Prolactin-Secreting Leiomyoma Causing Hyperprolactinaemia Unresponsive to Dopamine Agonist Therapy and Resolution following Myomectomy

Prolactin-secreting leiomyomas are rare, with only eight cases reported in the literature. This case describes a 37-year-old female with hyperprolactinaemia (1846 mIU/L; 85–500 mIU/L) refractory to cabergoline causing infertility and galactorrhea. MRI pituitary was normal. The patient had a known enlarging uterine leiomyoma on serial pelvic ultrasounds (15.2 cm × 9.1 cm × 12.1 cm). The serum prolactin returned to subnormal levels two days postmyomectomy and showed recovery to normal levels in the months following surgery. Immunostaining of the leiomyoma for prolactin was negative. Despite not staining for prolactin, quick resolution of the patient’s hyperprolactinaemia after myomectomy supports the diagnosis of a prolactin-secreting fibroid. A prolactin-secreting leiomyoma should be considered in patients with hyperprolactinaemia and normal pituitary MRI which is refractory to dopamine receptor agonist therapy who also have evidence of a uterine fibroid. In patients wishing to seek fertility, myomectomy should be considered to allow for normal ovulation and possibility of future fertility.

Anastrozole as add-on therapy for cabergoline-resistant prolactin-secreting pituitary adenomas: real-life experience in male patients

Introduction Prolactin-secreting adenoma (PRLoma) can present as large and invasive neoplasm, with increased markers of cellular proliferation. First-line approach is Dopamine Agonists (DAs) treatment; however, DA-resistance has been reported, especially in male patients. Estrogens induce lactotroph cell replication and PRL secretion: the use of anti-estrogen treatment in patients with PRLoma have been described in few cases. We reported our experience regarding treatment with the aromatase inhibitor anastrozole (ANA) as add-on therapy for male patients with DA resistant PRLoma. Materials and methods We describe four male patients (26, 38, 29 and 19 years old at diagnosis), with PRLoma (median diameter 26 mm, PRL 7730 μg/L). They were resistant to cabergoline (CAB, > 2 mg/week) in terms of PRL secretion and tumor size reduction. ANA 1 mg/day was added to the maximum tolerated dose of CAB for at least 1 year. Magnetic Resonance was performed at baseline, after 6 months of CAB + ANA combination and every 12 months afterward. Results PRL levels decreased in all patients after CAB + ANA (mean − 70%, range − 44/− 97%), achieving a normalization of PRL levels in one case. Tumor size decreased in all cases (mean − 47%, range − 24.5/− 68%). No severe adverse effects have been reported, a moderate weight gain has been observed in two cases. Conclusions Addition of an aromatase inhibitor (ANA) to the dopamine agonist therapy improved the control of prolactin levels and induced tumour regression.

526 Characteristics of Augmented RLS Patients on Dopamine Agonists at a Tertiary Referral Center: Where Do We Go From Here?

Introduction Augmentation is a management dilemma in RLS patients on dopaminergic therapy. Understanding the clinical characteristics of such patients may assist in better management strategies. Methods Consecutive new consultations for RLS from 4/2016-6/2020 were identified from a single tertiary referral center in Boston, USA. Patients were included in this analysis if they had augmentation and current treatment with a dopamine agonist. Clinical information from initial consultation was collected. RLS severity at time of consultation was determined retrospectively with a modified IRLSSG severity score (0–12), assessing RLS symptom frequency (0–4), duration (0–4), and severity (0–4). Results Out of 209 referrals with RLS, 105 patients had augmentation, of whom 88 were on dopamine agonists at initial evaluation. Average age was 67 years (SD 11 years, range 39–88); 62 were female (59%). Mean duration of RLS symptoms was 27 years (SD 20), and 91% had symptoms > 10 years. Mean duration of dopamine agonist therapy was 11 years; 72% had previously been treated with pramipexole, 65% with ropinirole, 73% with rotigotine, and 16% with levodopa; 72% of patients had been treated with alpha-2-delta ligands, and 28% with opioids. Common comorbidities included obstructive sleep apnea (47%), obesity (49%), and depression (44%). Serotonergic medications were currently used by 25%. Of the 88 augmented patients on dopamine agonist therapy, 97% had earlier onset of symptoms and 33% had symptoms in both morning and afternoon; 53% reported anatomical extension. The mean modified IRLSSG score was 8.4 (SD 3.2). 66% of patients had either ferritin <75 mcg/L or transferrin saturation <20%. At the time of initial assessment, 49% were on pramipexole, 47% on rotigotine, 5% on rotigotine and 7% on levodopa: mean daily dopamine agonist dose was 1.23 mg (SD 1.20) of pramipexole equivalent. 37% were on alpha-2-delta ligands: mean daily dose 1014 mg (SD 830, median 700 mg) of gabapentin equivalent. Conclusion Higher than FDA-recommended dopamine agonist dosing and high prevalence of iron deficiency in patients with augmented RLS represent a treatment gap in the care of RLS patients in the community. Controlled studies of guideline-based therapy are indicated to determine optimal management of augmented RLS. Support (if any) Baszucki Brain Research Fund

