hCG in Men With Idiopathic Hypogonadotropic Hypogonadism.

ORIGINAL

ARTICLE

Sequential versus Continual Purified Urinary FSH / hCG in Men with Idiopathic Hypogonadotropic Hypogonadism Manna Zhang1*, Guoyu Tong2*, Yanling Liu1*, Yiming Mu3, Jianping Weng4, Yaoming Xue5, Zuojie Luo6, Yuanming Xue7, Lixin Shi8, Xueyan Wu9, Shouyue Sun1, Yanhua Zhu4, Ying Cao5, Jie Zhang6, Hong Huang2, Ben Niu7, Hong Li8, Qinghua Guo3, Yan Gao3, Zhibin Li10, Guang Ning1, Dalong Zhu2, Xiaoying Li1, on behalf of HHIS study group 1

Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 2Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China; 3 Department of Endocrinology, General Hospital of Chinese People’s Liberation Army, Beijing, China; 4 Department of Endocrinology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 5 Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; 6Department of Endocrinology, Guangxi Medical University and First Affiliated Hospital, Guangxi, China; 7Department of Endocrinology, The First People’s Hospital of Yunnan Province, Yunnan, China; 8Department of Endocrinology, The Affiliated Hospital of Guiyang Medical College, Guizhou, China; 9Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China; 10Epidemiology Research Unit, The First Affiliated Hospital, Xiamen University, Xiamen, China. Trial registration: This trial is registered with ClinicalTrials.gov, number NCT 01403532.

Context: Gonadotropin therapy using a human chorionic gonadotropin (hCG) and follicle-stimulating hormone (FSH) preparation is an effective regimen in inducing masculinization and spermatogenesis in men with idiopathic hypogonadotropic hypogonadism (IHH). However, the high cost of medication and frequent injections affect compliance. Objective: This study aims to determine the efficacy of sequential use of highly purified urinary FSH (uFSH)/hCG in men with IHH. Design and setting: A randomized, open-label, prospective, controlled non-inferiority trial with 18 month follow-up was conducted in 9 tertiary hospitals. Patients and Intervention: 67 Chinese males with IHH were randomly allocated into Group A receiving continual uFSH (75 U, three times a week) and hCG ( 2000 U, twice a week) injection and Group B receiving sequential uFSH (75 U, three times a week every other three months) and hCG (2000 U, twice a week) injection. Main Outcome Measure: The primary outcome was the proportion of subjects with a sperm concentration ⱖ 1.0 ⫻106/ml during the 18 months. Comparison of efficacy between Groups A and B was analyzed for non-inferiority. Results: 17/33 (51.5%) of patients receiving continual uFSH/hCG and 19/34 (55.9%) of patients receiving sequential uFSH/hCG achieved sperm concentration ⱖ 1.0 ⫻ 106/ml. Efficacy in the sequential uFSH/hCG group was not inferior to that in the continual uFSH/hCG group (non-inferiority, p⫽0.008) by intention to treat analysis. ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received October 13, 2014. Accepted March 26, 2015.

doi: 10.1210/jc.2014-3802

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Sequential versus Continual uFSH / hCG in IHH


Conclusions: The efficacy of sequential uFSH/hCG regimen is not inferior to that of continual uFSH/hCG regimen in inducing spermatogenesis and masculinization of IHH patients.

ongenital idiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent or incomplete sexual maturation and infertility caused by an isolated defect of gonadotropin-releasing hormone (GnRH) release or action (1–3). IHH is classified as Kallmann syndrome (KS) in the presence of anosmia or hyposmia, and normosmic hypogonadotropic hypogonadism (nIHH) with intact sense of smell (2, 4). The goal of therapy for male IHH patients consists of achievement in physical and psychological sexual maturation and fertility. Pulsatile GnRH or exogenous gonadotropins are usually used to induce spermatogenesis and promote testicular enlargement (5–11). The regimen for gonadotropin replacement includes an initial use of human chorionic gonadotropin (hCG) for 6 –12 months, and then addition of follicular stimulating hormone (FSH) or human menopausal gonadotropin (hMG) until pregnancy (12). However, the current regimen is costly and poorly complied by patients. It was documented that spermatogenesis could be well maintained using hCG alone provided it was once induced by pulsatile GnRH or continual hCG/FSH treatment in some IHH patients (13, 14). It was also reported that hCG alone could induce spermatogenesis in IHH patients (7). Thus, the objective of this study was to explore the efficacy of intermittent or sequential use of FSH preparations in combination with hCG in inducing spermatogenesis in IHH patients. This modified regimen might greatly reduce the medication cost.

