeCherney AH, Brolinson M, Whiteley G, Legro RS, Santoro N. Is the “E” being removed from Reproductive Endocrinology to be replaced by a “G” for Genetics? Fertil Steril. 2022 Dec;118(6):1036-1043. doi: 10.1016/j.fertnstert.2022.10.011. Epub 2022 Nov 7. PMID: 36357198.

This is a divided discussion from physician researchers either supporting or challenging the mastery of genetics within the Reproductive Endocrinology and Infertility practice. Pro-genetics contributors summarize the historical and recent contributions from genetic screening to the field of reproductive medicine and implicate reproductive medicine’s reliance on genetic screening tools to diagnose and treat many causes of infertility. Those supporting the integration of genetics in the reproductive practice suggest that the reproductive endocrinologist should also exhibit expertise in genetics due to the integration and application of genetic tools within the practice. The opposing side indicates that while genetics are integral to the field, and the contributions from genetic testing have greatly enhanced the knowledge of reproductive endocrinologists, the field of genetics is far too in-depth to be added to the already expansive expertise of endocrinologists, and vice versa, a reproductive geneticist would be too specialized to be detrimental to the development of genetic technologies.

Cayton Vaught KC, Hazimeh D, Carter AS, Devine K, Maher JY, Maguire M, McGee EA, Driggers PH, Segars JH. AKAP13 Enhances CREB1 Activation by FSH in Granulosa Cells. Reprod Sci. 2022 Nov 18. doi: 10.1007/s43032-022-01097-5. Epub ahead of print. PMID: 36401072.

Johnson J, Kim SY, Sam PK, Asokan R, Cari EL, Bales ES, Luu TH, Perez L, Kallen AN, Nel-Themaat L, Polotsky AJ, Post MD, Orlicky DJ, Jordan KR, Bitler BG. Expression and T cell Regulatory Action of the PD-1 Immune Checkpoint in the Ovary and Fallopian Tube. Am J Reprod Immunol. 2022 Nov 17. doi: 10.1111/aji.13649. Epub ahead of print. PMID: 36394352.

This study was initiated to better understand how native ovary and fallopian tube cells interact with resident immune cells. Ovarian and fallopian tube samples were obtained, and PD-1 and ligan protein expression were assesed. Human follicular fluid was also obtained, of which protein expression was assessed, and treated with human T-cells to measure interferon gamma. Findings from this study suggest that soluble and membrane bound PD-1 pathway proteins are expressed in non-lymphoid/non-myeloid cells of the human ovary and were found in the fluid collected from peri-ovulatory follicles in egg retrieval procedures during IVF. Specifically, PD-1, PD-L2, and PD-L1, were present in the human ovarian cortex pre- and post-menopausally in various amounts. After menopause, PD-L1 was found distributed in the cortex more extensively compared to pre-menopause. Results also suggest that these ligands are present in human follicular fluid at levels capable of activating T-cells. The findings indicate that the PD-1 pathway dually helps to protect the ovary, oocytes, and embryos in the fallopian tubes from autoimmune reactions while also functioning as a protective immune system against infection.

Bakkensen JB, Flannagan KSJ, Mumford SL, Hutchinson AP, Cheung EO, Moreno PI, Jordan N, Feinberg EC, Goldman KN. A SART data cost-effectiveness analysis of planned oocyte cryopreservation versus in vitro fertilization with preimplantation genetic testing for aneuploidy considering ideal family size. Fertil Steril. 2022 Nov;118(5):875-884. doi: 10.1016/j.fertnstert.2022.07.022. Epub 2022 Sep 26. PMID: 36175208; PMCID: PMC9613595.

