Ovarian Pathology Notes

Ovarian Pathology

Disorders Affecting Ovarian Function

• This section will cover disorders affecting ovarian function, diagnosis, and treatment.

The Menstrual Cycle

• The menstrual cycle involves the interplay of the endometrium, hormones, and the ovary.
• The endometrium has a functional layer and a basilar layer.
• Key stages include the preovulatory phase, ovulation, and the postovulatory phase.
• The cycle includes the development of follicles, the Graafian follicle, and the corpus luteum.
• The typical menstrual cycle is approximately 28 days, but can range from 26-32 days. Day 1 is considered the first day of menses.

Puberty

• First Menarche: Typically occurs around 12.5 years of age, with 95% of individuals experiencing it between 11 and 15 years. Cycles are often irregular and anovulatory initially.
• Precocious Puberty: Defined by the start of secondary sexual characteristics (SSC) before the age of 8 years or menarche before the age of 10 years. Usually constitutional but can be neurological or due to tumors. Early growth spurt followed by early epiphyseal fusion can result in short stature. Treatment may involve GnRH agonists, progestins, or growth hormone.
• Delayed Puberty: Defined as a failure to menstruate by 16 years in the presence of normal SSC or by 14 years in the absence of other markers of puberty. Potential causes include haematocolpos (imperforate hymen, vaginal agenesis), resistant ovary syndrome, H-P problems, or constitutional delays.

Definitions

• Amenorrhea: Absence of menstrual cycles.
  • Primary Amenorrhea: Never having had a menstrual cycle.
  • Secondary Amenorrhea: Cessation of menstrual cycles for at least 6 months.
• Oligomenorrhea: Irregular cycles, defined as less than 9 cycles per year.

Presentation of Ovarian Dysfunction

• Oligomenorrhea
• Amenorrhea
• Infertility
• Oestrogen deficiency, leading to hot flushes, poor libido, dyspareunia
• Hirsutism, acne, androgenic alopecia
• Weight changes
• Galactorrhoea

Diagnosis

• Pregnancy test to rule out pregnancy.
• FSH/LH levels measured on day 2/3 of the cycle to assess ovarian reserve and identify HPG disorders.
• Progesterone levels measured on day 21 to confirm ovulation.

Progesterone Withdrawal Bleed

• Progesterone challenge test is used in amenorrheic women.
• Medroxyprogesterone acetate is administered for 5 days.
• A bleed should occur 2-7 days after completing the course.
• This indicates normal E2 levels, a functional endometrium, and a patent outflow tract.

Primary Causes of Ovarian Dysfunction

• Ovarian insensitivity or damage.
• Normal gonadotrophin secretion.
• High FSH/LH levels due to the absence of feedback from oestrogen, similar to menopause.
• Premature ovarian failure or primary ovarian insufficiency.
• Turner’s Syndrome (XO).
• Damage from chemotherapy or radiotherapy.

Central Causes of Ovarian Dysfunction

• Hyperprolactinaemia: Increased serum prolactin suppresses the release of FSH/LH. Can be caused by prolactin-secreting tumors or tumors affecting the pituitary stalk, suppressing dopamine release. Treatment involves surgery or dopamine agonists.
• Kallman Syndrome.
• Lifestyle factors such as anorexia, over-exercise, obesity, and stress.

Polycystic Ovarian Syndrome (PCOS)

• The most common endocrine condition, affecting approximately 10% of pre-menopausal women.
• Symptoms include:
  • Oligoamenorrhoea (80%)
  • Hirsutism (30%)
  • Obesity (40%)
  • Infertility (30%) due to anovulation
  • Polycystic ovaries on ultrasound
  • Hyperandrogenism
    • Increased testosterone and androstenedione
  • Increased LH/FSH ratio
• The exact cause is unknown, but insulin resistance may play a role, influenced by body weight.

Rotterdam Diagnostic Criteria for PCOS

• Need 2 out of 3 criteria for diagnosis:
  • Oligo- or Amenorrhea
  • Clinical or biochemical signs of hyperandrogenaemia
  • Polycystic Ovaries
• Developed by the European Society for Human Reproduction & Embryology/American Society for Reproductive Medicine (ESHRE/ASRM).

Polycystic Ovaries (USS) Ultrasound Criteria

• $(≥ 12) cysts
• 2-9 mm in diameter
• $(>10) ml ovarian volume
• PCO = PCOS
• PCO: 20-33% of the female population

Premature Ovarian Failure

• Also known as primary ovarian insufficiency.
• Characterized by amenorrhea, low oestrogen, and high FSH/LH levels prior to the age of 40 years.
• Affects 1% of women.
• Causes are often unknown but can include:
  • Congenital conditions like Turner’s syndrome (1:2500 live births, 45XO).
  • Autoimmune disorders.
  • Iatrogenic factors like chemotherapy, radiotherapy, and surgery.

Requirements for Fertility

• Production of normal sperm.
• Production of normal eggs.
• Sperm must traverse the female tract to reach the egg, including capacitation, under time constraints.
• Sperm must penetrate and fertilize the oocyte.
• Implantation of the embryo into the uterus.
• Normal pregnancy.