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Subjects and Methods Study design This randomized, open-label, multicenter, noninferiority trial was conducted between October 2009 and December 2012 in accordance with the ethical principles of the declaration of Helsinki and the principles of current Good Clinical Practices. The study protocol was reviewed and approved by the Institutional Review Board of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. The written informed consent was obtained from each participant. This study was conducted in nine tertiary hospitals in China. A complete medical history was recorded and physical examination performed by senior endocrinologists. The GnRH stimulating tests and hCG stimulating tests were performed at initial screening. 96 male IHH patients were initially screened and finally 67 patients met the inclusion criteria and randomly allocated into two groups; continual uFSH (Group A, n ⫽ 33) and sequential uFSH (Group B, n ⫽ 34) as shown in Figure 1. The patients were followed up every three months at 3, 6, 9, 12, 15 and 18 months after treatment initiation, including physical examination, semen analysis and hormone measurements.

Study subjects Eligibility criteria included 1) men at ages of 18 – 45 yrs; 2) without spontaneous puberty; 3) serum testosterone levels ⬍ 100 ng/dl (3.5 nmol/L) in the presence of low or normal gonadotropins; 4) otherwise, normal testing of the anterior pituitary gland. Exclusion criteria included 1) acquired hypogonadotropic hypogonadism; 2) previous exposure to pulsatile GnRH or FSHcontaining preparations; 3) patients ever receiving testosterone replacement for more than 6 months duration; 4) sperm concentration ⱖ 1.0 ⫻ 106/ml; 5) presence or history of unilateral or bilateral cryptorchidism; 6) serum testosterone level ⬍ 150 ng/dl (5.2 nmol/L) by a hCG stimulating test; 7) moderate or severe liver and renal dysfunction, including serum alanine aminotrans-

Figure 1. Flow chart of subjects randomization and follow-up


doi: 10.1210/jc.2014-3802

ferase (ALT) ⬎ 120 IU/L, aspartate aminotransferase (AST) ⬎ 80 IU/L, and serum creatinine ⬎ 115 ␮mol/L. A total of 96 patients were initially screened. Of those, 18 patients did not meet the inclusion criteria, 7 declined to participate and 4 declined to blood sampling. 12 patients did not complete the study, including 7 from Group A and 5 from Group B. The reasons for the drop-outs are indicated in Figure 1.


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of body height. Each subject was measured 3 times to the nearest 5 mm. Body mass index was calculated as body weight in kilograms divided by height in squared meters (kg/m2). Pubic and gonad Tanner stages were evaluated by a senior physician. Penis length was measured from the base all the way to the end of the tip. Testicular volumes were examined by ultrasound examinations of scrotal content (GE LOGIQ E9, GE LOGIQ 9,USA) and calculated by the formula of length⫻width⫻depth⫻0.71 (18).

Randomization and masking Participants were randomly assigned to group A and B (1:1). The randomization was conducted independently at a central office using a computer-generated random allocation sequence table with permuted blocks of six and with stratification by centers. Allocation concealment was performed by enclosing assignments in sequentially numbered, opaque, closed envelopes. Patients, investigators, trial staff, and statisticians were masked to treatment allocation.

Treatment The patients in both Groups A and B received injections of 2, 000 U human chorionic gonadotropin (hCG) twice a week from the start to the 18th month. In Group A, patients received injections of 75 U uFSH three times a week from the sixth to 18th month. In Group B, patients received injections of 75 U uFSH three times a week from the sixth to the 18th month every other three months. Both hCG and uFSH were injected via i.m. by nurses or the patients themselves.

Outcomes The primary outcome was defined as a sperm concentration of ⱖ 1.0 ⫻ 106/ml during the 18 month course of treatment. A value of 1.0 ⫻ 106/ml was commonly used in clinical trials as it is representative of sperm concentration that is compatible with achieving pregnancy (15–17). The secondary outcomes include single testicular volume, serum testosterone concentration, sperm activity, sperm count per ejaculate, and time of spermatogenesis. Self-reported pregnancy was also recorded.

