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Background First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size. Methods We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naïve patients; PRolaCT-2: patients with limited duration of DA treatment (4–6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months. Discussion Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine. Trial registration US National Library of Medicine registry (ClinicalTrials.gov) NCT04107480. Registered on 27 September 2019, registered retrospectively (by 2 months).

Background: Germline mutations in the succinate dehydrogenase B (SDHB) gene predispose to hereditary paraganglioma (PGL) syndrome type 4. The aim of this study was to evaluate the clinical characteristics and outcome of treatment strategies for patients with head and neck paraganglioma (HNPGL) carrying SDHB germline mutations. Methods: This was a retrospective evaluation of patients with HNPGL carrying SDHB germline mutations in the Netherlands. Results: In a Dutch nationwide cohort study of SDHB germline mutation carriers, 54 patients with a total of 62 HNPGLs were identified. Forty-one of 54 patients (76 per cent) visited the outpatient clinic because of associated complaints. Eight patients (15 per cent) had multiple PGLs. One patient (2 per cent) developed a phaeochromocytoma and three (6 per cent) developed a malignant PGL. Twenty-seven patients (50 per cent) had an operation for their HNPGL and 15 (28 per cent) received radiotherapy. Three patients with HNPGL (6 per cent) were diagnosed with additional non-paraganglionic tumours. Conclusion: If an SDHB germline mutation is identified in a patient with HNPGL, the clinician should be aware of the variable manifestations of the SDHB-linked tumour syndrome, the risk of catecholamine excess, concurrent phaeochromocytoma, and association with non-paraganglionic tumours.

This thesis addresses the pathophysiology of stress related diseases, taking two rare diseases, in which the hypothalamic-pituitary-adrenal axis and cortisol play a key role, as a model for stress vulnerability of the brain and the eye. The second aim of this thesis is to describe the organization of thromboprophylaxis management, and the outcome evaluation and quality of care for patients treated for Cushing’s syndrome. For more informatie, please refer tot he summary in the pdf of the thesis.

Main findings In chapter 2 we showed that estrone concentrations are not associated with change in body fat or breast development or in trans women receiving either oral or transdermal estradiol. Moreover, no difference in clinical outcomes was observed between oral and transdermal administration of estradiol, despite the fact that oral estradiol was clearly associated with much higher estrone levels compared with transdermal estradiol. This suggests that only estradiol and not estrone exerts effect on body fat distribution. In chapter 3 we demonstrated that in trans women, suppressing testosterone and increasing estradiol results in an increase in subcutaneous fat and a decrease in VAT/SAT ratio and liver fat. In trans men, we showed that the increase in testosterone concentrations in combination with lower estradiol concentrations results in an increase in visceral fat, VAT/ SAT ratio and liver fat. In chapter 4 we demonstrated that DXA is a valid method to estimate visceral fat in trans women and trans men at baseline and after 12 months of hormone treatment. However, the change in visceral fat after 12 months of hormone treatment is underestimated by DXA, compared to MRI. In chapter 5, we demonstrated a rapid increase in bone marrow fat fraction after testosterone and estradiol suppression in trans women, followed by a rapid decrease after start of estradiol treatment. In trans men, on the other hand, we observed a rapid increase in bone marrow fat fraction after testosterone treatment and suppression of estradiol by triptorelin and anastrozole. In trans men without anastrozole, the bone marrow fat fraction increased only after 12 weeks and decreased to baseline after 52 weeks. Together these results suggest that estradiol and not testosterone is the major sex steroid regulating the bone marrow fat fraction in both women and men. In chapter 6 we demonstrated that this effect of estradiol on bone marrow fat is not caused by a change in number of adipocytes, lipid droplet area or adipokine expression. The effect of estradiol on bone marrow fat might be exerted earlier in the differentiation of adipocytes or via other cell types. Finally, in chapter 7 we observed that gender affirming hormone treatment induces an increase in cheek tissue in trans women and a decrease in cheek tissue in trans men. The cheeks consist mostly of subcutaneous adipose tissue and therefore we can conclude that sex steroids exert the same effect on subcutaneous tissue in the abdomen and the face. Conclusions In conclusion, this thesis has shown that in trans women, suppressing testosterone and increasing estradiol results in an increase in subcutaneous fat, both abdominal and facial; and a decrease in VAT/SAT ratio, liver fat and bone marrow fat. In trans men, an increase in testosterone concentrations in combination with a decrease in estradiol concentrations results in an increase in visceral fat, VAT/SAT ratio, liver fat and bone marrow fat, and no significant changes in subcutaneous fat. These results suggest that estradiol is the major sex steroid regulating body fat distribution in women and men. However, estradiol does not seem to directly affect mature adipocytes with respect to adipocyte number, lipid droplet area or adipokine expression. The effect of testosterone on body fat distribution acts mainly through the aromatization of testosterone into estradiol.

