HAIR-AN Syndrome Research Articles

Diagnosis of hyperandrogenism-insulin resistance-acanthosis nigricans syndrome during transition: a case report

Diagnosis of hyperandrogenism-insulin resistance-acanthosis nigricans syndrome during transition: a case report

HAIR-AN syndrome: about a case

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Efficacy of liraglutide in weight reduction in a patient with HAIR-AN syndrome - case report

Efficacy of liraglutide in weight reduction in a patient with HAIR-AN syndrome - case report

An adolescent girl with coexisting ovarian mature cystic teratoma and HAIR-AN syndrome, an extreme subtype of polycystic ovarian syndrome.

SummaryPolycystic ovarian syndrome (PCOS) is associated with menstrual irregularities, ovulatory dysfunction, hirsutism, insulin resistance, obesity and metabolic syndrome but is rarely associated with severe hyperandrogenaemia and virilisation resulting in male pattern baldness and clitoromegaly. Total serum testosterone greater than twice the upper limit of the reference range or free androgen index of over five-fold elevated suggests a diagnosis other than PCOS. We reported a case of a 15 years old obese girl presented with secondary amenorrhoea, virilising signs: frontal baldness, clitoromegaly and prominent signs of insulin resistance and marked acanthosis nigricans. Her total testosterone level was markedly elevated at 9.4 nmol/L (0.5–1.7 nmol/L) and MRI pelvis revealed a right ovarian mass with fat and cystic component and a left polycystic ovary. The patient underwent laparoscopic right ovarian cystectomy and histologically confirmed mature cystic teratoma. Post-operatively, her testosterone level declined but did not normalise, menses resumed but remained irregular. Her fasting insulin was elevated 85.2 mIU/L (3–25 mIU/L) and HOMA-IR was high at 13.1 (>2) with persistent acanthosis nigricans suggesting co-existing HAIR-AN syndrome, an extreme phenotype of polycystic ovarian syndrome.Learning pointsRapid onset of hyperandrogenic symptoms, especially if associated with signs of virilisation must raise the suspicion of an androgen-secreting tumour.Total serum testosterone greater than twofold the upper limit of the reference range or free androgen indices over fivefold suggest a diagnosis other than polycystic ovarian syndrome (PCOS).High levels of testosterone with normal levels of the DHEA-S suggest an ovarian source.Ovarian androgen-secreting tumour and HAIR-AN syndrome, an extreme spectrum of PCOS can co-exist.

Hyperandrogenism, Insulin Resistance, and Acanthosis Nigricans (HAIR-AN) Syndrome Reflects Adipose Tissue Dysfunction (“Adiposopathy” or “Sick Fat”) in Asian Indian Girls

Background: Whether HAIR-AN syndrome and polycystic ovarian syndrome (PCOS) are distinct entities or represent a phenotypic spectrum of the same syndrome is still unclear. HAIR-AN syndrome is characterized by high insulin resistance, obesity, and hyperinsulinemia as compared to PCOS and could represent adipose tissue dysfunction as the primary pathophysiologic trigger. This study was undertaken to study the role of adipose tissue dysfunction in HAIR-AN syndrome and PCOS using adipocytokines as surrogate markers of “adiposopathy.” Materials and Methods: A cross-sectional observational study was conducted at a tertiary care hospital over a period of 1 year. Serum adiponectin, leptin, IL-6, and TNF-α levels were measured in 30 women with HAIR-AN syndrome and in 30 women with PCOS. Correlations between adipocytokines, inflammatory markers, serum testosterone, and serum insulin were determined. Data analysis was performed using the SPSS version 23.0 (IBM SPSS Statistics Inc., Chicago, IL, USA) software program. Results: Women with HAIR-AN syndrome had significantly higher hyperandrogenemia, hyperinsulinemia, and insulin resistance as compared to PCOS women. They also had high leptin levels and lower adiponectin levels (p < 0.001). However, the levels of inflammatory markers (TNF-α and IL-6) were similar in both the groups (p > 0.05). Serum adiponectin showed a negative correlation with HOMA-IR and testosterone levels, while leptin showed a positive correlation with both in HAIR-AN patients while no such correlation was found in the PCOS group. Conclusion: The significantly raised adipocytokines in HAIR-AN syndrome patients as compared to PCOS patients indicates the primary role of adipose tissue dysfunction (“adiposopathy”) in the pathogenesis of HAIR-AN syndrome while only a minor role, if any, in PCOS. Both these syndromes stand as distinct entities pathogenically with an overlapping phenotype.

