L16 Clinical Pharmacology Sex hormones

Overview

This lecture covers hormonal contraception, starting from where the sex steroids sit in the steroidogenesis pathway and how they act through nuclear receptors, then the hormonal control of the menstrual cycle, and how combined oral contraceptives (COCs) override that control to suppress ovulation, thicken cervical mucus and alter the endometrium. It then covers COC composition and dose regimens, the pharmacokinetics of ethinyloestradiol (first-pass metabolism, enterohepatic recycling, enzyme-inducer interactions), emergency contraception, and the adverse effect profile: common minor effects versus rare serious events (VTE, cardiovascular disease, hypertension, cancer risk), alongside the benefits.

Steroidogenesis and the sex steroids

All steroid hormones derive from cholesterol.

Full pathway (slide 3):

• Cholesterol → pregnenolone.
• Pregnenolone → (17-α-OH) → 17α-OH-pregnenolone → (3-β-dehydrogenase) → dehydroepiandrosterone → (3-β-dehydrogenase) → androstenedione → testosterone → the sex hormones: oestradiol, oestriol, oestrone.
• Parallel arm: pregnenolone → (3-β-dehydrogenase) → progesterone → (17α-OH) → 17α-OH-progesterone → (21-β-OH) → 11-β-OH → corticosterone/hydrocortisone → cortisone (the glucocorticoids), with a branch to aldosterone (the mineralocorticoids).

Regulators and inhibitors at their sites of action:

• ACTH and angiotensin II stimulate cholesterol → pregnenolone; aminoglutethimide inhibits the same step.
• Trilostane inhibits pregnenolone → progesterone.
• Metapyrone inhibits the 11-β-OH step.
• Carbenoxolone inhibits hydrocortisone → cortisone.
• Angiotensin II stimulates corticosterone → aldosterone.

Simplified sex-steroid route (slide 4): cholesterol → pregnenolone → progesterone, branching via 17α-hydroxyprogesterone or 20α-hydroxyprogesterone to the androgens (androstenedione, testosterone), which are converted by aromatase to the oestrogens (oestradiol, oestrone, oestriol).

Comparative potency

Oestrogens:

• Oestradiol 100%
• Oestriol 10%
• Oestrone 1%

Progestagens:

• Progesterone 100%
• 17α-hydroxyprogesterone 40-70%
• 20α-hydroxyprogesterone 5%

Mechanism of steroid hormone action

ERα and ERβ (oestrogen) and PR-A and PR-B (progesterone) are nuclear receptors. Hormone actions are determined by three things: the receptor subtype, the location of the receptor, and the potency of the hormone itself.

Genomic pathway, in order:

1. Steroid enters the cell by diffusion across the membrane.
2. Binds its steroid receptor in the cytoplasm.
3. The steroid-receptor complex translocates to the nucleus and binds an initiation site on DNA.
4. Gene activation and transcription (RNA/mRNA synthesis).
5. Protein synthesis at the endoplasmic reticulum.
6. Modified cell function.

In addition, some hormones bind to neurotransmitter receptors.

Hormonal control of the menstrual cycle

Axis: hypothalamus → GnRH → pituitary gland → LH/FSH → ovary → oestrogen/progesterone → uterus. Ovarian steroids feed back on both the hypothalamus and the pituitary: negative feedback over most of the cycle, positive feedback on days 12-14.

FSH (follicle-stimulating hormone):

• Secreted by the anterior pituitary.
• Stimulus: pulsatile GnRH from the hypothalamus.
• Stimulates growth of ovarian follicles; acts on granulosa cells to convert androgens to oestrogens; supports follicular development.

LH (luteinising hormone):

• Secreted by the anterior pituitary.
• Stimulus: pulsatile GnRH, with a surge triggered by sustained high oestrogen.
• Actions: stimulates androgen synthesis; triggers ovulation.

The feedback switch: oestrogen and progesterone from the ovary suppress LH and FSH for most of the cycle. When oestradiol is high enough and sustained for roughly 36-48 hours, the system flips briefly to positive feedback on LH and FSH, producing the surge that triggers ovulation. The mid-cycle LH surge triggers ovulation and supports progesterone production.

Hormone profile across the 28-day cycle: oestrogen rises through the follicular phase and peaks sharply with LH just before ovulation (about day 14-15), FSH shows a small peak at ovulation, then oestrogen dips and rises again alongside progesterone through the luteal phase (peaking about day 21-22), and all hormones decline toward day 28. Menstruation, follicular development, hormone curves and endometrial thickness/shedding all align to the same day axis.

