A Lung Cancer Patient Presenting With Gynecomastia: An Uncommon Paraneoplastic Syndrome.

Lung cancer is the most common neoplastic disorder associated with paraneoplastic syndromes. The most common paraneoplastic syndromes are the syndrome of inappropriate release of antidiuretic hormone (SIADH), hypercalcemia of malignancy, ectopic Cushing's syndrome, and various other neurological syndromes. A few case reports have reported gynecomastia as a paraneoplastic syndrome. Recognition of this uncommon presentation can aid in the early detection of associated malignancies, thus potentially improving outcomes. In this article, we are presenting the case of a male patient in his late sixties who, on presentation, had gynecomastia and was eventually diagnosed with non-small-cell lung cancer (NSCLC).

Is Breast Imaging in Male Patients With Benign Lumps Necessary? A Retrospective Study to Assess Concordance Between Clinical Diagnosis and Imaging Findings.

Objective: Breast imaging for male patients is a controversial topic due to the high prevalence of gynecomastia compared to male breast cancer. Worldwide, men are undergoing more breast imaging despite the low incidence of male breast cancer. Gynecomastia is a benign condition, but the anxiety it causes and unnecessary medical costs are still high. Materials and Methods: In accordance with Royal College of Radiology guidelines, a retrospective study was performed in two cycles to determine if mammography or ultrasound should be included in the workup of male patients who were referred to a breast care unit for a lump that was deemed benign by doctors. Results: There was 100% concordance between clinical diagnosis and imaging findings. Conclusion: In this population imaging was not necessary in cases of probable gynecomastia and benign conditions found during a clinical assessment. Standardised patient assessment methods can improve care and ensure accurate evaluation.

The Burden of Anabolic Androgenic Steroid-Induced Gynecomastia.

Introduction Gynecomastia is benign proliferation of male breast tissue that can be idiopathic or secondary to hormonal imbalance. Consumption of steroids plays a major role in the development of gynecomastia. The increased consumption of anabolic androgenic steroid (AAS) in youngsters to boost the physical strength and improve appearance is associated with increased prevalence of gynecomastia. True estimation of AAS-associated gynecomastia is difficult to calculate and prone to underestimation because of low social acceptance. Accurate estimation is required to assess future healthcare, for prevention and to give appropriate treatment. Aims and Objectives The aim of this study was to calculate the steroid consumption in gynecomastia patients accurately so that appropriate treatment can be given and their response to treatment could be analysed. Methods This is a prospective study done in a tertiary care hospital from June 2019 to June 2022. All the gynecomastia patients treated during this period in Burns & Plastic Surgery Department of PGIMS Rohtak were included in the study. Patient's detailed history was recorded and also after 3 months of surgery patients were again enquired about their history to record any change. Results Real prevalence of AAS-associated gynecomastia (39.19%) was much higher than that recorded in preoperative period (4.05%). Also, AAS users were having higher body mass index and a greater proportion of patients were bodybuilders. Conclusion Patients with high body mass index, athletic body, and history of recent weight gain should raise the suspicion of anabolic steroid intake. Surgery is not always indicated in AAS-associated gynecomastia. If gynecomastia persisted, surgery necessitates and it involves meticulous intraoperative hemostasis and careful glandular excision to minimize recurrence and achieve low complication rates.

Prevalence of men's health history in male breast cancer patients.

INTRODUCTION: Male breast carcinoma (MBC) is an uncommon disease, accounting for less than 0.5% of cancer diagnoses in men. Data on the prevalence thereof in Argentina are unknown. PRIMARY OBJECTIVE: To estimate the prevalence of a men's health history associated with MBC as well as the anthropometric and clinical characteristics of the study population. METHODS: This cross-sectional study included all men according to original biological sex over 18 years of age with a history of breast cancer who sought care at the Hospital Italiano de Buenos Aires [Italian Hospital of Buenos Aires] between January 2010 and December 2018. RESULTS: We included 57 men with breast cancer. Their median age was 71 years. Of them, 53.06% had obesity and 24.53% had diabetes. With respect to men's health history, 5.56% (2/36) had infertility, 29.17% (14/48) had gynaecomastia and 60.71% (17/28) had sexual dysfunction. Some 63% (7/11) had androgen deficiency based on laboratory diagnosis; of them, 45.45% (5/11) had high gonadotropins. CONCLUSION: We identified similarities with the literature as to the prevalence of obesity, diabetes and infertility in patients with MBC. The prevalence of testosterone deficiency was higher than reported for men of the same age. Many of these factors support the need to examine the role of endogenous hormones. Further research is required to help physicians care for and counsel men at higher risk of this disease.