Using the SART-CORS database, this study evaluated the cost-effectiveness of oocyte cryopreservation as a mean of deferred reproductive as opposed to no oocyte cryopreservation with IVF and PGT-A testing at advanced reproductive age in women desiring one or two live births. Notable findings from the study include for women desiring one child, a higher chance of live birth occurs if oocyte cryopreservation occurs before age 39, with the highest chance of live birth occurring when oocyte cryopreservation occurs before age 32. Women desiring two children saw the most success when one cycle of oocyte cryopreservation occurred before age 37 and two cycles before age 39 rather than IVF with PGT-A at an advanced age. In this group, women had highest success of live birth when two cycles of oocyte cryopreservation occurred before age 31. Analysis of the data suggests that oocyte cryopreservation is a cost-effective strategy for delayed childbearing. This study is important as more patients are choosing to delay childbearing and incorporate ART into their family building.

Combs A, Kimes MJ, Jaslow CR, Hayes H, O’Leary LB, Levy MJ, Kutteh WH. Perception of pain and the oocyte donor experience: a retrospective analysis of commercial US donors. Reprod Biomed Online. 2022 Nov;45(5):906-912. doi: 10.1016/j.rbmo.2022.06.013. Epub 2022 Jun 22. PMID: 36058796.

Pain is a commonly reported side effect among oocyte donors, but literature addressing donor pain perception is lacking. To better understand pain perception among donors and bring attention to the short-term effects of donation to donors, authors of the presented study emailed a 40-question quantitative and qualitative survey to a group of Donor Egg Bank USA donors who donated between 2016 and 2019. The survey covered subjects such as demographics, donor’s motivation for donating, reproductive history, and the consent and donor experience. Of the 503 oocyte donors who opened the survey link, 48.9% (246 participants) completed at least 90% of the survey. A large portion of women reported more pain than expected (42.7%). Particularly, the largest pain disparity between expectations and experience occurred in the week after retrieval (25.8%). Donors also reported high levels of satisfaction and felt that the consent process prepared them for retrieval, with 94% recalling being counselled on the potential for pain. This study provides information that may be helpful to women who are considering oocyte donation, but further studies should address the short-term, as well as long-term, effects of pain to oocyte donors.

Katler Q, Verrilli L. Patience and persistence: Is duration the missing piece for treating polycystic ovarian syndrome resistance? Fertil Steril. 2022 Nov 13:S0015-0282(22)02035-0. doi: 10.1016/j.fertnstert.2022.11.008. Epub ahead of print. PMID: 36379262.

This editorial discusses the strengths and weaknesses of an extended letrozole protocol for ovulation induction for patients with refractory PCOS undergoing IVF. The protocol involves extending the standard 5 mg letrozole protocol from 5 to 7 or 10 days, keeping the same letrozole dose, in women who did not respond after the initial 5 days of treatment. The editorial discusses limitations to the study, such as small sample size and the inability to analyze secondary outcomes, and study strengths, such as the potential to reduce financial barriers with this method by reducing the need for ovarian drilling.

Romanski P, Bortoletto P, Malmsten J, Tan KS, Spandorfer S. Pregnancy outcomes after oral and injectable ovulation induction in infertile women with low anti-müllerian hormone level compared to normal anti-müllerian hormone level. Fert Steril. 2022 Nov 12. doi: 10.1016/j.fertnstert.2022.09.010.

This retrospective cohort study was initiated to determine the ongoing pregnancy rate among women diagnosed with infertility with low level of antimullerian hormone level compared to those with normal antimullerian hormone levels after oral and injectable ovulation induction/intrauterine insemination (OI/IUI). A total of 7,169 OI/IUI cycles were included: 3,122 patients completed 5,539 oral antiestrogen cycles and 1,060 women completed 1,630 injectable gonadotropin cycles at a large academic center between 2015 and 2019. Significant findings from the study include: women over the age of 35 and 35-40 years old with low AMH treated with injectable gonadotropins had a significantly reduced ongoing pregnancy rate compared to women of similar age with normal AMH levels. The difference is likely due to an unexpectedly high ongoing pregnancy rate in the normal AMH group. The decline in ongoing pregnancy rate corresponds with a reduction in AMH from 1.0 ng/mL in this cohort of women.

Ávila C, Vinay JI, Arese M, Saso L, Rodrigo R. “Antioxidant Intervention against Male Infertility: Time to Design Novel Strategies”. Biomedicines. 2022 Nov. doi: 10.3390/biomedicines10123058.

