Understanding Late-Onset Male Hypogonadism
The Clinical Manifestations of Late-Onset Hypogonadism
Late-onset male hypogonadism is a clinically significant condition characterized by abnormally low levels of circulating testosterone. The clinical symptoms and signs associated with this condition include diminished libido and sexual function, depressed mood, decreased muscle strength and reduced energy. Overt hypogonadism results in reductions in bone mineral density, alterations in body composition and effects on mood, cognitive function, sexual function and several factors that increase cardiovascular risk. In the context of overt hypogonadism, androgen supplementation is clearly beneficial. The aim of androgen replacement therapy is to restore normal male secondary sexual characteristics, behavior and function, and to mimic the somatic action of testosterone on bone muscle and other tissues.
Dihydrotestosterone as a Potential Treatment for Hypogonadism
Dihydrotestosterone (DHT) is a natural androgen which, like testosterone, exerts its pharmacological activity by binding to the androgen receptor protein and stimulating its action. In fact, the in vitro affinity of DHT for the androgen receptor is approximately 10 times greater than that of testosterone. In addition, the DHT-androgen receptor complex is more stable than the testosterone-androgen receptor complex. Hence, DHT is generally regarded as a more potent androgen compared to testosterone. In addition, unlike testosterone, DHT does not lead to the production of estrogen and thus cannot produce the estrogen-specific side effects of systemic testosterone therapy, such as gynecomastia (enlargement of the male breast). Furthermore, systemic DHT administration leads to suppression of LH and FSH – and subsequent testosterone production – which, in turn, leads to lowered estrogen production.
ASCEND Therapeutics is developing transdermal DHT-Gel for androgen replacement therapy. This preparation has several potential advantages over available androgen products, including greater potential pharmacologic potency, ease of use (single, daily cutaneous application without the need for an occlusive patch), painless administration, avoidance of first-pass hepatic metabolism seen with oral steroid therapies and maintenance of stable androgen levels (in contrast to large shifts in testosterone levels following use of long-acting steroid esters or sublingual androgen preparations). Finally, it has been hypothesized that DHT may be a safer androgen for long-term therapy in older males.
Because DHT is believed to be a relevant androgen for stimulating prostatic growth, it is counterintuitive that DHT might be proposed as a selective androgen with less prostate stimulatory activity than testosterone. Nevertheless, a growing body of evidence supports this hypothesis. One pilot study of DHT-Gel has demonstrated that in 27 men treated for an average of 1.8 years, prostate size was significantly reduced based on prostate ultrasound measurements.
There are two plausible explanations for the proposed lack of prostate-stimulating effect by systemic DHT. First, administration of DHT leads to suppression of testosterone and thus estrogen production. There is substantial evidence that prostate hypertrophy requires the presence of both androgens and estrogens. Thus, the suppression of estrogen production by DHT may deprive the prostate of a needed co-factor for prostate growth. Second, systemic DHT may not be transported into the parenchyma of the prostate as effectively as testosterone. Thus, systemic testosterone may potentially produce higher intra-prostatic levels of DHT than systemic DHT.
ASCEND initially proposes to develop DHT-Gel for the following potential indication:
"Improvement of overall physical and sexual function in older men with symptoms associated with hypogonadism."
ASCEND has conducted a randomized, multi-center, double-blind, placebo-controlled clinical trial of DHT-Gel vs. placebo in male subjects ages 55-80 years with low serum testosterone and symptoms of hypogonadism in 21 centers in the U.S. This study is intended to define the safety, physiologic effects and potential clinical benefit of DHT therapy in this patient group. Study results will be available later in 2009.
ASCEND also has conducted a single-center, randomized, placebo-controlled safety study in normal male volunteers, the goal of which is to compare two years of DHT-Gel treatment and its effect on prostate volume vs. placebo. Results from the main portion of this study are also expected later in 2009.