Are Prepubertal Gynaecomastia and Premature Thelarche Linked to Topical Lavender and Tea Tree Oil Use?

Various studies, conducted since 2007, have reported a total of eight boys with prepubertal gynaecomastia and four girls with premature thelarche following exposure to lavender and/or tree tea oil. All patients experienced regression of the breast tissue after they stopped using these oils. Both of these essential oils, and several of their constituents, have oestrogenic and antiandrogenic activity in vitro. However, limited dermal penetration of some of the components means that the in vitro findings cannot be extrapolated to the in vivo situation. There are unanswered questions as to how much lavender or tea tree oil was actually present in the skincare products used by the children and a lack of information about exposure to other agents. Furthermore, since both prepubertal gynaecomastia and premature thelarche often spontaneously regress, it cannot be concluded that the use of lavender and/or tree tea oil is the cause of the gynaecomastia and thelarche in these children.

Efficacy of aromatase inhibitor therapy in a case with large cell calcifying Sertoli cell tumour-associated prepubertal gynaecomastia.

OBJECTIVES: Large cell calcifying Sertoli cell tumours (LCCSCTs) are one of the infrequent causes of prepubertal gynaecomastia. Most of these tumours are in the content of Peutz-Jeghers syndrome (PJS) or other familial syndromes (Carney complex). CASE PRESENTATION: Here, we report a long-term follow-up of an 8.5-year-old prepubertal boy with a diagnosis of PJS, who presented with bilateral gynaecomastia, advanced bone age and accelerated growth velocity, and were found to have bilateral multifocal testicular microcalcifications. As the findings were compatible with LCCSCT, anastrozole was initiated. Gynaecomastia completely regressed and growth velocity and pubertal development were appropriate for age during follow-up. Testicular lesions slightly increased in size. After four years of medication, anastrozole was discontinued but was restarted due to the recurrence of gynaecomastia after six months. CONCLUSIONS: Testicular tumour should be investigated in a patient with PJS who presents with prepubertal gynaecomastia. When findings are consistent with LCCSCT, aromatase inhibitors may be preferred in the treatment.

Morphological Features and Immunohistochemical Profiling of Male Breast Gynaecomastia; A Large Tissue Microarray Study.

Introduction: Gynaecomastia is the commonest male breast condition accounting for approximately 85% of male breast lesions. There is minimal information on the immunohistochemical profile of gynaecomastia. We aimed to comprehensively profile a large series of gynaecomastia samples for putative mammary diagnostic, predictive and prognostic markers. Methods: A total of 156 samples, were histologically reviewed, assembled onto tissue microarrays, and stained for oestrogen receptors (ERα, ERß1, ERß2), progesterone receptors (total PR, PRα), androgen receptor (AR), basal & luminal cytokeratins (CK5/6, CK14, CK8/18) and the proliferation marker Ki67. Relevant cut offs for marker positivity were defined based on existing literature: AR (10%), ERα and PR (Allred score >3/8), ERß (10% and 20%), cytokeratins (10%) and Ki67 (10% and 20%). Results: 108 samples from 86 patients aged 13-75 years were available for immunohistochemical assessment. 73.1% of the lesions were AR positive, compared to 99% for ERα and 100% for both ERß1 and ERß2. 98% of samples were positive for total PR and 97.1% for PRα. 69.8% expressed CK5/6 whilst 57% were CK14 positive. A tri-layered pattern of cytokeratin expression was also observed. Ki67 positivity was low with 17.1% and 6.7% classified as Ki67 positive using 10% and 20% cut off values respectively. A significant negative correlation was found between ERα expression and patient age (rs = -0.221, p=0.023). Bivariate correlations were produced, and comparisons made with previously published data regarding the immunohistochemical status in normal female breast tissue, proliferative and neoplastic breast diseases of the female and male breast. Conclusions: Hormone receptors, including oestrogen receptor α and ß isoforms as well as androgen receptors were abundantly expressed within the intraductal luminal hyperplastic epithelium in gynaecomastia supporting the hormonal role in the pathogenesis and treatment. ERα, ERß1 and ERß2 were expressed in a higher proportion of cells compared with their expression in the female breast benign lesions which further characterises gynaecomastia biology. The identification of a low Ki67 proliferative index and the mixed cytokeratin profile in gynaecomastia differentiates this benign condition from male breast cancer. Therefore, Ki67 and cytokeratins can help in the differential diagnosis from histological mimics in the routine diagnostic work up.

