Steroid-based Drugs

Adrenocortical
Hormones
right
adrenal
glandy.

BIMM118

I
kidney

kidney

Adrenocortical Hormones
Adrenal gland:

Medulla:
produces Epinephrine
(stimulated by sympathetic impulse)

Cortex:
Zona glomerulosa produces Aldosterone
(stimulated by Angiotensin II and ACTH)
Zona fasciculata produces Glucocorticoids
(stimulated by ACTH = Corticotropin)
Zona reticularis produces Androgens
(physiological role unclear)

BIMM118

Negative feedback

""-

Epinephrine stimulates

ACTI-!release

Adrenal

21

Steroid hormone synthesis:

27

26

C21

-+~

~_,rh....
..,-C" -CH,

C21 hydroxylase:

#i~CH,

P450C17 hydroxylase:
Produces 17-Keto-steroids (-> l)
=> Sex hormones

17a-OH
pregnenolone

i........-r

O
C2,

c.,

0
U

II ~;:,

HO

Dehydroepiandrosterone (DHEA)

C,

<,
g

11

m=rC-C-OH ~t;;-OH
O

11-Desoxycorticosterone

d
i

+1-

11 -Desoxycortisol
1.
1
Metopyrone
-i

OH,
II I

C2,

0 H,

~~~~-c-OH
~-,OH

~c-c-oH

t ""-'
t?:10

Etiocholanolone,
androsterone,
and other
1 7-ketosteroids

Androstenedione

o!

#0

c.,

kit

c.,

BIMM118

H
Cortisone (CpdE)

#OH_/
0

Testosterone

it y/c., s!
#OH HO

Estradiol

Dihydrotestosterone

Female sex steroid

Precursors
Mineralocort1coid

Male sex steroid

Intermediates

t!

C19

Estrone

Cortisol (CpdF)

#OH
Aldosterone

~,

HO

Corticosterone

im

,e&bf,O

1 7 r, -OHprogesterone

C2,

Pregnenolone

OH

Progesterone

C17 hydroxylase:

=> Sex hormones and glucocorticoids

,CU"-'

C_ct5tf.~21
17.f- CH,

HO

=> Only mineralocorticoids

Hydroxylation of C17 (-> f, g) can be followed
by hydroxylation of C11 and C21 (-> h, j, k)

.(1-J-~-CH,

~~!g

Pregnenolone synthesis is rate-limiting step

Prevents hydroxylation of C17 (-> c)

OH

Glucocorticoid

17-ketosleroid

21

Steroid hormone classification:

C21
C 3: =O

C17: -OH or =O

C2,

26

-+~

Progesterone:

27

OH

~1~~-CH,

,(XJ "-"

Cho estero
l

~~!g

A_A,rJh'"
-" C-CH

Mineralocorticoids:

Pregnenolone

OH

C2,

.f-CH3
HO

17t,-OH

OH

C21
C21, C17: -OH
C 3: =O
C11: -OH or =O
C18
C17: -OH or =O

im

J:)J'"

C2,

O
II ~2

ffc-C-OH

C2,

OH,
II

11-Desoxycortisol

0 H,

~-6-0H

~~

J :}

',OH

Etiocholanolone,
androsterone.
and other
1 7-ketosteroids

~,

Androstenedione

o!

1.,

-i

C2,

~c-c-oH

t '\."

C,9

Melopyrone

I-

Dehydroepiandrosterone (DHEA)

HO

corticosterone

di

OH

0 H
II ,1
~o

~-g;:-OH

t r-Desoxy-

CH,

1 7 r, -OHprogesterone

Estrogens :

pregnenolone

_ , ji:-J<:f-

Glucocorticoids :

4......-r

Progesterone

C21
C21: -OH
C3: =O

C,a

C19

tt

#OH_/

~o

HO

:)

'"
BIMM118

C 3: -OH

Androgens :

C19

Corticosterone

ei

Es tr one

Cortisol (CpdF)

kit

C2,
0

O H,

c.,

it y/

Testosterone

s!

C,9

C17: -OH

. :x:tr~-C-OH
'OH

C 3: =O

...J .
Aldosterone

#OH

#OH

HO

Cortisone (CpdE)

Estradiol

Dihydrotestosterone

Precursors
Minera1ocorticoid

Female sex steroid

Intermediates
Glucocorticoi
d

Male sex steroid

17-ketosteroid

Adrenocortical Hormones
Glucocorticoids (GC):

Inhibit all phases of inflammatory reaction

Promote fetal development (lungs)

Inhibit NFB nuclear translocation => transcription of proinflammatory
mediators is prevented

Upregulate lipocortin => inhibits PLA2 => no PG and LT synthesis

Undesirable effects of increased GC:

Immune suppression
