Ahead of print publication  

Gonadotropin treatment for male partial congenital hypogonadotropic hypogonadism in Chinese patients

1 NHC Key laboratory of Endocrinolog, Peking Union Medical College Hospital; Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
2 Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China

Date of Submission23-Mar-2019
Date of Acceptance20-Jun-2019
Date of Web Publication23-Aug-2019

Correspondence Address:
Jiang-Feng Mao,
NHC Key laboratory of Endocrinolog, Peking Union Medical College Hospital; Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730
Xue-Yan Wu,
NHC Key laboratory of Endocrinolog, Peking Union Medical College Hospital; Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aja.aja_88_19

PMID: 31464203


Partial congenital hypogonadotropic hypogonadism (PCHH) is caused by an insufficiency in, but not a complete lack of, gonadotropin secretion. This leads to reduced testosterone production, mild testicular enlargement, and partial pubertal development. No studies have shown the productivity of spermatogenesis in patients with PCHH. We compared the outcomes of gonadotropin-induced spermatogenesis between patients with PCHH and those with complete congenital hypogonadotropic hypogonadism (CCHH). This retrospective study included 587 patients with CHH who were treated in Peking Union Medical College Hospital (Beijing, China) from January 2008 to September 2016. A total of 465 cases were excluded from data analysis for testosterone or gonadotropin-releasing hormone treatment, cryptorchidism, poor compliance, or incomplete medical data. We defined male patients with PCHH as those with a testicular volume of ≥4 ml and patients with a testicular volume of <4 ml as CCHH. A total of 122 compliant, noncryptorchid patients with PCHH or CCHH received combined human chorionic gonadotropin and human menopausal gonadotropin and were monitored for 24 months. Testicular size, serum luteinizing hormone levels, follicle-stimulating hormone levels, serum total testosterone levels, and sperm count were recorded at each visit. After gonadotropin therapy, patients with PCHH had a higher spermatogenesis rate (92.3%) than did patients with CCHH (74.7%). During 24-month combined gonadotropin treatment, the PCHH group took significantly less time to begin producing sperm compared with the CCHH group (median time: 11.7 vs 17.8 months, P < 0.05). In conclusion, after combined gonadotropin treatment, patients with PCHH have a higher spermatogenesis success rate and sperm concentrations and require shorter treatment periods for sperm production.

Keywords: gonadotropin treatment; partial congenital hypogonadotropic hypogonadism; spermatogenesis

Article in PDF

How to cite this URL:
Hao M, Nie M, Yu BQ, Gao YJ, Wang X, Ma WL, Huang QB, Zhang R, Mao JF, Wu XY. Gonadotropin treatment for male partial congenital hypogonadotropic hypogonadism in Chinese patients. Asian J Androl [Epub ahead of print] [cited 2020 Sep 22]. Available from: http://www.ajandrology.com/preprintarticle.asp?id=265261

Ming Hao, Min Nie
These authors contributed equally to this work.

  Introduction Top

Congenital hypogonadotropic hypogonadism (CHH) is defined by isolated deficiency or dysfunction of gonadotropin-releasing hormone (GnRH).[1] CHH is clinically characterized by absent or incomplete development during puberty, resulting in small testes by the age of 18 years and infertility in adults. These patients have low circulating testosterone levels with low gonadotropin levels, whereas other pituitary hormones are normal.[2] Pulsatile GnRH or combined gonadotropin therapy is administered to treat infertility in patients with CHH. Because CHH presents with a wide range of gonadotropin deficiency, the clinical spectrum of associated reproductive phenotypes is wide. For most patients with CHH, puberty never occurs (absent puberty). In a less common situation, puberty is initiated and then arrested (partial puberty) in CHH.[1],[2],[3],[4],[5],[6]

According to the degree of pubertal development, patients with CHH can be divided into partial CHH (PCHH) and complete CHH (CCHH).[7] Patients who present with partial pubertal development can be diagnosed with PCHH. There is currently no definite diagnostic standard for PCHH. In this study, we defined male PCHH patients as those with a testicular volume of ≥4 ml and patients with a testicular volume of <4 ml as CCHH. PCHH typically presents with mild gonadotropin deficiency and partial pubertal development.[8],[9] Mutations in gonadotropin-releasing hormone receptor gene (GNRHR), fibroblast growth factor receptor 1 gene (FGFR1), tachykinin 3 (TAC3), and tachykinin receptor 3 gene (TACR3) cause PCHH.[10] Because of lack of clear diagnostic criteria, previous studies of PCHH were mainly limited to description of symptoms and characterization of mutant genes. There have been no reports on gonadotropin treatment for a Chinese population with PCHH.

