Assessing the Correlation Between Phospholipase C Zeta Measurements and Semen Parameters (PLCZeta)
29 de junio de 2026 actualizado por: Lamiya Mohiyiddeen, Fakih IVF Fertility Center
Assessing the Correlation Between Phospholipase C Zeta (PLCZeta) Measurements and Semen Parameters
With declining fertility rates Worldwide, Assisted Reproductive Technology is seen as a viable solution for infertility, however, individual success rates following ART remain relatively low, rarely exceeding ~50%. The European Society for Human Reproduction and Embryology (ESHRE) indicates pregnancy rates per embryo transfer remain below 50%. Additionally, male infertility is regarded as a leading contributor to global infertility with approximately a third of cases attributed to genetic causes while half of the cases remain unexplained.
In this observational study we investigate the correlation between phospholipase C Zeta (PLCζ ) measurements and semen parameters. PLCζ is a sperm-specific protein which is introduced into a mature egg (oocyte) following gamete fusion and upon introduction, PLCζ is believed to initiate a series of characteristic calcium ion oscillations which lead to oocyte activation and persist beyond the completion of meiosis.
Mounting evidence implicates defects in PLCζ in cases of male factor infertility where intracytoplasmic sperm injection (ICSI; whereby a single sperm is injected into the oocyte) is unsuccessful. Furthermore, defects in PLCζ are also increasingly implicated in cases of male sub-fertility, which affects a much larger proportion of the global population. Numerous studies now indicate that PLCζ not only holds significant value as a therapeutic to rescue cases of ICSI failure, but also as a prognostic diagnostic test of male fertility. Indeed, the reduction or absence of normal PLCζ within sperm has been linked to cases of male factor infertility in humans, either due to inactivation through mutation, due to abrogation of protein levels in sperm as a result of mutation in the PLCζ promoter, or mutations within coding exonic regions of the PLCζ gene. Such data indicate both therapeutic, and diagnostic applications for PLCζ within the fertility clinic. This study seeks to determine the effect of abnormal PLCζ on semen parameters and correlate that with downstream events including clinical pregnancy and live birth rates.
Descripción general del estudio
Estado
Estado
Reclutamiento
Condiciones
Condiciones
Intervención / Tratamiento
Intervención / Tratamiento
Descripción detallada
Despite advances in assisted reproductive technology (ART), significant gaps remain in understanding recurrent implantation failure and abortive embryogenesis. Male factor infertility is globally the leading cause of infertility, and is particularly prevalent in GCC countries, notably the UAE; where fertility rates have halved over the past decade, driven by cultural, lifestyle, and environmental shifts. Poor semen parameters (sperm count, motility, and morphology) account for 41% of infertility cases in the region.
The financial burden is substantial: a single ART cycle can exceed AED 30,000, with couples typically requiring 2-3 cycles (AED 60,000-100,000), translating to an estimated national expenditure of ~AED 0.5 billion annually in fertility treatments alone, excluding associated healthcare investigations.
A critical and underexplored mechanism underlying poor ART outcomes involves oocyte activation, initiated at fertilization by characteristic intracellular calcium (Ca²⁺) oscillations. These are triggered by phospholipase C zeta (PLCζ), a sperm-specific protein delivered into the oocyte upon gamete fusion. Ca²⁺ oscillation profiles directly govern cell cycle progression, embryo gene expression, and early developmental competence; deviations in amplitude or frequency compromise embryo quality. Notably, preimplantation mouse studies show that both insufficient and excessive PLCζ impair blastocyst development, with successful outcomes occurring within a ~4-fold effective dose range - mirroring the natural variation of PLCζ levels observed across fertile men.
Mounting clinical evidence links reduced or absent sperm PLCζ to fertilization failure following intracytoplasmic sperm injection (ICSI), as well as to broader male sub-fertility. PLCζ deficiencies may arise through point mutations, promoter alterations, or disrupted exonic regions, and correlate with known sperm defects including poor motility, globozoospermia, and elevated DNA fragmentation. Crucially, even when residual PLCζ is sufficient to trigger oocyte activation, it may be inadequate for full embryonic competence, a distinction with major clinical implications for sub-fertile men.
