A limited set of transcriptional programs define major cell types.

We have produced RNA sequencing data for 53 primary cells from different locations in the human body. The clustering of these primary cells reveals that most cells in the human body share a few broad transcriptional programs, which define five major cell types: epithelial, endothelial, mesenchymal, neural, and blood cells. These act as basic components of many tissues and organs. Based on gene expression, these cell types redefine the basic histological types by which tissues have been traditionally classified. We identified genes whose expression is specific to these cell types, and from these genes, we estimated the contribution of the major cell types to the composition of human tissues. We found this cellular composition to be a characteristic signature of tissues and to reflect tissue morphological heterogeneity and histology. We identified changes in cellular composition in different tissues associated with age and sex, and found that departures from the normal cellular composition correlate with histological phenotypes associated with disease.

The role of steroid receptors, peptides and growth factors in the aetiopathogenesis of idiopathic gynecomastia.

Idiopathic gynecomastia is a diagnosis of exclusion. We aimed to evaluate the role of steroids, peptides and growth factors in these patients. Those with bilateral idiopathic gynecomastia (n = 29) (Simon's grade IIb or III) who underwent gland excision were evaluated by immunohistochemical techniques using semi-quantitative grading for oestrogen receptor (ER), progesterone receptor (PR), aromatase, androgen receptor (AR), peptides (IGF-1, IGF-2, HER-2, parathyroid-hormone related peptide [PTHrP]) and growth factors (EGFR, TGFß). The cohort comprised 29 patients, with a mean age of 25.3 ± 5.1 years and a mean body mass index of 27.2 ± 2.3 kg/m2 . Grade IIb gynecomastia was present in 79.1% and moderate-to-severe insulin resistance (HOMA-IR >3) in 53.7% of patients. ER expression was positive in 100% samples, followed by AR (96.5%), aromatase (96.5%) and PR (93.1%). IGF-1 was expressed in 86.2% of the cohort, IGF2 in 27.5% and HER-2 in only two samples, with both showing weak immunoexpression. None of the patients had positive expression of EGFR, TGF-ß or PTHrP. There was no association between immunoexpression and gynecomastia grade. This study demonstrates the predominant role of oestrogen, aromatase and insulin resistance in the aetiopathogenesis of idiopathic gynecomastia and implicates the paracrine hyperestrogenic milieu in its causation as circulating hormones were normal.

Combined surgical and medical treatment in an adolescent with severe gynecomastia due to excessive estradiol secretion: a case report.

BACKGROUND: Gynecomastia develops due to the reversed estradiol-to-Testosterone ratio in adolescence, and symptoms typically improve within 2 years. The causes vary widely, including estrogen excess and tumors, and surgical treatment is usually given in late adolescence because postoperative symptoms may recur in adolescents. This study reports a case of a pediatric patient with severe gynecomastia due to excessive estradiol secretion who showed a positive outcome after receiving surgical treatment combined with aromatase inhibitor administration. CASE PRESENTATION: A 9-year old boy visited to the Department of Pediatric Endocrinology for breast budding. At that time, the patient showed breasts at Tanner stage II and no abnormality on hormone tests. During a follow-up, both gynecomastia had progressed to Tanner stage III-IV at age 13. Tamoxifen 10 mg bid was administered; however, the condition rapidly progressed to Tanner stage V at 13.5 years. The evaluation of pathologic gynecomastia showed an increase of estradiol to 296 pg/mL with normal range 10 ~ 36 pg/mL and microlithiasis in both testes. As the condition worsened, total mastectomy was performed at the age of 13.5 years. Based on the assessment that elevated aromatase activity had induced breast budding, we changed the medication to anastrozole (Arimidex) 1 mg once a day, after which the estradiol level improved to 38.5 pg/mL and was maintained well in the two-year postoperative follow-up. CONCLUSIONS: This case report shows a combined plastic surgery and appropriate medical management bring a positive outcome in severe gynecomastia patient.

Ovarian and uterine development and hormonal feedback mechanism in a 46 XX patient with CYP19A1 deficiency under low dose estrogen replacement.