Liraglutide administration improves hormonal/metabolic profile and reproductive features in women with HAIR-AN syndrome.

SummaryHAIR-AN syndrome, the coexistence of Hirsutism, Insulin Resistance (IR) and Acanthosis Nigricans, constitutes a rare nosologic entity. It is characterized from clinical and biochemical hyperandrogenism accompanied with severe insulin resistance, chronic anovulation and metabolic abnormalities. Literally, HAIR-AN represents an extreme case of polycystic ovary syndrome (PCOS). In everyday practice, the management of HAIR-AN constitutes a therapeutic challenge with the available pharmaceutical agents. Specifically, the degree of IR cannot be significantly ameliorated with metformin administration, whereas oral contraceptives chronic administration is associated with worsening of metabolic profile. Liraglutide and exenatide, in combination with metformin, have been introduced in the management of significantly obese women with PCOS with satisfactory results. Based on this notion, we prescribed liraglutide in five women with HAIR-AN. In all participants a significant improvement regarding the degree of IR, fat depositions, androgen levels and the pattern of menstrual cycle was observed, with minimal weight loss. Furthermore, one woman became pregnant during liraglutide treatment giving birth to a healthy child. Accordingly, we conclude that liraglutide constitutes an effective alternative in the management of women with HAIR-AN.Learning points:HAIR-AN management is challenging and classic therapeutic regimens are ineffective.Literally HAIR-AN syndrome, the coexistence of Hirsutism, Insulin Resistance and Acanthosis Nigricans, represents an extreme case of polycystic ovary syndrome.In cases of HAIR-AN, liraglutide constitutes an effective and safe choice.

SUN-004 Case Study: A 17-year-old Girl with HAIR-AN Syndrome, T2DM and Primary Amenorrhea

Introduction: HAIR-AN syndrome is a sub-type of polycystic ovarian syndrome which consists of virilization, insulin resistance and acanthosis nigricans. It may be associated with menstrual irregularity, and hyperandrogenic features such as hirsutism and masculinization. Aim: We report an adolescent girl with HAIR-AN syndrome, T2DM, a very high testosterone level (male range) and primary amenorrhea Case report: A 17-year-old female who had been investigated by pediatric endocrinology since the age of 13 because of hyperpigmentation which was proven to be acanthosis nigricans on skin biopsy. The patient was found to have insulin resistance with initially normal glucose level. She has hirsutism and hypertrichosis. There is no similar condition in her family, she has three siblings all are well. She developed T2DM with at the age of 14. She was started on Metformin 2 gram daily and them pioglitazone 30 mg was added when she was 16 years. She never had menarche. The clinical examination revealed an adolescent girl with normal BP 106/68 mmHg, and BMI 19.6kg/m2. She scored 24 onFerriman-Gallwey hirsutism scoring system. She had severe acanthosis nigricans on both axillae. She also had back and upper limbs hyperpigmentation.Lab tests revealed normal thyroid function tests, prolactin, cortisol, DHEA-S, and 17 hydroxy progesterone. Fasting glucose 7.2, insulin 123 μU/ml (2.6-24.9), c-peptide 964, HbA1c 8.2%. Total testosterone 24.61 nmol/L (0.069-2.715), SHBG 184.9 nmol/L, and Free testosterone index 13.31 (0.51-6.53). Her LH 8.9 and FSH 4.7.Radiological investigations revealed polycystic ovaries on pelvic ultrasound. MRI abdomen showed normal adrenals, and mildly enlarged ovaries with peripherally located follicles consistent with polycystic ovarian syndrome. The patient was started in Diane-35 (cyproterone acetate and ethinyl estradiol) oral pills. She started to have menarche three months after using Diane-35. Her Total testosterone had dropped from 24.61 to 1.69 nmol/L (0.069-2.715), SHBG 579 nmol/L, and Free testosterone index 0.29 (0.51-6.53). She reported that the hirsutism is getting less than before starting the treatment.Conclusion: Primary amenorrhea might be a manifestation of in HAIR-AN syndrome due to sever hyperandrogenism. The management of such condition is challenging. In addition to controlling the metabolic parameters, combined oral pills with antiandrogen effect might be effective.

