BACKGROUND: Aromatase deficiency is a rare disorder, with only a few cases reported in India. We describe a single-center experience in western India, with a systematic review of genetically proven 46,XX aromatase deficiency patients to evaluate hormonal parameters.
METHODS: Retrospective review of case records, collating phenotypic and genotypic data and molecular modeling. Systematic review of 46,XX aromatase deficiency, analyzing data on gonadotropins, estrogen and androgens.
RESULTS: In the seven patients from our center, presentation was frequent in childhood or adolescence (4/7: delayed puberty or hyperandrogenism), with maternal virilization (4/7), predominance of Prader III/IV (5/7), and initial rearing as females (6/7). Three patients had hypoplastic ovaries. One patient had spontaneous regular menses. We report three novel (p.Arg115Pro, p.Arg192Pro, and c.145+1_145+4delins) and two recurrent variants (p.Val370Met, and c.145+1_145+4delins) in western and northern India, respectively. On systematic review (n=43), gonadotropins were elevated (FSH>LH) across ages (except preterm infants), androgens were elevated in about one-third of cases during childhood and puberty, and estradiol was lower than in controls in mini-puberty and puberty. Spontaneous thelarche and streak ovaries were significantly more frequent in patients with non-truncating and truncating variants, respectively.
CONCLUSIONS: We report uncommon presentations with possible founder variants, and highlight hormonal parameters across ages. Serum FSH levels were elevated except in preterms, and can be used as a diagnostic marker.

Idiopathic unilateral breast enlargement (UBE) in males is a, commonly overlooked, diagnosis of exclusion that requires careful history, meticulous physical examination, and pertinent laboratory studies to exclude the possible pathologic causes. The aims of the present update are to review the current literature on UBE in subjects during adolescent age (10-19 years) in 18 cases, and to report the personal experience in 13 adolescents referred to our unit during the last four decades. In total, our survey and personal experience include 31 UBE cases, 10 of whom (32.2 %) being idiopathic or familial gynecomastia (GM). In 3/31 (9.6%) UBE was due to breast sarcoma/ carcinoma; one patient (11-years old) had a 5-year history of painless lump in the right breast, which increased gradually in size followed by bloody nipple discharge. In the personal cases of 13 adolescents, a moderate to marked UBE was secondary to: treatment with androgens (2 β-thalassemic patients with hypogonadism), high estrogen/androgen ratio in 2 Klinefelter syndrome patients, peripheral aromatization of androgens in 1 patient with non-classical 21-hydroxylase deficiency (NC-21-OH-D). One patient had subareolar hematoma due to injury. In 2 patients (15,3%) marked UBE was due to cystic lymphangioma (histologically proved). Furthermore, 5 patients were characterized as idiopathic UBE In clinical practice, the persistence of UBE for long period before diagnosis necessitates attention and further evaluation. Underlying causes should be treated, when possible, while surgery can be offered to patients with persistent or atypical signs and/or symptoms of UBE. For the optimal management of this condition, better collaboration between primary care physician and specialists is mandatory.

(1) Introduction: Erdheim-Chester disease (ECD) is a life-threatening condition and often a diagnostic challenge. It has recently been classified as a hematopoietic tumour, and the cases of ECD reported in the literature has dramatically increased during the last 15 years. (2) Methods: We describe the case of a 57-year-old male patient with severe gynecomastia, with a detailed description of his diagnostic iter and consequent surgical operation. We provide the first systematic review of the literature of breast involvement in ECD, following PRISMA guidelines, including 13 studies and 16 patients. (3) Results: Our report resulted to be the first case of gynecomastia as a single clinical and imaging feature of ECD described in English literature. A total of 81.3% of patients included were female. Among them, 76.9% had unilateral and nodular presentation, while male patients presented bilateral heterogeneous breast enlargement. Globally, 87.5% expressed breast alterations as their first manifestations of ECD. Only 50% presented skeletal involvement. (4) Conclusion: The reported case represents a unique addition to the literature. We found two different patterns in ECD-related breast involvement between male and female patients, an unusual M/F ratio, and a lower rate of bone involvement. Breast involvement is frequently the first clinical feature; therefore, breast caregivers should be aware of this dangerous and most likely underestimated condition.

