BIOL473 - Contraception

Why is human contraception considered a modern problem?

Non-reproductive mating has been a feature of humans since early evolution but signs of impending ovulation began to disappear! (As did monogamy!)

How has contraceptive use changed from 1990 to 2021?

more women use contraceptives, and a higher proportion of them use modern contraceptives (IUDs, hormone, vaginal barriers)

Compare the most popular contraceptive between North America, Southeast Asia, and Central Asia

North America/Europe → the Pill

East/Southeast Asia → IUD

Central → female sterilization

Why are most contraceptive strategies in humans aimed at females and not males?

Females have 1 egg released per month (400-500 lifetime ovulations) while males have 125 million sperm produced per day

What are the 3 main strategies for male contraception?

1. Physical barriers (condom, vasectomy)

2. Hormonal

3. Non-hormonal

How did the reversible blockage of Vas deferens work?

Injection of liquids into the vas deferens would form a gel plug that could be reversed by a second injection

What was RISUG? What happened to it?

Reversible inhibition of sperm under guidance → a small scale trial was done but it did not progress any further

What is the issue with inhibiting spermatogenesis by suppressing gonadotropins?

Gonadotropins (like FSH) also support body mass, sexual function, and other desirable effects of androgens

What has the most promising strategy for hormonal regulation of spermatogenesis been?

A combination of synthetic progestins (negative feedback) plus androgens to support non-gonadal roles

What were the results of the clinical trial involving testosterone + progestin contraceptives?

Injection of T + P was 96% effective at preventing pregnancy by lowering sperm count

What was the problem with the T + P clinical trial?

The trial was stopped early because 20 / 360 (6%) dropped out of the study due to mood swings, minor acne, excessive sweating, and feeling depressed

Why might the choice of synthetic steroids in the T + P approach be so important?

Bioidentical androgens (testosterone) have a short half-life, while dimethandrolone-undecanoate that is coupled to a fatty acid has a much longer half-life

What were the two main drawbacks of endocrine contraceptives in men?

1. Testicular shrinkage + changes to blood lipids

2. Inducing / stimulating prostate disease

For what two reasons would an endocrine approach not be effective when initially taken?

1. Inhibiting spermatogenesis doesn’t affect existing sperm (takes several months to come into effect

2. Some men still have spermatogenesis even when gonadotropins were low

Could spermatogenesis-specific proteins be a target for male contraceptives? Give one reason why and why not

Yes — 4% of the male genome codes for proteins specific to spermatogenesis

No — access to seminiferous tubules (especially for large molecules) is very restricted

What is a possible target for a spermatogenesis-specific protein?

Inhibit hyperactivation of sperm by inhibiting catspers (is already one of the most common causes of unexplained fertility in men)

What is the pathway to drug development for a contraceptive?

1. Identify your target (molecule/protein/process)

2. Validate in an animal model

3. Manipulate target to induce infertility

4. Pharmacokinetics

5. Efficacy testing

6. Phase 1/2/3 testing on humans

7. Submitting documentation for approval

What is BRDT?

“Bromodomain testis-specific” → chromatin associated protein expressed in spermatocytes and round spermatids

What is the function of BRDT?

Essential for chromatin remodelling during spermatogenesis

What happens in BRDT -/- mice?

They are sterile — produce fewer and morphologically abnormal sperm

Specifically what stages of sperm express BRDT?

Pachytene, diplotene (M1), and round spermatids (M2)

What is JQ1?

A small molecule inhibitor of BRDT that can cross the blood-testis barrier

What do results show for usage of JQ1 to inhibit spermatogenesis?

Decreased sperm count, motility while test, LH, and FSH are all very similar

What are the 3 cons of JQ1 (currently)?

1. Half-life is too short

2. Binds to somatic isoform (BRD4) with a higher affinity than BRDT (bad news!)

3. Decreased testes size

How does an intra-uterine device (IUD) work?

Consists of a plastic, copper-releasing / progestin-releasing contraceptive device

Compare the mode of action of copper IUDs vs progestin IUDS

Copper → is released into the fluids and is spermicidal

Progestin → thickens the cervical mucus

What is the danger of IUDs?

They set off a ‘foreign body’ reaction in the uterus that causes a local inflammatory reaction that could even spread through the tract

Compare the terms synthetic, natural, endogenous, and bioidentical

Synthetic = not of natural origin; prepared or made artificially

Natural = present in or produced by nature

Endogenous = originating or produced within an organism (humans)

Bioidentical = exact copies of endogenous human hormones

Can a bioidentical hormone be synthesized from a plant precursor? Can a non-bioidentical hormone be from a natural source?

Yes! And yes! (Phytoestrogen)

What is the history behind alternative progesterone synthesis?

Progesterone used to be extremely expensive → Russell Marker found a way to synthesize it from a precursor in sarsparilla plants (still sorta expensive) → then a yam plant that could be easily converted to progesterone

How has “the pill” evolved across time?

1. P + E 21/7

2. P + E 21/7 (much lower dose of estrogen)

3. P + E 24/4 (shorter hormone-free interval)

4. P + E 84/7 (four periods a year)

5. P + E 365 (no period!)

What is the main action of “the pill”

Estrogen and progesterone provide negative feedback that keeps FSH/LH low so that follicles don’t develop (no ovulation)

What are the advances in the ingredients of the Pill?

Lowered estrogen doses from 120 ug/day to 15ug/day estradiol equivalents

How did follicular activity change between the 7 day and the 4 day breaks?

7 day break → progressive increase in follicular activity and diameter that could cause selection of follicles and even ovulation!

4-day break → diameter of follicles never increase throughout the 4 day breaks

What were the pros and cons of the 4 times a year birth control?

Pros → convenience with little to no menstruation and no estrogen (avoid estrogen-cancers)

Cons → nor estrogen…

Why was Pfizer sued for their 84/7 contraception?

Caused a loss of bone mineral density due to taking Dope-Provera and having no estrogen

What do we know about bone density in women? How would Depo Provera influence this?

There is a slow, progressive loss in bone density past 30 years onward and a sharp drop at menopause (due to lack of estrogen) and during lactation → would be a risk factor for osteoporosis later in life!

Are repeated cycles harmful? In what ways?

Yes! → Ovarian cancers are highest in nulliparous women (women who have never given birth), endometriosis and uterine fibroids are higher, blood less is higher, and breast cancer is higher(?)

Compare breast cancer mortality between controls and nuns

There is a higher risk for nuns to have breast cancer to the control groups!

What are the two options for “natural” reproductive life histories in a modern Western society woman?

1. Opt out of hormonal contraception → experience decades of fluctuating levels of estrogens (increased risk of estrogen-dependent cancers)

2. Use hormonal contraception → create optimum hormonal environment for ovaries that should ovulate, breasts that shouldn’t lactate (unnatural…)