Endometrial and cervical effects, and why the two hormones are combined

• Rising oestrogen from the developing follicle stimulates endometrial regrowth and growth of the uterine glands, which secrete glycogen and nutrients.
• The lining thickens and its blood supply increases; at the cervix the mucus becomes thin and watery, allowing passage of sperm.
• After ovulation, progesterone makes the endometrium more vascular and receptive to implantation. At this point in the cycle the endometrium is at its thickest and most developed.

How COCs work

COCs exert negative feedback on the hypothalamus and pituitary, which suppresses follicle recruitment, follicular development and ovulation. They also thicken cervical mucus and alter the endometrium, so implantation does not occur.

On the three-panel comparison (nonpregnant cycle vs beginning of pregnancy vs COC cycle): in the COC cycle the LH/FSH and ovarian hormone traces are flat with no surge, and the endometrium stays thin, so neither ovulation nor implantation occurs.

COC composition

Synthetic oestrogen (one of):

• Ethinyloestradiol 20-50 µg, the best orally absorbed and most bioavailable of the oestrogens.
• Mestranol (Norinyl-1; 50 µg/1 mg), a pro-drug for ethinyloestradiol.

Progestogen (0.05-1 mg):

• 1st, 2nd or 3rd generation.
• All are synthetic analogues of progesterone, but differ in androgenic or anti-androgenic side effects.
• Cyproterone (2 mg) has anti-androgenic properties and is used in PCOS.

COCs vs the progestogen-only pill (POP)

Advantages of COCs:

• Higher contraceptive efficacy.
• Regular, predictable withdrawal bleeding, whereas POPs often cause irregular, unscheduled bleeding.
• Not androgenic, less endometriosis, and more forgiving of missed pills.

Advantage of POPs: less dangerous with smoking.

Effectiveness of contraceptive methods

Pregnancies (%) by method:

• Male sterilisation 0.15
• Norplant system 0.2
• Female sterilisation 0.4
• Oral contraceptives 3 (range 1-5)
• IUD 3
• Condom 12
• Diaphragm or sponge 18-28
• Spermicide 21
• None 85

Dose regimens

1. Fixed dose combination: 21-22 days of active tablets plus 6-7 days of placebo or no tablet.
2. Variable dose combination:
   • Biphasic: vary the progestogen dose.
   • Triphasic: vary both.

Variable dose regimens were heavily marketed in the 1980s, have not proven more effective, and remain an option in some cases.

Warning

The slide’s final line (“progestogen doses”) is cut off at the bottom edge with no visible continuation.

Pharmacokinetics of ethinyloestradiol

• Well absorbed orally, $t_{1/2}\approx 13-28$ hours.
• Metabolism: first-pass sulphation in the gut wall; hepatic hydroxylation and glucuronidation conjugation.
• Undergoes enterohepatic recycling.

Enterohepatic recycling mechanism: glucuronide-conjugated drug in the liver passes via the bile duct into the intestine (drugs of MW > 350), where ß-glucuronidase hydrolyses the conjugate to unconjugated drug, which is reabsorbed from the intestine back to the liver.

Important

Certain antibiotics raise the risk of unplanned pregnancy. Backup contraception is advised for severe GI upset, or when prescribed enzyme-inducing antibiotics (e.g. rifampicin, rifabutin), which increase hepatic metabolism and interrupt recycling.

Drugs that reduce COC cover

• Hepatic enzyme-inducing drugs, specifically CYP3A4 inducers.
• Including St John’s Wort (herbal antidepressant).
• Various antibiotics.

The summary slide names rifampicin, carbamazepine and St John’s wort as enzyme inducers that reduce efficacy.

Emergency (“rescue”) contraception

If unprotected sex occurred in the window where pills were missed:

• Levonorgestrel (a potent progestogen) 1.5 mg, within 72 hours.
• Ulipristal acetate (progesterone receptor antagonist/partial agonist) 30 mg, within 120 hours, but not if hormonal contraception has already been restarted.
• Copper IUD, up to 5 days, and the most effective option.

Adverse effects

Minor effects: incidence varies, and most settle within 1-3 months.

Potentially serious effects are rare: deep vein thrombosis (DVT) and pulmonary embolism (PE), risk about 2-4 per 10,000 person-years. The summary slide lists VTE and stroke as the rare serious events.

Side effects prompting users to call or visit their provider (approximate called/visited percentages, Family Planning Perspectives 1998):

• Breast tenderness/swelling ~55/54
• Effects on mood ~55/54
• Nausea ~46/53
• Spotting ~44/34
• Weight gain ~42/60
• Longer, heavier periods ~33/36
• Break-through bleeding ~33/30
• Hair growth, worsened acne ~32/39
• More severe menstrual cramps ~29/33

Cardiovascular and thromboembolic risk

Risk in context, deaths per year per 100,000 people at risk: smoking 20+/day 500; influenza 20; car driving 17; drinking one bottle of wine/day 7.5; run over 6; football 4; oral contraceptives 2. Smoking, car driving, drinking, football and oral contraceptives are classed as voluntary risks; influenza and being run over as involuntary.