Clinical measurements Body weight, height, body mass index (BMI), Tanner stage and penis length were evaluated at each visit. Body weight, expressed in 0.1-kg intervals, was measured at fasting states in the morning. Harpenden stadiometers were used for measurement

Biochemical measurements Blood samples were collected in the morning within 24 –72h after the last hCG and uFSH injections and immediately centrifuged. Serum was frozen at – 80°C until assayed. Serum LH, FSH, estradiol and testosterone were measured by chemiluminescence immunoassay (CLIA) (Abbott, USA). The normal range for LH is 1.1– 8.8 IU/L, FSH 1.6 – 6.4 IU/L and testosterone 160 – 800 ng/dl (5.6 –27.8 nmol/L) in men. Semen specimens were collected from the patients at each visit upon successful ejaculation and analyzed according to World Health Organization guidelines (19). All the samples were collected after 4 –7 days of sexual abstinence and obtained by masturbation. Azoospermia is defined as no sperm detected in semen. Sperm motility was classified as Grade A, B and C.

Statistical analysis 67 patients were randomly allocated at a ratio of 1:1 into 2 groups. Efficacy was compared between Groups A and B for noninferiority. The expected efficacy rate in the reference group (continual uFSH, Group A) was 70% (20). The margin of acceptable difference between Group B and Group A was set at 25%. The criterion for establishing noninferiority was that the lower bound of the two side 95% confidence interval (CI) for the differences in rates of Group B vs. Group A must exceed the predefined noninferiority margin of –3%. Under these assumptions, a sample size of 33 patients in each of the two treatment groups was needed to yield 80% power to conclude that group B was not inferior to group A with ␣⫽0.05. All efficacy analyses were performed based on intention-totreat (ITT). The primary outcome for noninferiority was also analyzed using per-protocol (PP) principle, which included the subjects who completed the whole process of the 18-month treatment. Student’s t test was utilized for normal distributed variables. Nonparametric Wilcoxon rank-sum test was performed for skewed parameters. Kaplan-Meier plots were used to analyze the time for the primary outcome and initiation of spermatogenesis, which were compared between groups with the use of the log-rank test. ␹2 or Fisher’s exact test was used for comparison of binary outcomes. Statistical analysis was performed using SAS version 8.1 software (SAS Institute, Cary, NC). The results were presented as mean ⫾SD or median (inter quartile range).

Results

Figure 2. Proportion of subjects with sperm concentration > 1.0 ⴛ 106/ml by intention-to-treat and per-protocol analysis after 18 month treatment

Baseline characteristics Clinical characteristics and hormonal profiles of the participants at baseline are shown in Table 1. The mean age was 23.1 ⫾ 5.1 yrs in Group A and 24.1 ⫾ 4.9 yrs in Group B. 14 (42.4%) individuals in Group A and 16 (47.1%) individuals in Group B presented with complete


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Figure 3. Proportion of subjects with sperm concentration > 0 ⴛ 106/ml, > 1.0 ⴛ 106/ml and > 15.0 ⴛ 106/ml by intention-to-treat at 0, sixth month and 18th month. 0 month: the patients had no treatment; sixth month: the patients had received 6 month of hCG monotherapy; 18th month: the patients had received 6 month of hCG monotherapy and additional 12 month of hCG and uFSH combination therapy.

anosmia or hyposmia. All the patients lacked signs of secondary sexual characteristics and had small testes and short penises. Serum testosterone, LH and FSH concentrations were reduced. Sperm count was null in the ejaculates at baseline. After 6 month hCG monotherapy, the clinical characteristics and hormone concentrations were shown in Supplemental Table 1 and Figure 3. Serum testosterone concentrations were markedly increased in the first 3 months in both groups (Supplemental Table 1; Figure 4b). The testis volumes and penis lengths were significantly increased at 6 months in both groups. However, there were no significant differences in those secondary characteristics between Group A and Group B at sixth month (P ⬎ .05). After 6 month hCG monotherapy, 4/33 (12.1%) of patients in Group A and 5/34(14.7%) in Group B had spermatogenesis (sperm density ⬎ 0 ⫻ 106/ml). 3/33 (9.1%) of patients in Group A and 4/34 (11.8%) of patients in Group B achieved a sperm density ⱖ 1.0 ⫻ 106/ml. However, there is no significant difference in spermatogenesis between the two groups (Figure 3). Primary outcome After additional 12 months of combination treatment, a sperm density ⱖ 1.0 ⫻ 106/ml was achieved in 17/33 (51.5%; 95%CI, 33.5%– 69.2%) of patients in Group A who received continual uFSH injection and 19/34 (55.9%; 95%CI, 37.9%–72.8%) of patients in Group B who received sequential uFSH injection by intention to treat (ITT) analysis (P ⫽ .008 for noninferiority) (Figure 2; Figure 3). A sperm density ⱖ 1.0 ⫻ 106/ml was achieved in 16/26 (61.5%; 95%CI, 40.6%–79.8%) of patients in Group A and 19/29 (65.5%; 95%CI, 45.7%– 82.1%) of patients in Group B by per-protocol principal analysis (P ⫽ .013 for noninferiority) (Figure 2).