Remitting Seronegative Symmetrical Synovitis With Subsequent IgA Hypergammaglobulinemia. A Case of Chronic Inflammation Causing Macroprolactinemia and a Misdiagnosis

Prolactin is a pituitary hormone that functions in breast development and milk production in women and also plays an important role in immunoregulation and human immune responses, including autoimmune diseases. Macroprolactin, known as “big-big prolactin”, is due to the presence of marked hyperprolactinemia associated with evidence of prolactin-Ig (typically IgG4 or less frequently IgA) circulating complexes. We describes a case of 51 year-old female, with more than a 4 year history of reported hyperprolcatinemia who was treated with Cabergoline 0.5 mg weekly. Prior to treatment, she reported menses every 30-40 days, but denied galactorrhea or symptoms of sellar mass effect. Our patient had mildly elevated prolactin levels of 40-50 ng/dl. Her Thyroid function test were within normal limits. Patient had two pituitary MRIs in 2017 and 2019 which did not show sellar abnormalities. Prior to cabergolibe initiation, she was diagnosed with RS3PE syndrome (Remitting seronegative symmetrical synovitis with pitting edema) due to bilateral swelling in the dorsum of her hands. She was found to have hypergammaglobulinemia which was related to IgA elevation from chronic inflammation. Further investigation showed actual bio-active monomeric prolactin level was normal (4.8 ng/dl) and macroprolactin elevation from hypergammagolbulinemia. Before diagnosing her paraproteinemia and her macroprolactin predominance, she had received years of dopamine agonist therapy which was discontinued after diagnosis. We report a novel association of IgA predominant hypergammaglobulinemia from a chronic rheumatologic condition, leading to a misdiagnosed hyperprolcatinemia. Care should be taken to determine monomeric Prolactin levels prior to treatment, specially when symptoms are equivocal and/or imaging studies are negative.

Prolactinoma in a Male to Female Transgender Woman on Gender Affirming Hormone Therapy

Background: Estrogen promotes prolactin secretion and its role in prolactin secreting adenomas is still under investigation. The genesis and resolution of prolactinomas may be affected by gender affirming hormone therapy. Case Description: A 50 year old transgender female presented with new onset tunnel vision and extremity parathesias for one day. She had been taking oral estrogen for six years. Physical exam showed bilateral gynecomastia as well as galactorrhea. Her visual fields were intact by confrontation. Her brain MRI revealed a pituitary macroadenoma measuring 1.4cm x 1.3cm x 1.3cm. Laboratory studies showed prolactin 538 ng/mL (<20 ng/mL), IGF-1 89.0 (66-303 ng/ml). TSH 1.7 (0.4-4.7 mcIU/mL), Free T4 0.997 (0.58-1.76 ng/dL) and estradiol 103 pg/ml (N/A). She was treated with bromocriptine 5mg daily. Three months later galactorrhea had resolved, but gynecomastia was unchanged. The patient had a prolactin level of 3 ng/mL. Follow up brain MRI at one and three years showed no significant decrease in size of macroadenoma. Discussion: Despite this patient’s biochemical and symptomatic response to dopamine agonist therapy, her pituitary adenoma did not decrease in size over 3 years, which is a common occurrence with macroprolactinomas. However, her prolactin levels declined and her galactorrhea resolved with therapy. Research into the long term effects of gender transition therapy remains mainly in the realm of case reports and retrospective studies. Our review of the medical literature suggests that some transgender patients on estrogen therapy may have an increased risk of developing pituitary adenomas. However, guidelines have not yet been published and currently there are no recommendations for routine imaging or biochemical assessment during follow-up of these patients. While there are established reference ranges for prolactin levels for men, non-pregnant and pregnant women, no established reference ranges for prolactin levels are available for transgender women on gender affirming hormone therapy. Studies indicate that 76-86% of patients have a reduction in the size of their prolactinomas after dopamine agonist therapy. However, the same may not be true for transgender women on transfeminine hormone therapy with estrogen. Conclusion: Prolactinomas may commonly occur and be masked in transgender women on gender affirming hormone therapy due to the expected symptoms of gynecomastia, erectile dysfunction, and diminished libido from reduced testosterone levels. Estrogen promotes prolactin secretion by the pituitary gland and may have a role in development and expansion of prolactinomas. More research is needed in regards to the assessment and monitoring of the pituitary gland in transgender women on gender affirming hormone therapy with estrogen.

