MPharm - Pregnancy, Menopause & Contraception Notes

Endocrinology of Pregnancy and Parturition

• Pre-implantation:
  • Follicular phase: Estrogen leads to the proliferation of the endometrial stroma.
  • Luteal phase: Progesterone leads to secretory, glandular, and decidualization changes.
  • Histiotrophic nutrition is essential.
  • Implantation window: Days 20-24, with estrogen stimulating the release of glandular secretions.
• Increased progesterone:estrogen ratio relaxes the isthmic sphincter.
• Approximately 1 week post-fertilization, the syncytiotrophoblast of the implanting embryo begins to secrete human Chorionic Gonadotrophin (hCG), which supports the corpus luteum.

Human Chorionic Gonadotrophin (hCG)

• hCG levels fall from week 8 but remain detectable throughout the pregnancy.
• The presence of hCG in urine or blood indicates a biochemical pregnancy.

Progesterone

• Progesterone is an absolute requirement throughout pregnancy.
• Mifepristone (RU486) acts as an anti-progesterone.
• Progesterone is produced from cholesterol by the syncytiotrophoblast. The placenta takes over from the corpus luteum around week 6 after ovariectomy.

Oestrogen

• Estrogen levels rise throughout pregnancy.
• Estriol is the predominant form of estrogen during pregnancy.
• Estrogen production is a cooperative effort by the placenta and the fetus. It involves:
  • Progesterone converted to Androgen in the fetal adrenal glands.
  • Androgen converted to Estrogen in the placenta.
• Estrogen is conjugated, making it water-soluble and inactive until deconjugated.

Human Placental Lactogen (hPL)

• Also known as chorionic somatomammotrophin.
• hPL levels rise as hCG levels fall.
• Produced by trophoblast cells.
• hPL acts as an anti-insulin agent, causing decreased insulin sensitivity and increased maternal blood glucose to provide for the fetus.
• It increases lipolysis, leading to the release of free fatty acids (FFA).
  • FFA is used by the mother.
  • FFA is converted to ketones, which are transported to the fetus via the placenta.

Prolactin (PRL)

• Prolactin levels rise linearly during pregnancy.
• Estrogen stimulates prolactin release by lactotroph cells of the anterior pituitary, with small amounts also produced by the decidua (amniotic fluid).

Endocrinology of Parturition

Stages of Parturition

• Stage 1: Contractions begin, leading to shortening/effacement and dilation of the cervix.
• Stage 2: Full dilation of the cervix, resulting in the delivery of the baby.
• Stage 3: Delivery of the placenta.

Cervical Ripening/Softening

• Occurs days or weeks preceding birth.
• Mediated by Prostaglandin E (PGE), relaxin, and Nitric Oxide (NO).
• PGE is used clinically in the induction of labor or abortion. It's also found in semen.

Myometrial Contractility

• During pregnancy, the myometrium must be kept quiescent, which is achieved by progesterone suppressing contractility via decreasing oxytocin receptor expression
• At term, the rising estrogen:progesterone ratio leads to increased oxytocin receptor levels.
• Oxytocin is synthesized in the hypothalamus and secreted by the posterior pituitary + decidual tissue and is upregulated at term by estrogen.

Ferguson Reflex

• Neuroendocrine reflex.
• Pressure/stretching of the cervix by the baby’s head stimulates further release of oxytocin, creating a positive feedback loop.

Fetus Triggers Timing of Parturition

• Maturation of the fetal hypothalamic-pituitary-adrenal (HPA) axis.
• Fetal glucocorticoids and corticotrophin-releasing hormone (CRH) increase at term, leading to increased estrogen and prostaglandin.
• Cortisol contributes to lung maturation and the synthesis of surfactants.
• Dexamethasone can be used in preterm labor.

Endocrinology of Lactation

Anatomy of the Breast

• Composed of 15-20 lobes of glandular tissue with fibrous/adipose tissue between the lobes.
• Lobes contain lobules of alveoli, blood vessels, and lactiferous ducts.
• Alveoli consist of epithelial cells (synthesize milk), myoepithelial cells, and a basement membrane.
  • Myoepithelial cells are contractile and move milk to lactiferous ducts for ejection.

