USE OF DANAZOL IN THE TREATMENT OF HYYPOGONADISM IN MEN
Androgen Deficiency in the Ageing Male, also referred to as 'The Male Climateric', 'The male menopause' and the 'Andropause' causes a highly characteristic pattern of symptoms which was first recognised nearly sixty years ago (Werner,A. JAMA 112,15,1441-3,1939). As described at that time, the syndrome includes loss of energy, drive and libido, depression, irritability, joint pains and stiffness, and even such typical symptoms of the female menopause as night sweats and hot flushes.
It has been found (Carruthers, M. 'The Male Menopause, Harpercollins', London, 1996) that the symptoms associated with this condition arise due to an absolute or relative insufficiency of testosterone, particularly the latter, caused by a reduction in the Free Active Testosterone (FAT); that is a lack of testosterone present in an unbound state in blood plasma. Testosterone in vivo can be bound to sex hormone binding globulin (SHBG) and to a lesser extent, albumin. When bound the testosterone is not freely available to the body or bioavailable. One of the best measures of this is the 'Free Androgen Index'(FAI). This is calculated by dividing the Total Testosterone (TT) by the 'Sex Hormone Binding Globulin' (SHBG) and multiplying by a hundred to express it as a percentage. In the healthy, asymptomatic male this is normally in the range 70-100%. Symptoms of the andropause regularly appear when this drops below 50%, except in a few cases where the TT is low and the body appears to compensate by reducing SHBG levels to maintain the FAI.
It has been found that hypogonadism and also the male menopause can be prevented or treated by freeing bound testosterone so that it becomes bioavailable again. Testosterone may be freed, for example,by:
· 1. decreasing the number of potential binding sites available for testosterone in vivo, for example by reducing the level of SHBG using compounds which antagonise the action of androgens in stimulating SHBG synthesis,and/or
· 2. introducing an agent which competes for the binding sites, thereby displacing bound testosterone which is returned to systemic circulation.
Pharmaceutical, pharmacological and biological compounds that may act effectively include ethisterone and ethisterone derivatives and/or precursors.
One such compound, danazol, is a well-established therapeutic agent which has been extensively used in the female for managing a wide range of conditions such as endometriosis, menorrhagia and benign breast conditions such as mastalgia and cystic disorders. Its use in the male is not widely known and has been limited to treatment of enlargement of the male breast (gynaecomastia) and limited research into its use as a male contraceptive. The previous uses of danazol in women and men have all been at relatively high concentrations, for example doses of 200 to 600 mg, and at these concentrations it has been shown that total plasma testosterone is reduced.
It has now been found that using danazol in the male at dose level reduced from that at which it would be conventionally used, for example at a daily dose of not more than 100 mg, reintroduction of testosterone to the systemic circulation in the form of Free Active Testosterone is remarkably effective; that is the FAT is increased leading to a highly effective treatment of the symptoms associated with hypogonadism and with the male menopause.
Danazol is effective, non-hepatotoxic, and does not have intrinsic androgenic, oestrogenic or progestogenic actions. It is an ideal agent for displacing and hence activating testosterone as it has a high affinity for androgen receptors, low affinity for progesterone receptors, and does not interact with oestrogen receptors to any significant extent.
The importance of only giving low doses of danazol, for example not more than 50 -100mg daily, to men being treated for hypogonadism is because at this low dose, as shown by the clinical studies described later in this application, there is direct suppression of SHBG synthesis by the liver, with a corresponding increase in FAI, apparently without reduction of endogenous total testosterone production.
Danazol may be for treatment of hypogonadism resulting from any biological or physical cause. In particular, Danazol may be for treatment of any condition where systemic free active testosterone is reduced due to raised levels of SHBG, for example, conditions caused by concurrent/prior treatment with estrogens, anti-convulsants and/or exposure to xeno-estrogens.
Preferably not more than 100 mg of danazol, preferably the daily dose between 25-100 mg. The dose is varied according to body weight, TT and SHBG concentrations.
Danazol may be administered on its own or as an adjunct to other methods of relieving sexual dysfunction problems in men such as libido disorders and impotence, such as applications of alprostadil (Caverject and Medicated Urethral Systems for Erection - MUSE), and drugs which enhance relaxation of the corpora cavernosae in the penis, for example those which increase nitric oxide production such as the oral preparation sildenafil (Viagra).
Danazol together with testosterone is used in the treatment of the male menopause.
The dosage level required for the activity is much lower than that used in known dose regimes where danazol is used in the female to treat, for example endometrosis. The preferred dosage is between 25 - 100 mg per day as opposed to 200 to 800 mg per day used previously in different treatments. The dose may be administered orally, nasally, as a solid implant, or intravenously, intramuscularly or transdermally.
In a preferred embodiment a dose of 25 mg of danazol is administered to the patient daily in the form of a capsule.
The usage of danazol, optionally in combination with low dosage testosterone treatment, appears to give for the first time a unique opportunity to adjust the level of TT, SHBG and hence FAI to mimic a normal youthful endocrine pattern even in middle-aged and elderly men. This should give clinical benefits in both treating hypogonadal men, and in the field of preventive medicine, where maintaining an adequate level of testosterone activity is being shown to be a key factor.
APS Pharmacy suggested dosing for Danazol
25mg (capsule or troche), once a day.
**Danazol can also be compounded together with Anastrozole in one capsule.
*** Danazol is a non-scheduled (non-controlled) medication