Hidradenitis suppurativa in a patient with hyperandrogenism, insulin-resistance and acanthosis nigricans (HAIR-AN syndrome)

The author reports a rare presentation of hidradenitis supprutiva (HS) in combination with hyperandrogenism, insulin-resistance and acanthosis nigricans (HAIR-AN syndrome) in a female patient. Recently many clues have improved the understanding of HS as a systemic disease rather as a disease only with dermatological manifestation. This report might give another hint emphasizing the endocrinological and hormonal role in HS.

HAIR-AN Syndrome: Inside Story

15-year-old adolescent girl presented with weight gain, irregular menstrual cycle, skin lesions suggestive of acanthosis nigricans and hirsutism. On evaluation, she was found to have elevated testosterone levels with normal FSH, LH and fasting blood sugar, decreased glucose insulin index suggestive of Insulin resistance. In view of above features, diagnosis of hyperandrogenism-insulin resistance-acanthosis nigricans syndrome (HAIR-AN syndrome) was made. This syndrome is considered as a sub-type of polycystic ovary syndrome (PCOS). HAIR-AN syndrome has varied presentation and is usually seen by primary care physician, gynaecologist or dermatologist. Life style modification with weight reduction and drugs such as metformin helps in alleviating the symptoms. With limited resources in our country, diagnosis is frequently delayed leading to systemic complications. Early diagnosis and appropriate treatment would help in preventing complications of obesity, insulin resistance leading to coronary artery disease, Type 2 diabetes mellitus, hyperlipidemia. Depression and suicidal behavior may be associated with it and should be aggressively addressed in young adults suffering from HAIR-AN syndrome.

Relationship between acne and insulin resistance

Acne is a chronic inflammatory disease of the pilosebaceous unit with predilection for adolescents. Hormones are the most important endogenous factor for the occurrence of acne. Recently, it has been found that besides androgen, insulin resistance and abnormal levels of insulin and insulin-like growth factor-1 (IGF-1) induced by insulin resistance were closely associated with acne. Concretely speaking, insulin and IGF-1 may participate in the occurrence of acne by indirectly stimulating androgen secretion and directly inducing keratinocyte proliferation, sebaceous lipogenesis and inflammatory responses. In addition, the fact that acne is an important clinical characteristic of some systemic diseases or syndromes, such as polycystic ovary syndrome (PCOS) and hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndrome, and associations of acne with diet, smoking and tumors, all provide evidence for the potential role of insulin resistance in the occurrence of acne. Key words: Acne vulgaris; Insulin-like growth factor I; Smoking; Food habits; Insulin resistance

Acanthosis Nigricans during an HAIR-AN syndrome: "The Tree That Hides the Forest"

Introduction: Acanthosis nigricans is broadly classified into malignant and benign forms. Recent attention has been directed toward its benign endocrine associations. Acanthosis nigricans is a significant marker for insulin resistance.Observation: A 20-years-old girl has consulted for macular, hyperpigmented, papillomatic lesions which were on the neck with overflows on the mandibular areas and the ears, in the vertebral groove, the armpits, and the umbilicus. These lesions were associated with a clinical syndrome of hyperandrogenism. The blood sample showed hyperglycemia at 1.3 g/dl, hyperprogesteronemia at 0.63 ng/mL, hypertestosteronemia at 0.87 ng/mL and hypercholesterolemia at 2.63 g/L. Ultrasound of the uterus showed polycystic ovaries. The diagnosis of HAIR-AN syndrome was concluded and the patient was treated.Conclusion: HAIR-AN syndrome is a rare condition which is characterized by an unusual multisystem disorder in women.

Sex hormones and acne

The skin is an endocrine organ with the expression of metabolizing enzymes and hormone receptors for diverse hormones. The sebaceous gland is the main site of hormone biosynthesis, especially for androgens, and acne is the classical androgen-mediated dermatosis. In sebocytes, conversion of 17-hydroxyprogesterone directly to dihydrotestosterone bypassing testosterone has been demonstrated, while type II 17β-hydroxysteroid dehydrogenase can inactivate the action of testosterone and dihydrotestosterone. The androgen receptor–dependent genomic effect of dihydrotestosterone on sebocytes is confirmed. Further evidence supports the PI3 K/Akt/FoxO1/mTOR signaling in the involvement of the interplay between androgens, insulin, insulin-like growth factor, and hyperglycemic diet in acne. Androgens not only regulate embryology and lipogenesis/sebum synthesis in sebocytes but also influence inflammation in acne. Genetic studies indicate that regulation of the androgen receptor is an important factor in severe acne. Further studies are required to understand the effect of estrogen and progesterone on sebaceous gland and comedogenesis, considering the change of acne in pregnancy and postmenopausal acne. Special attention should be paid to nonobese patients with polycystic ovarian syndrome and hyperandrogenism-insulin resistance-acanthosis nigricans syndrome. In spite of extensive gynecologic experience in the use of combined oral contraceptives for acne, evidence based on dermatologic observation should be intensified.