Increased glucose release (=> steroid diabetes)
Glucose coverted to fat => adiposity
Increased protein catabolism => muscle atrophy
Salt and water retention (increased GC lead to reduction in ACTH => decreases
levels of aldosterone) => hypertension
Osteoporosis

BIMM118

Adrenocortical Hormones
Glucocorticoids (GC):

Adrenal cortex failure (= Addisons disease)

Lack of GC production:

Chronic fatigue and muscle weakness.

Loss of appetite, inability to digest food, and weight loss.
Low blood pressure (hypotension)
Blotchy, dark tanning and freckling of the skin
(feedback missing => increased corticotropin)
Blood sugar abnormalities
Inability to cope with stress

Adrenal cortex tumors (= Cushing Syndrome)

GC overproduction

BIMM118

Upper body obesity

Buffalo hump
Red, round face
Hypertension
Water retention
Thin skin and bruising
Poor wound healing

Adrenocortical Hormones
Glucocorticoids (GC):

BIMM118

Clinical uses:

Allergic Rhinitis
Rheumatoid Arthritis
Asthma
Multiple Sclerosis
Carpal Tunnel Syndrome
Dermatitis
COPD
Osteoarthritis
Gout
Psoriasis
Inflammatory Bowel Disease
Sinusitis
Lupus Erythematosus

Many conditions flare up if GC therapy is discontinued due

to adreno-corticol atrophy

Adrenocortical Hormones
Glucocorticoids (GC):

Hydrocortison (= Cortisol)
Main glucocortocoid in humans
Also binds mineralocorticoid receptor
(Cortison does NOT)
Used for replacement therapy (Addisons Disease)
Otherwise mostly topical application due to
sodium-retaining effects

c
~0

c. .
I V

8c
8

..J

12:00 PM

BIMM118

1I

I I

6:00PM.

12;00A.M
Timo of day

-Mean value

cortl~ol
h)

drocortl~11e

Cortisol

Cortison

Trans,ont
fluctuations

6:00 A.M

12:00 PM
0

Ml'J3/10Dt

Glucocorticoids (GC):

Prednisone
Inactive until converted to

HO...........

Prednisolone

12
II

I')

Drug of choice for systemic application

Lower sodium-retaining effects

8
l'-Ol"liwl

ltydn)
('ortl~t-

Prednisolone

HO
CH3

BIMM118

Prednisone

O
CH3

OH

OH

O
CH3
O

O
CH3

OH

OH

Adrenocortical Hormones
Glucocorticoids (GC):

HO
CH3

Triamcinoline
Stronger anti-inflammatory (5x) than cortisol
No sodium-retaining effect

HO
CH3

Dexamethasone
30x more potent than cortisol
No water and sodium retaining effects

OH
O

O
CH3

OH

OH
CH3

F
O

HO
CH3
F
BIMM118

Halogenated GC
Betamethasone

O
CH3

O
CH3

OH
OH
CH3

Adrenocortical Hormones
Glucocorticoids (GC):

Administration

BIMM118

Oral
Nasal
Cutaneous
IV
Inhalation

Steroid-based Drugs

Sex Steroids

Deve~in:g oocyte
.irud h~l li' cle

lfu Ft l.!Jr~(!
follttl~
Rille.'.lS~.

BIMM118

cd

'llllltI!a (!Ffg

(Otl!}!Js:

lutelllm

Mmp~

fute1J.1m

Cauda
Epldldymls

Sex Steroids
Female reproductive cycle
(

Gonadotropin Releasing Hormone

(GnRH) = Gonadoliberin

Hypothalamus
I

v
I

GnRH

stimulates release of

Follicle stimulating hormone

(FSH) = Follitropin

Anterior p,tuttary
T
I

and
Luteinising Hormone
(LH) = Lutropin

G-F

which trigger production of

which in turn negatively regulate

'----

BIMM118

CL

~.:n
~
x.s .c:

Estrogens (E) and Gestagens (G)

Pituitary (E+G) and Hypothalamus (G)

hormone production

Matura~

Oestrogens

y\

,,,.-,,./

'

Progesterooe ---"

Act on reproductive tract and other tissues

 Female reproductive cycle

Cycle length varies from 21-35 days

