Hormonal Drugs

Question 1

Lecture Outcomes

Answer 1

Describe the basic structure of steroid hormones
Outline how endogenous steroid hormone levels are kept within a
normal range by feedback mechanisms
List other steroid hormones and therapeutic drugs related to them
Describe what male sex hormones, i.e. androgens, do in the body
Outline when androgen replacement therapy should be prescribed
Describe the difference between androgen misuse and abuse, i.e. one is
legal while the other is illegal but neither are appropriate
List the problems caused by androgen abuse

Question 2

What are Steroids?

Answer 2

Organic compounds with 4 carbon rings
Cholesterol
Rings are named A to D & carbons are numbered
Cholesterol side chain is cleaved off - SCC
To produce other endogenous steroids - steroid hormones

Question 3

What are
Hormones?

Answer 3

Endocrine glands such as:
thyroid
pancreas
adrenal glands
ovaries & testes
…secrete hormones that:
travel in the blood
to distant targets
(not all hormones are steroids, e.g. growth hormone)
Blood borne chemical messengers

Answer 4

Question 4

Hormone levels are actively kept
within limits - ‘normal range’

Answer 4

Answer 5

Question 6

Steroid Hormones

Answer 6

Many functions… - many drugs:
Androgens Inhaled glucocorticoids Oral contraceptives

Question 6

Steroid Hormones Include:

Answer 6

1. Corticosteroids -
   Glucocorticoids - cortisol/hydrocortisone etc.
   (Mineralocorticoids)
2. Female sex hormones -
   Oestrogens/estrogens
   Progesterone
3. Male sex hormones - Androgens incl. testosterone

Question 7

Corticosteroid
Side Effects

Answer 7

Severe, especially with:
high dose
systemic (oral)
CUSHINGOID:
fat deposition - moon face,
buffalo hump, central obesity
thin skin - bruising & stretch
marks
many other problems

Question 8

Endogenous Androgens

Answer 8

Testosterone
DHEA
Androstenedione
Produced mostly by the testes but a little by the
adrenal cortex

Testosterone is the primary natural androgen
Synthesis of endogenous testosterone is tightly controlled

Question 8

1. Corticosteroids - widely used
   in clinical practice

Answer 8

ANTI-INFLAMMATORY DRUGS
asthma
allergic rhinitis/hay fever
arthritis & joint injuries
dermatitis/eczema
inflammatory bowel disease
premature infants
eye disease
many more.

Question 9

2. Estrogens/Progestogens

Answer 9

Also very widely prescribed in clinical practice:
birth control
menstrual irregularities
hormone replacement therapy

Answer 10

Question 11

Control of Testosterone Synthesis

Answer 11

Question 12

Legal Clinical (Prescribed)
Uses of AAS

Answer 12

Appropriate AAS use = Androgen Deficiency:
congenital (born with) or acquired (disease or trauma)
life expectancy is normal
but significant effects - ↓ vigour, ↓ bone & muscle mass,
↓ red blood cells
treated by androgen replacement therapy (ART) wikipedia
AAS misuse - prescribed clinically by doctor - still legal but inappropriate:
prescribed with no acceptable medical indication - infertility or erectile dysfunction

Question 13

Illegal Use of AAS = Steroid Abuse

Answer 13

Involves using androgens obtained without a legal prescription
(i.e. no medical indication):
sporting - competitive, usually power sports
professional - bouncers, security, wrestling
recreational - bodybuilders, “body beautiful”

Question 13

The evolution of steroid abuse

Answer 13

Brown-Séquard - 19th century doctor/experimentalist
Injected himself with testicular extracts from guinea
pigs & dogs
“Restored vitality”
Recent study → testicular extract [testosterone] too
low for any effect!
1935 - testosterone first isolated & synthesized by Butenandt &
Ruzicka → Nobel Prize (1939)
Then used for medical purposes only but soon enough…

Question 14

When AAS must not be used

Answer 14

Question 15

Legal aspects

Answer 15

Anabolic steroids (performance & image enhancing drugs -
PIEDs) are controlled drugs in Australia
Therefore, it is illegal to possess, use, supply, manufacture,
import or trade PIEDs without a prescription or a licence
People convicted of importing PIEDs face maximum fines of
$110,000 &/or 5 years gaol!
“Supplements” are untested and often contain unlabelled
steroids → athletes beware

Question 16

The problems begin

Answer 16

WWII - testosterone apparently used by Nazi
soldiers to ↑ strength & aggression
1954 - USSR weightlifters dominate world championships
1950s - other power based sports - elite athletes only
1970s - competitive bodybuilders catch on
1975 - IOC bans anabolic steroids
1976 - East German ♀ - 11/13 golds at Montreal Olympics
1988 - Ben Johnson → out of competition testing

Question 17

It’s been going on for
many years…

Answer 17

Olympic marathon winner in 1904 - Thomas Hicks
Given strychnine & brandy during the race -
needed treatment by 4 physicians after!
Heroin, morphine & cocaine also used in early
Olympic Games

Question 18

Performance Enhancing Drugs in Sport

Answer 18

Question 19

WHY do athletes TAKE AAS?

