The first major contribution of Professor Labrie to clinical medicine has been the discovery and development of medical castration with GnRH (Gonadotropin-Releasing Hormone) agonists which quickly replaced surgical castration worldwide. This achievement was soon followed by the discovery and development of Combined Androgen Blockade (CAB), the first treatment shown to prolong life in prostate cancer. This was the first demonstration of intracrinology or the mechanisms by which dehydroepiandrosterone (DHEA) is transformed into androgens in the prostate. The strategy developed was to achieve simultaneously medical castration with GnRH agonist and blockade of the action of the androgen made locally in the prostate from DHEA. Medical castration with GnRH agonists and combined androgen blockade have become the standard hormonal therapy of prostate cancer worldwide. This has also been the first combination of drugs approved by Health Authorities, namely by Health Canada in 1984 and by the US FDA in 1989. This discovery on the role of locally made androgens is at the basis of the recent successful development of enzalutamide and abiraterone acetate to achieve blockade of the action and formation, respectively, of the androgens made locally in the prostate in castration-resistant prostate cancer.
Afterwards, Professor Labrie’s team discovered that a large proportion of androgens and estrogens in women (100% after menopause) are made in peripheral tissues from the same inactive precursor DHEA by the same mechanisms of intracrinology. DHEA is thus transformed locally and intracellularly into small amounts of androgens and estrogens in women according to the local needs without biologically significant release of the active sex steroids in the circulation, thus avoiding potentially negative systemic effects.
Following cessation of E2 secretion by the ovaries at menopause, serum E2 and testosterone are maintained at very low and biologically inactive concentrations with no activity outside the cells of origin, thus avoiding stimulation of any other tissue. DHEA then becomes the unique source of sex steroids after menopause. DHEA secretion, however, starts decreasing at about the age of 30 years at various rates in different women. Moreover, there is no feedback mechanism to increase DHEA secretion when the concentration of serum DHEA decreases.
Considering that this mechanism is unique to the human, it seems logical to replace DHEA locally in women suffering from vulvovaginal atrophy (genitourinary syndrome of menopause), a situation observed in 50% of postmenopausal women or in 32 million women in the United States. However, only 3% of women suffering from vulvovaginal atrophy are treated, due mainly to the fear of estrogens.
The clinical data obtained by the applicant using a small dose of intravaginal DHEA (prasterone) offer a physiological solution to vulvovaginal atrophy and confirm the mechanisms of intracrinology mentioned above which avoid biologically significant changes in serum E2 and testosterone. Consequently, IntrarosaTM has been accepted for commercialization in the US on November 16th, 2017 with, for the first time for this indication, no black box in the labelling.