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

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.

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)