An Aromatase-Producing Sex-Cord Tumor Resulting in Prepubertal Gynecomastia

Coen, Patricia; Kulin, Howard E.; Ballantine, Thomas V.N.; Zaino, Richard J.; Frauenhoffer, Elizabeth E.; Boal, Danielle K.; Inkster, S. E.; Brodie, Angela; Santen, Richard J.

doi:10.1056/nejm199101313240507

Cited by 123 publications

(67 citation statements)

References 31 publications

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“…Therefore, medical treatment was warranted to reduce the effects of increased estrogens on the breast and skeleton. Aromatase inhibitors are currently the best option to achieve this goal (19) and testolactone has been used previously (12,20). We used anastrozole, an effective third generation inhibitor of estrogen synthesis.…”

Section: Discussionmentioning

confidence: 99%

Prepubertal gynecomastia in Peutz-Jeghers syndrome: incomplete penetrance in a familial case and management with an aromatase inhibitor

Lefèvre

Bouvattier

Lahlou³

et al. 2006

eur j endocrinol

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Background: Peutz-Jeghers syndrome (PJS) is a rare autosomal-dominant disorder characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation and increased predisposition to various neoplasms. Endocrine manifestations in PJS include gynecomastia due to calcified Sertoli cell testicular tumors usually referred to as large-cell calcifying Sertoli cell tumors (LSCT). Objective: To evaluate the value of endocrine markers and aromatase inhibitor treatment in children with PJS and LSCT. Design and setting: Familial cases, followed in a tertiary care center. Patients: Two male siblings aged 7 and 9 years with PJS and LSCT. Intervention: Third generation aromatase inhibitor (anastrozole) in one of the patients. Main outcome measures: Longitudinal measurements of sex-steroids, gonadotropins, Sertoli cell markers and auxological evaluation. Results: The two male siblings with PJS had similar bilateral multifocal testicular calcifications and biochemical evidence of Sertoli cell dysfunction manifested by elevated plasma inhibin-a levels. Only one sibling had gynecomastia. Estradiol levels were normal in both. During treatment with anastrozole, estradiol levels, growth and skeletal maturation, as well as Sertoli cell markers (inhibin B, inhibin-a and anti-Mullerian hormone) decreased. Conclusions: Inhibin-a may be considered as a marker for LSCT in children with PJS, pointing to a specific defect in inhibin regulation in this condition. Moreover, the decrease in Sertoli cell markers during aromatase inhibitor treatment suggests that increased estrogen production is a primary event regulating downstream production of Sertoli cell peptides. Anastrozole is efficient in controlling the clinical features of the disease and should be proposed as an alternative to bilateral orchidectomy, which is often performed in this condition.

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Section: Discussionmentioning

confidence: 99%

Prepubertal gynecomastia in Peutz-Jeghers syndrome: incomplete penetrance in a familial case and management with an aromatase inhibitor

Lefèvre

Bouvattier

Lahlou³

et al. 2006

eur j endocrinol

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“…As a consequence of the regulatory mechanisms described below, this results in elevated aromatase expression in the breast and in germ cells. In the case of boys, this results in gynecomastia and oestrogen-producing Sertoli cell tumors (Coen et al 1991, Ham et al 2013. A severe case of an ectopic source of oestrogen was described in a boy with a hepatocellular carcinoma that secreted large quantities of oestradiol (Agarwal et al 1998).…”

Section: Phenotypes Of Oestrogen Excessmentioning

confidence: 99%

Celebrating 75 years of oestradiol

Simpson

Santen

2015

Journal of Molecular Endocrinology

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Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy's had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists. Discovery of oestrogenThe concept that substances secreted by one organ could then be transported internally to another via the blood stream is the underpinning of the field of endocrinology. The 'father of physiology', Claude Bernard, articulated the concept of internal secretion by describing how the liver produces glucose, which then travels to and is utilized by other tissues in the body. This concept underlies studies on the ovaries, which became a focus of investigation later in the century. In 1896, Emil Knauer, a 29-year-old Austrian, excised the ovaries of adult rabbits and then re-implanted pieces into different locations in the same animals (Watkins 2007 Doisy then enlisted a nurse in the obstetrics clinic to supply each pregnant patient with a 1 gal jug and ask for her urine. This provided the needed material but was fraught with difficulties. Suspected to be a bootlegger because of the large jugs of yellow material in his car, one of Doisy's drivers was nearly arrested until he suggested using the sniff test with the response 'My god, it is urine'. Doisy, then being recruited to St Louis University, continued his efforts to purify the active substance. Each extract was tested with a bioassay and its effect on uterine stimulation. Urine, the material of choice for study, was initially extracted with a very large countercurrent apparatus (Fig. 1). Costing the exorbitan...

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“…81 The tumors are typically benign and considered the equivalent of the ovarian sex cord tumor with annular tubules (SCTAT), commonly seen in females with PJS. 37 Interestingly, AROM + mice do not develop sex cord tumors, rather Leydig cell adenomas, which are exacerbated as a result of increasing testicular estradiol concentration. 67 Microscopically, SCTATs result in clusters of enlarged annular seminiferous tubules nestled among seminiferous tubules of normal size and appearance.…”

Section: Arommentioning

confidence: 99%

“…83 In terms of the testis, the sex cords are the site of tumorigenesis and a total of 35 boys with PJS have presented with testicular Sertoli cell tumors. 36,37,39,59,81,[84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100] In boys with PJS, there is an increase of aromatase expression and activity in these tumors, resulting in excess estradiol production that not only acts to feed local tumor growth, 36,39 but also accelerates testicular and extragonadal morphogenesis. For instance, the obvious clinical manifestations are enlarged testes, pre-pubertal gynecomastia and feminizing precocious puberty, and it has become increasingly numbers and the fact that spermatozoa in these mice display decreased motility, as evidenced by the proven inability to fertilize oocytes in vitro.…”

Section: Clinical Casesmentioning

confidence: 99%