Alopecia in a premenopausal breast cancer woman treated with letrozole and triptorelin
Authors: P. Carlini, S. Di Cosimo, G. Ferretti, P. Papaldo, A. Fabi, E.M. Ruggeri, M. Milella, F. Cognetti
Journal: Annals of Oncology (2003)

A 37-year-old premenopausal woman with relapsed breast cancer (BC) in the right supraclavicular nodes, after failed treatment with the combination luteinizing hormone releasing hormone-a (LHRHa; triptorelin) plus tamoxifen, was started on triptorelin 3.75 mg every 28 days plus letrozole 2.5 mg daily. Approximately 6 months after starting this therapy, she complained of a daily scalp hair loss while combing and progressively developed a diffuse non-scarring alopecia on her crown. There were no signs of virilization. A gynecological examination showed a normal looking vagina and uterine cervix. The uterus was normal in size and there were no ovarian masses at ultrasonography. Her previous medical history was unremarkable. She was not taking any other drug. Hematological parameters were normal. Blood examination ruled out pituitary or thyroid problems. There were no other possible causes that could induce alopecia, such as lupus erythematosus, HIV infection, secondary syphilis, or deficiencies of protein, iron, biotin or zinc (Table 1). A dermatologist prescribed topical minoxidil 2%, two local applications (2 ml) daily. Approximately 6–8 weeks after initiating minoxidil, hair loss stopped and hair regrowth became apparent.Table 1Hormonal tests at the most recent follow-up visitHormonal testResultsNormal valuesLH (mUI/ml)<0.5follicular phase 1–18ovulation 24–105lutheinic phase 0.4–20post-menopausal status 16–82men 2–12FSH (mIU/ml)8.89follicular phase 4–13ovulation 5–22lutheinic phase 2–13post-menopausal status 20–138men 1–817-β-estradiol (pg/ml)<28follicular phase 39–189ovulation 94–508lutheinic phase 48–309post-menopausal status <41men <77Estrone (pg/ml)29follicular phase 37.2–137.7ovulation 58.9–229.0lutheinic phase 49.8–114.0menopausal status 14.0–103.0men 30–90Progesterone (ng/ml)0.17follicular phase 0.15–1.40lutheinic phase 3.34–25.58menopausal status <0.73men 0.28–1.22Testosterone (ng/ml)0.30women 0.14–0.76men 2.4–8.2Androstenedione (ng/ml)0.81women 0.21–3.08men 0.30–3.10menopausal status 0.36–1.80SHBG (nM/l)35.8women 51–111men 33–122pregnancy 220–450Prolactin (ng/ml)6.0women 1.39–24.20men 1.61–18.77Cortisol (ng/ml)208.743–224FT3 (pg/ml)3.081.45–3.48FT4 (ng/dl)1.100.71–1.85FSH, follicle-stimulating hormone; FT3, free tri-iodothyronine; FT4, free thyroxine; LH, luteinizing hormone; SHBG, sex hormone-binding globulin. Open table in a new tab FSH, follicle-stimulating hormone; FT3, free tri-iodothyronine; FT4, free thyroxine; LH, luteinizing hormone; SHBG, sex hormone-binding globulin. Hormonal levels of premenopausal BC women treated with the association LHRHa plus an aromatase inhibitor (AI) are different from those of postmenopausal women treated with an AI alone [1.Dowsett M. Doody D. Miall S. et al.Vorozole results in greater oestrogen suppression than formestane in postmenopausal women and when added to goserelin in premenopausal women with advanced breast cancer.Breast Cancer Res Treat. 1999; 56: 25-34Crossref PubMed Scopus (45) Google Scholar]. Whether estradiol directly inhibits 5 α-reductase or whether the effect of estrogens might be explained by an increased conversion of testosterone to the weaker androgens, thereby diminishing the amount of testosterone available for the conversion to dihydrotestosterone (DHT), remains to be shown [2.Niiyama S. Happle R. Hoffmann R. Influence of estrogens on the androgen metabolism in different subunits of human hair follicle.Eur J Dermatol. 2001; 11: 195-198PubMed Google Scholar]. Additionally, aromatase levels have been demonstrated to be decreased in balding scalp [3.Sawaya M.E. Price V.H. Different levels of 5 α-reductase type I and II, aromatase and androgen receptor in hair follicles of women and men with androgenic alopecia.J Invest Dermatol. 1997; 109: 296-300Abstract Full Text PDF PubMed Scopus (385) Google Scholar]. This is the first report of alopecia related to the combination of LHRHa (triptorelin) with a non-steroidal AI. AIs alone lead to thinning hair, rather than baldness, with an incidence of 2.5–6%. One report suggested that LHRHa can also induce hair loss [4.Gateley C.A. Bundred N.J. Alopecia and breast disease.BMJ. 1997; 314: 481Crossref PubMed Google Scholar]. Consistent with the role of aromatase in avoiding androgen-mediated effects on androgen-dependent hair follicles is the observation that women taking AIs for the treatment of BC often experience androgenetic alopecia-like hair loss, as a consequence of the hormonal imbalance towards androgenization of the hair follicles. We could speculate that the LHRHa caused a fall in estradiol concentrations, leading to a relative hyperandrogenism. Additionally, the reduction of aromatase activity driven by letrozole may have resulted in a further relative increase in systemic and pilosebaceous testosterone available for conversion to DHT. This synergic action may explain why our patient did not show alopecia while taking triptorelin with tamoxifen. Moreover, minoxidil lengthened and enlarged the small vellus hairs and decreased shedding, highlighting the hypothesis of a relative hyperandrogenism as the cause of alopecia. Female sex hormone-binding globulin (SHBG) levels are inversely correlated with the grade of alopecia [5.Vexiau P. Chaspoux C. Boudou P. et al.Role of androgens in female-pattern androgenetic alopecia, either alone or associated with other symptoms of hyperandrogenism.Arch Dermatol Res. 2000; 292: 598-604Crossref PubMed Scopus (44) Google Scholar]. In our patient, the SHBG levels were low, potentially due to the AI effect. Considering the pivotal importance of pharmacological castration in premenopausal endocrine-responsive BC patients and the widespread use of AIs in the metastatic and, probably in the near future, adjuvant settings, potential alopecia should not be a determinant in making clinical decisions. However, oncologists must be aware of such atypical adverse events for treatment planning,in order to highlight its consequent distress and to provide psychological counseling, especially in young patients.