Sex Disparities in COVID-19 Severity and Outcome: Are Men Weaker or Women Stronger?

The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health issue which has profound effects on most aspects of societal well-being, including physical and mental health. A plethora of studies globally have suggested the existence of a sex disparity in the severity and outcome of COVID-19 patients, mainly due to mechanisms of virus infection, immune response to the virus, development of systemic inflammation, and consequent systemic complications, particularly thromboembolism. Epidemiological data report a sex difference in the severity of COVID-19, with a more favorable course of the disease in women compared to men regardless of age, although the rate of SARS-CoV-2 infection seems to be similar in both sexes. Sex hormones, including androgens and estrogens, may not only impact virus entry and load, but also shape the clinical manifestations, complications, and ultimately the outcome of the disease. The current review comprehensively summarizes the current literature on sex disparities in susceptibility and outcome of COVID-19 as well as the literature underpinning the pathophysiological and molecular mechanisms, which may provide a rationale to a sex disparity. These mechanisms include sex hormone influence on factors that facilitate virus entry and priming, immune and inflammatory response, as well as coagulation and thrombosis diathesis. Based on present evidence, women appear to be relatively protected from COVID-19 because of a more effective immune response and a less pronounced systemic inflammation, with consequent moderate clinical manifestations of the disease, together with a lesser predisposition to thromboembolism. Conversely, men appear to be particularly susceptible to COVID-19 because of a less effective immune response with consequent severe clinical manifestations of the disease, together with a greater predisposition to thromboembolism. In the elderly, generally characterized by the phenomenon of inflammaging, sex disparities in overall mortality following SARS-CoV-2 infection are even more palpable as elderly men appear to be more prone to severe COVID-19 because of a greater predisposition to infections, a weaker immune defense, and an enhanced thrombotic state compared to women. The information revealed from the review highlights potential novel therapeutic approaches employing the administration of hormonal or antihormonal therapy in combination with antiviral drugs in COVID-19 patients.

Dopamine Agonists: From the 1970s to Today.

The discovery of dopamine inhibitory effects on prolactin secretion has led to an era of successful dopaminergic therapy for prolactinomas. Herein we provide an overview of the evolution of dopamine agonists and their use in patients with PRL-secreting pituitary tumors, starting from the 1970s up to today, highlighting that normalization of PRL levels, restoration of eugonadism, and reduction of tumor mass can be achieved in the majority of patients by treatment with dopamine agonists.

Complications of acromegaly: cardiovascular, respiratory and metabolic comorbidities.

Acromegaly is associated with an enhanced mortality, with cardiovascular and respiratory complications representing not only the most frequent comorbidities but also two of the main causes of deaths, whereas a minor role is played by metabolic complications, and particularly diabetes mellitus. The most prevalent cardiovascular complications of acromegaly include a cardiomyopathy, characterized by cardiac hypertrophy and diastolic and systolic dysfunction together with arterial hypertension, cardiac rhythm disorders and valve diseases, as well as vascular endothelial dysfunction. Biochemical control of acromegaly significantly improves cardiovascular disease, albeit completely recovering to normal mainly in young patients with short disease duration. Respiratory complications, represented mainly by sleep-breathing disorders, particularly sleep apnea, and respiratory insufficiency, frequently occur at the early stage of the disease and, although their severity decreases with disease control, this improvement does not often change the indication for a specific therapy directed to improve respiratory function. Metabolic complications, including glucose and lipid disorders, are variably reported in acromegaly. Treatments of acromegaly may influence glucose metabolism, and the presence of diabetes mellitus in acromegaly may affect the choice of treatments, so that glucose homeostasis is worth being monitored during the entire course of the disease. Early diagnosis and prompt treatment of acromegaly, aimed at obtaining a strict control of hormone excess, are the best strategy to limit the development or reverse the complications and prevent the premature mortality.

The effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly.