Fertilization

• Occurs in the ampulla region of the uterine tube.
• Sperm remain capable of fertilization for approximately 5 days within the female tract.
• Oocytes remain viable for approximately 24 hours.
• Ovulation Prediction Kits (OPKs) which measure LH levels are available, but not recommended.

Clinical Definition of Infertility

• The National Institute for Clinical Excellence (NICE) defines infertility as the failure to conceive after regular unprotected sexual intercourse for 2 years in the absence of known reproductive pathology.
• People who have not conceived after 1 year of regular unprotected sexual intercourse should be offered further clinical investigation.
• This definition is based on data regarding natural conception rates.

Conception Rates

• Of 100 couples trying to conceive naturally:
  • 25 will conceive within one month
  • 85 will conceive within a year
  • 95 will conceive within two years

Infertility Statistics

• One in six UK couples have difficulty conceiving.
• After pregnancy, infertility is the commonest reason for women aged 20-45 to see their GP.
• Around 2.5% of all UK births are the result of fertility treatment, which equates to approximately 15,000 babies per year.

Causes of Infertility

• Female factors: 35%
• Male factors: 35%
• Combination: 15%
• Unknown: 15%

Female Factors Contributing to Infertility

• Ovulatory disorders account for 60% of female infertility cases.
• Disorders of the female tract include tubal damage, endometriosis, and uterine abnormalities.
• Issues related to implantation, growth, and development.

Unexplained Infertility

• Accounts for 15% of cases.
• Characterized by normal frequency and timing of unprotected intercourse.
• No obstructions or malformations in the female or male genital tracts.
• Ovulation is confirmed.
• Normozoospermic (normal sperm parameters).

Effect of Delayed Reproduction - Aging

• Age is a bigger factor for females, with fertility declining after the 20s and a sharp decline after 35.
• In males, age-related factors such as diabetes and hypertension can contribute to infertility.

Live Births from Fresh Embryos Using Own or Donor Eggs

• This section highlights the decline in live birth rates with increasing maternal age, both for own eggs and donor eggs.

Treatment for Infertility

• Assisted conception techniques are used to circumvent infertility, not cure it.
• Any technique that assists conception.

Slight Assistance – for Anovulation

• Ovulation induction with timed intercourse.
• Clomiphene: an oral anti-oestrogen taken for five days at the beginning of the cycle, which removes inhibition, leading to an increase in FSH.
• Requires monitoring the number of follicles.

A Little More Assistance… IUI (Intrauterine Insemination)

• Injection of prepared sperm into the uterine cavity.
• Bypasses cervical mucus.
• Allows for perfect timing, either stimulated or natural cycles.
• Fairly non-invasive.
• Low success rate: 5-20%.
• Multiple pregnancy rate: approximately 10%.
• Indications include:
  • Inability to have sexual intercourse
  • Need for sperm washing
  • Same-sex relationship
• Contraindicated in cases of unexplained infertility.

Major Help Required… In Vitro Fertilisation

$\50,000-100,000$ motile sperm added to an oocyte and left to fertilise.

IntraCytoplasmic Sperm Injection (ICSI)

• Involves injecting a single sperm per egg.
• Indications:
  • Severe male factor
  • Failure at IVF
  • Epididymal or testicular sperm

Ovarian Stimulation

1. Pituitary suppression (GnRH agonist/antagonist)
2. Ovarian stimulation (rFSH)
   • Aim: multifollicular development
3. Monitoring of follicular growth
4. hCG triggering (c.f. LH surge)
   • Aim: Final egg maturation

• 24 hours later - egg collection
  GnRH agonist vs. antagonist?
• Agonist – initially stimulatory ‘flare’ followed by down-regulation of GnRHR – suppression of gonadotrophin release – longer protocol
• Antagonist – immediate suppression of gonadotrophin release

Egg Collection

• Ovary is viewed via ultrasound.

Post-Egg Collection Procedures

• Insemination/injection
• Embryo culture (day 2/3 or day 5/6)
• Embryo transfer (1 or 2 embryos)
• Luteal support (cf. corpus luteum function in natural pregnancy).

Blastocyst Culture

• Culture of embryos for 5-6 days before transfer.
• Development to the blastocyst stage passes significant hurdles:
  • Switching on of embryonic genome.
  • Past stages of totipotency to first differentiation.
• Selects best embryos, potentially improving success rates.

Success Rates for IVF/ICSI

• HFEA 2019 data for IVF/ICSI (using own egg and partner’s sperm):
  • Under 35: 32% live birth per embryo transferred
  • 35-37: 25%
  • 38-39: 19%
  • 40-42: 11%
  • 43-44: 5%
  • Over 44: 4%

Risks of IVF/ICSI

• Multiple pregnancies
• Ovarian Hyperstimulation Syndrome (OHSS), particularly in women with PCOS
• Very invasive for women
• Risk of congenital abnormalities/long-term maternal risks/imprinting disorders
• Inheritance of male infertility