Relative risk of cardiovascular disease in OC users, non-smoking vs smoking (RCOP Lancet 1981): age 25-34, ~1.6 vs ~3.5; age 35-44, ~3.3 vs ~4.2 (statistically significant); age 45 and over, ~4.6 vs ~7.4 (statistically significant). Risk rises with age and is markedly higher in smokers.

VTE risk by pill type:

• 3rd generation pills: ≈ 25/100,000, about 5-6 times normal risk.
• 2nd generation pills with > 50 µg oestrogen: risk may be > 25/100,000.

Risk of clot per 10,000 years:

• POP / healthy non-drug taker: 0.5-1
• COCs with 2nd generation progestogens: 2
• COCs with 3rd generation progestogens: 3-4

Hypertension

• Pills with high oestrogen content: about 5% of users become clinically hypertensive.
• Pills with low oestrogen: risk of developing hypertension about twice that of non-users.
• Mechanism is not well understood.

Cancer risk

• Breast cancer: small increased risk.
• Ovarian and endometrial cancers: reduced risk, by up to 50%.
• Hepatic cancer: small increased risk.

Cumulative breast cancers per 10,000 women, diagnosed during 5 years of use and up to 10 years after stopping, never-users vs 5 years of COC use, by age started (and age cancers counted to): under 20 / age 30, 4 vs 4.5; 20-24 / 35, 16 vs 17.5; 25-29 / 40, 44 vs 48.7; 30-34 / 45, 100 vs 111; 35-39 / 50, 160 vs 181; 40-44 / 55, 230 vs 262.

Benefits of COCs

• Reduced risk of gynaecological cancers.
• Menstrual improvements.
• Possible benefits: increased bone mineral density, prevention of atherosclerosis, prevention of rheumatoid arthritis.

Summary points

• COCs combine oestrogen and progestogen to give highly effective contraception by suppressing ovulation and altering cervical mucus and endometrium.
• Progestogens differ by generation, with trade-offs between androgenic and thrombotic risk.
• Regimens may be fixed or variable dose; variable dose mimics physiology but offers little practical benefit.
• Oestrogens undergo first-pass metabolism and enterohepatic recycling; enzyme inducers reduce efficacy.
• Common mild adverse effects usually settle; rare serious events include VTE and stroke.

Self-test

1. List the steps converting cholesterol to oestradiol via the androgen route, naming the enzyme that converts androgens to oestrogens.
2. Name the inhibitor acting at each of these steps: cholesterol to pregnenolone, pregnenolone to progesterone, the 11-β-OH step, and hydrocortisone to cortisone.
3. Rank the three oestrogens and the three progestagens by relative potency, giving the percentage values.
4. Describe the six steps of the genomic pathway of steroid hormone action.
5. Distinguish the actions of FSH from those of LH in the ovary.
6. Explain how sustained high oestradiol changes the feedback relationship with the pituitary, and how long it must be sustained.
7. Describe what oestrogen does to the endometrium and cervical mucus in the follicular phase, and what progesterone adds after ovulation.
8. Explain the three mechanisms by which a COC prevents pregnancy.
9. Name the two synthetic oestrogens used in COCs with their doses, and state the relationship between them.
10. Which progestogen has anti-androgenic properties, at what dose, and in what condition is it used?
11. Distinguish COCs from POPs on efficacy, bleeding pattern and safety with smoking.
12. Describe the fixed dose regimen, and distinguish biphasic from triphasic variable dose regimens.
13. Describe how ethinyloestradiol undergoes enterohepatic recycling, naming the enzyme involved and where it acts.
14. Predict what happens to COC efficacy if a patient is started on rifampicin, and explain why.
15. List the three emergency contraception options with their doses and time windows, and state which is most effective.
16. What is the risk of DVT and PE in COC users, expressed per person-years?
17. Compare the risk of clot per 10,000 years for the POP, 2nd generation COCs and 3rd generation COCs.
18. A 38-year-old smoker asks about starting a COC. Using the RCOP data, explain how her age and smoking status affect her relative risk of cardiovascular disease.
19. Describe the effect of COCs on breast, ovarian, endometrial and hepatic cancer risk.
20. What proportion of users of high-oestrogen pills become clinically hypertensive, and how does low-oestrogen pill use change hypertension risk?
21. Integrative: a patient on a 3rd generation COC who smokes is prescribed carbamazepine. Explain the contraceptive and the cardiovascular consequences, drawing on the mechanism of COC action, the drug interaction and the risk data.

