Clinical management of androgen excess and defect in women.

INTRODUCTION: Hyperandrogenism and hypoandrogenism are complex disorders involving multiple-organ systems. While androgen excess is a well-characterized condition, androgen deficiency still needs diagnostic criteria, as there are no specific cutoffs. AREAS COVERED: We highlight the most recent findings on the role of androgens in female pathophysiology, investigating clinically relevant conditions of androgen insufficiency or excess throughout a woman's life, and their possible therapeutic management. EXPERT OPINION: Combined oral contraceptives (COCs) should be considered as first-line therapy for the management of menstrual irregularity and/or clinical hyperandrogenism in adolescents with a clear diagnosis of polycystic ovary syndrome (PCOS). There are limited evidence-based data regarding specific types or doses of COCs for management of PCOS in women; however, the lowest effective estrogen dose should be considered for treatment. Despite evidence regarding safety, efficacy, and clinical use, testosterone therapy has not been approved for women by most regulatory agencies for treatment of hypoactive sexual desire disorder (HSDD). The long-term safety for treatments with testosterone is still to be evaluated, and this review highlights the need for more research in this area.

Spotlight on Compounded Bioidentical Hormones.

BACKGROUND: The role of hormonal replacement therapy in menopause is under debate. The premature closure of the Women's Health Initiative (WHI) study in 2002 is still a source of concern among treating physicians. OBJECTIVES: The interest in alternatives to conventional hormone therapy has significantly increased. The adoption of personalized steroid hormone galenic preparations, formulated by compounding pharmacies, has recently spread. METHODS: In June 2023, an extensive literature search was conducted by different authors to identify relevant studies in various databases (MEDLINE, Embase, PubMed, and Cochrane). The studies that met the inclusion and exclusion criteria were further analyzed, and relevant data were extracted and analyzed for each paper. Any discrepancies between the investigators were resolved through a consensus approach. OUTCOMES: The primary outcomes observed included the clinical utility of CBHT. This study reviewed the current evidence on the utility of compounded bioidentical hormones, concluding that improving knowledge and awareness of bioidentical hormones is necessary to consider their use in clinical practice. CONCLUSION AND OUTLOOK: These formulations might provide effective options to best tailor therapies to each patient.

Pituitary adenoma consistency affects postoperative hormone function: a retrospective study.

BACKGROUND: Tumor consistency recently emerged as a key factor in surgical planning for pituitary adenomas, but its impact on postoperative endocrine function is still unclear. Our study aimed to evaluate the impact of tumor consistency on the development of postoperative pituitary deficiencies. METHODS: Single-center, retrospective analysis of consecutive pituitary surgeries performed between January 2017 and January 2021 at Policlinico Umberto I in Rome. All patients underwent radiological and biochemical evaluations at baseline, and hormone assessments 3 and 6 months after pituitary surgery. Postoperative MRI studies were used to determine resection rates following surgery. Data on tumor consistency, macroscopic appearance, neurosurgical approach, and intraoperative complications were collected. RESULTS: Fifty patients [24 women, mean age 57 ± 13 years, median tumor volume 4800 mm3 [95% CI 620-8828], were included. Greater tumor volume (χ2 = 14.621, p = 0.006) and male sex (χ2 = 12.178, p < 0.001) were associated with worse preoperative endocrine function. All patients underwent transsphenoidal adenomectomy. Fibrous consistency was observed in 10% of patients and was associated with a Ki-67 greater than 3% (χ2 = 8.154, p = 0.04), greater risk of developing postoperative hormone deficiencies (χ2 = 4.485, p = 0.05, OR = 8.571; 95% CI: 0.876-83.908), and lower resection rates (χ2 = 8.148, p = 0.004; OR 1.385, 95% CI; 1.040-1.844). Similarly, worse resection rates were observed in tumors with suprasellar extension (χ2 = 5.048, p = 0.02; OR = 6.000, 95% CI; 1.129-31.880) and CSI (χ2 = 4.000, p = 0.04; OR = 3.857, 95% CI; 0.997-14.916). CONCLUSIONS: Tumor consistency might provide useful information about postoperative pituitary function, likely due to its impact on surgical procedures. Further prospective studies with larger cohorts are needed to confirm our preliminary findings.

Fertility in Acromegaly: A Single-Center Experience of Female Patients During Active Disease and After Disease Remission.