HAIR-AN Syndrome Associated with Scleroderma

The HAIR-AN syndrome is a rare multisystem disorder in women, that consists of hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). The IR is likely due to a primary defect of the insulin receptor. We report the case of a 25-year-old Caucasian woman with HAIR-AN syndrome, impaired glucose tolerance (IGT), mild hyperlipemia, and hypertension, associated with sclerodermatous skin changes on the extremities and trunk. Though scleroderma may coexist with other autoimmune diseases, its presentation with HAIR-AN syndrome has not yet been described.

Hyperandrogenism-Insulin Resistance-Acanthosis Nigricans Syndrome.

Introduction. Female hyperandrogenism is a frequent motive of consultation. It is revealed by hirsutism, acne or seborrhea, and disorders in menstruation cycle combined or not with virilisation signs. Several etiologies are incriminated but the hyperandrogenism-insulin resistance-acanthosis nigricans syndrome is rare. Observation. A 20-year-old girl, having had a five-year-old secondary amenorrhea. The exam revealed a patient, normotensive with a body mass index at 30 kg/m2 and a waist measurement of 120 cm, a severe hirsutism assessed to be 29 according to Ferriman Gallwey scale, virilisation signs of male morphotype, clitoridic hypertrophy and frontal alopecia, and an acanthosis nigricans behind the neck, in the armpits and elbows. The assessment carried out revealed testosteronemia at 1.28 ng/mL, which is more than twice the upper norm of the laboratory. Imaging studies were negative for both ovarian and adrenal masses. The retained diagnosis is HAIR-AN syndrome probably related to ovarian hyperthecosis and she was provided with androcur 50 mg/day and estradiol pills 2 mg/day and under hygiene-dietetic conditions. Conclusion. This case proves that HAIR-AN syndrome could be responsible for severe hyperandrogenism with virilisation signs. It must be retained after discarding the tumoral causes and when there are signs of insulin resistance.

Acne as a chronic systemic disease

Acne is the most common skin disorder. In the majority of cases, acne is a disease that changes its skin distribution and severity over time; moreover, it can be a physically (scar development) and psychologically damaging condition that lasts for years. According to its clinical characteristics, it can be defined as a chronic disease according to the World Health Organization criteria. Acne is also a cardinal component of many systemic diseases or syndromes, such as congenital adrenal hyperplasia, seborrhea-acne-hirsutism-androgenetic alopecia syndrome, polycystic ovarian syndrome, hyperandrogenism-insulin resistance-acanthosis nigricans syndrome, Apert syndrome, synovitis-acne-pustulosis-hyperostosis-osteitis syndrome, and pyogenic arthritis-pyoderma gangrenosum-acne syndrome. Recent studies on the Ache hunter gatherers of Paraguay detected the lack of acne in association with markedly lower rates of obesity, diabetes mellitus, hyperlipidemia, and cardiovascular diseases, a finding that indicates either a nutritional or a genetic background of this impressive concomitance.

The clinical evaluation of hirsutism

Hirsutism is a disorder of excess growth of terminal hairs in androgen-dependent areas in women. Other cutaneous conditions associated with androgen excess are androgenetic alopecia, acanthosis nigricans, and acne. Hirsutism is often associated with measurably elevated androgen levels, but not in all cases. Androgens in women arise from the ovary and adrenal glands, and peripherally from skin and fat. The most common cause of hirsutism is polycystic ovarian syndrome. Patients with "idiopathic" hirsutism have normal ovulatory cycles and androgen levels. Other causes are late onset congenital adrenal hyperplasia, Cushing's syndrome, and the HAIR-AN syndrome. Pituitary, ovarian, and adrenal tumors are important, but rare causes of hirsutism. A thorough history and examination are important. Laboratory investigation is essential in women with moderate to severe, sudden onset or rapidly progressing hirsutism. Identification of the underlying etiology does not alter management, but detects patients at risk for infertility, diabetes, cardiovascular disease and endometrial carcinoma.

