Association between preexisting mental illnesses and mortality among medicaid-insured women diagnosed with breast cancer.

BACKGROUND: We investigated the impact of preexisting mental illnesses on all-cause and cause-specific mortality among Medicaid-insured women diagnosed with breast cancer. METHODS: Data from the New York State Cancer Registry for 10,444 women diagnosed with breast cancer from 2004 to 2016 and aged <65 years at diagnosis were linked with Medicaid claims. Women were categorized as having depression or a severe mental illness (SMI) if they had at least three relevant diagnosis claims with at least one claim within three years prior to breast cancer diagnosis. SMI included schizophrenia, bipolar disorder, and other psychotic disorders. Estimated menopausal status was determined by age (premenopausal age <50; postmenopausal age ≥50). Hazard ratios (HR) and 95% confidence intervals (95%CI) were calculated with Cox proportional hazards regression, adjusting for potential confounders. RESULTS: Preexisting SMI was associated with greater all-cause (HR = 1.36; 95%CI 1.18, 1.57) and cancer-specific (HR = 1.21; 95%CI 1.03, 1.44) mortality compared to those with no mental illnesses. No association was observed between preexisting depression and mortality. Among racial/ethnic subgroups, the association between SMI and all-cause mortality was observed among non-Hispanic white (HR = 1.47; 95%CI 1.19, 1.83) and non-Hispanic Asian/Pacific Islander (HR = 2.59; 95% 1.15, 5.87) women. Additionally, mortality hazards were greatest among women with preexisting SMI that were postmenopausal (HR = 1.49; 95%CI 1.25, 1.78), obese (HR = 1.58; 95%CI 1.26, 1.98), and had documented tobacco use (HR = 1.42; 95%CI 1.13, 1.78). CONCLUSION: Women with preexisting SMI prior to breast cancer diagnosis have an elevated mortality hazard and should be monitored and treated by a coordinated cross-functional clinical team.

Impact of preexisting type 2 diabetes mellitus and antidiabetic drugs on all-cause and cause-specific mortality among Medicaid-insured women diagnosed with breast cancer.

BACKGROUND: We investigated the influence preexisting type 2 diabetes mellitus (T2DM) and antidiabetic drugs have on all-cause and cause-specific mortality among Medicaid-insured women diagnosed with breast cancer. METHODS: 9221 women aged <64 years diagnosed with breast cancer and reported to the New York State (NYS) Cancer Registry from 2004 to 2016 were linked with Medicaid claims. Preexisting T2DM was determined by three diagnosis claims for T2DM with at least one claim prior to breast cancer diagnosis and a prescription claim for an antidiabetic drug within three months following breast cancer diagnosis. Estimated menopausal status was determined by age (premenopausal age <50; postmenopausal age ≥50). Hazard ratios (HR) and 95 % confidence intervals (95 %CI) were calculated with Cox proportional hazards regression, adjusting for confounders. RESULTS: Women with preexisting T2DM had greater all-cause (HR = 1.40; 95 %CI 1.21, 1.63), cancer-specific (HR = 1.24; 95 %CI 1.04, 1.47), and cardiovascular-specific (HR = 2.46; 95 %CI 1.54, 3.90) mortality hazard compared to nondiabetic women. In subgroup analyses, the association between T2DM and all-cause mortality was found among non-Hispanic White (HR 1.78 95 %CI 1.38, 2.30) and postmenopausal (HR = 1.47; 95 %CI 1.23, 1.77) women, but not among other race/ethnicity groups or premenopausal women. Additionally, compared to women prescribed metformin, all-cause mortality hazard was elevated among women prescribed sulfonylurea (HR = 1.44; 95 %CI 1.06, 1.94) or insulin (HR = 1.54; 95 %CI 1.12, 2.11). CONCLUSION: Among Medicaid-insured women with breast cancer, those with preexisting T2DM have an increased mortality hazard, especially when prescribed sulfonylurea or insulin. Further research is warranted to determine the role antidiabetic drugs have on survival among women with breast cancer.

Changing Demographics in Transgender Individuals Seeking Hormonal Therapy: Are Trans Women More Common Than Trans Men?

