Normal Prolactin Research Articles

J-Shaped Relationship Between Serum Prolactin and Metabolic-Associated Fatty Liver Disease in Female Patients With Type 2 Diabetes.

BackgroundMetabolic-associated fatty liver disease (MAFLD) has become a worldwide epidemic. Prolactin (PRL), a pituitary hormone, has been linked to MAFLD. As a result, we set out to look into the relationship between serum PRL and the risk of MAFLD in patients with type 2 diabetes mellitus (T2DM).MethodsA total of 724 adults with T2DM were enrolled and categorized as MAFLD and non-MAFLD groups. Anthropometric data, biochemical parameters, and serum PRL levels were collected. Liver steatosis and fibrosis were assessed using FibroScan. Patients were stratified into normal PRL (NP) and high PRL (HP) groups and divided into four groups based on serum PRL quartiles. Multivariate logistic regression analysis was performed to evaluate the association between serum PRL and MAFLD risk.ResultsFemale but not male patients with MAFLD, liver steatosis, and fibrosis had significantly lower PRL levels in the NP group but higher PRL levels in the HP group than their counterparts. The proportions of MAFLD, liver steatosis, and fibrosis were significantly decreased in the NP group but increased in the HP group across the PRL quartiles in females but not in males. After multivariate adjustment, the adjusted ORs (AORs) and 95% CI for MAFLD among females were 18.165 (3.425–96.336), 1.784 (0.658–5.002), 1.744 (0.608–4.832), and 1.00 (reference) in the NP group (Q1–Q4, P-trend < 0.001) and 1.00 (reference), 11.098 (1.819–110.356), 15.225 (1.996–116.112), and 18.211 (2.579–128.568) in the HP group (Q1–Q4, P-trend = 0.020). Such associations were also found between serum PRL and liver fibrosis in females but not in males.ConclusionWe observed a J-shaped association between serum PRL and the risk of MAFLD and liver fibrosis in females but not in males with T2DM, indicating that PRL may be relevant to MAFLD and its progression in a gender-specific manner.Clinical Trial RegistrationChinese Clinical Trial Registry, number ChiCTR-OCS-12002381.

Mullerian agenesis coexisting with gonadal dysgenesis in a lady with 46, XX karyotype: A rare case report

Mullerian agenesis also known as Mayer-Rokitansky-Kauster-Hauser (MRKH) syndrome is a congenital disorder associated with aplasia of the upper part of vagina, cervix in a female with normal karyotype (46, XX) and well developed secondary sexual characteristics. This was a rare case of combined Mullerian agenesis and gonadal dysgenesis in an eighteen-year-old Nigerian lady who presented with primary amenorrhoea and poorly developed secondary sexual features. She had no history of cyclical abdominal pain, and attempts at penetrative vaginal intercourse. Physical examination revealed a phenotypical female with height and weight of 155cm and 42 kg respectively. Hormone profile revealed markedly elevated Luteinizing Hormone (LH) and Follicle stimulating Hormone (FSH); and raised testosterone, normal prolactin and thyroid function test. Magnetic resonance imaging revealed an absent uterus, tubes and ovaries. Chromosomal studies revealed normal female karyotype 46, XX. Intravenous urography, ultrasonography and skeletal survey showed no associated renal and skeletal abnormalities. Hormone replacement therapy with estrogen was instituted for development and maturation of secondary sexual characteristics followed by serial vaginal dilatation to enhance sexual activities. Patient is on follow up and doing well. MRKH syndrome is a rare case and can coexist with gonadal dysgenesis. This knowledge would be helpful to clinicians in the diagnosis and management of primary amenorrhoea.

Effect of liver cirrhosis on erectile function in rats: A study combining bioinformatics analysis and experimental research.

To explore the mechanism through which liver cirrhosis (LC) causes erectile dysfunction (ED). Bioinformatic analysis was used to predict the potential signalling pathways in LC-induced ED, and N-nitrosodiethylamine was used to establish a rat model of LC. H&E staining, Western blotting and RT-qPCR were used to detect pathological tissue damage and changes in mRNA and protein expression levels. In addition, the expression levels of sex hormones such as estradiol (E2), prolactin (PRL) and testosterone (T) were measured. The hypoxia-inducible factor (HIF) pathway was an important pathway in our bioinformatics prediction. Pathological damages were detected in the liver and penile tissues of the model rats. Compared with the normal group's serum hormone levels, E2 and PRL were increased in LC rats, while T was decreased (p<0.01). The mRNA and protein expression results from penis tissues showed that endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) were both downregulated, and HIF-1α was upregulated in the model group compared to the normal group (p<0.01). These data suggest that LC hinders erectile function and causes histopathological changes in the penis by affecting the expression of HIF-1α, eNOS, iNOS, E2, PRL and T.

The Expression of Prolactin Receptors in Benign Breast Tumors Is Not Associated with Serum Prolactin Level.