Radiological and pathological correlation of a rare case of primary breast follicular lymphoma in a male patient, presenting as gynaecomastia.

We present an exceptionally rare case of primary breast follicular lymphoma in a male patient, who presented to us with gynaecomastia for investigation. To our knowledge there have only been two other cases published in the literature to date. In Western Australia, there have been no cases in at least the past 10 years. This particular case highlights the importance of radiological and pathological correlation in making the diagnosis, particularly in the assessment of breast lumps in a male patient, where imaging and clinical findings alone could not make the diagnosis.

Male breast cancer: an update.

Male breast cancer (MBC) is rare, accounting for less than 1% of all breast cancer but the incidence has increased worldwide. Risk factors include increased longevity, obesity, testicular diseases and tumours, and germline mutations of BRCA2. BRCA2 carriers have 80 times the risk of the general population. Men generally present with breast cancer at an older age compared with women. Histologically, MBC is often of grade 2, hormone receptor positive, HER2 negative, and no special type carcinoma although in situ and invasive papillary carcinomas are common. Reporting and staging are similar to female breast cancer. Metastatic lesions to the male breast do occur and should be differentiated from primary carcinomas. Until recently, MBC was thought to be similar to the usual ER positive post-menopausal female counterpart. However, advances in MBC research and trials have highlighted significant differences between the two. This review provides an up to date overview of the biology, genetics, and histology of MBC with comparison to female breast cancers and differential diagnosis from histological mimics.

Assessing the impact of a gynaecomastia assessment and treatment infographic in primary care in Greater Manchester.

INTRODUCTION: Men with gynaecomastia are routinely referred to breast clinics, yet most do not require breast surgical intervention. The aim of this study was to assess the impact of a novel point-of-care gynaecomastia decision infographic in primary care on the assessment, management and referral practices to tertiary breast surgical services. METHODS: A study was carried out of male patient referrals from primary care in Greater Manchester to a tertiary breast centre between January and March in 2018-2020. Referral patterns were compared before and after the infographic went live in general practices in Greater Manchester in January 2020. Data were collected for gynaecomastia referrals, including aetiology, investigation and management. RESULTS: In total, 394 men were referred to a tertiary breast centre from 163 general practices, of which 271 (68.8%) had a diagnosis of gynaecomastia. Use of the decision infographic by primary healthcare providers was associated with a decrease in male breast referrals with gynaecomastia (79.6% to 62.0%). Fewer gynaecomastia patients were referred with a benign physiological or drug-related cause after implementation of the infographic (52.2% vs 41.8%). Only 10 (3.7%) patients with gynaecomastia underwent breast surgery during the study period. CONCLUSION: Implementation of a gynaecomastia infographic in primary care in Manchester was associated with a reduction in gynaecomastia referrals to secondary care. We hypothesise that implementation of the infographic into primary care nationally may potentially translate to hundreds of patients receiving more specialty-appropriate referrals, improving overall management of gynaecomastia. Further study is warranted to test this hypothesis.

Should the 'normal' and 'ideal' nipple position in a male influence the surgeon when planning severe gynaecomastia correction?

BACKGROUND: The ideal nipple areolar complex (NAC) position of the male chest following gynaecomastia surgery is well documented; however, with increased development of the chest muscles, the NAC placement can change, leading to the medial displacement of the nipple giving a poor aesthetic outcome. Therefore, we believe that these measurements need to be applied to the patients' build and take into consideration the future fitness goals of the patients. METHOD: We have analysed the photographs of three groups of men: super athletes, athletes and individuals with severe gynaecomastia. We have assessed the proportions of the chest in relation to the NAC, degree of ptosis and TAP index. RESULTS: There was a wide variation between the athlete and the super athlete group, with minor variations within each group. The range of measurement in the severe gynaecomastia group was significantly larger than those in the other groups. We feel that based on this research study, surgeons should however be somewhat circumspect in their choice of nipple position as there is a wide variation in what can be considered as normal, and positioning of the NAC too early in the recovery process may lead to an abnormal aesthetic appearance following muscle development. CONCLUSION: Despite the multitude of techniques available in the literature to determine the position of nipple, there is a lack of understanding on how the NAC position changes with muscle development. Adopting a dogmatic approach may result in a very aesthetically displeasing outcome, which can be very difficult to correct in men.