Answer 19

supra-physiological AAS doses → users moderately ↑ muscle
mass & strength
swifter recovery
steroid abusers stack (40-100x) → increases&raquo_space; normal limits
testosterone levels in ♀<♂/10 → ♀ benefit more from steroid
abuse
♀ - 0.4 sec, ♂ - 0.2 s over 100m (Victor Conte)

Question 20

Use of synthetic androgens

Answer 20

Endogenous anabolic androgenic steroids have 2 problems:
strong androgenic effects (+ oestrogen effects)
cannot be taken orally

AND anabolic steroid abusers tend
to use very high doses (stacking)

Synthetic androgens developed to:
maximise anabolic effects
↓↓ oestrogen effects and ↓
androgen effects
oral rather than injected
BUT no synthetic androgens are
purely anabolic

Question 21

Adverse effects of AAS

Answer 21

Answer 22

Answer 22

Answer 22

Answer 23

Question 24

What’s New? - SARMs

Answer 24

Selective Androgen Receptor Modulators (SARMs):
androgen receptor agonists
but are not steroids
stimulate muscle growth
developed to treat muscle wasting and osteoporosis of ageing

None have been approved for medical use
but they’ve been hijacked for their androgenic effects
found in ‘dietary supplements’
athletes - Shayna Jack in 2019, GB 4x100m relay Tokyo

Question 25

Learning
outcomes

Answer 25

1. To describe how the human
   reproductive cycle works, including
   the function of pre
   -Pill contraceptive
   interventions.
2. To identify key individuals and events
   in the development of an effective
   hormonal
   -based form
   of contraception.
3. To identify issues around the FDA
   approval and post
   -marketing impact
   of the Pill to the present day.
4. To describe new directions in
   hormonal contraceptive
   development.

Question 26

How to
make an
entirely new
human being

Answer 26

 Penis into vagina – with or
without male orgasm.
 Any live sperm can reach a
viable egg if the woman is
ovulating.
 Fertilisation can take place
within minutes -> up to five
days later.
 Sperm can live up to five days
in the uterus and fallopian
tubes.

Question 27

The human
reproductive
cycle and
‘surprise
pregnancies’

Answer 27

 Reproduction is a major drive in any species.
 Dimorphic sexual intercourse is the normal means by
which the human species reproduces.
 Timing of intercourse is not determined by oestrus
cycle (as in animals): choices.
 Sexual intercourse is specifically designed to produce
new human beings.
 This is why no form of contraception is 100% effective.
 This is why there should be no such thing as a
surprise pregnancy!

Question 28

Fertility
control before
the Pill – the
ancient world

Answer 28

 Most ancient cultures believed that
men and women both contributed to
baby-making.
 However, only women were believed
to be infertile – like a field or a tree.
 Most ancient cultures were desperate
to have more children to maintain and
increase their populations.
 High infant mortality, early mortality,
death in childbirth, risk of invasion.
 Cultures with sick or disabled children
exposed them at birth or sacrificed
them.
 Contraceptive attempts very often
found in records relating to
prostitution.

Question 28

Fertility control
before the Pill
– the ancient
world

Answer 28

Barrier methods: vaginal suppositories - inserted
plugs of gum or fibre.
 Breast-feeding: suppresses ovulation.
 Coitus interruptus/withdrawal = fewer sperm
present.
 Douching = highly risky; can push sperm further into
the uterus.
 Abstinence = 100% effective.
Fallback:
 Use of abortifacients and infanticide.

Question 29

Why prevent
pregnancy?

