Lecture 57: Female physiology, menstrual cycle and mechanisms of contraception

In the absence of the SRY protein, which part of the bipotential gonad develops into an ovary?

The gonadal cortex

What presence/absence of factors determine the development of male or female reproductive structures?

Females: absence of SRY gene, testis determining factor (TDF), AMH, testosterone and dihydrotestosterone (DHT), but contains multiple female genes

Males: contain all

In female embryonic development, the Mullerian duct develops into what? And what happens to the Wolffian duct due to the absence of testosterone?

Develops into fallopian tubes, uterus and upper vagina

Wolffian duct regresses

What is gametogenesis?

Involves duplication of germ cells through mitosis followed by meiosis to form gametes (oocytes)

What are gonadotropins?

FSH - stimulates ovaries to grow follicles (each containing an egg) and matures the egg

LH - triggers ovulation (release of egg), causes ovary to produce oestrogen and progesterone

How are gonadotropins controlled via hypothalamus, pituitary and gonads?

Hypothalamus → releases GnRH

Pituitary → releases LH & FSH

Gonads → release oestrogen, progesterone, testosterone

In terms of hormonal feedback, what effect do low levels of oestrogen/androgen have on gonadotropin release?

Nothing is there telling the brain to slow down, so increases GnRH → increases FSH & LH

Occurs with menopause, ovaries don't respond anymore, which is why these blood tests would show ↑FSH, ↑LH

In terms of hormonal feedback, what effect do moderate (normal) levels of oestrogen/androgen have on gonadotropin release?

Brain knows about the healthy level, so hypothalamus reduces GnRH, then pituitary reduces FSH & LH

Showing a working negative feedback loop as levels remain healthy

In terms of hormonal feedback, what effect do high levels of androgens have on gonadotropin release?

Stronger negative feedback

When testosterone becomes very high, brain pushes the brake hard, so GnRH decreases significantly, then FSH & LH decreases significantly

In terms of hormonal feedback, what effect do sustained high levels of oestrogen have on gonadotropin release?

If oestrogen stays high for ~48 hours in females, brain suddenly presses gas not brake, hypothalamus ↑GnRH and pituitary releases LH surge

Positive feedback mechanism

This happens because the body wants to trigger ovulation - LH surge causes follicle from FSH to rupture and releases the egg

Which hormone, produced by granulosa cells, specifically suppresses the secretion of FSH?

Inhibin

What are the 3 main phases of the menstrual cycle?

Follicular phase = Day 1 → ~14

• Day 1 = first day of bleeding

Ovulation = ~Day 14

• Triggered by the LH surge, follicle ruptures, egg released, oestrogen briefly dips, progesterone begins to rise

Luteal phase = Day 14 → 28

What happens in the luteal phase of the menstrual cycle?

Follicle becomes corpus luteum which produces progesterone (main hormone now), with some oestrogen

Progesterone makes lining thick and spongy to support/prepare the uterus for implantation

What happens if no pregnancy occurs within the body?

Corpus luteum dies (usually lasts around 14 days after ovulation) → oestrogen and progesterone drop

Hormone withdrawals causes the uterine lining sheds (what has just been grown), period begins, back to day 1

When the corpus luteum degenerates at the end of the luteal phase, it becomes a fibrous scar called the _

Corpus albicans

What is the primary contraceptive mechanism of Combined Hormonal Contraception (CHC)?

The inhibition of ovulation through lack of FSH and LH because it tricks the brain thinking there is already enough oestrogen and progesterone in the body

How does the progestogen component of contraceptives prevent pregnancy?

It increases the thickness and viscosity of the mucus to impair sperm motility and prevents hyperplasia (excessive growth of lining) by opposing proliferative effects of oestrogen

What are types of hormonal contraceptives?

Oral contraceptives, patches, vaginal rings, injections, implants, and hormonal IUDs

What are some types of non-hormonal contraceptives?

Copper IUD and barrier methods (diaphragm, condoms)

What are the 3 forms of combined contraceptives available in the UK?

Combined oral contraceptive (COC), combined transdermal patch, combined vaginal ring

What are the 3 mechanisms of action of POPs?

1. Prevents implantation of ovum (egg) by keeping lining thin

2. Delays egg transport

3. Increases viscosity of cervical mucus to impair sperm motility

What is the difference between monophasic and multiphasic pills?

Monophasic - amount of oestrogen and progestogen is the same throughout the pill cycle

Multiphasic - amount of oestrogen and progestogen varies throughout pill cycle

What does an assessment for contraceptive use involve?

Exclude pregnancy, record BP, BMI, smoking status

Identify relevant medical conditions, medication, lifestyle factors that could affect contraception

Discuss: obstetric history, need for it, future pregnancy plans, view in contraception

Sexual health risks - promote barrier methods for prevention

Provide verbal and/or written advice about alternative methods of contraception

According to the UK Medical Eligibility Criteria (UKMEC), what do the 4 categories signify for who can safely use contraceptives?

Category 1 = no restriction

Category 2 = advantages outweigh the risks

Category 3 = risks outweigh the advantages

Category 4 = unacceptable health risk if method is used so do not use

How to choose a suitable COC?

