Your Fertility Pharmacist

The most rigorously designed trial of intraovarian PRP (to date) demonstrated no improvements in # of mature oocytes obtained or # of live births versus placebo.

WHAT

• Comparison of intraovarian platelet-rich plasma (PRP) to placebo for improving the number of mature oocytes (MII) obtained after controlled ovarian stimulation in women with a history of poor ovarian response (POR) with in-vitro fertilization (IVF)

WHY

• Low and modest quality research has shown promising results with PRP for POR

• High-quality study is needed to investigate PRP’s impact for POR with IVF

WHERE/WHEN

• Two academically affiliated reproductive centers (one in the USA and one in Turkey)

• January 2020 - November 2022

WHO

Inclusion Criteria:

• females ages 18-37 with POR defined as at least two IVF cycles cancelled due to poor follicle growth or just 0-2 follicles developing despite max FSH daily injections or 0-3 mature oocytes retrieved

• male partner must have 100k or greater total motile sperm count

Female Exclusion Criteria:

• BMI >35 kg/m2, surgically obtained sperm, or continued use of adjuncts that could result in improved ovarian response to treatment (specified CoQ10, DHEA, but presumably others per clinician’s discretion)

• for additional exclusion criteria, see p 2 within article

HOW

• Randomized at each site in 1:1 ratio via computer-generated block schema to PRP or no injection (control)

• Unblinded: patients + physicians performing PRP administration

• Blinded: physicians performing oocyte retrievals + physicians performing ultrasounds for antral follicle count (AFC) + all involved embryologists

• Used intention-to-treat analysis (ITT); tests varied by normality of distibution of variables

• Primary outcome = 0 for randomized patients who withdrew from study, who lacked mature oocytes, or had cycles cancelled

• Characteristics: 224 screened —> 112 eligible —> 87 enrolled —> 83 randomized into the two groups —> 76 proceeded with oocyte retrieval (PRP = 39, control = 37)

• Efficacy: no improvements found in markers of ovarian reserve (AMH, AFC), # mature oocytes retrieved, # blastocysts formed, or implantation rates with PRP vs. control

• Safety: no women experienced infections or hematomas with the PRP injection, though most of them were in mild discomfort for three days after getting PRP

• Increased rigor of this study design (inclusion of control group + randomization) may explain results that differ from previous PRP studies

• Additional strengths were validated PGT-A platform, strong patient adherence/retention, and stringent inclusion criteria

• Study limitations were PRP prep is not necessarily universally generalizable (though used commercially available product), PRP composition was not analyzed, randomization method might have been predictable, and results not generalizable beyond POR

• PRP will not improve IVF results in POR

  Conclusions

This is the highest-quality PRP trial conducted thus far, which randomized, blinded, and compared PRP injections to no injections in infertile women with poor ovarian response. Results showed that PRP does not improve fertility markers nor outcomes compared to not giving the PRP. Future studies should be conducted with similar methodology (but recruiting additional participants at more study sites) to confirm results, especially since the results from this study conflict with previous, albeit lower-quality studies.

Resources

Cakiroglu Y, Yuceturk A, Karaosmanoglu O, et al. Ovarian reserve parameters and IVF outcomes in 510 women with poor ovarian response (POR) treated with intraovarian injection of autologous platelet rich plasma (PRP). Aging (Albany NY). 2022;14(6):2513-2523. doi:10.18632/aging.203972

Herlihy NS, Cakiroglu Y, Whitehead C, et al. Effect of intraovarian platelet-rich plasma injection on IVF outcomes in women with poor ovarian response: the PROVA randomized controlled trial. Hum Reprod. Published online May 9, 2024. doi:10.1093/humrep/deae093

Food and Drug Administration. BK210591 - Platelet-Rich Plasma (PRP) Procedure Pack. Accessed September 7, 2024. BK210591 - Platelet-Rich Plasma (PRP) Procedure Pack | FDA

Resources

Bronson R. and Kruljac I, Butorac D, Vrkljan M. and Legro RS, Zhang H; Eunice Kennedy Shriver NICHD Reproductive Medicine Network. Letrozole or clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(15):1463-1464. doi:10.1056/NEJMc1409550

Centers for Disease Control and Prevention. PCOS (Polycystic Ovary Syndrome) and Diabetes. https://www.cdc.gov/diabetes/basics/pcos.html. Accessed April 21, 2024.