An atypical presentation of a pathogenic STK11 gene variant in siblings not fulfilling the clinical diagnostic criteria for Peutz-Jeghers Syndrome.

OBJECTIVES: To report an atypical presentation of a pathogenic STK11 gene variant in siblings not fulfilling the clinical diagnostic criteria for Peutz-Jeghers Syndrome (PJS). CASE PRESENTATION: Two siblings presented with prepubertal gynaecomastia and bilateral macro-orchidism, without mucocutaneous pigmentation or gastrointestinal symptoms. There was no family history of PJS. Sibling 1 had unilateral gynaecomastia. Sibling 2 had bilateral gynaecomastia, advanced bone age and bilateral testicular microlithiasis, not indicative of a large-cell calcifying Sertoli cell tumour. Genetics revealed a paternally inherited heterozygous pathogenic STK11 variant (910C>T) in both siblings. The diagnosis was confirmed following the identification of multiple intestinal polyps in their father. CONCLUSIONS: Prepubertal gynaecomastia and prepubertal macro-orchidism (testicular enlargement without virilisation), always warrant endocrinological investigation, with PJS being an important differential diagnosis. Children may not fulfil the clinical criteria for a diagnosis of PJS at presentation. Genetic testing and gastroenterological investigation of parents may aid diagnosis.

GYNAECOMASTIA APPEARED THREE DAYS AFTER STARTING METHIMAZOLE.

We reported that in a 29-year-old male patient with hyperthyroidism, bilateral breast swelling appeared in three days after starting methimazole and gradually aggravated. Several days later, a small amount of transparent liquid could be squeezed out from bilateral mammary glands. Breast ultrasound confirmed gynaecomastia. The level of testosterone, estradiol and luteinizing hormone increased. After the patient continued taking methimazole for a while, gynaecomastia relieved. Testosterone, luteinizing hormone and thyroid functions restored to normal. The possible mechanisms included increased levels of serum total cholesterol and relatively decreased T3 after initiating methimazole.

Possible association between methylphenidate treatment in a child with autism spectrum disorder and subsequent gynecomastia / Lehetséges összefüggés egy autizmusspektrum-zavarban érintett gyermek metilfenidát-kezelése és az azt követoen kialakult gynaecomastia között.

Összefoglaló. Bár a figyelemhiányos hiperaktivitási zavar kezelése során alkalmazott metilfenidát-monoterápiával összefüggésben jelentkezo gynaecomastiáról bizonyos nemkívánatos hatások adatbázisai beszámolnak, a szakirodalom áttekintése alapján ez idáig mindössze 5 esettanulmányt publikáltak a témában. Tanulmányunkban egy autizmusspektrum-zavarral és figyelemhiányos hiperaktivitási zavarral egyaránt diagnosztizált gyermek esetét mutatjuk be, akinél 6 hónapon át tartó, folyamatos metilfenidát-monoterápiájával összefüggésben kétoldali gynaecomastia kialakulását tapasztaltuk. A kezelés azonnali leállítása mellett 10 napos klomifénkezelés történt. A metilfenidát-terápia azonnali leállítását követoen 14 nappal a gynaecomastia mindkét oldalon visszahúzódott. 3 hónapos, gyermekpszichiátriai szempontból gyógyszermentes idoszakot követoen a metilfenidát-terápia újraindítása történt, de 1 hónap elteltével a nem kívánt mellékhatás ismét jelentkezett. A metilfenidát-terápia és a gynaecomastia kialakulása közötti kapcsolat számos mechanizmussal kapcsolatban kérdéseket vet fel. Gyermekpszichiátriai szempontból érdekes kérdés, hogy releváns lehet-e a gyógyszeres terápia következményeként kialakuló nemkívánatos mellékhatás megjelenésében az autizmusspektrum-zavar és a figyelemhiányos hiperaktivitási zavar komorbid fennállása. A jelenség hátterében felmerül továbbá a neuroendokrin-immunológiai rendszer szabályozásának esetleges megváltozása. Esettanulmányunk felhívja a gyakorló orvoskollégák figyelmét a metilfenidát-terápia alkalmazása mellett potenciálisan kialakuló gynaecomastia monitorozására. Orv Hetil. 2021; 162(42): 1703-1708. Summary. Although gynecomastia associated with methylphenidate monotherapy in the treatment of attention deficit hyperactivity disorder has already been reported in some adverse event databases, based on a review of the literature it appears that only five case reports have been published. In our study, we present the case of a child diagnosed with both autism spectrum disorder and attention deficit/hyperactivity disorder, who developed bilateral gynecomastia in association with continuous methylphenidate monotherapy for 6 months. With immediate cessation of methylphenidate therapy, clomiphene treatment was given for 10 days. A total of 14 days after cessation of methylphenidate treatment gynecomastia receded on both sides. After a methylphenidate drug-free period of 3 months, methylphenidate therapy was restarted, but 1 month later the side effect reappeared. The relationship between methylphenidate and the development of gynecomastia raises questions about a number of mechanisms. From a child psychiatrist point of view, it is an interesting question whether the presence of comorbid autism spectrum disorder and attention deficit/hyperactivity disorder may be relevant in the onset of adverse events by medication. The phenomenon may also be caused by altered regulation of the neuroendocrine-immune system. Our case report draws the attention of practicing physicians to monitoring of potential gynecomastia during methylphenidate therapy. Orv Hetil. 2021; 162(42): 1703-1708.