Adequate serum thyroid hormone concentrations in women are crucial for an uncomplicated pregnancy and optimal fetal growth and development. Pregnancy has a profound impact on the thyroid gland and its function. Various changes occur during pregnancy to maintain normal thyroid hormone concentrations. The pregnancy specific alterations and the increased demand for thyroid hormone, causes women with pre-existing mild thyroid dysfunction to be exposed to gestational thyroid disease. Several pregnancy complications have been associated with thyroid disorders, such as (recurrent) pregnancy loss, pre-eclampsia, intrauterine growth restriction and premature delivery, as well as effects upon fetal neurocognitive development. In this thesis the focus was on recurrent pregnancy loss (RPL), which has a strong association with subclinical thyroid disease, including subclinical hypothyroidism and thyroid auto-immunity. The higher prevalence of subclinical thyroid disease makes it an important public health issue, although the risks of adverse pregnancy outcomes in case of subclinical hypothyroidism and thyroid auto-immunity are lower than in case of overt thyroid disease, such as hypo- and hyperthyroidism. RPL is a distressing condition for most couples and a significant health problem. It affects the physical and psychological well-being of prospective parents. It is also experienced as a frustrating problem for the physician because in the majority of cases there is no known therapy which increases the chance of a live born baby. As a result, in addition to lifestyle advices and supportive care, the doctor feels he or she cannot offer the couple much. In this thesis we studied the associations between thyroid disorders and pregnancy outcomes, we developed a diagnostic strategy for recurrent pregnancy loos and determined the efficacy of treatment with levothyroxine.

In this thesis we explored the association between bone marrow adipose tissue (BMAT) and bone metabolism, to ultimately determine if BMAT might be a potential new imaging biomarker or potential new treatment target for osteoporosis. As patients with osteoporosis have low bone mineral density (BMD) combined with high BMAT, and bone marrow adipocytes (BMAds) and osteoblasts share a common progenitor, it is hypothesized that preferential differentiation towards adipocytes causes increased bone marrow adiposity and decreased bone formation. A second hypothesis is that BMAds have paracrine effects on bone metabolism. BMAT is a dynamic tissue. Neonates have little BMAT and during our life BMAT increases from the extremities in a centripetal way. In chapter 2 we show the specific pattern of BMAT distribution within the spine, pelvis, femur and tibia in a group of healthy subjects. BMAT increased from cranial to caudal within the spine, from proximal to distal within femora and showed a small, but consistent decrease from proximal to distal within tibiae. Furthermore, we show that the age-related increase in BMAT is gender and location dependent. As BMAT fatty acid unsaturation is associated with fractures, we also quantified BMAT fatty acid unsaturation. The association between BMAT and BMAT fatty acid unsaturation was opposed, depending on the location. Within the spine, BMAT and unsaturation were negatively correlated, while in the femora and tibiae BMAT and unsaturation were positively correlated. The gender specific differences in BMAT patterns observed in chapter 2 could possibly be mediated by sex steroids as estrogen treatment decreases BMAT and increases BMD. In chapter 3 we found no effect of raloxifene (a selective estrogen receptor modulator, registered for treatment of osteoporosis) on BMAT, adipocyte size or number, quantified in bone biopsies of postmenopausal women with osteoporosis. We found that BMAT volume and bone marrow adipocyte size both were negatively associated with osteoclast number, suggesting an association between BMAT and bone resorption. Furthermore, we found that women with osteoporosis and vertebral fractures had higher BMAT compared to women with osteoporosis without vertebral fractures, while there was no difference in bone volume between these groups, which could possibly indicate that BMAT is associated with fracture risk independent of bone volume. The negative association between BMAT and bone resorption could potentially be mediated by receptor activator of nuclear factor κ-B ligand (RANKL). Bone resorption is regulated by RANKL, which is expressed by osteocytes, osteoblasts and bone marrow precursor cells. In chapter 4 we showed that mature bone marrow adipocytes also express RANKL in a mouse model of postmenopausal osteoporosis (ovariectomy). Furthermore, we showed that estrogen deficiency caused by ovariectomy, not only increased BMAT, but also increased the percentage of RANKL positive BMAds. In chapter 5, we sought to inhibit adipogenesis by administration of a PPARγ antagonist, in the same mouse model of postmenopausal osteoporosis, to determine if we could prevent bone loss caused by estrogen deficiency. However, in these animals, administration of the PPARγ antagonist had no effect on BMAT, bone turnover, bone volume nor on bone strength. Postmenopausal estrogen deficiency is associated with increased visceral adipose tissue (VAT), and increased VAT is associated with increased BMAT and decreased BMD, suggesting an association between body composition and BMAT. Furthermore, patients with anorexia nervosa have high BMAT and low BMD. In chapter 6 we explore the effect of weight loss by gastric bypass surgery on BMAT and BMD in morbidly obese postmenopausal women. We found that both BMAT and BMD decreases after weight loss due to gastric bypass surgery, suggesting that BMAT does not contribute to bone loss after gastric bypass in postmenopausal women.