The role of prolactin (PRL) and its receptors in the initiation and development of benign breast tumors (BBT) has not been sufficiently studied. An imbalance in the system of hormone homeostasis is crucial in the development of BBT. In particular, an association between elevated prolactin levels and the development of BBT has been reported. Our study showed no significant differences between PRL receptor (PRL-R) expression in BBT tissue under normal and elevated serum PRL levels. There was also no significant correlation between age, PRL-R expression in BBT tissue, intact tissue, and PRL level in the serum. There was a strong significant correlation (p < 0.01; r = 0.92) between PRL-R expression in BBT samples and intact breast tissue, which did not depend on the serum PRL level. There was also no significant difference in the expression of the proliferative marker Ki-67 in BBT tissues from women with normal and elevated levels of serum PRL (p > 0.05). No signs of PRL and its receptors were detected in the BBT cystic fluid women with elevated serum PRL levels. In summary, our prospective study showed that the expression of PRL-R in the tissue of BBT and physiological breast tissue does not depend on the level of serum PRL.

Increased Serum Prolactin and Excessive Daytime Sleepiness: An Attempt of Proof-of-Concept Study.

The objectives of this study were: (1) to identify subjects with hyperprolactinemia in a clinical sample of patients; (2) to compare the neurologic, psychiatric, and sleep conditions found in patients subgrouped by excessive daytime sleepiness (EDS) and hyperprolactinemia; and (3) to identify patients with hyperprolactinemia and EDS not supported by the presence of any other neurologic, psychiatric, or sleep disorder, or substance/medication use. A retrospective chart review of inpatients was carried out in order to identify all patients in whom the prolactin (PRL) serum levels were determined. A total of 130 subjects were retrieved: 55 had increased levels of PRL, while the remaining 75 participants had normal PRL levels. EDS was reported by 32 (58.2%) participants with increased PRL and 34 (45.3%) with normal PRL. Obstructive sleep apnea or other sleep or neurologic/psychiatric conditions could explain EDS in all participants with normal PRL. Among subjects with increased PRL, eight had no other neurologic/psychiatric or sleep disorder (or drug) potentially causing EDS; these participants, at polysomnography, had time in bed, sleep period time, and total sleep time longer than those with EDS associated to another condition. These findings can be considered as a preliminary indication of a role of hyperprolactinemia in EDS and represent a basis for future controlled studies able to test this hypothesis in a reliable, objective, and methodologically more appropriate way.

Prolactinoma Outcome After Pregnancy and Lactation: A Cohort Study.

Context:Prolactinoma is the most frequent pituitary tumor among women of childbearing age. Fewer studies have addressed the outcome of prolactinomas after gestation.Objective:The aim was to study the spontaneous remission rate and change in tumor size after pregnancy and/or lactation in women with prolactinomas.Patients and Methods:Retrospective study conducted at a tertiary care center of north India. Records of 25 women with 31 pregnancies (20 microprolactinomas and 11 macroprolactinomas), who conceived on dopamine agonist (cabergoline) were studied. Cabergoline was stopped at conception in 24 pregnancies and continued in 7. Serum prolactin was noted 3 months after delivery and/or lactation. Magnetic resonance imaging available at last visit after delivery and/or lactation was also noted. Remission was defined as normal serum prolactin after pregnancy and/or lactation without use of cabergoline.Results:Among patients in whom cabergoline was stopped during pregnancy (n = 24), 41.6% (n = 10) had prolactin in normal range (achieved remission) after pregnancy and/or lactation. In 25% (n = 6) of women, adenoma size decreased by more than 50%, in 33%(n = 8), there was no change in adenoma size, and in 42% (n = 10), decrease in adenoma size was less than 50% after pregnancy and/or lactation. The median duration of cabergoline treatment before pregnancy among patients who achieved remission was 60 months against 24 months in those who did not achieve remission. The median pre-pregnancy adenoma size was 5.5 mm in women with remission against 8 mm in women who did not achieve remission.Conclusion:Pregnancy-induced remission of hyperprolactinemia was seen in 41.6% prolactinomas. Longer duration of dopamine agonist treatment before pregnancy, small pre-pregnancy adenoma size, and lower baseline prolactin were associated with high likelihood of remission, though not statistically significant.

Management of prolactinomas in children and adolescents; which factors define the response to treatment?

Prevalence, presentation and clinical outcome of prolactinomas vary in children and adults. In this study, we evaluated the clinical features and outcome of children and adolescents with prolactinoma to identify the differences from that of adults, and thus to establish the management strategies for this age group. Patients with prolactinoma diagnosed before 18 years of age from a single center in the last 20-years were included. Clinical and laboratory data, radiological findings and treatment outcome were evaluated retrospectively. Twenty-eight patients (23 female; 82.1%) with prolactinoma were included. Median age at diagnosis was 15.2 years (12.6-17.7 years) in girls, 12.9 years (12.0-16.7 years) in boys. First line treatment was cabergoline in 82% of patients and normal prolactin level was achieved with maximum dose of 2mg/week in 78%. Surgery was required in 28% of patients. Adenomas < 13.5 mm responded conventional doses of CAB. Adenomas > 30 mm were drug resistant or required surgery. Adenomas between 13.5 mm and 30 mm with invasion/extension were more likely to have drug resistance. CAB had to be continued following surgery in all patients. One macroprolactinoma had an increase in size which was accompanied with increasing prolactin level. All microprolactinomas responded well to DA treatment. However, all adenomas larger than 30 mm was resistant to CAB or required surgery. Probability of drug resistance and requirement of second line therapy were higher in adenomas between 13.5 mm and 30 mm with invasion/extension. Doses over 2mg/week of CAB in drug-resistant patients may not provide additional benefit. The frequency of follow-up MRI could be determined based on prolactin levels and emergence of new neurological symptoms.

