Nippoldt, Todd B.

Abstract Context Transgender and gender diverse (TGD) individuals have greater access to genital surgery (GS) with improved insurance coverage and access to trained surgeons and interdisciplinary gender-affirming providers. Objective To determine perioperative medical and behavioral health outcomes in transfeminine (TF) individuals undergoing GS, with use of a specific gender-affirming hormone therapy (GAHT) algorithm based on individualized risk factor assessment. Methods In this retrospective observational cohort study, we collected preoperative and postoperative data from 183 TF individuals at a single tertiary referral center from 2017 to 2022, grouping patients by those who continued estradiol (Group 1) vs those who had temporarily discontinued estradiol for 2 to 6 weeks preoperatively (Group 2). Data included clinical and biochemical assessment, GAHT regimens, validated behavioral health measures, and postoperative complications. Main outcomes included venous thromboembolism (VTE) incidence, non-VTE postoperative complication incidence, and change in behavioral health assessments. Results The majority of individuals continued estradiol perioperatively (Group 1; 138 [75.4%]). Individuals who temporarily held estradiol preoperatively (Group 2; 45 [24.6%]) were statistically older (P < .01), had higher incidence of cardiometabolic comorbidities (P < .01), and higher Caprini scores (P < .01). Group 1 was statistically more likely to use oral estradiol (P < .01). One episode (0.05%) of VTE occurred (Group 1). There was no significant difference in postoperative complications or behavioral health measures between groups. Conclusion An individualized algorithm for preoperative hormone management for TF GS resulted in perioperative continuation of GAHT for the majority of individuals without significantly increasing the risk for postoperative surgical complications, while maintaining stable behavioral health measures perioperatively.

Abstract Context Interpretation of dexamethasone suppression test (DST) may be influenced by dexamethasone absorption and metabolism and by the altered cortisol binding. Objective We aimed to determine the normal ranges of free cortisol during DST in participants without adrenal disorders and to identify the population of patients where post-DST free cortisol measurements add value to the diagnostic workup. Design and Setting Cross-sectional study conducted in a tertiary medical center. Participants Adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy [OCP], 66 women not on OCP, 55 men) and patients undergoing evaluation for hypercortisolism (n = 196; 16 women on OCP). Measurements Post-DST dexamethasone and free cortisol (mass spectrometry) and total cortisol (immunoassay). Main Outcome Measures Reference range for post-DST free cortisol, diagnostic accuracy of post-DST total cortisol. Results Adequate dexamethasone concentrations (≥0.1 mcg/dL) were seen in 97.6% volunteers and 96.3% patients. Only 25.5% of women volunteers on OCP had abnormal post-DST total cortisol (>1.8 mcg/dL). In volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not on OCP, and 79 ng/dL in women on OCP. When compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol was 87.3% (95% CI, 81.7-91.7); all false-positive results occurred in patients with post-DST cortisol between 1.8 and 5 mcg/dL. OCP use was the only factor associated with false-positive results (21.1% vs 4.9%, P = 0.02). Conclusions Post-DST free cortisol measurements are valuable in patients with optimal dexamethasone concentrations and post-DST total cortisol between 1.8 and 5 mcg/dL.

AbstractNonsuppressed levels of testosterone are seen in up to a quarter of transgender women on gender-affirming feminizing hormonal treatment. Multiple factors contribute to this situation, including patient, medication, laboratory, and organ-specific concerns. We propose a stepwise approach to determine the etiology of nonsuppressed levels of testosterone in transgender women. This may lead to an appropriate feminizing hormonal therapy regimen and diagnosis of manageable medical conditions.