In the present study, we retrospectively analyzed 587 patients with CHH who were treated in Peking Union Medical College Hospital, Beijing, China, from January 2008 to September 2016. Patients with poor compliance and cryptorchidism were excluded. We then compared the clinical features and treatment outcomes between patients with CCHH and those with PCHH who received combined human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) and were monitored for 24 months.

  Patients and Methods Top


Patients with all of the following criteria were diagnosed with CHH: a male patient without puberty development before 18 years, a serum testosterone level <100 ng dl−1 (3.5 nmol l−1) with low or inappropriately normal gonadotropin levels, normal levels of other pituitary hormones, and negative findings by sellar magnetic resonance imaging (MRI).

This study includes CHH patients who met the following conditions: (1) patients did not receive any therapy before the earliest noted date in this study, including pulsatile GnRH, combined gonadotropins, and testosterone; (2) patients were azoospermic before treatment; (3) patients had no history of cryptorchidism; and (4) patients received HCG/HMG treatment for at least 24 months. The study was approved by the ethics committee of the Peking Union Medical College Hospital, Beijing, China. Informed consent has been obtained from each patient after full explanation of the purpose of this study.

Treatment and follow-up

HCG (2000–5000 U, Livzon Pharmaceutical Co., Zhuhai, China) was injected into the muscle twice weekly for 3 months followed by intramuscular HMG (75–150 U, Livzon Pharmaceutical Co.) injection twice weekly, combined to HCG. Regular follow-ups were conducted at 3-month intervals during the therapy. Gonadotropin dosages were adjusted to maintain plasma testosterone at about 300 ng dl−1.

Luteinizing hormone (LH), follicle-stimulating hormone (FSH), testicular size (measured by Prader orchidometer), testosterone, and sperm count were measured at each visit. Plasma gonadotropins (FSH and LH) and testosterone were measured 48 h after HCG injection by chemiluminescence using a commercial kit (ACS 180 Automatic Chemiluminescence System, Bayer, Germany).

Semen samples were collected by masturbation and analyzed according to the standard World Health Organization method (before 2010, according to 1999 WHO method;[11] after 2010, according to 2010 WHO method[12]). Successful spermatogenesis was defined as the observation of one sperm by microscope in concentrifugated seminal fluid.

Targeted next-generation sequencing

Blood samples were collected from 87 of 122 patients. Genomic DNA was extracted from the peripheral blood leukocytes using Qiagen DNA Blood kit (Qiagen, Hilden, Germany). A gene panel (NimblegenSeqCap EZ system, Roche, Basel, Switzerland) was designed to capture all exons and 10 bp flanking intron sequences of the 31 CHH-related genes [Supplementary Table 1 [Additional file 1]]. The DNA samples were subjected to massive parallel sequencing (100 bp paired-end reads) on an Illumina HiSeq2500 sequencing system (Illumina, Inc., San Diego, CA, USA) after hybridization to the capture array. Bioinformatic analysis including quality control, reads alignment, and variants calling (including single-nucleotide variations [SNVs] and small indels) was performed following the pipelines previously described.[13]

Statistical analyses

SPSS version 17.0 (SPSS Inc., Chicago, IL, USA) was used for data analysis. Normal distributive data are expressed as the mean ± standard deviation (s.d.), and nonnormal distribution data are listed as median (quartiles). Gonadotropins, testosterone, testicular size, sperm count, and sperm production periods were compared between groups with partial and complete CHH by independent sample's t-test. Cox regression models were built to analyze the predictors for successful spermatogenesis. The age at the start of HCG/HMG treatment, body mass index (BMI), height, peak LH and FSH after GnRH (triptorelin, 100 mg) stimulation, family histories of delayed puberty (0 = no, 1 = yes), and basal testicular volume were considered as variables in the Cox regression model and multivariate linear regression model. Sperm concentrations were compared by Mann–Whitney U test. Kaplan–Meier analyses were used to estimate the median time to achieve a threshold sperm level. Statistical significance was set at P < 0.05.