Despite this evidence, the direct relationship between sperm PLCζ parameters and downstream outcomes including embryonic efficacy, recurrent implantation failure, and ART success rates has not yet been systematically investigated. We propose that abnormalities in PLCζ-mediated Ca²⁺ oscillations represent a significant and underappreciated contributor to poor global ART outcomes. Establishing this link would position PLCζ as both a prognostic diagnostic marker of sperm health and a therapeutic agent, with the potential to improve outcomes across a broad spectrum of infertility presentations beyond complete fertilization failure.
Tipo de estudio
Tipo de estudio
De observación
Inscripción (Estimado)
Inscripción
200
Contactos y Ubicaciones
Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.
Estudio Contacto
Estudio Contacto
- Nombre: Dr. Lamiya Mohiyiddeen, MD, FRCOG
- Número de teléfono: +971543676002
- Correo electrónico: lamiya.mohiyiddeen@fakihivf.com
Copia de seguridad de contactos de estudio
- Nombre: Fatma Bathawab, PhD
- Número de teléfono: +971585707393
- Correo electrónico: fatma.bathawab@fakihivf.com
Ubicaciones de estudio
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Abu Dhabi, Emiratos Árabes Unidos
- Reclutamiento
- Fakih IVF
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Contacto:
- Dr. Lamiya Mohiyiddeen, MD, FRCOG
- Número de teléfono: +971543676002
- Correo electrónico: lamiya.mohiyiddeen@fakihivf.com
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Contacto:
- Fatma Bathawab, PhD
- Número de teléfono: +971585707393
- Correo electrónico: fatma.bathawab@fakihivf.com
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Investigador principal:
- Michael Fakih, MD
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Investigador principal:
- Dr. Lamiya Mohiyiddeen, MD FRCOG
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Abu Dhabi, Emiratos Árabes Unidos
- Activo, no reclutando
- Khalifa University
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Criterios de participación
Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.
Criterio de elegibilidad
Criterio de elegibilidad
Edades elegibles para estudiar
- Niño
- Adulto
- Adulto Mayor
Acepta Voluntarios Saludables
No
Método de muestreo
Muestra no probabilística
Población de estudio
Male partners in couples suffering from infertility and seeking IVF treatment at the FAKIH IVF clinics in the UAE.
Descripción
Couple inclusion criteria:
- Presenting to the IVF clinic for IVF/ICSI treatment or routine semen analysis
- Semen sample must have a total sperm count of ≥1 million sperm/ml
- Availability of excess, leftover sperm after clinical treatment procedures
- Couples must have experienced infertility for at least one year and be undergoing fertility treatment
- Undergoing standard clinical treatment protocols (including embryo culture and, when applicable, PGTA) with routinely collected treatment outcome data
- Sufficient ovarian reserve and/or meeting the clinic's standard criteria for fertility treatment
Couple exclusion criteria:
- Known genetic disorders affecting fertility
- History of vasectomy or other irreversible sterilization procedures
- Current use of medications known to affect sperm parameters (e.g., exogenous androgens, chemotherapeutic agents, or other drugs specifically impacting spermatogenesis)
- Recent history of chemotherapy or radiation therapy
- Female age >38 years old
- Known chromosomal abnormalities or genetic disorders that directly affect oocyte quality or embryo development
- Presence of severe uterine or pelvic pathology (e.g., significant uterine anomalies, advanced endometriosis)
- Documented ovarian failure or extremely diminished ovarian reserve as determined by AMH levels (AMH >1 ng/mL, AFC ≥5)
- Use of medications or undergoing treatments that could significantly alter oocyte quality or embryogenesis (outside standard ART protocols).
Plan de estudios
Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.
¿Cómo está diseñado el estudio?
Detalles de diseño
Número de grupos/cohortes
1
Cohortes e Intervenciones
Grupo / CohorteGrupo / Cohorte |
Intervención / TratamientoIntervención / Tratamiento |
|---|---|
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IVF-couples
Male partners in couples seeking fertility treatment via IVF and excluding any couples with factors known to negatively affect in spermatogenesis and embryogenesis.
Couples must be experiencing infertility for 1 year or more before beginning IVF treatment.
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This is a cohort observational study and there will be no intervention of any type.
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¿Qué mide el estudio?
Medidas de resultado primarias
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Biochemical pregnancy
Periodo de tiempo: From enrollment to clinical pregnancy result and delivery where applicable.