Answer 29

 Not all unplanned pregnancies are
unwanted!
 When and why is a pregnancy
unwanted?
 Physical reasons:
 Women: 9 months, discomfort, painful
birth, need to provide for child
afterwards.
 Cultural/social reasons:
Women: shame, embarrassment, child is
not the putative father’s, public
humiliation, financial inconvenience,
evidence of infidelity, possible death
sentence in some cultures.
Men: financial obligation to raise child;
child is not putative father’s, evidence
of infidelity

Question 30

Fertility
control -
condoms

Answer 30

 First used as early as 15th century?
 Used primarily to prevent
transmission of STDs such as
syphilis.
 Made from linen, animal intestines
or bladder, thin leather.
 First rubber condom produced mid19th century.
 Latex used 1930s onwards.
Fallback:
Use of abortifacients and infanticide.

Question 30

Abortifacients –
for pregnancies
that had
already begun

Answer 30

 Ancient and medieval world:
 Herbal preparations which would induce uterine
cramping and expel a pregnancy.
 Traditional herbs included rue, pennyroyal, ergot,
nutmeg.
 Use of alcohol to kill foetus.
 Hot baths, jumping, falls.
 Induced abortions using sharp objects.
 Not always considered immoral if the pregnancy had
not ‘quickened’ = mother had not felt child moving

Question 30

19th century fertility
control

Answer 30

Industrialisation - rubber, latex.
 Popular press and advertising.
 Cervical caps, vaginal sponges, primitive
intra-uterine devices (IUDs), diaphragms,
douching.
 Use of elaborate language in advertising to
conceal effects: ‘menstrual regulation’,
‘hygiene’.
 1873: US Comstock Law declared
contraception to be both obscene and illegal.
 1803: Britain first passed anti-abortion laws,
which then became stricter throughout the
century

Question 30

Early feminism
and abortion
(18th – 19th
centuries)

Answer 30

Early feminist thinkers opposed contraception and
abortion as ‘male solutions’.
 Argued that they damaged women, destroyed
children, but liberated men from financial and moral
responsibility.
 Asked: what is so wrong with pregnancy?
 Identified male domination/fear as factor that led
women to seek dangerous illegal abortions.
 Female power seen as linked to motherhood and
family.
 Envisioned a radical future where any woman could
welcome any child in safety and comfort.

Question 31

Women who
supported
fertility control

Answer 31

Dr Marie Stopes (1880-1958)
 Palaeobotanist
 1919: A Letter to Working
Mothers on how to have
healthy children and avoid
weakening pregnancies.
 1921: first Mothers’ Clinic
opened in London – provided
contraceptive advice.
 Stopes did not support
abortion.

Question 32

Women who
supported
fertility control

Answer 32

 Katherine McCormick (1875-
1967) - husband developed
schizophrenia.
 Decided not to have any
children because of fears of
heritable disease.
 Upon husband’s death,
McCormick inherited around
US$15 million.
 Financed early Pill research.

Question 32

Women who
supported
fertility control

Answer 32

Margaret Sanger (1879-1966)
– mother died after 11
children
 “I associated poverty, toil,
unemployment, drunkenness,
cruelty, quarreling, fighting,
debts, jails with large
families.”
 Published Birth Control Review.
 founded the American Birth
Control League in 1921.
 Later known as Planned
Parenthood.

Answer 33

Answer 33

The ‘Pro Race’ diaphragm/cervical
cap - designed by Marie Stopes
and manufactured and sold in
London at her Mothers’ Clinic.

Question 33

Racist and
eugenic links

Answer 33

Margaret Sanger and Marie Stopes were both eugenicists
 Both targeted working-class women - ‘too fertile’.
 Other pro-contraception pioneers such as Havelock Ellis
(sexologist) criticised Stopes’ anti-Semitism.
 Today: contraceptive rollout in developing countries still raises
Issues of class, race, medical imperialism, neo-colonialism.
 2020: Margaret Sanger’s name removed from Manhattan
Planned Parenthood clinic
 https://time.com/5869743/planned-parenthood-margaretsanger/

Question 34

New
advances in
physiology:
ovulation

Answer 34

 Calendar-based methods had long
history but were unreliable.
 little accurate physiological
knowledge of women’s bodies.
 1905: Dutch physician Dr Theodore
van der Velde = women ovulate
once per cycle.
 1920s: Ogino and Knaus pinpointed
ovulation as most commonly
occurring 14 days before next
menstrual period.
 1930: Drs John Smulders, Knaus and
Ogino developed first calendarbased method of birth control.

Question 35

Where did the Pill come from?