Franik S, Kremer JA, Nelen WL, Farquhar C. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2014;(2):CD010287. Published 2014 Feb 24. doi:10.1002/14651858.CD010287.pub2

Franik S, Le QK, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2022;9(9):CD010287. Published 2022 Sep 27. doi:10.1002/14651858.CD010287.pub4

Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome [published correction appears in N Engl J Med. 2014 Oct 9;317(15):1465]. N Engl J Med. 2014;371(2):119-129. doi:10.1056/NEJMoa1313517

Legro RS, Diamond MP, Coutifaris C, et al. Pregnancy registry: three-year follow-up of children conceived from letrozole, clomiphene, or gonadotropins. Fertil Steril. 2020;113(5):1005-1013. doi:10.1016/j.fertnstert.2019.12.023

Palomba S, Santagni S, Falbo A, La Sala GB. Complications and challenges associated with polycystic ovary syndrome: current perspectives. Int J Womens Health. 2015;7:745-763
https://doi.org/10.2147/IJWH.S70314

World Health Organization. Polycystic Ovary Syndrome. World Health Organization; 2023. Accessed April 21, 2024. https://www.who.int/news-room/fact-sheets/detail/polycystic-ovary-syndrome

Zhang H. Pregnancy in Polycystic Ovary Syndrome II (PPCOSII). ClinicalTrials.gov identifier: NCT00719186 . Updated June 14, 2018. Accessed April 20, 2020. https://classic.clinicaltrials.gov/ct2/show/NCT00719186

A new study examines the associations between COVID-19 infection with pregnancy and miscarriage rates, looking at the first ten weeks after fresh embryo transfer.

A study compared fertility and sexual markers in obese men with low testosterone and erectile dysfunction who took liraglutide, uFSH + HCG, or testosterone. These men were separated into three groups based on their plans for parenthood; results showed impressive improvements on the GLP-1 agonist liraglutide.

Resources

Giagulli VA, Carbone MD, Ramunni MI, et al. Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology. 2015;3(6):1094-1103. doi:10.1111/andr.12099

Jensterle M, Podbregar A, Goricar K, Gregoric N, Janez A. Effects of liraglutide on obesity-associated functional hypogonadism in men. Endocr Connect. 2019;8(3):195-202. doi:10.1530/EC-18-0514

Latif W, Lambrinos KJ, Rodriguez R. Compare and Contrast the Glucagon-Like Peptide-1 Receptor Agonists (GLP1RAs). In: StatPearls. Treasure Island (FL): StatPearls Publishing; March 27, 2023.

La Vignera S, Condorelli RA, Calogero AE, Cannarella R, Aversa A. Sexual and Reproductive Outcomes in Obese Fertile Men with Functional Hypogonadism after Treatment with Liraglutide: Preliminary Results. J Clin Med. 2023;12(2):672. Published 2023 Jan 14. doi:10.3390/jcm12020672

Papadakis G. Sex Steroids Balance for Metabolic and Reproductive Health in Klinefelter Syndrome (KLIN-HEALTH). ClinicalTrials.gov identifier: NCT05586802. Updated April 4, 2023. Accessed September 27, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05586802

A recent study compared GnRH antagonists in egg donor ovarian stimulation cycles. The first drug is a newer agent, elagolix (Orilissa), that is taken as a tablet at night. The older drug is an injectable agent called ganirelix (Fyremadel). How did Orilissa stack up in terms of eggs retrieved and embryos formed vs. ganirelix? Were there adverse events, like ovarian hyperstimulation or early LH surge? Results explored in this episode and what they mean for upcoming egg donor cycles.

