S5 Insulin and Sex Steroid Hormones

Question 1

Diabetes mellitus

Answer 1

A group of metabolic disorders characterised my chronic hyperglycaemia due to insulin deficiency, insulin resistance or both. It is associated with elevated glucose levels in urine.

Question 2

Diagnosis of DM

Answer 2

Diabetes is diagnosed in the presence of symptoms i.e. polyuria, polydipsia and unexplained weight loss, plus venous plasma glucose concentration:
• normal range 3.3-6mmol/L plasma glucose
• fasting ≥7.0mM, random ≥11.1mM both indicate DM
Also need to do laboratory tests to confirm;
• HbA1c - Glucose in the blood reacts with Hb to produce HbA1c. Poorly controlled diabetics can have HbA1c value >6.5%.

Type 1 diabetes is insulin deficiency, type 2 is insulin resistance.

Question 3

What is the role of insulin?

Answer 3

Stimulates uptake of glucose into liver, muscle and adipose tissue. Decreases hepatic glucose output via inhibition of gluconeogenesis. Inhibits glycogenolysis.

Question 4

Types of insulin

Answer 4

Animal Porcine & Bovine. Recombinant DNA technology allows development of analogues; by modifying insulin (B26-30 region) to alter pharmacokinetic properties such as absorption. 6 main insulin categories, all absorbed into blood stream via subcutaneous injection;• Ultrafast acting (e.g aspart) fast onset
• Rapid acting (novorapid), lasts 4-6h
• Short acting (actrapid), lasts 8-10h
• Intermediate acting (isophane), lasts 12-20h
• Long acting & very long acting (glargine), slow onset, lasts 50+h

Question 5

Insulin adverse effects

Answer 5

Hypo (too much) & hyperglycaemia (too little), lipodystrophy (death of fat cells), Painful injections, Insulin allergies

Question 6

Oral hypoglycaemic agents

Answer 6

Blood glucose can rise due to insulin deficiency (beta cell failure) or resistance.

Question 7

Treatment of type 2 diabetes

Answer 7

Lifestyle plus non-insulin therapies e.g sulphonylureas. Weight gain and hypoglycaemia can affect drug adherence. Target is HbA1c 6.5 to 7.5%.

Question 8

Metformin

Answer 8

• Reduces Insulin resistance leading to increased glucose uptake by tissues
• Reduces hepatic glucose production (gluconeogenesis)
• Limits weight gain
• Side effects include GI symptoms

Question 9

Sulphonylureas (gliclazide)

Answer 9

• Stimulate beta cells to release insulin

* Side effects: Weight gain, Hypoglycaemia

Question 10

Acarbose: α glucosidase inhibitor

Answer 10

• Inhibits breakdown of carbohydrates to glucose by blocking action of the enzyme α Glucosidase.
• Side effects: flatulence

Question 11

Glitazones

Answer 11

• E.g Pioglitazone, Rosiglitazone

* Increase insulin sensitivity in muscle and adipose tissue and decrease hepatic glucose output by binding PPARs

Question 12

Glucagon Like Peptide 1 Therapies

Answer 12

• E.g Exenatide, Liraglutide
• Increase insulin secretion from the beta cells
• Decreases Glucagon production from alpha cells
• GLP1 agonist side effects: nausea, GORD

Question 13

Gliptins or DPP-4 inhibitors

Answer 13

• E.g Linagliptin, Sitagliptin
• Inhibit enzyme (DPP4) that breaks down GLP1
• Side effects: GI upset

Question 14

Glifozins

Answer 14

• Selectively inhibits SGLT2 (Na glucose cotransporter) in proximal tubule
• Prone to UTI due to peeing out glucose
• Side effects: increased risk of LUTS, polyuria

Question 15

Different sex steroid hormones

Answer 15

All synthesised from cholesterol; cholesterolpregnenoloneprogesterone17-hydroxyprogesteronetestosteroneoestrogen.

