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| ID | Type | Description | Link |
|---|---|---|---|
| U54HD028138 | U.S. NIH Grant/Contract | View source |
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Recruitment was at a standstill. We are currently preparing our results for publication.
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Men with idiopathic hypogonadotropic hypogonadism (IHH, Kallmann Syndrome) may have small testicular size, low testosterone levels, no history of puberty, and infertility. These men lack a hormone called gonadotropin releasing hormone (GnRH) that stimulates the development and maturation of the testes. This study will investigate the impact of hormonal treatments on men with IHH. The goal of hormonal therapy is to maximize the potential fertility in these individuals.
Though steroid output of the testes is minimal during childhood, important changes take place that impact spermatogenic potential. Specifically, the number of Sertoli cells increases until testosterone secretion rises during puberty. In animal models, the proliferation of Sertoli cells appears to be regulated by follicle stimulating hormone (FSH) even though FSH levels in childhood are relatively low. At puberty, the number of Sertoli cells becomes fixed; however, the existing cell population then undergoes functional maturation. This switch from proliferation to maturation of Sertoli cells appears to result from rising levels of intratesticular testosterone.
FSH deficiency during testicular development results in decreased numbers of Sertoli cells, even if physiologic hormonal replacement therapy is introduced in adolescence or adulthood. The number of mature Sertoli cells appears to correlate with testicular size, sperm count, and future fertility. An improved understanding of the specific roles of FSH, luteinizing hormone (LH), and testosterone in testicular development may have direct clinical applications in the treatment of male infertility. This study will define the role of FSH in stimulating Sertoli cell proliferation in the human male.
Patients in this study will be randomized to receive either FSH and GnRH (Group 1) or GnRH alone (Group 2). Patients in Group 1 will receive subcutaneous FSH injections daily, titrated to achieve a FSH level of 4-8 IU/L, for 4 months. Patients will then receive GnRH therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. Patients in Group 2 will receive the same regimen of exogenous GnRH for 18 months without prior FSH administration.
All patients will undergo an initial assessment that includes an overnight 12-hour frequent blood sampling study, testicular ultrasound, and testicular biopsy. Patients will be followed through monthly study visits with blood tests and seminal fluid analysis. Patients will also have serial testicular ultrasounds to measure testicular growth. Patients in Group 1 will also have a second frequent blood sampling to measure LH, FSH, and testosterone and to confirm the absence of LH pulses.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1 (FSH) | Experimental | Patients in Group 1 will receive subcutaneous follicle stimulating hormone (FSH) injections daily, titrated to achieve a FSH level of 4-8 IU/L, for 4 months. Patients will then receive gonadotropin releasing hormone (GnRH) therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. |
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| Group 2 (GnRH) | Active Comparator | Patients in Group 2 will receive gonadotropin releasing hormone (GnRH) therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. Patients in Group 2 will not receive prior FSH administration. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Testicular biopsy | Procedure | Outpatient surgical procedure. |
| |
| Measure | Description | Time Frame |
|---|---|---|
| LH | Average Luteinizing Hormone levels after treatment. | month 4 of GnRH treatment |
| FSH | Average Follicle Stimulating Hormone levels after treatment. | month 4 of GnRH treatment |
| Testosterone | Average Testosterone levels after treatment. | month 4 of GnRH treatment |
| Inhibin B | Average Inhibin B Levels after treatment. | month 4 of GnRH treatment |
| Testicular Size (Volume) | Average testicular volume after treatment. | at baseline and month 4 of GnRH treatment |
| Sperm Count | Average sperm count after treatment. | month 4 of GnRH treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Fertility | Participants actively seeking to conceive. | 24 months |
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Inclusion Criteria
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| William F Crowley, Jr., MD | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12213860 | Background | Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF Jr. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002 Sep;87(9):4128-36. doi: 10.1210/jc.2002-020518. | |
| 11788640 | Background | Pitteloud N, Hayes FJ, Boepple PA, DeCruz S, Seminara SB, MacLaughlin DT, Crowley WF Jr. 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 Jan;87(1):152-60. doi: 10.1210/jcem.87.1.8131. |
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Two subjects were deemed ineligible for the study. One subject was lost to follow up before being assigned to Group 1 or Group 2.