Breast Development

• At birth, mostly lactiferous ducts are present with few alveoli.
• During puberty, estrogen stimulates lactiferous duct sprouting and branching, alveoli start to develop, and fat and connective tissue is deposited.

Pregnancy and Lactation

• Up to the 4th month of pregnancy, estrogen and progesterone further develop the alveoli and dilate the lumens.
• Prolactin (PRL) rises throughout pregnancy.
• Estrogen and progesterone inhibit milk secretion until parturition by making cells unresponsive to prolactin.
• Post-partum, steroid levels fall dramatically, while PRL levels fall more slowly (3-4 weeks), and negative feedback is lost.
• Suckling stimulates PRL synthesis, leading to milk synthesis.

Milk Ejection/Let-Down Reflex

• Stimulation of the nipple leads to oxytocin release, causing contraction of myoepithelium and ejection of milk.
• Oxytocin also stimulates PRL, leading to milk synthesis, which creates a positive feedback loop.
• Hyperprolactinaemia leads to lactational amenorrhea by inhibiting FSH/LH release.

Menopause

The Life of a Human Egg

• Primordial germ cell migration to the genital ridge during early development.
• Primary oogonium arrested at prophase I in utero.
• Ovulation occurs at puberty.
• Secondary oocyte arrested at metaphase II.
• Fertilization leads to pronuclear fusion, forming a female zygote with male and female pronuclei.

Oogonia and Oocytes Count

• PGC migration starts with ~ 170 cells.
• Reaches 600,000 around 8/40 (likely referring to gestational weeks).
• Peaks at 7,000,000 around 20/40 (likely referring to gestational weeks).
• Decreases to 2,000,000 at birth.
• Further decreases to 400,000 at puberty.
• A small number are ovulated during a woman's reproductive years.

Perimenopause/Climacteric

• Period of reproductive change that precedes menopause. It can last up to ten years.
• Symptoms include:
  • Oligomenorrhea.
  • Mood changes.
  • Loss of libido.
  • Hot flushes.
• Hormonal changes include falling estrogen and rising FSH/LH levels.
• Menopause is defined as:
  • 12 months of amenorrhea (over 50 years old).
  • 24 months of amenorrhea (under 50 years old).
• Estrone predominates, produced by the adrenals and adipose tissue.

Consequences of Estrogen Withdrawal

• Loss of anti-PTH activity, leading to bone catabolism and osteoporosis.
• Change in blood lipid ratios, increasing the risk of coronary thrombosis.
• Reduction in vaginal lubrication, leading to dyspareunia.
• Behavioral changes which may be endocrine or psychological.

Hormone Replacement Therapy (HRT)

• Usually a combination of synthetic progesterone and estrogen.
• Estrogen-only HRT is only suitable for women who have had a hysterectomy.
• Unopposed estrogen can lead to endometrial hyperplasia and endometrial cancer.
• HRT can increase the risk of CVD and breast cancer.

Contraception

Global Statistics (United Nations)

• 121 million unintended pregnancies per year (approximately 50%).
• 60% of unintended pregnancies end in abortion.
• 45% of abortions are unsafe, leading to approximately 10% of maternal deaths.
• 257 million women who want to avoid pregnancy do not have access to safe modern contraception.
• Every two minutes:
  • A woman dies from a pregnancy-related cause.
  • 1400 people are diagnosed with a sexually transmitted infection (STI). About 1 in 25 people have an STI.

Types of Contraception

• Hormonal.
• Barrier.
• Intrauterine Devices (IUDs).
• Permanent.
• Natural.

Efficacy

• Pearl index:
  • The number of failures per 100 woman years of exposure.
  • For example, 100 women using a contraceptive for 12 months or 10 women using it for ten years.
  • A lower value indicates a more effective method.
• Percentage effectiveness is more commonly quoted.
• There are perfect use rates versus typical use rates.

1. Hormonal Methods

• Mimic hormonal levels during pregnancy, leading to feedback inhibition by progesterone (and estrogen) on the hypothalamic-pituitary-gonadal (HPG) axis.
• Constant exposure to progesterone suppresses ovulation.
• Progesterone also thickens the cervical mucus and decreases endometrial receptivity.
• Estrogen exerts additional negative feedback and induces progesterone receptor (PR) expression, increasing the effect of progesterone.