Giant Prolactinomas: An Experience From South India

Giant prolactinomas are large lactotroph adenomas, defined as those with maximum dimension of >4cm. They constitute <5% of all prolactin secreting tumors, and are more frequently seen in men. They present with features of hyperprolactinemia and hypopitutarism and are responsive to dopamine agonist therapies. In the current study we have shared our experience on management of giant prolactinomas over the last 15 years. We collected clinical data retrospectively from medical records of patients with giant prolactinoma managed at our institute over the last 15 years. This study describes the symptomatology, tumor characteristics and response to therapy. Our study included 21 patients with 15 males and 6 females. The mean age of presentation was 32 ± 10.3 years, ranging between 10 to 53 years. Vision defect was the predominant complaint (57%, 12 patients), followed by headache (52%, 11 patients). Erectile dysfunction was a presenting feature in 13% of men (2 patients) and amenorrhea/galactorrhea in 33% of women (2 patients). Seizure was seen in 10% of the patients (2 patients) and 10% (2 patients) were diagnosed with giant prolactinoma on evaluation for primary infertility. Tumor associated pituitary dysfunction manifested as hypogonadism in 67%, 14 patients, central hypothyroidism in 38%, 8 patients, and hypocortisolism in 1 patient. The median maximum tumor dimension was 4.4 cm with median basal PRL of 7168 ng/ml. Five patients underwent debulking surgery (24% of the patients) prior to endocrinology referral for indications such as apoplexy/raised intracranial tension. All patients received cabergoline and a mean dose of 2.1 ± 1.7 mg/week (range, 1-7 mg/week) was prescribed to attain a median nadir prolactin level of 48 ng/ml over a median period of 4 months (range, 1-40 months). The follow-up MRI data was analysed for 13 patients. Tumor shrinkage of >50% from the baseline was seen in all but 1 patient (92%) and 2 patients had disappearance of radiologically detectable tumor. Although giant prolactinomas have a greater tumor burden than the more common macroprolactinomas, the responsiveness to dopamine agonist therapy is excellent and surgical therapy is reserved for any exceedingly large tumors to relieve compression on vital structures.

Adverse body composition and lipid parameters in patients with prolactinoma: a case-control study

Background Hyperprolactinaemia might cause adverse metabolic effects. The aim of our study was to compare parameters of body composition, glucose and lipid metabolism between untreated patients with prolactinoma and controls and to assess changes after initiation of cabergoline. Methods Case-control study with a retrospectively analyzed follow-up in patients with prolactinoma after initiation of cabergoline therapy. Results 21 patients with prolactinoma (9 micro- and 12 macroprolactinomas; 7 females) and 30 controls were analyzed. Patients with prolactinoma had significantly higher BMI than controls; fat mass did not differ between groups. Only men - but not women - with prolactinoma had significantly higher fat mass at all six sites measured compared to controls. Levels of LDL (130 (107–147.5) vs. 94.5 (80–127.5) mg/dl, p < 0.001) were significantly higher, levels of HDL (56 ± 16.7 vs. 69.2 ± 14.6 mg/dl, p = 0.004) significantly lower than in controls. Fasting glucose, HOMA-IR, HbA1c, adiponectin, CRP, and homocysteine did not differ between groups. After a median of 10 weeks (IQR 7–18 weeks) after initiation of cabergoline, total (from 212.5 ± 36.2 to 196.9 ± 40.6 mg/dl, p = 0.018) and LDL cholesterol (130 (107–147.5) to 106.5 (94.3–148) mg/dl, p = 0.018) had significantly decreased. Analyzing men and women separately, this change occurred in men only. Conclusions Reasons for the association between prolactin and metabolic parameters include direct effects of prolactin on adipose tissue, hyperprolactinaemia-triggered hypogonadism and dopamine-agonist therapy per se. Altered lipid metabolism in patients with prolactinoma might imply an increased cardiovascular risk, highlighting the necessity to monitor metabolic parameters in these patients.

Impulse Control Disorders in Parkinson’s Disease: From Bench to Bedside

Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by symptoms that impact both motor and non-motor domains. Outside of motor impairments, PD patients are at risk for impulse control disorders (ICDs), which include excessively disabling impulsive and compulsive behaviors. ICD symptoms in PD (PD + ICD) can be broadly conceptualized as a synergistic interaction between dopamine agonist therapy and the many molecular and circuit-level changes intrinsic to PD. Aside from discontinuing dopamine agonist treatment, there remains a lack of consensus on how to best address ICD symptoms in PD. In this review, we explore recent advances in the molecular and neuroanatomical mechanisms underlying ICD symptoms in PD by summarizing a rapidly accumulating body of clinical and preclinical studies, with a special focus on the utility of rodent models in gaining new insights into the neurochemical basis of PD + ICD. We also discuss the relevance of these findings to the broader problem of impulsive and compulsive behaviors that impact a range of neuropsychiatric syndromes.