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

United States Department of Health and Human Services (HHS)

Status and phase: Terminated; Phase 2

Conditions: Kallmann Syndrome; Hypogonadism

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

Study type: Interventional

Funder types: NIH

Identifiers

NCT00064987

U54HD028138-457

U54HD028138 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 19 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

19 participants in 2 patient groups

Group 1 (FSH)

Experimental group

Description:

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.

Treatment:

Procedure: Testicular biopsy

Drug: follicle stimulating hormone (FSH)

Drug: gonadotropin releasing hormone (GnRH)

Group 2 (GnRH)

Active Comparator group

Description:

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.

Treatment:

Procedure: Testicular biopsy

Drug: gonadotropin releasing hormone (GnRH)