Table 4 Main characteristics of all studies on the genotype of FSHR rs6165, rs6166 and rs1394205 included in the meta-analysis

Gharesi-Fard B

Caucasian

HP

PCR-RELP

rs6165

rs6166

AA:47/64, AG:85/91, GG:68/57;

AA:40/33,AG:107/128,GG:53/51;

0.047

0.291

This case control study was performed on 212 primary azoospermic patients and 200 healthy men. Azoospermia was confirmed based on two separate semen analysis. Inclusion criteria for NOA were, having no history of genital infections and existence of bilateral vas deferens and the exclusion criteria were, having history of surgery or vasectomy. All OA cases were selected among men with primary idiopathic epididymis obstruction. Excluding criteria for OA cases were azoospermia due vas deferens or ejaculatory duct. Moreover, patients with genital infections, vasectomy, or other iatrogenic injuries to the male reproductive tract were excluded from the study.

Wu X

Asian

HP

Sequence

rs6165

rs6166

AA:80/95, AG:75/95, GG:9/22;

AA:82/100, AG:72/92, GG:10/20;

0.108

0.261

The patients selected consisted of infertile men with idiopathic infertility ranging from oligospermia to azoospermia. Other diseases that could cause secondary infertility, such as obstructive azoospermia, karyotype abnormalities, Y chromosome microdeletions, and cryptorchidism, were excluded. The controls consisted of normospermic patients who were from couples suffering infertility due to the woman’s issues and no genetic or reproductive tract disease.

Grigorova M

Caucasian

PB

Sequence

rs1394205

GG:552/380,AG:362/228,AA:68/33

0.412

The inclusion criterion for male partners of infertile couples entering the study was sperm concentration below 20 × 10⁶/ml. All men with causal factors for male factor infertility (obstruction, cryptorchidism, chromosomal abnormalities, Y chromosome deletions, hypogonadotrophic hypogonadisn, testicular diseases, sexual dysfunctions, androgen abuse, severe traumas and operation in genital area, chemo- and radio- therapy) were excluded.

Grigorova M

Caucasian

HP

PCR-RELP

rs6166

AA:379/261,AG:506/353,GG:167/124;

0.930

The inclusion criterion for male partners of infertile couples entering the study was sperm concentration below 20 × 10⁶/ml. All men with causal factors for male factor infertility (obstruction, cryptorchidism, chromosomal abnormalities, Y chromosome deletions, hypogonadotrophic hypogonadisn, testicular diseases, sexual dysfunctions, androgen abuse, severe traumas and operation in genital area, chemo- and radio- therapy) were excluded.

Lazaros L

Caucasian

HP

PCR-RELP

rs6165

rs6166

AA:65/49, AG:132/92, GG:53/59;

AA:65/49, AG:132/92, GG:53/59;

0.356

0.356

The study population was consisted of 450 Greek men, 250 normozoospermic and 200 oligozoospermic men, who were referred to the in vitro fertilization (IVF) Unit, which was based on World Health Organization criteria (WHO, 1999).

Song D

Asian

HP

Sequence

rs6165

rs6166

AA:81/65, AG:88/63, GG:31/22;

AA: 86/69, AG:87/58, GG:27/23;

0.386

0.506

Inclusion criteria were as follows: (I) diagnosed as idiopathic infertility or severe oligoasthenozoospermic (ii) sperm count below 10 × 10⁶/ml, sperm motility (a + b) = 1.19%–9.99% and normal sperm morphology >4% as determined by at least three semen analyses. Patients were excluded if they had: (I) hypogonadotrophic hypogonadism or abuse of androgenic (anabolic) steroids (ii) obstructive azoospermia (iii) underwent treatment with chemotherapeutic agents or radiotherapy. Azoospermic and severely oligozoospermic men with karyotype abnormalities and Y chromosome long arm microdeletions were excluded.

Ghirelli-Filho M

Brazilian

HP

Taqman

rs6165

rs6166

AA:74/33, AG:89/72, GG:54/33;

AA: 49/32, AG:88/66, GG:80/40;

0.011

0.011

Infertile men with severe oligozoospermia (SO) and non-obstructive azoospermia (NOA), with at least 1 year of infertility were included in this study. Individuals with known causes of infertility including genetic factors (chromosome anomalies, AZF [azoospermia factor] microdeletions), clinical factors (varicocele, cryptorchidism) and men whose partner had factors involved in infertility were excluded from this study. To compose the control group, 217 fertile men, who have at least 2 children by direct survey and who lacked any history of requiring assisted reproduction technology, were selected.

Li Y

Asian

HP

PCR-RELP

rs6165

rs6166

rs1394205

AA:189/75,AG:230/88,GG:50/13;

AA:203/80,AG:220/82,GG:46/14;

GG:118/101,AG:250/96,AA:101/38

0.103

0.221

0.144

Those with a history of orchitis, cryptorchidism, varicocoele, obstruction of vas deferens, karyotype abnormality, and Y chromosome microdeletions were excluded. Additionally, subjects having special occupational exposure which may be suspected to affect semen quality (such as pesticides or other agents) were precluded. Then 364 idiopathic infertile patients were divided into three groups: 97 males with non-obstructive azoospermia, 79 with oligozoospemia (sperm count < 40 × 10⁶/ejaculum), 188 with normozoospermia (sperm count ≥ 40 × 10⁶/ ejaculum). The control group consisted of 285 subjects with normal semen parameters, all of which had fathered at least one child without assisted reproductive technologies.