A cannulated prolactin series reduces the need for further investigations in women with infertility and lowers the number of false positive screening prolactin measurements.

The prevalence of hyperprolactinaemia in women presenting for infertility investigation has been found to be up to 17%, and many of these women are asymptomatic. Prolactin levels may be elevated by stress, including phlebotomy and not be of clinical significance. A cannulated prolactin study may be a useful way to discriminate this. To determine the utility of a cannulated prolactin series in women presenting with infertility who have a raised prolactin measurement at referral for first fertility consultation. All women referred to two fertility centres had a prolactin level measured prior to first appointment over a two-year period. If the level remained elevated on the second measure after macroprolactin precipitation, women were referred for a cannulated prolactin series. If the prolactin concentration fell within the reference range during the series then the result was regarded as normal. Forty-four (2.7%) of 1660 women seen for a first specialist appointment had persistently raised prolactin concentrations after two samples and were referred for a cannulated series. The proportion of women whose prolactin was found to be normal during the cannulated prolactin series was 61% (95% CI 47-74%). Even in patients with a referral prolactin of greater than 1000mU/L, 45% had a normal two-hour cannulated series. A high proportion (61%) of women with raised prolactin at time of referral for first specialist appointment had a normal prolactin after a two-hour cannulated series. A cannulated prolactin study can avoid unnecessary further investigations in these women.

Is there an increased cardiovascular risk in patients with prolactinoma? A challenging question.

Epicardial adipose tissue thickness (EATT) is considered to be a surrogate for visceral fat and a novel cardiovascular risk indicator. Hyperprolactinemia has been shown to be associated with increased cardiovascular risk. The aim was to evaluate the association between EATT, carotid intima media thickness (CIMT), and cardiac functions in patients with prolactinoma. Patients with the diagnosis of prolactinoma were included. The control group consisted of healthy age matched individuals with normal prolactin levels. Prolactin, fasting blood glucose (FBG), insulin, hemoglobin A1c (HbA1c), alanine aminotransferase (ALT), total cholesterol, triglycerides, and high (HDL) and low density lipoprotein (LDL) cholesterol were measured. EATT, CIMT, cardiac systolic, and diastolic functions were determined using echocardiography. We evaluated 67 patients with prolactinoma (aged 40.7 ± 11.9 years, F/M: 51/16) and 57 controls (aged 42.5 ± 7.4 years, F/M: 36/21). Of the 67 patients, 24 had normal prolactin levels. FBG level was higher in prolactinoma patients than in controls. Patients and controls had similar HbA1c, HOMA-IR, ALT, total, HDL, LDL cholesterol, and triglycerides levels, and similar cardiac systolic and diastolic functions. Prolactinoma patients had greater EATT (3.0 ± 0.5 mm vs. 2.6 ± 0.4 mm, p < 0.001) and CIMT (0.57 ± 0.08 mm vs. 0.52 ± 0.04 mm, p=0.03) than controls. EATT was correlated with body mass index, FBG, HbA1c, and triglyceride levels. EATT and CIMT were greater in patients with prolactinoma, although they had normal cardiac systolic and diastolic functions.

Effect of sertraline on depression severity and prolactin levels in women with polycystic ovary syndrome: a placebo-controlled randomized trial.

There is a paucity of data regarding the safety and efficacy of antidepressant therapy in women with polycystic ovary syndrome and depression. The effect of antidepressant medications on circulating prolactin levels is of concern in this patient population. We aimed to evaluate the effect of sertraline on depression severity and serum prolactin levels in women with polycystic ovary syndrome and mild-to-moderate depression. In a parallel-design, two-center, randomized controlled trial, we stratified participants according to their baseline prolactin level into normal (<25 ng/mL) and high (≥25 ng/mL) prolactin groups. Each group was randomized to receive 50 mg daily sertraline (up-titrated after 25 mg daily for 1 week) or placebo. The enrolling physicians, outcome assessors, and study subjects were all blind to the treatment. Depression severity was assessed by the Hamilton depression rating scale at baseline, the third, and the sixth weeks. The primary efficacy outcome was a change in depression severity. Prolactin levels were checked at baseline and after 6 weeks, and the safety outcome was the alteration in prolactin levels. Overall, 513 women were screened for eligibility in two outpatient clinics. Ultimately, 74 (38 normal prolactin and 36 high prolactin level) individuals were randomized. After 6 weeks of follow-up, depression severity was significantly reduced among patients who received sertraline regardless of the baseline prolactin levels (all between subjects P < 0.001). Furthermore, there was no difference in prolactin levels between the sertraline and placebo arms in normal (P = 0.80) or high prolactin (P = 0.21) groups. Sertraline is a well-tolerated and effective choice for treating depression in women with polycystic ovary syndrome. Future studies with longer follow-up periods are required to draw more robust conclusions.