CONTEXT: Fertility represents a major concern in patients with acromegaly. OBJECTIVE: The current retrospective study aimed to investigate gonadal function and fertility rates in acromegalic women. METHODS: In this referral-center study, 50 acromegalic women with disease onset within reproductive age were evaluated for prevalence of gonadal dysfunction and infertility. Anthropometric, metabolic, hormonal parameters, and gynecological ultrasound were evaluated at diagnosis and after disease control. Data about menstrual disturbances, pregnancy, and polycystic ovarian morphology (PCOM) were investigated at disease onset, at diagnosis, and after disease control. RESULTS: At presumed disease onset, menstrual disturbances were reported in 32% of patients. Uterine leiomyoma, ovarian cysts, and PCOM were diagnosed in 18%, 12%, and 8%, respectively; 36.8% of patients were infertile. At diagnosis, menstrual disturbances were found in 58.1% (P = .02), being significantly more prevalent in patients with higher insulin-like growth factor-I quartiles (Q) (P = .03, Q1 vs Q4). Gynecological ultrasound revealed uterine leiomyoma, ovarian cysts, and PCOM in 39.1% (P = .04), 28.2% (P = .09), and 13% (P = .55), respectively. The infertility rate was 100% (P = .02). At disease control, menstrual disturbances were slightly decreased as compared to diagnosis (P = .09). Noteworthy, menstrual disturbances (P = .05) and particularly amenorrhea (P = .03) were significantly more frequent in patients with active disease duration greater than 5 years (median) as compared to those achieving disease control in less than 5 years. Among patients with pregnancy desire, 73.3% conceived at least once, with resulting infertility significantly decreased compared to diagnosis (26.7%; P = .01). At-term deliveries, preterm deliveries, and spontaneous abortions were recorded in 86.7%, 6.6%, and 6.6%, respectively, of the 15 pregnancies reported by the patients. No neonatal malformations and/or abnormalities were recorded. CONCLUSION: Gonadal dysfunction and infertility are common in acromegalic women within reproductive age, being directly influenced by disease status and/or duration.

Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool.

Objective: Registry data show that Cushing's syndrome (CS) and adrenal insufficiency (AI) increase mortality rates associated with infectious diseases. Little information is available on susceptibility to milder forms of infections, especially those not requiring hospitalization. This study aimed to investigate infectious diseases in patients with glucocorticoid disorders through the development of a specific tool. Methods: We developed and administered the InfeCtions in pAtients with endocRinOpathies (ICARO) questionnaire, addressing infectious events over a 12-month observation period, to 1017 outpatients referred to 4 University Hospitals. The ICARO questionnaire showed good test-retest reliability. The odds of infection (OR (95% CI)) were estimated after adjustment for confounders and collated into the ICARO score, reflecting the frequency and duration of infections. Results: In total, 780 patients met the inclusion criteria: 43 with CS, 32 with adrenal incidentaloma and mild autonomous cortisol secretion (MACS), and 135 with AI, plus 570 controls. Compared to controls, CS was associated with higher odds of urinary tract infections (UTIs) (5.1 (2.3-9.9)), mycoses (4.4 (2.1-8.8)), and flu (2.9 (1.4-5.8)). Patients with adrenal incidentaloma and MACS also showed an increased risk of UTIs (3.7 (1.7-8.0)) and flu (3.2 (1.5-6.9)). Post-dexamethasone cortisol levels correlated with the ICARO score in patients with CS. AI was associated with higher odds of UTIs (2.5 (1.6-3.9)), mycoses (2.3 (1.4-3.8)), and gastrointestinal infections (2.2 (1.5-3.3)), independently of any glucocorticoid replacement dose. Conclusions: The ICARO tool revealed a high prevalence of self-reported infections in patients with glucocorticoid disorders. ICARO is the first of its kind questionnaire, which could be a valuable tool for monitoring infections in various clinical settings.

Effects of licorice on sex hormones and the reproductive system.

OBJECTIVES: The potential clinical effects of licorice (Glycyrrhiza spp.) and its extracts have been investigated since ancient times. Whether pseudohyperaldosteronism, with consequent arterial hypertension, is the only endocrine effect produced by licorice is uncertain, and a role in the reproductive system has been proposed. This review aimed to summarize the current knowledge on the pharmacologic effects of licorice on male and female reproductive systems. METHODS: Overall, 1462 records were extracted from electronic databases and systematically examined. A total of 28 studies were included in the final analysis. RESULTS: Preclinical and clinical studies revealed estrogen-like activity of licorice components, especially flavonoids, isoflavonoids, and chalcones, showing a potential role of licorice in ameliorating symptoms associated with estrogen insufficiency. Preclinical studies also showed weak antiandrogen properties and beneficial effects of licorice on gonadal function in both sexes, but clinical studies yield to poor and conflicting results depending on the type and dose of licorice. CONCLUSIONS: Licorice consumption can affect the reproductive system. However, its role needs to be further explored, especially due to the great variability of bioactive compounds used in existing studies.