Thyroid hormone and estrogen both play an essential role in energy metabolism. The current thesis investigated the possible central effects of these hormones in the control of energy metabolism by administrating triiodothyronine (T3), estradiol (E2) and thyrotropin-releasing hormone (TRH) in distinct hypothalamic nuclei. We evaluated various aspects of metabolic alterations including glucose and lipid metabolism, food intake, body weight, body temperature, locomotor activity, energy expenditure and bone remodelling, from gene expression to behavioural changes. For these experiments, we used different experimental techniques. For example, we used slow-releasing pellets for chronic T3 or E2 administration and microdialysis for acute TRH or E2 administration into hypothalamus. We used metabolic cages to monitor caloric parameters including energy expenditure, carbohydrate oxidation and locomotor activity. We used positron emission tomography (PET) and micro computed tomography (μ-CT) scans to examine brown adipose tissue (BAT) activation and bone morphology, respectively. A number of different surgeries have been applied such as ovariectomy, liver denervation, brain cannulation and jugular vein catheterization, to help explicating specific research questions. Our results suggest an essential role of hypothalamus in the estrogenic regulation of fat and bone metabolism as well as in the TRH regulation of glucose and body temperature. Our T3 experiments also suggest that the timing and route of central T3 administration may be important determinants of metabolic effect size. We believe these new findings not only extend our physiological understanding of hypothalamic regulation of metabolism, but also indicate potential therapeutic possibilities for metabolic diseases.

Life evolved in conditions of a 24-hour rhythm of light and darkness, as dictated by the rotation of the earth. To prepare for the resulting behavioral rhythms of feeding/fasting and activity/sleep, mammals possess a circadian timing system, consisting of a central brain clock and peripheral clocks in tissues such as liver, pancreas and adipose tissue. The central clock in the brain is synchronized by environmental light. Nowadays, artificial light and fridges enable people to turn on the light, consume food, and perform activities at any time they desire. For this thesis, we hypothesized that the resulting desynchrony between the clocks in the circadian timing system and the rhythms of feeding/fasting, activity/sleep, and light/darkness, contributes to the pathophysiology of type 2 diabetes. In a rat study, dim light at night caused major disturbances of sleep-wake behavior, feeding rhythms and metabolic rhythms. In healthy humans and patients with type 2 diabetes, bright ambient light directly influenced plasma glucose and lipid levels. In a subsequent study, patients with type 2 diabetes showed reduced daily rhythms of glucose metabolism and adipose tissue gene expression compared to healthy subjects. In a randomized clinical trial, a breakfast intervention (based on the observed reduced morning glucose tolerance) in patients with type 2 diabetes, reduced morning postprandial glucose levels without effect on long-term glycemic control. Together, our data provide support for the desynchrony-hypothesis.