INTRODUCTION: In nearly all cases, acromegaly is caused by excess GH from a pituitary adenoma, resulting in elevated circulating levels of GH and, subsequently, IGF-1. Treatment goals are to eliminate morbidity and restore the increased mortality to normal rates. Therapeutic strategies aim to minimize tumor mass and normalize GH and IGF-1 levels. Somatostatin analogues are the medical treatment of choice in acromegaly, as first-line or post-surgical therapy, and have proven efficacy in pituitary tumor volume reduction (TVR). METHODS: Here we review the effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly. RESULTS: TVR with somatostatin analogues may be mediated by direct anti-proliferative effects via activation of somatostatin receptors, or by indirect effects, such as angiogenesis inhibition, and is more pronounced when they are administered as first-line therapy. Various studies of first-line treatment with octreotide LAR have shown significant TVR in ≥73% of patients. First-line treatment with lanreotide Autogel has shown evidence of TVR, although more studies are needed. In a recent randomized, double-blind, 12-month trial in 358 medical-treatment-naïve acromegaly patients, significant TVR was achieved by 81% of patients administered pasireotide LAR and 77% administered octreotide LAR. Pre-operative somatostatin analogue therapy may also induce TVR and improve post-operative disease control compared with surgery alone. TVR is progressive with prolonged treatment, and decreased IGF-1 levels may be its best predictor, followed by age and degree of GH decrease. However, TVR does not always correlate with degree of biochemical control. CONCLUSION: Somatostatin analogues (first- or second-line treatment) are the mainstay of medical therapy and, as first-line medical therapy, are associated with significant pituitary TVR in most patients.

Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly.

CONTEXT: The somatostatin analogues octreotide LAR and lanreotide Autogel have been evaluated for the treatment of acromegaly in numerous clinical trials, with considerable heterogeneity in reported biochemical response rates. This review examines and attempts to account for these differences in response rates reported in the literature. EVIDENCE ACQUISITION: PubMed was searched for English-language studies of a minimum duration of 24 weeks that evaluated ≥10 patients with acromegaly treated with octreotide LAR or lanreotide Autogel from 1990 to March 2015 and reported GH and/or IGF-1 data as the primary objective of the study. EVIDENCE SYNTHESIS: Of the 190 clinical trials found, 18 octreotide LAR and 15 lanreotide Autogel studies fulfilled the criteria for analysis. It is evident from the protocols of these studies that multiple factors are capable of impacting on reported response rates. Prospective studies reporting an intention-to-treat analysis that evaluated medically naïve patients and used the composite endpoint of both GH and IGF-1 control were associated with lower response rates. The use of non-composite biochemical control endpoints, heterogeneous patient populations, analyses that exclude treatment non-responders, assay variability and prior responsiveness to medical therapy are just a few of the factors identified that likely contribute to higher success rates. CONCLUSIONS: The wide range of reported response rates with somatostatin analogues may be confusing and could lead to misinterpretation by both the patient and the physician in certain situations. Understanding the factors that potentially drive the variation in response rates should allow clinicians to better gauge treatment expectations in specific patients.

Effect of chronic cabergoline treatment and testosterone replacement on metabolism in male patients with prolactinomas.

INTRODUCTION: Hyperprolactinemia and hypogonadism are reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of testosterone replacement and cabergoline (CAB) treatment on the metabolic profile in male hyperprolactinemic patients. PATIENTS AND METHODS: Thirty-two men with prolactinomas, including 22 with total testosterone (TT) <8 nmol/l (HG, 69%) and 10 with TT >8 nmol/l (non-HG, 31%), were entered in the study. In all patients, metabolic parameters were assessed at diagnosis and after 12- and 24-month treatment. RESULTS: Compared to non-HG patients, at baseline the HG patients had higher waist circumference (WC). TT significantly correlated with body mass index (BMI). Twelve-month CAB induced PRL normalization in 84%. HG prevalence significantly decreased (28%) and non-HG prevalence significantly increased (72%). Anthropometric and lipid parameters, fasting insulin (FI), insulin sensitivity index (ISI0), homeostatic model assessment of insulin secretion (HOMA-ß) and homeostatic model assessment of insulin resistance (HOMA-IR) significantly improved compared to baseline. TT was the best predictor for FI. Percent change (Δ) of TT significantly correlated with ΔCholesterol, ΔWeight and ΔBMI. Compared to non-HG patients, the HG patients had a higher weight, BMI, WC and HOMA-ß. In HG, testosterone replacement was started. After 24 months, PRL normalized in 97%. HG prevalence significantly decreased (6%) and non-HG prevalence significantly increased (94%). Anthropometric and lipid parameters, FI, ISI0, HOMA-ß and HOMA-IR significantly improved compared to baseline, with FI, ISI0, HOMA-ß and HOMA-IR further ameliorating compared to the 12-month evaluation. Compared to non-HG patients, the HG patients still had a higher weight, BMI and WC. CONCLUSIONS: In hyperprolactinemic hypogonal men, proper testosterone replacement induces a significant improvement in the metabolic profile, even though the amelioration in the lipid profile might reflect the direct action of CAB.