Testis volume and penis length Testis volumes and penis length were not significantly different between Group A and Group B at 18th month (Supplemental Table 1). The median single testicular volume was increased from 1.7 ml to 4.8 ml in Group A and from 1.5 ml to 5.3 ml in Group B at 18th month (Supplemental Table 1; Figure 4a). Median penis length was increased from 3.9 cm to 6.7 cm in Group A and from 4.3 cm to 6.9 cm in Group B (P ⫽ .912, Supplemental Table 1).

Serum hormone concentrations Serum testosterone concentrations were not significantly different between Group A and Group B at 18 months (P ⫽ .288, Supplemental Table 1). The Tanner stage for pubic hair was increased from 1.9 at baseline to 4.3 at 18 months in Group A and from 2.1 at baseline to 4.6 at 18 months in Group B (P ⫽ .963, Supplemental Table 1). The genital Tanner stage was increased from 1.6 to 4.3 in Group A and from 1.7 to 4.3 in Group B (P ⫽ .626, Supplemental Table 1). In addition, obvious beard growth and voice changes were observed in all subjects in both groups. Sperm count and motility 18/33 (54.6%; 95%CI, 36.4%–71.9%) of patients in Group A and 22/34 (64.7%; 95%CI, 46.5%– 80.3%) of patients in Group B had spermatogenesis during 18 month treatment by ITT analysis (P ⫽ .397; Figure 3). Median sperm concentrations were 1.1 ⫻ 106/ml in Group A and 1.5 ⫻ 106/ml in Group B, which was not significantly different (P ⫽ .317, Supplemental Table 1). 5/33 (15.2%) of patients in Group A and 10/34 (29.4%) in Group B achieved sperm concentrations of greater than 15 ⫻ 106/ml (P ⫽ .162, Figure 3). Median sperm activity was 32.8% in Group A and 44.7% in Group B (P ⫽ .745, Supplemental Table 1). Timing of spermatogenesis Kaplan-Meier survival analysis showed that the median time for initial spermatogenesis was 9 months in Group A and 6 months in Group B after hCG and uFSH combination treatment (Figure 5a). The median time to achieve the primary outcome was 9 months in both groups after hCG and uFSH combination treatment (Figure 5b). There were no significant differences between the two groups in the timing of initial spermatogenesis and achievement of the primary outcome.


doi: 10.1210/jc.2014-3802

Table 1.


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Baseline characteristics of the study participants Continual uFSH (Group A, n ⴝ 33)

Age (yrs) Height (cm) BMI (kg/m2) Penis length (cm) Testicular volume (ml) Pubic hair stage Genital Tanner stage Plasma LH ( IU/liter) Plasma FSH ( IU/liter) Plasma testosterone (ng/dl)

23.1 ⫾ 5.1 172.1 ⫾ 7.1 21.3 ⫾ 4.5 3.9 ⫾ 1.4 1.7 (0.9 –3.4) 1.9 ⫾ 0.9 1.6 ⫾ 0.9 0.3 (0.1– 0.7) 0.8 (0.4 –1.6) 40 (30 –50)

Sequential uFSH (Group B, n ⴝ 34) 24.1 ⫾ 4.9 172.6 ⫾ 6.4 22.2 ⫾ 6.6 4.3 ⫾ 1.0 1.5 (1.0 –3.0) 2.1 ⫾ 1.0 1.7 ⫾ 0.7 0.3 (0.1– 0.8) 1.0 (0.5–1.4) 40 (30 –50)

P value 0.413 0.730 0.537 0.193 0.783 0.302 0.401 0.580 0.624 0.841

Data are presented as mean ⫾ SD or median (inter quartile range). Abbreviation: BMI, Body Mass Index; LH, Luteinizing hormone; FSH, Follicle stimulating hormone.