Resources

Boniface C, Schnorr JN, Gray J, et al. The role of elagolix in the suppression of ovulation in donor oocyte cycles. F S Rep. 2023;4(2):179-182. Published 2023 Mar 25. doi:10.1016/j.xfre.2023.03.006

Check JH, Brasile D, Choe JK, Amui J, Wilson C. The effect of cetrorelix vs. ganirelix on pregnancy outcome using minimal gonadotropin stimulation in women with elevated day 3 serum follicle stimulating hormone levels. Clin Exp Obstet Gynecol. 2009;36(3):148-149.

Fyremadel [package insert]. Parsippany, NJ: Ferring Pharmaceuticals, Inc.; 2022. manufactured by Sun Pharma (India)

Kay, C. Contaminated Drugs, Shredded Papers: US FDA Uncovers Failures in India Pharma Factories. May 31, 2013. Accessed July 11, 2023. https://www.bloomberg.com/news/articles/2023-05-31/us-finds-contaminated-drugs-further-lapses-in-india-pharma-factories-post-covid#xj4y7vzkg

Keenan, J. Sun Pharma pauses US drug exports from India plant after FDA scolding. April 27, 2023. Accessed July 10, 2023. https://www.fiercepharma.com/manufacturing/sun-pharma-hits-pause-mohali-plant-response-fda-letter/

Orilissa [package insert]. North Chicago, IL: Abbvie; 2021.

Zhang J, Zhou X, Chen Y, et al. Nan Fang Yi Ke Da Xue Xue Bao. 2019;39(10):1207-1212. doi:10.12122/j.issn.1673-4254.2019.10.12

A new trial tested a new way to give FSH to improve ovarian function in obese women without PCOS who are struggling to conceive.

Resources

Borgert BJ, Bacchus MW, Hernandez AD, Potts SN, Campbell KJ. The availability of gonadotropin therapy from FDA-approved pharmacies for men with hypogonadism and infertility. Sex Med. 2023;11(2):qfad004. Published 2023 Apr 10. doi:10.1093/sexmed/qfad004

Kumar TR. Rerouting of follicle-stimulating hormone secretion and gonadal function. Fertil Steril. 2023;119(2):180-183. doi:10.1016/j.fertnstert.2022.12.005

Luu TH, Kuhn K, Bradford AP, Wempe MF, Wittenburg L, Johnson RL, Carlson NE, Kumar TR, Polotsky AJ, Effects of Pulsatile IV FSH Treatment on Ovarian Function in Women with Obesity, Fertility and Sterility (2023), doi: https://doi.org/10.1016/j.fertnstert.2023.05.170

University of Colorado, Denver. Dysregulation of FSH in Obesity: Functional and Statistical Analysis. ClinicalTrials.gov identifier: NCT02478775. Updated April 7, 2022. Accessed June 12, 2023. https://clinicaltrials.gov/ct2/show/NCT02478775

New study on combining low-dose dexamethasone with letrozole in women with PCOS who failed to ovulate with letrozole alone. This study looked at ovulation, pregnancy, and live birth rates and took place at the Mayo Clinic from 2019 to 2022.

Resources

Barbieri RL and Ehrmann DA. Diagnosis of polycystic ovary syndrome in adults. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2034. www.uptodate.com. Accessed May 20, 2023.

Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome [published correction appears in N Engl J Med. 2014 Oct 9;317(15):1465]. N Engl J Med. 2014;371(2):119-129. doi:10.1056/NEJMoa1313517

Neblett MF 2nd, Baumgarten SC, Babayev SN, Shenoy CC. Ovulation induction with letrozole and dexamethasone in infertile patients with letrozole-resistant polycystic ovary syndrome [published online ahead of print, 2023 May 2]. J Assist Reprod Genet. 2023;10.1007/s10815-023-02817-9. doi:10.1007/s10815-023-02817-9

Women report their use of herbs and supplements to a fertility clinic that assesses their herb-drug interactions.

Resources

Friedman J, Sheeder J, Lazorwitz A, Polotsky AJ. Herbal supplement use among reproductive-aged women in an academic infertility practice. F S Rep. 2022;4(1):104-111. Published 2022 Dec 17. doi:10.1016/j.xfre.2022.12.001

Natural Medicines Database Checker. Therapeutic Research Center. Updated 2023. Accessed April 26, 2023. https://naturalmedicines.therapeuticresearch.com

Does vaginal progesterone prevent miscarriages after early pregnancy bleeding? The research world has yet to agree, but a recently published Australian study (aka "the STOP trial") attempted to tackle this question.