Pituitary tumors and pregnancy: the interplay between a pathologic condition and a physiologic status.

Pregnancy is becoming a relatively common event in patients with pituitary tumors (PT), due to the increasing availability of medical treatments, which control pituitary diseases associated with the development of PT. However, the presence of PT and its treatment may be a disturbing factor for pregnancy, and pregnancy significantly influences the course and the management of PT. This review summarizes the knowledge about the management of PT during pregnancy and the occurrence of pregnancy in patients with pre-existent PT, focusing on secreting PT characterized by hormonal excess and on clinically non-functioning PT often associated to hormone deficiency, which configure the hypopituitaric syndrome.

Investigational drugs for the treatment of acromegaly: new agents to transform therapy.

INTRODUCTION: Disease control is essential to decrease morbidity burden and mortality in acromegaly patients. In the last decades, the availability of new drugs increased the rate of disease control. However, up to 55% of patients remain uncontrolled despite available treatment strategies in real-world data. The reasons for this finding may include poor adherence, inadequate tolerability, therapeutic inertia, and high costs. Since acromegaly is a chronic disease and medical therapy is usually life-long, patient's adherence to treatment is fundamental in both achieving and maintaining disease control. Less invasive routes of administration could improve adherence and concur to increase disease control rate. AREAS COVERED: The aim of current review is to provide a detailed update about investigational drugs for acromegaly treatment currently under investigation as paltusotine, ONO-5788, AP102, GT-02037, ISIS 766720, CAM2024, Lanreotide PRF, DP1038, MTD201, solid dose injection of octreotide. EXPERT OPINION: Medical therapy of acromegaly is an evolving field. Current studies are addressing patient's need for both new molecules and less invasive routes of administration for already existing drugs. It cannot be ruled out that drugs currently used for other diseases such as cancer could be considered in the future for the treatment of acromegaly.

Risk Assessment of Diabetes Mellitus during and after Pregnancy in Women with Prolactinomas.

CONTEXT: Prolactin (PRL) is a crucial mediator of gluco-insulinemic metabolism. OBJECTIVE: Dissecting glucose metabolism during and after pregnancy in patients with prolactinomas. METHODS: 52 patients treated with cabergoline (CAB) were evaluated before conception, during pregnancy and up to 10 years after delivery. During pregnancy, CAB was discontinued, while it was restarted in 57.7 % of patients after delivery, due to recurrent hyperprolactinemia (RH). Hormonal (serum PRL) and metabolic (HbA1c, fasting glucose/FG, glucose tolerance) parameters were assessed. RESULTS: During pregnancy, PRL gradually increased, while FG remained stable. An inverse correlation between PRL and FG was found in the first (p=0.032) and third (p=0.048) trimester. PRL percent increase across pregnancy was inversely correlated with third trimester FG. Serum PRL before conception emerged as predictive biomarker of third trimester FG (τ=2.603; p=0.048). Elderly patients with lower HbA1c at first trimester and lower FG at 3 years postpartum, delivered infants with reduced birth weight. Breastfeeding up to 6 months correlated with lower FG at 4 and 10 years postpartum. A positive correlation between BMI and FG at 10 years after delivery (p=0.03) was observed, particularly in overweight/obese patients requiring higher CAB doses. Patients with RH who had to restart CAB showed shorter breastfeeding duration and higher FG at 2 years postpartum. CONCLUSIONS: Low PRL levels before pregnancy may be detrimental to FG during pregnancy. CAB duration and dose may influence long-term glucose tolerance, besides family history and BMI. Pre-conceptional metabolic management should be recommended to reduce the risk of gestational and type 2 diabetes mellitus.

Effect of cabergoline on metabolism in prolactinomas.