UNASSIGNED: Pubertal gynecomastia (PG), a benign condition with varied reported prevalence, typically appears at 13-14 years-old and is mostly idiopathic and self-limited. Psychologic impairments are common among adolescents with gynecomastia. Surgical intervention is reserved to severe cases and is offered towards the end of puberty. Pharmacological treatment is seldom given by clinicians mainly due to insufficient published data. We conducted this systematic literature review to assess the efficacy, safety, side effects, and complications of pharmacological treatments published.
UNASSIGNED: MEDLINE, Embase, and Cochrane CENTRAL were searched for the terms \"gynecomastia\", \"pubertal\", and \"adolescent\" in conjunction with medications from the Selective Estrogen Receptor Modulator (SERM), aromatase inhibitors (AI), and androgens groups in different combinations to optimize the search results. Exclusion criteria included: studies based on expert opinion, similar evidence-based medicine levels studies, and studies which discuss gynecomastia in adults. Selected articles were assessed by two authors. Data collected included: the level of evidence, population size, treatment regimen, follow-up, outcomes, complications, and side effects.
UNASSIGNED: Of 1,425 published studies found and examined meticulously by the authors, only 24 publications met all the study research goals. These were divided into 16 publications of patients treated with SERM, of whom four had AI and four androgens. In general, the data regarding pharmacologic therapy for PG is partial, with insufficient evidence-based research. Tamoxifen and SERM drugs have long been used as treatments for PG. Tamoxifen was the chosen drug of treatment in most of the reviewed studies and found to be effective, safe, and with minimal side effects.
UNASSIGNED: Pharmacological treatment as a new standard of care has an advantage in relieving behavioral and psychological distress. Although high quality publications are lacking, pharmacological intervention with tamoxifen is appropriate in select patients. Conduction large-scale high-quality studies are warranted with various drugs.

The 17-beta-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) enzyme converts androstenedione to testosterone and is encoded by the HSD17B3 gene. Homozygous or compound heterozygous HSD17B3 mutations block the synthesis of testosterone in the fetal testis, resulting in a Disorder of Sex Development (DSD). We describe a child raised as a female in whom the discovery of testes in the inguinal canals led to a genetic study by whole exome sequencing (WES) and to the identification of a compound heterozygous mutation of the HSD17B3 gene (c.608C>T, p.Ala203Val, and c.645A>T, p.Glu215Asp). Furthermore, we review all HSD17B3 mutations published so far in cases of 17-β-HSD3 deficiency. A total of 70 different HSD17B3 mutations have so far been reported in 239 patients from 187 families. A total of 118 families had homozygous mutations, 63 had compound heterozygous mutations and six had undetermined genotypes. Mutations occurred in all 11 exons and were missense (55%), splice-site (29%), small deletions and insertions (7%), nonsense (5%), and multiple exon deletions and duplications (2%). Several mutations were recurrent and missense mutations at codon 80 and the splice-site mutation c.277+4A>T each represented 17% of all mutated alleles. These findings may be useful to those involved in the clinical management and genetic diagnosis of this disorder.

UNASSIGNED: Fibroadenoma of the male breast is a rarely diagnosed lesion that often occurs concurrently with gynecomastia and the intake of medications that alter sex hormone levels. Herein, we report the first case of fibroadenoma of the male breast, presenting with medullary thyroid cancer. In addition, we reviewed the current management strategies for fibroadenoma of the male breast in the literature.
UNASSIGNED: A 25-year-old male patient presented to our surgical unit with medullary thyroid cancer (MTC). The physical examination revealed an unnoticed lump in his left breast. We delayed the planned thyroid surgery to determine whether the breast mass was associated with metastasis from MTC. We performed pathological tests from excised breast mass and confirmed the diagnosis of fibroadenoma. After confirming the benign nature of the breast mass, the patient underwent total thyroidectomy with selective neck dissection for MTC.
UNASSIGNED: Fibroadenoma of the male breast was diagnosed based on clinical presentation and histopathological findings. Fibroadenoma of the male breast is a rarely diagnosed lesion: and is often associated with gynecomastia and altered serum sex hormone level. The presentation of this case without those concurrences is even rarer, as revealed in our case. The management for suspected fibroadenoma of the male breast presented with MTC should include delaying the thyroid surgery to rule out the presence of malignancy and metastasis.
UNASSIGNED: The finding indicates that fibroadenoma can be considered a differential diagnosis in the male breast even in the absence of those concurrences. The timely diagnosis and orderly management of fibroadenoma of the male breast and MTC could help to improve the patient outcome.

To date, various surgical techniques were developed for gynecomastia and pseudogynecomastia surgery, providing surgeons vast range of options. These variations of techniques, however, may have different efficacy and results depending on the severity of patients\' conditions.
This review aims to delineate comprehensively the variations of surgical approaches to gynecomastia and pseudogynecomastia in relation to surgical and patients\' outcomes.
Database search (October 28, 2020) from PubMed, Scopus, Science Direct, and Cochrane Library was performed to identify relevant studies using the keywords (\"gynecomastia\" OR \"pseudogynecomastia\") AND (\"surgery\" AND \"mastectomy\" OR \"liposuction\") within January 2011-November 2020, published in English. Inclusion criteria were approached according to patients, intervention, comparator, outcomes, and study design (PICOS). Data from the included studies were extracted based on study and subjects\' characteristics, type of intervention, and outcome measures.
Out of all relevant studies revealed, 53 studies met inclusion criteria with 5345 subjects included. Most subjects, from 44 studies, were classified as Simon\'s Grade II (68.49%) with idiopathic cause (94.51%). Most cases were approached using the minimally invasive techniques (37.50%) and were highly satisfied. Among intervention groups, complication rates vary from 12.12-22.30%, with the minimally invasive approach having the lowest rate. Hematoma and bruise were the most reported complications. However, the risk of bias was relatively high due to missing data.
Different surgical approaches for gynecomastia treatment have been described and were consistent with good outcomes. To achieve a low rate of complications, the minimally invasive techniques can be considered, since most patients seem to be satisfied.