Selenium Supplementation in Pregnant Women with Autoimmune Thyroiditis: A Practical Approach.

Selenium (Se) is an essential trace element with antioxidant and anti-inflammatory properties and a pivotal role in thyroid metabolism. Ensuring a sufficient Se supply is possible via a balanced, wholesome diet; however, Se content in foods may be different throughout geographical areas. Se supplementation is expected to improve inflammatory status in patients with autoimmune thyroiditis, especially in those with high activity, and has been demonstrated as effective in reducing the thyroid peroxidase antibodies titer. Se status seems to affect thyroid function in pregnancy, which prompts the potential role of Se supplementation in such patients. Few clinical trials have investigated the effectiveness of Se supplementation in pregnant women with thyroiditis, and their results suggest the safety and effectiveness of this element in reducing autoantibody levels and preventing postpartum thyroiditis development, although limited. Hence, more robust evidence is needed to confirm these data. The current study aims to summarize published data on the relationship between Se and thyroid status in pregnant women with thyroiditis and the potential use of Se. Moreover, an algorithm for Se supplementation is proposed for pregnant women with thyroiditis to help endocrinologists in daily clinical practice to consider Se status.

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors.

Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.

Paediatric Cushing's disease: Epidemiology, pathogenesis, clinical management and outcome.

Cushing's disease (CD) is rare in paediatric practice but requires prompt investigation, diagnosis and therapy to prevent long-term complications. Key presenting features are a change in facial appearance, weight gain, growth failure, virilization, disturbed puberty and psychological disturbance. Close consultation with an adult endocrinology department is recommended regarding diagnosis and therapy. The incidence of CD, a form of ACTH-dependent Cushing's syndrome (CS), is equal to approximately 5% of that seen in adults. The majority of ACTH-secreting adenomas are monoclonal and sporadic, although recent studies of pituitary tumours have shown links to several deubiquitination gene defects. Diagnosis requires confirmation of hypercortisolism followed by demonstration of ACTH-dependence. Identification of the corticotroph adenoma by pituitary MRI and/or bilateral inferior petrosal sampling for ACTH may contribute to localisation before pituitary surgery. Transsphenoidal surgery (TSS) with selective microadenomectomy is first-line therapy, followed by external pituitary irradiation if surgery is not curative. Medical therapy to suppress adrenal steroid synthesis is effective in the short-term and bilateral adrenalectomy should be considered in cases unfit for TSS or radiotherapy or when urgent remission is needed after unsuccessful surgery. TSS induces remission of hypercortisolism and improvement of symptoms in 70-100% of cases, particularly when performed by a surgeon with experience in children. Post-TSS complications include pituitary hormone deficiencies, sub-optimal catch-up growth, and persisting excess of BMI. Recurrence of hypercortisolism following remission is recognised but infrequent, being less common than in adult CD patients. With experienced specialist medical and surgical care, the overall prognosis is good. Early referral to an experienced endocrine centre is advised.

The Immune System in Cushing's Syndrome.

Cushing's syndrome (CS), or chronic hypercortisolism, induces a variety of alterations in the immune system, often leading to severe clinical complications such as sepsis and opportunistic infections. Prolonged exposure to high levels of glucocorticoids (GC), changes in the circadian rhythm, and the comorbidities associated therewith all combine to cause profound changes in the immune profile of affected patients. While traditionally associated with generalized immune suppression, such changes actually comprise a much more complex scenario, sharing traits with chronic inflammatory disorders. Persistently increased levels of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα) and adipose tissue infiltration by immune cells lead to a chronic, nonresolving, inflammatory state. The combination of low-grade inflammation and selectively impaired immune response is thought to play a major role in the pathogenesis of clinical complications of CS, including diabetes, lipodystrophy, visceral adiposity, atherosclerosis, osteoporosis, and cognitive impairment. This dysregulation also explains rebound phenomena when CS is treated, involving new clinical complications sustained by an excessive immune response and autoimmunity. The aim of this review is to summarize the available evidence on the immune system in chronic hypercortisolism, while describing the main mechanisms of immune derangement and their role in the increased mortality and morbidity seen in this complex disease. A better understanding of immune system alterations in CS could help improve risk stratification, offer novel biomarkers, and provide the basis for more tailored therapies and post-remission follow-up.

Late Effects of Parasellar Lesion Treatment: Hypogonadism and Infertility.