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Blood tested positive/ negative for pregnancy
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From enrollment to clinical pregnancy result and delivery where applicable.
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Clinical Pregnancy result
Periodo de tiempo: From enrollment to delivery (live birth or miscarriage)
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Confirmation of presence or absence of a gestational sac and fetal heartbeat using ultrasound detection.
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From enrollment to delivery (live birth or miscarriage)
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PLC Zeta measurement
Periodo de tiempo: From enrollment to submission of sperm (1 day)
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Measurement of PLC Zeta by Immunofluorescence and Western Blotting
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From enrollment to submission of sperm (1 day)
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Medidas de resultado secundarias
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Live birth or miscarriage
Periodo de tiempo: From enrollment to delivery or miscarriage.
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Live birth rates/ Miscarriage rates
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From enrollment to delivery or miscarriage.
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Colaboradores e Investigadores
Aquí es donde encontrará personas y organizaciones involucradas en este estudio.
Patrocinador
Patrocinador
Colaboradores
Colaboradores
Investigadores
Investigadores
- Investigador principal: Michael Fakih, MD, Fakih IVF Abu Dhabi
- Investigador principal: Junaid Kashir, PhD, Khalifa University
- Investigador principal: Dr. Lamiya Mohiyiddeen, MD, Fakih IVF Abu Dhabi
Publicaciones y enlaces útiles
La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.
Publicaciones Generales
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- World Health Organization, 2010, Fifth Edition. ISBN: 978 92 4 154778 9.
- Yamaguchi et al., Cell Calcium 2017;pii: S0143-4160(16)30191-9.
- Janghorban-Laricheh E, Ghazavi-Khorasgani N, Tavalaee M, Zohrabi D, Abbasi H, Nasr-Esfahani MH. An association between sperm PLCzeta levels and varicocele? J Assist Reprod Genet. 2016 Dec;33(12):1649-1655. doi: 10.1007/s10815-016-0802-5. Epub 2016 Sep 9.
- Kamali-Dolat Abadi M, Tavalaee M, Shahverdi A, Nasr-Esfahani MH. Evaluation of PLCzeta and PAWP Expression in Globozoospermic Individuals. Cell J. 2016 Fall;18(3):438-45. doi: 10.22074/cellj.2016.4572. Epub 2016 Aug 24.
- Miyazaki S, Ito M. Calcium signals for egg activation in mammals. J Pharmacol Sci. 2006;100(5):545-52. doi: 10.1254/jphs.cpj06003x.
- Fulton BP, Whittingham DG. Activation of mammalian oocytes by intracellular injection of calcium. Nature. 1978 May 11;273(5658):149-51. doi: 10.1038/273149a0. No abstract available.
- Ducibella T, Schultz RM, Ozil JP. Role of calcium signals in early development. Semin Cell Dev Biol. 2006 Apr;17(2):324-32. doi: 10.1016/j.semcdb.2006.02.010. Epub 2006 Mar 2.
- Ducibella T, Huneau D, Angelichio E, Xu Z, Schultz RM, Kopf GS, Fissore R, Madoux S, Ozil JP. Egg-to-embryo transition is driven by differential responses to Ca(2+) oscillation number. Dev Biol. 2002 Oct 15;250(2):280-91.
- Escoffier J, Lee HC, Yassine S, Zouari R, Martinez G, Karaouzene T, Coutton C, Kherraf ZE, Halouani L, Triki C, Nef S, Thierry-Mieg N, Savinov SN, Fissore R, Ray PF, Arnoult C. Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP. Hum Mol Genet. 2016 Mar 1;25(5):878-91. doi: 10.1093/hmg/ddv617. Epub 2015 Dec 31.
- Ferrer-Vaquer A, Barragan M, Freour T, Vernaeve V, Vassena R. PLCzeta sequence, protein levels, and distribution in human sperm do not correlate with semen characteristics and fertilization rates after ICSI. J Assist Reprod Genet. 2016 Jun;33(6):747-56. doi: 10.1007/s10815-016-0718-0. Epub 2016 May 2.
