Table 1.

Case-control studies depicting the importance of INSL3 and its receptors in testicular descent in both children and animals.

Authors, Year	Study Sample	Aims	Main Results
Özdamar et al., 2019 [8]	-15 cremasteric muscle complex (CM) samples from 15 patients aged 1–6 years-UDG (undescended group) -15 male patients-9 to 12 years-CG (control group)	-To investigate if insulin-like growth factor receptor-1(IGFR1) is retrieved in the cremaster muscle complex (CM) and the association between testicular descent and INSL3	-IGFR1 density in the CM was significant lower in the UT cases compared to CG -INSL3 and testosterone are required in the rearrangement of the gubernaculum, and with IGFR1 they induce testicular descent, promoting the inguinoscrotal phase
Abou El-Ella et al., 2020 [9]	-160 children: 80 non syndromic UDT (undescended testis) and 80 healthy.	-To investigate the association between G178A/INSL3 polymorphism and cryptorchidism	-Allele of G178A INSL3 variant is significantly found in the UDT (26.2% vs. 12.5% in controls) -G178A—INSL3 gene polymorphism is a predisposing factor for cryptorchidism, and is seen often in cases with a family history -Family history is a significant predictive risk factor for cryptorchidism, especially associated with consanguinity
Anand-Ivell et al., 2018 [10]	-25,105 samples of live-born male (offspring pregnancies) amniotic fluid samples (collected by routine amniocentesis)	-To investigate if cryptorchidism is significantly associated with increased amniotic concentration of INSL3 (13–16 weeks of gestation)	-In the second trimester, concentration of INSL3 in the amniotic fluid is maximal -Cryptorchid cases have significantly higher INSL3 concentration compared to controls
Harrison SM et al., 2019 [7]	-12 human male umbilical cord blood samples -7 human male testes from fetuses in of fetal life	-To measure INSL3 serum levels in fetal umbilical cord and determine its concentrations during fetal life -To measure INSL3 serum levels and mRNA in the fetal testes	-INSL3 serum concentrations during fetal life (between weeks 15 to 20) were discovered to be 2 to 4 times higher than published prepubertal male levels -Testicular fetal INSL3 mRNA relative expression is proven to be decreased in weeks 14 to 16, rose significantly between 17 and 18 weeks, and returned to decreased values in the 21th week
Yuan et al., 2020 [11]	-Animal research: 6 Ziwuling black goats: 3 pairs with normal and cryptorchid testes—extracted at the age of 6 month (by orchidectomy).	-To investigate anatomical alterations in cryptorchism and to study expression and distribution of INSL-3 in descended/cryptorchid testicular tissues	-A decreased level expression of INSL-3 is remarked in cryptorchid goats compared to controls -The presence of undescended testes caused an important reduction in the spermatogenic epithelium and tubule section
Sinopidis et al., 2019 [12]	-Blood samples -46 male patients-non-syndromic cryptorchidism -43 age-matched controls. =Data grouped according to testicular location.	-To assess the existence of INSL3 allelic variations in the physiopathology of cryptorchidism and to estimate potential consequences on fertility	-Seven forms of a single nucleotide (SNVs) were identified -The cumulative percentage of mutations reported in males with an undescended testis, in contrast to control group–1.8% for INSL3 associated with 2.9% for LGR8 and 4.7% for both -The described variations (A24L, V43L and A60T, and I604V) are discovered in patients with cryptorchidism and also in controls
van Brakel et al., 2017 [13]	-118 adult human males antecedents of UDT (undescended testis) -CUDT (congenital undescended testis (N = 55, 6 bilateral), -AUDT (acquired undescended testis) N = 63 (15 bilateral)	-To detect differences in both Leydig and Sertoli cell function in congenital UDT and acquired UDT using INSL3 and anti-Müllerian hormone (AMH).	-There were no differences found in the function of Leydig on the basis of INSL3 levels between CUDT group and AUDT group -AMH levels for bilateral CUDT were significantly lower compared to bilateral AUDT (6.4 vs. 13.2) -AMH levels in unilateral CUDT is significantly higher compared to bilateral CUDT (12.1 vs. 6.4)
Nowacka-Woszuk et al., 2020 [14]	-Animal studies: dogs -16 undescended testes -21 tests from healthy controls	-To compare the levels of INSL3 in dogs with unilateral cryptorchidism to normal male dogs	-The study showed a significantly different expression of INSL3 genes between cryptorchid dogs and controls -INSL3 transcript level was significantly elevated in undescended testes -The mRNA level of RXFP2 was significantly lower in the undescended gonads compared to scrotal testes