After seven years of recruiting ~300 women, the STOP trial was stopped prematurely based on early results.

Hurdles with study execution plus thinly-disguised jabs at other research made for an interesting paper.

Bordewijk EM, Li W, Gurrin LC, Thornton JG, van Wely M, Mol BW. An investigation of seven other publications by the first author of a retracted paper due to doubts about data integrity. Eur J Obstet Gynecol Reprod Biol. 2021;261:236-241. doi:10.1016/j.ejogrb.2021.04.018

Carmichael SL, Shaw GM, Laurent C, Croughan MS, Olney RS, Lammer EJ. Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med. 2005 Oct;159(10):957-62. doi: 10.1001/archpedi.159.10.957. PMID: 16203941.

Casarramona G, Lalmahomed T, Lemmen C, et al. The efficacy and safety of luteal phase support with progesterone following ovarian stimulation and intrauterine insemination: A systematic review and meta-analysis. Front Endocrinol (Lausanne). 2022;13:960393. Published 2022 Sep 2. doi:10.3389/fendo.2022.960393

Coomarasamy A, Devall AJ, Cheed V, et al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy. N Engl J Med. 2019;380(19):1815-1824. doi:10.1056/NEJMoa1813730.

Devall AJ, Papadopoulou A, Podesek M, et al. Progestogens for preventing miscarriage: a network meta-analysis. Cochrane Database Syst Rev. 2021;4(4):CD013792. Published 2021 Apr 19. doi:10.1002/14651858.CD013792.pub2

McLindon LA, James G, Beckmann MM, et al. Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial [published online ahead of print, 2023 Feb 20]. Hum Reprod. 2023;dead029. doi:10.1093/humrep/dead029

Meurer WJ, Tolles J. Interim Analyses During Group Sequential Clinical Trials. JAMA. 2021;326(15):1524-1525. doi:10.1001/jama.2021.10174

Oripro (progesterone pessary used in clinical trial) accessible at https://www.healthdirect.gov.au/medicines/brand/amt,124041000036109/oripro

Şükür YE, Göç G, Köse O, et al. The effects of subchorionic hematoma on pregnancy outcome in patients with threatened abortion. J Turk Ger Gynecol Assoc. 2014;15(4):239-242. Published 2014 Dec 1. doi:10.5152/jtgga.2014.14170

Yan X, Xu H, Li J, Xu Z, Niu Y, Wang Y. Subchorionic hematoma and risk of preterm delivery: a systematic review and meta-analysis. Am J Obstet Gynecol MFM. 2023;5(1):100791. doi:10.1016/j.ajogmf.2022.100791

This is the first randomized controlled multi-arm trial comparing how three hCG trigger doses impact endogenous progesterone levels in IVF- fresh embryo transfer cycles.

Resources

Abdalla HI, Ah-Moye M, Brinsden P, Howe DL, Okonofua F, Craft I. The effect of the dose of human chorionic gonadotropin and the type of gonadotropin stimulation on oocyte recovery rates in an in vitro fertilization program. Fertil Steril. 1987;48(6):958-963. doi:10.1016/s0015-0282(16)59591-0

Pabuçcu E, Pabuçcu R, Gürgan T, Tavmergen E. Luteal phase support in fresh and frozen embryo transfer cycles [published online ahead of print, 2020 Jun 22]. J Gynecol Obstet Hum Reprod. 2020;101838. doi:10.1016/j.jogoh.2020.101838

Svenstrup L, Möller S, Fedder J, et al. Does the HCG trigger dose used for IVF impact luteal progesterone concentrations? a randomized controlled trial. Reprod Biomed Online. 2022;45(4):793-804. doi:10.1016/j.rbmo.2022.04.019

Vuong LN, Ho TM, Pham TD, Ho VNA, Andersen CY, Humaidan P. The early luteal hormonal profile in IVF patients triggered with hCG. Hum Reprod. 2020;35(1):157-166. doi:10.1093/humrep/dez235