BACKGROUND: Aromatase deficiency may result in a complete block of estrogen synthesis because of the failure to convert androgens to estrogens. In females, this results in virilisation at birth, ovarian cysts in prepuberty and lack of pubertal development but virilisation, thereafter. OBJECTIVE AND METHODS: We studied the impact of oral 17ß-estradiol treatment on ovarian and uterine development, and on LH/FSH and inhibin B during the long-term follow-up of a girl harboring compound heterozygote point mutations in the CYP19A1 gene. RESULTS: In early childhood, low doses of oral 17ß-estradiol were needed. During prepuberty treatment with slowly increasing doses of E2 resulted in normal uterine and almost normal development of ovarian volume, as well as number and size of follicles. Regarding hormonal feedback mechanisms, inhibin B levels were in the upper normal range during childhood and puberty. Low doses of estradiol did not suffice to achieve physiological gonadotropin levels in late prepuberty and puberty. However, when estradiol doses were further increased in late puberty levels of both FSH and LH declined with estradiol levels within normal range. CONCLUSION: Complete aromatase deficiency provides an excellent model of how ovarian and uterine development in relation to E2, LH, FSH and inhibin B feedback progresses from infancy to adolescence.

Deciphering the molecular landscape: evolutionary progression from gynecomastia to aggressive male breast cancer.

BACKGROUND: Gynecomastia denotes the benign proliferation of glandular breast tissue and stands as a recognized risk factor for male breast cancer. Nonetheless, the underlying carcinogenic mechanisms orchestrating the progression from gynecomastia to cancer remain poorly understood. METHODS: This study employed single-cell RNA sequencing (scRNA-seq) to meticulously dissect the cellular landscape of gynecomastia and unravel potential associations with male breast cancer at a single-cell resolution. Pseudotime and evolutionary analyses were executed to delineate the distinct features characterizing gynecomastia and male breast cancer. The TCGA database, along with cell-cell communication analysis and immunohistochemistry staining, was harnessed to validate differential gene expression, specifically focusing on CD13. RESULT: From the copy number variation profiles and evolutionary tree, we inferred shared mutation characteristics (18p+ and 18q+) underpinning both conditions. The developmental trajectory unveiled an intriguing overlap between gynecomastia and malignant epithelial cells. Moreover, the differential gene CD13 emerged as a common denominator in both gynecomastia and male breast cancer when compared with normal mammary tissue. Cell-cell interaction analysis and communication dynamics within the tumor microenvironment spotlighted distinctions between CD13+ and CD13- subsets, with the former exhibiting elevated expression of FGFR1-FGF7. CONCLUSIONS: Our investigation provides novel insights into the evolutionary progression from gynecomastia to male breast cancer, shedding light on the pivotal role of CD13 in driving this transition. The identification of CD13 as a potential therapeutic target suggests the feasibility of CD13-targeted interventions, specifically tailored for male breast cancer treatment.

Differential expression of estrogen receptor α and ß transcripts in tissues and in primary culture cells from pubertal gynecomastia.

BACKGROUND: Pubertal gynecomastia is a common problem occurring in up to 65% of adolescent boys. Gynecomastia comes at a time when self-image awareness is at its greatest and psychologically could be a psychologically disabling condition. Surgery is considered the mainstay of treatment for severe or persistent cases. A medical management aimed at altering the effective androgen/estrogen ratio has been suggested with inconstant results. Some promising results have been obtained by using anti-estrogens. Surprisingly there are no data on the estrogen receptor (ER) α and ß RNA expression in gynecomastia. AIM: We studied ER RNA subtypes in pubertal gynecomastia. METHODS: ERα and ß RNA were determined by real time RT-PCR in 50 mammary samples from pubertal boys with idiopathic gynecomastia subjected to reductive mammoplasty. To study ERα and ß pattern of expression, epithelial and stromal primary cell cultures were set up from fresh tissues. RESULTS: These analyses indicated that in all stromal cells ERß was expressed at higher level than ERα and in epithelial cells both ERα and ERß were barely detectable. CONCLUSIONS: Our data suggest that also stromal cells are involved in the pathophysiology of pubertal gynecomastia. The high level of expression of ERß seen in pubertal gynecomastia adds new insight on validation of ERß as a target for candidate diseases and exploration of ERß as a marker for clinical decision-making and treatment in pubertal gynecomastia. This could drive to search for new and selective anti-estrogen drugs for medical treatment of pubertal gynecomastia with a particular attention to the ERß-selective ligand.

Two cases of male nipple leiomyoma: idiopathic leiomyoma and gynecomastia-associated leiomyoma.