Types of Hormonal Contraceptives

• Oral Contraceptive (Birth Control Pill):
  • Combined Oral Contraceptive (COC): 92-99.7% effective with daily intake.
  • Progesterone-only pill (POP): 97-99.7% effective with daily intake.
• Injection (Depo Provera):
  • Progesterone only.
  • 99.5% effective. 12 weeks - LARC (Long-Acting Reversible Contraception).
• Implant (Nexplanon):
  • Progesterone only.
  • 99.5% effective. 3 years - LARC (Long-Acting Reversible Contraception).
• Vaginal Ring (Nuvaring):
  • CHC 92-99.7% effective 1 per week.
• Patch (Evra):
  • CHC 92-99.7% effective 3 weeks on, 1 week off.

Emergency Contraceptive Pill (Morning After Pill)

• Contains higher levels of hormones than normal contraceptive pills.
  • Progesterone only: Levonelle (Levonorgestrel) - effective up to 72 hours.
• Prevents/delays ovulation and alters the environment of the uterus, decreasing the chance of implantation.
• EllaOne:
  • A selective progesterone receptor modulator.
  • Effective up to 120 hours.

2. Barrier Methods

• Prevent pregnancy by blocking the egg and sperm from meeting.
• Barrier methods have higher failure rates than hormonal methods due to design and human error.
• Often combined with spermicides (75% effectiveness).

Types of Barrier Methods

• Condom:
  • Most common and effective barrier method when used properly.
  • Effectiveness rate: 85-98%.
  • Used in the prevention of pregnancy and spread of STIs.
  • Available for both males and females.
• Diaphragm and Cap:
  • Latex barriers placed inside the vagina before intercourse.
  • Used with spermicidal jelly before insertion.
  • Effectiveness: 84-94%.

3. Intrauterine Devices (IUDs)

• Cu-IUD (Copper IUD):
  • Placed in the uterus.
  • Lasts 5-12 years - LARC.
  • Extremely effective without using hormones (>99%).

Mechanism of Action (Cu-IUD)

• Release of leukocytes and prostaglandins by the endometrium, creating an environment hostile to both sperm and embryos.
• The presence of copper increases the spermicidal effect.
• Post-fertilization mechanisms contribute to their effectiveness (emergency contraception).
• Side effects include heavy periods and an increased risk of ectopic pregnancy.

LNG-IUD (Levonorgestrel-releasing IUD)

• Lasts 5 years - LARC.
• Continuously releases small amounts of progestin (levonorgestrel), leading to atrophy of the endometrium.
• The majority of women will become anovulatory or only ovulate occasionally after the first year.
• Reduction in menorrhagia & dysmenorrhea.
• Has product licenses for contraception and menorrhagia.
• 99.9% effective.

4. Permanent Sterilisation

Female Sterilisation = Tubal Ligation

• Major surgical procedure, often combined with Cesarean section (CS).
• Uterine tubes are cut/tied/cauterized/clipped.
• Prevents eggs from reaching sperm.
• Failure rate: ~0.5%.

Male Sterilisation = Vasectomy

• Ligation of the Vas Deferens tube.
• Usually an outpatient procedure taking about half an hour.
• Faster and easier recovery than a tubal ligation and about ¼ of the cost.
• Failure rate: 0.1%.

5. Natural Methods

• Coitus interruptus/withdrawal: 73% effective.
• Rhythm method (menstrual cycle): ~75% effective.
• Fertility Awareness method (temperature, cervical mucus, and position): 76-99% effective (e.g., Natural Cycles app).
• Natural family spacing (lactational amenorrhoea): 98% effective (6 months postpartum, feeding <5 hours, amenorrheic).
• Abstinence: 100% effective.

UKMEC (UK Medical Eligibility Criteria for Contraceptive Use)

• Provides guidance to providers of contraception on who can use contraceptive methods safely.
• Does not indicate a best method for a woman or take into account efficacy, just the possible methods that could be used safely by individuals with certain health conditions or characteristics (e.g., age).
• Available at: https://www.fsrh.org/Common/Uploaded%20files/documents/fsrh-ukmec-summary-september-2019.pdf