Adenomyosis and ART

NCT05937490 | Unknown Phase 4 DMC

• 1 other identifier: ENDO-2021-12371935
• Study Type: interventional
• Target: 500
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to:

• Prospectively investigate the association of Adenomyosis with fertility outcomes in relation to COH protocols for ART (long or ultra- long protocol) with a preventive high-dose anti-inflammatory progestin such as DNG and to assess their association with pregnancy and neonatal outcomes (preterm delivery,pre-eclampsia,Caesarean section,fetal malpresentation,small for gestational age,low birth weight and postpartum hemorrhage).
• Understand how the endometrial interface by studying the response of progesterone and DNG stimulated decidualization markers, correlating them with the success of ART protocol stimulation and to pregnancy specific outcomes
• Evaluate the immune changes during the implantation period and in the different trimesters of the pregnancies after ART conception.

Conditions

Adenomyosis

Keywords

Adenomyosis; Assisted reproductive technology; ART

Outcome Measures

Primary Outcomes (1)

• live birth after ART

  Primary Outcome:Number of live birth after ART attempt defined as delivery of one or more live-born infant at \>22 weeks of gestation.

  Through study completion, an average of 2 year

Secondary Outcomes (11)

• Other ART and pregnancy outcomes

  Through study completion, an average of 2 year

• Other ART and pregnancy outcomes

  Through study completion, an average of 2 year

• Other ART and pregnancy outcomes

  Through study completion, an average of 2 year

• Other ART and pregnancy outcomes

  Through study completion, an average of 2 year

• Other ART and pregnancy outcomes

  Immediately after the childbirth

Study Arms (4)

Group 1 (Long)

EXPERIMENTAL

COH will be performed using a long GnRH agonist protocol(administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle). COH will be commenced when pituitary desensitization was achieved(\~14 days after the initiation of GnRH agonists) as evidenced by the absence of ovarian follicles \>10 mm and endometrial thickness \<4 mm on TV-US examination.

Drug: Enantone

Group 2 (Long + high dose DNG)

EXPERIMENTAL

Before COH, patients will be treated with DNG at high dose (2 mg+2 mg/day) for 28 days, from the first day of previous menstrual cycle. COH will be performed using a long GnRH agonist protocol (administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle). COH will be commenced when pituitary desensitization was achieved (\~14 days after the initiation of GnRH agonists), as defined above.

Drug: Dienogest 2 MG (milligram); Drug: Enantone

Group 3 (ultra-long):

EXPERIMENTAL

COH will be performed using a ultra-long GnRH agonist protocol (administration of the first depot leuprorelin 3.75 mg on day 21 of menstrual cycle, repeated after 28 days for other two times). COH will be commenced when pituitary desensitization was achieved (\~14 days after the initiation of GnRH agonists), as described above.

Drug: Enantone

Control group (without adenomyosis)

OTHER

COH will be performed by using a long GnRH agonist protocol as previous described or using a flexible GnRH antagonist protocol. During TV-US monitoring, when at least one follicle reached 14 mm in diameter, to achieve LH (luteinizing hormone) suppression avoiding spontaneous ovulation, GnRH antagonist 0.25 mg/day will be added subcutaneously until the day of HCG administration.

Drug: long GnRH agonist or flexible GnRH antagonist protocol.

Interventions

Enantone DRUG

administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle.

Group 1 (Long)

Dienogest 2 MG (milligram) DRUG

Before COH, patients will be treated with DNG at high dose (2 mg+2 mg/day) for 28 days, from the first day of previous menstrual cycle. COH will be performed using a long GnRH agonist protocol (administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle).

Also known as: Enantone

Group 2 (Long + high dose DNG)

long GnRH agonist or flexible GnRH antagonist protocol. DRUG

During TV-US monitoring, when at least one follicle reached 14 mm in diameter, to achieve LH suppression avoiding spontaneous ovulation, GnRH antagonist 0.25 mg/day will be added subcutaneously until the day of HCG administration.