We describe 2 cases of male nipple leiomyoma. A 70-year-old man had a painful subcutaneous tumor on his left nipple of 6 months duration. Histopathology disclosed dermal spindle cells with oval-shaped nuclei forming interlacing bundles with irregular pattern. Glandular elements were absent. The spindle cells were positive to α-smooth muscle actin, desmin, and vimentin. Estrogen receptor (ER) and progesterone receptor (PrR) were negative. We diagnosed this case as male leiomyoma of the nipple. Another patient was a 61-year-old man with gynecomastia induced by spironolactone of 6 months duration. He also had a painful nodule on his left nipple and histopathology disclosed spindle-shaped tumor cells as in the previous patient. The tumor was accompanied by glandular elements in the deep dermis and subcutaneous tissue, which showed apocrine secretion and were positive for α-smooth muscle actin, ER, and PrR. These glandular elements were interpreted as mammary gland. But ER and PrR stain did not show positive results for leiomyoma in the upper dermis. To the best of our knowledge, this is the first report of male idiopathic and gynecomastia-induced leiomyoma with ER and PrR staining.

Congenital disorders of estrogen biosynthesis and action.

Estrogens regulate pubertal development and reproductive function in women, spermatogenesis in men, and bone turnover and metabolic conditions in individuals of both sexes. Estradiol, the major estrogen in humans, is synthesized from testosterone by the action of aromatase and exerts its effects though binding to estrogen receptors. Germline loss- and gain-of-function variants in CYP19A1, the gene encoding aromatase, lead to aromatase deficiency and aromatase excess syndrome, respectively. Germline loss-of-function variants in ESR1, the gene encoding estrogen receptor α, are known to cause of estrogen insensitivity/resistance. In addition, rare variants in ESR1 and ESR2 have been implicated in various disease phenotypes. Clinical studies on these rare endocrine disorders provided clues to understand the biological functions of estrogens in the human body. This review introduces the genetic basis, phenotypes, and current management procedures of congenital disorders in estrogen biosynthesis and action.

Sex Hormone Profile in Pubertal Boys With Gynecomastia and Pseudogynecomastia.

CONTENT: Gynecomastia (defined by proliferation of glandular elements) and pseudogynecomastia (defined by adipose tissue) are frequent in pubertal boys. An association with sex hormones and the growth hormone axis has been discussed. OBJECTIVE: The objective of this work is to compare sex hormones, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor binding protein 3 (IGFBP-3) between boys with gynecomastia and pseudogynecomastia (separation by ultrasound). DESIGN: An observational study was performed. SETTING: The setting of this study was an outpatient clinic. PARTICIPANTS: A total of 124 pubertal boys (mean age 14 ±â€…2 years) with breast enlargement and 84 healthy boys (mean age 14 ±â€…2 years) without breast enlargement participated in this study. INTERVENTIONS: No interventions were performed. MAIN OUTCOME MEASURES: Measurements were taken for sex hormones (progesterone, estradiol [E2], estriol, estrone, androstendione, testosterone [T], dihydrotestosterone) measured by liquid chromatography-tandem mass spectrometry, as well as gonadotropins, prolactin, IGF-1, and IGFBP-3. RESULTS: Eighty-six boys suffered from gynecomastia and 38 from pseudogynecomastia. In boys with gynecomastia, the E2/T ratio (median 22, interquartile range [IQR] 8-75) was significantly (P < .05) higher compared to boys with pseudogynecomastia (median 12, IQR 5-21) or healthy controls without breast enlargement (median 18, IQR 6-44) even after adjustment for testes volume. T concentrations were significantly (P < .05) lower in boys with gynecomastia (median 1.8, IQR 0.7-4.2 nM/L) compared to boys with pseudogynecomastia (median 4.3, IQR 1.4-6.9 nM/L) or healthy controls without breast enlargement (median 3.1, IQR 0.6-7.6 nM/L). Boys with gynecomastia did not differ from boys with pseudogynecomastia according to other sex hormones, prolactin, IGF-1, or IGFBP-3 concentrations. CONCLUSIONS: True gynecomastia is characterized by a relative T deficiency to E2 concentrations in contrast to pseudogynecomastia.

Testicular ultrasound inhomogeneity is an informative parameter for fertility evaluation.