Recent findings in research have indicated that reactive oxygen species pathophysiology influences male infertility, but an antioxidant therapy to treat male infertility has yet to be introduced. This review provides an in-depth analysis of the literature regarding antioxidants and oxidative stress as contributors to male infertility and identifies gaps in the current literature. Authors identify a need for therapeutics and interventions that are based on the time course of spermatogenesis and oxidative stress, as well as provide a summary of sources of reactive oxygen species that may contribute to male infertility.

Evans-Hoeker E, Wang Z, Groen H, Cantineau AEP, Thurin-Kjellberg A, Bergh C, Laven JSE, Dietz de Loos A, Jiskoot G, Baillargeon JP, Palomba S, Sim K, Moran LJ, Espinós JJ, Moholdt T, Rothberg AE, Shoupe D, Hoek A, Legro RS, Mol BW, Wang R; Venus-IPD Collaboration. Dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatment: protocol for a systematic review and individual participant data meta-analysis. BMJ Open. 2022 Nov 7;12(11):e065206. doi: 10.1136/bmjopen-2022-065206. PMID: 36344004; PMCID: PMC9644352.

The Venus-IPD group presents a protocol to establish a meta-analysis to understand the effectiveness and safety of dietary and/or physical activity interventions in overweight or obese women prior to beginning fertility treatments. Data will be gathered from retrospective cohort studies that involved dietary and/or physical activity interventions and compared outcomes from patients who received standard advice concerning healthy lifestyle to patients without intervention. Quasi-RCTs and women who underwent bariatric surgery are to be excluded. Studies will be identified from the following databases: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Leading authors from the included studies will receive a list of requested data. The main analysis will be based on the intention-to-treat principle. Results from this study have the potential to advise clinicians on the value of postposing fertility treatment for overweight or obese women to receive dietary and/or physical activity interventions to improve reproductive, maternal, and perinatal outcomes.

Romanello JP, Sun B, Hill MJ, Singer T, O’Brien JE. The impact of the COVID-19 pandemic on gestational carriers. J Assist Reprod Genet. 2022 Oct;39(10):2365-2372. doi: 10.1007/s10815-022-02622-w. Epub 2022 Sep 24. PMID: 36152113; PMCID: PMC9510232.

The COVID-19 pandemic required ART practice centers to reevaluate and adapt their practice processes, having a particularly negative effect on the gestational carrier process. This article provides a comprehensive review of the changes made at the practice level to accommodate the required precautions during the COVID-19 pandemic for couples utilizing a gestational carrier, and gestational carriers themselves. Topics include the added psychological stress unto gestational carriers from the pandemic, changes to the gestational carrier process, patient safety during pregnancy and the pandemic, vaccination counseling, and the new normal in the REI practice.

Awadalla MS, Agarwal R, Ho JR, McGinnis LK, Ahmady A. Effect of trophectoderm biopsy for PGT-A on live birth rate per embryo in good prognosis patients. Arch Gynecol Obstet. 2022 Oct;306(4):1321-1327. doi: 10.1007/s00404-022-06679-x. Epub 2022 Jul 12. PMID: 35821525; PMCID: PMC9470687.

Punjani N, Bortoletto P, Romanski PA, Kashanian J, Spandorfer S. Advancing paternal age does not negatively impact fresh embryo transfer cycle outcomes. Reprod Biomed Online. 2022 Oct;45(4):737-744. doi: 10.1016/j.rbmo.2022.04.014. Epub 2022 Apr 29. PMID: 35840498.

Romanski PA, Bortoletto P, Pfeifer SM, Lindheim SR. An overview and video tutorial to the new interactive website for the American Society for Reproductive Medicine Müllerian Anomalies Classification 2021. Am J Obstet Gynecol. 2022 Oct;227(4):644-647. doi: 10.1016/j.ajog.2022.06.049. Epub 2022 Jun 28. PMID: 35777427. , Bortoletto P, Pfeifer SM, Lindheim SR. An overview and video tutorial to the new interactive website for the American Society for Reproductive Medicine Müllerian Anomalies Classification 2021. Am J Obstet Gynecol. 2022 Oct;227(4):644-647. doi: 10.1016/j.ajog.2022.06.049. Epub 2022 Jun 28. PMID: 35777427.