  Results Top

Clinical characteristics of patients with CHH

From January 2008 to September 2016, a total of 587 patients with CHH were retrospectively evaluated. A total of 181 cases were excluded because of accepting testosterone replacement therapy or pulsatile GnRH therapy, 56 were excluded for cryptorchidism, and 228 were excluded for poor compliance or incomplete medical data. Therefore, this study included a total of 122 male patients with CHH who received combined gonadotropin treatment for at least 24 months [Figure 1]. These patients were in overall good health with normal blood and urine routine test results and normal liver and renal function. Thyroid hormone, adrenal glucocorticoid, and growth hormone levels were all within normal range. Baseline median (quartiles) serum levels of LH were 0.24 (0, 0.50) IU l−1 and GnRH agonist-stimulated peak LH levels were 3.80 (1.10, 6.60) IU l−1. Baseline median (quartiles) serum levels of FSH were 1.10 (0.40, 1.30) IU l−1 and GnRH agonist-stimulated peak FSH levels were 3.00 (1.50, 4.90) IU l−1. The patients' mean testicular volume was 3.5 (s.d.= 3.3) ml [Table 1].
Figure 1: Flowchart of screening patients. CHH: congenital hypogonadotropic hypogonadism; GnRH: gonadotropin-releasing hormone; HCG: combined human chorionic gonadotropin; HMG: human menopausal gonadotropin.

Click here to view
Table 1: Baseline features of congenital hypogonadotropic hypogonadism patients

Click here to view

Spermatogenesis in patients with PCHH and those with CCHH

Patients were divided into PCHH (n = 39) and CCHH (n = 83) groups, according to their testicular volume. The PCHH group had significantly larger basal testicular volume (P < 0.001), higher basal LH levels (P < 0.001), and peak LH levels after triptorelin stimulation (P = 0.001) compared with the CCHH group. Patients in the PCHH group had a higher height (P = 0.001) and height after treatment (P = 0.004) compared with those in the CCHH group. However, the two groups had a similar age of initiating treatment, BMI, rate of a family history, rate of dysosmia, and basal FSH and peak FSH levels after triptorelin stimulation [Table 1].

Patients in the PCHH group had a higher spermatogenesis rate (P = 0.023) and a shorter time of first sperm appearance compared with those in the CCHH group (P < 0.001). The median (quartiles) sperm concentrations at 6, 12, 18, and 24 months were 0 (0, 3.50) × 106 ml−1, 0 (0, 6.67) × 106 ml−1, 2.25 (0, 16.35) × 106 ml−1, and 9.99 (0, 22.01) × 106 ml−1 in the PCHH group and 0 (0, 0) × 106 ml−1, 0 (0, 0) × 106 ml−1, 0 (0, 3.43) × 106 ml−1, and 0.49 (0, 16.45) × 106 ml−1 in the CCHH group. Sperm concentrations in the PCHH group were significantly higher than those in the CCHH group at 6, 12, and 14 months (P < 0.05). The PCHH group also tended to produce higher sperm concentrations than did the CCHH group. During the follow-up, 50% of the patients with PCHH produced their first sperm within 12 months, whereas the CCHH group took until the 18-month follow-up to produce their first sperm [Figure 2].
Figure 2: Mean sperm count increased during gonadotropin therapy in both groups. During 24-month combined gonadotropin therapy, PCHH group had a higher sperm concentration than CCHH group. The differences between two groups were statistically significant (*P < 0.05) at 6, 12, and 24 months. CCHH: complete congenital hypogonadotropic hypogonadism; PCHH: partial congenital hypogonadotropic hypogonadism.