Testicular volume (TV) is proposed to be a positive predictor of male fertility status, because of the relation known between the TV and the seminiferous tubule content. Independently of the measurement methodology, the role of TV and testicular ultrasound (US) assessments is still debated in andrological clinical practice. In this retrospective cohort study, we evaluated TV and testis US role in the diagnostic workup of andrological patients. All consecutive outpatients undergoing single-operator testis US (Modena, Italy) from March 2012 to March 2018 were enrolled, matching sonographic, hormonal, and seminal data. A total of 302 men were referred and evaluated for gynecomastia, suspected hypogonadism, couple infertility (CI), or sexual dysfunction. In the hypogonadal group, TV was lower compared to that in other groups (P < 0.001), and a significant, direct correlation between TV and testosterone level was observed in nonandrogen-treated patients (R = 0.911, P < 0.001), suggesting that testicular size could be related to the testosterone-secreting compartment. In the CI group, normozoospermic patients showed higher TV compared to men with impaired semen quality (P = 0.003) and azoospermia (P = 0.003). However, TV was not able to discriminate between patients presenting normal and altered semen quality. On the contrary, testis US inhomogeneity was more frequent in patients with impaired sperm quality (55.0%; P = 0.007) and azoospermia (40.0%; P = 0.012), compared to patients with normozoospermia (5%), identifying thereby the sonographic pattern as an informative parameter of the fertility status. Therefore, in the CI workup, US evaluation seems to be more informative than the TV assessment alone.

MicroRNA expression profiling of male breast cancer.

INTRODUCTION: MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. To test the hypothesis that there is a specific miRNA expression signature which characterizes male breast cancers, we performed miRNA microarray analysis in a series of male breast cancers and compared them with cases of male gynecomastia and female breast cancers. METHODS: Paraffin blocks were obtained at the Department of Pathology of Thomas Jefferson University from 28 male patients including 23 breast cancers and five cases of male gynecomastia, and from 10 female ductal breast carcinomas. The RNA harvested was hybridized to miRNA microarrays (~1,100 miRNA probes, including 326 human and 249 mouse miRNA genes, spotted in duplicate). To further support the microarray data, an immunohistochemical analysis for two specific miRNA gene targets (HOXD10 and VEGF) was performed in a small series of male breast carcinoma and gynecomastia samples. RESULTS: We identified a male breast cancer miRNA signature composed of a large portion of underexpressed miRNAs. In particular, 17 miRNAs with increased expression and 26 miRNAs with decreased expression were identified in male breast cancer compared with gynecomastia. Among these miRNAs, some had well-characterized cancer development association and some showed a deregulation in cancer specimens similar to the one previously observed in the published signatures of female breast cancer. Comparing male with female breast cancer miRNA expression signatures, 17 significantly deregulated miRNAs were observed (four overexpressed and 13 underexpressed in male breast cancers). The HOXD10 and VEGF gene immunohistochemical expression significantly follows the corresponding miRNA deregulation. CONCLUSIONS: Our results suggest that specific miRNAs may be directly involved in male breast cancer development and that they may represent a novel diagnostic tool in the characterization of specific cancer gene targets.

Incidental Uptake in Benign Gynecomastia on 68Ga-DOTATATE PET/CT.

A 54-year-old man with mesenteric carcinoid tumor metastatic to the liver completed staging Ga-DOTATATE PET/CT demonstrating uptake in multiple hepatic lesions consistent with liver metastases with additional asymmetric increased uptake in the right greater than the left breast. Subsequent bilateral diagnostic mammogram revealed benign right greater than left gynecomastia without suspicious underlying mass. With Food and Drug Administration approval of Ga-DOTATATE and the increased use of this analog in neuroendocrine tumor imaging, this case illustrates a relevant example of uptake that can potentially mimic malignancy.

Incidental 18F-NaF Uptake in Drug-Induced Gynecomastia.

Gynecomastia is not uncommon in men older than 50 years of age and is characterized by glandular proliferation of breast tissue. Non-physiologic gynecomastia is mostly caused by a variety of external medical interventions. Medications that belong to classes of antiandrogens, antipsychotics, or antibiotics alter the levels of estrogen and testosterone and are commonly implicated in patients with gynecomastia. We are presenting a case of bilateral F-NaF uptake in the breast tissue of a 56-year-old man with known history of prostate cancer.

Is gynecomastia related to the disease characteristics and prognosis in testicular germ cell tumor patients?