BACKGROUND: Gynecomastia is nowadays a very common disease, affecting a large cohort of patients with different ages. The aim of this literature review is to assess the incidence of complications with all proposed techniques and for combined procedures versus single approach procedures in gynecomastia correction.
METHODS: A systematic review of the literature was performed to identify all reported techniques for gynecomastia correction covering a period from January 1, 1987 to November 1, 2020. For all selected papers, demographic data, proposed technique, and complications\' incidence have been recorded.
RESULTS: A total number of 3970 results was obtained from database analysis. A final total number of 94 articles was obtained for 7294 patients analyzed. Patients have been divided into three groups: aspiration techniques, consisting in 874 patients (11,98%), surgical excision techniques, consisting in 2764 patients (37,90%), and combined techniques, consisting in 3656 patients (50,12%). Complications have been recorded for all groups, for a total number of 1407, of which 130 among \"Aspiration techniques\" group (14,87%), 847 among \"Surgical excision techniques\" group (30,64%), and 430 in \"Combined techniques\" group (11,76%).
CONCLUSIONS: Several techniques have been proposed in the literature to address gynecomastia, with the potential to greatly improve self-confidence and overall appearance of affected patients. The combined use of surgical excision and aspiration techniques seems to reduce the rate of complications compared to surgical excision alone, but the lack of unique classification and the presence of several surgical techniques still represents a bias in the literature review.
METHODS: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

This study was performed to describe a rare case of granulomatous lobular mastitis (GLM) that was successfully treated with bromocriptine in a male patient with gynecomastia and hyperprolactinemia. A 20-year-old man presented with a 1-year history of breast enlargement and galactorrhea. Physical examination revealed bilateral breast enlargement, porous discharge, and a 3-cm left breast lump in the 10-o\'clock quadrant. Magnetic resonance imaging of the brain showed a 1.2-mm pituitary tumor. Laboratory analysis revealed hyperprolactinemia with low serum testosterone and elevated prolactin and estradiol levels. The lump in the left breast was examined by ultrasonography and mammography, and a core needle biopsy revealed chronic inflammation. The patient\'s galactorrhea and breast lump disappeared after 3 months of treatment with bromocriptine at 2.5 mg once a day. His serum prolactin level also normalized. Following a review of this case, the patient was diagnosed with gynecomastia with hyperprolactinemia complicated by rare GLM. To the best of our knowledge, this is the first reported case of concurrent gynecomastia and GLM.

OBJECTIVE: To review the evidence concerning treatment-related gynecomastia in patients taking spironolactone, antiandrogens, 5 alpha-reductase inhibitors, lipid-lowering and psychotropic drugs.
METHODS: A search of Medline and EMBASE was performed up to 30 June 2021. We included randomized controlled trials comparing the effects of a drug belonging to these classes versus placebo or versus a drug of the same class.
RESULTS: A total of 32 randomized controlled trials were included in the final review. There was an increased odds of gynecomastia in men receiving antiandrogens (OR = 17.38, 95% CI: 11.26 to 26.82; 6 trials, 9599 participants) and 5 alpha-reductase inhibitors compared to controls (OR = 1.77, 95% CI: 1.53 to 2.06; 7 series out of 6 trials, 34860 participants). The use of spironolactone in mixed gender populations was characterized by significantly higher odds of having gynecomastia compared to controls (OR = 8.39, 95% CI: 5.03 to 13.99; 14 trials, 3745 participants). No placebo-controlled trials focusing on the risk of gynecomastia in patients taking antipsychotic drugs was available, although there was a significant difference in the odds of having gynecomastia in a comparison between risperidone and quetiapine (OR = 4.32, 95% CI: 1.31 to 14.27; 3 trials, 343 participants). Limited evidence about the effects of statins on mammary glands was found.
CONCLUSIONS: Antiandrogens and to a lesser extent 5 alphareductase inhibitors and spironolactone are associated with an increased risk of developing gynecomastia. Such effect can be explained by a modification of the testosterone to estradiol ratio. Gynecomastia (and galactorrhea) associated to the use of conventional and certain atypical antipsychotics can be related to high prolactin levels.