Hormonal treatment in Nonmalignant Gynaecological Conditions

Question 1

What is the only situation where you use only oestrogen therapy?

Answer 1

For HRT in women that have undergone hysterecomy.

This is because oestrogen alone = Causes proliferation of uterine endometrium/endometrial hyperplasia. And irregular menstrual bleeding in premenopausal women

Question 2

Describe the three types of oestrogen, describe their potency and there production prior to menopause

Answer 2

Most potent = E2 = Produced in ovaries

Second potent = E1 = Derviced from aromatisation of androstenedione from adrenal glands and ovaries

Least potent = E3 = Not from ovary, instead from irreversible metabolism of E1

Question 3

Describe the three types of oestrogen, describe their potency and there production after the menopause

Answer 3

After menopause E1 becomes most potent oestrogen = Because ovarian secretion of oestrogens cease.

Instead the remaining production of E2 and E1 comes from peripheral aromatisation of circulating androstenedione in adipose tissue

Question 4

Describe the different types of oestrogen receptor and where it is expressed

Answer 4

Alpha + beta oestrogen receptors

Alpha = Endometrium, bone, breast cancer cells, ovarian stroma cells, hypothalamus

Beta = Kidney, Brain, Bone, Heart, Lungs, intestines, prostate, endothelial cells

Question 5

Which oestrogen receptor mainly regulates oestrogens actions of the skeleton/bone

Answer 5

Alpha

Question 6

Which oestrogens bind more to which receptor

Answer 6

They can all bind to everyone one, But

E2 = Binds to both alpha and beta equally

E1 + Raloxifene = Prefers alpha (better for bone)

E3 + Genistein = Prefers beta

Question 7

Describe the metabolism and excretion of estrogens

Answer 7

Primarily done in liver

Phase 1 = Hydroxylation by cytochrome p450.

Phase 2 = Conjugation by glucuronyl transferases + Sulphotransferases.

E2 overall is rapidly cleared and only has a half life of 1.7hrs in circulation

BUT it lasts longer generally = Since it can be converted to E1 that acts also = And the oestrogen conjugates are excreted in bile and undergo
enetrohepatic recirculation

Half life or E1 = 4 times longer.

Question 8

How does SHBG levels effect the physiological effect of oestrogens. What increases/decreases SHBG levels

Answer 8

E2 that is bound to SHBG = Is not biologically active.

Throxine + E2 = Promotes SHBG meaning less overall activity

Androgens, insulin, corticoids, progesterons, and GH = Suppress SHBG production, meaning more overall activity

Question 9

How come oestrogens can be taken orally and still get absorbed and make it through first pass hepatic metabolism?

Answer 9

Normal oestrogens would bascially be all gone from hepatic metabolism

Ethinyl oestradiol = The addition of an ethinyl group prevents its inactivation and promotes absorption.

Question 10

Talk to me about SERMS

Answer 10

They bind to oestrogen receptors, having some agonist effects in some areas and antagonistic effects in other areas

Question 11

Describe 3 SERMs, their uses, their areas of action.

Answer 11

Clomiphene = First one discovered. Used in PCOS and ovulation infuction. Centrally blocks negative feedback of oestrogen, so you get a FSH and LH surge. Shown that it also slows bone loss if opphorectomised rats

Tamoxifen = Oestrogen antagonist at the breast, but agonist in skeleton and cardiovascular system. But it does cause endometrial hyperplasia +/- adenocarcinoma. (so also acts in uterus)

Raloxifene = Inhibits bone mineral density loss, but does not stimulate endometrium, and is antagonist at breast. So does not increase risk of breast/endometrial cancer. But helps bones.

Question 12

What areas of body produce endogenous progesterone? Outside of pregnany what is the biggest source of progesterone endogenously?

Answer 12

Largest source outside pregnancy = Corpus luteum

Other production areas = Adrenal cortex + glial cells in CNS produce small amounts.

Question 13

What effects does progesteron have on an oestrogen primed endometrium, and what effects on oestrogens

Answer 13

Overall progesterones have an anti-oestrogen effect

Progesterones downregulate E2 receptors by reducing synthesis.

They promote differentiation of glands/stroma and decidualisation

Progesterones also stimulate IGF-1

And stimulation 17-hydroxysteroid dehydrogenase production = Which converts E2 to weaker E1 sulphate version.