PURPOSE: We aimed to assess the relationship between gynecomastia and tumor markers, histologic subtypes, and prognosis in patients with testicular germ cell tumors. METHODS: This study included 73 testicular germ cell cancer patients with pretreatment chest, abdomen and pelvis computed tomography (CT) scans and tumor markers (ß-human chorionic gonadotropin [ß-hCG], lactate dehydrogenase [LDH], α-fetoprotein [AFP]). The volumetric analysis of the breast glandular tissue, the presence of gynecomastia and metastatic disease were determined using CT scans. Patients were classified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification. The association between gynecomastia, breast glandular tissue volume, tumor markers, metastatic disease, and disease prognosis were evaluated. RESULTS: Thirty-four of the patients (46.6%) had gynecomastia. A breast volume cutoff value of 0.78 cm3 to diagnose gynecomastia led to 85% sensitivity and 95% specificity. Serum ß-hCG level correlated with the breast glandular tissue volume weakly (r=0.242, P = 0.039). Gynecomastia was more common in patients with elevated ß-hCG levels (P = 0.047), and was not associated with pulmonary, nonpulmonary distant, or nodal metastases (P = 0.378, P = 0.884, P = 0.333, respectively). No significant association was found between the disease prognosis and gynecomastia (P = 0.556). CONCLUSION: Gynecomastia was common among testicular germ cell cancer patients with elevated ß-hCG. However, it was not associated with metastatic disease and prognosis.

Prolactin receptor expression in gynaecomastia and male breast carcinoma.

AIMS: Despite the well-established function of prolactin (PRL) in normal breast development, its role in breast cancer pathogenesis is still controversial. PRL activity is dependent on the activation of a transmembrane protein, the PRL receptor (PRLR). The aim was to evaluate and compare PRLR expression in gynaecomastia and male breast carcinoma (MBC). METHODS AND RESULTS: PRLR expression was detected immunohistochemically in 30 cases of gynaecomastia and 30 cases of MBC. The whole series was also assessed for oestrogen receptors (ER), progesterone receptors (PR) and androgen receptors (AR). A cut-off of 10% was used as the criterion for positivity. Histological type and tumour differentiation were evaluated. Pathological stage was assessed [Tumour Node Metastasis (TNM)-International Union Against Cancer system]. Statistical analysis was performed with Fisher's exact test. PRLR positivity was seen in 20% of gynaecomastia cases and in 60% of MBC cases (P = 0.003). In gynaecomastia immunoreactivity was predominantly observed in luminal cell borders, whereas in MBC the reactivity was heterogeneous and mainly cytoplasmic. There was no statistically significant correlation between PRLR expression and ER, PR, AR, pTNM, or histological grade. CONCLUSIONS: PRLR is significantly more expressed in MBC than in gynaecomastia, and with different patterns of reactivity, suggesting a role for PRL in male breast carcinogenesis.

Gynecomastia in adolescents.

PURPOSE OF REVIEW: Gynecomastia is a common finding in adolescent men. The primary care provider should feel equipped to thoroughly evaluate this condition and to differentiate physiologic from pathologic breast enlargement. The present review focuses on the epidemiology, pathogenesis, evaluation, and treatment of gynecomastia during adolescence. RECENT FINDINGS: While gynecomastia has long been attributed to an imbalance between estrogen and androgen concentrations, recent literature has begun to illuminate other potential mechanisms for breast development in adolescent men. Increased leptin levels, as well as human chorionic gonadotropin and luteinizing hormone receptors on male breast tissue, may play a role. Newer treatment strategies, such as the antiestrogen raloxifene, have shown promising results; however, further studies are needed to determine long-term efficacy. As a result of the limited pharmaceutical treatment options, many more adolescents are seeking surgical intervention. SUMMARY: Gynecomastia is frequently encountered in the primary care setting. During adolescence, male breast enlargement is most often benign and rarely represents a pathologic mechanism. Careful attention should be paid to both the breast and testicular examination. A detailed history should include an inquiry regarding the use of illicit substances, anabolic-androgenic steroids, herbal products, and medications. The impact of gynecomastia on the adolescent's mental health should be assessed. A workup for pathologic causes is rarely required. Reassurance remains the standard of care for physiologic gynecomastia.

Characterising the adipose-inflammatory microenvironment in male breast cancer.