Control group (without adenomyosis)

Eligibility Criteria

• Age: 18 Years - 42 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Adenomyosis of the uterus defined with at least one of the following features: (1) heterogeneous myometrium; (2) hypoechoic striation in the myometrium; (3) myometrial anechoic lacunae or cysts; (4) asymmetrical myometrial thickening of the uterine walls.
• Couples who are undergoing a cycle of IVF/ICSI, where a cycle is defined as egg collection following ovarian stimulation.
• First or second IVF or ICSI attempt.
• Absence of severe premature ovarian insufficiency defined by antral follicle count \< 8 and AMH (anti-mullerian hormone) \< 1ng/ml
• Meet the criteria from the Italian law to be included in a ART program.
• The female partner is ≥18 and \< 42 years of age.
• The female partner has a BMI \<30.
• Both partners are willing and able to provide written informed consent.

You may not qualify if:

• Concurrent and/or recent involvement in other research that is likely to interfere with the intervention within the previous 3 months of study enrolment.
• Other potential causes of implantation failure: in situ leiomyoma, hydrosalpinx, malformed uterus (unicornis, bicornis, septate, duplex), antiphospholipid syndrome
• Uterine fibroids (untreated FIGO, International Federation of Gynecology and Obstetrics, Type 0-I-II and type III-IV fibroids \> 3 cm)
• Use of GnRH analogues within previous 3 months.
• Extremely severe male factor infertility (sperm count \< 1x 10 6 /ml, use o surgically retrieved spermatozoa)
• Couples unable to give fully informed consent to the study.

Sponsors & Collaborators

• Azienda Ospedaliero-Universitaria di Modena: lead
• University of Modena and Reggio Emilia: collaborator
• Ministero della Salute, Italy: collaborator

Study Sites (1)

Azienda Ospedaliero-Universitaria di Modena

Modena, 41124, Italy

RECRUITING

Related Publications (25)

• Abbott JA. Adenomyosis and Abnormal Uterine Bleeding (AUB-A)-Pathogenesis, diagnosis, and management. Best Pract Res Clin Obstet Gynaecol. 2017 Apr;40:68-81. doi: 10.1016/j.bpobgyn.2016.09.006. Epub 2016 Sep 30.

  PMID: 27810281 BACKGROUND

• Chapron C, Vannuccini S, Santulli P, Abrao MS, Carmona F, Fraser IS, Gordts S, Guo SW, Just PA, Noel JC, Pistofidis G, Van den Bosch T, Petraglia F. Diagnosing adenomyosis: an integrated clinical and imaging approach. Hum Reprod Update. 2020 Apr 15;26(3):392-411. doi: 10.1093/humupd/dmz049.

  PMID: 32097456 BACKGROUND

• Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012 Sep;98(3):511-9. doi: 10.1016/j.fertnstert.2012.06.029. Epub 2012 Jul 20.

  PMID: 22819144 BACKGROUND

• Lalani S, Choudhry AJ, Firth B, Bacal V, Walker M, Wen SW, Singh S, Amath A, Hodge M, Chen I. Endometriosis and adverse maternal, fetal and neonatal outcomes, a systematic review and meta-analysis. Hum Reprod. 2018 Oct 1;33(10):1854-1865. doi: 10.1093/humrep/dey269.

  PMID: 30239732 BACKGROUND

• Koot YE, van Hooff SR, Boomsma CM, van Leenen D, Groot Koerkamp MJ, Goddijn M, Eijkemans MJ, Fauser BC, Holstege FC, Macklon NS. An endometrial gene expression signature accurately predicts recurrent implantation failure after IVF. Sci Rep. 2016 Jan 22;6:19411. doi: 10.1038/srep19411.

  PMID: 26797113 BACKGROUND

• Peng Y et al. Biol Reprod. 2021 Feb 2:ioab017.

  BACKGROUND

• Nirgianakis K, Kalaitzopoulos DR, Schwartz ASK, Spaanderman M, Kramer BW, Mueller MD, Mueller M. Fertility, pregnancy and neonatal outcomes of patients with adenomyosis: a systematic review and meta-analysis. Reprod Biomed Online. 2021 Jan;42(1):185-206. doi: 10.1016/j.rbmo.2020.09.023. Epub 2020 Oct 4.