INTRODUCTION: Hyperprolactinemia has been implicated in the pathogenesis of obesity and glucose intolerance and is reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of 12- and 60-month treatment with cabergoline (CAB) on metabolic syndrome (MetS) in patients with prolactinomas. PATIENTS AND METHODS: 61 patients with prolactinomas (13 men, 48 women, 41 with microadenoma, 20 with macroadenoma), aged 34.4 ± 10.3 years, entered the study. In all patients, prolactin (PRL) and metabolic parameters were assessed at diagnosis and after 12 and 60 months of continuous CAB treatment. MetS was diagnosed according to NCEP-ATP III criteria. RESULTS: Compared to baseline, CAB induced a significant decrease in PRL with complete normalization in 93% of patients after the 60-month treatment. At baseline, MetS prevalence was significantly higher in patients with PRL above (34.5%) than in those with PRL lower (12.5%) than the median (129 µg/l, p = 0.03). MetS prevalence significantly decreased after 12 (11.5%, p = 0.039) and 60 (5.0%, p = 0.001) months compared to baseline (28.0%). At both evaluations the lipid profile significantly improved compared to baseline. Fasting insulin and homeostatic model assessment of insulin resistance significantly decreased after 1 year of CAB (p = 0.012 and p = 0.002, respectively) and further improved after 60 months (p = 0.000). The visceral adiposity index significantly decreased after the 60-month treatment (p = 0.000) compared to baseline. At the 5-year evaluation CAB dose was the best predictor of percent decrease in fasting insulin (t = 2.35, p = 0.022). CONCLUSIONS: CAB significantly reduces MetS prevalence and improves the adipose tissue dysfunction index. The improvement in PRL, insulin sensitivity and other metabolic parameters might reflect the direct effect of CAB.

Approach to the Patient With Prolactinoma.

Prolactinomas are the most common pituitary tumor histotype, with microprolactinomas being prevalent in women and macroprolactinomas in men. Hyperprolactinemia is among the most common causes of hypogonadotropic hypogonadism in both sexes, prompting medical advice for hypogonadism (infertility, oligo-amenorrhea, impotence, osteoporosis/osteopenia) in both sexes, and for signs and symptoms of mass effects (hypopituitarism, visual loss, optic chiasm compression, cranial nerve deficits, headaches) predominantly in men. Diagnostic workup involves a single prolactin measurement and pituitary imaging, but some laboratory artifacts (ie, the "hook effect" and macroprolactin) can complicate or delay the diagnosis. The treatment of choice for prolactinomas is represented by dopamine agonists, mainly cabergoline, which are able to induce disease control, restore fertility in both sexes, and definitively cure one-third of patients, thus permitting treatment discontinuation. Pregnancy and menopause may promote spontaneous prolactin decline and anticipate cabergoline discontinuation in women. Surgery and/or radiotherapy are indicated in case of resistance to cabergoline not overcome by the increase in drug dose up to the maximally tolerated or the patient's personal choice of surgery. The evidence of resistance to cabergoline in invasive and proliferative tumors may indicate biological aggressiveness, thus requiring alternative therapeutic approaches mainly based on temozolomide use as monotherapy or combined with radiotherapy. In uncontrolled patients, new medical approaches (alternative hormonal treatments, cytotoxic drugs, peptide receptor radionuclide therapy, mTOR/Akt inhibitors, tyrosine kinase inhibitors, or immunotherapy) may be offered but the experience collected to date is still very scant. This article reviews different facets of prolactinomas and discusses approaches to the condition in more common clinical situations.

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.

Metabolic effects of prolactin.

Over the last years, the metabolic role of PRL has emerged. PRL excess is known to promote weight gain, obesity, metabolic syndrome, and impairment in gluco-insulinemic and lipid profiles, likely due to the suppression of physiologic dopaminergic tone. Prolactin receptors and dopamine receptors type 2 have been demonstrated to be expressed on both human pancreatic ß- cell and adipocytes, supporting a key role of prolactin and dopamine in peripheral metabolic regulation. Medical treatment with the dopamine agonists bromocriptine and cabergoline has been demonstrated to decrease the prevalence of metabolic syndrome and obesity, and significantly improve gluco-insulinemic and lipid profiles. In hyperprolactinemic men with concomitant hypogonadism, correction of hyperprolactinaemia and testosterone replacement has been proven to restore metabolic impairment. In turn, low prolactin levels have also been demonstrated to exert a detrimental effect on weight gain, glucose and lipid metabolism, thus leading to an increased prevalence of metabolic syndrome. Therefore, PRL values ranging from 25 to 100 mg/L, in absence of other recognizable pathological causes, have been proposed to represent a physiological response to the request for an increase in metabolic activity, and nowadays classify the so-called HomeoFIT- PRL as a promoter of metabolic homeostasis. The current review focuses mainly on the effects of hyperprolactinemia and its control by medical treatment with DAs on the modulation of food intake, body weight, gluco-insulinemic and lipid profile. Furthermore, it provides the latest knowledge about the metabolic impact of hypoprolactinemia.

Growth hormone nadir during oral glucose load depends on waist circumference, gender and age: normative data in 231 healthy subjects.