- Kashir J, Konstantinidis M, Jones C, Heindryckx B, De Sutter P, Parrington J, Wells D, Coward K. Characterization of two heterozygous mutations of the oocyte activation factor phospholipase C zeta (PLCzeta) from an infertile man by use of minisequencing of individual sperm and expression in somatic cells. Fertil Steril. 2012 Aug;98(2):423-31. doi: 10.1016/j.fertnstert.2012.05.002. Epub 2012 May 24.
- Kashir J, Konstantinidis M, Jones C, Lemmon B, Lee HC, Hamer R, Heindryckx B, Deane CM, De Sutter P, Fissore RA, Parrington J, Wells D, Coward K. A maternally inherited autosomal point mutation in human phospholipase C zeta (PLCzeta) leads to male infertility. Hum Reprod. 2012 Jan;27(1):222-31. doi: 10.1093/humrep/der384. Epub 2011 Nov 16.
- Kashir J, Buntwal L, Nomikos M, Calver BL, Stamatiadis P, Ashley P, Vassilakopoulou V, Sanders D, Knaggs P, Livaniou E, Bunkheila A, Swann K, Lai FA. Antigen unmasking enhances visualization efficacy of the oocyte activation factor, phospholipase C zeta, in mammalian sperm. Mol Hum Reprod. 2017 Jan;23(1):54-67. doi: 10.1093/molehr/gaw073. Epub 2016 Dec 8.
- Theodoridou M, Nomikos M, Parthimos D, Gonzalez-Garcia JR, Elgmati K, Calver BL, Sideratou Z, Nounesis G, Swann K, Lai FA. Chimeras of sperm PLCzeta reveal disparate protein domain functions in the generation of intracellular Ca2+ oscillations in mammalian eggs at fertilization. Mol Hum Reprod. 2013 Dec;19(12):852-64. doi: 10.1093/molehr/gat070. Epub 2013 Oct 23.
- Kashir J, Nomikos M, Lai FA, Swann K. Sperm-induced Ca2+ release during egg activation in mammals. Biochem Biophys Res Commun. 2014 Aug 1;450(3):1204-11. doi: 10.1016/j.bbrc.2014.04.078. Epub 2014 Apr 21.
- Kashir J, Heynen A, Jones C, Durrans C, Craig J, Gadea J, Turner K, Parrington J, Coward K. Effects of cryopreservation and density-gradient washing on phospholipase C zeta concentrations in human spermatozoa. Reprod Biomed Online. 2011 Aug;23(2):263-7. doi: 10.1016/j.rbmo.2011.04.006. Epub 2011 May 7.
- Kashir J, Jones C, Lee HC, Rietdorf K, Nikiforaki D, Durrans C, Ruas M, Tee ST, Heindryckx B, Galione A, De Sutter P, Fissore RA, Parrington J, Coward K. Loss of activity mutations in phospholipase C zeta (PLCzeta) abolishes calcium oscillatory ability of human recombinant protein in mouse oocytes. Hum Reprod. 2011 Dec;26(12):3372-87. doi: 10.1093/humrep/der336. Epub 2011 Oct 18.
- Yoon SY, Jellerette T, Salicioni AM, Lee HC, Yoo MS, Coward K, Parrington J, Grow D, Cibelli JB, Visconti PE, Mager J, Fissore RA. Human sperm devoid of PLC, zeta 1 fail to induce Ca(2+) release and are unable to initiate the first step of embryo development. J Clin Invest. 2008 Nov;118(11):3671-81. doi: 10.1172/JCI36942. Epub 2008 Oct 16.
- Saunders CM, Larman MG, Parrington J, Cox LJ, Royse J, Blayney LM, Swann K, Lai FA. PLC zeta: a sperm-specific trigger of Ca(2+) oscillations in eggs and embryo development. Development. 2002 Aug;129(15):3533-44. doi: 10.1242/dev.129.15.3533.
- Ito J, Parrington J, Fissore RA. PLCzeta and its role as a trigger of development in vertebrates. Mol Reprod Dev. 2011 Oct-Nov;78(10-11):846-53. doi: 10.1002/mrd.21359. Epub 2011 Aug 5.
- Swann K, Yu Y. The dynamics of calcium oscillations that activate mammalian eggs. Int J Dev Biol. 2008;52(5-6):585-94. doi: 10.1387/ijdb.072530ks.
- Publicover S, Harper CV, Barratt C. [Ca2+]i signalling in sperm--making the most of what you've got. Nat Cell Biol. 2007 Mar;9(3):235-42. doi: 10.1038/ncb0307-235.
