Endocrine Abstracts

Introduction: Most cases of prepubertal gynecomastia are classified as idiopathic. However, an exogenous or endogenous hyperestrogenism (from estrogen producing testis or adrenal tumors) has always to be excluded. Other rare underlying endocrine causes are congenital adrenal hyperplasia, aromatase excess, hyperthyroidism and hyperprolactinemia^1,2.

We report a transient hyperprolactinemia, beside other ignored clinical and hormonal signs of estrogen impregnation, in a prepuberal boy investigated for gynecomastia as an alarming sign of hyperestrogenism, related to indirect exposure to a nonformulary estrogen cream in the mother.

Case report: A 9 year and 10 month old boy was referred for non-prolactinoma related hyperprolactinemia. He presented with a recent history of bilateral breast enlargement and slight pubic hair development. He had no previous medical or surgical history. His father had no gynecomastia during childhood or adolescence. Neither a familial history of precocious puberty or Peutz-Jeghers syndrome was present. He had no neurological or ophthalmological complaints. Gynecomastia and areolar pigmentation was noted for two months, but without body odor or axillary hair development. He had been taken commercial Perilla oil tablets, for 6 months, because of diminished concentration and memory, but these supplements had been stopped one month before the breast development. He did not take any other food supplements or herbal products. He was not using cosmetic ointments or any medications since the start of gynecomastia. He had a normal diet.

Biochemical evaluation showed a normal BUN, creatinine and transaminases, but slightly elevated alkaline phosphatases (450 IU/L). Hormonal analysis showed an elevated prolactin (29 μg/l (4–15.2), a slightly elevated TSH (5.85 ng/l (0.6–4.8), normal FT4, normal cortisol and undetectable gonadotrophins and estradiol. A MRI of the pituitary was normal. Bone age was 11.5 years.

At referral, body height was 144 cm, weight 33 kg and blood pressure 125/65 mmHg. Tanner stage was A1P2G1. Testes were 3 ml without palpable nodules. Bilateral breast development was scored as Tanner 3 stage with 4 cm of glandular tissue and dark brown areolar pigmentation. No galactorrhea was present at breast manipulation. No thyromegaly, hepatosplenomegaly and cutaneous lesions or aberrant skin pigmentation were present.

Repeated basal hormonology showed a normal PRL (11 μg/l) TSH, DHEAS, androstenedione, 17-OH progesterone, estradiol, estrone, testosterone and β-hCG, but a very high SHBG (500 nmol/l) and suppressed FSH (0.1 IU/l) and unmeasurable LH (<0.1 IU/l). Ultrasound of the testes and adrenal were normal. During the GnRH stimulation test, no LH and FSH response were observed.

On obtaining further history, his mother confirmed that she was using for several months before the breast development a nonformulary estrogen cream, obtained at an anti-aging clinic. Handwashing after cream application was not always performed and she and son were using the same towels. The mother was asked to stop the estrogen applications. To further control the effects of suspected estrogen contamination and limit further excessive bone maturation, letrozole was administered for 4 months with a rapid regression of the gynecomastia. Bone age did not progress after 6 months and pubic hair disappeared, while the intense areolar pigmentation remained.

Discussion: The areolar hyperpigmentation made us to suspect rather hyperestrogenism as an underlying cause for the gynecomastia, in addition of the typical hormonal profile, showing completely suppressed gonadotrophins, both at baseline and after GnRH stimulation, and the very elevated SHBG. Prolactin elevation has been observed after high estrogen exposure in men, as in transgenders³. Also the contrasting finding of pubic hair and normal adrenal androgens is an additional argument for exposure to estrogens in our patient, since pubic hair growth can be seen by treating patients with gonadal dysfunction with estrogens⁴.

The use of estrogen cream was initially not disclosed by the mother, but was afterwards confirmed by her and the prescribing physician. We cannot exclude some priming role of the use of perilla seeds, known to have a high content of phytosterols, especially B sitosterol⁵.

Beside indirect exposure to nonformulary estrogen cream used by mothers as hormone replacement, estrogen contaminated poultry as well hair cream has been reported other sources of exogenous estrogens leading to prepubertal gynecomastia^6,7. These potential estrogen sources were not revealed by the boy and his mother. On the other hand, repeated topical application of product containing laverder and tea tree oils, having both estrogenic and antiandrogenic activities, are another reason for breast development in males, but were not used by our patient.

Bone age advancement by cutaneous estrogen application is especially apparent in prepubertal children, who in addition are also more likely to develop gynecomastia than adolescents because of unopposed effects of testosterone. Non-classical adrenal hyperplasia and aromatase excess can also present with gynecomastia, early pubic hair development and advanced bone maturation^8,9. The normal adrenal androgen as well as the normal estradiol and estrone concentrations do not support the diagnosis of these diseases.

In conclusion, in the evaluation of prepubertal gynecomastia, not only the use of cosmetics, herbal medicines or topical medications, including estrogens should not only be questioned in the child, but also in the parents and other close caregivers.

References: 1. Cohen PR, Robinson FW, Gray JM. Prolactinoma can be associated with gynecomastia. Skinmed. 2010;8(4):201–2.

2. Furtado SV, Saikiran NA, Ghosal N, Hegde AS. Giant, solid, invasive prolactinoma in a prepubescent boy with gynecomastia. Pediatr Neurol. 2010;42(1):72–4.

3. Nota NM, Dekker MJHJ, Klaver M, Wiepjes CM, van Trotsenburg MA, Heijboer AC et al. Prolactin levels during short- and long-term cross-sex hormone treatment: an observational study in transgender persons. Andrologia. 2017;49(6).

4. Sklar CA, Kaplan SL, Grumbach MM. Lack of effect of oestrogens on adrenal androgen secretion in children and adolescents with a comment on oestrogens and pubic hair growth. Clin Endocrinol (Oxf). 1981;14(3):311–20.

5. Ciftci ON, Przybylski R, Rudzińska M. Lipid components of flax, perilla, and chia seeds. European Journal of Lipid Science and Technology. 2012;114(7):794-800.

6. Edidin DV, Levitsky LL. Prepubertal gynecomastia associated with estrogen-containing hair cream. Am J Dis Child. 1982;136(7):587–8.

7. Felner EI, White PC. Prepubertal gynecomastia: indirect exposure to estrogen cream. Pediatrics. 2000;105(4):E55.

8. Wasniewska M, Raiola G, Galati MC, Salzano G, Rulli I, Zirilli G et al. Non-classical 21-hydroxylase deficiency in boys with prepubertal or pubertal gynecomastia. Eur J Pediatr. 2008;167(9):1083–4.

9. Binder G, Iliev DI, Dufke A, Wabitsch M, Schweizer R, Ranke MB et al. Dominant transmission of prepubertal gynecomastia due to serum estrone excess: hormonal, biochemical, and genetic analysis in a large kindred. J Clin Endocrinol Metab. 2005;90(1):484–92.