Navigating Adolescence with a Chronic Health Condition: A Perspective on the Psychological Effects of HAIR-AN Syndrome on Adolescent Girls

HAIR-AN syndrome is a subphenotype of polycystic ovary syndrome and is characterized by acne, obesity, hirsutism, and acanthosis nigricans. It usually manifests in early adolescence, a time of significant developmental change in females across physical, cognitive, social, and emotional domains. We contend that adolescent development for females is difficult, even in the best of circumstances, and having a chronic health condition, like HAIR-AN syndrome, will likely impact the afflicted individuals development and psychological well-being. While many researchers have discussed the long-term health effects of HAIR-AN and similar disorders, little has been written about the potential psychological sequelae of HAIR-AN on the adolescent girl. We discuss the normal developmental sequence for adolescent girls across early, middle, and late adolescence; discuss common mental health problems that adolescents experience; define HAIR-AN syndrome and its clinical manifestations; and discuss its likely psychological impact on adolescent girls. We also make suggestions for future clinical interventions and research in the area of HAIR-AN syndrome and its psychological sequelae.

Androgen Excess Disorders in Women: The Severe Insulin-Resistant Hyperandrogenic Syndrome, HAIR-AN

HAIR-AN syndrome (hyperandrogenism, insulin resistance, acanthosis nigricans) is a subset of the polycystic ovary syndrome, where the patients demonstrate severe insulin resistance. It is theorized that both genetic and environmental factors, such as obesity, give rise to the development of HAIR-AN. Diagnosis is primarily clinical, with laboratory values lending further support. Treatment is aimed at decreasing insulin resistance, regulating ovulation, and decreasing acne, acanthosis nigricans, and hirsutism.

Biliopancreatic Diversion as a Novel Approach to the HAIR-AN Syndrome

The HAIR-AN syndrome is a rare multisystem disorder in women, that consists of hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). The IR is likely due to a primary defect of the insulin receptor. We report the case of a 42-year-old Caucasian woman with HAIR-AN syndrome, impaired glucose tolerance (IGT), mild hyperlipemia, and hypertension, who underwent biliopancreatic diversion (BPD). Within 24 months follow-up after BPD, impaired glucose tolerance, mild hyperlipemia, and hypertension completely reversed. Although insulin sensitivity, estimated by the euglycemic hyperinsulinemic clamp, did not improve, signs and symptoms of hyperandrogenism and acanthosis nigricans resolved fully. In HAIR-AN syndrome, malabsorptive bariatric surgery is effective in improving hyperandrogenism and acanthosis nigricans, with noteworthy esthetic consequences. BPD was followed by disappearance of co-morbidities of the syndrome, such as IGT, hypertension and hyperlipemia.

Islets secretory capacity determines glucose homoeostasis in the face of insulin resistance.

Debate surrounds the relative importance of impaired beta-cell secretory function versus insulin resistance in type 2 diabetes. We therefore defined insulin secretion and sensitivity in patients with impaired glucose homoeostasis of varying aetiology and duration. 126 consecutive patients undergoing an oral glucose tolerance test (OGTT) between 1999 and 2003 were included. Whole-body insulin sensitivity index (ISI) and insulinogenic index derived from the OGTT were determined in 32 healthy controls, 65 type 2 diabetic patients, 15 patients with acromegaly, 10 patients with insulinoma, and 4 patients with HAIRAN syndrome. Median ISI (quartiles Q25-Q75) of healthy controls and of patients with insulinoma were similar (3.5 [2.8-5.6] and 3.2 [1.7-4.2] respectively) but significantly decreased in patients with acromegaly, type 2 diabetes, and HAIRAN syndrome (2.8 [1.8-3.3], 1.9 [1.4-3], and 0.8 [0.6-1.3] respectively). Despite the decrease in ISI, patients with HAIRAN syndrome and acromegaly maintained normal glucose tolerance by adapting insulin secretion as reflected in the insulinogenic index (106.5 [90.4-127.5] and 49 [24.4-89] in HAIRAN and acromegaly respectively, versus 46.9 [27.3-66.7] in controls). In contrast, type 2 diabetic patients failed to adapt and displayed severely hampered insulin secretion (insulinogenic index of 7.6 [3.8-14.7]). Furthermore, the level of the insulinogenic index correlated significantly with duration of diabetes and HbA1c, which was not the case for the ISI. Insulinoma patients had a decreased insulinogenic index (38.7 [32-83.8]), leading to impaired glucose tolerance despite normal ISI. The data are compatible with the notion that beta-cell function rather than insulin sensitivity determines the evolution of hyperglycaemia.