OBJECTIVE: (i) To analyse the predictors of GH suppression after standard glucose load (oGTT) in the healthy population and (ii) to establish the 97th percentile of GH nadir post-oGTT according to these variables. Design Analytical, retrospective. MEASUREMENTS: GH nadir after oGTT. SUBJECTS: Two hundred and thirty-one healthy subjects (113 women, 118 men 15-80years) were studied. RESULTS: The GH nadir after glucose load ranged from 0·01 (88 cm in women and 102 cm in men (97th percentile 0·16 µg/l). CONCLUSIONS The results of this study show that GH nadir after oGTT should be analysed according to gender, menopausal status and waist circumference. The GH cut-off should be limited to the assay used.

Hyperprolactinemia after menopause: Diagnosis and management.

Most prolactinomas are diagnosed in women of reproductive age and are generally microadenomas. Prolactinomas diagnosed in postmenopausal women are less common and are not usually associated with the typical syndrome induced by prolactin excess, including infertility and oligo-amenorrhea. This implies that the diagnosis of prolactinomas after menopause may be delayed and require greater clinical effort. Limited data are available on the management and prognosis of prolactinomas in postmenopausal women. However, the physiologic decline of prolactin levels during menopause and the lack of fertility concerns, which represent specific indications for medical treatment with dopamine agonists, might require a careful reassessment of therapeutic management in such patients. Postmenopausal women with microprolactinoma may be successfully withdrawn from medical therapy with dopamine agonists, whereas in those with macroprolactinomas greater caution is advisable before dopamine agonists are discontinued, considering the potential, although rare, tumor enlargement. This review focuses on the diagnostic challenges and therapeutic management of prolactinomas in postmenopausal women.

The Vaginal Microbiome: A Long Urogenital Colonization Throughout Woman Life.

Vaginal microbial niche is a dynamic ecosystem, composed by more than 200 bacterial species which are influenced by genes, ethnic background and environmental-behavioral factors. Several lines of evidence have well documented that vaginal microbiome constantly changes over the course of woman's life, so to exert an important impact on woman quality of life, from newborn to post-menopausal ages. This review aims at analyzing the role of vaginal microbiome in the maintenance of woman's homeostasis and at tracking critical changes that commonly occur across woman's lifetime. The role of hormone replacement therapy in the modulation of vaginal microbiome composition and in the improvement of vaginal wellness in postmenopausal women with decreasing levels of circulating estrogen is discussed.

Effects of Pituitary Surgery and High-Dose Cabergoline Therapy on Metabolic Profile in Patients With Prolactinoma Resistant to Conventional Cabergoline Treatment.

Objective: Control of prolactin excess is associated with the improvement in gluco-insulinemic and lipid profile. The current study aimed at investigating the effects of pituitary surgery and medical therapy with high dose cabergoline (≥2mg/week) on metabolic profile in patients with prolactinoma resistant to cabergoline conventional doses (<2mg/week). Design: Thirty-four patients (22 men, 12 women, aged 33.9 ± 12.5 years) with prolactinoma (4 microadenomas and 30 macroadenomas) were included in the present study. Among them 17 (50%) received pituitary surgery (PS, Group1) and 17 (50%) medical therapy with high dose cabergoline (Group 2). Methods: In the whole patient cohort, anthropometric (weight, BMI) and biochemical (fasting glucose and insulin, triglycerides, total, HDL and LDL-cholesterol, HOMA-IR, HOMA-ß and ISI0) parameters were evaluated before and within 12 months after treatment. Results: In Group 1, prolactin (p=0.002), total cholesterol (p=0.012), and triglycerides (p=0.030) significantly decreased after pituitary surgery compared to the baseline. Prolactin significantly correlated with fasting glucose (r=0.056, p=0.025). In Group 2, fasting insulin (p=0.033), HOMA-ß (p=0.011) and ISI0 (p=0.011) significantly improved compared to baseline. Postoperative cabergoline dose significantly correlated with Δfasting glucose (r=-0.556, p=0.039) and ΔLDL cholesterol (r=- 0.521, p=0.046), and was the best predictor of ΔLDL cholesterol (r2 = 0.59, p=0.002) in Group 1. Conclusions: The rapid decrease in PRL levels induced by PS might improve lipid metabolism, whereas HD-CAB might exert a beneficial impact on both insulin secretion and peripheral sensitivity, thus inducing a global metabolic improvement.

Cardiovascular disease in Cushing's syndrome: heart versus vasculature.

