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

Phase 2

Terminated

Conditions: Hypogonadism
Kallmann Syndrome

Interventions: Procedure: Testicular biopsy
Drug: gonadotropin releasing hormone (GnRH)
Drug: follicle stimulating hormone (FSH)

Registration Number: NCT00064987

Lead Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: Male

Target Recruitment: 19

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 2 (GnRH)	Testicular biopsy	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.
Group 1 (FSH)	Testicular biopsy	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.
Group 1 (FSH)	gonadotropin releasing hormone (GnRH)	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.
Group 1 (FSH)	follicle stimulating hormone (FSH)	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.
Group 2 (GnRH)	gonadotropin releasing hormone (GnRH)	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.

Primary Outcome Measures

Name	Time	Method
LH	month 4 of GnRH treatment	Average Luteinizing Hormone levels after treatment.
Inhibin B	month 4 of GnRH treatment	Average Inhibin B Levels after treatment.
Sperm Count	month 4 of GnRH treatment	Average sperm count after treatment.
FSH	month 4 of GnRH treatment	Average Follicle Stimulating Hormone levels after treatment.
Testosterone	month 4 of GnRH treatment	Average Testosterone levels after treatment.
Testicular Size (Volume)	at baseline and month 4 of GnRH treatment	Average testicular volume after treatment.