  PMID: 33191131 BACKGROUND

• Grandi G, Barra F, Ferrero S, Sileo FG, Bertucci E, Napolitano A, Facchinetti F. Hormonal contraception in women with endometriosis: a systematic review. Eur J Contracept Reprod Health Care. 2019 Feb;24(1):61-70. doi: 10.1080/13625187.2018.1550576. Epub 2019 Jan 21.

  PMID: 30664383 BACKGROUND

• Grandi G, Mueller MD, Bersinger NA, Facchinetti F, McKinnon BD. The association between progestins, nuclear receptors expression and inflammation in endometrial stromal cells from women with endometriosis. Gynecol Endocrinol. 2017 Sep;33(9):712-715. doi: 10.1080/09513590.2017.1314458. Epub 2017 Apr 17.

  PMID: 28412861 BACKGROUND

• Grandi G, Mueller M, Bersinger N, Papadia A, Nirgianakis K, Cagnacci A, McKinnon B. Progestin suppressed inflammation and cell viability of tumor necrosis factor-alpha-stimulated endometriotic stromal cells. Am J Reprod Immunol. 2016 Oct;76(4):292-8. doi: 10.1111/aji.12552. Epub 2016 Aug 12.

  PMID: 27515307 BACKGROUND

• Grandi G, Mueller MD, Papadia A, Kocbek V, Bersinger NA, Petraglia F, Cagnacci A, McKinnon B. Inflammation influences steroid hormone receptors targeted by progestins in endometrial stromal cells from women with endometriosis. J Reprod Immunol. 2016 Sep;117:30-8. doi: 10.1016/j.jri.2016.06.004. Epub 2016 Jun 17.

  PMID: 27371899 BACKGROUND

• Grandi G, Mueller M, Bersinger NA, Cagnacci A, Volpe A, McKinnon B. Does dienogest influence the inflammatory response of endometriotic cells? A systematic review. Inflamm Res. 2016 Mar;65(3):183-92. doi: 10.1007/s00011-015-0909-7. Epub 2015 Dec 9.

  PMID: 26650031 BACKGROUND

• Grandi G, Xholli A, Napolitano A, Palma F, Cagnacci A. Pelvic pain and quality of life of women with endometriosis during quadriphasic estradiol valerate/dienogest oral contraceptive: a patient-preference prospective 24-week pilot study. Reprod Sci. 2015 May;22(5):626-32. doi: 10.1177/1933719114556488. Epub 2014 Nov 13.

  PMID: 25394646 BACKGROUND

• Grandi G, Ferrari S, Xholli A, Cannoletta M, Palma F, Romani C, Volpe A, Cagnacci A. Prevalence of menstrual pain in young women: what is dysmenorrhea? J Pain Res. 2012;5:169-74. doi: 10.2147/JPR.S30602. Epub 2012 Jun 20.

  PMID: 22792003 BACKGROUND

• Grandi G, Xholli A, Ferrari S, Cannoletta M, Volpe A, Cagnacci A. Intermenstrual pelvic pain, quality of life and mood. Gynecol Obstet Invest. 2013;75(2):97-100. doi: 10.1159/000343997. Epub 2012 Nov 23.

  PMID: 23182853 BACKGROUND

• Nirgianakis K, Grandi G, McKinnon B, Bersinger N, Cagnacci A, Mueller M. Dienogest mediates midkine suppression in endometriosis. Hum Reprod. 2016 Sep;31(9):1981-6. doi: 10.1093/humrep/dew180. Epub 2016 Jul 13.

  PMID: 27412246 BACKGROUND

• Barra F, Romano A, Grandi G, Facchinetti F, Ferrero S. Future directions in endometriosis treatment: discovery and development of novel inhibitors of estrogen biosynthesis. Expert Opin Investig Drugs. 2019 Jun;28(6):501-504. doi: 10.1080/13543784.2019.1618269. Epub 2019 May 17. No abstract available.