Click here to view

Kaplan–Meier analysis showed that the median time to begin sperm production in the PCHH and CCHH groups was 12.9 (95% CI: 10.7–15.0) months and 17.7 (95% CI: 16.4–19.0) months, respectively (P = 0.01, [Figure 3]a. Patients with PCHH showed a tendency for a shorter time of beginning sperm production than did those in the CCHH group. The median time to reach a sperm threshold ≥5 × 106 ml−1 was 16.2 (95% CI: 14.0–18.5) months in the PCHH group and 21.4 (95% CI: 20.3–22.5) months in the CCHH group (P = 0.004, [Figure 3]b. Reaching a sperm threshold ≥10 × 106 ml−1 took a median time of 24 (95% CI: 15.8–32.2) months in the PCHH group [Figure 3]c. These data were not available for the CCHH group (P = 0.01). The estimated median time to reach a sperm concentration ≥15 × 106 ml−1 could not be obtained for either group because of the limited number of patients who produced sperm above this concentration (P = 0.046, [Figure 3]d.
Figure 3: A time-to-event analysis showed that the PCHH group had a higher success rate of spermatogenesis than CCHH group. (a) The median time of begin sperm production (≥1 sperm) in PCHH group is shorter than that in CCHH group. (b) The median time of reaching a sperm threshold ≥5 × 106 ml−1 in PCHH group is shorter than that in the CCHH group. (c) The median time of reaching sperm threshold ≥10 × 106 ml−1 in PCHH group is shorter than that in the CCHH group. (d) The median time of reaching sperm threshold ≥15 × 106 ml−1 in PCHH group is shorter than that in the CCHH group. The differences between two groups were statistically significant (P < 0.05) at ad. CCHH: complete congenital hypogonadotropic hypogonadism; PCHH: partial congenital hypogonadotropic hypogonadism.

Click here to view

Subgroup analysis

A total of 80.3% (98/122) of patients with CHH achieved successful spermatogenesis after gonadotropin therapy. According to the patients' testicular volume, they were divided into the nonspermatogenesis subgroup (n = 24) and the spermatogenesis subgroup (n = 98). The two subgroups of patients generally had similar clinical characteristics, except for basal testicular volume. Patients in the spermatogenesis subgroup had significantly larger basal testicular volume than did those in the nonspermatogenesis subgroup (mean ± s.d.: 3.8 ± 3.6 ml vs 2.3 ± 1.2 ml, P = 0.042) [Table 1].{Figure 2}

Cox-related regression analysis (including the variables of age, BMI, basal LH, peak LH, family history, and basal testicular volume) showed that larger basal testicular volume (β = 0.082, P = 0.041) was the only favorable predictor for a shorter time to produce sperm [Table 2].
Table 2: Predictors for spermatogenesis (correlated Cox analysis)

Click here to view

Mutational analysis

A total of 87 patients underwent targeted next-generation sequencing. Thirty-three patients with CHH had CHH-related variants by targeted next-generation sequencing with a detection rate of approximately 37.9% (33/87). FGFR1, Kallmann syndrome 1 gene (KAL1), prokineticin receptor 2 gene (PROKR2), and chromodomain helicase DNA binding protein 7 (CHD7) mutations were found in the PCHH and CCHH groups. Luteinizing hormone beta polypeptide gene (LHB) and NMDA receptor synaptonuclear signaling and neuronal migration factor gene (NELF) mutations were only found in the PCHH group. GNRHR, kisspeptin receptor gene (KISS1R), fibroblast growth factor 8 gene (FGF8), and prokineticin 2 gene (PROK2) mutations were found in the CCHH group. However, these mutations were not detected in the PCHH group [Table 3].
Table 3: The frequency of known causal genes in the 87 probands

Click here to view

  Discussion Top

We found that compliant, noncryptorchid patients with PCHH responded better to gonadotropin therapy for spermatogenesis than did patients with CCHH. During 24 months of combined gonadotropin treatment, patients with PCHH required less time to achieve sperm and produced higher sperm counts than did those with CCHH.

We defined PCHH as a testicular volume of ≥4 ml. This definition was based on the following considerations. First, the marker of onset of puberty is the size of testicular volume. Most previous studies used testicular volume (≥4 ml) as the standard,[1],[2],[3],[5],[6],[7] while a few studies used testicular volume (>3 ml) as the standard.[14],[15] Testicular volume is assessed by the Prader orchidometer. Therefore, a testicular volume of ≥4 ml or >3 ml represents the same group of patients. In this study, we chose the criterion for testicular volume that was used by most recent studies (≥4 ml).[1],[2],[3],[5],[6],[7] Second, patients with CHH with a large testicular size have a higher chance of reversal of function of the hypothalamus–pituitary–testis axis.[2],[16] Raivio et al.[16] described 15 patients with reversal of CHH, 11 of whom had testicular volumes ≥4 ml. Another study showed that 12 of 16 patients with CHH who experienced reversal had testicular volumes ≥4 ml.[17] Third, baseline testicular volume is the most important predictor of gonadotropin-induced spermatogenesis. Larger testicular size correlates with a higher chance of spermatogenesis.[18],[19],[20] Accordingly, we defined patients with a testicular volume of ≥4 ml as having PCHH and those with <4 ml as having CCHH.