The Development of Hypogonadotropic Hypogonadism After Starting Low Dose Mifepristone for Cushing’s Syndrome

Background: Mifepristone is an antiprogesterone that has been studied in females and has shown central effects including suppressing LH surges. There is a paucity of information about how it effects males. Clinical Case: 65-year-old male with bilateral adrenal macronodular hyperplasia noted on a past surveillance CT scan presented to endocrinology. He had a history of coronary artery disease, type 2 diabetes, obesity, and treated sleep apnea. He had progressively worsening abdominal weight gain, supraclavicular fat pads, thin bruising skin, and hypertension. He had several abnormal 1 mg overnight dexamethasone suppression tests (ACTH 3 & <1 pg/ml and cortisol 10 ug/dL & 11.1 ug/dL). He had several abnormal midnight salivary cortisol tests (109 ng/dL, 147ng/dL, and 152 ng/dL, reference <100 ng/dL). He elected to have medical treatment for his Cushing’s Syndrome after worsening hypertension and several episodes of hypertensive urgency. He was deemed a non-surgical candidate. He was started on mifepristone 300 mg/day and spironolactone 12.5 mg/day given eGFR 47 mL/min/1.73sq m. His mifepristone dose was dropped to 300 mg every other day after he had several episodes of orthostatic hypotension, nausea, and hot flashes. On lower dose mifepristone, his hypertension control improved without orthostatic hypotension or nausea. His hot flashes remained and he developed breast enlargement and tenderness. A repeat testosterone was found to be low, but the rest of his evaluation for gynecomastia was negative otherwise. His pre-treatment am testosterone was 281 ng/dL (normal 250–1100 ng/dL) and post mifepristone treatment am testosterone level was <7 ng/dL. He had suppressed gonadotrophins (LH <0.2 mIU/mL; normal 1.4–7.77 mIU/mL, FSH <0.2 mIU/mL; normal 2.5–17.1 mIU/mL), normal prolactin (PRL 11 ng/mL; normal 2.6–12 ng/mL) and a normal pituitary MRI. Conclusion: This is the first case demonstrating severe hypogonadotropic hypogonadism in a male using low dose mifepristone treatment for mild ACTH independent Cushing’s Syndrome. Reference: Escudero, E. and et al. Mifepristone Is an Effective Oral Alternative for the Prevention of Premature Luteinizing Hormone Surges and/or Premature Luteinization in Women Undergoing Controlled Ovarian Hyperstimulation for in Vitro Fertilization. J Clin Endocrinol Metab. 2005; 90(4):2081–2088.

Biotin Supplementation Creates the Misleading Diagnosis of Secondary Adrenal Insufficiency

Introduction: Biotin (vitamin B7) is a water-soluble vitamin and an essential cofactor for the metabolism of fatty acids, glucose, and amino acids. Cases of biotin interference with laboratory testing have been described, most of which involve interference with thyroid function tests. Interference with gonadal steroids, adrenal, and pituitary hormones are rare. We report a case of T3 thyrotoxicosis in which biotin supplementation created the appearance of secondary adrenal insufficiency (AI).Case: A 66-year-old woman was referred for the evaluation of low TSH. She had chronic fatigue, low libido, and dizziness on standing. Vitals were stable with BP 135/64 mmHg and BMI 23.5. No evidence of mucosal or cutaneous hyperpigmentation. Laboratory evaluation revealed low ACTH <5 (7.2–63.3 pg/mL), low morning cortisol 3.8 and high DHEA-S 174 (13–130 ug/dL). TSH was low at 0.32 (0.32–5.60 uIU/mL) with normal prolactin and appropriately elevated FSH and LH. The labs raised concern for secondary AI. Cosyntropin stimulation test (CST) was done with a peak cortisol of 17.4 ug/dL. In the setting of suppressed ACTH and failed CST, she was started on Hydrocortisone therapy. Subsequently, CT of abdomen was obtained due to high DHEA-S which showed normal appearance of both adrenals. Pituitary MRI was normal. A detailed review of the medication list revealed that the patient was taking a Biotin containing multivitamin. Repeat labs 1 week after stopping biotin showed normalization of ACTH 13.8 (7.2–63.3). Repeat CST showed a peak cortisol response of 24 ug/dL. Hydrocortisone was discontinued and the patient remained stable on subsequent follow-ups, without the need for further glucocorticoid replacement therapy. Thyroid lab abnormalities persisted after biotin cessation which led to the diagnosis of T3 thyrotoxicosis, the treatment of which caused resolution of the patient’s symptoms.Discussion: The recommended daily intake of biotin for adults is 30 µg/d. Many over-the-counter products, specifically those marketed for hair, skin, and nail growth, contain biotin 100-fold higher than the recommended intake. Biotin interference with competitive immunoassays can cause falsely elevated hormone levels, whereas biotin interference with immunometric “sandwich” assays falsely lowers hormone levels. In our case, low ACTH was clinically misleading, prompting numerous unnecessary radiographic and laboratory testing and treatment with hydrocortisone. The US Food and Drug Administration issued a safety communication regarding biotin interference with laboratory tests. Education and communication between laboratorians, providers, and patients play an important role in investigating potential lab interference and the need for alternative lab assays for an accurate diagnosis. Patients should be asked to stop taking biotin supplements for at least 48 hours prior to specimen collection if possible.

