Does testosterone affect the normal menstrual cycle?

In order to throw further light on the role of androgens in the aetiology of the polycystic ovary syndrome (PCO) we have examined the effect of artificially increasing serum testosterone levels on menstrual function in a group of ovulating women. Six women were studied who had either severe premenstrual syndrome or loss of libido for which they were treated with 100 mg testosterone by s.c. implantation. All had regular menstrual cycles. For 1 month before implantation serum LH, FSH, oestradiol (E2), progesterone and testosterone were measured three times per week. All women showed normal cyclical variation of LH, FSH, E2 and progesterone. Following implantation, three times weekly blood samples were taken during the first and third cycles. No patient had any disturbance of menstrual pattern. All continued to show cyclical changes of LH, FSH, E2 and progesterone. Serum E2 and progesterone were lower but not significantly so in the luteal phase of the treated cycles. This was despite a mean serum testosterone which rose from 1.3 to 7.1 nmol/l at the end of the third week following implantation and to 4.1 nmol/l at the end of the third month. Sex hormone binding globulin levels fell as expected by 18.5% during the first cycle. The lack of significant effect of a markedly elevated serum testosterone level on cyclical hormone changes is indirect evidence that in PCO the primary cause of the menstrual disturbance is not excessive production of ovarian or adrenal testosterone.

The treatment of hirsutism with a combination of desogestrel and ethinyl oestradiol.

Some available oral contraceptive agents are unsuitable for the treatment of hirsutism since, although they suppress endogenous gonadotrophins and so ovarian androgen production, they contain a progestogen which is itself androgenic. The combination of 30 micrograms ethinyl oestradiol (EE2) and 150 micrograms desogestrel (Marvelon) does not suffer from this drawback. We have therefore assessed its value in 15 hirsute women treated for one year. Mean +/- SE androgen-dependent hair growth, assessed photographically fell from 0.31 +/- 0.01 to 0.23 +/- 0.01 mm/d at 1 year (P less than 0.001). Ten of the fifteen patients reported definite subjective improvement. Treatment was associated with a marked rise in SHBG concentration identical to that seen with 30 micrograms EE2 alone. By four months there were significant falls in serum levels of androstenedione and LH throughout the cycle, but not for testosterone, dihydrotestosterone or 5 alpha-androstane 3 alpha, beta 17 -diol. Calculated free testosterone levels were significantly suppressed. All the biochemical changes were maintained after seven months of treatment. We conclude that this preparation is a suitable oral contraceptive for the treatment of hirsute women.

Clinical experience with the use of two diphosphonates in the treatment of Paget's disease.

The effects of EHDP (20 mg/kd/day) and APD (4.5 mg/kg/day) given for three months to patients with severe symptomatic Paget's disease have been compared in an open trial of 17 patients. Both drugs were equally effective in producing a prompt reduction in pair scores, urine hydroxyproline, and serum alkaline phosphatase levels. The remission was maintained for a variable period after stopping treatment. Both drugs were well tolerated, and a one-month course of either drug was not effective. Comparison with published responses from previous studies indicates that EHDP given at this dose as a relatively short course is more effective than a lower dose for a longer period of time; the present study does not suggest that APD has significant advantages.

The effect of endogenous progesterone on serum levels of 5 alpha-reduced androgens in hirsute women.

This study was to examine indirectly the effect of endogenous progesterone, a known competitor for 5 alpha-reductase, on androgen metabolism in target organs in hirsute women. Serum levels of progesterone, testosterone (T), androstenedione (A), dihydrotestosterone (DHT) and 5 alpha-androstane 3 alpha 17 beta-diol (3 alpha-diol) and sex hormone binding globulin (SHBG) were assessed serially over a four week period in normal women, six hirsute women with regular menstrual cycles, eight hirsute women with oligomenorrhoea (and presumptive polycystic ovaries) and seven non-hirsute women with oligomenorrhoea. Serum T and A levels were significantly higher than normal in both hirsute and non-hirsute women with oligomenorrhoea, while serum SHBG was significantly lower than normal in the two groups of hirsute women. The calculated free T level was higher than normal in all three groups of patients. DHT levels were not significantly different from normal in any of the three groups of patients. The 3 alpha-diol level showed considerable overlap with normal in all groups of patients and was only significantly higher than normal in hirsute women with oligomenorrhoea (P less than 0.05). There was a small fall in DHT in the late luteal phase of the cycle of those women with a sustained rise in serum progesterone in the second half of the cycle, but no change in serum 3 alpha-diol. These studies suggest that serum 3 alpha-diol may not be as good an indicator of peripheral androgen metabolism in hirsute women as previously reported and that a rise in serum progesterone has only a minimal effect on circulating levels of the active 5 alpha-reduced androgen metabolites. Although in vitro 3 alpha-diol has been shown to be a potent inhibitor of 5 alpha-reductase this casts doubt on its role in this regard in vivo.

Which testosterone replacement therapy?

Three different forms of testosterone (T) replacement therapy were compared; they were the intramuscular injection of mixed testosterone esters 250 mg; the subcutaneous implantation of 6 X 100 mg pellets of fused testosterone; and the oral administration of testosterone undecanoate (TU) 80 mg twice daily. Six hypogonadal males were treated with oral TU for an eight week period, during which time serial serum hormonal estimations were performed over 10 h at the initiation and after four and eight weeks of therapy. Serum T levels showed marked variability both between subjects and within the same subject on different occasions. We attribute this to variability in absorption of TU, which is formulated in oleic acid. The overall mean T level calculated from the areas under the profiles of TU was 12.0 nmol/l. Hormone responses to injected T esters were studied in nine hypogonadal males. Serum T rose to supraphysiological peak concentrations (mean 71 nmol/l) 24-48 h after an injection, followed by an exponential decay to reach baseline concentrations after 2-3 weeks. The overall calculated mean T level in subjects receiving testosterone esters 250 mg every three weeks was 27.7 nmol/l. Subcutaneous implantation of testosterone in six hypogonadal men produced a gradual rise in serum T followed by a slow decline, with T levels remaining within the normal range for 4-5 months. The calculated overall mean T level over 21 weeks after implantation was 17.0 nmol/l. Serum oestradiol (E2) levels remained within the normal male range throughout the study periods on both TU and T implant therapy but showed a supraphysiological peak (mean 347 pmol/l) 24-48 h after a T injection. 5 alpha-dihydrotestosterone (DHT) levels appeared to parallel those of T on the three forms of therapy, with DHT:T ratios being highest for TU therapy. This was also true for the target organ metabolite 5 alpha-androstane-3 alpha,17 beta-diol. At the doses studied drug costs were similar for T implantation (every 5 months) and T ester injections (every 3 weeks), but were 7-8 times higher for TU (80 mg twice a day). We conclude that T implantation remains overall the most physiological form of androgen replacement therapy, is generally well accepted and attended by few side effects; TU may have a useful role in the initial phases of therapy.

Experience with trilostane in the treatment of Cushing's syndrome.

Five patients with pituitary dependent Cushing's syndrome and two with adrenal carcinoma were treated with increasing doses of trilostane (up to 1440 mg daily). There was no consistent fall in serum cortisol levels. In addition there was no rise in the levels of precursors immediately preceding the proposed site of action of trilostane. These results suggest that trilostane does not effectively block the enzyme 3 beta-hydroxysteroid dehydrogenase delta 4,delta 5 isomerase in patients with Cushing's syndrome and that it should no longer be recommended for their treatment.