This induces endometrial sloughing and uterine bleeding

Question 14

Talk to me about metabolism and excretion of progesterones

Answer 14

Hepatic metabolism

Metabolised to pregnanetriols and preganediols which are also conjugated with glucoronides and sulphates (like oestrogens)

Then metabolites excreted in bile, with LITTLE enterohepatic recirulcation

Question 15

Talk to me about how progesterones can be given orally, including the 2 main types

Answer 15

The natural ones cannot be given orally as they are just metabolised by microrganisms and digested

Natural ones can be used transvaginally or transrectally however

But for oral = Need to use synthetic preperations. There are 2 types

1) 21 carbon steroids derived from 17alpha hydroxyprogesterone
2) 19 carbon steroids derived from nortestosterone

Question 16

Talk to me about the 21 carbon steroid synthetic progesterons. Include examples and when they are used

Answer 16

Examples = Medroxyprogesterone acetate and dydrogesterone

These = Simulate profile of progesterone closer. Esp their effects on HPA and on carb and lipid metabolism.

Medroxyprogesterone = Probably most widely used in this group in depot contraception. And in oral form for HRT and treatment of endometriosis and menorrhagia

Question 17

Talk to me about the 19 carbon steroid synthetic progesterons. Include examples and when they are used

Answer 17

This group can be further divided into 2

Compounds related to norethisterone (estranes) 
Or levonorgestrel (gonanes). 

Norethisterone (estranes) = Has androgenic properties.
Widely used in OCP. Various types include norethisterone acetate and etynodiole diacetate = Both all of these are converted in vivo to norethisterone because they are active.

levonorgestrel (gonanes)= This is northisterone with additional methyl group. All drugs in this class act by eventually turning into levonorgestrel 
Norgestimate for example = Is a prodrug that turns into levonorgestrel. 
Gestodene + Desogestrel are 2 other similar examples used for OCP and HRT.

Question 18

Talk to me about levonorgestrel oxime, what group is it in, and where is it used

Answer 18

This is a progesterone in the gonane/levonorgesterel group.

This levonorgestrel oxime version can be given as a weekly contraceptive patch

Question 19

Talk to me about drospirenone, what is it, what group is it in, and where is it used

Answer 19

This is a new progesterone in the gonane/levonorgestrel group.

Chemically similar to spirnolactone and has potent progesteron activity
Can be used as antimeral corticoid and to antiandrogenic effect

Question 20

What is the purpose of adding progesteron to HRT

Answer 20

To prevent endometrial hyperplasia and/or cancer in women that have a utuerus

To counter the effects of the oestrogen.

Routes = oral, transdermal patch, or as IUS

Question 21

What sort of progesterone is given in an IUS

Answer 21

Levornogestrel = Remember this is from the 19 carbon steroid group, and further subclassed into the gonanes/levornogestrel group

Question 22

Whats in yasmin pill, what is it used for

Answer 22

This contains ethinyl oestradiol

And the progesterone is Drospirenone = This is the newer progesterone that has potent antimineraloid and antiandrogenic effect

This is why the Yasmin or Yas pill is used for acne and contraception

Question 23

Talk to me about the general common side effects of progesterones

Answer 23

Weight gain
Acne (except for some special ones discusse in a moment)
Fluid retention
Headaches
Breast tenderness
Sedation + Mood changes reflect progesterone binding to GABA in CNS.

Question 24

Describe how some progesterones actually have anti-androgenic effect. And name these

Answer 24

SOOOOO
19 carbon steroid progesterones generally if used alone = Have androgenic effects like acne and hisutism becuase of their similarities to testosterone.

HOWEVER = When they are used in combination with a ethinyl estradiol they suppress ovarian androgens and have a beneficial effect on SHBG = MEANING overal antiandrogenic.

So all the acne pills will have ethinyl oestradiol + some sort of 19carbon progesterone.

Question 25

Which progesterone in a OCP will cause less bloating and weight gain and why

Answer 25

Drospirenon = Remember this is new one with antimineraloid and antiandrogenic effect

Therefore causes less bloating and weight gain (as less aldosterone means you lose water).

Question 26

Describe what danazol is. What effects it has on the body, and the side effects

Answer 26

Danazol = A derivative of ethinyl testoesterone.

Action = orally active. It inhibits pituitary gonadotrophins. But also has androgenic effects, and milder oestrogenic and progesteronic activity

Side effects = Mainly androgen related things like weight gain, acne, and seorrhoea, mild hirsuitium, oedema, hair loss, voice change, or deepening of voice pitch.

Indication = Can be used to treat endometriosis, but this has mainly been replaced by GnRH analogues as these have less masculinising side effects.

Question 27

What effect do synthetic GnRH antagonists have on the HPA

Answer 27

GnRH antagonists = These prevent the endogenous GnRH from binding and therefore causing a pharmacological hypophysectomy.

Question 28

Describe the mechanism of action of giving non-pulsatile GnRH agonist. The effect it has, and the indications, as well as the ‘flare’

Answer 28

Effect of nonpulsatile GnRH = causes downregulation of GnRH receptors, but exact mechanism is unclear.