Gynaecomastia in a male neutered cat with an adrenal tumour and associated hyperprogesteronism, hypercortisolism and hyperaldosteronism.

CASE SUMMARY: A 7-year-old male neutered domestic longhair cat was presented with chronic progressive gynaecomastia, polydipsia, polyphagia, weight loss and poor fur regrowth. Sexualised behavioural changes were not reported and virilisation was not present on physical examination. Pertinent haematology, biochemistry and urinalysis findings at the time of referral included mild hypokalaemia. Left adrenomegaly and mild prostatomegaly were identified on a CT scan. Evaluation of adrenal hormones with a low-dose dexamethasone suppression test, serum progesterone, testosterone, oestradiol, plasma aldosterone, renin, plasma metanephrine and normetanephrine measurement supported a diagnosis of hyperprogesteronism, hyperaldosteronism and hypercortisolism. Adrenalectomy was performed and histopathology was consistent with an adrenocortical tumour. Clinical signs and hormone elevations resolved postoperatively. RELEVANCE AND NOVEL INFORMATION: To our knowledge, this is the second report of gynaecomastia secondary to an adrenal tumour in a male neutered cat and the first associated with hyperprogesteronism.

Incidence of gynaecomastia in Klinefelter syndrome adolescents and outcome of testosterone treatment.

The aim was to define the true incidence of gynaecomastia in adolescent boys with Klinefelter syndrome (KS) and to observe testosterone treatment effects on its duration by examination of the prospectively collected data from a specialist referral clinic for boys with KS, with comparison being made with KS boys identified by a historical newborn chromosome screening programme, together with chromosomally normal controls. Fifty-nine boys over age 13 years were referred to a specialist KS clinic; 21 developed gynaecomastia. The comparator was 14 KS boys identified at birth and 94 chromosomally normal control boys. Testosterone was routinely started at the onset of puberty if gynaecomastia, a manifestation of clinical hypogonadism, was present. Oral or transdermal testosterone was administered in the morning, in a reverse physiological rhythm, and doses were increased according to standard pubertal regimens. The incidence of gynaecomastia was not increased in both the KS cohorts compared with controls. The incidence and age of onset of gynaecomastia was 35.6%, at 12.3 (1.8) years in the KS clinic group; 36.0%, at 13.7 (0.6) years in the newborn survey group; and 34.0%, at 13.6 (0.8) years in the controls. Full resolution of the gynaecomastia occurred in the 12/14 KS clinic boys on testosterone treatment who had completed puberty and as long as adherence was maintained.Conclusion: The incidence of gynaecomastia in KS boys (overall 35.6%) is not increased over typically developing boys. Commencing testosterone when gynaecomastia develops with physiological dose escalation and full adherence can result in the resolution of the gynaecomastia. What is Known: • Gynaecomastia is a common feature in Klinefelter syndrome men. • Hypogonadism occurs from mid-puberty onwards with the absence of the usual rise in testosterone levels. What is New: • The incidence of pubertal gynaecomastia in Klinefelter syndrome is not different from typically developing boys. • Early and prompt starting of testosterone gel treatment and increasing the dose physiologically may help to resolve the gynaecomastia without the need for surgery.

Biochemical features of eugonadal patients with idiopathic gynaecomastia: A retrospective cross-sectional study.