Economic effectiveness The estimated medication cost was $4,800 ($175 for hCG and $4,625 for uFSH) for Group A and $2,490 ($175 for hCG and $2,315 for uFSH) for Group B for the 18

Figure 4. The changes of testicular volume and serum testosterone concentration throughout the period of the 18-month follow-up Single testicular volume (a) and serum testosterone concentration (b) in continual uFSH group and sequential uFSH group through the 18-month treatment period. The data are presented as the mean ⫾ SD.

month treatment. Compared with the continual uFSH regimen in Group A, the sequential uFSH regimen in Group

Figure 5. Kaplan-Meier survival analysis for the median time of spermatogenesis (a) and achievement of sperm concentration > 1.0 ⴛ 106 /ml (b) The median time of spermatogenesis and achievement of the primary outcome were 15 months in the continual uFSH group. The median time of spermatogenesis was 12 months and achievement of the primary outcome 15 months in the sequential uFSH group. There were no significant differences between these two groups in the median time of spermatogenesis and achievement of the primary outcome (P ⬎ .05).


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B reduced cost by $2,310 for each patient to achieve the noninferior efficacy in spermatogenesis, which could be a tremendous saving for ordinary families with IHH patients in China.

Discussion In the American Association of Clinical Endocrinology guidelines, it is described that hCG combined with FSH preparations is an effective regimen in inducing spermatogenesis for male IHH patients (12). However, the frequent injections and costly medication result in poor compliance. In our present study, the intermittent use of uFSH every other three months harbored noninferior efficacy as with the continual use of uFSH in inducing spermatogenesis. The modified regimen was meaningful in reducing medication cost. The efficacy of continual use of uFSH in achieving sperm concentration ⱖ 1.0 ⫻ 106/ml was 51.5%, which is lower compared with that in other studies (17, 21–24). This may be attributed to the shorter term (1 year), fewer courses, severe IHH, a fixed dose (75U) and lack of pretreatment of FSH preparation in our present study; whereas uFSH dosage could be increased from 75 U to 150 U according to the response (21–24), one or more courses of pretreatment with hMG or FSH had been received in IHH patients in other studies (20, 26). What’s more, the extracted urine FSH was not as pure as the recombinant FSH used in other studies (22, 24, 25, 27). It was reported that biological efficacy of 150 U rhFSH might be comparable with 225 U uFSH (50 U rhFSH vs 75 U uFSH) (28). Although hMG and uFSH preparations have been replaced by rhFSH in many countries, hMG and uFSH are still mostly used in IHH patients in China due to its low cost. Liu PY et al reported that the median sperm concentrations for unassisted pregnancies in infertile Chinese men were ⬎ 8.0 million/ml (26). In our study, we found that 8/33 (24.2%) of patients in continual uFSH group and 13/34 (38.2%) of patients in sequential uFSH group achieved this outcome by ITT analysis, which was not significantly different between those two groups (P ⫽ .217). As reported by OGAWA and colleagues (29), the intermittent use of FSH-containing preparations was also assessed in HH patients with growth hormone (GH) deficiency. Their regimen included 3000 U of hCG 2 or 3 times a week for the first 6 months and then addition of 75 U of HMG for 3 months, and was repeated until the patients were married. All the four patients achieved spermatogenesis at a concentration of 24 –100 ⫻ 106/ml in


several years by intermittent use of HMG. Another study showed that spermatogenesis induced by treatment with GnRH or hCG/FSH could be maintained for 3–24 months by hCG treatment alone in HH patients (7, 13). It was also reported that spermatogenesis could be maintained longer by using hCG alone in hypophysectomized patients (14). Those findings indicate that Sertoli cells in the testis could maintain functional even while receiving intermittent stimulation of FSH. As expected, testicular volumes, penis length and pubic hair were progressively increased during the period of treatment. Serum testosterone concentration was abruptly increased by use of hCG alone. The testicular volumes were measured by ultrasonography and calculated by formula of length⫻width⫻depth⫻0.71 in our present study. The baseline median single testicular volume was 1.7 ml and 1.5 ml in Group A and B, which indicates that the subjects had severe IHH. Sakamoto proposed that the measurement of testicular volume by ultrasonography was more accurate than that by the Prader orchidometer (18). However, we also measured the testicular volume using Prader orchidometer. The average single testicular volumes were 3.0 ml in both groups at baseline, 13.0 ml in Group A and 12.0 ml in Group B after 18 month treatment by Prader orchidometer. The median motile sperms (Grade A, B and C) were 32.8% in Group A and 44.7% in Group B, which is similar with that in other studies (17, 22). The median time to induce spermatogenesis was 15 months in Group A and 12 months in Group B since the treatment initiated. The median time of achieving primary outcomes was 15 months, which is consistent with other studies (24, 27, 29, 30). The intermittent use of FSH has a trend for an earlier induction of spermatogenesis although there is no significant difference between the two groups. The impregnate condition was recorded in 3.0% (1/33) patients in continual FSH treatment group and 14.7% (5/34) patients in sequential FSH treatment group 6 months after the end of the trial. Most patients (80%) in our study had no desire for an immediate pregnancy since they were not yet married during this study. The cost of gonadotropins and frequent injections are the two major obstacles for IHH patients to receive this medication. Our data showed that the sequential FSH regimen could almost reduce the cost by half and injection times. However, the improvement of compliance was not assessed in this present RCT study. It should be noted that the recombinant human (rh) FSH and hCG could be administered subcutaneously, which can definitely improve the compliance of the patients. Our current study has several limitations, 1) An open labeled rather than blind trial was performed due to the