Indication = Used to treat endometriosis, or any other condition where you want to suppress oestrogen. Like with wanting to shrink fibroids prior to surgery.

Flare = Obviously as an agonist you initially get a gonadotrophin rise = Therefore need to warn that there is a temporary worsening of symptoms in the first 2 weeks.

Question 29

Describe the side effects of GnRH agonists. As well as the methods of devliery

Answer 29

Methods of delivery = 3 months injection, monthly or even daily infections. Also can be nasal spray

Side effects = Get symptoms like with menopause as you are lowering oestrogen. So hot flushes, night sweats, insomnia, decreased libido, headaches, mood swings, vaginal dryness, change in breast size, acne, muscle pains, poor mood.

Bone = You also get fall in bone density just like in menopause. But most of this bone loss is regained 18-24 months after finishing treatment.

Question 30

Talk to me about using progesterones alone for treatment of menorrhagia

Answer 30

You need to take a full 21 day course of progesterones for it to work to reduce menorrhagia

Progesterone = A variety including both 21 and 19 carbond progesterones can be used.

IUS = Cochraine showed it worked but pills were less acceptable then IUS levonorgestrel

Side effects = Cochrane also showed that half of women taking oral progesterones did not feel well or very well. Only 22% choosing to continue treatment after 3 months.

Question 31

Talk to me about efficacy of using OCP for menorrhagia

Answer 31

Anecdotally + historically = Been used for many years to treat menorrhagia.

But a Cochrane review from 1997 showed limited evidence to support COCP over mefenamic acid, low dose danazol or naproxen.

Question 32

Talk to me about using IUS for menorrhagia, and the pros and cons over the other methods

Answer 32

IUS levonorgestrel = Appears to actually be more effective then 21 day progesterone for heavy menorrhagia.

More women with IUS are satisfied and happy to continue treatment

BUT main side effects with IUS = Intermenstrual bleeding, and breast tenderness.

Question 33

Talk to me about using danazol for menorrhagia, and the reasons we tend to njot

Answer 33

Evidence = Danazol actually has evidence to work well for menorrhagia, actually better then progesterons, NSAIDs and COCP.

Danazol also significantly lowers duration of menses = Compared to NSAIDs and IUS.

But = Use is heavily limited by androgenic SEs.

Question 34

What is the evidence for COCP and dysmenorrhoea

Answer 34

Cochrane review = Shows actually very limited evidence for COCP. And no evidence between the different COCP preperations

Question 35

How much and for how long should we be giving progesterones in adittion to oestrogens in HRT for women with uterus

Answer 35

Remember = We add on progesterone because unopposed oestrogen increases risk of endometrial cancer and hyperplasia

Evidence = Need at least 12-14 days of progesterone each cycle to protect. Less then this and still get risk of endometrial abnormalities.

Question 36

What are the different routes of administration of oestrogen in HRT, and what are the pros and cons

Answer 36

Patch = Changed every 1-2 weeks. Main thing is skin reactions that stop use in 5% of patients.

Implants = Changed every 3-6 months, and very simple to insert in subcut fat. This is no longer used in UK as can cause tachyphylaxis and you need to get new ones isnerted at ever decreasing intervals.

Oral = Increases risk of CVD as there is fist pass metabolism?? smth like this.

Question 37

What are the long term risks of HRT

Answer 37

VTE = Partly because of reduction in antithrombin 3 levels.

Other risks = Gallbladder disease, stroke, breast cancer (esp with longer term therapy). But the actual risk of these conditions individually is small.

Question 38

What is the benefit of using progesterones alone for HRT

Answer 38

Benefit = Has actually been shown to help with hot flushes. Things like oral norethisterone or oral medroyxprogesterone or oral megestrol/

No evidence to show it helps with other symptoms

Bone = Some data to show that progesterone allow may preserve some bone density

Question 39

Talk to me about tibolone for HRT. What is it, what are the benefits, and the main side effects

Answer 39

Tibolone = Synthetic steroid that has all 3 of oestrogenic, progestrogenic, and androgenic effects and is often given orally as an alternative of classical HRT>

No withdrawal bleed = The tibolone is broken down into different isomers. The particular isomer present in endometrium has a prostogenic effect, so the endometrium atrophies. Meaning no stimulation and therefore no withdrawal bleed.

Benefit = So it can be used for menopausal symptoms + Prevention of bone loss with no withdrawal bleed

Side effects = Reflect androgenic and prostogenic actvitiy, include mainly weight change, ankle swelling, dizziness, headache, vaginal bleeding, GI sympotoms, hirsutism, depression, and joint pains.