Aromatase Inhibitors in Erectile Dysfunction

Hyperestrogenism may cause erectile dysfunction(ED) by impeding normal penile development,increasing venous vascular permeability and leakage(via VEGF) and by inhibiting testosterone(T)production. Estrogen excess can impair spermatogenesis and may increase the risk of estrogen-sensitive cancers(viz.breast cancer)[1,2]Weekly and biweekly letrozole(2.5 mg),an aromatase inhibitor,has been reported to normalize serum T in males with obesity related hypogonadism and poor sperm quality,respectively.[3,4]A 40-year old insulin requiring,normotensive,obese(BMI-26.9),diabetic(12 years duration) was evaluated for ED.T was 187 ng/dl and estradiol(E2) was 69 pg/ml(normal-11-44 pg/ml) with normal LH and prolactin levels. There was normalization of T(increased to 487 ng/dl) with 2.5 mg letrozole every 3 weeks. Another patient,55 year old male, insulin requiring,hypertensive,obese(BMI-28.8),diabetic(21 years duration) had normalization of T(401 ng/dl) with baseline low T(224.4 ng/dl) and normal E2(33 pg/ml) with T-E2 ratio of less than 10,with weekly 2.5 mg letrozole. There was one kg weight gain and 0.2 ng/ml increase in PSA in two years. These cases highlight the significance of estimating both T and E2 in the evaluation of ED. Moreover,it also highlights the efficacy and safety of weekly and even every 3-week 2.5 mg letrozole therapy.

Pachydermoperiostosis: A Rare Masquerader of Acromegaly and Thyroid Acropachy

Background: Pachydermoperiostoasis is a rare disease of prostaglandin metabolism that presents with extensive clubbing, skin thickening, and enlargement of hands and feet, often misdiagnosed as acromegaly or thyroid acropachy. Clinical Case: A 29-year-old male presented with progressive enlargement of hands and feet for the past three years, with increased sweating, seborrhea, acne, arthralgia, and photophobia. On examination, facial furrowing and severe clubbing in all fingers and toes was noticed, with palmoplantar hyperhidrosis, tenderness and widening around distal forearms, and increased heel pad thickness. He had nodulocystic acne, injected right eye with ptosis, normal pupil, and visual field. Slit-lamp examination showed extensive pannus formation, with yellow nodules, suggestive of phlyctenular conjunctivitis, secondary to a systemic inflammatory process. No prominent supraorbital ridge, prognathism, proptosis, goiter, or pretibial myxedema. No family history of a similar condition. Labs showed normal cell counts and metabolic panel. Normal IGF-1 (112 ng/mL, n 84-250 ng/ml), TSH (3.82 mIU/L, n 0.27-4.2 mIU/L), fT4 (1.19 ng/dL, n 0.93-1.7 ng/dL), Testosterone (354 ng/dL, n 249-836 ng/dL) and Prolactin (15.2 ng/mL, n 2.1-17.7 ng/mL). Inflammatory markers were elevated with ESR of 54 mm/hr (n 0-15 mm/hr) and CRP of 12.45 mg/L (n 1-4 mg/L). ANA, RF, anti-CCP, and HLA-B27 were negative. C3 and C4 levels were normal as well. Interferon-gamma release assay was negative. Imaging showed a normal chest X-ray. Brain MRI showed normal pituitary gland and increased scalp skin thickness with cutis verticis gyrata “undulating skin sign.” X-ray of hands and feet showed diffuse periosteal reaction. A diagnosis of pachydermoperiostosis (PDP) was made based on clinical criteria (thickened skin, periosteal reaction, and finger clubbing). PDP is a genetic disorder of prostaglandin metabolism with variable expression and incomplete penetrance. It manifests after puberty and affects males more than females with a 7:1 ratio. PDP has been recently shown to go through an inflammatory phase, in which patients may benefit from immunosuppressants or NSAIDs. PDP should be distinguished from hypertrophic pulmonary osteoarthropathy, thyroid acropachy, and acromegaly. Our patient had a normal chest radiograph and normal hormone levels (TSH, T4, and IGF-1). The patient received topical steroids and antibiotics with artificial tears for his eyes, which resulted in a good response, and was referred to a rheumatology clinic for further management. Clinical Lesson: PDP can be mistaken for acromegaly or thyroid acropachy and should be considered in any patient with acromegaloid features with normal IGF-1 and no evident pituitary pathology. Awareness of this condition can help in reaching the diagnosis promptly.