Question 16

sex steroid hormone: Oestrogen

Answer 16

• Effects: Stimulates growth of the endometrium and breast
• Action: mild anabolic, Na & H2O retention, decrease bone resorption
• Side effects: breast tenderness, nausea, water retention

Question 17

Progesterone

Answer 17

• Effects: Stimulates growth of the endometrium and breast; maintains pregnancy
• Action: anabolic, increases bone density
• Side effects: weight gain, acne, fluid retention

Question 18

Testosterone

Answer 18

• Effects: Stimulates male characteristics e.g pubes, deep voice
• Action: anabolic, male characteristics
• Side effects: acne, aggression, high LDL

Question 19

Contraceptive Routes of Administration

Answer 19

Oral, transdermal patch, implants, nasal, vaginal

Question 20

Sex steroid hormone transport and pharmacokinetics

Answer 20

• Transport bound to SHBG (sex hormone binding globule, production upregulated by oestrogen) and albumin
• Liver metabolism: progesterone & oestrogen metabolised in one passage through liver
• Sex steroids stored in fatty tissue which increases half life
• Metabolites excreted in faeces and urine
• Bind to nuclear receptors: ER alpha & beta, PR A&B, AR 1&2

Question 21

Oral contraceptive pills

Combined oral contraceptive pill

Answer 21

• Oestrogen (ethinyloestradiol) + progesterone (levonorgestrel)
• Monophasic: fixed amount of oes and prog
• Biphasic: fixed oes, increasing prog
• Triphasic: variable oes, increasing prog
• Mechanism: prevents ovulation (inhibits FSH LH), thickening of cervical mucous and endometrium (prevents sperm entry)
• Adverse effects: Venous thromboembolism, MI, Hypertension
o Metabolised by CP450, so there efficacy is reduced by enzyme inducing drugs;
 Phenytoin, Carbamazapine, Rifampicin, Rifabutin (as all increase CP450)
o Broad-spectrum antibiotics can reduce efficacy of COCP as they affect flora reducing uptake of COCP
o Soya protein products enhance oestrogen absorption and reduce its storage

Question 22

Progestin-only pill

Answer 22

• Thickens cervical mucus so impenetrable to sperm.
• E.g: levonorgestrel, norethisterone, medroxyprogesterone
• Adverse effects: menstrual problems common

Question 23

Missed pill advice

Answer 23

Take last pill immediately and continue others as normal. May need extra contraception for next 7 days.

Question 24

Emergency contraception

Answer 24

Levonorgestrel (72h after sex), ulipristal acetate (120h after sex).

NB Remember: for the drugs to work, receptor needs to be present and because progesterone receptor expression is dependent upon oestrogen action, the oestrogen must be supplied either continuously or prior to the progestin.

Question 25

Postmenopausal Hormone Replacement Therapy

Answer 25

Can have unopposed oestrogen (E)RT or opposed oestrogen HRT. Help reduce menopausal symptoms e.g hot flushes, sweats, dyspareunia, osteoporosis.
Risks: can develop endometrial or ovarian cancers (ERT), breast cancer & thromboembolism (HRT), heart disease.
However can increase HDL and decrease LDL.
Administration routes: Oral, transdermal patch, implants, nasal, vaginal

Question 26

Inhibitors & antagonists

Answer 26

Weak oestrogens that block receptors.

Question 27

Clomiphene

Answer 27

• Ovulation induction: inhibits oestrogen to its receptor in the anterior pituitary, inhibits negative feedback, so results in increased FSH, LH expression

Question 28

Tamoxifen

Answer 28

• Reduces risk of breast cancer: Binds to oestrogen receptor in breast tissue and blocks oestrogen-stimulated myoepithelial cell division

Question 29

Anti-progestins

Answer 29

• E.g mifepristone: Partial agonist to progesterone receptor; inhibits progesterone action. Sensitises the uterus to prostaglandins, is used for termination of pregnancy and induction of labour

Question 30

Anti-androgens

Answer 30

• E.g Cyproterone: Partial agonist at progesterone receptor, that competes with DHT. Used to treat prostate cancer.

Question 31

Mixed agonists/antagonistsSelective estrogen receptor modulators (SERMs)

Answer 31

• E.g raloxifene; Protects against osteoporosis. Reduced risk of invasive breast cancer in postmenopausal women with osteoporosis

Question 32

Androgen replacement therapy

Answer 32

Implants – Testosterone/ Finasteride (prevent hair loss)

Can also be oral or intramuscular.