Estrogen inhibits
LH and FSH
release
0

Estrogen stimulates
LH and FSH
release

10

15

Menstruation 3-6 days

First (= Proliferative) phase:

:tu;;tio~fo~\~ (j

BIMM118

Consists of thecal and granulosa cells

which surround the ovum

10

20

25

_,,--/
Lu teinizing
hormone

mulating

Follicle-sti
Variable (7-21 days)
hormone
FSH and LH promote follicle development I
One follicle becomes the Graafian follicle
Oocyte
De':'eloping
(the rest degenerate)
Graaffian Follicle:

Estrogen inhibits
H and FSH
release

Ovulation

Corpus luteum

~ ~

15

Day of uterine cycle

20

Developing

fffiflyte

25

FSH-stimulated granulosa cells produce

estrogens from androgen precursors
generated by LH-stimulated thecal cells
Estrogens are responsible for the
proliferative phase: increase in thickness
and vascularity of endometrium; secretion 0
5
10
15
20
25
Day of uterine cycle
of protein+ carbo-rich mucus
Constant low estrogen inhibits LH/FSH production BUT high estrogen cause
surge of LH production => swellign and rupture of Graafian follicle = Ovulation

 Female reproductive cycle

Second (= Secretory) phase:
Secretory phase constant (~ 14 days)
LH-stimulated ruptured follicle develops
into Corpus luteum which secrets
Progesterone
Progesterone (Pg) is responsible for the
secretory phase: endometrium becomes
suitable for implantation; mucus thickens
Thermogenic effects of Pg =>

BIMM118

body temperature increase 0.5 C

Without implantation: Pg secretion stops
=> menstuation is triggered
With implantation: continued Pg production
which (via inhibition of LH and FSH prod.)
blocks further ovulation
Chorion (precursor of placenta) secretes
human chorionic gonadotropin (HCG) which
maintains endometrium lining throughout
pregnancy (HCG -> see pregnancy test)

Estrogen inhibits
LH and FSH
release

Estrogen stimulates Estrogen inhibits

LH and FSH
LH and FSH
release
release

15

10

20

25

/L uteinizing
hormone
Follicle-stimulating
hormone

Oocyte

De':'eloping

Ovulation

:tu;tio~fo~e C, (j
0

Corpus luteum

{ffJ/lyte

~ ~

25

10
15
20
Day of uterine cycle

10
15
Day of uterine cycle

Developing

20

25

 Female reproductive cycle

Menstrual c:yde

g0r\300tro,pic
h of rh0f'ltt

C\'t'nts

BIMM118

in ovary

uterine
lining
5

10

15

20

[).)~ ol tbe rncnstruol <:ydc

25

c,,

Estrogens

21

27

26

21

-+~

All produced from androgen precursors

"-"'

~~!

Cho estero

OH

Pregnenolone

C21

Three main endogenous estrogens:

~~-CH,

~,-....,..r.-1-11CCH
3

.~-CH,
OH
HO

17a-OH

Estradiol

Primary estrogen in humans

Breast development
Improving bone density
Growth of the uterus

Progesterone

i~r

+m

ff?,O

O#t~CH,
1 7 a -OHprogesterone
HO

e stradiol

*C-C-OH ~~;-OH
O
II

C21

7:.>

corticosterone

c,,

di

0 H
II

t '\.'

11

i+

C,,

0 H,

',OH
0

C2,

Androstenedione

oi ~'
1a

O
H,I
O
I
~,c-C-OH

C1a

t+

C19

0
Estrone

(CpdF)

kit

Etiocholanolone,

androsterone,
and other

C19

HO
Cortisol

Corticosterone

H 18 0
'c ~ 0 H,
ffg_C-OH

#0

11 -Desoxycortisol

~Y~~on-e ~

f-

OH,

C21

HO Dehydroepiandrosterone (DHEA)

1'.

c,,

II

HO

C19

Accelerating bone maturation and epiphyses closure

Development of the endometrium to support pregnancy
Promoting vaginal mucosal thickness and secretions