Unexpected but Not Uncommon - a Case of Adrenal Insufficiency

Abstract Background: Herbal remedies are widely available and whilst portrayed as generally harmless, they may contain a variety of potent medications that can cause unintended and potentially serious consequences. This danger is further amplified as their use is typically inadvertently not divulged to clinicians, such as in this case. Clinical Case: A 65-year-old gentleman was referred to Endocrinology for assessment of adrenal insufficiency (AI) as a cause of his lethargy. He was found to have serum cortisol levels of 38 nmol/L and 68 nmol/L (150 – 700 nmol/L) on two separate mornings. No identified recent use of inhaled, topical, intra-articular or oral exogenous steroid therapy was noted. He had an inadequate response to Synacthen stimulation with peak serum cortisol of 150 pmol/L at 60-minutes (Adequate response – Post-Synacthen cortisol &amp;gt;430 pmol/L). Baseline plasma ACTH was low - 1.1 pmol/L(2.0 – 10 pmol/L) and secondary (pituitary) AI was suspected. He had normal thyroid function and prolactin. The patient subsequently admitted to taking an herbal medication, “Montalin” for a few months. It was obtained over-the-counter in Indonesia for symptomatic relief of “muscle pains”. The tablet underwent analysis to investigate for presence of corticosteroid components. An intact Montalin capsule was partly dissolved and the soluble content was diluted and analysed via LCMS/MS. Presence of dexamethasone/betamethasone was confirmed at an approximate concentration of 69.8 nmol/L constituting 0.548mg and 0.81% of the tablet. At the time, betamethasone and dexamethasone could not be distinguished due to stereoisomerism, but since has been confirmed to be dexamethasone. The patient likely had suppression of the hypothalamic-pituitary-adrenal axis from unintended exogenous corticosteroid use, causing a picture of secondary AI. He requires ongoing corticosteroid replacement pending recovery of endogenous production. Although Montalin is marketed as an herbal over-the-counter medication it was confirmed to be adulterated with a potent corticosteroid. An alert issued by the Singaporean government details two further cases of adverse effects from Montalin and warns against its use. Conclusion: Herbal remedies with undisclosed potent ingredients may unknowingly cause serious adverse effects. With advances in LCMS/MS technology, laboratory analysis of either the tablets or the patient’s serum could be utilised to identify potential exogenous corticosteroid exposure.

Headache, Pituitary Apoplexy and Diabetes insipidus: Suspect Necrotizing Hypophysitis

Background: Necrotizing hypophysitis (NH) is an exceedingly rare clinical entity; we found only 5 reported cases in a literature review. CASE: A 34-year-old female with a history of primary hypothyroidism developed a headache, double vision, nausea, vomiting, decrease in appetite, galactorrhea, and weight loss. An MRI of the brain showed a 0.9 cm T2 hyperintense pituitary lesion with features suggestive of cystic degeneration or apoplexy of an adenoma There was effacement of the optic nerve anterior to the optic chiasm. Eye examination revealed optic nerve edema and a cranial nerve VI palsy. Laboratory studies revealed a normal prolactin 20.0 (3.3-26.7 ng/ml), and IGF-1 189 (RR: 66 - 303 ng/ml). The pituitary-adrenal axis and pituitary-gonadal axis appeared intact. After short treatment with dexamethasone, her primary symptom of severe headache improved but she later developed polyuria. The evaluation confirmed diabetes insipidus. Her headache worsened after the completion of the brief course of steroids. After a repeat MRI showed mild interval enlargement of the hypo-enhancing posterior pituitary, she underwent transsphenoidal pituitary tumor surgery. A biopsy showed necrotizing inflammation with foci of acute necrosis accompanied by polymorphonuclear cells. There was no granuloma seen. Special stains were negative for fungal, acid-fast, and bacterial organisms. Laboratory studies revealed negative ANA, negative ANCA, PR-3 Ab, MPO Ab, and anti-TPO Abs. The ACE enzyme was elevated at 85 (RR: 8-53 U/l), but the repeat test was within the normal range. A chest CT was not suggestive of pulmonary sarcoidosis. A post-surgery MRI demonstrated a decrease in pituitary size. Her headache worsened with a reduction in prednisone below 20 mg daily. In order to attempt further reduction in prednisone, azathioprine was started as a steroid-sparing agent. Titration of azathioprine up to 175 mg allowed prednisone to be reduced to the replacement dose of prednisone 5 mg daily. An MRI showed the pituitary mass to be unchanged. DISCUSSION: Hypophysitis is associated with diffuse enlargement and dysfunction of the pituitary gland. This case of NH is of unclear cause. There was no evidence of other inflammatory causes such as sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, or infectious cause. As with typical lymphocytic hypophysitis, NH can present with sudden-onset hypopituitarism, neural compression, diabetes insipidus, and radiologic features of ischemic pituitary apoplexy. Signs and symptoms at diagnosis, as well as pituitary hormone abnormalities, vary on the degree of pituitary involvement. Pituitary adenoma commonly does not cause diabetes Insipidus. Radiologic findings consistent with ischemic pituitary apoplexy coupled with the presence of diabetes insipidus is suggestive of NH. A definitive diagnosis of NH, however, requires histopathology.

Prolactinoma in Two Brothers - Unidentified Genetic Cause Versus Co-Incidence?