Cushing's syndrome (CS) causes metabolic abnormalities that determine an increased cardiovascular risk not only during the active phase of the disease but also for a long time after cure. Cardiovascular complications, such as premature atherosclerosis, coronary artery disease, heart failure, and stroke, in patients with CS cause a mortality rate higher than that observed in a normal population. The increased cardiovascular risk is mainly due to metabolic complications, such as metabolic syndrome, but also to vascular and cardiac alterations such as atherosclerosis and cardiac structural and functional changes. In the clinical management of patients with CS the focus should be on identifying the global cardiovascular risk and the aim should be to control not only hypertension but also other correlated risk factors, such as obesity, glucose intolerance, insulin resistance, dyslipidemia, endothelial dysfunction and the prothrombotic state. Considering that remission from hypercortisolism is often difficult to achieve and that the cardiovascular risk can persist even during disease remission, care and control of all cardiovascular risk factors should be one of the primary goals during the follow-up of these patients.

The Interplay Between Prolactin and Reproductive System: Focus on Uterine Pathophysiology.

Over the last years, increasing evidence has focused on crucial pathogenetic role of PRL on malignant, premalignant and benign uterine diseases. Studies in animals and humans have documented that PRL receptors (PRL-Rs) are widely expressed on uterine cells and that PRL is directly synthesized by the endometrium under the stimulatory action of progesterone. Uterine PRL secretion is finely modulated by autocrine/paracrine mechanisms which do not depend on the same control factors implied in the regulation of PRL secretion from pituitary. On the other hand, PRL is synthesized also in the myometrium and directly promotes uterine smooth muscle cell growth and proliferation. Therefore, PRL and PRL-Rs appear to play an important role for the activation of signaling pathways involved in uterine cancers and preneoplastic lesions. Circulating PRL levels are reportedly increased in patients with cervical or endometrial cancers, as well as uterine premalignant lesions, and might be used as discriminative biomarker in patients with uterine cancers. Similarly, increased PRL levels have been implicated in the endometriosis-induced infertility, albeit a clear a causative role for PRL in the pathogenesis of endometriosis is yet to be demonstrated. This evidence has suggested the potential application of dopamine agonists in the therapeutic algorithm of women with malignant, premalignant and benign uterine lesions. This review focuses on the role of PRL as tumorigenic factor for uterus and the outcome of medical treatment with dopamine agonists in patients with malignant and benign uterine disease.

Impact of somatostatin analogs versus surgery on glucose metabolism in acromegaly: results of a 5-year observational, open, prospective study.

OBJECTIVE: The aim of the study was to investigate the 5-yr impact of surgery and somatostatin analogs (SSA) on glucose metabolism in acromegaly. DESIGN: We conducted an observational, prospective, comparative, nonrandomized study. PATIENTS: The 100 patients (48 women, 52 men; median age, 49 yr) in the study were grouped as follows for treatment: SSA only (group A; n = 34); SSA followed by surgery (group B; n = 20); surgery only (group C; n = 30); and surgery followed by SSA (group D; n = 16). RESULTS: At diagnosis, 28% had impaired glucose tolerance, and 22% had diabetes mellitus; fasting glucose levels (4.13-10.60 mmol/liter) were best predicted by age (t = 2.88; P = 0.0049) and disease duration (t = 1.99; P = 0.049). After 60 months, fasting glucose levels reduced (-4.9 +/- 19.7%) in group A only, whereas they did not change in the other groups. In the 68 nondiabetic patients at baseline, fasting glucose levels increased by 0.7 +/- 11.2%, 7.5 +/- 10.3%, 4.3 +/- 10.4%, and 4.3 +/- 14.8% (P = 0.28), from groups A to D, respectively. Percentage change of fasting glucose in all patients receiving SSA was 1.9 +/- 12.3%, and in those not receiving SSA it was 6.4 +/- 10.8% (P = 0.13). Overall, prevalence of new onset of diabetes during SSA treatment was nine of 55 (16.4%) vs. three of 23 after surgery (13.0%, P = 0.98). Deterioration of glucose tolerance was correlated with increased body mass index (r = 0.49, P < 0.0001) and not with use of SSA or surgery (r = 0.06; P = 0.53), control or not of GH (r = -0.10, P = 0.31) and IGF-I (r = -0.12; P = 0.22). CONCLUSIONS: The results of this study demonstrate a similar deterioration of glucose tolerance after 60 months in patients receiving SSA or cured with surgery. Increase in body mass index was the major predictor of deterioration of glucose tolerance.