Increase HDL

Estrone

pregnenolone

it y/

*OH

C19

#OH

Testosterone

s+

Estriol

BIMM118

only during pregnancy (made by fetus)

0
Aldosterone

HO
Cortisone (Cp@

Estradiol

Precursors

Mineralocorticoid

Female sex steroid

Intermediates
ketosteroid

Glucocorticoid

Male sex steroid

H
Dihydrotestosterone

17-

Estrogens
Estrogens induce expression of progesterone receptors
Progesterone inhibits expression of estrogen receptors
Two types of estrogen receptors => potential for selective drugs

Estradiol
Not suitable for oral administration (rapid hepatic elimination)
=> stable derivatives:

Ethinylestradiol

HO

Diethyl-Stilbestrol

BIMM118

Stilbene derivative

HO

Estrogens

Mestranol
Used in oral contraceptives
Inactive => Cleavage of C3-methoxy group
yields ethinylestradiol

HJC

<, 0

Mestranol

Raloxifene
Selective estrogen receptor modifier (=SERM)
Antiestrogenic effects on breast and endometrium
Estrogenic effects on bone and lipid metabolism
=> use in postmenopausal osteoporosis

BIMM118

Clinical uses of estrogens:

Replacement therapy (Turner syndrome; menopause)
Contraception
Cancer therapy

OH

Anti-Estrogens

Tamoxifen
Antiestrogenic effects on mammary tissue
Weak estrogenic effects on bone and lipid
metabolism
'-....N/'...._/0

I
tarnoxren

Clomiphene
Inhibits estrogen binding in the pituitary
=> prevention of negative feedback=> ovulation

Clinical uses of anti-estrogens:

Breast cancer therapy (Tamoxifen)
Infertility (Clomiphen)

/N~O
CJom.iphene

Progesterons

Progesterone
Inhibits rhythmic contractions of the myometrium
Not suitable for oral administration
(rapid hepatic elimination) => stable derivatives:

Hydroxyprogesterone

Medroxyprogesterone

CH:3

BIMM118

17-Alpha-hydroxyprogesterone

l\'ledroxyirogesterone

Progesterons
Testosterone derivatives with progesterone activity:

Norethindrone

CH OH
3

c-cH

Norgestrel
0

BIMM118

Desogestrel

no rethin
drone

norgestrel

Anti-Progesterons

Mifepristone (RU486)
developed during the early 1980s by the French company Roussel Uclaf
while investigating glucocorticoid receptor antagonists, they discovered compounds
that blocked the similarly shaped progesterone receptor. Further refinement led to the
production of RU 486
Clinical testing of mifepristone as a means of inducing medical abortion began in
France in 1982. Results from these trials showed that when used as a single agent,
mifepristone induced a complete abortion in up to 80% of women up to 49 days
gestation.
Addition of small doses of a prostaglandin analogue (=> see misoprostol) a few days
later to stimulate uterine contractions, a complete medical abortion is achieved in
nearly 100 percent of women
approved in the US in 2000 for the termination of
early pregnancy (defined as 49 days or less)
CH OH

BIMM118

"'~-3""' c=

RU486: Mifepristone

CCf\

 Male reproductive system

J----

Gonadotropin Releasing Hormone

(GnRH) = Gonadoliberin

~~lamus

stimulates release of

Follicle stimulating hormone (FSH)

(Stimulates Sertoli cells =>
promotes gametogenesis)
and

Testosterone (T) (by Leydig cells)

]
Allte,riorpituitary"" ----<.:=>---,

+
I

ICSH
Sertoli

cell

_ , .: ; .
0
tWn

G~1ogenesis
semoin
nttheerous
_,,
tubules

which in turn negatively regulates