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| ID | Title | Description |
|---|---|---|
| FG000 | Group 1 (FSH) | Patients in Group 1 will receive subcutaneous FSH injections daily, titrated to achieve a FSH level of 4-8 IU/L, for 4 months. Patients will then receive GnRH therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| gonadotropin releasing hormone (GnRH) |
| Drug |
Pulsatile GnRH (25 ng/kg per bolus every two hours via microinfusion pump titrated to reach normal serum testosterone levels) |
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| follicle stimulating hormone (FSH) | Drug | 75 IU subcutaneous injection daily for four months. |
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| 11701733 | Background | Hayes FJ, Pitteloud N, DeCruz S, Crowley WF Jr, Boepple PA. Importance of inhibin B in the regulation of FSH secretion in the human male. J Clin Endocrinol Metab. 2001 Nov;86(11):5541-6. doi: 10.1210/jcem.86.11.8031. |
| 16396935 | Background | Kumar PA, Pitteloud N, Andrews PA, Dwyer A, Hayes F, Crowley WF Jr, Dym M. Testis morphology in patients with idiopathic hypogonadotropic hypogonadism. Hum Reprod. 2006 Apr;21(4):1033-40. doi: 10.1093/humrep/dei444. Epub 2006 Jan 5. |
| 24037890 | Derived | Dwyer AA, Sykiotis GP, Hayes FJ, Boepple PA, Lee H, Loughlin KR, Dym M, Sluss PM, Crowley WF Jr, Pitteloud N. Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013 Nov;98(11):E1790-5. doi: 10.1210/jc.2013-2518. Epub 2013 Sep 13. |
| Group 2 (GnRH) |
Patients in Group 2 will receive GnRH therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. Patients in Group 2 will not receive prior FSH administration. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Group 1 (FSH) | Patients in Group 1 will receive subcutaneous FSH injections daily, titrated to achieve a FSH level of 4-8 IU/L, for 4 months. Patients will then receive GnRH therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. |
| BG001 | Group 2 (GnRH) | Patients in Group 2 will receive GnRH therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. Patients in Group 2 will not receive prior FSH administration. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | LH | Average Luteinizing Hormone levels after treatment. | Posted | Mean | Standard Deviation | IU/L | month 4 of GnRH treatment |
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| Primary | FSH | Average Follicle Stimulating Hormone levels after treatment. | Posted | Mean | Standard Deviation | IU/L | month 4 of GnRH treatment |
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| Primary | Testosterone | Average Testosterone levels after treatment. | Posted | Mean | Standard Deviation | ng/dL | month 4 of GnRH treatment |
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| Primary | Inhibin B | Average Inhibin B Levels after treatment. | Posted | Mean | Standard Deviation | pg/mL | month 4 of GnRH treatment |
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| Primary | Testicular Size (Volume) | Average testicular volume after treatment. | Posted | Mean | Standard Deviation | mL | at baseline and month 4 of GnRH treatment |
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| Primary | Sperm Count | Average sperm count after treatment. | Posted | Mean | Standard Deviation | 10^6 sperms/mL | month 4 of GnRH treatment |
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| Secondary | Fertility | Participants actively seeking to conceive. | Four subjects in Group 1 and two subjects in Group 2 were actively trying to conceive. Fertility was not tracked in subjects not trying to conceive. | Posted | Count of Participants | Participants | 24 months |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Group 1 (FSH) | Patients in Group 1 will receive subcutaneous FSH injections daily, titrated to achieve a FSH level of 4-8 IU/L, for 4 months. Patients will then receive GnRH therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. | 0 | 10 | 0 | 10 | 0 | 10 |
| EG001 | Group 2 (GnRH) | Patients in Group 2 will receive GnRH therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. Patients in Group 2 will not receive prior FSH administration. | 0 | 6 | 0 | 6 | 0 | 6 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. William Crowley | Massachusetts General Hospital | 617-724-2470 | wcrowley@partners.org |
| ID | Term |
|---|---|
| D007006 | Hypogonadism |
| D017436 | Kallmann Syndrome |
| ID | Term |
|---|---|
| D006058 | Gonadal Disorders |
| D004700 | Endocrine System Diseases |
| D058490 | Disorder of Sex Development, 46,XY |
| D012734 | Disorders of Sex Development |
| D014564 | Urogenital Abnormalities |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
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| ID | Term |
|---|---|
| D007987 | Gonadotropin-Releasing Hormone |
| D005640 | Follicle Stimulating Hormone |
| C571801 | follitropin alfa |
| ID | Term |
|---|---|
| D010906 | Pituitary Hormone-Releasing Hormones |
| D007028 | Hypothalamic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D006065 | Gonadotropins, Pituitary |
| D006062 | Gonadotropins |
| D010908 | Pituitary Hormones, Anterior |
| D010907 | Pituitary Hormones |
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| >=65 years |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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