Introduction: The number of individuals seeking sex hormone therapy for gender dysphoria has been increasing. The prevalence gender dysphoria has recently been estimated as high as 390 to 460 per 100,000 with a consistently greater prevalence of trans women (MTF) than trans men (FTM). We report here the changing demographics encountered in our experience over the past 2 decades. Methods: We collected data on individuals receiving hormonal therapy in the transgender clinic at Albany Medical Center in upstate New York from 1990 to 2017. We analyzed temporal changes in the number, age, and gender identity of transgender individuals. Results: Through June 2017, a total of 421 transgender individuals were seen who initiated hormonal therapy after 1990. Over the past 25 years, there has been a significant increase in the number of individuals seen. The mean age at initiation has remained higher in MTF than in FTM but has decreased steadily in both groups with the overall average dropping <30 years since 2015 (27.5±10.6). Since 1990, there has been a steady increase in the percentage of FTM such that it is now equivalent to MTF. Conclusion: Consistent with many reports, we are seeing an increasing number of gender dysphoric individuals seeking hormonal therapy. The age at initiation has been dropping over the past 25 years, and we have seen a steady increase in the number of FTM such that the incidence now equals that of MTF. Possible reasons for these changes are discussed.

The Effect of Efavirenz on Estradiol Metabolism in Transgender Women.

The goal of hormonal therapy in treating gender dysphoria is to maintain cross-sex hormone levels in the normal physiological range for the desired gender. Estrogen is the mainstay of hormonal therapy for male to female transgender patients. Efavirenz, a non-nucleoside reverse-transcriptase inhibitor, has been one of the most commonly prescribed antiretroviral therapies (ARTs). However, this regimen has also given rise to the most clinically significant drug-drug interactions between ARTs and hormone-based contraceptives. We discuss here three transgender HIV-positive women in whom efavirenz effected the metabolism of orally administered estradiol (and probably medroxyprogesterone).

Hormonal Treatment of Transgender Women with Oral Estradiol.

Purpose: Maintaining cross-sex hormone levels in the normal physiologic range for the desired gender is the cornerstone of transgender hormonal therapy, but there are limited data on how to achieve this. We investigated the effectiveness of oral estradiol therapy in achieving this goal. Methods: We analyzed data on all transgender females seen in our clinic since 2008 treated with oral estradiol. We looked at the success of achieving serum levels of testosterone and 17-ß estradiol in the normal range on various doses of estradiol (with and without antiandrogens spironolactone and finasteride). Results: There was a positive correlation between estradiol dose and 17-ß estradiol, but testosterone suppression was less well correlated. Over 70% achieved treatment goals (adequate 17-ß estradiol levels and testosterone suppression) on 4 mg daily or more. Nearly a third of patients did not achieve adequate treatment goals on 6 or even 8 mg daily of estradiol. Spironolactone, but not finasteride, use was associated with impairment of obtaining desired 17-ß estradiol levels. Spironolactone did not enhance testosterone suppression, and finasteride was associated with higher testosterone levels. Conclusions: Oral estradiol was effective in achieving desired serum levels of 17-ß estradiol, but there was wide individual variability in the amount required. Oral estradiol alone was not infrequently unable to achieve adequate testosterone suppression. Spironolactone did not aid testosterone suppression and seemed to impair achievement of goal serum 17-ß estradiol levels. Testosterone levels were higher with finasteride use. We recommend that transgender women receiving estradiol therapy have hormone levels monitored so that therapy can be individualized.

Endocrine treatment of transsexual persons: extensive personal experience.

OBJECTIVE: The Endocrine Society's recently published clinical practice guidelines for the treatment of transsexual persons acknowledged the need for further information on transsexual health. We report here the experience of one provider with the endocrine treatment of transsexual persons over the past 2 decades. METHODS: Data on demographics, clinical response to treatment, and psychosocial status were collected on all transsexual persons receiving cross-sex hormone therapy since 1991 at the endocrinology clinic at Albany Medical Center, a tertiary care referral center serving upstate New York. RESULTS: Through 2009, a total 192 male-to-female (MTF) and 50 female-to-male (FTM) transsexual persons were seen. These patients had a high prevalence of mental health and psychiatric problems (over 50%), with low rates of employment and high levels of disability. Mental health and psychiatric problems were inversely correlated with age at presentation. The prevalence of sex reassignment surgery was low (31% for MTF). The number of persons seeking treatment has increased substantially in recent years. Cross-sex hormone therapy achieves very good results in FTM persons and is most successful in MTF persons when initiated at younger ages. CONCLUSION: Transsexual persons seeking hormonal therapy are being seen with increasing frequency. The dysphoria present in many transsexual persons is associated with significant mood disorders that interfere with successful careers. Starting therapy at an earlier age may lessen the negative impact on mental health and lead to improved social outcomes. However, significant barriers exist, such as insufficient insurance coverage, which limit comprehensive care.

[D-Leu-4]-OB3, an orally bioavailable leptin-related synthetic peptide insulin sensitizer: a study comparing the efficacies of [D-Leu-4]-OB3 and metformin on energy balance and glycemic regulation in insulin-deficient male Swiss Webster mice.