Central hypogonadism, also defined as hypogonadotropic hypogonadism, is a recognized complication of hypothalamic-pituitary-gonadal axis damage following treatment of sellar and parasellar masses. In addition to radiotherapy and surgery, CTLA4-blocking antibodies and alkylating agents such as temozolomide can also lead to hypogonadism, through different mechanisms. Central hypogonadism in boys and girls may lead to pubertal delay or arrest, impairing full development of the genitalia and secondary sexual characteristics. Alternatively, cranial irradiation or ectopic hormone production may instead cause early puberty, affecting hypothalamic control of the gonadostat. Given the reproductive risks, discussion of fertility preservation options and referral to reproductive specialists before treatment is essential. Steroid hormone replacement can interfere with other replacement therapies and may require specific dose adjustments. Adequate gonadotropin stimulation therapy may enable patients to restore gametogenesis and conceive spontaneously. When assisted reproductive technology is needed, protocols must be tailored to account for possible long-term gonadotropin insufficiency prior to stimulation. The aim of this review was to provide an overview of the risk factors for hypogonadism and infertility in patients treated for parasellar lesions and to give a summary of the current recommendations for management and follow-up of these dysfunctions in such patients. We have also briefly summarized evidence on the physiological role of pituitary hormones during pregnancy, focusing on the management of pituitary deficiencies.

Abnormal linear growth in paediatric adrenal diseases: Pathogenesis, prevalence and management.

Abnormal adrenal function can interfere with linear growth, potentially causing either acceleration or impairment of growth in paediatric patients. These abnormalities can be caused by direct effects of adrenal hormones, particularly glucocorticoids and sex steroids, or be mediated by indirect mechanisms such as the disturbance of the growth hormone-insulin-like growth factor-1 axis and aromatization of androgens to oestrogens. The early diagnosis and optimal treatment of adrenal disorders can prevent or minimize growth disturbance and facilitate improved height gain. Mechanisms of growth disturbance in the following abnormal states will be discussed; hypercortisolaemia, hyperandrogenaemia and obesity. Prevalence and features of growth disturbance will be discussed in ACTH-dependent and ACTH-independent Cushing's syndrome, adrenocortical tumours, premature adrenarche, congenital adrenal hyperplasia and adrenal insufficiency disorders. Recommendations for management have been included.

Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas.

BACKGROUND: Low-grade incomplete post-dexamethasone cortisol suppression in patients with adrenal incidentalomas - recently defined as possible autonomous cortisol secretion (pACS) - has been associated with increased cardiovascular events and mortality. However, prospective studies documenting cardiac abnormalities in these patients are lacking. SUBJECTS AND METHODS: Between July 2016 and September 2017, 71 consecutive patients with adrenal lesions were prospectively screened for hypercortisolism by dexamethasone suppression test (NCT 02611258). Complete anthropometric, metabolic and hormonal parameters were recorded along with full cardiac ultrasound assessment and noninvasive measurement of arterial stiffness. All patients underwent chemical-shift magnetic resonance imaging to characterize the lesions. Cardiovascular outcomes were recorded in blind. RESULTS: According to post-dexamethasone suppression cortisol values (post-DST), 34 patients had pACS and 37 non-functioning adenomas (NFA). The two groups were similar in sex, BMI, age distribution, cardiovascular risk factors and comorbidities. Left ventricular mass index (LVMIBSA) was increased in pACS compared to NFA (P = 0.006) and mildly correlated to the post-DST cortisol level (rho = 0.347; P = 0.004). The post-DST cortisol levels explained up to 13.7% of LVMIBSA variance (P = 0.002). Compared to NFA, patients with pACS had a higher prevalence of diastolic dysfunction (35.1% vs 82.6%; P = 0.001) and worse arterial stiffness assessed by pulse wave velocity (P = 0.033). CONCLUSIONS: In apparently asymptomatic patients, mild autonomous cortisol secretion can sustain early cardiac and vascular remodeling, independently of other risk factors. The morphological and functional cardiovascular changes observed in pACS underline the need for further studies to correctly define the long-term management of this relatively common condition.

Somatic and germline mutations in NETs: Implications for their diagnosis and management.

It is now understood that specific somatic and germline mutations may lead to the development of the neuroendocrine tumours (NETs). NETs usually occur as sporadic isolated tumours, although they also may present as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2), Von Hippel-Lindau (VHL) and neurofibromatosis syndromes, tuberous sclerosis, Carney triad and dyad, Reed syndrome and polycythaemia-paraganglioma syndromes. Only in MEN2 syndrome is there a specific genotype-phenotype correlation, although in both sporadic and syndromic NETs some gene mutations are associated with specific clinico-pathological features and prognosis. There have been several advances in our understanding of the NETs leading to earlier detection and targeted therapeutic treatment, but given the poor prognosis associated with metastatic NETs, it will be necessary to find new biomarkers for the prediction of malignant potential and to find novel therapeutic targets for NETs.