Background: Most prolactinomas occur sporadically. Familial prolactinomas are uncommon. Clinical Case(s): A 35 YO male with no significant past medical history presented to endocrine clinic with c/o fatigue, decreased libido, and erectile dysfunction. Labs showed low total testosterone of 177 ng/dl (normal range 250-1100 ng/dl), low free testosterone of 19.9 pg/ml (normal range 46-224), low LH 1.1 (normal range 1.5-9.3 mIU/ml) with elevated prolactin of 47 ng/ml (normal range 2-18). MRI pituitary showed a 4.2x4x6 mm pituitary microadenoma. Physical exam was unremarkable except for obese body habitus. No known family history of MEN syndromes or parathyroid /calcium disorders. Dopamine agonist therapy resulted in significant improvement in testosterone levels, fatigue, and libido. One year after patient’s diagnosis his 32 YO younger brother was evaluated for c/o fatigue, inability to lose weight, left breast enlargement, galactorrhea, and decreased libido. Work up showed markedly elevated prolactin levels of 2405 ng/ml (normal range 4-15), decreased total testosterone of 70 ng/dl (normal range 249-836), low free testosterone of 4.8 pg/ml (normal range 8.7 to 25.1), FSH <0.1 mIU/ml (normal range 1.4-15.4), LH < 0.1 mIU/ml (normal range 1.7-8.6). MRI Pituitary showed a 25x28x20 mm pituitary macroadenoma invading the right cavernous sinus, encasing the right internal carotid artery, and abutting the optic chiasma. Our patient had genetic testing done for sequencing and deletion/duplication analysis of MEN1 and AIP (Aryl hydrocarbon receptor interacting protein) genes—two well identified causes of familial pituitary adenomas—and tested negative for both. His brother was treated with dopamine agonists with marked improvement in Prolactin to undetectable levels within a few weeks. His energy levels, headaches, and sexual function improved and galactorrhea resolved. However, testosterone levels remained below normal range even after 11 months, despite normal prolactin levels. Discussion: Prolactinomas are the most common functional pituitary adenomas, majority of them sporadic. Familial pituitary adenomas in non-syndromic form are rare. Familial isolated pituitary adenoma (FIPA) and Multiple endocrine neoplasia type 1(MEN 1) are two main causes of familial pituitary adenomas. In FIPA, pituitary adenomas occur as a result of mutations or deletions in aryl hydrocarbon receptor interacting protein gene (AIP). Identifying these mutations is important as pituitary adenomas in FIPA tend to be more aggressive, present at a younger age and are resistant to treatment. Our patient tested negative for both MEN 1 and AIP gene mutations. Whether our patient has an unidentified genetic cause or whether it was a coincidence that two brothers have prolactinomas is unclear.

Hypothalamic Dysregulation; A Hidden Culprit in Multiple Sclerosis Symptoms

Background: A possible association between multiple sclerosis (MS) and dysregulation of hypothalamic-pituitary axis has been reported and its endocrine manifestations can be confused with many nonspecific symptomatology attributed to MS. We report such a case and present the improvement of symptoms independent of MS therapy. Clinical Case: Case of a 45 years-old female with history of type 2 diabetes mellitus, dyslipidemia, HTN, obesity class I and MS that was evaluated for follow up with complaints of fatigue, weakness, somnolence and memory problems. No menstrual disturbances with regular cycles. Denies weight changes, anorexia, nausea, vomiting or abdominal discomfort. Previous hormonal workup showed normal levels of cortisol, ACTH, prolactin and TSH. Nonetheless, on repeated hormonal profile due to nonspecific complaints, patient was found with normal TSH (2.65 mIU/mL, 0.3-3.0 mIU/mL) and low free T4 (0.65 ng/dL, 0.78-2.19 ng/dL). Repeated thyroid function tests by equilibrium dialysis showed a borderline low FT4 (0.8 ng/dL, 0.78-2.19 ng/dL), despite a persistently normal TSH (2.26 mIU/mL, 0.3-3.0 mIU/mL). Suspecting hypopituitarism, a complete hormonal workup revealed a low normal serum cortisol in early morning of 8.39 mcg/dL and ACTH of 16.7 pg/mL, normal prolactin of 10.5 ng/mL and a first IGF-1 evaluation of 68.9 ng/mL, which was low for female age range (98-261 ng/mL). Due to concerns for possible complications during an insulin tolerance test, a cosyntropin stimulation test was performed with adequate peak cortisol response at 30.5 mcg/dL. Most recent brain MRI without pituitary protocol was remarkable for multiple bilateral demyelinating plaques compatible with MS diagnosis that also involved the left thalamus, although no other area adjacent to the hypothalamus or pituitary gland was described. The patient was subsequently started on levothyroxine replacement to a goal of free T4 at the upper normal range, with overall improvement in symptoms and quality of life. Growth hormone status and gonadal axis to be reevaluated. This case emphasizes the importance of clinical judgement and reminds us that overlapping symptoms can lead to misdiagnosis, particularly in conditions with nonspecific symptomatology as MS. Conclusion: This is an unusual case of a patient with multiple sclerosis presenting with hypopituitarism suggesting the possibility of hypothalamic disturbance as the etiology. It has been proposed that demyelinating MS lesions in fiber bundles in and adjacent to the hypothalamus may compromise hypothalamic function. Mechanisms for fatigue in MS have been mostly associated with hyperactivity of HPA axis, not found in our patient. Hypothalamic dysfunction can be frequently overlooked due to overlapping symptoms with MS, despite being a treatable condition that can greatly improve quality of life in these patients.