1st-line options are monophasic, consider woman’s preference as any COC can be offered

Prescribe up to 12 months for woman initiating/continuing treatment

What are the advantages associated with COC use?

Reversible, reduced dysmenorrhoea/menorrhagia/PMS, decreased risk of colorectal, ovarian and endometrial cancer

What are the cautions (contraindications) of COC use?

Family history of VTE, smoking, migraine, obesity (BMI close to 35), ages >35, diabetes mellitis, hypertension

What are the disadvantages associated with COC use?

User depended for effectiveness

Doesn’t protect against STDs

Less effective than other forms of contraception

Not suitable for all patients

Adverse effects

What are common adverse effects of COC use?

N/V, abdominal pain, headaches, breast pain, menstrual irregularities, hypertension, changes in lipid metabolism, weight gain?, mood changes

What are the common drug interactions with COCs?

Enzyme-inducing drugs reduce COC therapeutic effect

Antibiotics, antiepileptics, antiretrovirals, St John’s wort, lamotrigine (reduce each other’s effectiveness - HFI conc spikes)

Why is it recommended to withhold all COC use four weeks prior to major surgery?

To reduce the risk of postoperative Venous Thromboembolism (VTE) associated with prolonged immobility

What is the standard regimen for monophasic COC use?

21/7 days - designed to induce a bleed each month, mimicking a naturally occurring cycle

What are the 4 possible tailored regimens for taking monophasic COCs?

Shortened HFI: 21/4

Extended use (tricycling): 9 weeks continuous use followed by 4/7 day HFI

Flexible extended use: continuous use for 21 days, followed by 4 day HFI when breakthrough bleed happens

Continuous use: no HFI

What are the red flag symptoms for when to stop taking COCs?

Sudden chest pain/SOB, unexplained swelling, severe pain in calf of one leg, jaundice, severe neurological effects, raised BP

In an OSCE, what is the pharmacists role when prescribing COCs?

Discuss mechanism of action, benefits and risks, efficacy, what happens when stopped?

Give advice on:

• Importance of taking the pill correctly

• How to manage missed pills

• What to do if vomiting/diarrhoea occurs after taking the pill

• Side effects including menstrual irregularities

• Drug interactions

What are the traditional POPs used in the UK and how do they primarily work?

Levonorgestrel (LNG), norethisterone

Effectiveness relies on cervical mucus being altered rather than ovulation inhibition

What are the newer POPs used in the UK and how do they primarily work?

Desogestrel (DSG), drospirenone (DRSP) (very new)

Have anti-gonadotrophic effect that inhibits ovulation

How do bleeding patterns and HFIs work when taking POPs?

No HFI

Bleeding pattern unpredictable and varies between individuals, depend on progesterone used, dose, circulating estradiol levels etc

What is Slynd?

New POP, licensed in Jan 2024

Suppresses ovulation with effects on cervical mucus and endometrium

Same efficacy of other POPs

Must be started on day 1 of cycle, has 4 day HFI

What are the timings for a missed POP pill?

LNG/norethisterone - missed pill if >3 hours late

DSG - missed pill if >12 hours late

Slynd - missed pill if >24 hours late

How can a patient start taking a POP when they are not on any other contraception, compared to when switching from another POP?

New - start on days 1-5 of cycle, if started at any other time then use barrier methods

Switch - start at any time

How can a patient start taking a POP when they are switching from a COC or Cu-IUD/LNG-IUS?

COC - start POP on days 1-7 of HFI

Cu-IUD/LNG-IUS - start POP at least 2 days before removal of coil

What are the adverse effects and risks of POPs?

Menstrual irregularities, refer if unusual bleeding >3 months, don’t issue >55 years old

What is involved in a follow-up review in patients taking COCs/POPs?

At least annually to review continued medical eligibility, satisfaction, adherence, drug interactions, consideration of other contraceptives annually

BMI and BP checked annually

COCs available under Pharmacy Contraception Service (PCS) via PGD

What is GnRH?

Gonadotropin-releasing hormone

Controls reproductive hormone system by signalling pituitary gland to release LH and FSH

What occurs with the LH surge?

One follicle becomes dominant producing increasing oestrogen (other follicles denature)

At first, oestrogen inhibits LH and FSH through negative feedback

When oestrogen is high for ~48 hours it changes to positive feedback

Now stimulates hypothalamus producing more LH (surge)

What is the 3 step mechanism of action of contraceptives?

1. Oestrogen and progestin prevent eggs from being released from the ovaries

2. Progestin causes thinning of the endometrium, which prevents implantation of a fertilised egg

3. Progestin thickens the mucus in the cervix, preventing sperm from reaching the eggs

What are the functions of oestrogen and progesterone in the menstrual cycle?

Oestrogen

• Rebuilds and thickens the endometrium

• Stimulates follicle development in the Ovary

• High levels trigger LH surge → ovulation

• Makes cervical mucus thinner to help sperm pass

Progesterone

• Maintains the uterine lining after ovulation

• Prepares uterus for implantation

• Thickens cervical mucus