Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men With Hypogonadism

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Role of FSH in Human Gonadal Development

Conditions
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Hypogonadism, Kallmann Syndrome

Intervention / Treatment
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* Procedure: Testicular biopsy
* Drug: gonadotropin releasing hormone (GnRH)
* Drug: follicle stimulating hormone (FSH)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria no history of spontaneous puberty clinical hypogonadism infantile testes (< 3 ml) no reproductive hormone therapy except testosterone Complete absence of normal LH pulses during 12-hour baseline frequent blood sampling and serum testosterone < 100 ng/dl Normal testing of the anterior pituitary gland Negative MRI of the hypothalamic-pituitary area Exclusion Criteria Prior therapy with gonadotropins (FSH, hCG, or GnRH)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (FSH)<br>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. | Procedure: Testicular biopsy<br>* Outpatient surgical procedure.<br>Drug: gonadotropin releasing hormone (GnRH)<br>* Pulsatile GnRH (25 ng/kg per bolus every two hours via microinfusion pump titrated to reach normal serum testosterone levels)<br>Drug: follicle stimulating hormone (FSH)<br>* 75 IU subcutaneous injection daily for four months.<br>* Other names: Gonal-F;|
| Active Comparator: Group 2 (GnRH)<br>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. | Procedure: Testicular biopsy<br>* Outpatient surgical procedure.<br>Drug: gonadotropin releasing hormone (GnRH)<br>* Pulsatile GnRH (25 ng/kg per bolus every two hours via microinfusion pump titrated to reach normal serum testosterone levels)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fertility | Participants actively seeking to conceive. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Male reproduction hormones, Hypogonadotropic hypogonadism, FSH, LH, GnRH