Answer 35

 US doctor and researcher Gregory Pincus (1903-
1967)
 Began studying hormonal biology and steroidal
hormones
 1934: produced successful in-vitro fertilization in rabbits
 1951: Margaret Sanger approached Pincus to undertake
research into oral contraception
 Pincus confirmed that progesterone inhibits ovulation
 First product called Enovid - 5 and 10 milligram dose

Question 36

Puerto Rico
trials

Answer 36

Human trials conducted in Massachusetts, US, and
Puerto Rico
 In Puerto Rico, women were not initially told what the Pill
was meant to do
 Women dropped out of the study due to severe side
effects, but testing continued
 Once women were told what the Pill was designed to do,
they volunteered freely
 However, they were not told they were part of a clinical
trial of an experimental treatment
 17% of participants reported serious side effects
 3 women died, but were not autopsied to check for
correlation with Pill use
 Dr. Edris Rice-Wray, medical director of the Puerto Rico
Family Planning Association, said that Pill was not safe to
use in its current formula
 Pill was nonetheless released by Searle & Co.

Question 36

What’s in
hormonal
contraceptives?

Answer 36

 Most oral contraceptive formulations contain a
combination of synthetic oestrogen and
progestogen (ethinylestradiol and progestin/s).
 The quantities and proportions can vary, and some
contain progestin only.
 Progestins are steroids, and bind to steroid
receptors in the brain, as well as to the sex
hormone binding globuline (SHG).
 They can affect blood glucose levels, lipid levels, and
can stimulate other hormone production in the
body.
 Older progestins could stimulate androgens
(masculinising hormones), whereas modern
progestins are anti-androgenic.
 However, research into hormonal contraception’s
effects on the brain is still scanty.

Question 37

How does the
Pill work?

Answer 37

Oestrogen inhibits the pituitary gland’s secretion of FollicleStimulating Hormone (FSH), and so suppresses the
development of follicles containing eggs on the ovary.
 Meanwhile, progestogen works at the same time to inhibit
the pituitary gland’s production of luteinising hormone (LH),
another hormone which helps to produce egg follicles.
 Progestogen also changes the cervical mucus, which
impedes sperm movement.
 Because no modern hormonal contraceptive
formula completely suppresses ovulation 100% of the
time, hormonal contraception also works to
prevent implantation.
 Both oestrogen and progestogen work together to affect the
ability of the Fallopian tubes to collect and move a fertilised
gamete
 They change the womb lining (endometrium) so that a
fertilised gamete will not attach or implant.

Question 38

How was the
Pill
approved?

Answer 38

 1962: G D Searle & Co
(manufacturer) received reports
of 132 cases of blood clots in
Pill users
 11 cases resulted in death
 Searle denied that the Pill
caused deaths
 Food and Drug Administration
(FDA) assured doctors the drug
was safe

Question 38

The Pill and doctors

Answer 38

Some doctors were not fully informed of the Pill’s
dangers.
 Some doctors did not consider it necessary to inform
female patients about risks of Pill.
 1970 US Gallup poll: two-thirds of the women surveyed
said that their doctors had never warned them about
risks of the Pill.
 Complications arising from the Pill were rare enough for
some doctors to believe that the benefit was worth the
risk for their female patients.

Question 39

Responses to the
complaints of side-effects

Answer 39

Anecdotally, women’s health complaints were
brushed aside or trivialised
 Multiple health providers: eg. depression =
psychiatrist; stroke = neurologist
 Lack of proper medical history-taking and
information-sharing
 Took 10 years from Pill’s initial approval to
prove the statistical link between serious health
risks and oral contraceptives

Question 39

The ‘danger’ of pregnancy

Answer 39

Pill approved by FDA on the grounds of ‘safety’ – but the
‘danger’ in this case was pregnancy
 The Pill only met the FDA safety requirement because it
was so effective at preventing pregnancy
 This was considered sufficient to offset possible risk factors
such as blood clots, strokes and death
 Pill was approved prior to revelations about the dangers of
thalidomide and prior to passage of the 1962 Drug
Amendments in US
 By 1960, Searle making $37 million a year from prescriptions

Question 40

1970 US Senate hearings
into Pill safety

Answer 40

Women disrupted the hearings in protest at the
lack of evidence taken directly from Pill users
 Also angry at the consistent presentation of
evidence that the Pill had known risks which were
not explained to women prescribed it
 Outcome: U.S. government introduced the ‘patient
information sheet’, with complete information on
side effects in every package of birth control pills
sold.

Question 41

Outcomes for the developing
Pill

Answer 41

Post-1970: hormone levels in the Pill were lowered to
a fraction of the original doses
 Discontinued 1998
 Smaller hormone doses meant fewer side-effects
 Also increased risk of unplanned pregnancy

Question 41

What followed
the Pill?