Recovery of Male Hypogonadism Following Successful Treatment of Prolactinoma: The Experience of an Integrated Health Network

Background: Hypogonadism is the most prevalent deficiency in male patients with prolactinomas (PrL). The recovery rates of hypogonadism (HGo) following treatment of PrL is variable and can be as high as 62%. In this study we aimed to identify predictors of HGo recovery in mean with PrL. We hypothesized that younger and leaner men and smaller tumor size predict HGo recovery after successful PrL treatment. We also hypothesized that higher baseline serum T predicts HGo recovery. Methods: We conducted a retrospective review of the electronic medical records of adult males with a diagnosis of hyperprolactinemia or PrL who were treated at Allegheny Health Network (Pittsburgh, PA) between January 1, 2016 and December 31, 2019. Serum prolactin and testosterone (T) levels, and pituitary tumor size (microadenoma <10mm, macroadenoma 10-39mm, or giant adenoma ≥ 40 mm) on MRI scan at diagnosis and up to 2 years follow up were analyzed. HGo was defined as serum T below reference range at diagnosis. HGo recovery was defined as total T in the reference range within 2 years from PrL treatment onset in the absence of T replacement. Results: We screened 215 male patients who met initial search criteria. Of the 37 subjects who met eligibility criteria, 26 had HGo while 11 had normal serum T (Fig 1). Mean age of men with HGo was 44.6 ± 13.7 years (range 21 – 64). Median serum prolactin at diagnosis was 283.5 ng/mL (range 31-14,830), and mean serum T was 167.07 ± 61.12 ng/dL. Median tumor (max) diameter was 17.5 mm (range 4-81mm). Of the included 26 patients 20 (77%) achieved normal prolactin with therapy after a median of 5 months. Only 10 of the 26 men with HGo (38.5%) attained recovery of HGo following treatment of PrL, and the mean time to recovery was 8.8 ± 6.9 months. HGo recovery was predictably more common in persons with microadenoma (n=6) while none of patients with giant Prl achieved HGo recovery. Baseline serum prolactin and T levels and baseline tumor size predicted subsequent HGo recovery, while age did not. Baseline serum prolactin was lower in men whose HGo recovered (median = 105 ng/mL, IQR = 202) than in men who did not (median = 931 ng/mL, IQR = 3714); p = 0.014. Baseline serum T was higher in men who attained HGo recovery (173.2 ± 59.6) than in men who failed to do so (103.1 ± 85.9); p = 0.03. Mean tumor size was significantly smaller in men who attained HGo recovery (max diam: 9.8 ± 5.5 mm) than in men who did not (31.8 ± 20.3 mm); p = .003. There were no statistically significant differences between men categorized by remission status with respect to age (p = .367) nor weight at the time of diagnosis (p = .591). Conclusion: In this retrospective study of 26 males with PrL and low T at presentation, 38.5% achieved HGo recovery. Lower baseline serum prolactin, smaller tumor size and higher baseline T predicted recovery of HGo, while presenting age and weight did not. This study was limited by its retrospective nature and small sample size.

Primary Amenorrhea and Hyperandrogenism: Presenting Features of a Growth Hormone Producing Pituitary Adenoma in a Female Adolescent

Background: The combination of obesity, metabolic syndrome, hyperandrogenism and amenorrhea can be a common presentation of conditions such as polycystic ovarian syndrome. Growth hormone (GH) secreting pituitary adenomas are rare in children, but can present with a similar picture. Clinical Case: A 15-year 4-month old female was evaluated for primary amenorrhea and metabolic syndrome. Her weight was +2.96 SD, height +3.0 SD (mid-parental height 44th percentile, -0.1 SD) and BMI +2.53 SD, all >99th percentile. Weight and BMI were >99th percentile (weight +3.0 SD, BMI +2.4 SD) since 11 years of age and height was >99th percentile (+ 2.7 SD) since 8 years of age. Physical exam was remarkable for acanthosis, deepened voice, no hirsutism, Tanner III breasts and Tanner IV pubic hair. Laboratory evaluation was notable for prolactin (PRL) 147.8 ng/dL (2.6-18.0), LH <0.02 mIU/mL, FSH <0.09 mIU/mL, estradiol 23 pg/mL, total testosterone 81 ng/dL (<41), androstenedione 673 ng/mL (43-180), DHEA-S 627 mcg/dL (42-162), dyslipidemia and normal 17 hydroxy-progesterone and thyroid function tests. Bone age was 16 years. Brain MRI showed a 15x7mm pituitary macroadenoma without suprasellar invasion. Pituitary evaluation revealed IGF-1 619 ng/mL (192-568), IGF-BP3 5.15 mg/L (2.64-6.43) and adrenal insufficiency. Treatment with cabergoline 0.5 mg/week and maintenance hydrocortisone were initiated. An OGTT demonstrated baseline GH 4.9 ng/mL (0-6) and nadir 3.62 ng/mL (normal <1) consistent with GH excess. Surgery for the pituitary adenoma was recommended but unfortunately postponed. Four months later, her BP was elevated, she had clinical signs of diabetes insipidus (DI), PRL was 43.2 ng/dL and she failed a repeat GH suppression test. Follow-up MRI showed pituitary mass enlargement (17x9mm). Patient underwent total trans-sphenoidal tumor resection. Pathology confirmed a sparsely granulated (SG) GH adenoma immunoreactive for GH, PRL and estrogen receptor. Post-operative OGTT showed adequate GH suppression, normal prolactin levels, persistent testosterone elevation and DI. Conclusions: Hyperprolactinemia, hyperandrogenism and metabolic syndrome could be the presenting features of pituitary GH adenomas even in the absence of acromegalic features. Specifically, SG pituitary adenomas are frequently seen in young adults, are larger, more invasive and less likely to respond to medical treatment. Timely diagnosis and surgical treatment of GH adenomas is essential to prevent the high morbidity and mortality.