Siegel DR, Grau L, Sammel M, Nel-Themaaat L, Santoro N, Polotsky AJ. Anti-Müllerian Hormone and Follicle-Stimulating Hormone Are Poor Independent Predictors of Live Birth After Assisted Reproductive Technology. Reprod Sci. 2022 Oct 4. doi: 10.1007/s43032-022-01099-3. Epub ahead of print. PMID: 36194358.

Selter JH, Price TM, Harris BS. Fibroids in pregnancy: a growing or shrinking issue? Fertil Steril. 2022 Oct;118(4):666-667. doi: 10.1016/j.fertnstert.2022.08.001. Epub 2022 Sep 2. PMID: 36064663.

Dilday E, Gigg M, Hoyos L, Quinn M, Markovic D, Kroener L. Luteal phase support with progesterone does not improve pregnancy rates in patients undergoing ovarian stimulation with letrozole. Reprod Biomed Online. 2023 Jan;46(1):123-128. doi: 10.1016/j.rbmo.2022.09.012. Epub 2022 Sep 20. PMID: 36396533.

Supplemental progesterone is routinely used as luteal phase support in non-IVF fertility treatments, despite limited data to support its use. This was a retrospective cohort study that included 273 patients undergoing ovarian stimulation with letrozole paired with IUI or timed intercourse between January 2018 and October 2021. A total of 492 letrozole ovarian cycles were included. Ovulation stimulation protocol included baseline transvaginal ultrasound on cycle day 2 or 3, and letrozole (2.5, 5, or 7.5 mg) daily for five days. When given, vaginal progesterone (Prometrium, 200 mg) was initiated two days post-IUI or 4 days post-hCG trigger in timed intercourse cycles, twice or three times daily. Of these cycles, there was not a significant difference in multifollicular development between those who did and those who did not receive progesterone (P=0.337), as well as no difference in unadjusted clinical pregnancy rate between those who did and those who did not receive progesterone (P=0.645). Live birth rate and infant weight at delivery were similarly not significantly different between groups (P=0.599, 0.076, respectively).

Plowden TC, Mumford SL, Wild RA, Cedars MI, Steiner AZ, Franasiak JM, Diamond MP, Santoro N. Probability of Pregnancy With Mono vs Multiple Folliculogenesis in Women With Unexplained Infertility. J Endocr Soc. 2022 Sep 15;7(1):bvac142. doi: 10.1210/jendso/bvac142. PMID: 36447958; PMCID: PMC9692188.

This study was conducted as a secondary analysis of a randomized controlled trial that included 12 clinical sites across the US. The trial ‘Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation with 3 treatment arms: gonadotropins, clomiphene, or letrozole, combine with intrauterine insemination (AMIGOS trial)’ included women aged 18 to 40 years old with a normal uterine cavity, at least 1 patent fallopian tube, and male partners with ≥5 million total motile sperm. A total of 900 couples were enrolled. In the overall cohort, women with one mature follicle ≥16 mm at the time of hCG trigger were less likely to have a clinical pregnancy (RR, 0.70; 95% CI, 0.54-0.89) and live birth (RR, 0.67; 95% CI, 0.54-0.89) compared to women with ≥2 follicles larger than 16 mm. Comparable outcomes were observed when follicle size cutoff was ≥18 mm; women with one follicle were less likely to have a clinical pregnancy (RR, 0.77; 95% CI, 0.60-0.98) and live birth (RR, 0.75; 95% CI 0.58-0.97). When stratified by treatment modality, women using letrozole saw no difference in chance of live birth and follicle number, while women using clomiphene or gonadotropins were more likely to have a clinical pregnancy and live birth when having ≥2 follicles as opposed to one follicle.