Endocrinology and Reproduction Part 2

Elisabet Stener-Victorin, Professor, PhD Reproductive Endocrinology and Metabolism (REM) group Department of Physiology and Pharmacology Karolinska Institutet, Stockholm, Sweden [email protected] Understand function in the different hormonal systems by dysfunction i.e. endocrine disorders: 1. Dwarfism, gigantism, acromegaly 2. Cretinism 3. Goiter 4. Hyperthyroidism 5. Hypothyroidism 6. Cushings syndrome and Cushings disorder 7. Type 1 diabetes and Type 2 diabetes 8. Polycystic Ovary Syndrome 9. Hypothalamic insufficiency 10.Osteoporosis Growth Hormone (GH) → IGF-1

Childhood - before closure of epiphysis: . Growth hormone deficiency → pituitary dwarfism . Excessiv secretion of GH → gigantism . GH can be used to treat children that are more than 2 SD below their growht curve

Adulthood: . Excessiv secretion of GH → acromegali . Long bones cannot growth in adults, instead abnormal growth of bones in the face, hands, feet, and certain organs such as liver . Cause: adenoma Thyroid dysfunction(s)

. Cretinism . Iodine deficiency during fetal development to childhood . Leads to: . Short stature . Skeletal growth is more (”stocky” & obese appearance, enlarged tongue) . Mental retardation

. Goiter – iodine deficiency (indigenous hypothyroidism) Hypothyroidism . Primary hypothyroidism . Hashimoto disease,an autoimmune disease causing impaired hormone synthesis . Secondary hypothyroidism . Can be heritable and affect the biosynthesis of thyroid hormones . Surgery . Radioiodine . Symptoms . Extreme tiredness, muscle weakness . Frozen . Weight gain – low metabolic rate . Dry skin . Slow in mind . Treatment . Supplement with levaxin Hyperthyroidism • Primary hyperthyroidism • Graves Disease, autoimmune disorder is the most common cause • Adenoma, less common – secrete thyroid hormone

• Symptoms • Exopthalmos • High metabolic rate • Increased appetite, but decrease in weight • Tachycardia Goiter • Tremor, nervous etc

• Treatment • Thyreostatics and radioactive iodin • Β-blocker • Surgery • Supplement with levaxin Hypercalcemia . Hypercalcemia is abnormally high levels of Ca2+ levels in the blood . Cause of hypercalcemia: . Primary hyperparathyroidism caused by a benign tumor in parathyroid gland(s) . Certain types of cancer can lead to humoral hypercalcemia of malignancy . Excessive ingestion of vitamin D can lead to hypercalcemia despite the fact that PTH levels will be very low . Hypercalcemia symptoms: . Tiredness . Lethargy with muscle weakness . Nausea and vomiting (due to effects on the GI tract) . Bones soften and deform . Elevated Ca2+ depresses the nervous system and contributes to kidney stones

7 Hypocalcemia . Hypocalcemia is abnormally low levels of Ca2+ levels in the blood . Causes: . Primary hypoparathyroidism: Surgical loss of parathyroid gland function . Pseudohypoparathyroidism: Resistance to the effects of PTH in target tissue, even though PTH levels in the blood tend to be elevated . Secondary hyperparathyroidism: failure to absorb vitamin D from the gastrointestinal tract, or decreased kidney 1,25-(OH)2D production . The symptoms of hypocalcemia are: . Increases the excitability of nerves and muscles (seizures, muscle spasms (hypocalcemic tetany), and nerve excitability) . Results in tetany, respiratory paralysis, and death . Treatment: 2+ . Calcium salts and 1,25-(OH)2D (calcitriol), supplemental dietary Ca and high doses of dietary vitamin D, injections of vitamin D Patophysiology - osteoporos

Receptor activator of nuclear factor kappa-Β ligand (RANKL)

Osteoprotegerin (OPG)

