Endocrinology The hard stuff

1. Endocrinology � The hard stuff

2. Topics Covered Oral Contraceptives HRT SERMs Metabolic Bone Disorders & their treatment

3. Oral contraceptives, HRT and SERMs.

4. OCP 3 types -Combined oral contraceptives (COCs) -Progesterone only contraceptives -�Emergency� contraception

5. Combined oral contraceptives (COCs) Orally active estrogen (ethinyl estradiol) + progestogen (eg norethisterone) = efficacy at minimal drug concentrations to suppress fertility

6. COCs E upregulates P receptors? increasing the sensitivity to P E & P suppress the HPG by �ve feedback to the hypothalamus & pituitary P mimics the luteal phase of the cycle P reduces volume and increases the thickness of cervical mucus ? inhospitable environment for sperm

7. COCs Inhibit follicular development and prevent ovulation (high P levels mimics luteal phase of cycle) Inhibits penetration of sperm through the cervix Take for 21 days followed by 7 days of placebo pill Withdrawal bleed during the 7 days of placebo pill

9. COCs- unwanted effects of E Increased incidence of thromboembolic disease Increased risk of endometrial cancer Breast discomfort Increased risk of breast cancer (?) Increase weight due to fat deposition Exacerbates cardiac failure, kidney disease due to oedema

10. Progesterone only contraceptives May be used when oestrogens are contra-indicated CVS problems, history of thrombosis (stroke, MI, PE) prior to major surgery, during lactation.

11. �Emergency� contraception 2 types combined E & P (prescription only) P alone (over-the-counter pill) when E contraindicated � 2 doses 12 hours apart, beginning asap and within 72 hours of intercourse � nausea and vomiting co-administered with an antiemetic

12. HRT & SERMs

13. HRT For management of menopausal symptoms Oestrogen�only HRT ONLY if previous Hx of hysterectomy Combined HRT for everyone else Progestagen to prevent endometrial hyperplasia.

14. HRT � ADVANTAGES control vasomotor symptoms (flushes) HRT is the first line choice if these are the only symptoms delay osteoporosis Ischaemic heart disease (IHD) (?) HRT should NOT be given to prevent IHD & avoided in those at high risk of IHD symptoms of Alzheimer�s disease (?)

15. HRT � DISADVANTAGES endometrial carcinoma * A WOMAN WHO HAS A UTERUS MUST NEVER TAKE UNOPPOSED OESTROGEN * breast cancer - increases risk after 5 years of use - contra-indicated if previous diagnosis of breast CA

16. HRT � DISADVANTAGES high risk of venous thromboembolism contra-indicated if high risk of VTE (overweight, FH, previous VTE) transdermal HRT less risk increases risk of CVA

17. HRT Benefits of treatment should outweigh risks Ultimately it is the patients choice 50% women discontinue after 1 year Treat: normal menopausal women for 5-7 years premature menopause until normal menopause age

18. HRT- routes of administration HRT formulations oral Transdermal HRT (patch / gel) Percutaneous slow release implant Intranasal spray Intravaginal oestrogens Learn advantages and disadvantages of each.

20. SERMsSelective Estrogen Receptor Modulator Do not have the classical steroid structure tissue selective action Can have both Oestrogenic and Anti-Oestrogenic effects

21. Tissue specific actions of SERMs

22. Tamoxifen- anti-cancer drug Breast tissue antagonist used to treat oestrogen-dependent breast tumours and metastatic breast cancers Has oestrogen-like effects on: Liver - lowers cholesterol bone - increased bone density endometrial tissue - increased risk of CA

23. TAMOXIFEN� side effects Endometrial changes (hyperplasia, polyps, cancer) Bone pain with bony metastases Hot flushes Menstrual irregularities Gastrointestinal disturbances

24. Raloxifene-treatment & prevention of postmenopausal osteoporosis ADVANTAGES: Reduced risk vertebral fractures (agonist) Decreased risk breast ca (antagonist) No increase in MI DISADVANTAGES: Increased risk venous thrombo-embolism/ Stroke Does not reduce vasomotor symptoms

25. Clomiphene fertility drug ?promotes ovulation Anti-oestrogenic in the hypothalamo-pituitary axis binds to hypothalamic ERs; blocks the normal negative feedback; the secretion of GnRH and gonadotrophins are increased

27. Clomiphene- Side effects Ovarian hyperstimulation leading to multiple pregnancies abdominal discomfort Hot flushes Endometriosis Nausea, vomiting, headache

28. Metabolic Bone Disorders Vitamin D deficiency Vitamin D excess Paget's Disease

29. Vitamin D Effects are: Stimulate intestinal absorption of Ca2+ (and Mg2+) and PO43-. This provides the ions necessary for normal bone mineralization. Also stimulates; osteoclast formation (bone resorption) and activity osteoblasts (bone formation) matrix protein synthesis or repression.

30. Vitamin D deficiency Definition: lack of mineralization in bone Results in �softening� of bone, bone deformities, bone pain; severe proximal myopathy. In children - RICKETS In adults - OSTEOMALACIA

31. Causes of Vitamin D deficiency Diet Lack of sunlight Gastrointestinal malabsorptive states Renal Failure Receptor defects (autosomal recessive)

46. Unwanted actions The increase in non-mineral osteoid may pre-dispose to fractures. Gastric pain and gastrointestinal upsets. Oseophagitis Bone pain These are important to note since they decrease patient compliance

47. Estrogenic Compounds Estrogens Tissue selective ER antagonists Tamoxifen (breast) Raloxifen (breast and uterus) Remember � Estrogenic effects are to inhibit PTH and osteoclast activity

48. Calcitonin Inhibits osteoclasts and 1a hydroxylase in the kidney. Treats osteoporosis, Pagets and hypercalcaemia Given i.m and resistance via antibody formation can occur. Learn the side effects (N&V generally a safe option)

49. Ergocalciferol 1. To prevent osteomalacia (defects in bone mineralisation due to vitamin D deficiency) and rickets (a juvenile form of osteomalacia) and disorders of vitamin D absorption. 2. To treat hypocalcaemias associated with hypoparathyroidism (preferable to PTH treatment - expensive, parenteral, more side-effects)

50. Practice Questions 3) What are 2 unrelated symptoms of adult GH defiency? (1) How would you administer GH in hormone therapy? (1) What is the main tissue mediator involved in GH linked growth? (1) Give 2 side effects of GH therapy (2) Name 4 endocrine causes of short stature in children (2) Name 4 non-endocrine causes (2) What suppression test would you use to diagnose hypothalamic GH deficiency? ( 1)