CHH is caused by defects in GnRH release, activity, or both.[21] Partial activation of hypothalamus–pituitary–testis axis function could result from multiple defects. Fewer GnRH neurons in the hypothalamus may produce less GnRH and gonadotropins. Interestingly, mutation of FGF8 can cause decreased GnRH neurons and peptide concentrations in the hypothalamus.[22] In addition, if GnRH is not secreted at a sufficient level, it cannot fully activate function of the gonadal axis. The human GNRH1 gene encodes a preprohormone, which is ultimately processed to the GnRH decapeptide. In vitro studies have shown that mutations of the GnRH decapeptide reduce its binding capacity to the GnRH receptor.[23],[24] Furthermore, decreased expression of the GnRH receptor at the cell surface leads to reduced GnRH signaling. This is supported by the finding that GNRHR mutations can cause partial GnRH resistance.[7] In our study, we found that patients with PCHH had KAL1, FGFR1, PROKR2, CHD7, LHB, and NELF mutations.

We found that a favorable response to gonadotropin therapy for patients with PCHH could be attributable to a larger testicular size. Testicular mass is mainly determined by the seminiferous tubules,[25],[26] and a larger testicular volume is indicative of greater spermatogenesis capacity in normal adult males.[26] Testicular mass is also an important predictive factor in estimating spermatogenesis in infertile men,[27],[28],[29],[30],[31],[32],[33],[34] including patients with CHH.[2],[33]

A better response to gonadotropin therapy in patients with PCHH may have other causes. First, KAL1 and FGFR1 can directly damage testicular development and spermatogenesis.[35],[36],[37] Some patients with CHH have testicular impairment,[37] which cannot be diagnosed unless gonadotropin therapy is initiated. Patients with PCHH have a higher probability of normal testicular function than do patients with CCHH because they have larger testicles after low levels of endogenous gonadotropin stimulation. However, patients with CCHH do not undergo endogenous gonadotropin screening. Second, basal LH and peak LH levels after triptorelin stimulation in the PCHH group were higher than those in the CCHH group. This finding suggested that the hypothalamic–pituitary–gonadal axis of the PCHH group had better reserve function than that in the CCHH group.

In this study, the rate of spermatogenesis in all patients with CHH was 80.3%, which is higher than that (64%–75%) in other studies.[18],[38] This discrepancy between studies may be attributable to the following factors. First, our participants had a larger basal testicular size than other studies (3.5 ml vs 2.1 ml).[18] Second, we excluded patients with cryptorchidism (56 cases). Cryptorchidism is a poor predictor for spermatogenesis, and patients with cryptorchidism require a longer time to obtain sperm.[38],[39] Third, patients who were included in our study had a longer treatment time than did those in other studies. In our study, patients with poor compliance or incomplete medical data were excluded (228 cases). Our participants underwent gonadotropin therapy for 2 years, whereas patients from other studies underwent treatment for 6–40 months.[18],[38]

There are some limitations to our study. First, although the follow-up time in this study was as long as 24 months, more patients could have produced sperm with a longer follow-up time. Second, HMG mainly acts as FSH and has little effect on LH. Treatment with pure FSH, such as urofollitropin, would have been preferable. Third, inhibin B is closely related to reproductive capacity, but it was not tested in this study because of limitation of research conditions.

In conclusion, diagnosis of PCHH is associated with a higher spermatogenesis success rate, higher sperm concentrations, and shorter therapeutic period for sperm production compared with diagnosis of CCHH.

  Author Contributions Top

JFM and XYW designed experiment and revised the article. MH and MN carried out the follow-up reviews and participated in clinical data collection. XW, WLM, QBH, and RZ analyzed data. BQY and YJG wrote the article. All authors read and approved the final manuscript.

  Competing Interests Top

All authors declare no competing interests.