Pituitary and Hypothalamus hormone production
BIMM118

ct'

'

Luteinising Hormone (LH) =

Interstitial Cell Stimulating Hormone (ICSH)
which triggers production of

GnRH

-,
TestoVsterone ---

Dlh ydrote'Its' tosteron

seccocary sex organs

Sex Steroids
Androgens

Testosterone

CH3 OH

Primary androgen in humans

Possesses androgenic and anabolic effects:

CH3

Androgenic effects:

Growth and development of male sex organs

O
Important for (male) sex drive and performance
Development of secondary sexual characteristics
Important role in spermatogenesis

Anabolic effects:

Development of muscle mass

Reverse catabolic or tissue-depleting processes

CH3 OH

Dihydro-Testosterone

CH3

BIMM118

Active metabolite
Mediates most of testosterone actions

Sex Steroids
Androgens

R
CH3 OH

Testosterone
Hepatic elimination after oral administration
Also short half-life after injection => ester derivatives:
Proprionate, enanthate, cypionate

CH3

Fluoxymesterone
Hepatic elimination after oral administration
HO
CH3
F

BIMM118

CH3 OH
CH3

Sex Steroids

CH3 OH
CH3

Anabolic Androgens
Testosterone derivatives: anabolic effects dominant

Nandrolone
CH3 OH

Injection
H
O

Stanozolol
oral administration
CH3 OH
CH3
CH3

BIMM118

HN
N

Sex Steroids
Anabolic Androgens

Dehydroepiandrosterone (DHEA)
Popular item in health food stores: DHEA was prescription only until
recently when changes in federal law labeled it as a nutritional
supplement (DHEA sales now equal that of melatonin)
Is actually a testosterone precursor
Supposedly by maintaining youthful DHEA levels one can improve mood,
memory, energy and libido, while preserving lean body mass and counteracting
the effects of stress hormones.
DHEA may have serious side effects:

BIMM118

If it abnormally increases testosterone, then testosterone side effects may be

expected, including acne, testicular atrophy and increased risk of prostate cancer.
Women taking excessive doses of DHEA have reported acne and facial hair.

DHEA can also be converted into estrogen, so high levels of DHEA can lead to
estrogen side effects as well, including gynaecomasty and increased risk of
breast cancer.
DHEA is often marketed as an anabolic steroid: This is misleading since as an
androgen precursor its metabolism will produce testosterone which has anabolic
properties

Sex Steroids
Anti-Androgens

Flutamide
HN

Non-steroidal receptor antagonist

CH3

Used in prostate cancer treatment

CF3

CH3

NO2

Finasteride
Inhibits 5-reductase => prevent conversion of
testosterone into the more potent dihydrotestosterone (DHT)
Used to treat prostate gland enlargement and hair loss
(bald man have higher average levels of DHT)
O
CH3

BIMM118

CH3

N
H H

N
H

CH3
CH3
CH3

Sex Steroids
GnRH analogs/modifiers

Inhibits GnRH release => no FSH/LH production

=> no steroid production
Used to treat endometriosis
(growth of endometrial tissue outside of the uterus)

CH3 OH

Danazol
CH3
N
O

Synthetic GnRH (Gonadorelin, Buserelin, Leuprorelin)

BIMM118

Up to 200x more potent than GnRH

If given in pulses (s.c.) stimulate gonadotropin release => induce ovulation
If given continously they desensitize the GnRH receptors => gonadal
suppression (medical castration)