The effects of oral delivery of exenatide or pramlintide acetate in dodecyl maltoside (DDM) on energy balance and glycemic control in insulin-resistant obese db/db mice are enhanced when given in combination with [D-Leu-4]-OB3. To examine the anti-hyperglycemic influence of [D-Leu-4]-OB3 in a non-obese insulin-deficient animal model, we compared the effects of metformin (200mg/kg) and [D-Leu-4]-OB3 (40 mg/kg) on energy balance and glycemic control in streptozotocin (STZ)-induced diabetic male Swiss Webster (SW) mice. Diabetic mice were given insulin (Levemir(®), sc) alone, or in combination with metformin or [D-Leu-4]-OB3 orally in DDM, for 14 days. Body weight and food and water intake were measured daily. Fasting blood glucose levels were determined every other day. Serum C-peptide was measured by ELISA. Diabetic mice receiving insulin alone for 14 days gained significantly more weight than DDM-treated control mice, or mice given insulin in combination with metformin or [D-Leu-4]-OB3. The weight gain seen in mice given insulin alone was accompanied by significant increases in both food and water intake. Mice treated with insulin in combination with metformin or [D-Leu-4]-OB3, consumed significantly less food and water. Blood glucose levels in STZ-treated mice receiving insulin alone were reduced to 65.3% of initial levels, while mice receiving insulin with metformin or [D-Leu-4]-OB3 were reduced to 44.5% and 38.9%, respectively. Our results indicate that [D-Leu-4]-OB3 is as effective as metformin in preventing the body weight gain associated with insulin therapy, and on a molar basis, that the efficacy of [D-Leu-4]-OB3 as an insulin sensitizer may equal or surpass that of metformin.

Use of insulin pump therapy in patients with type 2 diabetes after failure of multiple daily injections.

OBJECTIVE: To determine the effectiveness of insulin pump use (continuous subcutaneous insulin infusion; CSII) in patients with type 2 diabetes (DM2) who have failed multiple daily injection (MDI) therapy. METHODS: In this retrospective study, charts of patients with DM2 who were started on CSII after failure of MDI were reviewed. Patients were categorized as primarily manual (fixed) bolus users or calculated (using pump software) bolus users. The change in hemoglobin A1c (HbA1c), weight, and basal insulin dose from baseline to 6 months was determined. RESULTS: Fifty-seven patients (20 men and 37 women) ranging in age from 13 to 71 were identified in the study. A significant reduction in HbA1c was observed from 8.75 to 7.69% (P<.001). There was an increase in body mass index (BMI) from a mean of 36.53 to a mean of 37.21. A decrease in basal insulin requirement per kilogram of weight (-0.10 U/kg) was noted (P = .03). Seven patients using U-500 insulin in the pump also had a significant decrease in HbA1C of 1.1 % (P<.001), along with a 0.071 U/kg drop in basal insulin requirements (P<.001). When comparing calculated bolus users to manual bolus users, there was no difference in HbA1C improvement (P = .58). CONCLUSION: We found that CSII improves glucose control in patients with DM2 who have failed MDI despite a decrease in overall insulin requirements. This includes patients with severe insulin resistance using U-500 insulin. Use of frequent bolus adjustment incorporating carbohydrate counting and current glucose level does not appear to be required for this benefit.

[D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, augments the effects of orally delivered exenatide and pramlintide acetate on energy balance and glycemic control in insulin-resistant male C57BLK/6-m db/db mice.