Male breast cancer (MBC) incidence seems to parallel global increases in obesity. The stromal microenvironment contributes to carcinogenesis; yet, the role of adipocytes in this is understudied in MBC. We identified four cohorts of male breast tissues diagnosed when obesity was rare (archival cohort) and more common (contemporary cohort). We examined the microenvironment of archival and contemporary cohorts of MBC, diagnosed 1940-1970 and 1998-2006, respectively, with two cohorts of, archival and contemporary gynaecomastia, diagnosed 1940-1979 and 1996-2011, respectively, serving as controls. We quantified adipocytes, crown-like structures (CLS) and the presence of CD8, α smooth muscle actin (αSMA) and CD68+ macrophages in both cohorts, and determined how these affected survival, in the contemporary MBC cohort. In both MBC cohorts, mean adipocyte diameter was larger in the distant stroma compared with stroma close to the invading tumour (92.2 µm vs 66.7 µm). This was not seen in gynaecomastia. CLS were more frequent in both MBC cohorts than gynaecomastia (44/55 (80%) vs 11/18 (61%), P < 0.001). No relationship was found between CLS number and adipocyte size, although there were greater numbers of CLS in contemporary MBC > archival MBC > gynaecomastia. CD8 and CD68 expression in the stroma was significantly associated with reduced survival, with no effects seen with αSMA. Changes in the adipose-inflammatory microenvironment may be a contributing factor to the increase seen in MBC diagnosis.

Is There a Rationale behind Pharmacotherapy in Idiopathic Gynecomastia?

BACKGROUND/AIMS: The aim of this research was to analyze digit ratio in relation to estrogen receptor (ER) and progesterone receptor (PR) expression and to verify digit ratio (2D: 4D) as a marker of ER and PR overexpression in the male breast. METHODS: This study included 35 patients who underwent breast reduction due to the idiopathic form of gynecomastia. The average age of the studied individuals was 25.7 years (SD = 7.8). ER and PR expression was detected in breasts, and digit ratios were calculated in patients with idiopathic gynecomastia. RESULTS: ER expression did not correlate with the right (p = 0.51) and left 2D: 4D (p = 0.97). Also, there was no correlation between PR expression and 2D: 4D. A lack of correlation between these variables may result from the fact that the analyzed group of men with idiopathic gynecomastia was small in number, but at the same time, it appeared to be homogenous in these aspects (positive ER and/or PR expression and high digit ratio). CONCLUSION: High digit ratio in men with gynecomastia may tend to be a marker of overexpression of ER and PR. This may justify an early use of tamoxifen in men with gynecomastia and a high digit ratio.

46,XY Disorder of Sex Development due to 17-Beta Hydroxysteroid Dehydrogenase Type 3 Deficiency in an Infant of Greek Origin.

17-beta hydroxysteroid dehydrogenase type 3 (17ßHSD-3) enzyme catalyzes the conversion of androstenedione (Δ4) to testosterone (T) in the testes of the developing fetus, thus playing a crucial role in the differentiation of the gonads and in establishing the male sex phenotype. Any mutation in the encoding gene (HSD17B3) can lead to varying degrees of undervirilization of the affected male, ranging from completely undervirilized external female genitalia to predominantly male with micropenis and hypospadias. We present here an infant who was referred to our clinic because of ambiguous genitalia at birth. Gonads were palpable in the inguinal canal bilaterally and no Müllerian structures were identified on pelvic ultrasound. Because of a low T/Δ4 ratio after a human chorionic gonadotropin stimulation test, a tentative diagnosis of 17ßHSD-3 deficiency was made which was confirmed after genetic analysis of the HSD17B3 gene of the patient. The molecular analysis identified compound heterozygosity of two previously described mutations and could offer some further validation for the idea of a founder effect for 655-1;G→A mutation in the Greek population.

Familial gynecomastia with increased extraglandular aromatization of plasma carbon19-steroids.

We evaluated a family in which gynecomastia occurred in five males in two generations. In each affected subject, gynecomastia and male sexual maturation began at an early age. The ratio of the concentration of plasma estradiol-17 beta to that of plasma testosterone was elevated in each affected subject. In the three siblings with gynecomastia, the transfer constant of conversion of androstenedione to estrone (i.e., the fraction of plasma androstenedione that was converted to estrone as measured in the urine) was 10 times that of normal persons. The transfer constant of conversion of testosterone to estradiol-17 beta in the one subject studied also was 8-10 times that of normal men, whereas the transfer constants of conversion of estrone to estradiol-17 beta and of estradiol-17 beta to estrone were normal. Despite the elevation in extraglandular aromatase activity, there was a normal response of the hypothalamic-pituitary axis to provocative stimuli. This is the second documentation of gynecomastia that is associated with increased extraglandular aromatase activity, and the first time that the defect was found to be familial with a probable X-linked (or autosomal dominant, sex limited) mode of inheritance.