doi: 10.1210/jc.2014-3802

injection preparations; 2) uFSH dosage could not be adjusted according to the spermatogenesis response; 3) Those patients who had a history of cryptorchidism and a poor response to hCG (serum testosterone peak ⬍ 150 ng/dl by hCG stimulation) were excluded; 4) A sperm concentration of 1.0 million/ml was used as the endpoint, which might be weakly compatible for unassisted pregnancies. In conclusion, our results indicate that sequential use of FSH preparations every other three months is also effective in inducing spermatogenesis in IHH patients. This approach would greatly reduce medication cost for IHH patients.

Acknowledgments We are indebted to all the patients who participated in this study. This work was supported by the grants from Shanghai Shenkang Hospital Development Center (SHDC12012102) and Shanghai Science and Technology Committee (No. 09DJ1400402). The clinical trial registration number identifier (clinicaltrials.gov) is NCT 01 403 532.


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Address all correspondence and requests for reprints to: Dalong Zhu, MD, Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, China, Email: [email protected], Xiaoying Li, MD, Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin second Road, Shanghai 200 025, Tel: ⫹86 –21–54 660 108, Fax: ⫹86 –21– 54 660 108, Email:[email protected]. This work was supported by . * These authors equally contribute to this work. Disclosure Summary: The authors have nothing to disclose.

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Hormonal therapy (hCG and rhFSH) for infertile men with adult-onset idiopathic hypogonadotropic hypogonadism.

Hypogonadotropic hypogonadism in men with hereditary hemochromatosis.

Effect of hCG or hCG+ treatments in young thalassemic patients with hypogonadotropic hypogonadism.

Effects of androgen replacement therapy on cornea and tear function in men with idiopathic hypogonadotropic hypogonadism.

Lymphocyte subset distribution and natural killer cell activity in men with idiopathic hypogonadotropic hypogonadism.

Pituitary glycoprotein hormone alpha-subunit secretion after thyrotropin-releasing hormone stimulation in normal men and men with idiopathic hypogonadotropic hypogonadism.

Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1.

Clinical and laboratory heterogeneity in idiopathic hypogonadotropic hypogonadism.

A network investigation on idiopathic hypogonadotropic hypogonadism in china.

Familial hypogonadotropic hypogonadism with alopecia.

Moebius syndrome in association with hypogonadotropic hypogonadism.

A female patient with normosmic idiopathic hypogonadotropic hypogonadism carrying a novel mutation in FGFR1.

Study on KAL1 Gene Mutations in Idiopathic Hypogonadotropic Hypogonadism Patients with X-Linked Recessive Inheritance.

Leydig cell differentiation induced by stimulation with HCG and HMG in two patients affected with hypogonadotropic hypogonadism.

Unexpected difficult airway with hypogonadotropic hypogonadism.

The effect of pubertal delay on adult height in men with isolated hypogonadotropic hypogonadism.

Psychosexual development in men with congenital hypogonadotropic hypogonadism on long-term treatment: a mixed methods study.

The effectiveness of zinc supplementation in men with isolated hypogonadotropic hypogonadism.

An idiopathic hypogonadotropic hypogonadism patient with metabolic disorder and diabetes: case report.

Clinical characteristics of 138 Chinese female patients with idiopathic hypogonadotropic hypogonadism.

Sexual behavior of men with isolated hypogonadotropic hypogonadism or prepubertal anterior panhypopituitarism.

Genetics of congenital hypogonadotropic hypogonadism in Denmark.

Hypogonadotropic hypogonadism in idiopathic hemochromatosis: evidence for combined hypothalamic and pituitary involvement.

Hormonal control of spermatogenesis in men: therapeutic aspects in hypogonadotropic hypogonadism.