  PMID: 31072144 BACKGROUND

• Barra F, Grandi G, Tantari M, Scala C, Facchinetti F, Ferrero S. A comprehensive review of hormonal and biological therapies for endometriosis: latest developments. Expert Opin Biol Ther. 2019 Apr;19(4):343-360. doi: 10.1080/14712598.2019.1581761. Epub 2019 Feb 27.

  PMID: 30763525 BACKGROUND

• Kocbek V, Grandi G, Blank F, Wotzkow C, Bersinger NA, Mueller MD, Kyo S, McKinnon BD. TNFalpha-induced IKKbeta complex activation influences epithelial, but not stromal cell survival in endometriosis. Mol Hum Reprod. 2016 Nov;22(11):768-777. doi: 10.1093/molehr/gaw054. Epub 2016 Aug 19.

  PMID: 27542948 BACKGROUND

• Cagnacci A, Bellafronte M, Xholli A, Palma F, Carbone MM, Di Carlo C, Grandi G. Impact of laparoscopic cystectomy of endometriotic and non-endometriotic cysts on ovarian volume, antral follicle count (AFC) and ovarian doppler velocimetry. Gynecol Endocrinol. 2016;32(4):298-301. doi: 10.3109/09513590.2016.1142523. Epub 2016 Feb 5.

  PMID: 26850447 BACKGROUND

• Pinzauti S, Lazzeri L, Tosti C, Centini G, Orlandini C, Luisi S, Zupi E, Exacoustos C, Petraglia F. Transvaginal sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis: association with symptoms. Ultrasound Obstet Gynecol. 2015 Dec;46(6):730-6. doi: 10.1002/uog.14834.

  PMID: 25728241 BACKGROUND

• Berkhout RP, Lambalk CB, Repping S, Hamer G, Mastenbroek S. Premature expression of the decidualization marker prolactin is associated with repeated implantation failure. Gynecol Endocrinol. 2020 Apr;36(4):360-364. doi: 10.1080/09513590.2019.1650344. Epub 2019 Aug 7.

  PMID: 31389284 BACKGROUND

• Berneau SC, Ruane PT, Brison DR, Kimber SJ, Westwood M, Aplin JD. Characterisation of Osteopontin in an In Vitro Model of Embryo Implantation. Cells. 2019 May 9;8(5):432. doi: 10.3390/cells8050432.

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• Park CW, Choi MH, Yang KM, Song IO. Pregnancy rate in women with adenomyosis undergoing fresh or frozen embryo transfer cycles following gonadotropin-releasing hormone agonist treatment. Clin Exp Reprod Med. 2016 Sep;43(3):169-73. doi: 10.5653/cerm.2016.43.3.169. Epub 2016 Sep 22.

  PMID: 27689040 BACKGROUND

• Niu Z, Chen Q, Sun Y, Feng Y. Long-term pituitary downregulation before frozen embryo transfer could improve pregnancy outcomes in women with adenomyosis. Gynecol Endocrinol. 2013 Dec;29(12):1026-30. doi: 10.3109/09513590.2013.824960. Epub 2013 Sep 5.

  PMID: 24006906 BACKGROUND

MeSH Terms

Conditions

Adenomyosis

Interventions

Leuprolide; dienogest; Magnesium

Condition Hierarchy (Ancestors)

Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Metals, Alkaline Earth; Elements; Inorganic Chemicals; Metals, Light; Metals

Central Study Contacts

Facchinetti Fabio, Medical Doctor (MD)

CONTACT

0594222512/3335824079; facchi@unimore.it/fabio.facchinetti@unimore.it

Grandi Giovanni, Medical Doctor

CONTACT

00390594222830; dott.grandi@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Obstetrics and Gynecology at the University Hospital unimore

Study Record Dates

• First Submitted: June 13, 2023
• First Posted: July 10, 2023
• Study Start: March 27, 2023
• Primary Completion: March 1, 2025
• Study Completion: March 1, 2025
• Last Updated: July 10, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)