Tamoxifen in the medical therapy of gynecomastia
Gynecomastia (GM) is a condition of volume increase of the mammary gland in the male, which can recognize different clinical conditions 1:
– situations dependent on a hyperplasia of the glandular tissue (so-called “true” GM);
– situations where the increase in volume depends on the accumulation of adipose tissue (“fake” GM or lipomastia);
– mixed hyperplasia, with increase in different proportions of both glandular and adipose components.
The most frequent situation is pubertal or post – puberal GM where – usually without identifiable hormonal anomalies – we are witnessing the development of a GM that tends to regress to acceptable levels during 2 – 3 years after puberation . These situations, also defined as “physiological” GM, are attributed to a high sensitivity of the mammary tissues to the stimulation of the hormones that appear during the pubertal process.
In clinical practice we can identify situations (28 – 40% depending on the series) where the problem is in temporal relation with the intake of drugs (see table em>). For this reason – especially in adults where the problem is recently onset – the recent pharmacological anamnesis is particularly important 2.
The situations resulting from systemic hormone alterations are the minority but the initial clinical evaluation can not disregard the research of the levels of estradiol, total testosterone, LH, FSH, prolactin and HCG in order to identify hypogonadism, hyperprolactinemia or very rare cases of secretive estrogen neoplasms or paraneoplastic syndromes of HCG.
In most cases where there are no significant hormonal changes and it is not possible to trace any drug, the “idiopathic” GM condition is attributed to hypersensitivity of the breast tissue to circulating estrogens. In these cases it can lead to persistent situations, sometimes – especially in adolescents – with a strong emotional impact: this is generally an aesthetic problem or, less frequently, a painful disorder, for which there are few alternatives to the surgical solution 3. However, the demand for a “non-surgical” approach that can achieve the most durable results with well-tolerated and convenient products is common.
Since the pathogenesis is attributed to an excessive response of estrogen receptors, attention has been focused on drugs with antiestrogenic effect whereas dopamine – agonist drugs have proved effective only in cases (the minority) with documented hyperprolactinemia 4 – 5. Experiences with synthetic anti-estrogens used in the 70’s (clomiphene and cyclophenyl) 6 to 9 had provided contradictory results for which the experimentation focused mainly on tamoxifen, a very widely used molecule in hormonal therapy of breast cancer.
The tamoxifene em> (Tam) is a synthetic non-steroidal molecule belonging to the so-called SERM (Selective Estrogen Receptor Modulators), drugs able to behave as receptor antagonists in certain tissues and agonists in other organs. Tam plays an antagonist role on breast tissue and bone agonist receptors while it is a partial agonist on the endometrium 10. This drug for its antiestrogen effect on the breast tissue, has been evaluated in numerous studies carried out in patients with puberal GM, but also in patients suffering from GM secondary to drugs, especially the cases resulting from treatment with antiandrogens in the androgenic block for adenocarcinoma prostate.
Overall, the published studies provide data on 869 patients treated with Tam: most of the results come from studies in which the drug was used: – in idiopathic GM, in males without provable systemic hormone diseases; – in antiandrogenic therapy in patients with prostatic carcinoma.
In idiopathic GM, the most evaluated dose was 20 mg / day in one or two 11 – 15 administrations. Minor data are 10 or 40 mg. The duration of the studies was variable: for periods of 3 to 6 months therapy the result, assessed clinically or with ultrasound, was judged favorable in 70 – 80% of cases. The treatment effect is inevitably transitory and – in clinical practice – it is usual to discontinue the therapy after 6 – 8 months followed by a waiting period to monitor the evolution of the problem. In cases of recurrence, additional treatment periods are often reproposed, but data on the subject deriving from randomized clinical trials are completely lacking. Tam was generally well tolerated even in monga duration 16 – 17; the adverse effects reported were mild and only in 6 cases led to discontinuation of treatment. There are no reports of serious adverse events, particularly liver damage or thrombotic episodes. The use of Tam induced the predictable hormonal responses according to its receptor action profile and did not lead to alterations of the hemocoagulative parameters or other risk factors 18 – 19. The effectiveness was higher than that of danazol, compared to which the Tam is also better tolerated 20. The efficacy of Tam was slightly lower than that of raloxifene in the only comparison study 21.
The efficacy of Tam is clinically more evident and longer lasting in cases of GM secondary to drugs 22. The 20 mg / day dose administered to patients with prostate adenocarcinoma, operated or unopered, was effective both in therapy and in the prevention of GM by bicalutamide 23 – 24. At this same dose, anastrozole 25 – 26 and radiotherapy of the mammary region 27 – 28 were also more effective. Treatment with Tam was poorly effective at 20 mg weekly doses after pretreatment with 20 mg / day 29. One study compared the preventive administration of 10 mg of Tam for one year vs em>. therapeutic administration of 20 mg with better results on symptoms in previously treated patients. Treatment with 10 or 20 mg had no significant effect on the course of prostate disease 30. Overall, despite the concerns 31 related to the overall quality of the studies very modest (lack of data from randomized and controlled studies, low number of samples studied) the efficacy of therapy with Tam seems to result from all studies. Several reviews support its use in all types of GM for a period of 3 – 6 months 32 – 34. Given the mechanism of action, it is still important to adopt a position of caution in cases of patients still in the growth phase because the drug could affect the maturation of long bones.
For none of the treatments described there is an indication for gynecomastia, which therefore represents an “off – label” prescription condition to be managed with the procedures required by Legislative Decree 17 February 1998, n. 23, with prescription in band C, except in cases documented and presented to individual local commissions (where existing) that may determine the gratuity of the drug.