Used in sex hormone-dependent conditions (prostate, breast cancer;
endometriosis; uterine fibroids)
Side effects: menopausal symptoms

CH

Sex Steroids
Oral Contraceptives

History
1937: Investigators demonstrated that the female
hormone progesterone could halt ovulation in rabbits
1949: Scientists at the University of Pennsylvania
achieved the production of synthetic progestins
1953: Margaret Sanger, Katherine McCormick and Gregory Pincus team up to
develop a reliable contraceptive
1950s: Large scale testing of the pill was successful
1960: FDA approves first oral contraceptive
(Early pill formulations contained up to 150 micrograms (mcg) of estrogen!)

BIMM118

1982/84: Introduction of the bi- and tri-stage formulation

1988: FDA recognized several severe long-term side effects (high estrogen!)
Currently used by 16 mill. women in the US (40% of women between 18 and 24

Sex Steroids
Oral Contraceptives
Either combination estrogen/progesterone of progesterone alone

Combination pills:

Highly effective
Estrogen component is mostly ethinylestradiol, sometimes mestranol
Progesterone component varies
21 day cycle with 7 day break (causes withdrawal bleeding)
Can be mono- or biphasic

BIMM118

Mechanism:
Estrogen inhibits FSH secretion (neg. feedback loop!)
=> suppression of follicle development
Progesterone inhibits LH secretion (neg. feedback loop!)
=> inhibition of ovulation; also increases mucus viscosity
Both steroids alter endometrium => prevent implantation

Sex Steroids
Oral Contraceptives
-

Estrogen

--

....

: ..

,.,

....

..

,
..

i>;/

Days of cycle

14.

r'

' -,::

tT

. .

:--

'.(.

(.:

~:~, ~:::

;.

'fi,'. ~j: :f.

'

Monophasic preparations

.. i>'
;. r , ..
)};
. ;., ,..- {~~
}J} '

l1

';'.
'"').

,.

lh~ ;~1 ~}l "_:.:-r .:.::~:: .J/,.. . ...

~},; it''. ?1 ~f:;{
"'

-,..,

: ~

,.,,,

1;,,.~

,::

,..T

One-stage regimen

.
-- k

, ..,

:--

-' , ...

r .. r~

:~-~ k,

jJ

:t, -. 'I~
,.,_
_

BIMM118

It~ ~!1; n1:::. '.:tt/~~-:j r,,, . II!~

~i ::

(:'

Two-stage regimen

~
-:

-,

...

.
;

,.-'"

'

Three-stage regimen

Contraceptives

Mini Pill:

Contains only a progesterone (Levonorgestrel, Ethynodiol)

Used when estrogen in contraindicated (e.g. thrombosis)
Taken daily without interruption
Acts mainly by increasing viscosity of mucus
(Mucolytica in cough medicine can cause failure)
Less reliable than combination pill

OepoProvera---

---

'

--

Postcoital contraceptives (Morning after pill)

High dose of progesterone (Levonorgestrel)
Must be taken within 72 hrs
Nausea and vomiting are common side effects

Depot and patch formulations

BIMM118

Injection of oily depot formulations every 3 month

Transdermal delivery systems

m.l.

__
_ __

occt,0:,.......C,

0,,.1,..Wt

100

...

mu

Oral Contraceptives
Side effects:

Thrombosis
Hypertension
Intermittant bleeding
Weight gain
Depression
Nausea
Loss of libido

J'UST WMAT ffi WUSIWIO

NttDSANOTJ.lER .:XCVSE
TO

GAIN 'WEICIIT AND HAVE

./'\OOD S\./INGS/

Drug interactions:
Steroids are metabolized by P450 enzymes
Minimal dose of steroid is used to prevent risk of thrombosis
Any increase in clearance by P450-inducing drugs can result in contraception failure

BIMM118

Frequent cause of OC failure is diarrhea (diminished time for absorption)