The escalation predicted for the incidence of both type 2 diabetes mellitus and obesity has prompted investigators to search for additional pharmacotherapeutic approaches to their treatment. Two of these approaches, combination pharmacotherapy and utilization of leptin-related bioactive synthetic peptides as anti-diabetes/anti-obesity agents, were used in the present study. Exenatide or pramlintide acetate was reconstituted in dodecyl maltoside (DDM) in the absence or presence of [D-Leu-4]-OB3, and delivered orally by gavage to insulin-resistant male C57BLK/6-m db/db mice twice daily for 14 days. Body weight gain, food and water intake, blood glucose, and serum insulin levels were measured. Mice given DDM alone for 14 days were 19.7% heavier than they were at the beginning of the study, while oral delivery of exenatide or [D-Leu-4]-OB3 in DDM reduced body weight gain to only 13.9% and 11.5%, respectively, of initial body weight. Mice receiving exenatide and [D-Leu-4]-OB3 were 4.2% lighter than they were at the beginning of the study. In another study, Intravail® treated control mice gained 38.2% of their initial body weight, while mice receiving pramlintide acetate or [D-Leu-4]-OB3 were only 26.8% and 25.4% heavier, respectively, at the end of the study, Co-administration of pramlintide acetate and [D-Leu-4]-OB3 did not further enhance the effect of pramlintide acetate on body weight gain. Food intake was reduced by exenatide, pramlintide acetate, and [D-Leu-4]-OB3 alone, and co-delivery with [D-Leu-4]-OB3 did not induce a further decrease. Water intake was not affected by exenatide, pramlintide acetate, or [D-Leu-4]-OB3 alone, but co-delivery of exenatide or pramlintide acetate with [D-Leu-4]-OB3 resulted in a significant reduction in water intake. Oral delivery of exenatide or pramlintide acetate in DDM significantly lowered blood glucose levels by 20.4% and 30.2%, respectively. Co-delivery with [D-Leu-4]-OB3 further reduced blood glucose by 38.3% and 50.5%, respectively. A concentration-dependent increase in serum insulin was observed in response to increasing concentrations of exenatide, and [D-Leu-4]-OB3 slightly reduced the insulin response to exenatide at all concentrations tested. Increasing concentrations of pramlintide acetate alone did not elevate serum insulin, and when given in combination with [D-Leu-4]-OB3, serum insulin levels fell below those of DDM-treated control mice. Our data indicate that (1) exenatide and pramlintide acetate, currently administered by subcutaneous injection, can be given orally in DDM; (2) the bioactivity of exenatide and pramlintide acetate is retained following oral delivery in DDM; and (3) the effects of exenatide and pramlintide acetate on energy balance and glycemic control can be enhanced by co-administration with [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity.

Oral delivery of mouse [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, in male Swiss Webster mice: a study comparing the pharmacokinetics of oral delivery to intraperitoneal, subcutaneous, intramuscular, and intranasal administration.

We have recently shown that intranasal administration of mouse [D-Leu-4]-OB3 reconstituted in Intravail to male Swiss Webster mice resulted in significantly higher bioavailability than commonly used injection methods of delivery. The absorption profile associated with intranasal delivery of mouse [D-Leu-4]-OB3 showed an early peak representing rapid uptake across the nasal mucosa, and a later peak suggesting a gastrointestinal site of absorption. In the present study, we show that gastrointestinal absorption of mouse [D-Leu-4]-OB3 does occur, and that reformulation of mouse [D-Leu-4-OB3 with Intravail significantly enhances its uptake. The pharmacokinetics of orally delivered (by gavage) mouse [D-Leu-4]-OB3 in the absence or presence of Intravail were examined, and compared to previously reported pharmacokinetic parameters of mouse [D-Leu-4]-OB3 following intraperitoneal (ip), subcutaneous (sc), intramuscular (im), and intranasal administration. When compared to oral delivery in PBS, Intravai significantly enhanced the total uptake (552,710 ng/ml/min vs.137,585 ng/ml/min) and relative bioavailability (4.0 vs. 1.0) of mouse [D-Leu-4-OB3. The relative oral bioavailabilities of mouse [D-Leu-4]-OB3 when compared to ip, sc, im, and intranasal delivery were 52.2%, 47.3%, 37.8% and 12.9%, respectively. The results of this study indicate that oral delivery of mouse [D-Leu-4]-OB3 in Intravail is an effective method of administration achieving relatively high serum levels of the bioactive peptide when compared to commonly used methods of injection. In addition to intranasal administration, oral delivery of mouse [D-Leu-4]-OB3 in Intravail may have potential as a novel, non-invasive approach to the treatment of obesity and its associated metabolic dysfunctions in humans.

Intranasal administration of mouse [D-Leu-4]OB3, a synthetic peptide amide with leptin-like activity, enhances total uptake and bioavailability in Swiss Webster mice when compared to intraperitoneal, subcutaneous, and intramuscular delivery systems.