Safarinejad MR

Caucasian

HP

PCR-RELP

rs6165

rs6166

AA:78/62, AG:74/90, GG:20/20;

AA: 85/69, AG:72/80, GG:15/23;

0.702

0.964

All the infertile patients had to have a history of primary infertility for at least 24 months with no known etiology for their infertility. A history of the following: cryptorchidism, varicocele, testicular torsion or genital surgery; azoospermia; UTIs; any endocrinopathy; Y chromosome microdeletions or karyotype abnormalities; use of cytotoxic drugs, immunosuppressants, anticonvulsives, androgens or antiandrogens; leukocytospermia (more than 106 white blood cells per mL), or a positive mixed agglutination reaction test were exclusion criteria. Participants with a history of hepatobiliary disease, significant renal insufficiency, drug or alcohol abuse or dependence, tobacco use, occupational and environmental exposures to potential reproductive toxins, and a body mass index (BMI) of ≥30 kg/m² were also excluded.

Balkan M

Caucasian

HP

PCR-RELP

rs6166

rs1394205

AA:154/176,AG:49/59,GG:37/35;

GG:178/203,AG:49/53, AA:13/14

0.000

0.001

The study population consisted of 240 proven fathers (sperm count > 20 × 10⁶/ml and serum FSH levels < 7 IU/L), and infertile men (150 non-obstructive azoospermic and 120 severe oligozoospemic in which sperm count < 10 × 10⁶/ml). And karyotype abnormalities and Y chromosome microdeletions were exclusion criteria.

Lend AK

Caucasian

HP

PCR-RELP

rs6165

rs6166

rs1394205

AA:67/50, AG:106/72, GG:35/28;

AA:66/50, AG:107/73, GG:35/27;

GG: 110/78, AG:85/61, AA:13/11

0.526

0451

0.522

Patients with non-obstructive idiopathic azoospermia (n = 36) or oligozoospermia (sperm count <20 × 10⁶/ml, n = 114) and without any obvious cause of infertility were considered as infertile cases for the study. The controls group consisted of 208 military conscripts selected based on their sperm count of ≥75 × 10⁶/ml.

Shimoda C

Asian

HP

PCR-RELP

rs6165

rs6166

AA:68/118,AG:61/179,GG:17/46;

AA:72/131,AG:62/164,GG:12/45;

0.560

0.791

All patients presented with non-obstructive azoospermia and elevated basal FSH concentrations (>10.0 mIU/mL), without Y chromosome microdeletion and normal karyotypes. Fertility status was proven by the fact that each of the control subjects had fathered one or more children.

Zalata AA

Caucasian

HP

PCR-RELP

rs6166

AA: 14/18, AG:10/20, GG:6/14;

0.122

The 82 Caucasian men were divided into group (gp)1 (n = 30) normozoospermic, fertile and healthy volunteers who had achieved conception with 1 year, and gp2 (n = 52) infertile oligoasthenozoospermic males. Exclusion criteria were varicocele, cryptorchidism, karyotype anomalies, Y chromosome microdeletions and leucocytospermia.

Pengo M

Caucasian

HP

PCR-RELP

rs6165

rs6166

rs1394205

AA:114/75,AG:153/96,GG:84/44;

AA:114/75,AG:153/96,GG:84/44;

GG:203/126,AG:121/73,AA:27/16

0.022

0.023

0.139

Inclusion criteria were as follows: (i) a minimum of 1 year of infertility (ii) sperm count below 20 × 106/ml as determined by at least two semen analyses. Patients were excluded if they had: (i) hypogonadotrophic hypogonadism or abuse of androgenic (anabolic) steroids (ii) obstructive azoospermia (iii) undergone treatment with chemotherapeutic agents or radiotherapy. Azoospermic and severely oligozoospermic men with karyotype abnormalities and Y chromosome long arm microdeletions were excluded.

Galan JJ

Caucasian

PB

PCR-RELP

rs6166

AA:26/38, AG:51/49, GG:18/17;

0.428

104 Caucasoid men with idiopathic non-obstructive oligozoospermia or azoospermia (sperm counts < 5 × 10⁶/ml) were recruited during this work, which did not consider Y chromosome microdeletions as a confounding factor because of the low frequency of Y chromosome microdeletions.

Ahda Y

Caucasian

PB

Taqman

rs6165

rs6166

rs1394205

AA:74/101,AG:77/166,GG:35/74;

AA:74/101,AG:77/166,GG:35/74;

GG:102/164,AG:74/150,AA:10/27

0.068

0.068

0.466

The study population consisted of 186 men with normal semen values according to WHO criteria (1999) and normal serum FSH levels (<7 IU/L), recruited for contraceptve trials through advertisement in the local newspaper, and 341 infertile men with nonobstructive azoospermia and elevated FSH levels (≥7 IU/L) attending our infertility clinic. Hypogonadotropic hypogonadism and genetic defects causing azoospemia (Klinefelter syndrome or deletions of the Y chromosome) were exclusion criteria.

This study

Asian

HP

Mass-array

rs6165

rs6166

rs1394205

AA:163/210,AG:144/199,GG:33/52;

AA:169/230,AG:146/187,GG:25/44;

GG:78/112,AG:170/233,AA:92/116

0.884

0.391

0.975

The study consisted of 255 infertile men, including 166 azoospermic or severe oligozoospermia (sperm concentration < 5 ×10⁶/ml), and 89 oligozoospermia (sperm concentration5–15×10⁶/ml), with at least 1 year of infertility. Individuals with known causes of infertility including genetic factors (chromosome anomalies), AZF microdeletions, clinical factors (varicocele, crytorchidism) and infections were excluded from this study.