  Acknowledgments Top

The study was funded by the National Key Research and Development Program of China (No. 2016YFC0905102, No. 2016YFA0101003), CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2016-I2M-1-002, No. 2017-I2M-3-007), and the Project of National Natural Science Foundation of China (No. 81771576).

Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.

  References Top

Bonomi M, Vezzoli V, Krausz C, Guizzardi F, Vezzani S, et al. Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH). Eur J Endocrinol 2018; 178: 23–32.  Back to cited text no. 1
Boehm U, Bouloux PM, Dattani MT, Roux ND, Young J, et al. Expert consensus document: European consensus statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2015; 11: 547–64.  Back to cited text no. 2
Pitteloud N, Hayes FJ, Boepple PA, DeCruz S, Seminara SB, et al. The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2002; 87: 152–60.  Back to cited text no. 3
Shaw ND, Seminara SB, Welt CK, Au MG, Plummer L,et al. Expanding the phenotype and genotype of female GnRH deficiency. J Clin Endocrinol Metab 2011; 96: E566–76.  Back to cited text no. 4
Young J. Approach to the male patient with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2012; 97: 707–18.  Back to cited text no. 5
Palmert MR, Dunkel L. Delayed puberty. N Engl J Med 2012; 366: 443–53.  Back to cited text no. 6
Beneduzzi D, Trarbach EB, Min L, Jorge AA, Garmes HM,et al. Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. Fertil Steril 2014; 102: 838–46.  Back to cited text no. 7
de Roux N, Young J, Misrahi M, Genet R, Chanson P, et al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med 1997; 337: 1597–602.  Back to cited text no. 8
Chevrier L, Guimiot F, de Roux N. GnRH receptor mutations in isolated gonadotropic deficiency. Mol Cell Endocrinol 2011; 346: 21–8.  Back to cited text no. 9
Hietamäki J, Hero M, Holopainen E, Känsäkoski J, Vaaralahti K, et al. GnRH receptor gene mutations in adolescents and young adults presenting with signs of partial gonadotropin deficiency. PLoS One 2017; 5: 730–41.  Back to cited text no. 10
World Health Organization. WHO Laboratory Manual for Examination of Human Semen and Sperm-Cervical Mucus Interaction. 4th ed. Cambridge: Cambridge University Press; 1999.  Back to cited text no. 11
World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. 5th ed. Geneva: World Health Organization Press; 2010.  Back to cited text no. 12
Yu B, Liu Z, Gao Y, Mao J, Wang X, et al. Novel NR5A1 mutations found in Chinese patients with 46, XY disorders of sex development. Clin Endocrinol (Oxf) 2018; 89: 613–20.  Back to cited text no. 13
Euling SY, Herman-Giddens ME, Lee PA, Selevan SG, Juul A, et al. Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics 2008; 121 Suppl 3: S172–91.  Back to cited text no. 14
Carlsen E, Andersen AG, Buchreitz L, Jørgensen N, Magnus O, et al. Inter-observer variation in the results of the clinical andrological examination including estimation of testicular size. Int J Androl 2000; 23: 248–53.  Back to cited text no. 15
Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007; 357: 863–73.  Back to cited text no. 16
Mao JF, Xu HL, Duan J, Chen RR, Li L, et al. Reversal of idiopathic hypogonadotropic hypogonadism: a cohort study in Chinese patients. Asian J Androl 2015; 1: 497–502.  Back to cited text no. 17
Liu Z, Mao J, Wu X, Xu H, Wang X, et al. Efficacy and outcome predictors of gonadotropin treatment for male congenital hypogonadotropic hypogonadism: a retrospective study of 223 patients. Medicine 2016; 95: e2867.  Back to cited text no. 18
Bahk JY, Jung JH, Jin LM, Min SK. Cut-off value of testes volume in young adults and correlation among testes volume, body mass index, hormonal level, and seminal profiles. Urology 2010; 75: 1318–23.  Back to cited text no. 19
Liu PY, Baker HW, Jayadev V, Zacharin M, Conway AJ, et al. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab 2009; 94: 801–8.  Back to cited text no. 20
Seminara SB, Hayes FJ, Crowley WF Jr. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations. Endocr Rev 1998; 19: 521–39.  Back to cited text no. 21
Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L,et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest 2008; 118: 2822–31.  Back to cited text no. 22
Mason AJ, Hayflick JS, Zoeller RT, Young WS, Phillips HS, et al. A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the hpg mouse. Science 1986; 234: 1366–71.  Back to cited text no. 23
Mengen E, Tunc S, Kotan LD, Nalbantoglu O, Demir K, et al. Complete idiopathic hypogonadotropic hypogonadism due to homozygous GNRH1 mutations in the mutational hot spots in the region encoding the decapeptide. Horm Res Paediatr 2016; 85: 107–11.  Back to cited text no. 24
Sakamoto H, Ogawa Y, Yoshida H. Relationship between testicular volume and testicular function: comparison of the Prader orchidometric and ultrasonographic measurements in patients with infertility. Asian J Androl 2008; 10: 319–24.  Back to cited text no. 25
Johnson L, Petty CS, Neaves WB. Age-related variation in seminiferous tubules in men. A stereologic evaluation. J Androl 1986; 7: 316–22.  Back to cited text no. 26
Arai T, Kitahara S, Horiuchi S, Sumi S, Yoshida K. Relationship of testicular volume to semen profiles and serum hormone concentrations in infertile Japanese males. Int J Fertil Womens Med 1998; 43: 40–7.  Back to cited text no. 27
Takihara H, Cosentino MJ, Sakatoku J, Cockett AT. Significance of testicular size measurement in andrology. II. Correlation of testicular size with testicular function. J Urol 1987; 137: 416–9.  Back to cited text no. 28
Bujan L, Mieusset R, Mansat A, Moatti JP, Mondinat C,et al. Testicular size in infertile men: relationship to semen characteristics and hormonal blood levels. Br J Urol 1989; 64: 632–7.  Back to cited text no. 29
Sobowale OB, Akiwumi O. Testicular volume and seminal fluid profile in fertile and infertile males in Ilorin, Nigeria. Int J Gynecol Obstet 1989; 28: 155–61.  Back to cited text no. 30
Comhaire FH, de Kretser A, Farley TM. The significance of physical characteristics and laboratory investigations for the diagnosis of male infertility. Int J Androl 1987; 7: S19–33.  Back to cited text no. 31
Lenz S, Giwercman A, Elsborg A, Cohr KH, Jelnes JE, et al. Ultrasonic testicular texture and size in 444 men from the general population: correlation to semen quality. Eur Urol 1993; 24: 231–8.  Back to cited text no. 32
Lenz S, Thomsen JK, Giwercman A, Hertel NT, Hertz J, et al. Ultrasonic texture and volume of testicles in infertile men. Hum Reprod 1994; 9: 878–81.  Back to cited text no. 33
Aribarg A, Kenkeerati W, Vorapaiboonsak V, Leepipatpaiboon S, Farley TM. Testicular volume, semen profile and serum hormone levels in infertile Thai males. Int J Androl 1986; 9: 170–80.  Back to cited text no. 34
Hadziselimovic NO, de Geyter CH, Demougin P, Oakeley EJ, Hadziselimovic F. Decreased expression ofFGFR1, SOS1, RAF1 genes in cryptorchidism. Urol Int 2010; 84: 353–61.  Back to cited text no. 35
Nishio H, Mizuno K, Moritoki Y, Kamisawa H, Kojima Y, et al. Clinical features and testicular morphology in patients with Kallmann syndrome. Urology 2012; 79: 684–6.  Back to cited text no. 36
Salenave S, Chanson P, Bry H, Pugeat M, Cabrol S, et al. Kallmann's syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2mutations. J Clin Endocrinol Metab 2008; 93: 758.  Back to cited text no. 37
Rastrelli G, Corona G, Mannucci E, Maggi M. Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic study. Andrology 2014; 2: 794–808.  Back to cited text no. 38
Punab M, Poolamets O, Paju P, Vihljajev V, Pomm K, et al. Causes of male infertility: a 9-year prospective monocentre study on 1737 patients with reduced total sperm counts. Hum Reprod 2017; 32: 18–31.  Back to cited text no. 39


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]


 Search Pubmed for
    -  Hao M
    -  Nie M
    -  Yu BQ
    -  Gao YJ
    -  Wang X
    -  Ma WL
    -  Huang QB
    -  Zhang R
    -  Mao JF
    -  Wu XY
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)  

  In this article
Patients and Methods
Author Contributions
Competing Interests
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded472    

Recommend this journal