Patients with idiopathic gynaecomastia have greater BMI and an unfavourable lipid profile compared with age-matched controls. Twenty-five adult eugonadal patients with idiopathic gynaecomastia and 50 age- and BMI-matched controls were selected. Clinical and biochemical parameters and ultrasound testis volume were reviewed retrospectively. Patients and controls differed for no biochemical parameter, except for LH levels, which were 31% higher in patients (p = 0.019), although within the normal range. Compared with controls, patients had a threefold greater rate of elevated LDL-c (p = 0.025). Patients ≥ 25 years had higher levels of serum LDL-c compared with either patients < 25 years (p = 0.006) or controls ≥ 25 years (p = 0.012). In patients, both at bivariate analysis and at linear regression, age correlated positively with total cholesterol and LDL-c, the latter correlated inversely with total testosterone. Negative interactions were found for age and total testosterone with LDL-c, for LH and estradiol to testosterone ratio (E2:T) with LDL-c, and for age and E2:T with total cholesterol. Our data suggest inadequate local androgen action in patients with idiopathic gynaecomastia. This partial androgen resistance might blunt the beneficial effects of testosterone on lipid metabolism. Further studies are needed to verify whether this metabolic derangement impacts the cardiovascular health of these patients.

Transition from gynaecomastia to lipomastia in pubertal boys.

OBJECTIVE: Gynaecomastia is frequent in pubertal boys and is regarded as a self-limiting abnormality. However, longitudinal studies proving this hypothesis are scarce. DESIGN: Longitudinal follow-up study (median 2.4, range 1.0-4.8 years). METHODS: The regression of breast diameter was analysed in 31 pubertal boys aged 11.7-16.1 (median 13.2) years with gynaecomastia. Furthermore, weight changes (as BMI-SDS) and pubertal stage, oestradiol [E2], oestriol, oestrone, androstenedione, testosterone [T], dihydrotestosterone, gonadotropins, IGF-1, and IGFBP-3 serum concentrations determined at first clinical presentation were related to breast diameter regression determined by palpation and disappearance of breast glandular tissue in ultrasound in follow-up to identify possible predictors of breast regression. RESULTS: During the observation period, the breast diameter decreased (in median -1 (interquartile range [IQR] -5 to +1) cm). At follow-up, 6% of boys had no breast enlargement any more, and 65% developed lipomastia. Gynaecomastia was still present in 29%. None of the analysed hormones was related significantly to breast diameter regression or disappearance of breast glandular tissue. In multiple linear regression analyses adjusted for observational period, as well as age and BMI-SDS at first presentation, changes in BMI-SDS (ß-coefficient 6.0 ± 2.3, p = .015) but not the E2/T ratio or any other hormone determined at baseline was related to changes in breast diameter. CONCLUSIONS: Breast diameter regression seems not to be predictable by a hormone profile in pubertal boys with gynaecomastia. In pubertal boys presenting with gynaecomastia, conversion to lipomastia of smaller volume is common. The reduction of weight status was the best predictor of breast diameter regression.

Structural analysis of the impact of a novel androgen receptor gene mutation in two adult patients with mild androgen insensitivity syndrome.

Androgen receptor gene (AR) mutations are responsible for androgen insensitivity syndrome (AIS) presenting with a clinical phenotype that ranges from gynaecomastia and/ or infertility in mild AIS (MAIS) to complete testicular feminisation in complete AIS. We report a novel AR gene mutation in two unrelated adult patients with MAIS and we studied its functional impact using 3D modelling. Patient 1, referred for infertility, presented with gynaecomastia, mild hypospadias and bilateral testicular hypotrophy contrasting with high testosterone levels, an elevated FSH, an elevated androgen sensitivity index (ASI) and oligoasthenoteratospermia. In vitro fertilisation and intracytoplasmic sperm injection resulted in a successful twin pregnancy. Patient 2 referred for a decrease in athletic performance had surgically treated gynaecomastia, oligoasthenospermia, high testosterone levels and an elevated ASI. Despite his impaired spermogram, he fathered two children without assisted reproductive technology. AR gene sequencing in the two patients revealed a common novel missense mutation, Ala699Thr, in exon 4 within the ligand-binding domain. 3D modelling studies showed that this mutation may impact dimer stability upon ligand binding or may affect allosteric changes upon dimerisation. This study illustrates the value of structural analysis for the functional study of mutations and expands the database of AR gene mutations.