Answer 41

 Metal intrauterine devices – IUDs - had been used as contraceptive inserts
since the early 1900s.
 Stimulate an immune response which makes uterus averse to implantation;
copper IUDs are also spermicidal.
 Hormonal IUDs slowly release progestins to limit ovulation.
 Development of silicone during WWII led to silicon rod experimentation as a
form of drug delivery.
 Progestin-delivering silicon rods were first used in the US from the early
1980s.
 Depo Provera (progestin-type long-acting injection) introduced in 1959 in the
US and approved for contraceptive purposes in 1992.
 In the 1960s, researchers in the US and Europe began investigating methods
of administering medications and steroids through the vagina with a plastic
ring.
 The NuvaRing was one of the first monthly vaginal rings used for
contraception - provides a self-administered method of birth control which
can be more accessible for some users.

Question 41

The Pill and mortality rates

Answer 41

The research literature on oral contraception-related deaths is nonconclusive.
 However, this could be affected by medical or coronial unwillingness to
attribute deaths to the Pill:
 Death of Maria Santa, aged 17, 2016, UK
 Experienced massive headaches and sought medical attention 4 times
 Died of blood clot on brain two days after collapsing
 Two doctors testified to inquest that blood clot was probably caused by
oral contraceptive
 BUT: coroner Simon Nelson recorded a conclusion of death by natural
causes
 Off-label prescription may also affect recording of deaths caused by
Pill-type medications.
 Risks of CVD deaths / blood clots increase with a combination of the Pill
and smoking.

Answer 42

Question 42

Hormonal contraception and
depression in women?

Answer 42

Skovlund et al (2016), Association of hormonal
contraception with depression, JAMA Psychiatry.
(September 28, 2016;
doi:10.1001/jamapsychiatry.2016.2387)
de Wit et al (2021). Hormonal contraceptive use and
depressive symptoms: systematic review and network
meta-analysis of randomised trials. BJPsych open, 7(4),
e110. https://doi.org/10.1192/bjo.2021.64

Question 43

New
advances in
physiology

Answer 43

 1953: Australian doctor John Billings discovered
link between cervical mucus states and fertility
in women.
 Developed first ‘fertility awareness’ approach
to conception and contraception.
 ‘Fertility awareness’ combines calendar and
observation of physiological signs of fertility to
avoid intercourse at fertile times:
 Elevated basal body temperature on
waking
 Cervical mucus state (‘egg white’ = highly
fertile)
 Sexual desire
 Front breast tenderness
 Physical symptoms: headaches,
constipation, gas, bloating
 Mittelschmerz (ovulation pain; usually
unilateral; sharp or dull)

Question 44

An evo-psych
perspective?

Answer 44

 We ‘are’ our hormones.
 Women’s bodies are still
not well understood by
medical science.
 Hormonal contraceptives
change many aspects of
women’s lives and their
perceptions.
 How does the Pill affect
mate selection?

Question 45

New drugbased
contraceptives
for men in
development

Answer 45

 dimethandrolone undecanoate (DMAU) and 11-β
methyl nortestosterone dodecylcarbonate ( 11βMNTDC)
 These are progestogenic-androgens - single molecules
with two functions.
 The progestogenic function should lower pituitary
production of gonadotropin hormones (FSH and LH) -
like the Pill in women.
 Inhibiting LH leads to lower testosterone in the testis
– theoretically, sperm production should be inhibited by
this.
 The androgenic function supports sexual and other
bodily functions in men that need adequate
testosterone levels.
 These progestogenic-androgens have good oral
bioavailability = a single daily pill is possible.

Question 45

New drugbased
contraceptives
for men in
development

Answer 45

 December 2023:YourChoice Therapeutics, Inc.
began dosing male volunteers in a Phase One clinical
study of YCT-529, a drug candidate designed to offer
the first hormone-free male birth control pill.
 Retinoic acid receptor-alpha (RAR-alpha) inhibitor
-YCT-529 prevents sperm production by blocking
access to vitamin A.
 YCT-529 was 99% effective in preventing mouse
pregnancies and decreasing monkey sperm counts
after two weeks of dosing.
 Fully reversible in animal models.

Answer 46

Question 47

Summing up

Answer 47

 Attempts to prevent unwanted pregnancy are as old as
humanity.
 External- and internal-use products developed in the
early 20th century were more effective than primitive
methods.
 The Pill was the first chemical attempt to suppress
ovulation.
 The Pill was tested and approved under questionable
conditions
 There are known serious side-effects to the use of the
Pill which are considered less risky than pregnancy.
 What’s happening with hormonal contraception today?