Answers

Reveal answers

1. Cholesterol → pregnenolone → 17α-OH-pregnenolone (17-α-OH) → dehydroepiandrosterone (3-β-dehydrogenase) → androstenedione (3-β-dehydrogenase) → testosterone → oestradiol/oestriol/oestrone. Aromatase converts androgens to oestrogens.
2. Cholesterol to pregnenolone: aminoglutethimide. Pregnenolone to progesterone: trilostane. 11-β-OH step: metapyrone. Hydrocortisone to cortisone: carbenoxolone.
3. Oestrogens: oestradiol 100%, oestriol 10%, oestrone 1%. Progestagens: progesterone 100%, 17α-hydroxyprogesterone 40-70%, 20α-hydroxyprogesterone 5%.
4. Diffusion of the steroid into the cell; binding to the steroid receptor; translocation of the complex to the nucleus and binding to a DNA initiation site; gene activation and transcription (mRNA); protein synthesis; modified cell function.
5. FSH stimulates growth of ovarian follicles, acts on granulosa cells to convert androgens to oestrogens, and supports follicular development. LH stimulates androgen synthesis, triggers ovulation and supports progesterone production.
6. For most of the cycle oestrogen and progesterone exert negative feedback suppressing LH and FSH. When oestradiol is high enough and sustained for about 36-48 hours, feedback briefly switches to positive on LH and FSH, producing the surge that triggers ovulation.
7. Rising oestrogen stimulates endometrial regrowth and growth of the uterine glands (which secrete glycogen and nutrients), thickens the lining, increases blood supply, and makes cervical mucus thin and watery so sperm can pass. After ovulation progesterone makes the endometrium more vascular and receptive to implantation, at its thickest and most developed.
8. Negative feedback on the hypothalamus and pituitary suppressing follicle recruitment, development and ovulation; thickening of cervical mucus; alteration of the endometrium so implantation does not occur.
9. Ethinyloestradiol 20-50 µg, the best orally absorbed and most bioavailable oestrogen, and mestranol 50 µg/1 mg, which is a pro-drug for ethinyloestradiol.
10. Cyproterone, 2 mg, used in PCOS.
11. COCs have higher contraceptive efficacy, give regular predictable withdrawal bleeding (POPs often cause irregular unscheduled bleeding), are not androgenic, cause less endometriosis and are more forgiving of missed pills. POPs are less dangerous with smoking.
12. Fixed dose: 21-22 days of active tablets plus 6-7 days of placebo or no tablet. Biphasic varies the progestogen dose only; triphasic varies both hormones.
13. Ethinyloestradiol is glucuronide-conjugated in the liver and excreted via the bile duct (drugs MW > 350) into the intestine, where ß-glucuronidase hydrolyses the conjugate back to unconjugated drug, which is reabsorbed from the intestine to the liver.
14. Efficacy falls and the risk of unplanned pregnancy rises, so backup contraception is advised. Rifampicin is an enzyme inducer that increases hepatic metabolism and interrupts enterohepatic recycling.
15. Levonorgestrel 1.5 mg within 72 hours; ulipristal acetate 30 mg within 120 hours (not if hormonal contraception has already been restarted); copper IUD up to 5 days, which is the most effective.
16. About 2-4 per 10,000 person-years.
17. POP or healthy non-drug taker 0.5-1; COCs with 2nd generation progestogens 2; COCs with 3rd generation progestogens 3-4 per 10,000 years.
18. In the 35-44 age group relative risk of cardiovascular disease is about 3.3 for non-smokers and about 4.2 for smokers, a statistically significant difference, and both are higher than in the 25-34 group (~1.6 non-smoking vs ~3.5 smoking). Risk rises further at 45 and over (~4.6 vs ~7.4). Her age and smoking together raise her risk substantially.
19. Small increased risk of breast cancer; reduced risk of ovarian and endometrial cancer, by up to 50%; small increased risk of hepatic cancer.
20. With high-oestrogen pills about 5% of users become clinically hypertensive; with low-oestrogen pills the risk of developing hypertension is about twice that of non-users. The mechanism is not well understood.
21. Carbamazepine is a hepatic enzyme inducer that increases metabolism of ethinyloestradiol and interrupts enterohepatic recycling, so the oestrogen level may no longer sustain negative feedback on the hypothalamus and pituitary, follicle development and ovulation may resume, and contraceptive cover is reduced (backup contraception needed). Meanwhile a 3rd generation pill already carries the highest VTE risk (3-4 clots per 10,000 years, ≈ 25/100,000, about 5-6 times normal) and smoking raises the relative risk of cardiovascular disease at every age band, so she carries both a failure risk and an elevated thrombotic/cardiovascular risk.