Using a synthetic peptide strategy, we localized an active domain in mouse leptin to a sequence between amino acids 106 and 140. Intraperitoneal (ip) administration of a number of synthetic peptide amides encompassed by this domain reduced body weight gain, food and water intake, blood glucose levels, and increased insulin sensitivity in genetically obese mice. In the present study, we examined the pharmacokinetics of mouse [D-Leu-4]OB3, our most potent peptide, in male Swiss Webster mice following ip, subcutaneous (sc), and intramuscular (im) injection, and after intranasal administration with Intravail, a new class of patented transmucosal delivery enhancement agents. Total uptake (1,072,270, 1,182,498; 1,481,060; ng/ml/min), serum half-life (48.8; 34.0; 30.0 min) and relative bioavailability (1.0, 1.1; 1.4;) of mouse [D-Leu-4]OB3 were similar when the peptide was given by ip, sc, or im injection, respectively. Total uptake and relative bioavailability were enhanced following intranasal delivery (4,336,963 ng/ml/min and 4.0, respectively), and serum half-life was 41.1 min. These results indicate that intranasal delivery of mouse [D-Leu-4]OB3 with Intravail is a more effective method of peptide administration than injection methods, and suggest that it may have potential as a novel, non-invasive approach to the treatment of obesity and its associated metabolic dysfunctions in humans.

The effects of age on uptake, serum half-life and bioavailability of mouse [D-Leu-4]OB3, a synthetic peptide amide with leptin-like activity, in male C57BL/6J mice.

We have previously shown that the activity of a synthetic peptide amide corresponding to amino acid residues 116-130 of mouse leptin is contained in a restricted sequence at the amino terminus of the peptide, between residues 116 and 122 (Ser-Cys-Ser-Leu-Pro-Glu-Thr). This peptide was named mouse OB3. The potency of OB3 was improved by replacing the L-leucine residue at position four with its D-isomer. Intraperitoneal administration (i.p.) of mouse OB3 or [D-Leu-4]OB3 to ob/ob and db/db mice reduces food intake, body weight gain and serum glucose levels, and enhances insulin sensitivity. These effects of OB3 and [D-Leu-4]OB3 are very pronounced in young mice and diminish with age. In the present study, we measured uptake, serum half-life, and bioavailability of mouse [D-Leu-4]OB3 in mice of different ages. Groups of male C57BL/6J mice, six and 25 weeks of age, were given a single i.p. injection of 1 mg mouse [D-Leu-4]OB3 in PBS. Five, 10, 20, 40, 60, 120, or 180 min after injection, the mice were anesthetized and exsanguinated. Serum samples were prepared and assayed for mouse [D-Leu-4]OB3 content by competitive ELISA. In six week-old mice, the maximum concentration of mouse [D-Leu-4]OB3 was reached in 10 min, and the serum half-life was approximately 52.5 min. In 25 week-old mice, however, mouse [D-Leu-4]OB3 peaked in 5 min, and the serum half-life was approximately 30.6 min. The relative bioavailability of mouse [D-Leu-4]OB3 in six and 25 week-old mice was determined by measuring the area under the uptake curves. Bioavailability of mouse [D-Leu-4]OB3 was approximately 20% greater in six week-old mice than in 25 week-old mice. The results of this study indicate that at least some pharmacokinetic parameters of peptide uptake change as mice age. They also suggest that differences in uptake, serum half-life, and relative bioavailability of mouse [D-Leu-4]OB3 may contribute, at least in part, to the reduced efficacy of bioactive leptin-related peptides we have consistently observed in ob/ob and db/db mice as they age.

Exogenous Cushing's syndrome and glucocorticoid withdrawal.

Glucocorticoid therapy in various forms is extremely common for a wide range of inflammatory, autoimmune, and neoplastic disorders. It is therefore important for the physician to be aware of the possibility of both iatrogenic and factitious Cushing's syndrome. Although most common with oral therapy, it is also important to be alert to the fact that all forms of glucocorticoid delivery have the potential to cause Cushing's syndrome. Withdrawal from chronic glucocorticoid therapy presents significant challenges. These include the possibility of adrenal insufficiency after discontinuation of steroid therapy, recurrence of underlying disease as the glucocorticoid is being withdrawn, and the possibility of steroid withdrawal symptoms. Nonetheless, with patience and persistence, a reasonable approach to withdrawal of glucocorticoid therapy can be achieved.

Leptin and the treatment of obesity: its current status.

Leptin, the protein product of the ob gene, is primarily an adipocyte-secreted hormone, whose functional significance is rapidly expanding. Although early research efforts were focused on defining leptin's role in reversing obesity in rodents, there is now substantial evidence indicating that its influence extends to several hypothalamic-pituitary-endocrine axes, including gonadal, adrenal, thyroid, growth hormone, and pancreatic islets. A role for leptin in hematopoiesis, angiogenesis, immune function, osteogenesis, and wound healing has also been documented. The results of recent clinical trials with recombinant human leptin indicated that its effectiveness in restoring energy balance and correcting obesity-related endocrinopathies in genetically obese rodent models extended only partially to the management of human obesity. New efforts in drug development have focused on leptin-related synthetic peptide agonists as potential anti-obesity pharmacophores.