Davis, S. R. et al. (2015) Menopause Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.4 Homeostatic Imbalances of Cortisol • Hypersecretion—Cushing’s syndrome • Caused by excessive medication or by tumor in adrenal cortex • Symptoms: • High blood pressure, abdominal fat accumulation, round face, a fat lump between shoulders, muscle hypotrophy (thin arms and legs) • Weak bones, fragile skin, hyperglycemia, mode change etc. • Inhibits inflammation and depresses the immune system • Cushing’s disease • Caused by adenoma → ↑ ACTH → ↑ cortisol • → negative feed-back does not work Homeostatic Imbalances of Cortisol

• Hyposecretion—Addison’s disease (rare) • Primary adrenal cortex insufficiency, caused by damage of the immune system, certain infections, or various rarer causes • Symptoms due to lack of both cortisol and aldosterone • Decrease in glucose and Na+ levels • Weight loss, severe dehydration, and hypotension • Lack of axillar and pubic hair in women • Melanin pigmentation – due to increase in MSH release Classification of diabetes mellitus according to WHO, 1999

•Type I diabetes (insulin-dependent diabetes mellitus (IDDM) • Insulin deficiency → caused by destruction of the B cells in pancreatic islets • autoimmune (autoimmune positive) • idiopathic (autoimmune negative) •Type 2 diabetes (non insulin-dependent diabetes mellitus (NIDDM) • Insulin resistance and impaired insulin secretion • Genetic component stronger for type 2 diabetes compared with type 1 •Other specific types of diabetes (e.g.) • Genetics disruption of B cell function • Genetic dysfunction of insulin effects • Endocrine disease (PCOS, Acromegaly, Cushing) • Disease in exocrine pancreas • Infection diseases • Pharmacological induced diabetes •Gestational diabetes Diabetes symptoms Classical symptoms • Hyperglycemia → excessive blood glucose • Glycosuria → glucose in urine → Loss of calories • Polyuria → excessive urination • Polydipsia → excessive thirst • Weight loss → despite polyphagia (increased appetite) • Ketosis → signs of ketosis; nausea, vomiting, and stomach pain • Risk for coma Complications • Cardiovascular disease • Small vessel disease • Eye vision • Kidney • Polyneuropathy Treatment of Type 2 Diabetes

• Life style changes • Diet, exercise, stop smoking • Pharmacological treatment • Suppress hepatic glucose output (Biguanides e.g. metformin) • Insulin sensitizing drugs (Tiazolidinediones e.g. rosiglitazone) • Insulin releasing drugs (Sulfonureides e.g. glyburide, Glinidines e.g. repaglinidine, GLP-1 agonist) • Insulin Polycystic Ovary Syndrome (PCOS)

The most common endocrine and metabolic disorder in women

. Hyperandrogenism . Oligo-, anovulation . Polycystic ovaries

. Obesity . Metabolic and CVD disease . Anxiety and Depression

Despite detrimental impact on women’s health, the etiology of PCOS is not well understood, but genetic, epigenetic, and environmental factors have all been implicated in its development. Pathogenesis in PCOS Pituitary

 LH Genetics /= FSH Sympathetic Hyperactivity

Ovary Chronic Adipose Tissue Anovulation

Impaired Follicle Obesity Development Adrenal

Insulin Resistance Hyperinsulinemia Hyperandrogenism

SHBG Hirsutism Acne Alopecia

Hypothalamic insufficiency

The GnRH slow down or stop → low LH and FSH Common characteristics of women with hypothalamic amenorrhea include: . Low body weight . Low percentage of body fat . Very low intake of calories or fat . Emotional stress . Strenuous exercise that burns more calories than are taken in through food . Deficiency of leptin, a protein hormone that regulates appetite and metabolism . Some medical conditions or illnesses

How does OCP work?

. Inhibits ovulation . Cervix secret → thick and impermeable for sperms . Endometrie → atrophy and enable implantation . Very effective → ~ 100%