Abstract Introduction: Low or borderline cortisol concentrations and impaired response to dynamic testing have been reported in patients with fibromyalgia, potentially related to hypothalamus-pituitary dysfunction.1,2 Superimposed adrenal insufficiency (AI) may contribute to some fibromyalgia symptoms or delay improvement in patients enrolled in fibromyalgia treatment programs. We hypothesized that a subset of patients with fibromyalgia have: 1) partial secondary AI and concomitant growth hormone (GH) deficiency 2) a discordance in Cosyntropin stimulation test and 3) improvement in fibromyalgia symptoms with initiation of glucocorticoid and/or GH replacement. Design: This was a retrospective study of patients with fibromyalgia diagnosed with partial secondary AI based on abnormal insulin tolerance test (peak cortisol < 18 mcg/dL) at our institution from June 2002 to August 2019. Patients were excluded if they had other reasons for adrenal insufficiency, including steroid exposure and opioid use. Results: We identified 22 patients (18 women, 82%) diagnosed with partial AI at a median age of 38 years (range 19-65). The fibromyalgia symptoms included fatigue (n=22, 100%), pain (n=22, 100%), sleep disturbance (n=15, 68%), and bowel changes (n=13, 59%). The median morning cortisol concentration was 8.6 mcg/dL (range 1.1-11); 9 patients (41%) had a morning cortisol concentration below the normal range (7 mcg/dL). The median ACTH level was 15.5 pg/mL (range 7.7-54). Nineteen patients had baseline IGF1 levels, with a median z-score of -0.94 (range -1.96 to 1.70). MRI pituitary imaging was performed in 20 patients and showed no significant pituitary pathology. All patients achieved hypoglycemia <=40 mg/dL during the insulin tolerance test. Peak median cortisol level was 11 mcg/dL (range 5.4-17). Nineteen patients (86%) also had partial GH deficiency (defined as a peak GH < 4 ng/mL) with a median GH level of 0.36 ng/mL (range 0.03-3.83). Cosyntropin stimulation test was performed in 13 patients (59%) with a 1 mcg dose in 2 patients and 250 mcg dose in 11 patients. The peak cortisol was >=18 mcg/dL in 10 (77%) patients. All patients were started on physiologic glucocorticoid replacement, and 12 patients were started on GH replacement. Endocrinology follow-up information was available for 13 patients, and 8 (62%) reported symptom improvement after starting treatment. Conclusions: Patients with fibromyalgia can have co-existing partial secondary AI and GH deficiency as defined by insulin-induced hypoglycemia. Cosyntropin stimulation test can be used in patients with fibromyalgia, but a normal test does not rule out partial secondary AI. Replacing the underlying deficiency improved symptoms in some patients demonstrating certain fibromyalgia symptoms may overlap with AI and GH deficiency. 1Gur et al. Ann Rheum Dis. 2004. 63(11):1504-1506. 2Kirnap et al. Clin Endocrinol (Oxf). 2001. 55(4):455-459.

OBJECTIVENelson-Salassa syndrome (NSS) is a rare consequence of bilateral adrenalectomy (ADX) for refractory hypercortisolism due to Cushing disease (CD). Although classically defined by rapid growth of a large, invasive, adrenocorticotropin hormone (ACTH)–secreting pituitary tumor after bilateral ADX that causes cutaneous hyperpigmentation, visual disturbance, and high levels of ACTH, clinical experience suggests more variability.METHODSThe authors conducted a retrospective chart review of all patients 18 years and older with a history of bilateral ADX for CD, adequate pituitary MRI, and at least 2 years of clinical follow-up. Statistical tests included Student's t-test, chi-square test, Fisher's exact test, multivariate analysis, and derived receiver operating characteristic curves.RESULTSBetween 1956 and 2015, 302 patients underwent bilateral ADX for the treatment of hypercortisolism caused by CD; 88 had requisite imaging and follow-up (mean 16 years). Forty-seven patients (53%) had radiographic progression of pituitary disease and were diagnosed with NSS. Compared with patients who did not experience progression, those who developed NSS were significantly younger at the time of CD diagnosis (33 vs 44 years, p = 0.007) and at the time of bilateral ADX (35 vs 49 years, p = 0.007), had larger tumors at the time of CD diagnosis (6 mm vs 1 mm, p = 0.03), and were more likely to have undergone external-beam radiation therapy (EBRT, 43% vs 12%, p = 0.005). Among NSS patients, the mean tumor growth was 7 mm/yr (SE 6 mm/yr); the median tumor growth was 3 mm/yr. Prevalence of pathognomonic symptoms was low; the classic triad occurred in 9%, while hyperpigmentation without visual field deficit was observed in 23%, and 68% remained asymptomatic despite radiographic disease progression. NSS required treatment in 14 patients (30%).CONCLUSIONSNSS is a prevalent sequela of CD after bilateral ADX and affects more than 50% of patients. However, although radiological evidence of NSS is common, it is most often clinically indolent, with only a small minority of patients developing the more aggressive disease phenotype characterized by clinically meaningful symptoms and indications for treatment. Young age at the time of CD diagnosis or treatment with bilateral ADX, large tumor size at CD diagnosis, and EBRT are associated with progression to NSS and may be markers of aggressiveness.

We describe four cases of symptomatic pneumocranium, a rare, potentially life-threatening complication of transsphenoidal pituitary surgery. Symptomatic pneumocranium manifested as impaired mental status, headaches, and grand mal seizures, early in the postoperative course after transsphenoidal pituitary surgery. Furthermore, a Cushing response, including systemic hypertension and bradycardia (secondary to intracranial hypertension) was seen, which has not been previously described in association with symptomatic pneumocranium. We describe a previously unreported risk factor for tension pneumocranium, untreated obstructive sleep apnea. Other factors predisposing to tension pneumocranium in our patients included: cerebrospinal fluid leaks, postoperative positive-pressure mask ventilation, large pituitary tumors, and intraoperative lumbar drainage catheters. Surgical drainage of the pneumocranium and repair of any coexistent cerebrospinal fluid leak markedly improved neurologic status. Symptomatic pneumocranium occurring early in the postoperative course after transsphenoidal pituitary surgery is rare, but prompt recognition and treatment of this condition can be life-saving.