This thesis explores the association between thyroid disorders and adverse pregnancy outcomes, the underlying pathophysiology and treatment possibilities. The association between thyroid disorders and adverse pregnancy outcomes is investigated in a systematic review and two retrospective cohort studies. Women with subclinical hypothyroidism and/or thyroid autoimmunity in pregnancy have an increased risk for unexplained subfertility, (recurrent) miscarriage, preterm birth, pre-eclampsia, breech presentation, perinatal mortality and maternal post-partum thyroiditis. Observational data show that thyroid function disorders and thyroid peroxidase antibodies are associated with disturbed folliculogenesis, spermatogenesis, lower fertilisation rates and lower embryo quality. Available evidence shows that thyroid hormone transporters and receptors are expressed in the ovary, the early embryo, endometrium, uterus and placenta suggesting that thyroid hormone has a direct effect on reproduction and pregnancy. However, the exact underlying pathophysiology of these associations remains unclear. There are no data on the mechanisms underlying the association between thyroid peroxidase autoantibodies and reproduction. Treatment possibilities of thyroid disorders in pregnancy have been studied in a systematic review and a retrospective cohort study. Treatment of hyperthyroidism reduces the risk of preterm delivery, pre-eclampsia and low birth weight. Levothyroxine is effective in reducing the risk of miscarriage and preterm delivery. Current evidence is insufficient to advise treatment of subclinical hypothyroidism or thyroid autoimmunity. To further investigate the effect of levothyroxine treatment in pregnant women with thyroid autoimmunity, a multicentre, international, randomized controlled study has been started and the study protocol is described in this thesis.

Classically, the skeleton is defined by its mechanical properties, as a site for hematopoiesis and in mineral homeostasis. In recent years, a further-reaching role has been suggested for the skeleton. In this thesis, we investigate three novel aspects of human bone metabolism. In the first part we performed a series of experiments to investigate the role of the sympathetic nervous system in human bone remodeling. There was no effect of a beta-adrenergic agonist and an antagonist on bone turnover in healthy, postmenopausal women in a randomized controlled trial. Next, we showed that bone resorption is increased in healthy volunteers receiving a selective alpha-2 adrenergic receptor agonist (clonidine). In vitro osteoclast formation and activity was not affected by clonidine. Furthermore, we did not find an association between polymorphisms in the alpha-2 adrenergic receptor and fracture risk or bone mineral density in a large international consortium. In the second part of this thesis we focused on the humoral control of bone. We described the variation in bone marrow fat during the menstrual cycle and we showed a large decrease in bone marrow fat during two weeks of estradiol treatment in postmenopausal women. In addition, we showed that an eucaloric high-fat, low-carbohydrate diet decreases, while an eucaloric low-fat, high-carbohydrate diet increases bone resorption. Finally, we investigated the role of osteocalcin, a bone-specific protein synthesized by osteoblasts, in the regulation of glucose homeostasis and testosterone levels in humans, but could not find an endocrine or metabolic role for bone.

The skeleton is perhaps the most multifunctional part of our body. It not only provides outer strength, a protective shell and enables locomotion, but it also hosts the bone marrow and serves many metabolic and endocrine functions. This thesis investigates two aspects of human bone metabolism, firstly the role of the sympathetic nervous system (SNS) in human bone metabolism and hematopoiesis and secondly the hormonal control and activity of bone and bone marrow. In the first part of this thesis we used a clinical approach, a genetic approach, and a pharmacological approach to study the SNS and bone metabolism. We showed that bone resorption is increased in pheochromocytoma patients as a model of sympathetic overstimulation and decreases following adrenalectomy. But we did not find an association between polymorphisms in the beta-2 adrenergic receptor and fracture risk or bone mineral density in two large, Dutch cohorts and a large international consortium. Furthermore, there was no effect of a beta-adrenergic agonist and an antagonist on bone turnover or circulating CD34+ hematopoietic stem cells in healthy, postmenopausal women in a randomized controlled trial. In the second part of this thesis we described the variation in bone marrow fat during the menstrual cycle and we showed a large decrease in bone marrow fat during two weeks of estradiol treatment in postmenopausal women. Finally, we put into clinical perspective the evidence concerning the interaction between human bone metabolism and glucose metabolism.

Sex differences have been found in many homeostatic domains, including the stress response, energy metabolism and fat distribution. In the present thesis, I study the involvement of the female hormone estrogen in the occurrence of these sex-differences, more specifically I focused on the brain-mediated effects of estrogen on the regulation of a number of neuroendocrine responses.

The main objective of this thesis is to increase our understanding of hypothalamic (dys)function in patients with pituitary insufficiency. This goal is driven by the clinical experience of persisting symptoms in patients adequately treated for pituitary insufficiency. We focus primarily on patients with a history of compression of the optic chiasm (CC), cranial radiotherapy (CRT) and/or pituitary surgery to optimize the chance of the presence of functional damage to the hypothalamus.