- Swann K, Ozil JP. Dynamics of the calcium signal that triggers mammalian egg activation. Int Rev Cytol. 1994;152:183-222. doi: 10.1016/s0074-7696(08)62557-7. No abstract available.
- Kline D, Kline JT. Repetitive calcium transients and the role of calcium in exocytosis and cell cycle activation in the mouse egg. Dev Biol. 1992 Jan;149(1):80-9. doi: 10.1016/0012-1606(92)90265-i.
- Alshahrani S, Ahmed AF, Gabr AH, Abalhassan M, Ahmad G. The impact of body mass index on semen parameters in infertile men. Andrologia. 2016 Dec;48(10):1125-1129. doi: 10.1111/and.12549. Epub 2016 Feb 5.
- Al-Turki HA. A 5-year analysis of semen parameters in Saudi Arabian men attending infertility clinics. J Int Med Res. 2016 Jun;44(3):656-61. doi: 10.1177/0300060516632108. Epub 2016 Apr 1.
- Harton GL, Tempest HG. Chromosomal disorders and male infertility. Asian J Androl. 2012 Jan;14(1):32-9. doi: 10.1038/aja.2011.66. Epub 2011 Nov 28.
- Hotaling JM. Genetics of male infertility. Urol Clin North Am. 2014 Feb;41(1):1-17. doi: 10.1016/j.ucl.2013.08.009. Epub 2013 Oct 23.
- Gunes S, Arslan MA, Hekim GNT, Asci R. The role of epigenetics in idiopathic male infertility. J Assist Reprod Genet. 2016 May;33(5):553-569. doi: 10.1007/s10815-016-0682-8. Epub 2016 Mar 3.
- Pelinck MJ, Hoek A, Simons AH, Heineman MJ, van Echten-Arends J, Arts EG. Embryo quality and impact of specific embryo characteristics on ongoing implantation in unselected embryos derived from modified natural cycle in vitro fertilization. Fertil Steril. 2010 Jul;94(2):527-34. doi: 10.1016/j.fertnstert.2009.03.076. Epub 2009 May 12.
- Fauque P, Leandri R, Merlet F, Juillard JC, Epelboin S, Guibert J, Jouannet P, Patrat C. Pregnancy outcome and live birth after IVF and ICSI according to embryo quality. J Assist Reprod Genet. 2007 May;24(5):159-65. doi: 10.1007/s10815-007-9115-z. Epub 2007 Mar 6.
- Ramadan WM, Kashir J, Jones C, Coward K. Oocyte activation and phospholipase C zeta (PLCzeta): diagnostic and therapeutic implications for assisted reproductive technology. Cell Commun Signal. 2012 Jul 9;10(1):12. doi: 10.1186/1478-811X-10-12.
- Kashir J, Heindryckx B, Jones C, De Sutter P, Parrington J, Coward K. Oocyte activation, phospholipase C zeta and human infertility. Hum Reprod Update. 2010 Nov-Dec;16(6):690-703. doi: 10.1093/humupd/dmq018. Epub 2010 Jun 23.
Fechas de registro del estudio
Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.
Fechas importantes del estudio
Inicio del estudio (Estimado)
Inicio del estudio
1 de julio de 2026
Finalización primaria (Estimado)
Finalización primaria
1 de julio de 2027
Finalización del estudio (Estimado)
Finalización del estudio
1 de agosto de 2027
Fechas de registro del estudio
Enviado por primera vez
Enviado por primera vez
29 de junio de 2026
Primero enviado que cumplió con los criterios de control de calidad
Primero enviado que cumplió con los criterios de control de calidad
29 de junio de 2026
Publicado por primera vez (Actual)
Publicado por primera vez
6 de julio de 2026
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización publicada
6 de julio de 2026
Última actualización enviada que cumplió con los criterios de control de calidad
Última actualización enviada que cumplió con los criterios de control de calidad
29 de junio de 2026
Última verificación
Última verificación
1 de junio de 2026
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
Otros números de identificación del estudio
- FAKIHIVF-001
- DOH/ADHRTC/2024/2075 (Otro identificador: Department of Health Abu Dhabi)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
NO
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
No
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
No
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .